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1,900 | 24,907,283 | Additional evidence is required to support the use of specific regional anaesthesia techniques to improve postoperative pain for several surgical procedures ( craniectomy , adenotonsillectomy , appendectomy , cardiac surgery , umbilical hernia repair , upper and lower extremity ) in paediatric patients .
Currently , only a very limited number of regional anaesthesia techniques have demonstrated significant improvement on postoperative pain outcomes for a restricted number of surgical procedures . | Summary The development of analgesic interventions in paediatric surgical patients is often limited by the inherent difficulties of conducting large r and omized clinical trials to test interventions in those patients .
Regional anaesthesia is a valid strategy to improve postoperative pain in the adult surgical population , but the effects of regional anaesthesia on postoperative pain outcomes in paediatric patients are currently not well defined .
The main objective of the current review was to systematic ally evaluate the use of regional anaesthesia techniques to minimize postoperative pain in paediatric patients . | Background Pediatric r and omized controlled trials ( RCTs ) are susceptible to a high risk of bias . We examined the barriers and facilitators that pediatric trialists face in the design and conduct of unbiased trials . Methods We used a mixed methods design , with semi-structured interviews building upon the results of a quantitative survey . We surveyed Canadian ( n=253 ) and international ( n=600 ) pediatric trialists regarding their knowledge and awareness of bias and their perceived barriers and facilitators in conducting clinical trials . We then interviewed 13 participants from different subspecialties and geographic locations to gain a more detailed description of how their experiences and attitudes towards research interacted with trial design and conduct . Results The survey response rate was 23.0 % ( 186/807 ) . 68.1 % of respondents agreed that bias is a problem in pediatric RCTs and 72.0 % felt that there is sufficient evidence to support changing some aspects of how trials are conducted . Knowledge related to bias was variable , with inconsistent awareness of study design features that may introduce bias into a study . Interview participants highlighted a lack of formal training in research methods , a negative research culture , and the pragmatics of trial conduct as barriers . Facilitators included contact with knowledgeable and supportive colleagues and infrastructure for research . Conclusions A lack of awareness of bias and negative attitudes towards research present significant barriers in terms of conducting method ologically rigorous pediatric RCTs . Knowledge translation efforts must focus on these issues to ensure the relevance and validity of trial results Background : Administration of bupivacaine caudally has been used for postoperative analgesia after urogenital , rectal and lower abdominal surgery in children . Caudal opioids may offer analgesic advantages over bupivacaine alone but have been associated with side effects such as respiratory depression . Tramadol is an analgesic assumed to lack a respiratory depressant effect and has been shown to provide effective , long‐lasting analgesia after epidural administration in adults and children . The aim of this study was to determine whether the addition of tramadol to bupivacaine caudally prolongs the duration of analgesia compared with bupivacaine alone , with respect to side effects , and whether caudal tramadol alone provides satisfactory analgesia OBJECT Stable hemodynamics , normocapnia , and adequate pain relief are considered important factors in the reduction of neurological complications in pediatric patients undergoing encephaloduroarteriomyosynangiosis ( EDAMS ) operations for the treatment of moyamoya disease . A preoperative skull block may reduce hemodynamic fluctuations and hypo- or hyperventilation due to emergence delirium or oversedation and provide adequate pain relief , thereby reducing postoperative morbidity . METHODS Pediatric patients ( age 3 - 13 years ) undergoing EDAMS surgery for moyamoya disease were r and omly divided into a nerve block ( NB ) group ( 18 cases ) or control group ( 21 cases ) . The treatment group patients received a preoperative NB ( 0.25 % 5 - 8 ml bupivacaine mixed with 20 - 40 mg methylprednisolone ) targeting the supraorbital , supratrochlear , auriculotemporal , and posterior auricular nerves . Patients in the control group did not receive NB . General anesthesia with sevoflurane was induced in both groups . RESULTS In the NB group , stable hemodynamic parameters were obtained with a lower sevoflurane concentration than in the control group . For delirious awakening , the odds ratio in the control group was 4.9 compared with the NB group . Pain and analgesic requirement were higher in the control patients than in the NB-treated patients during the postanesthesia care unit stay . However , the arterial CO(2 ) tension in the postanesthesia care unit did not differ between the 2 groups . The odds ratio in the control group for the rate of morbidity ( cerebral infa rct ion and reversible ischemic neurological deficits ) during the first 24 hours following the operation was 3.2 compared with the NB group . CONCLUSIONS The use of skull block during EDAMS surgery provided easy hemodynamic control , calm awakening , and better pain relief and may be related to the reduced postoperative morbidity BACKGROUND : The classical response to nerve stimulation may be altered in cases of radial club h and . Ultrasound guidance may prove to be a useful tool in such situations . In this study , we compared the success rate of ultrasound-guided infraclavicular brachial plexus block with nerve stimulation for children undergoing radial club h and repair . METHODS : Fifty children , aged 1 - 2 yr , undergoing radial club h and repair were r and omly assigned to receive infraclavicular brachial plexus block guided by nerve stimulator ( Group NS ) or ultrasound ( Group U ) in combination with light general anesthetic . Bupivacaine 0.5 mL/kg of 0.5 % was injected in both groups . Pain response to surgical stimulus was considered as block failure . The Children ’s Hospital Eastern Ontario Pain Scale pain score was recorded at 1 , 4 , 6 , 8 , and 10 postoperative hours . RESULTS : In Group NS , the blocks were successful in 16 of 25 patients ( 64 % ) , whereas in Group U , 24 of 25 patients had successful blocks ( P = 0.0053 ) . There was no difference in the time to first analgesia or analgesic consumption in the 10-h study period . CONCLUSION : Ultrasound-guided infraclavicular brachial plexus block improves the success rate in patients with radial club h and s when compared with nerve stimulation in patients undergoing radial club h and correction We compared in a r and omized double-blind study , the postoperative analgesia and degree of motor block produced by the new local anaesthetic ropivacaine , with bupivacaine , for caudal anaesthesia in children . Eighty children , 2 - 5-years-old , ASA I , received one of two local anaesthetics ; either ropivacaine 0.25 % ( 1.0 ml x kg(-1 ) ) or bupivacaine 0.25 % ( 1.0 ml x kg(-1 ) ) . They were se date d with a continuous infusion of propofol ( 200 microg x kg(-1 ) min(-1 ) . The lungs were ventilated with a mixture of 50 % nitrous oxide with oxygen . 60 min after local anaesthetic injection , and every 60 min , the extent of the motor block in the recovery room was scored as 1 - 3 , according to a modified Bromage scale . Adverse events and the time to the first analgesic requirement were reported . Patients in the two groups did not differ with respect to age , weight and height . There were no differences in heart rate and arterial pressure between the two groups(P>0.05 ) . No adverse events were observed . The ropivacaine group showed a shorter duration of motor block than the bupivacaine group ( P<0.05 ) . The first postoperative analgesic requirement was a mean ( sd ) of 5 h+/-4.32 after the operation in the ropivacaine group and 5 h+/-3.81 for the bupivacaine group . These findings suggest that caudal anaesthesia with ropivacaine 0.25 % in paediatric patients can be effective , with less motor blockade in the postoperative period OBJECTIVE We set out to compare a eutectic mixture of local anesthetic cream ( lidocaine and prilocaine ) to dorsal penile nerve block with lidocaine for anesthesia during circumcision . STUDY DESIGN In a double-blind study , term newborns were r and omized to local anesthetic cream and sodium chloride solution dorsal penile nerve block ( n = 31 ) or to placebo cream and lidocaine dorsal penile nerve block ( n = 29 ) . Pain was assessed by determination of heart rate , respiratory rate , and behavioral distress scoring . Group differences were evaluated with repeat- measures analyses of variance . RESULTS Distress scores and heart rates were significantly higher in the eutectic mixture group than in the lidocaine group . Respiratory rates were higher in the eutectic mixture group but did not reach statistical significance . CONCLUSIONS Distress scores and heart rates were significantly higher in infants treated with the anesthetic mixture than in infants treated with lidocaine . Dorsal penile nerve block with lidocaine is a more efficacious means of providing anesthesia for neonatal circumcision than the mixture of local anesthetics BACKGROUND We attempted to determine the efficacy of a one plane ilioinguinal and iliohypogastric nerve block with a single shot and double shot techniques . METHODS In a r and omized single blind study , 90 children , aged 2 - 12 years , received a single shot ( SS ) or a double shot ( DS ) technique for ilioinguinal and iliohypogastric ( IG-IH ) nerve block for inguinal hernia repair . In the SS group , 0.25 ml x kg(-1 ) of 0.25 % bupivacaine was given one fingerbreadth medial to the anterior superior iliac spine under the external oblique aponeurosis . In the DS group , one-third of the total dose of bupivacaine was given as for the SS group . The remaining two-thirds was deposited 0.5 cm above and lateral to the mid-inguinal point deep to the external oblique aponeurosis . RESULTS The success rates of both techniques were similar , at 72 % , although the presence of local anaesthetic in the inguinal canal was significantly higher with the DS technique . The incidence of femoral nerve block was 4.5 % with the SS and 9 % with the DS technique ( P > 0.05 ) . Parental satisfaction with postoperative pain relief was high , at 94 % . CONCLUSIONS The DS technique , while technically more difficult , does not improve the success rate of the IG-IH nerve block compared with the SS technique BACKGROUND Dorsal penile nerve block ( DPNB ) is a commonly performed regional anesthetic technique for male circumcision . Traditionally , DPNB is based on an anatomical l and mark technique . Recently , an ultrasound-guided technique for DPNB has been described . OBJECTIVES The aim of our study was to compare the anatomical l and mark technique with this ultrasound-guided technique . The hypothesis to be tested was that ultrasound guidance of DPNB would lead to less administration of opioid when compared to the anatomical l and mark technique . METHODS Boys of ASA status I/II scheduled for day case circumcision were prospect ively recruited and r and omized . DPNB was performed under general anesthesia using the anatomical l and mark technique or ultrasound guidance . Fentanyl was administered intraoperatively and immediately postoperatively if patients demonstrated signs of pain . Similarly , oral codeine was given prior to discharge if required . The primary outcome measure was the number of patients requiring fentanyl . Secondary outcome measures included initial pain score on emergence from general anesthesia , requirement for codeine predischarge , and time to perform block . RESULTS A total of 32 patients were recruited to the l and mark group and 34 to the ultrasound group . There was no significant difference between the two groups in terms of fentanyl administration . The ultrasound technique took longer to perform but was associated with a reduction in codeine requirement prior to discharge . CONCLUSIONS This study does not support the routine use of ultrasound for the performance of DPNB in male pediatric circumcision . Nonetheless , an associated reduction in codeine administration postoperatively suggests some benefit in terms of postoperative pain We compared the effects of pre- and postsurgical axillary block on pain after h and and forearm surgery in 55 children in a double-blind r and omized study . The successful blocks are reported here ( n=49 ) . Children aged 1 - 11 years and ASA I or II were allocated r and omly to receive axillary block with 2 mg.kg-1 of 0.25 % bupivacaine , either after induction but before the surgery ( presurgical group , n=25 ) or immediately after surgery , before the end of anaesthesia ( postsurgical , n=24 ) . In all patients , a st and ard general anaesthesia technique was used . The Faces Pain Scale ( FPS ) and analgesic requirements were recorded for 24 h at various times after operation . Eight patients ( 32 % ) in the presurgical group and 20 patients ( 83.33 % ) in the postsurgical group did not require additional analgesic within the first 24 h after operation ( P < 0.05 ) . In patients who had pain during the observation period , the pain started 13.66+/-2.61 h in the presurgical group and 13.14+/-2.34 h in the postsurgical group after performing block ( P > 0.05 ) . The FPS scores were similar in both groups during the first 8 h in the postoperative period ( P > 0.05 ) . There was a significant difference at 10 h after surgery ( P < 0.05 ) . Cumulative FPS score was higher in the presurgical group ( 10.50+/-1.06 ) than in the postsurgical group ( 9.45+/-1.28 ) ( P < 0.05 ) , but both groups had effective analgesia overall , the mean FPS score being less than 2 . Additional analgesic consumption was similar in these patients in both groups . A lower isoflurane concentration was used in the presurgical group ( 0.68 % vs 1.72 % , P < 0.001 ) . We did not demonstrate the superiority of preemptive analgesia , but our results indicate that presurgical axillary block with 0.25 % bupivacaine allows the use of inhalational anaesthetics at lower concentrations while providing a reasonably painless postoperative period OBJECTIVE The objective of this study was to assess the effectiveness of 0.5 % ropivacaine used for parasternal intercostal blocks for postoperative analgesia in pediatric patients undergoing cardiac surgery . DESIGN A r and omized , controlled , prospect i ve , double-blind study . SETTING A tertiary care teaching hospital . PARTICIPANTS Thirty children scheduled for cardiac surgery with a median sternotomy . INTERVENTIONS A 0.5 % ropivacaine injection with 5 doses of 0.5 to 2.0 mL on each side in the 2nd to 6th parasternal intercostal space with a total dose of ropivacaine below 5 mg/kg or the same volume of saline before sternal wound closure . MEASUREMENTS AND MAIN RESULTS The time to extubation was significantly lower in patients administered the parasternal blocks with ropivacaine than in the control group ; the mean values were 2.66 hours and 5.31 hours , respectively ( p < 0.001 ) . The pain scores were lower in the ropivacaine group compared with the saline group ; mean values were 2.20 for the ropivacaine group and 4.83 for the saline group on a scale of 10 . The cumulative fentanyl dose requirement over a 24-hour period was higher in the saline group than the ropivacaine group ( p < 0.001 ) . CONCLUSIONS Parasternal blocks with ropivacaine appear to be a simple , safe , and useful technique of supplementation of postoperative analgesia in pediatric patients undergoing cardiac surgery with a median sternotomy BACKGROUND : Perioperative ketamine infusion reduces postoperative pain ; perioperative lidocaine infusion reduces postoperative narcotic consumption , speeds recovery of intestinal function , improves postoperative fatigue , and shortens hospital stay . However , it is unknown whether perioperative IV lidocaine and /or ketamine enhances acute functional recovery . We therefore tested the primary hypothesis that perioperative IV lidocaine and /or ketamine in patients undergoing open abdominal hysterectomy improves rehabilitation as measured by a 6-minute walk distance ( 6-MWD ) on the second postoperative morning . METHODS : Women having open hysterectomy were anesthetized with sevoflurane , followed by patient-controlled morphine . Patients were factorially r and omized to one of the following groups : ( 1 ) lidocaine and placebo , ( 2 ) placebo and ketamine , ( 3 ) placebo and placebo , or ( 4 ) lidocaine and ketamine . Lidocaine was given as a bolus ( 1.5 mg/kg ) , followed by lidocaine infusion of 2 mg/kg/h for the first 2 hours , and then 1.2 mg/kg/h for 24 postoperative hours . Ketamine was given as a bolus ( 0.35 mg/kg ) , followed by ketamine infusion of 0.2 mg/kg/h for the first 2 hours , and then 0.12 mg/kg/h for 24 postoperative hours . The primary double-blind outcome was 6-MWD on the second postoperative morning ; secondary outcomes included pain scores , opioid consumption , postoperative nausea and vomiting , and fatigue score . RESULTS : The study was stopped after a planned interim analysis of 64 patients showed that lidocaine crossed the preplanned futility boundary , with mean ± SD of 202 ± 66 m versus 202 ± 73 m for lidocaine versus placebo , respectively , and mean difference ( interim adjusted 97.5 % confidence interval ) of 0.93 m ( −52 , 54 ) ( P = 0.96 ) ; the ketamine effect also crossed the futility boundary , with mean ± SD of 193 ± 77 m versus 210 ± 61 m for ketamine versus placebo , respectively , and mean difference ( interim adjusted 97.5 % confidence interval ) of −11 m ( −65 , 44 ) ( P = 0.54 ) . No interaction between the 2 intervention effects was observed ( P = 0.96 ) . Neither intervention significantly influenced any of the secondary outcomes . CONCLUSION : Our results do not support use of lidocaine or ketamine for improving 6-MWD on the second postoperative day after open hysterectomy The aim of this study was to compare the efficacy of nerve stimulator guided paravertebral block with ilio‐inguinal nerve block in children undergoing inguinal herniorrhaphy . Eighty children were r and omly allocated to receive either paravertebral block or ilio‐inguinal nerve block . Each block was evaluated in terms of intra‐operative haemodynamic stability , postoperative pain scores at rest , on movement and during activity , requirement for supplemental analgesia and parental satisfaction . Haemodynamic stability was maintained significantly better during sac traction in the paravertebral block group ( p < 0.005 ) . Pain scores and analgesic consumption were significantly lower in the paravertebral block group during the postoperative follow‐up period ( p < 0.05 ) . Parental satisfaction ( 93%vs 69 % ) and surgeon satisfaction ( 93%vs 64 % ) were significantly higher in the paravertebral block group ( p < 0.05 ) . Paravertebral blockade improved and prolonged postoperative analgesia , and was associated with greater parental and surgeon satisfaction when compared to ilio‐inguinal nerve block BACKGROUND Ultrasound-guided transversus abdominis plane ( TAP ) block has shown promise for analgesia after pediatric inguinal surgery . This prospect i ve , r and omized study tested the hypothesis that the TAP block would provide comparable analgesia after pediatric inguinal surgery compared with a conventional ultrasound-guided ilioinguinal block . METHODS After induction of general anesthesia , infants and children presenting for elective inguinal surgery were r and omly assigned to receive an ultrasound-guided TAP block ( needle cephalad of the iliac crest at the anterior axillary line ) ( n = 20 ) or ilioinguinal block ( needle immediately anteromedial to the anterior superior iliac spine ) ( n = 21 ) . Supplemental analgesia consisted of as-required intraoperative fentanyl , regular acetaminophen , as-required ibuprofen , and rescue morphine . Patients were assessed in the recovery room , the day-stay unit ( 30 min to 2 h after surgery ) and at 24 h for age appropriate numerical pain score , analgesic consumption , and parental satisfaction . RESULTS In the day-stay unit , pain was more frequent ( 76 % vs 45 % , P = 0.040 ) , and ibuprofen use was higher ( 62 % vs 30 % , P = 0.037 ) in the TAP group . Recovery room pain , morphine consumption and postdischarge ibuprofen use , comfort and satisfaction scores were similar between groups . Ultrasound image quality was poorer , and needle time under the skin was longer ( median [ interquartile range ] 81 [ 66 - 120 ] vs 46 [ 40 - 51 ] , P < 0.001 ) for the ilioinguinal group . CONCLUSIONS Following pediatric inguinal surgery , ilioinguinal block provides more effective analgesia than the TAP block BACKGROUND Vitreoretinal ( VR ) surgery is associated with moderate to severe pain and significant postoperative nausea and vomiting ( PONV ) . The study aim ed to assess the effectiveness of sub-Tenon 's block for providing perioperative analgesia in children undergoing VR surgery . METHODS In a r and omized , observer-blinded trial , after obtaining institutional ethical committee approval and parental consent , 200 ASA grade I-II children aged 5 - 16 yr were allocated to receive either a sub-Tenon 's block ( Group SB ) or 2 microg kg(-1 ) i.v . fentanyl ( Group F ) after induction of anaesthesia and topical anaesthesia of the conjunctiva with proparacaine 0.5 % drops . Patients in Group F received fentanyl 0.5 microg kg(-1 ) and those in Group SB were given a corresponding volume of normal saline i.v . every hour from preloaded syringes . Increases in heart rate or mean arterial pressure by more than 20 % of baseline were treated with additional 0.5 microg kg(-1 ) i.v . fentanyl boluses in both groups . The incidence of oculocardiac reflex ( OCR ) , need for additional analgesics , postoperative pain , and PONV were recorded for the first 24 h after surgery . RESULTS More patients in Group F ( 47.96 % ) had moderate to severe pain in the first 24 h when compared with Group SB ( 31.36 % ) ( P=0.023 ) . The need for postoperative ibuprofen was higher in Group F ( 66.3 % ) compared with Group SB ( 47.95 % ) ( P=0.012 ) . The incidence of OCR was significantly higher in Group F ( 31.6 % ) compared with Group SB ( 5.1 % ) ( P<0.001 ) . The incidence of PONV was similar in both groups . CONCLUSIONS Sub-Tenon 's block provides more effective analgesia than i.v . fentanyl for paediatric VR surgery BACKGROUND : Dexmedetomidine , an & agr;2-receptor agonist , prolongs analgesia when used in neuraxial and IV blocks . We evaluated the effect of dexmedetomidine added to ropivacaine for tibial nerve block on the duration of the sensory blockade . METHODS : For this prospect i ve , r and omized , controlled , double-blind , crossover trial , 14 healthy volunteers were allocated to 2 groups . All volunteers received an ultrasound-guided tibial nerve block 4 to 5 cm proximally to the medial malleolus . In group R , 10 mL of 0.5 % ropivacaine was injected for the block ; in group RD , 10 mL of a solution containing 0.5 % ropivacaine with 1 & mgr;g/kg of dexmedetomidine was administered . After the injection , monitoring of vital signs , evaluation of onset and resolution of sensory block , and level of sedation ( Observer 's Assessment of Alertness/Sedation scale ) were performed . Three weeks later , the same procedure was repeated , but the study subjects were allocated to the other group in a crossover fashion . The primary end point was the duration of sensory blockade . The time and carryover effects were also evaluated . Secondary outcomes were the onset time and the presence of adverse effects such as hypotension , bradycardia , hypoxia , and sedation . RESULTS : Sensory blocks lasted longer in group RD than in group R ( 21.5 vs 16.2 hours ; mean pairwise difference 5.3 hours [ 95 % confidence interval : 3.9–6.7 hours ] ; P < 0.0001 ) . Onset times were similar between groups . The mean systolic and diastolic blood pressure levels were stable throughout the study period in group R. In group RD , a noticeable decrease in systolic and diastolic blood pressure was observed between 60 and 480 minutes ( P < 0.05 ) ; 2 volunteers experienced a 30 % decrease in systolic blood pressure when compared with the baseline value as compared with none in group R. Heart rate was similar between groups except at 60 minutes ( P < 0.01 ) . CONCLUSION : Dexmedetomidine added to ropivacaine for tibial nerve block prolongs the duration of sensory blockade with similar onset time . However , patients should be monitored for potential adverse effects such as hypotension , bradycardia , and sedation BACKGROUND Umbilical hernia repair , a common day-surgery procedure in children , is associated with considerable postoperative discomfort . Possible modes of postoperative analgesia for umbilical hernia repair are rectus sheath block ( RSB ) and local anaesthetic infiltration of the surgical site ( LAI ) . METHODS We undertook an observer-blinded , r and omized , prospect i ve , observational study to compare the efficacy of ultrasound-guided RSB and LAI in providing postoperative analgesia for umbilical hernia repair . Our primary objective was to compare the use of opioid medication between patients who receive RSB and those who receive LAI . Our secondary objectives were to compare the duration of analgesia based on time to first rescue analgesic , to compare the quality of analgesia based on revised FACES scale , and to determine the incidence of side-effects . RESULTS Fifty-two patients ( 26 in each group ) completed the study . There was a statistically significant difference in the perioperative opioid medication consumption between the LAI group [ mean : 0.13 mg kg(-1 ) , confidence interval ( 0.09 - 0.17 mg kg⁻¹ ) ] and the RSB group [ mean : 0.07 mg kg⁻¹ , confidence interval ( 0.05 - 0.09 mg kg⁻¹ ) ] ( P=0.008 ) . When we compared the postoperative opioid consumption between the LAI group [ mean : 0.1 mg kg⁻¹ , 95 % confidence interval ( 0.07 - 0.13 mg kg⁻¹ ) ] and the RSB group [ mean : 0.07 mg kg(-1 ) , 95 % confidence interval ( 0.05 - 0.09 mg kg⁻¹ ) ] ( P=0.09 ) , there was a trend towards statistical significance between the two groups . The difference in time to rescue analgesic administration between the RSB group [ 49.7 ( 36.9 ) min ] and the LAI group [ 32.4 ( 29.4 ) min ] was not statistically significant ( P=0.11 ) . CONCLUSIONS This study demonstrates that ultrasound-guided RSB provides superior analgesia in the perioperative period compared with infiltration of the surgical site after umbilical hernia repair . In comparing only the postoperative period , analgesia provided by an ultrasound-guided RSB showed a trend towards statistically significant improvement compared with infiltration of the surgical site BACKGROUND Penile nerve block ( PNB ) is a well-established technique used for circumcision ; it requires the injection of local anesthetics close to the dorsal nerve of the penis . The goal of this study was to compare the efficacy of ultrasound-guided PNB versus the classical l and mark-based technique ( LBT ) in children undergoing circumcision . METHODS Forty boys , aged 1 - 14 years old that were scheduled for circumcision were r and omly assigned to ultrasound-guided and l and mark-based groups . All patients were placed under st and ard anesthesia with sevoflurane . In each group , patients received the penile block with ropivacaine , 0.75 mg·kg(-1 ) per side , and 0.05 mg·kg(-1 ) at the penis base . Groups were compared for intraoperative failure rate of the block , anesthesia time , postoperative pain scale , time of first required dose of paracetamol , time to first micturition , and average duration of stay in the postanesthesia care unit . RESULTS The failure rate of dorsal PNB was not statistically different between groups ( P = 0.5 ) . Ultrasound guidance improved the efficacy of the PNB compared to the LBT in terms of postoperative pain scores on arrival in the PACU ( P < 0.01 ) and after 30 min ( P < 0.01 ) . The ultrasound-guided technique also delayed the time to the first paracetamol dose administration ( P < 0.0001 ) , but the duration of the procedure , defined as the time between anesthesia induction and the end of surgery , was increased by 10 min in the US-guided group ( P = 0.001 ) . CONCLUSION Ultrasound-guided PNB improved the efficacy of the block compared with the LBT in terms of the postoperative pain during the first postoperative hour and the time to the first requirement for postoperative analgesia Tonsillectomy is one of the most frequently performed ambulatory surgical procedures in children ( Litman et al. in Anesth Analg 78:478–481 , 1994 ) . Several techniques have been described for alleviation of pain ( Ginstrom et al. in Acta Otolaryngol 125:972–975 , 2005 ) . the objective of this study determination of the postoperative analgesic efficacy of the pre-surgical intravenous administration of dexamethasone together with glossopharyngeal nerve block ( GNB ) in children undergoing tonsillectomy . Prospect i ve double blind r and omized control study using both pre-operative injection of 0.5 mg/kg dexamethasone iv and 3 ml of 0.5 % bupivacaine local injection for bilateral glossopharyngeal nerve block . Patients in group B had significantly less visual analogue scale values , longer absolute analgesia time , lesser swallowing difficulty and they were discharged earlier from the hospital when compared to patients in both groups D and G. Using both pre-operative dexamethasone IV injection with GNB has reduced postoperative pain and morbidity to a great extent than using either alone BACKGROUND Ilioinguinal and iliohypogastric ( IG-IH ) nerve block has been widely used in children undergoing inguinal hernia repair . This technique may provide insufficient analgesia for intraoperative management as the inguinal region may receive sensory innervation from genitofemoral nerve . We proposed that addition of a genitofemoral nerve block might improve the quality of analgesia . METHODS Ninety-eight children undergoing inguinal hernia repair were assigned r and omly to receive either IG-IH nerve block ( Group I ) or IG-IH and genitofemoral nerve blocks ( Group II ) . Systolic arterial pressure ( SAP ) and heart rate ( HR ) were recorded before surgery ( control ) , after skin incision , at sac traction and at the end of surgery . Postoperative analgesic requirements and incidence of complications were recorded until discharge . RESULTS At sac traction , SAP and HR were significantly higher in Group I ( P<0.05 ) , and the incidence of episodes of increased HR was also significantly higher in Group II ( 29 vs 12 % , respectively , P<0.05 ) . There were no significant differences in SAP and HR at other time points , postoperative analgesic requirements or incidence of complications between the groups . CONCLUSIONS The benefit of the additional genitofemoral nerve block to IG-IH nerve block was limited only to the time of sac traction without any postoperative effect . This suggests there is little clinical benefit in the addition of a genitofemoral nerve block BACKGROUND Supraclavicular brachial plexus blocks are not common in children because of risk of pneumothorax . However , infraclavicular brachial plexus blocks have been described in paediatric patients both with nerve stimulation and ultrasound (US)-guidance . US-guidance reduces the risk of complications in supraclavicular brachial plexus blocks in adults . OBJECTIVE To compare the success rate , complications and time of performance of US-guided supraclavicular vs infraclavicular brachial plexus blocks in children . MATERIAL AND METHODS Eighty children , 5 - 15 years old , scheduled for upper limb surgery were divided into two r and omized groups : group S ( supraclavicular ) , n = 40 , and group I ( infraclavicular ) , n = 40 . All blocks performed were exclusively US-guided , by a senior anaesthesiologist with at least 6 months of experience in US-guided blocks . For supraclavicular blocks the probe was placed in coronal-oblique-plane in the supraclavicular fossa and the puncture was in-plane ( IP ) from lateral to medial . For infraclavicular blocks the probe was placed parallel and below the clavicle and the puncture was out-of-plane . Ropivacaine 0.5 % was administered up to a maximum of 0.5 ml x kg(-1 ) until appropriate US-guided-spread was achieved . Block duration and volumes of ropivacaine used ( mean+/-1SD ) in the supraclavicular approach were recorded . Success rate ( mean + /- 1 SD , 95%confidence interval ) , complications rate and time to perform the block ( two-tailed Student 's test ) were recorded both for supraclavicular and infraclavicular approaches . RESULTS In the US-guided supraclavicular brachial plexus blocks , the duration of the sensory block was 6.5 + /- 2 h and of the motor block was 4 + /- 1 h. The volume of ropivacaine used in this group was 6 + /- 2 ml . In group I , 88 % of blocks achieved surgical anaesthesia without any supplemental analgesia compared with 95 % in group S ( P = 0.39 ; difference=7 % ; 95 % CI : -10 % to 24 % ) . Failures in group I were because of arterial puncture and insufficient ulnar or radial sensory block . Failures in group S were because of insufficient ulnar sensory block . No pneumothorax or Horner 's syndrome was recorded in either group . The mean time ( SD ) to perform the block was in group I : 13 min ( range 5 - 16 ) and in group S : 9 min ( range 7 - 12 ) ; the 95 % CI for this difference was 2 - 6 min and was statistically significant ( P < 0.05 ) . CONCLUSIONS ( i ) Ultrasound-guided supraclavicular and infraclavicular brachial plexus blocks are effective in children . ( ii ) There has been no pneumothorax in 40 US-guided supraclavicular brachial plexus blocks performed by anaesthesiologists already trained in US-guided regional anaesthesia using an IP technique in children > or = 5 years old . ( iii ) In this study , the supraclavicular approach of the brachial plexus was faster to perform than the infraclavicular one Background and objectives : To establish whether caudal with ketamine or penile block provide superior postoperative analgesia for paediatric circumcision . Method : This was a single centre , prospect i ve , r and omized , controlled , double‐blind trial . Forty males ( aged between 18 months and 16 yr ) were r and omized to receive either a penile block using 0.25 mL kg−1 0.5 % bupivacaine ( Group P ) , or a caudal block using 0.5 mL kg−1 0.25 % bupivacaine with 0.5 mg kg−1 ketamine ( Group C ) . All of them were given a st and ard anaesthetic and rectal paracetamol 40 mg kg−1 and diclofenac 1‐1.5 mg kg−1 . Postoperative pain scores were assessed in recovery and the time to first analgesia , micturition and walking were recorded . Results : There were no failures in either group . The time to first analgesia was longer in Group C ( C median = 459 min , interquartile range 374‐553 min ; P median = 374 min , interquartile range 224‐507 min ; P < 0.05 ) . There was a delay in time to walking in Group C ( C median = 162 min , interquartile range 119‐208 min ; P median = 120 min , interquartile range 92‐132 min ; P < 0.05 ) . There was no difference between the groups in time to waking or micturition , or the incidence of vomiting , abnormal behaviour or bleeding . Conclusion : Caudal bupivacaine with ketamine and penile block both provide effective postoperative analgesia for circumcision when given with non‐steroidal anti‐inflammatory drugs . This study shows that caudal bupivacaine with ketamine provides a longer duration of analgesia than penile block , but also causes delay in walking BACKGROUND The effect of adding transversus abdominis plane ( TAP ) blocks to local anaesthetic infiltration on morphine consumption and postoperative pain in children undergoing laparoscopic appendicectomy is unknown . METHODS After r and om allocation , 93 children aged 7 - 16 were r and omized to receive ultrasound-guided TAP blocks placed before surgery or not ( control ) . All subjects had port sites infiltrated with ropivacaine and were prescribed i.v . patient-controlled analgesia ( PCA ) with morphine and oral paracetamol for postoperative pain . The primary outcome was the proportion of subjects using > 200 µg kg(-1 ) morphine . Secondary outcomes included PCA morphine use , pain scores , time intervals to the first use of PCA and other analgesics , sedation scores , postoperative nausea or vomiting , and time to hospital discharge . RESULTS The procedure duration was longer in the TAP group ( 111 compared with 97 min for controls , P=0.03 ) . The duration in the recovery ward and that of the hospital stay were similar . There was no difference in the proportion of subjects requiring > 200 µg kg(-1 ) of PCA morphine [ control 31/45 ( 69 % ) , TAP 29/42 ( 69 % ) , P=0.99 ] . There was no significant difference in PCA morphine use , time intervals to the first use of PCA or other analgesics , or amounts of other analgesics . More patients in the TAP group had complicated appendicitis [ TAP 13/42 ( 31 % ) , control 5/45 ( 11 % ) , P=0.02 ] . Pain scores were reduced for the TAP group in the recovery ward only ( median score 0 vs 2 , 95 % confidence interval 0 - 3 , P=0.03 ) . CONCLUSIONS TAP blocks increased anaesthesia time by 14 min on average but offered no clinical ly important benefit over local anaesthetic port-site infiltration to paediatric patients undergoing laparoscopic appendicectomy PURPOSE We evaluated whether clonidine , when added to bupivacaine , would significantly prolong caudal analgesia and decrease opioid requirements in children undergoing ureteroneocystostomy . MATERIAL S AND METHODS A total of 35 children 1 to 10 years old undergoing ureteroneocystostomy received a st and ardized regimen of general anesthesia , and were r and omized to receive a preincision caudal block consisting of either 1 ml/kg 0.125 % bupivacaine ( controls ) or 1 ml/kg 0.125 % bupivacaine with 1 microg/kg clonidine ( treatment group ) . Caudal solutions also contained 1:400,000 epinephrine . Following the surgical procedure a second caudal block was performed with half of the original dose of medications . Caregivers were blinded to which caudal solution was administered . Postoperative outcome measures included pain scores , morphine requirements , duration of caudal analgesia and sedation scores . Statistical analysis was performed using ANOVA . RESULTS The 2 study groups were similar for mean age , weight and length of surgical procedure . Two patients in the control group were excluded because of protocol violation . Intravenous morphine requirements for rescue therapy were 0.02 mg/kg in the postanesthesia care unit and 0.1 mg/kg on postoperative day 1 for the treatment group , compared to 0.05 mg/kg and 0.2 mg/kg , respectively , for controls ( p < 0.05 ) . Mean interval from anesthesia finish time to first administered dose of morphine was 8.0 hours for the treatment group and 3.9 hours for controls ( p = 0.01 ) . Five of 18 patients in the clonidine-bupivacaine group received no postoperative morphine , compared to 1 of 15 in the bupivacaine group . No patient had development of hemodynamic instability , respiratory depression or sedation requiring treatment . CONCLUSIONS The addition of clonidine to bupivacaine significantly increases the duration of caudal analgesia and decreases postoperative morphine requirements in children undergoing ureteroneocystostomy Objective . To compare the efficacy of the dorsal penile nerve block ( DPNB ) with a less invasive form of local anesthesia , eutectic mixture of local anesthetic ( EMLA ) cream , for reduction of pain during neonatal circumcision . Design . Prospect i ve , blinded , r and omized , controlled trial . Setting . Tertiary referral , neonatal intensive care nursery in a university teaching hospital . Patients . Fifty infants ≥34½ weeks postmenstrual age and stable for discharge at time of circumcision ; gestational age at birth 25 to 41 weeks ; birth weight 600 to 4390 g ; age at study 3 to 105 days . An additional cohort of term newborns ( n = 20 ) , who were not r and omized , were circumcised without anesthesia . Interventions . Administration of either EMLA cream ( 0.5 g topically 1 hour before circumcision ) or 1 % lidocaine ( 0.7–1.0 mL subcutaneously 3 minutes before circumcision ) . Outcome Measures . Primary : Neonatal Infant Pain Scale ( NIPS ) score ; secondary : heart rate , respiratory rate . All outcome measures were assessed by an individual who was blinded to the group assignment and did not perform the circumcision . Results . NIPS scores were significantly lower in the DPNB infants ( 2.3 ± 1.8 ) compared with the EMLA infants ( 4.8 ± 0.7 ) . NIPS scores in patients circumcised without anesthesia indicated severe pain . There was a significantly greater increase in heart rate over the duration of the circumcision in the EMLA group than in the DPNB group ( 49 vs 9 beats per minute ) . Adverse effects included small hematomas at the site of injection in DPNB infants ( 10/23 ) , mild erythema at 1 and /or 24 hours after circumcision in the EMLA infants ( 3/21 ) , and penile edema noted 5 days after circumcision requiring removal of the circumcision bell in 1 DPNB infant . Conclusions . DPNB provides better pain reduction during neonatal circumcision than EMLA cream . EMLA cream may provide pain reduction compared with no anesthesia during neonatal circumcision BACKGROUND : Postoperative pain can delay functional recovery after outpatient surgery . Multimodal analgesia can improve pain and possibly improve quality of recovery . In this study , we evaluated the dose-dependent effects of a preoperative transversus abdominis plane ( TAP ) block on patient recovery using the Quality of Recovery 40 ( QoR-40 ) question naire after ambulatory gynecological laparoscopic surgery . Global QoR-40 scores range from 40 to 200 , representing very poor to outst and ing quality of recovery , respectively . METHODS : Healthy women undergoing outpatient gynecological laparoscopy were r and omly allocated to receive a preoperative TAP block using saline , ropivacaine 0.25 % , or ropivacaine 0.5 % . Needle placement for the TAP blocks was performed using ultrasound guidance and 15 mL of the study solution was injected bilaterally by a blinded investigator . QoR-40 score and analgesic use were assessed 24 hours postoperatively . The primary outcome was global QoR-40 score at 24 hours after surgery . Data were analyzed using the Kruskal-Wallis test . Post hoc pairwise comparisons were made using the Dunn test with P values and 95 % confidence intervals Bonferroni corrected for 6 comparisons . RESULTS : Seventy-five subjects were enrolled and 70 subjects completed the study . The median ( range ) for the QoR-40 score after the TAP block was 157 ( 127–193 ) , 173 ( 133–195 ) , and 172 ( 130–196 ) for the saline group and 0.25 % and 0.5 % ropivacaine groups , respectively . The median difference ( 99.2 % confidence interval ) in QoR-40 score for 0.5 % bupivacaine ( 16 [ 1–30 ] , P = 0.03 ) and 0.25 % bupivacaine ( 17 [ 2–31 ] , P = 0.01 ) was more than saline but not significantly different between ropivacaine groups ( −1 [ −16 to 12 ] , P = 1.0 ) . Increased global QoR-40 scores correlated with decreased area under the pain score time curve during postanesthesia recovery room stay ( & rgr ; = −0.56 , 99.2 % upper confidence limit [ UCL ] = −0.28 ) , 24-hour opioid consumption ( & rgr ; = −0.61 , 99.2 % UCL = −0.34 ) , pain score ( 0–10 scale ) at 24 hours ( & rgr ; = −0.53 , 99.2 % UCL = −0.25 ) , and time to discharge readiness ( & rgr ; = −0.65 , 99.2 % UCL = −0.42 ) . The aforementioned variables were lower in the TAP block groups receiving ropivacaine compared with saline . CONCLUSIONS : The TAP block is an effective adjunct in a multimodal analgesic strategy for ambulatory laparoscopic procedures . TAP blocks with ropivacaine 0.25 % and 0.5 % reduced pain , decreased opioid consumption , and provided earlier discharge readiness that was associated with better quality of recovery BACKGROUND The ilioinguinal/iliohypogastric nerve block is a popular regional anaesthetic technique for children undergoing inguinal surgery . The success rate is only 70 - 80 % and complications may occur . A prospect i ve r and omized double-blinded study was design ed to compare the use of ultrasonography with the conventional ilioinguinal/iliohypogastric nerve block technique . METHODS One hundred children ( age range , 1 month-8 years ) scheduled for inguinal hernia repair , orchidopexy or hydrocele repair were included in the study . Following induction of general anaesthesia , the children received an ilioinguinal/iliohypogastric block performed either under ultrasound guidance using levobupivacaine 0.25 % until both nerves were surrounded by the local anaesthetic or by the conventional ' fascial click ' method using levobupivacaine 0.25 % ( 0.3 ml kg(-1 ) ) . Additional intra- and postoperative analgesic requirements were recorded . RESULTS Ultrasonographic visualization of the ilioinguinal/iliohypogastric nerves was possible in all cases . The amount of local anaesthetic used in the ultrasound group was significantly lower than in the ' fascial click ' group ( 0.19 ( SD 0.05 ) ml kg(-1 ) vs 0.3 ml kg(-1 ) , P<0.0001 ) . During the intraoperative period 4 % of the children in the ultrasound group received additional analgesics compared with 26 % in the fascial click group ( P=0.004 ) . Only three children ( 6 % ) in the ultrasound-guided group needed postoperative rectal acetaminophen compared with 20 children ( 40 % ) in the fascial click group ( P<0.0001 ) . CONCLUSIONS Ultrasound-guided ilioinguinal/iliohypogastric nerve blocks can be achieved with significantly smaller volumes of local anaesthetics . The intra- and postoperative requirements for additional analgesia are significantly lower than with the conventional method OBJECTIVE To investigate the efficacy and safety of dorsal penile nerve block ( DPNB ) and eutectic mixture of lidocaine ( EMLA ) for palliation of pain associated with circumcision in low-birth-weight infants . DESIGN R and omized , blinded , controlled trial . SETTING Intensive care nursery ( step down unit ) at Georgetown University Medical Center , Washington , DC . PARTICIPANTS Fifty neonates with weights of 1600 to 2500 g at the time of circumcision who were discharged from the hospital between May 1994 and June 1995 were r and omly assigned to the DPNB , EMLA , or control group . Twenty-five infants who were otherwise eligible were excluded because of parental refusal of consent to participate . INTERVENTIONS Infants in the DPNB and EMLA groups received anesthesia with subcutaneous injection of 1 % lidocaine hydrochloride or topical EMLA , respectively . The control group received sham anesthesia with topical placebo ( acid mantle cream ) . MAIN OUTCOME MEASURES Changes in physiologic variables ( heart rate , blood pressure , oxygen saturation , and respiratory rate ) and behavioral score 20 minutes before , during , and 5 and 20 minutes after circumcision between DPNB and control groups . Surgical complications and adverse effects were also monitored . RESULTS Fifty infants were enrolled in the study : 19 r and omized to the DPNB group , 19 to the control group , and 12 to the EMLA group . Enrollment into the EMLA group was suspended early because of redness and blistering of the foreskin in 2 infants , and this entire group was excluded from further analysis . The clinical course was similar in all groups of infants . All circumcisions were performed without complication or technical difficulty . Statistically significant differences were noted in heart rate , respiratory rate , and behavioral score when comparing the DPNB group with controls during and after circumcision . CONCLUSION Dorsal penile nerve block is safe and effective in controlling pain associated with circumcision in low-birth-weight infants Purpose Children scheduled to undergo otoplasty experience severe pain postoperatively . Nausea and vomiting is also a problem . This study was design ed to compare two analgesic techniques ( i ) regional nerve blockade ( ii ) local anaesthetic infiltration , with respect to quality and duration of analgesia , opioid requirements and the incidence of postoperative nausea and vomiting ( PONV ) . Methods Forty three children , ASA I – II , aged 3–15 yr , were studied and followed for 24 hr postoperatively . Patients were r and omised into two groups . Patients in Group A received local infiltration with lidocaine 1 % with adrenaline 1:200,000 0.4 ml·kg−1 ( n = 21 ) . Patients in Group B ( n = 22 ) received nerve blockade , bupivacaine 0.5 % , 0.4 ml·kg−1 . No other form of analgesia was used intraoperatively . Quality and duration of analgesia were assessed using pain and sedation scores recorded by a blinded observer at 0 , 5 , 10 , 15 , 30 , 45 min with Recovery Room , and at 0 , 30 , 60 , 90 , 120 , 180 , 240 , 360 , 480 min on the ward . Pain score > 6 was treated with fentanyl 1 μg·kg−1 iv ( recovery ) and morphine 0.2 mg·kg−1 i m or mefenamic acid 8 mg · kg−1 po on the ward . Time to first supple-mental analgesia was noted . Mean duration of analgesia was 8.6 ( 1,1–24 ) hr , Group A and 10.5 ( 1,3–24 ) hr , Group B ( P > 0.7 ) . 24 % per cent of children ( Group A ) and 27 % ( Group B ) required no supplemental analgesia ( P > 0.6 ) . The degree of pain control result ed in a low requirement for opioids , Group A : 24 % , Group B : 14 % ( P : NS ) . The overall incidence of PONV was 43 % ( Group A ) and 36 % ( Group B ) ( P : NS ) : PONV correlated with opioid use . There were no differences between the groups with regard to pain/sedation scores , quality / duration of analgesia , opioid requirements and incidence of PONV . Conclusion Both techniques provided excellent postoperative analgesia . Lidocaine 1 % infiltration ( adrenaline 1:200,000 ) has the added advantage of improving surgical field and haemostasis . Thus , we advocate use of the simpler technique . RésuméObjectifsL’otoplastie chez l’enfant provoque des douleurs postopératoires très intenses . De plus , les nausées et les vomissements sont fréquents . Cette étude a permis de comparer deux méthodes d’analgésie : i ) le bloc régional avec ii ) l’infiltration locale , au regard de la qualité et de l’analgésie , des besoins en morphiniques et de l’incidence des nausées et vomissements postopératoires (NVPO).MéthodeQuarante-trois enfants ASA I et II âgés de 3 à 15 ans ont été inclus dans l’étude et suivis pendant 24 h après l’opération . Ils ont été répartis aléatoirement en deux groupes : les patients du groupe A ( n = 21 ) ont reçu une infiltration de lidocaïne 1 % adrénalinée à 1:200,000 0,4 ml·kg−1 ; ceux du groupe B ( n = 22 ) , un bloc nerveux à la bupivacaïne 0,5 % , 0,4 ml · kg−1 . Aucune autre forme d’analgésie postopératoire n’a été administrée pendant l’intervention . La qualité et la durée de l’analgésie ont été évaluées sur des échelles de douleur et de sédation et enregistrées par un observateur neutre à 0 , 5 , 10 , 30 et 45 min à la salle de réveil et à 0 , 30 , 60 , 90 , 120 , 180 , 240 , 360 , 480 min après le retour dans le service . Lorsque les scores de douleur dépassaient 6 , l’enfant recevait fentanyl 1 μg·kg−1 ( salle de réveil ) et morphine 0,2 μg · kg−1 i m ou de l’acide méfénamique 8 mg · kg−1 po ( dans le service ) . Le moment de l’administration supplément d’analgésique a été noté . La durée moyenne de l’analgésie a été de 8,6 ( 1,1–24 ) h pour le groupe A ; de 10,5 ( 1,3–24 ) h pour le groupe B ( P > 0,7 ) . Vingt-quatre pour cent des enfants du groupe A et 27 % du groupe B n’ont pas eu besoin de supplément d’analgésie ( P > 0,6 ) . La qualité du contrôle de la douleur permis de réduire les besoins de morphiniques de 24 % dans le groupe A et de 14 % dans le groupe B ( P : NS ) . L’incidence totale de NVPO a été de 43 % ( groupe A ) et de 36 % ( groupe B ) ( P : NS ) . On a trouvé une corrélation entre les NVPO et les morphiniques . Il n’y a pas eu de différences entre les groupes au regard des scores de douleur et de sédation , de la qualité et la durée de l’analgésie , des besoins en morphiniques et de l’incidence de NVPO , les deux techniques procurant une analgésie postopératoire excellente . Conclusion L’infiltration de lidocaïne 1 % adrénalinée à 1:200,000 a l’avantage de faciliter la technique chirurgicale et de favoriser l’hémostase . Les auteurs conseillent d’utiliser cette technique parce qu’elle est la plus simple The purpose of this study was to compare the effect of local anaesthesia ( LA ) with that of caudal anaesthesia ( CA ) on postoperative care of children undergoing inguinal hernia repair . This was a r and omized , single-blind investigation of 202 children aged 1–13 yr . Anaesthesia was induced with N2O/O2 and halothane or propofol and maintained with N2O/O2/halothane . Local anaesthesia included ilioinguinal and iliohypogastric nerve block plus subcutaneous injection by the surgeon of up to 0.3 ml · kg−1 bupivacaine 0.25 % with 5 μg · kg−1 adrenaline . The dose for caudal anaesthesia was 1 ml · kg−1 up to 20 ml bupivacaine 0.2 % with 5 μg · kg−1 adrenaline . Postoperative pain was assessed with mCHEOPS in the anaesthesia recovery room , with postoperative usage of opioid and acetaminophen in the hospital , and with parental assessment of pain with a VAS . Vomiting , time to first ambulation and first urination were recorded . The postoperative pain scores and opioid usage were similar ; however , the LA-group required more acetaminophen in the Day Care Surgical Unit . The incidence of vomiting and the times to first ambulation and first urination were similar . The LA- patients had a shorter recovery room stay ( 40 ± 9 vs 45 ± 15 min , P < 0.02 ) . The postoperative stay was prolonged in the CA group ( 176 ± 32 vs 165 ± 26 min , P = 0.02 ) . We conclude that LA and CA have similar effects on postoperative care with only slight differences . RésuméCette étude vise à comparer les effets de l’anesthésie locale ( AL ) avec ceux de l’anesthésie caudale ( AC ) sur le suivi postopératoire d’enfants soumis à une cure de hernie inguinale . Cette étude r and omisée et à l’aveugle porte sur 202 enfants âgés de 1 à 13 ans . L’anesthésie est induite au N2O/O2 avec halothane ou au propofol et entretenue avec N2O/O2/halothane . L’anesthésie locale comprend le bloc ilioinguinal et iliohypogastrique avec injection maximale par le chirurgien de 0,3 ml · kg−1 de bupivacaïne 0,25 avec 5 μg · kg−1 d’adrénaline . Pour l’anesthésie caudale , on utilise 1 ml · kg−1 jusqu’à un maximum de 20 ml de bupivacaine 0,2 % avec 5 μg · kg−1 d’adrénaline . La douleur postopératoire est évaluée par mCHEOPS à la salle de réveil , par la dose de morphinique et d’acétaminophène durant la séjour hospitalier et par l’évaluation sur l’EVA des parents . Les vomissements , le délai jusqu’à l’ambulation et la première miction sont enregistrés . Les scores sur l’échelle de la douleur et l’utilisation de morphinique sont identiques , mais le groupe AL reçoit plus d’acétaminophène à l’unité de chirurgie d’un jour . L’incidence des vomissements et les délais à l’ambulation et à la première miction ne diffèrent pas . Les patients du groupe AL demeurent moins longtemps à la salle de réveil ( 40 ± 9 vs 45 ± 15 min , P < 0,02 ) . Le séjour postopératoire est prolongé dans le groupe AC ( 176 ± 32 vs 165 ± 26 min , P = 0,02 ) . Nous concluons que l’AL et l’AC , à l’exception de minimes différences , ont des effets identiques sur les soins postopératoires BACKGROUND : Bilateral breast augmentation is an increasingly popular day-case procedure . Local infiltration with sedation is routinely used for its ease of application compared with the more complex and potentially riskier paravertebral blockade ( PVB ) . We hypothesized that ropivacaine injected by experienced anesthesia providers into the paravertebral space as a PVB was more effective than ropivacaine injected by the operating surgeon ( plastic surgeon ) directly into the zone of surgical dissection . METHODS : Forty female patients who were ASA physical status I or II and undergoing bilateral subpectoral cosmetic breast augmentation were recruited for participation in a prospect i ve , r and omized , single-blind study . Patients were r and omized to 1 of 2 groups : ropivacaine via PVB , or surgical infiltration of ropivacaine . In both groups , the surgeon was asked to infiltrate the appropriate area with either saline ( PVB group ) or ropivacaine ( local infiltration group ) . Both groups were se date d with propofol , titrated to effect . The plastic surgeon was blinded to the solution injected . Data collected included demographic characteristics , intraoperative cooperation scores , recovery room postoperative nausea and vomiting , analgesia use , and visual analog scale pain scores . All patients were asked to complete a preoperative anxiety and quality of recovery question naire and to record their pain scores and analgesia requirements on discharge . The outcome measures were ( i ) intraoperative patient cooperation as assessed by the plastic surgeon , ( ii ) propofol requirement , ( iii ) postoperative pain , and ( iv ) quality of recovery . RESULTS : Forty patients completed the study . PVB improved intraoperative cooperation ( significance of difference P < 0.001 , WMWodds = 6.69 with 95 % 1-sided confidence interval CI ≥2.85 ) , reduced propofol requirement ( significance of difference P = 0.005 , WMWodds = 0.35 , CI < 0.69 ) , and decreased average postoperative pain in the home environment ( significance of difference P = 0.007 , WMWodds = 0.38 , CI < 0.73 ) . There were no PVB complications . Only patients from the surgical infiltration group required rescue analgesics ( 30 % , significance of difference = 0.01 ) . CONCLUSIONS : In a limited number of patients , we found that PVB is superior to direct surgical infiltration of ropivacaine for bilateral breast augmentation in same-day surgery . These advantages need to be balanced against the potential risks of PVB , especially in an office setting Purpose Somatic paravertebral block ( SPVB ) appears to provide effective and prolonged nerve block in children ; however , study of its use in this population is limited . We compared SPVB with no block in children undergoing appendectomy . Methods Thirty-six children aged 3 - 16 yr undergoing open appendectomy were involved in this prospect i ve r and omized controlled study . Anesthesia was induced with propofol and maintained with isoflurane in N2O/oxygen . All subjects received fentanyl , acetaminophen and ketorolac during anesthesia . Group I ( SPVB ) subjects received a right SPVB at T11 , T12 , and L1 using 0.2 % ropivacaine 0.25 mL·kg−1 with epinephrine 1:200,000 preoperatively . Group II ( Control ) had only b and aids applied to skin . Both groups were given morphine 0.05 mg·kg−1iv every 2 hr if pain scores reached 5/10 on a visual analogue scale . Acetaminophen was administered postoperatively every 6 hr to both groups . Time to first dose of morphine , total dose of morphine in 24 hr , and any adverse effects up to 24 hr after surgery were recorded . Results Group I ( SPVB ) subjects required significantly less morphine than Group II ( Control ) patients ( 0.12 ± 0.07 vs 0.34 ± 0.15 mg·kg−1 , respectively ; P < 0.001 ) , and time to their first dose was significantly longer ( 7.1 ± 4.4 vs 2.5 ± 1.6 hr , respectively ; P < 0.001 ) . Incidence of vomiting was 11 % with Group I and 27 % with Group II ( P = 0.21 ) . No other adverse effects were observed in either group . Conclusions In children undergoing appendectomy , SPVB provides better pain relief than no block and reduces opioid requirements . Side effects were not statistically different between groups . RésuméObjectifLes blocs paravertébraux des nerfs somatiques ( BPVS ) semblent procurer un bloc nerveux efficace et prolongé chez les enfants ; toutefois , les études examinant son utilisation chez cette population sont peu nombreuses . Nous avons comparé l’utilisation d’un BPVS à une technique sans bloc chez des enfants subissant une appendicectomie . MéthodeTrente-six enfants âgés de 3 à 16 ans et subissant une appendicectomie ouverte ont participé à cette étude r and omisée contrôlée prospect i ve . L’anesthésie a été induite à l’aide de propofol et maintenue avec de l’isoflurane et du N2O/oxygène . Tous les patients ont reçu du fentanyl , de l’acétaminophène et du kétorolac pendant l’anesthésie . Les patients du Groupe I ( BPVS ) ont reçu un BPVS droit aux niveaux T11 , T12 , et L1 avec 0,25 mL·kg−1 de ropivacaïne à 0,2 % et de l’épinéphrine 1:200 000 avant l’opération . Dans le Groupe II ( témoin ) , seuls des pansements ont été appliqués sur la peau . Les deux groupes ont reçu de la morphine 0,05 mg·kg−1iv toutes les 2 h si les scores de douleur atteignaient 5/10 sur une échelle visuelle analogique . Après l’opération , de l’acétaminophène a été administrée toutes les 6 h aux deux groupes . Le temps écoulé jusqu’à la première dose de morphine , la dose totale de morphine en 24 h et tous les effets indésirables observés jusqu’à 24 h après la chirurgie ont été enregistrés . RésultatsLes patients du Groupe I ( BPVS ) ont manifesté des besoins en morphine significativement moins prononcés que les patients du Groupe II ( témoin ) ( 0,12 ± 0,07 vs 0,34 ± 0,15 mg·kg−1 , respectivement ; P < 0,001 ) , et le temps écoulé jusqu’à la première dose était significativement plus long dans le Groupe I ( 7,1 ± 4,4 vs 2,5 ± 1,6 h , respectivement ; P < 0,001 ) . L’incidence de vomissements était de 11 % dans le Groupe I et de 27 % dans le Groupe II ( P = 0,21 ) . Aucun autre effet secondaire n’a été observé dans l’un ou l’autre groupe . Conclusion Pour les enfants subissant une appendicectomie , le BPVS procure un meilleur soulagement de la douleur que l’absence de bloc et réduit les besoins en opioïdes . Les effets secondaires n’étaient pas statistiquement différents entre les groupes BACKGROUND : Regional anesthesia is increasingly used in pediatric patients to provide postoperative analgesia and to supplement intraoperative anesthesia . The Pediatric Regional Anesthesia Network was formed to obtain highly audited data on practice patterns and complications and to facilitate collaborative research in regional anesthetic techniques in infants and children . METHODS : We constructed a central ized data base to collect detailed prospect i ve data on all regional anesthetics performed by anesthesiologists at the participating centers . Data were uploaded via a secure Internet connection to a central server . Data were rigorously audited for accuracy and errors were corrected . All anesthetic records were scrutinized to ensure that every block that was performed was captured in the data base . Intraoperative and postoperative complications were tracked until their resolution . Blocks were categorized by type and as single-injection or catheter ( continuous ) blocks . RESULTS : A total of 14,917 regional blocks , performed on 13,725 patients , were accrued from April 1 , 2007 through March 31 , 2010 . There were no deaths or complications with sequelae lasting > 3 months ( 95 % CI 0–2:10,000 ) . Single-injection blocks had fewer adverse events than continuous blocks , although the most frequent events ( 33 % of all events ) in the latter group were catheter-related problems . Ninety-five percent of blocks were placed while patients were under general anesthesia . Single-injection caudal blocks were the most frequently performed ( 40 % ) , but peripheral nerve blocks were also frequently used ( 35 % ) , possibly driven by the widespread use of ultrasound ( 83 % of upper extremity and 69 % of lower extremity blocks ) . CONCLUSIONS : Regional anesthesia in children as commonly performed in the United States has a very low rate of complications , comparable to that seen in the large multicenter European studies . Ultrasound may be increasing the use of peripheral nerve blocks . Multicenter collaborative networks such as the Pediatric Regional Anesthesia Network can facilitate the collection of detailed prospect i ve data for research and quality improvement BACKGROUND The addition of clonidine to peripheral nerve blocks is controversial in children . OBJECTIVE The aim of our study was to evaluate the effect of clonidine added to ropivacaine in pediatric axillary brachial plexus block ( ABPB ) . METHODS Children aged 1 - 6 years , scheduled to undergo forearm or h and surgery , were recruited into this prospect i ve , double-blind controlled trial . Patients were r and omly allocated to receive an ABPB either with ropivacaine 0.2 % 0.4 ml · kg(-1 ) plus saline in 1 ml ( RS ) or ropivacaine 0.2 % 0.4 ml · kg(-1 ) plus clonidine 1 μg · kg(-1 ) in 1 ml ( RC ) . Primary endpoints were quality of postoperative analgesia as assessed by pain scores and total 24-h postoperative analgesia requirements . Secondary outcomes were time to first analgesia request and duration of motor blockade . RESULTS Sixty patients were recruited ( n = 30 per group ) into the study . Pain scores were comparable throughout the first 24 h between the two groups . Ten children in the ( RS ) and six in ( RC ) groups required supplementary analgesia during the first 24 h ( P = 0.24 ) . Children who required further analgesia did so after 288 ± 94 min in the ( RS ) and 437 ± 204 min in the ( RC ) group ( P = 0.06 ) . There was no difference in the duration of motor block [ 186 ± 71 and 154 ± 56 min , P = 0.12 for ( RS ) and ( RC ) , respectively ] . CONCLUSION Ropivacaine ( 0.2 % 0.4 ml · kg(-1 ) ) for ABPB provides sufficient postoperative analgesia in children scheduled for forearm or h and surgery . The addition of clonidine to ABPB does not improve overall postoperative analgesia but may increase the time to first analgesia request AIM To determine the efficacy and safety of a continuous subcutaneous local anesthetic ( LA ) infusion in pediatric patients following open heart surgery . BACKGROUND The use of a continuous LA infusion has been shown to be beneficial following adult cardiac surgery . To date there are no studies in the pediatric population . METHODS / MATERIAL S Using a prospect i ve , r and omized , and double blind design , we compared LA , either 0.25 % levobupivacaine or bupivacaine ( Treatment Group ) to saline ( Placebo Group ) delivered subcutaneously via a continuous infusion for 72 h after open heart surgery in 72 patients . Requirements for postoperative analgesics and pain scores were recorded for 72 h and plasma levels of local anesthetic were measured . Secondary outcomes measures included time to first oral intake , time to first bowel movement , time to urinary catheter removal , length of stay , requirements for antiemetics and additional sedation . RESULTS Total morphine requirements over the first 24 h were less in the Treatment Group than the Placebo Group ( 0.05 mg x kg(-1 ) vs 0.2 mg x kg(-1 ) , P = 0.007 ) ; this was true for all patient groups except those patients weighing less than 6.3 kg . The number of patients requiring no morphine was greater in the Treatment Group ( 7/35 vs 1/37 , P = 0.02 ) . The Treatment Group also received less midazolam , lorazepam , and ketorolac than the Placebo Group over 72 h due to the reduced clinical need for these agents in patients weighing less than 31 kg . There were no differences in secondary outcomes . CONCLUSIONS A continuous incisional infusion of LA reduced postoperative analgesic requirement and sedative use in pediatric patients undergoing a median sternotomy incision . Dosed at a maximum rate of 0.4 mg x kg(-1 ) x h(-1 ) , a continuous incisional infusion of LA is effective and safe for up to 72 h , with plasma levels of local anesthetic well below the toxic threshold Background : Lower-limb peripheral nerve blocks in pediatrics have gained much more popularity in the last few decades . Our purpose of this study was to compare the postoperative analgesic effects between psoas compartment block ( PCB ) and caudal block in small children undergoing open hip reduction/osteotomies . Methods : Forty American Society of Anesthesiologists physical status I-II children aged 1 to 6 years planned to undergo open hip reduction/osteotomies were administered general anesthesia and then r and omly assigned to receive 1 of 2 regional anesthetics : caudal block ( group C , n = 20 ) or PCB ( group P , n = 20 ) . Ropivacaine 0.25 % with epinephrine ( 5 & mgr;g/mL ) was used in both blocks . The primary outcome of the study was the total consumption of morphine in the first 24 postoperative hrs . Secondary outcomes included dose of intraoperative fentanyl , occurrence of intraoperative hypotension or bradycardia , postoperative pain scores , time to first morphine analgesia , and occurrence of postoperative vomiting or urine retention . Results : The cumulative dose of morphine administered in the ward in the first postoperative 24 hrs and the time to first rescue morphine dose were higher in group C than in group P ( P < 0.001 ) . There were no differences between the 2 groups regarding intraoperative and postoperative complications except for the incidence of urine retention , which was higher in group C than in group P ( P = 0.037 ) . Conclusions : Use of single-shot PCB is superior to single-shot caudal block regarding length of postoperative analgesia and cumulative dose of morphine in small children undergoing open hip reduction/osteotomies BACKGROUND Caudal anaesthesia is recommended for most surgical procedures of the lower part of the body , mainly below the umbilicus . It has been well established that a dorsal penile nerve block immediately after surgery decreases postoperative pain in children undergoing hypospadias repair . This study aim ed to compare caudal or penile nerve block using bupivacaine in postoperative pain control in hypospadias repair in children . PATIENTS AND METHODS After local ethical committee approval and obtaining informed parental consent , 85 American society of Anesthesiologists status I and II patients , aged 6 months to 6 years old , undergoing hypospadias repair , were prospect ively enrolled in this study . The patients were r and omly divided into the following two groups : Caudal block was performed in 44 and penile block was performed in 41 patients . Cardiorespiratory systems data , analgesic requirement and complications were compared between the groups . RESULTS There were statistically significant haemodynamic ( blood pressure and heart rate ) alteration during operation in each group ( P<0.01 ) . The haemodynamic parameters were stable during operation in successful blocks in both groups . Caudal block success rate is 97.7 % , whereas in penile block is 92.6 % . Nineteen of 43 patients ( 44 % ) in caudal group and 29 of 41 patients ( 70 % ) in penile group received analgesia in the postoperative period and this difference was significant between the two groups ( P = 0.025 ) . CONCLUSIONS Without ultrasonography and with blind block , with anatomic l and marks only , the caudal block success rate is high and if there is no contraindication for caudal block , it is the best choice in children under 6 years old ( or 25 kg ) for hypospadias repair BACKGROUND : Patients undergoing abdominal hysterectomy often have significant postoperative pain despite the use of concurrent multimodal pain strategies . Neuraxial anesthesia has opioid-sparing effects and may provide better postoperative recovery to patients when compared with general anesthesia . Our main objective in this study was to compare the effects of neuraxial and general anesthesia on postoperative quality of recovery after abdominal hysterectomy . METHODS : The study was a prospect i ve , r and omized , controlled clinical trial . Seventy healthy females were recruited and r and omized to a general anesthesia or neuraxial technique as their primary anesthetic regimen . The primary outcome was the global quality of recovery—40 question naire ( QoR–40 ) at 24 hours after the surgical procedure . Other data collected included postoperative pain scores and opioid consumption . Data were analyzed using the Mann – Whitney U test , Fisher 's exact test , and linear regression . A P value < 0.05 was considered statistically significant . RESULTS : The median difference ( 95 % confidence interval [ CI ] ) in the global QoR–40 score at 24 hours between the neuraxial and general anesthesia groups was 17 ( 11 to 21.5 ) ( P < 0.001 ) . Patients in the neuraxial anesthesia group had better quality of recovery scores in all the QoR–40 subcomponents than did the general anesthesia group ( all P < 0.005 ) . The median difference in global QoR–40 scores at 48 hours between the neuraxial anesthesia and the general anesthesia groups was 8 ( 6–10 ) ( P < 0.001 ) . Postoperative opioid consumption and pain scores were higher in the general anesthesia group than in the neuraxial anesthesia group . There was an inverse linear relationship between opioid consumption and postoperative quality of recovery at 24 hours , r 2 = 0.67 ( P < 0.0001 , 95 % CI of 0.77 to 0.51 ) , and at 48 hours , r 2 = 0.58 ( P < 0.0001 , 95 % CI of 0.72 to 0.42 ) . CONCLUSION : Neuraxial anesthesia provides better quality of recovery than does general anesthesia for patients undergoing abdominal hysterectomy . The opioid-sparing effects of neuraxial anesthesia were associated with a better quality of recovery in patients after the surgical procedure . In the absence of contraindications , neuraxial anesthesia seems to be a better anesthetic plan for those patients Background : Improvement of the duration of postoperative analgesia is desirable in children undergoing inguinal hernia repair . Methods : Fifty children aged 5–12 yr were prospect ively r and omized to receive either paravertebral nerve blockade or general anesthesia ( sevoflurane – fentanyl – nitrous oxide – oxygen ) combined with st and ardized postoperative systemic analgesia , both combined with light sevoflurane anesthesia , for inguinal hernia repair . Results : Mean pain scores were significantly lower in paravertebral nerve blockade patients compared with patients treated with systemic analgesia during the entire 48-h observational period ( P < 0.05 ) . Analgesic consumption was significantly higher in the systemic analgesia group ( 88 % ) compared with the paravertebral nerve blockade group ( 32 % ) ( P < 0.001 ) . Parental satisfaction was significantly higher ( 80 vs. 48 % ; P < 0.05 ) and same-day discharge was possible in a higher proportion of patients in the paravertebral blockade group ( 80 % vs. 52 % ; P < 0.05 ) . Conclusions : Paravertebral nerve blockade was associated with improved postoperative pain relief ; reduced analgesic consumption , and faster hospital discharge compared with a systemic analgesia protocol in children undergoing herniorrhaphy Background and objective The effect of dexmedetomidine on the duration of sensory blockade has not been studied in humans . We evaluated the effect of adding dexmedetomidine to bupivacaine on the duration of postoperative analgesia in children who underwent repair of a cleft palate . Methods Thirty children who were scheduled for repair of a complete cleft palate using a combination of general anaesthesia and greater palatine nerve block were allocated r and omly into one of two equal groups ( n = 15 ) . In both groups , the greater palatine nerve block was performed bilaterally using 0.5 ml of solution on each side . The B group received bupivacaine 0.25 % , whereas the BD group received bupivacaine 0.25 % with 1 μg kg−1 dexmedetomidine . Heart rate , systolic blood pressure , pain score , the time to the first request for analgesia , and the degree of sedation were recorded . Results There was no difference in haemodynamic variables between the two groups . The pain score was significantly higher in the B group as compared with the BD group . The time to the first request for analgesia was significantly longer in children in the BD group ( mean 22 h , range 20.6–23.7 h ) as compared with those who received bupivacaine alone ( 14.2 h , 13–15 h ) . Sedation scores in the postoperative period did not differ between the study groups . Conclusion Greater palatine nerve block with a combination of dexmedetomidine and bupivacaine increased the duration of analgesia after repair of a cleft palate by 50 % with no clinical ly relevant side effects BACKGROUND : General anesthesia with opioids provides good operative conditions for ocular surgery in children ; however , postoperative pain management remains a significant problem . Regional anesthesia is commonly used as an adjunct to general anesthesia in children . We compared the efficacy and safety of subtenon block ( SB ) versus IV fentanyl for perioperative analgesia in pediatric cataract surgery . We hypothesized that perioperative analgesia using SB may reduce the requirement of postoperative rescue analgesia compared with fentanyl . METHODS : This was a prospect i ve , r and omized , controlled , double-blind trial . One hundred fourteen ASA I and II children ( 6 mo–6 yr ) undergoing elective cataract surgery in one eye under general anesthesia were studied . Children were r and omly allocated to one of the two groups , i.e. , Group SB ( n = 58 ) or Group F ( n = 56 ) after securing the airway . Children in Group SB received SB with 0.06–0.08 mL/kg of 2 % lidocaine and 0.5 % bupivacaine ( 50:50 ) mixture and simultaneous 0.2 mL/kg normal saline IV , whereas children in Group F received 1 & mgr;g/kg ( 0.2 mL/kg of 5 & mgr;g/kg ) of fentanyl IV and simultaneous subtenon injection with normal saline ( 0.06–0.08 mL/kg ) . Surgery started after 5 min of study drug administration . Postoperative assessment for pain , sedation , and nausea/vomiting was done at 0.5 , 1 , 2 , 3 , 4 , and 24 h. The primary outcome was number of patients requiring rescue analgesia during the 24-h study period . Secondary outcomes assessed were pain and sedation scores , time to first rescue analgesia , incidence of occulocardiac reflex , and nausea/vomiting . RESULTS : The number of patients requiring rescue analgesia during the 24 h was significantly less in Group SB ( n = 17/58 , 29.3 % ) compared with Group F ( n = 39/56 , 69.6 % , P < 0.001 ) . The postoperative pain scores were statistically lower in Group SB at all time intervals . The median ( range ) time to first analgesic requirement was significantly prolonged in Group SB ( 16 [ 2–13 ] vs 4 [ 0.5–8.5 ] h in Group F ) ( P < 0.001 ) . Sedation scores at ½ h were comparable , after which significantly more children were anxious or crying in Group F compared with Group SB in which more children were calm , sitting , or lying with eyes open and relaxed ( P < 0.05 ) . A significantly higher incidence of oculocardiac reflex was recorded in Group F versus Group SB ( P = 0.019 ) . No complication related to SB was noticed . CONCLUSIONS : SB is a safe and superior alternative to IV fentanyl for perioperative analgesia in pediatric cataract surgery Background and Objectives Vitreoretinal ( VR ) surgery with or without scleral buckling is associated with significant postoperative pain and emesis in adults , and recent studies have addressed the effect of retro or peribulbar block on these parameters . VR surgery in children has received little attention regarding the incidence of pain and emesis , and the role of regional anesthesia in modifying these parameters . In this study , we compared peribulbar block with conventional opioid analgesia in children undergoing VR surgery . Methods In a prospect i ve , r and omized , single-blind study , 85 children ( ages 6 to 13 years ) were allocated to receive peribulbar block ( n = 42 ) or intravenous meperidine 1 mg/kg ( n = 43 ) after induction of general anesthesia . Parameters compared were : intraoperative incidence of oculocardiac reflex and requirement for additional analgesic ; postoperative pain intensity ; incidence of postoperative emesis ; time to first analgesic , total number of postoperative analgesic supplements ; and parental assessment of the child ’s postoperative comfort at 24 hours . Results The incidence of intraoperative oculocardiac reflex was significantly less in the peribulbar group ( P = .0001 ) . Significantly more children receiving peribulbar block were pain free on awakening ( P = .0004 ) and throughout the postoperative period . The number of children requiring opioid was significantly lower with peribulbar block ( P = .008 ) , and a significant number of children did not vomit throughout the postoperative period ( P = .001 ) . Conclusions Peribulbar block appears to be a safe and clinical ly superior alternative to intravenous opioid for pediatric VR surgery . Reg Anesth Pain Med 2003;28:43 - 47 BACKGROUND : The transversus abdominis plane ( TAP ) block provides effective postoperative analgesia in adults undergoing major abdominal surgery . Its efficacy in children remains unclear , with no r and omized clinical trials in this population . In this study , we evaluated its analgesic efficacy over the first 48 postoperative hours after appendectomy performed through an open abdominal incision , in a r and omized , controlled , double-blind clinical trial . METHODS : Forty children undergoing appendectomy were r and omized to undergo unilateral TAP block with ropivacaine ( n = 19 ) versus placebo ( n = 21 ) in addition to st and ard postoperative analgesia comprising IV morphine analgesia and regular diclofenac and acetaminophen . All patients received a st and ard general anesthetic , and after induction of anesthesia , a TAP block was performed using the l and mark technique with 2.5 mg · kg−1 ropivacaine 0.75 % or an equal volume ( 0.3 mL · kg−1 ) of saline on the ipsilateral side to the incision . RESULTS : The TAP block with ropivacaine reduced mean ( ±SD ) morphine requirements in the first 48 postoperative hours ( 10.3 ± 12.7 vs 22.3 ± 14.7 mg ; P < 0.01 ) compared with placebo block . The TAP block also reduced postoperative visual analog scale pain scores at rest and on movement compared with placebo . Interval morphine consumption was reduced over the first 24 postoperative hours . There were no between-group differences in the incidence of sedation or nausea and vomiting . There were no complications attributable to the TAP block . CONCLUSIONS : Unilateral TAP block , as a component of a multimodal analgesic regimen , provided superior analgesia compared with placebo in the first 48 postoperative hours after appendectomy in children BACKGROUND Prevention of postoperative pain in children is one of the most important objectives of the anesthesiologist . Preoperative ilioinguinal and iliohypogastric nerve blocks have been widely used to provide analgesia in children undergoing herniorrhaphy . Tramadol is an analgesic with micro-opioid and nonopioid activity . In this study we compared the usage of intravenous tramadol with ilioinguinal and iliohypogastric nerve blocks for control of post-herniorrhaphy pain in children aged 2 - 7 years . METHODS Sixty patients were r and omly allocated to two groups of thirty . One group received tramadol 1.5 mg.kg(-1 ) i.v . before induction of general anesthesia and the other had an ilioinguinal and iliohypogastric nerve block with 0.5 % bupivacaine ( 0.25 ml.kg(-1 ) ) before skin incision . We assessed pain using the Children 's Hospital of Eastern Ontario Pain Scale and the Categorical Pain Scale . RESULTS At 1 , 4 and 24 h after surgery the two groups had identical pain scores . At 2 and 3 h after surgery the tramadol group experienced significantly less pain ( P < 0.05 ) . The rescue drug for residual pain , was used equally in the two groups . None of the 60 patients had respiratory depression but the tramadol group patients were found to have more episodes of nausea and vomiting ( P < 0.05 ) . CONCLUSIONS We concluded that tramadol can have at least the same analgesic effect as that of ilioinguinal and iliohypogastric nerve blocks for post-herniorrhaphy pain in children , with even a superior effect at the time of maximal analgesia . We also highlight the troublesome side-effect of nausea and vomiting which brings into question the benefits of using this opioid that seems to lack respiratory depression This prospect i ve , r and omised , double blind study compared the efficacy of pethidine as an adjuvant to bupivacaine with the efficacy of bupivacaine alone for infra‐orbital nerve block in alleviating postoperative pain in children undergoing cleft lip repair . Forty paediatric patients aged between 5 and 60 months undergoing cleft lip repair were r and omly allocated to two groups of 20 . After tracheal intubation , group B received bilateral intra‐oral , infra‐orbital nerve block with 1 ml of 0.25 % bupivacaine on each side and group P received 1 ml of 0.25 % bupivacaine along with 0.25 mg.kg−1 body weight pethidine . Sedation after recovery from anaesthesia was assessed using the University of Michigan Sedation Scale ( UMSS ) and pain was assessed postoperatively up to 36 h using the FLACC scale ( Face , Legs , Activity , Cry , Consolability ) . The median ( IQR ) duration of analgesia from the time of administration of block in group B was 18 h ( 14.2–20 ) compared to 29.1 h ( 24–36 ) in group P ( p = 0.001 ) . Addition of pethidine as an adjunct to local anaesthetic significantly prolonged the duration of postoperative analgesia without any adverse effects AIM The aim of this study was to investigate the use of a novel regional anesthetic technique for the management of pain in the postoperative period in infants and children undergoing myringotomy and tube placement . METHODS After institutional review board ( IRB ) approval was obtained , 200 children were r and omized in this double blind , prospect i ve , r and omized controlled trial to receive either a nerve block of the auricular branch of the Vagus ( Nerve of Arnold ) with 0.2 ml of 0.25 % bupivacaine or receive intranasal fentanyl 2 mcg.kg(-1 ) after induction of general anesthesia . Patients were monitored in the recovery room for analgesia , need for additional analgesia , incidence of nausea and vomiting , and time to discharge from the hospital . Additional analgesics administered in the PACU , surgical short-stay unit as well as at home were also recorded . RESULTS There was no difference in the pain scores between groups ( P = 0.53 ) ; there was no difference in the amount of rescue medications between groups ( P = 0.86 ) ; there was no difference in the incidence of nausea and vomiting between groups ( P = 0.34 ) ; there was no difference in the time to discharge between groups ( P = 0.5 ) . CONCLUSIONS This pilot study demonstrates the efficacy of a peripheral nerve block for management of postoperative pain in infants and children undergoing myringotomy and tube placement . This may be a viable alternative for postoperative pain control in this population . Future multi-center , r and omized controlled trials may be necessary to vali date the efficacy of this block in infants and children BACKGROUND Recent studies have shown that ultrasound guidance for paediatric regional anaesthesia can improve the quality of upper extremity and neuraxial blocks . We therefore investigated whether ultrasound guidance for sciatic and femoral nerve blocks prolongs sensory blockade in comparison with nerve stimulator guidance in children . METHODS Forty-six children scheduled for surgery of one lower extremity were r and omized to receive a sciatic and femoral nerve block under either ultrasound or nerve stimulator guidance . After induction of general anaesthesia , the blocks were performed using an ultrasound-guided multiple injection technique until the nerves were surrounded by levobupivacaine , or by nerve stimulator guidance using a predefined dose of 0.3 ml kg(-1 ) of levobupivacaine . An increase in heart rate of more than 15 % of baseline during surgery defined a failed block . The duration of the block was determined from the injection of local anaesthetic to the time when the patient received the first postoperative analgesic . RESULTS Two blocks in the nerve stimulator group failed . There were no failures in the ultrasound group . The duration of analgesia was longer in the ultrasound group mean ( sd ) 508 ( 178 ) vs 335 ( 169 ) min ( P < 0.05 ) . The volume of local anaesthetic in sciatic and femoral nerve blocks was reduced with ultrasound compared with nerve stimulator guidance [ 0.2 ( 0.06 ) vs 0.3 ml kg(-1 ) ( P < 0.001 ) and 0.15 ( 0.04 ) vs 0.3 ml kg(-1 ) ( P < 0.001 ) , respectively ] . CONCLUSIONS Ultrasound guidance for sciatic and femoral nerve blocks in children increased the duration of sensory blockade in comparison with nerve stimulator guidance . Prolonged sensory blockade was achieved with smaller volumes of local anaesthetic when using ultrasound guidance BACKGROUND The adjunctive use of clonidine to local anaesthetics has been reported to enhance analgesia both after spinal and peripheral administration . However , no attempt has been made to compare spinal and peripheral application of clonidine in the same surgical context in order to further explore the mechanism for the analgesic action of clonidine when administered together with local anaesthetics . METHODS Using a prospect i ve , r and omized , observer-blinded study design , 40 patients , aged 1 - 7 years , who were undergoing elective surgery for inguinal hernia repair or orchidopexy , were r and omly allocated to receive either a caudal block ( group C : n = 20 ; ropivacaine 0.2 % , 1 ml.kg-1 + clonidine 2 micro g.kg-1 ) or an ilioinguinal-iliohypogastric nerve block ( group I : n = 20 ; ropivacaine 0.2 % , 0.4 ml.kg-1 + clonidine 2 micro g.kg-1 ) following the induction of a st and ardized sevoflurane based anaesthetic . Postoperative analgesia [ maximum Objective Pain Scale ( OPS ) score and requirement for supplemental analgesia ] and sedation ( three-point scale ) were assessed at predetermined intervals during the first 24 h postoperatively . RESULTS Fourteen children in group I and nine children in group C did not require rescue analgesia ( P = 0.17 ) . No difference in maximum OPS scores could be detected between the two study groups . The mean time to full recovery regarding sedation was 149 min and 153 min in groups C and I , respectively . CONCLUSIONS This pilot study demonstrates a trend for better postoperative analgesia following peripheral administration of clonidine compared with central application . However , the main mechanism for the adjunct analgesic effect of clonidine when administered together with local anaesthetics requires further study BACKGROUND Coadministration of clonidine with local anesthetics is associated with improvement of the quality of peripheral nerve block and significant prolongation of postoperative analgesia . Better analgesia has been reported with clonidine in ilioinguinal nerve block compared with caudal use . The object of this study was to determine whether adding of 1 microg.kg(-1 ) clonidine to bupivacaine 0.25 % in ilioinguinal-iliohypogastric nerve block prolongs postoperative analgesia in children . METHODS Ninety-eight children ASA I-II aged between 1 and 12 years , scheduled for elective outpatient herniorrhaphy or orchidopexy were r and omly allocated to receive an ilioinguinal-iliohypogastric nerve block either with 0.3 ml.kg(-1 ) bupivacaine 0.25 % plus 1 microg.kg(-1 ) clonidine or only bupivacaine . Postoperative analgesic needs , time to the first analgesic supplementation and sedation score were assessed in hospital for 6 h postoperatively and at home by telephone call . RESULTS Demographic data were similar in both groups . There was no statistical difference in the rate of rescue analgesia between the two groups during the first six postoperative hours ( 20.4 % group clonidine vs 30.6 % group no clonidine ) ( P = 0.17 ) . A slight decrease in systolic blood pressure during surgery was reported in the clonidine group . There was no difference in the scores of sedation between the two groups . At home , 10 patients in the clonidine group and nine patients in the nonclonidine group received analgesic medication . There was no difference between the two groups regarding the number of patients receiving analgesic rescue during the first 24 h ( log rank = 0.39 ) . Parental satisfaction was high in both groups . CONCLUSIONS Our study failed to demonstrate any advantage in addition of 1 microg.kg(-1 ) clonidine to 0.25 % bupivacaine for ilioinguinal-iliohypogastric nerve block compared with bupivacaine 0.25 % alone BACKGROUND AND OBJECTIVES Correction of congenital clubfoot ( CCF ) is associated with severe postoperative pain . Caudal epidural block associated with general anesthesia is the anesthetic technique used more often in children , but it is limited by the short duration of the postoperative analgesia . Peripheral nerve blocks are associated with a low incidence of complications and prolonged analgesia . The objective of this study was to compare the duration of analgesia in peripheral nerve blocks and caudal block , as well as morphine consumption in the first 24 hours after correction of CCF in children . METHODS This is a r and omized , double-blind study with children undergoing surgeries for posteromedial release of CCF , who were divided in four groups according to the anesthetic technique : caudal ( ACa ) , sciatic and femoral block ( IF ) , sciatic and saphenous block ( IS ) , and sciatic block and local anesthesia ( IL ) , associated with general anesthesia . In the first 24 hours , patients received oral dypirone and acetaminophen , and they were evaluated by anesthesiologists who were unaware of the technique used . Oral morphine ( 0.19 mg x kg(1 ) per day ) was administered according to the scores of the CHIPPS ( Children 's and infants ' postoperative pain scale ) scale . RESULTS One hundred and eighteen children separated into four groups : ACa ( 30 ) , IF ( 32 ) , IS ( 28 ) , and IL ( 28 ) participated in this study . The mean time between the blockade and the first dose of morphine was 6.16 hours in group ACa , 7.05 hours in group IF , 7.58 in IS , and 8.18 hours in IL . Morphine consumption was 0.3 mg.kg-1 per day in all four groups . Significant differences were not observed among the groups . CONCLUSIONS peripheral nerve blocks did not promote longer lasting analgesia or a decrease in morphine consumption in the first 24 hours in children undergoing CCF correction when compared to caudal epidural block BACKGROUND The efficacy of analgesia with bilateral infraorbital nerve block and intravenous ( i.v . ) fentanyl were compared for cleft lip surgery in children . METHODS Eighty-two children aged 3 months to 10 years undergoing cleft lip repair were prospect ively r and omized to one of two groups : bilateral infraorbital nerve block ( Group B ) , or i.v . fentanyl ( Group F ) . Group B ( n = 41 ) received bilateral infraorbital injection of 1 ml 0.25 % bupivacaine and 2 ml i.v . saline as control . Group F ( n = 41 ) received 2 microg x kg(-1 ) i.v . fentanyl , and bilateral infraorbital injection of 1 ml saline as control . Pain was evaluated by the incidence of tachycardia , hypertension , and /or modified pain score > or = 4 . The time to awakening , time to first cry and time to feeding were noted . RESULTS Thirty four children ( 82.9 % ) in Group B had adequate analgesia compared with 15 ( 36.6 % ) in Group F ( P < 0.0001 , RR of failure 0.27 for Group B ) . Group B had a mean time to awakening of 5.65 + /- 2.52 min ( Group F : 9.37 + /- 4.50 min ; P < 0.0001 ) , time to first cry 32.14 + /- 18.22 min ( Group F : 28.00 + /- 16.27 min ; P = 0.3 ) , time to feed 62.05 + /- 20.06 min ( Group F : 72.44 + /- 17.72 ; P = 0.015 ) , and pain score 2.81 + /- 1.38 ( Group F : 4.71 + /- 1.89 ; P < 0.0001 ) . There were no major complications . CONCLUSIONS Bilateral infraorbital block is superior to fentanyl in terms of analgesia , and time to awakening and feeding STUDY OBJECTIVE To compare the postoperative analgesia of three different concentrations of levobupivacaine for ilioinguinal/iliohypogastric ( II/IH ) block in children undergoing inguinal hernia repair . DESIGN Double-blind , prospect i ve , r and omized , controlled trial . SETTING Operating room and postoperative recovery area of a university hospital . PATIENTS 73 ASA physical status I and II children , aged one to 6 years , scheduled for outpatient inguinal hernia repair . INTERVENTIONS Patients were r and omized to receive one of three levobupivacaine concentrations : 0.125 % ( L0.125 ) , 0.25 % ( L0.25 ) , or 0.375 % ( L0.375 ) . All patients received st and ard anesthesia with sevoflurane and II/IH nerve block . MEASUREMENTS Heart rate ( HR ) , non invasive blood pressure ( NIBP ) , respiratory rate , end-tidal carbon dioxide concentration ( ETCO(2 ) ) , and oxygen saturation via pulse oximetry ( SpO(2 ) ) were monitored during surgery . Postoperative pain scores with CHEOPS ( Children 's Hospital of Eastern Ontario Pain Scale ) and need for rescue analgesia postoperatively were measured and recorded . MAIN RESULTS 60 patients entered the postoperative observational period . The number of patients who received rescue analgesia was comparable in the three groups . In Group L0.125 , mean CHEOPS score was significantly higher , and time to first administration of rescue analgesia was shorter , than in the other two groups ( P < 0.05 ) . Pain scores and time to first administration of rescue analgesia were comparable between Groups L0.25 and L0.375 . CONCLUSIONS II/IH nerve block using 0.4 mL kg(-1 ) of 0.25 % levobupivacaine provided satisfactory postoperative pain relief after inguinal herniorraphy BACKGROUND This prospect i ve r and omized controlled study was undertaken to evaluate the efficacy of palatal block i.e. blocking of naso palatine , greater and also lesser palatine nerves in children with cleft palate undergoing palatoplasty by evaluating its effects on intraoperative anesthetic requirement , postoperative analgesia and parental satisfaction . METHODS Forty-five pediatric patients aged below five undergoing cleft palate repair were r and omly allocated to three groups of 15 each . After tracheal intubation , Group NB received no block for control , group S received 0.5 ml of normal saline and group B received 0.5 ml of 0.25 % bupivacaine for palatal block . Postoperative pain score , the time to first dem and of analgesia and number of rescue analgesic dem and s were noted . Finally , the parental satisfaction was grade d. RESULTS The block had no anesthetic sparing effect . The mean pain scores were significantly lower in patients who received block than in the group NB . The mean area under curve for FLACC score in group NB was 29 with 95 % CI of 25 - 32 , group S was 15 with 95 % CI of 8.9 - 22.3 and in group B , it was 10 with 95 % CI of 6 - 14 . The time to first dem and of analgesia was 6 [ 4.5 - 6 ] h in group NB , 18 [ 6 - 18 ] h in group S and 18 [ 18 - 18 ] h in group B ( P-0.000 ) . The number of dem and s of rescue analgesia was significantly less in group B 0 [ 0 - 0.25 ] , 0 [ 0 - 2 ] in S group compared to group NB 3 [ 3 - 3 ] ( P-0.000 ) . The parental satisfaction was good in patients who received block and poor in group NB . CONCLUSION Palatal block is technically simple , safe and effectively provides postoperative analgesia with good parental satisfaction . Injection of saline also produced palatal nerve block ; however , the effect was not consistent The objective of this study was to evaluate the effectiveness of bilateral extraoral infraorbital nerve block with 0.25 % bupivacaine administered at the end of surgery in postoperative pain relief after cleft lip repair . Forty ASA I-II children were r and omly divided into 2 groups . Group I received 1.5 mL 0.25 % bupivacaine and group II received 1.5 mL saline . FLACC scores of the patients in the recovery room in group I were 4 times less than in group II ( P = 0.001 ) and in the first 4 hours postoperatively were apparently less in group I ( P = 0.001 ) . Mean time to first paracetamol requirement was longer in group I ( P = 0.001 ) . Total paracetamol consumption was lower in group I ( P = 0.001 ) . None of the patients required rescue tramadol in group I , whereas all patients in group II needed . In group I , parent satisfaction scores were higher ( P = 0.001 ) . Vomiting incidence was higher in group II ( P = 0.028 ) . Bilateral extraoral , infraorbital nerve block administered at the end of surgery provides satisfactory analgesia with high parental satisfaction and lower complication rates and reduces rescue analgesic consumption in patients undergoing repair of cleft lip PURPOSE It has been well established that a dorsal penile nerve block immediately after surgery decreases postoperative pain in children undergoing hypospadias repair . However , to our knowledge the efficacy of a penile block immediately before versus immediately after surgery for postoperative pain control has not been previously studied in such children . MATERIAL S AND METHODS We evaluated 98 healthy boys 6 months to 12 years old undergoing hypospadias repair . General anesthesia was induced and maintained in a st and ard fashion . Patients were r and omly assigned to receive a penile block with the same total dose of bupivacaine at the completion of surgery , before the incision or before and at the completion of surgery . No other analgesic was administered intraoperatively . Pain was assessed using a modified objective pain-discomfort scale at 15 minutes , and 3 , 12 and 24 hours after surgery . The number of doses of acetaminophen required to control postoperative pain was also recorded . RESULTS Pain scores were defined in a range of 0-no pain to 6-greatest pain . During recovery median pain scores in the 30 , 36 and 32 boys who received a penile block after , before , and before and after surgery were 3 , 1.5 and 0 at 15 minutes ; 2.5 , 1 and 0 at 3 hours ; 3 , 2 and 0 at 12 hours ; and 1 , 0 and 0 at 24 hours , respectively . There was no difference in acetaminophen doses required 15 minutes and 3 hours postoperatively in the 3 groups . By 12 hours after surgery the number of acetaminophen doses required for pain control was significantly lower in the before and after , and before groups than in the after group . By 24 hours boys in the before and after group required significantly fewer doses of analgesics than those in the after and before groups . There was no statistically significant difference between the after and before groups . CONCLUSIONS Two penile blocks performed at the beginning and conclusion of hypospadias repair , respectively , provide better postoperative pain control than 1 penile block done before or after surgery ( p < 0.05 ) . These patients require less analgesic than those who receive a penile block only before or only after surgery METHODS Fifty children ( age 5 - 14 years , ASA I-II ) undergoing elective ophthalmic surgery were chosen for the study . Of these , 25 received intravenous pethidine ( control group ) and 25 received a peribulbar block ( block group ) for perioperative analgesia , and were monitored intraoperatively and postoperatively by an investigator blinded to the analgesic technique . RESULTS Intraoperative values of haemodynamic variables were significantly higher in the control group ( P < 0.01 ) . Requirement for intraoperative rescue analgesic and postoperative analgesia was higher in the control group ( P < 0.05 and P < 0.001 , respectively ) . Children in the block group had lower postoperative pain scores at all times . Incidence of oculocardiac reflex was significantly higher ( P < 0.001 ) in the control group . Seventy-six percent of children in the control group had postoperative nausea and vomiting compared to 20 % children in the block group ( P < 0.001 ) . CONCLUSION There were no complications related to the block . Peribulbar block appears to be a safe and useful analgesic technique for paediatric ophthalmic surgery BACKGROUND The aim of our study was to compare postoperative analgesic efficacy , analgesic duration and motor blockade of levobupivacaine , ropivacaine and bupivacaine administered caudally in equal concentrations to children undergoing elective minor surgery . METHODS In the study , 182 children , aged 1 - 7 years , undergoing either inguinal hernia repair or orchidopexy , were r and omly allocated to one of the three groups . They received via a caudal extradural either 1 ml x kg(-1 ) levobupivacaine 0.2 % ( Group L ) or 1 ml x kg(-1 ) ropivacaine 0.2 % ( Group R ) or 1 ml x kg(-1 ) bupivacaine 0.2 % ( Group B ) . RESULTS No statistically significant difference was noted in age , weight , duration of the operation or level of the caudal block between the groups . The onset of analgesia was significantly later after levobupivacaine . Postoperative pain scoring evaluated with Children 's and Infant 's Postoperative Pain Scale observational scale showed no statistical difference between groups . Median postoperative analgesia was 5.75 h ( SEMed : + /- 0.65 ) in Group L , 5.7 h ( SEMed : + /- 0.8 ) in Group R and 5.35 h ( SEMed : + /- 1.3 ) in Group B the difference being statistically nonsignificant . CONCLUSIONS The degree of motor block was significantly less after ropivacaine and levobupivacaine during the first 2 h postoperatively Purpose Circumcision is performed under general anaesthesia ( GA ) with dorsal penile nerve block ( DPNB ) as an analgesic technique for postoperative pain . The purpose of this study was to compare DPNB as the sole anaesthetic procedure vs GA and DPNB for circumcision in children as an outpatient procedure . Methods In a six-month prospect i ve study , 250 boys aged 6 to 17 yr ( mean age 11.5 ± 3.5 yr ) were r and omized into two groups . Group A ( n = 122 ) received DPNB only prior to circumcision , and Group B ( n = 128 ) received GA + DPNB . The groups were compared for complications of the block , effectiveness of anaesthesia , operating room time , postoperative time and ease of recovery . Results There were no major operative complications in the two groups . Minor block complications , including oedema and haematoma , occurred in 16 ( 13.1 % ) boys in Group A and 27 ( 21.10 % ) boys in Group B ( NS ) . At surgery , 3 ( 2.6 % ) from Group A received additional GA and 1 ( 0.8 % ) received additional local anaesthesia . They represent a DPNB failure rate of 3.3 % . Mean operating room time was 11 ± 2.5 min in Group A and 19 ± 3.5 min in Group B , and post-anaesthesia care unit ( PACU ) time was 51 ± 10 min in Group A and 101 ± 14.5 min in Group B ( P < 0.001 ) . Nausea and vomiting in the PACU were noted in one patient in Group A and in 15 in Group B ( P < 0.05 ) . Only patients in Group B required additional analgesia and tranquilizers in the PACU ( 0 versus 20 ; P < 0.05 ) . Conclusions These data confirm that DPNB has advantages over GA + DPNB for paediatric circumcision in day-care surgery . RésuméObjectifLa circoncision est réalisée sous anesthésie générale ( AG ) associée au bloc du nerf dorsal de la verge ( BNDV ) pour l’analgésie postopératoire . Cette étude visait à comparer chez des enfant opérés en chirurgie ambulatoire le BNDV seul et l’anesthésie générale avec BNDV.MéthodesPendant une étude prospect i ve de six mois , 250 garçons âgés de 6 à 17 ans ( âge moyen 11,5 ± 3,5 ans ) avaient été répartis au hasard entre deux groupes . Le groupe A ( n = 122 ) recevait un BNDV seul avant la circoncision et le groupe B ( n = 128 ) recevait AG + BNDV . Les groupes étaient comparés au regard des complications du bloc , de l’efficacité de l’anesthésie , de la durée de l’intervention , de la durée de la période postopératoire et du confort du patient . RésultatsIl n’y a pas eu de complication opératoires majeures dans aucun des groupes . Des complications mineures dues au bloc , do nt l’oedéme et l’hématome sont survenues chez 16 ( 13,3 % ) des garçons du groupe A et chez 27 ( 21,10 % ) du groupe B ( NS ) . Au moment de la chirurgie , dans le groupe A , on a complété avec de l’anesthésie générale chez trois enfants ( 2,6 % ) et avec un anesthésique local chez un enfant ( 0,8 % ) . Ce qui établi le taux d’échec du BNDV à 3,3 % . La durée moyenne de l’utilisation de la salle d’opération était de 11 ± 2,5 min pour le groupe A et de 19 ± 3,5 min pour le groupe B. La durée du séjour à l’unité de soins postanesthésiques ( USPA ) était 51 ± 10 min pour le groupe A et de 101 ±14,5 min pour le groupe B ( P < 0,001 ) . À l’USPA , des nausées et vomissements sont survenus chez un patient du groupe A et chez 15 du groupe B ( P < 0,05 ) . À l’USPA , seuls les patients du groupe B ont eu besoin d’analgésie additionnelle et de tranquillisants ( 0 vs 20 ; P < 0,05 ) . Conclusion Ces données confirment certains avantages de BNDV sur AG + BNDV pour la circoncision en chirurgie ambulatoire BACKGROUND Inguinal hernia repair , hydrocelectomy , and orchidopexy are commonly performed surgical procedures in children . Postoperative pain control is usually provided with a single-shot caudal block . Blockade of the ilioinguinal nerve may lead to additional analgesia . The aim of this double-blind , r and omized controlled trial was to evaluate the efficacy of an adjuvant blockade of the ilioinguinal nerve using ultrasound ( US ) guidance at the end of the procedure with local anesthetic vs normal saline and to explore the potential for prolongation of analgesia with decreased need for postoperative pain medication . METHODS Fifty children ages 1 - 6 years scheduled for unilateral inguinal hernia repair , hydrocelectomy , orchidopexy , or orchiectomy were prospect ively r and omized into one of two groups : Group S that received an US-guided ilioinguinal nerve block with 0.1 ml x kg(-1 ) of preservative-free normal saline and Group B that received an US-guided nerve block with 0.1 ml x kg(-1 ) of 0.25 % bupivacaine with 1 : 200,000 epinephrine at the conclusion of the surgery . After induction of anesthesia but prior to surgical incision , all patients received caudal anesthesia with 0.7 ml x kg(-1 ) of 0.125 % bupivacaine with 1 : 200,000 epinephrine . Patients were observed by a blinded observer for ( i ) pain scores using the Children and Infants Postoperative Pain Scale , ( ii ) need for rescue medication in the PACU , ( iii ) need for oral pain medications given by the parents at home . RESULTS Forty-eight patients , consisting of 46 males and two females , with a mean age of 3.98 ( SD + /- 1.88 ) were enrolled in the study . Two patients were excluded from the study because of study protocol violation and /or alteration in surgical procedure . The average pain scores reported for the entire duration spent in the recovery room for the caudal and caudal/ilioinguinal block groups were 1.92 ( SD + /- 1.59 ) and 1.18 ( SD + /- 1.31 ) , respectively . The average pain score difference was 0.72 ( SD + /- 0.58 ) and was statistically significant ( P < 0.05 ) . In addition , when examined by procedure type , it was found that the difference in the average pain scores between the caudal and caudal/ilioinguinal block groups was statistically significant for the inguinal hernia repair patients ( P < 0.05 ) but not for the other groin surgery patients ( P = 0.13 ) . For all groin surgery patients , six of the 23 patients in the caudal group and eight of the 25 patients in the caudal/ilioinguinal block group required pain rescue medications throughout their entire hospital stay or at home ( P = 0.76 ) . Overall , the caudal group received an average of 0.54 ( SD + /- 1.14 ) pain rescue medication doses , while the caudal/ilioinguinal block group received an average of 0.77 ( SD + /- 1.70 ) pain rescue medication doses ; this was , however , not statistically significant ( P = 0.58 ) . CONCLUSIONS The addition of an US-guided ilioinguinal nerve block to a single-shot caudal block decreases the severity of pain experienced by pediatric groin surgery patients . The decrease in pain scores were particularly pronounced in inguinal hernia repair patients BACKGROUND The aim of this double blind , r and omized , comparative study was to assess the analgesic efficacy and incidence of motor block after caudal block using three different concentrations of ropivacaine , 1 , 2 and 3 mg x l(-1 ) , in children 4 - 12-year-old . METHODS One hundred and ten children ASA I-II , scheduled for inguinal surgery , were included in the study . After induction of a st and ardized general anaesthetic technique , all patients received 1 ml x kg(-1 ) of the ropivacaine solution for a caudal block and were assessed for 8 h after the injection . RESULTS The ropivacaine was well tolerated in all patients . Median time to treatment with analgesics was 3.3 , 4.5 and 4.2 h in the 1 , 2 and 3 mg x ml(-1 ) groups , respectively . During the first 4 h , the pain scores for both a 6- grade d faces scale and a 4- grade d observer scale were higher in the 1 mg x ml(-1 ) group than the 3 mg x ml(-1 ) group . The median sensory block reached T12 in all groups 1 h after the caudal block . Thereafter , the speed of regression was correlated with the ropivacaine concentration . In the patients with a sensory block from T12 and above , the median time to treatment with analgesics was longer than in the children with a sensory block below T12 . The incidence of motor block was 28 % in the 3 mg x ml(-1 ) group in comparison with 0 and 13 % in the 1 and 2 mg x ml(-1 ) groups . CONCLUSIONS It was concluded that 1 ml x kg(-1 ) of ropivacaine 2 mg x ml(-1 ) for caudal block provided satisfactory postoperative pain relief after inguinal surgery in 4 - 12-year-old children . Ropivacaine 1 mg x ml(-1 ) showed less efficacy while the use of ropivacaine 3 mg x ml(-1 ) was associated with a higher incidence of motor block with minimal improvement in postoperative pain relief Cleft lip repair is a common operation in infants and requires that the child is pain-free during the postoperative period so that h and ling does not affect the integrity of the delicate surgical site . This study was design ed to compare the efficacy and duration of effect of 0.125 % bupivacaine given preoperatively as a bilateral infraorbital nerve block with peri-incisional infiltration of the same local anaesthetic for postoperative analgesia in cleft lip repair . It was a r and omised , double blind , prospect i ve study in 30 children aged 4 - 20 months ( ASA grade 1 ) . After a st and ard induction , group A ( n = 15 ) were given a bilateral infraorbital nerve block with 0.125 % bupivacaine and group B ( n = 15 ) had peri-incisional infiltration with the same solution . No additional systemic analgesics were given before or during the operation . Intraoperative monitoring comprised measurement of heart rate and blood pressure and post-operatively pain relief was recorded using a behavioural pain relief score . The heart rate , respiratory rate , and blood pressure were also monitored at 0 , 1 , 2 , 4 , 8 , and 24 hours after tracheal extubation . The results showed that group A had significantly better pain relief ( higher scores ) than group B for eight hours postoperatively ( p < 0.05 ) . The analgesic requirement in group B became significant at two hours postoperatively , while group A had significant analgesic requirements only after eight hours . The significant rise in heart rate and blood pressure that accompanied tracheal intubation in both groups suggested that while both methods of analgesia may be adequate to prevent responses to skin incision , they do not substitute for adequate systemic analgesia during the operation . We conclude that infraorbital nerve block with 0.125 % bupivacaine provides better and more prolonged analgesia than peri-incisional infiltration in cleft lip repair OBJECTIVES The aim of the present study was to compare the analgesic effects of ripovacaine when used as high concentration/small volume , versus its use as high volume/low concentration , in ilioinguinal-iliohypogastric nerve block in children . METHODS This is a prospect i ve single-blind r and omized study consisting of 72 children ASA I & II , 3 - 9 years of age , scheduled for outpatient elective surgery . Children were r and omly assigned into two equal groups ( 36 each ) , to receive ropivacaine 0.8 mg.kg(-1 ) , for ilioinguinal-iliohypogastsric block , either as : 1 mg.ml(-1 ) ( 0.8 ml.kg(-1 ) ) G1 group , or 2 mg.ml(-1 ) ( 0.4 ml.kg(-1 ) ) G2 group . The postoperative pain was assessed using the Children 's Hospital of Eastern Ontario Pain Scale ( CHEOPS ) , at the end of surgery ( H0 ) , at one ( H1 ) , tow ( H2 ) , four ( H4 ) and six ( H6 ) postoperative hours . Parents were requested to record their child 's pain every 6 hours during the first 24 postoperative hours , using the postoperative pain measurement for Parent Scale . RESULTS CHEOPS score H0 was significantly lower in G2 as compared to G1 group ( p = 0.03 ) . Only 2 children in G2 as compared to 8 children in G1 group , required i.v . paracetamol administration after surgery ( p = 0.04 ) . In group G1 , two children required paracetamol at home and three developed a postoperative transitory femoral nerve block ( p = 0.23 ) . CONCLUSIONS Ropivacaine when used with high concentration/small volume is more efficient than when used a high volume/low concentration , for ilioinguinal-iliohypogastric nerve block in children BACKGROUND Umbilical hernia repair , a common day surgery procedure in children , is associated with significant postoperative discomfort . The rectus sheath block may offer improved pain management following umbilical hernia repair . In this pilot study , we compared the efficacy of the rectus sheath block with that of our current st and ard practice --local anesthetic infiltration into the surgical wound -- for pain control after umbilical hernia repair in children . METHODS Fourteen children , aged 1 - 8 years , undergoing umbilical hernia repair were r and omly assigned to receive either a rectus sheath block or local anesthetic infiltration into the surgical wound at completion of surgery . Anesthetic management was st and ardized . Each analgesic technique was performed using 0.8 ml x kg(-1 ) of 0.25 % bupivacaine with epinephrine 1:200,000 . Postoperatively , an investigator who was blinded to the analgesic technique recorded the Children 's Hospital of Eastern Ontario Pain Scale ( CHEOPS ) scores and sedation scores every 10 min , and administered intravenous morphine 50 microg x kg(-1 ) for cases with CHEOPS scores > or = 8 . Total morphine dose was recorded . Parents were telephoned the day after surgery to determine the overall satisfaction with pain control . RESULTS Total postoperative morphine consumption did not differ significantly between groups , averaging 0.10 + /- 0.09 and 0.10 + /- 0.07 mg x kg(-1 ) for the local infiltration and rectus sheath groups , respectively . There were no significant differences in pain or sedation scores , and no complications related to either analgesic technique . DISCUSSION Our results suggest that the rectus sheath block has no advantage over infiltration of local anesthetic into the surgical wound for postoperative pain management in children undergoing umbilical hernia repair The goal of this double-blind prospect i ve study was to compare the effect of a single injection versus multiple fractionated doses on the onset time and quality of motor and sensory block , obtained in 70 children anaesthetized with axillary block alone . The brachial plexus was identified with a peripheral nerve stimulator , and blocked with 0.5 ml.kg-1 of 1.5 % lignocaine with adrenaline . In Group S ( single injection ) , the total volume was injected after location of one nerve . In Group M ( multiple fractionated doses ) , two nerves were located , including necessarily one nerve implicated in the surgical territory . Motor and sensory blocks were assessed according to Lanz 's scale before surgery by a blinded observer . A block was considered complete if there was no feeling in at least three nerve territories at 30 min . No difference was found between groups for motor and sensory block quality . However the onset time of the block was faster after multiple fractionated doses ( Group M , 25+/-7 min vs Group S , 29+/-4 min ) and was faster in younger children ( 5 - 9 years : M=23+/-7 min vs S=28+/-5 min , 10 - 15 years : no difference ) . There was a significant difference in the quality of the sensory blockade of the musculocutaneous nerve : 18 versus 8 complete blocks , 10 versus 14 incomplete blocks , respectively for Group M versus Group S. No adverse effect was observed and analgesia was prolonged for more than 4 h. We can conclude that , unlike adults , fractionated doses in chilren bring no benefit to the quality of sensory and motor block . Selective block of the musculocutaneous nerve is recommended when a surgical procedure takes place in this territory Purpose To compare caudal and penile block for post-operative analgesia in children undergoing circumcision with respect to efficacy , complication rates , and parental satisfaction . Methods The study population consisted of 100 ASA 1 and 2 boys aged 3 to 8 years who were undergoing circumcision for religious reasons . In all participants , inhalation anesthesia was administered with oxygen : nitrous oxide ( 1 : 2 ) and halothane . The participants were allocated r and omly into two groups of 50 children each . Group 1 received penile block and Group 2 caudal block . The penile block was achieved by injecting bupivacaine into the two compartments of the subpubic space , with an additional ventral infiltration of a small volume of bupivacaine along the raphe of the penis . For caudal block , 1 ml·kg−1 body weight of 0.25 % bupivacaine was administered . Results Penile block shortened the induction-incision time and enabled earlier discharge home compared with caudal block . One patient undergoing penile block and nine patients undergoing caudal block vomited . Conclusions Penile and caudal block are equally effective for postcircumcision analgesia and neither is associated with serious complications . Anesthesiologist preference should be the deciding factor in choosing one technique over the other Objective To determine whether a difference in the behavioral and physiologic response to circumcision can be demonstrated between neonates undergoing the procedure with ring block and those receiving no anesthesia . Methods Forty healthy male newborns were assigned r and omly to receive either ring block or no anesthesia . Indices of perceived pain including crying time , behavioral state , oxygen saturation , and heart and respiratory rates were recorded at baseline and at intervals during the circumcision . Infants were reassessed 2 minutes and 2 hours postoperatively . Results Infants receiving ring block cried less than did controls ( P < .001 ) . Anesthetized infants had smaller increases in heart rate ( P < .005 ) and demonstrated less arousal ( P < .005 ) during each operative interval . For all operative intervals combined , anesthetized infants had a smaller decrease in oxygen saturation ( P < .001 ) and a smaller increase in respiratory rate ( P = .005 ) than did controls . Two minutes postoperatively , anesthetized infants had returned to their baseline behavioral state , whereas controls remained significantly more aroused ( P < .005 ) . Two hours postoperatively , there were no significant differences in any variables between the groups , nor between each group and its baseline . There were no complications related to anesthesia administration . Conclusion Neonatal circumcision causes behavioral and physiologic changes consistent with the perception of pain . Ring block is an effective method of anesthesia for this procedure BACKGROUND We have compared ropivacaine with bupivacaine and lidocaine for ilioinguinal block in thirty children undergoing ambulatory inguinal hernia repair . METHODS Patients were assigned r and omly to receive 0.5 ml.kg(-1 ) of 0.2 % ropivacaine ( Group R , n = 10 ) , 0.25 % bupivacaine ( Group B , n = 10 ) or 1 % lidocaine ( Group L , n = 10 ) . The patients ' parents , who were not informed of the type of local anaesthetic employed , evaluated the postoperative pain at 2 h and 6 h after operation using the Wong-Baker FACES Pain Rating Scale . RESULTS There was a significant difference in the face scale score between Group R and Group L , and Group B and Group L. There was no difference in the face scale score between Group R and Group B. There were no complications or clinical evidence of local anaesthetic toxicity . CONCLUSIONS We have confirmed that bupivacaine and ropivacaine are more effective than lidocaine in the prevention of postoperative pain after children 's inguinal hernia repair . We suggest that ropivacaine 0.2 % is an alternative to bupivacaine 0.25 % for ilioinguinal block in ambulatory paediatric surgery Peripheral nerve blocks of the surgical site can reduce the need for perioperative opioids thereby decreasing their unwanted adverse effects , such as postoperative nausea and vomiting . In this prospect i ve , r and omized , double-blinded study , we examined the efficacy of a great auricular nerve ( GAN ) block compared with IV morphine sulfate in children undergoing tympanomastoid surgery . After the induction of general anesthesia , children were r and omized to receive either a GAN block with 2 mL of 0.25 % bupivacaine with epinephrine ( 1:200,000 ) and a sham IV injection of 2 mL of saline solution or a sham GAN block with 2 mL of saline solution with an IV injection of 0.1 mg/kg morphine sulfate diluted to 2 mL. Patients ’ objective pain scores were assessed by a blinded observer and the incidence of vomiting was recorded . The GAN-Block patients as a group required more pain rescue in the postanesthesia care unit ; this difference was not statistically different from the IV-morphine group ( P = 0.084 ) . Nine GAN-Block patients never received opioid or other analgesics at any time in the first 24 h after surgery . The group that received the GAN block also had a less frequent incidence of vomiting requiring intervention ( 7 versus 19 ) during their entire hospitalization or at home ( P = 0.027 ) . The GAN-Block group also had more patients who never experienced vomiting ( 13 of 20 versus 5 of 20 , P = 0.026 ) . In this cohort , a peripheral nerve block decreased the overall incidence of postoperative vomiting thereby reducing associated costs STUDY OBJECTIVE To compare the femoral nerve block with the fascia iliaca block for postoperative analgesia in adolescents undergoing reconstructive knee surgery . DESIGN R and omized , single-blinded study . SETTING Full-service pediatric medical center . PATIENTS 23 ASA physical status I and II patients , aged 8 to 16 years , undergoing anterior cruciate ligament ( ACL ) repair . INTERVENTIONS Patients received either fascia iliaca or femoral nerve block prior to reconstructive surgery . MEASUREMENTS Pain scores by visual analog scale ( VAS ; 0 - 10 ) and morphine use were routinely recorded through to discharge from the hospital . Pain scores were assessed on days 1 and 2 at home post-discharge . MAIN RESULTS There was no difference between the femoral nerve block and the fascia iliaca nerve block in VAS pain scores or postoperative morphine consumption . CONCLUSION Either the femoral nerve block or the fascia iliaca block , followed by patient-controlled analgesia with morphine , provides efficacious analgesia for adolescents undergoing ACL reconstruction We conducted a prospect i ve , r and omized , double-blinded trial comparing preoperative application of EMLA cream and sodium chloride solution dorsal penile block ( n = 31 ) with placebo cream and bupivacaine dorsal penile nerve block ( n = 32 ) for postcircumcision analgesia . Pain was assessed using modified Children 's Hospital of Eastern Ontario Pain Scale and the duration of block by the time to requirement of first dose of postoperative analgesic . There was no difference in Children 's Hospital of Eastern Ontario Pain Scale between the two groups , but bupivacaine dorsal penile nerve block result ed in longer analgesia ( P = 0.003 ) . There were no local or systemic complications related to either technique , and there was a very small incidence of vomiting . We conclude that preoperative application of EMLA cream is an effective and simple method to produce postcircumcision analgesia with a very small incidence of adverse effects STUDY OBJECTIVE To determine whether fascia iliaca compartment block ( FICB ) reduces emergence agitation . DESIGN Prospect i ve , r and omized , blinded clinical trial . SETTING Operating room and Postanesthesia Care Unit ( PACU ) of a university hospital . PATIENTS 64 ASA physical status 1 and 2 pediatric patients aged three to 7 years , scheduled for orthopedic surgery involving the anterior or lateral thigh . INTERVENTIONS Patients enrolled in the FICB group received FICB immediately after the operation , while control group patients received intravenous ( IV ) patient/parent-controlled analgesia ( PCA ) with fentanyl . MEASUREMENTS Severity of agitation and pain were evaluated using the Pediatric Agitation and Emergence Delirium ( PAED ) scale and the Children 's Hospital of Eastern Ontario Pain Scale ( CHEOPS ) . Data were collected at 10-minute intervals in the PACU . The results were analyzed using the t-test . MAIN RESULTS PAED scores in the FICB group were significantly lower than those of the control group on arrival at the PACU ( 7.3 ± 2.9 vs 10.4 ± 3.2 , P < 0.001 ) . The FICB group also had significantly lower CHEOPS pain scores than the control group , both on arrival at the PACU and 10 minutes after arrival ( 6.4 ± 1.5 vs 10.4 ± 1.8 , P < 0.001 and 6.7 ± 1.6 vs 8.0 ± 1.4 , P = 0.009 , respectively ) . CONCLUSION In children having surgery on the thigh , FICB effectively reduced the severity of emergence agitation and postoperative pain during the immediate postoperative period Paravertebral block ( PVB ) has been used for postoperative analgesia in children since 1992 . There are no prospect i ve r and omised studies comparing the use of PVB versus caudal block ( CB ) for outpatient inguinal hernia repair surgery . The hypothesis of this study is that a single level , single injection PVB can provide a longer duration of analgesia and less requirement for supplemental analgesia than single shot CB for children undergoing inguinal surgery . Seventy children , aged three to seven , American Society of Anesthesiologists score I to II , having unilateral inguinal surgery were enrolled in the study . The patients were divided into two r and omised groups . In group PVB , a single shot of 0.2 ml/kg levobupivacaine was administered via the lumbar paravertebral route and in group CB , patients were given 1 ml/kg levobupivacaine caudally . Sevoflurane concentration was evaluated after induction and recorded during incision , sac traction and closure . Face , legs , activity , cry and consolability ( FLACC ) scores , heart rate , blood pressure and SpO2 were evaluated postoperatively . Only four ( 11.4 % ) patients in the PVB group needed rescue analgesic drugs compared to 12 ( 34.3 % ) patients in the CB group ( P=0.044 ) . Patients were given tramadol as rescue analgesia in the first four postoperative hours . No other supplemental analgesic drug was given apart from tramadol . FLACC scores were the same in the both groups . Parental satisfaction was significantly higher in the PVB group compared to the CB group ( 74.3 vs 40 % , P=0.01 ) . This study has demonstrated that a single level single injection paravertebral block provides superior intraoperative and postoperative analgesia when compared to a caudal block for unilateral inguinal hernia repair Background and Objectives . Postoperative pain management in pediatric strabismus patients is infrequently studied . Pediatric patients can be mobilized earlier if postoperative pain is minimized . In this study , two different regional anesthetic techniques , retrobulbar block and local infiltration , were compared with a “ no block ” control group for the postoperative management of pain in pediatric patients undergoing elective strabismus surgery . Methods . Thirty patients were r and omly allocated to one of the study groups : group 1 ( n = 10 ) control , group 2 ( n = 10 ) retrobulbar block , and group 3 ( n = 10 ) subconjunctival bupivacaine infiltration . The parameters that were evaluated during the early postoperative period ( 6 hours ) were circulatory , pain scores by Visual Analog Scale ( VAS ) and Modified Pediatric Objective Pain Scale ( MPOPS ) , additional analgesic requirement , nausea , and vomiting . The parameters that were evaluated after discharge from the hospital ( on postoperative days 1 and 2 ) through question naires were additional analgesic requirement , nausea , vomiting , sleep disturbances , activity , and appetite . Results . Group 3 had significantly higher VAS and MPOPS scores at postoperative 120 , 180 , 240 , 300 , and 360 minutes than groups 1 and 2 ( P < .05 ) . Patients in group 2 seemed to have a higher incidence of nausea and vomiting both in the early ( 6 hours ) and late postoperative ( postoperative days 1 and 2 ) periods ; however , the difference was not statistically significant . Group 2 required less analgesic compared with groups 1 and 3 during the late postoperative period . Late postoperative activity and appetite were better in groups 2 and 3 . Conclusions . Because there was no significant difference in terms of postoperative analgesia in the retrobulbar block or subconjunctival local anesthetic infiltration groups compared with the control group , we suggest that conventional methods of pain treatment are adequate for postoperative analgesia in strabismus surgery Background and objective The aim of this prospect i ve r and omized study was to evaluate the quality of analgesia , postoperative comfort and subsequent duration of hospitalization after distal h and surgery and peripheral nerve block at the wrist for paediatric out patients . Methods Sixty consecutive ASA I or II children were r and omly assigned to the following groups : in group B ( block ) , intraoperative and postoperative analgesia was provided by peripheral nerve block ; and in group O ( opioids ) , intraoperative and postoperative analgesia was provided by intravenous opioids . The patients ' age , sex and type of surgery were recorded as were the postoperative pain management and postoperative vomiting . Time to discharge from the recovery room , the postoperative ward and the time to discharge home were also noted . Results The two groups were similar with respect to age , sex , ASA physical status , weight , height and types of injuries . The incidence of postoperative pain ( CHEOPS score ≥7 ) and the incidence of postoperative vomiting were significantly higher in group O than in group B : 26.6 versus 3.3 % ; P = 0.025 , and 33.3 versus 6.6 % ; P = 0.011 , respectively . The time before oral intake was significantly longer in group O than in group B [ 187 ( 75–265 ) min versus 60 ( 32–125 ) min , respectively , P = 0.0002 ] . The time to meet discharge home criteria was 277 ( 230–330 ) min in group O versus 210 ( 145–260 ) min in group B ( P = 0.0039 ) . Conclusion The present study demonstrates for the first time that , after distal h and surgery in children , peripheral nerve block improves pain management , opioid analgesia-induced side effects and provides a shorter postoperative recovery time than systemic analgesia with opioids BACKGROUND Primary cleft lip repair is performed in infants under 1 year of age . The efficacy of an infraorbital nerve block vs intravenous fentanyl was compared in our prospect i ve , r and omized controlled trial . METHODS Forty-six infants scheduled for primary cleft lip repair were prospect ively r and omized to one of two groups : group F that received 2 mcg x kg(-1 ) of fentanyl intravenously and an infraorbital nerve block with 0.5 ml on each side of preservative-free normal saline , and , group B that received bilateral infraorbital nerve blocks with 0.5 ml on each side of 0.25 % bupivacaine and 2 ml of preservative-free saline solution intravenously after induction of anesthesia but prior to surgical incision . Patients were observed by a blinded observer for ( i ) pain scores using neonatal infant pain score ; ( ii ) need for rescue medication in the anesthesia care unit ( PACU ) , in the short stay unit ( SSU ) and at home and ( iii ) feeding parameters including difficulty in feeding , time to first feeding and volume of feeds in the PACU , SSU and at home . RESULTS There were no significant differences in pain scores between the two groups over time ( P = 0.98 ) ; there were no differences between groups in the number of rescue medications in the PACU , in the SSU as well as at home ; however , the time to first rescue medication was greater in the block group compared with the fentanyl group ( P = 0.07 ) . There were no significant differences in feeding volumes between groups in the PACU ( P = 0.46 ) , SSU ( P = 0.57 ) and at home ( P = 0.15 ) . There were no differences in time to initiate feeding between the two groups ( P = 0.81 ) . However , there was difficulty with feeding in the block groups compared with the fentanyl group ( P = 0.01 ) . CONCLUSIONS The infraorbital nerve block can be effectively used for pain control in infants undergoing primary cleft lip repair . Although children undergoing a nerve block experienced minor difficulties in feeding , there were no differences in feeding volumes or other feeding parameters . This study has shed light into postoperative outcomes besides pain control on children undergoing cleft lip repairs |
1,901 | 26,590,818 | Clearance of jaundice is related to the age at KPE in infants who receive high-dose steroids .
Native liver survival appears to be improved as a result of this .
This is the first study to show tangible longer-term benefit from high-dose steroids in biliary atresia | The use of adjuvant steroids following Kasai porteoenterostomy ( KPE ) for biliary atresia is controversial .
The aim of this study was twofold : a systematic review of published literature and an up date of the clinical Kings College Hospital series to look for evidence of an effect of age on the outcome in a group of BA infants treated with high-dose steroids . | Abstract Purpose We aim ed to evaluate early response to two different corticosteroids doses after Kasai portoenterostomy for biliary atresia ( BA ) . Methods A prospect i ve , r and omized trial was performed in infants from the nationwide BA registry with type 3 BA . Sixty-nine infants were r and omized to receive either 4 mg/kg/day ( group A , n = 35 ) or 2 mg/kg/day prednisolone ( group B , n = 34 ) . The corticosteroids were started on postoperative day 7 , and the dose was tapered toward day 30 . Results of liver function tests on days 31 and 60 were compared between the groups . Results Mean bilirubin , AST , ALT , and GGT levels did not significantly differ between the groups . However , the levels of total and direct bilirubin of infants < 70 days old at surgery significantly differed between the groups . Four patients from group A and five from group B , dropped out of the study . Complications during the first month after PE were comparable between the groups . Conclusions An initial 4 mg/kg/day dose did not significantly improve liver function , except that bilirubin levels were lower in the subgroup of infants < 70 days old at surgery . There were no significant complications with either dose of corticosteroids Objective : To identify the epidemiological characteristics of infants with biliary atresia in Engl and and Wales , since central isation of its management in 1999 . Methods : The care of infants with biliary atresia ( BA ) in Engl and and Wales is central ised to only three centres . All infants ( treated from January 1999 to December 2006 ) were identified from a prospect i ve national data base ; demographic details were ascertained from medical records and compared between two groups based on presumed aetiology ( isolated biliary atresia ( IBA ) and developmental biliary atresia ( DBA ) ( for example , syndromic infants , biliary atresia splenic malformation , cystic biliary atresia ) ) . Results : There were 302 ( 133 male ( 44 % ) ) infants with BA that could be divided into IBA ( n = 219 , 73 % ) and DBA ( n = 76 , 25 % ) . The overall incidence was 0.58/10 000 ( 1 in 17 049 ) live births with marked regional differences along a north-west/south-east axis varying from 0.38 ( north-west Engl and ) to 0.78 ( south-east Engl and ) /10 000 live births ( OR 2.05 ( 95 % CI 1.26–3.41 ) ; p = 0.002 ) . The commonest month of birth was September with December being the least common , although there was no evidence for significant seasonal variation ( p = 0.2 ) . Infants with DBA were more likely to be female ( p<0.001 ) , of white background ( p = 0.01 ) , first-born ( p = 0.04 ) and to be formula-fed ( p = 0.07 ) . Infants of south Asian origin came to surgery at an older age ( 59 ( IQ 45–75 ) versus 52 ( IQ 42–65 ) days ; p = 0.03 ) . Conclusions : There is a remarkable variation of incidence of biliary atresia within Engl and and Wales , some of which may have been caused by factors related to a different aetiological and racial background OBJECTIVE : Postoperative adjuvant steroid treatment is reported to improve jaundice-free survival in biliary atresia ( BA ) patients and to reduce the need for early liver transplantation . However , evidence of all retrospective studies is very limited , although high-dose corticosteroids were favored . The aim of this dosage finding study was to test the most promising corticosteroid protocol in a smaller but representative series , in order to optimize the setting s of upcoming prospect i ve and long-term multicenter studies . METHODS : Our prospect i ve single-center and open-labeled pilot study on high-dose steroids included 49 consecutive BA patients . Basic data of the study group were not different from 29 controls . In the study group , 20 consecutive patients were treated after the Kasai with methylprednisolone ( 10 mg/kg day 1 to 5 and 1 mg/kg day 6 to 28 ) . RESULTS : Overall survival with native liver was 63 % after 6 months and 31 % after 2 yr , with no statistical difference between the study and control groups . After 2 yr , 27 % of all patients were still jaundice-free . With regard to predictive parameters , we found , 6 months after the Kasai , bilirubin < 20 μmol/L as highly sensitive ( 97 % ) and specific ( 93 % ) for jaundice-free survival with native liver . CONCLUSIONS : In contrast to previous reports , this pilot study shows that high-dose steroid pulses after Kasai procedure are not effective in postoperative adjuvant therapy protocol s and should be avoided in upcoming multicenter steroid studies . Therefore , we recommend extended and r and omized multicenter studies to pre-evaluate the supposed effectiveness of alternative steroid protocol s , by comparing , 6 months after the Kasai procedure , the number of patients with normal bilirubin BACKGROUND AND AIMS Perinatal cytomegalovirus ( CMV ) infection is a possible cause or trigger of biliary atresia though clinical evidence is scant . We hypothesised that CMV IgM+ve biliary atresia is a separate clinical entity compared to CMV IgM-ve biliary atresia . METHODS Prospect i ve single-centre study . 210 infants with histologically confirmed biliary atresia were treated in our institution ( Jan. 2004 to Dec. 2011 ) ; of these 20 ( 9.5 % ) were CMV IgM+ve at presentation . We compared these with 111 infants who were CMV IgM-ve ( controls ) for clinical features , biochemistry at presentation and outcome following Kasai portoenterostomy ( KPE ) . A blinded comparison of age-matched liver histology was also performed . Data are quoted as median ( interquartile range ) . A P value ≤ 0.05 was regarded as significant . RESULTS Infants with CMV IgM+ve biliary atresia were older at Kasai portoenterostomy ( or laparotomy ) [ 70 ( 60 - 80 ) days vs. 56 (44 - 75)days ; P = 0.003 ] and were more jaundiced [ 175 ( 147 - 224 ) vs. 140 ( 121 - 181 ) μmol/L ; P = 0.002 + with higher AST*287 ( 157 - 403 ) vs. 180 ( 133 - 254 ) IU/L ; P = 0.005 ] and aspartate aminotransferase-to-platelet ratio index [ 1.1 ( 0.79 - 3.0 ) vs. 0.63 ( 0.43 - 0.95 ) ] levels . Liver histology : CMV IgM+ve biliary atresia was characterised by a greater degree of inflammation ( P < 0.0001 ) and fibrosis ( P = 0.02 ) , whereas CMV IgM-ve isolated biliary atresia had a higher degree of lobular cholestasis ( P = 0.001 ) . This effect was independent of the effects of age at KPE . OUTCOME CMV IgM+ve biliary atresia had a poorer outcome with a reduced clearance of jaundice ( 15 % vs. 52.2 % ; P = 0.002 ) , native liver survival ( P < 0.0001 ) and increased mortality ( P = 0.002 ) . CONCLUSIONS CMV IgM+ve biliary atresia is a distinct clinical and pathological entity with a diminished response to Kasai portoenterostomy IMPORTANCE Biliary atresia is the most common cause of end-stage liver disease in children . Controversy exists as to whether use of steroids after hepatoportoenterostomy improves clinical outcome . OBJECTIVE To determine whether the addition of high-dose corticosteroids after hepatoportoenterostomy is superior to surgery alone in improving biliary drainage and survival with the native liver . DESIGN , SETTING , AND PATIENTS The multicenter , double-blind Steroids in Biliary Atresia R and omized Trial ( START ) was conducted in 140 infants ( mean age , 2.3 months ) between September 2005 and February 2011 in the United States ; follow-up ended in January 2013 . INTERVENTIONS Participants were r and omized to receive intravenous methylprednisolone ( 4 mg/kg/d for 2 weeks ) and oral prednisolone ( 2 mg/kg/d for 2 weeks ) followed by a tapering protocol for 9 weeks ( n = 70 ) or placebo ( n = 70 ) initiated within 72 hours of hepatoportoenterostomy . MAIN OUTCOMES AND MEASURES The primary end point ( powered to detect a 25 % absolute treatment difference ) was the percentage of participants with a serum total bilirubin level of less than 1.5 mg/dL with his/her native liver at 6 months posthepatoportoenterostomy . Secondary outcomes included survival with native liver at 24 months of age and serious adverse events . RESULTS The proportion of participants with improved bile drainage was not statistically significantly improved by steroids at 6 months posthepatoportoenterostomy ( 58.6 % [ 41/70 ] of steroids group vs 48.6 % [ 34/70 ] of placebo group ; adjusted relative risk , 1.14 [ 95 % CI , 0.83 to 1.57 ] ; P = .43 ) . The adjusted absolute risk difference was 8.7 % ( 95 % CI , -10.4 % to 27.7 % ) . Transplant-free survival was 58.7 % in the steroids group vs 59.4 % in the placebo group ( adjusted hazard ratio , 1.0 [ 95 % CI , 0.6 to 1.8 ] ; P = .99 ) at 24 months of age . The percentage of participants with serious adverse events was 81.4 % [ 57/70 ] of the steroids group and 80.0 % [ 56/70 ] of the placebo group ( P > .99 ) ; however , participants receiving steroids had an earlier time of onset of their first serious adverse event by 30 days posthepatoportoenterostomy ( 37.2 % [ 95 % CI , 26.9 % to 50.0 % ] of steroids group vs 19.0 % [ 95 % CI , 11.5 % to 30.4 % ] of placebo group ; P = .008 ) . CONCLUSIONS AND RELEVANCE Among infants with biliary atresia who have undergone hepatoportoenterostomy , high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months , although a small clinical benefit could not be excluded . Steroid treatment was associated with earlier onset of serious adverse events in children with biliary atresia . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00294684 BACKGROUND We studied the outcomes at school age in children who had participated in a double-blind , placebo-controlled trial of early postnatal dexamethasone therapy ( initiated within 12 hours after birth ) for the prevention of chronic lung disease of prematurity . METHODS Of the 262 children included in the initial study , 159 lived to school age . Of these children , 146 ( 72 in the dexamethasone group and 74 in the control group ) were included in our study . All the infants had had severe respiratory distress syndrome requiring mechanical ventilation shortly after birth . In the dexamethasone group , 0.25 mg of dexamethasone per kilogram of body weight was given intravenously every 12 hours for one week , and then the dose was tapered . We evaluated the children 's growth , neurologic and motor function , cognition , and school performance . RESULTS Children in the dexamethasone group were significantly shorter than the controls ( P=0.03 for boys , P=0.01 for girls , and P=0.03 for all children ) and had a significantly smaller head circumference ( P=0.04 ) . Children in the dexamethasone group had significantly poorer motor skills ( P<0.001 ) , motor coordination ( P<0.001 ) , and visual-motor integration ( P=0.02 ) . As compared with the controls , children in the dexamethasone group also had significantly lower full IQ scores ( mean [ + /-SD ] , 78.2+/-15.0 vs. 84.4+/-12.6 ; P=0.008 ) , verbal IQ scores ( 84.1+/-13.2 vs. 88.4+/-11.8 , P=0.04 ) , and performance IQ scores ( 76.5+/-14.6 vs. 84.5+/-12.7 , P=0.001 ) . The frequency of clinical ly significant disabilities was higher among children in the dexamethasone group than among controls ( 28 of 72 [ 39 percent ] vs. 16 of 74 [ 22 percent ] , P=0.04 ) . CONCLUSIONS Early postnatal dexamethasone therapy should not be recommended for the routine prevention or treatment of chronic lung disease , because it leads to substantial adverse effects on neuromotor and cognitive function at school age BACKGROUND & AIMS The effect of adjuvant steroids in infants with biliary atresia ( BA ) is not clear and evidence of benefit is lacking . METHODS During the period Jan. 2000-Dec . 2011 , 153 infants with isolated ( CMV IgM-ve ) BA underwent Kasai portoenterostomy ( KPE ) at<70 days . They were divided into three groups : LOW-dose steroid ( from a previous r and omized trial ; starting prednisolone 2mg/kg/day , n=18 ) , HIGH-dose steroid ( starting prednisolone 5mg/kg/day , n=44 ) , and NO steroid [ n=72 + 19 placebo ( from r and omized trial)=91 ] . Outcome was assessed by early liver biochemistry , clearance of jaundice ( < 20 μmol/L ) , and actuarial native liver survival . Data are quoted as median ( IQ range ) and compared with non-parametric ANOVA , Chi or Log-rank tests as appropriate . p ≤ 0.05 was regarded as significant . RESULTS All three groups were comparable for age ( ANOVA , p=0.31 ) and a surrogate marker of liver fibrosis [ aspartate-aminotransferase index ( APRi ) , ANOVA , p=0.67 ] . At 1 month post KPE , there was a significant reduction in bilirubin [ 58 ( 25 - 91 ) vs. 91 (52 - 145)μmol/L , p=0.0015 ] , AST [ 118 ( 91 - 159 ) vs. 155 (108 - 193)IU/L , p=0.0015 ] , and APRi [ 0.49 ( 0.28 - 0.89 ) vs. 0.82 ( 0.45 - 1.2 ) , p=0.005 ] for HIGH vs. NO steroid . There was a significant increase in % clearance of jaundice with the use of steroids [ 47/91 ( 52 % ) vs. 12/18 ( 67 % ) vs. 29/44 ( 66 % ) ; steroids vs. no steroids , p=0.037 ] . There was no statistical difference in 4-year patient survival ( 96 % vs. 94 % vs. 95 % ) or native liver survival ( 4 year=46 % vs. 50 vs. 57 % ) . CONCLUSIONS The adjuvant use of prednisolone significantly improved early post-operative liver biochemistry ( especially at the higher dose ) , and increased the proportion of infants who cleared their jaundice at 6 months post-KPE Controversy exists regarding the efficacy of corticosteroids on bile flow after Kasai portoenterostomy in biliary atresia ( BA ) . Fourteen patients who had BA and underwent Kasai portojejunostomy between November 1990 and March 1996 were subject of this study . Corticosteroid therapy ( " blast " type ) was used for inadequate bile drainage . Corticosteroid support was unnecessary in one patient with good bile drainage , and corticosteroids were aggressively used in the remaining 13 patients . Two patients who had no response to an initial blast subsequently responded and now are doing well . The remaining 11 patients responded to corticosteroids with varying degrees . Three had a limited response , and two ultimately underwent liver transplantation . There was one death caused by subdural hematoma . Three had an excellent initial response . However , one subsequently deteriorated because of intractable cholangitis , requiring liver transplantation . Ten survivors with native liver are anicteric with satisfactory growth and quality of life . Aggressive corticosteroid therapy is an important part of the management after Kasai portoenterostomy . The initial response to steroids does not necessarily reflect the final outcome PURPOSE This study tests the hypothesis that steroid administration improves the outcome of biliary atresia ( BA ) by evaluating the efficacy of postoperative steroid use on surgical outcomes in infants with BA . METHODS Steroid use and outcomes in patients with BA were retrospectively analyzed at a tertiary pediatric hospital . Institutional review board approval was obtained . RESULTS Kasai portoenterostomy ( PE ) was performed in 43 patients with BA treated from 1992 to 2004 ( 16 boys and 27 girls ) . Twenty-one PE patients received steroids and 22 did not . Portoenterostomy was successful in 24 patients ( 55.8 % ) with consistent serum bilirubin less than 2 mg/dL. Sixteen ( 66 % ) received postoperative steroids . A normal postoperative bilirubin was achieved at 6 months in 16 ( 76 % ) of 21 patients with steroids compared with 8 ( 37 % ) of 22 in untreated controls ( Fisher 's Exact test , P = .01 ) . Of the 43 patients , 19 ( 44 % ) required liver transplantation , including 7 ( 37 % ) of 19 with steroids vs 12 ( 63 % ) of 19 without ( P = .2 ) . Twenty-eight infants developed cholangitis ( fever with and without changes in hepatic function ) : 25 after PE and 3 after transplant . Of the 25 , 12 ( 48 % ) received steroids . Seven died ( 16 % ) ( range , 7 months to 4 years ) : 2 while awaiting transplantation ( received steroids ) and 5 after transplantation ( 1 received steroids and 4 were untreated ) . Survival was 86 % ( 18/21 ) in patients with steroids and 82 % ( 18/22 ) in those without . Transplant survival ( 74 % ) was comparable to previously reported historical controls ( 82 % ) . CONCLUSIONS The Kasai PE continues to be the procedure of choice in infants with BA younger than 3 months . A significantly improved clearance of postoperative jaundice and lower serum bilirubin levels were observed in patients receiving steroids . However , steroids had no effect on the incidence of cholangitis , need for liver transplantation , and overall survival . A prospect i ve study with st and ardized dose and length of steroid administration and longer period of follow-up is necessary to more accurately assess the effectiveness of steroids after PE BACKGROUND Progressive destruction of intrahepatic bile ducts may determine outcome in extrahepatic biliary atresia ( EHBA ) despite successful portoenterostomy . The aim of this study was to characterize the inflammatory infiltrate of a large series of cases of biliary atresia and relate these findings to clinical outcome . METHODS Immunohistochemical analysis was performed on frozen tissue sections of extrahepatic biliary tree and liver biopsies obtained ( August 1996 to March 1998 ) from 28 infants with EHBA and 8 liver biopsy specimens from age-matched controls with other cholestatic liver disorders . A semiquantitative scoring system was design ed to evaluate the staining with a panel of antibodies to the CD4 , CD8 , CD25 , CD56 , CD68 , CD71 antigens and to HLA-DR , ICAM-1 , VCAM-1 , E-selectin and LFA-1 . The infants then underwent followup prospect ively and divided into 2 prognostic groups at 12 months postoperatively : those who had cleared their jaundice ( grade d as a good outcome [ n = 19 ] ) , and those who required liver transplantation or who had failed to clear their jaundice ( defined as > 50 micromol/L ; grade d as poor outcome [ n = 9 ] ) . RESULTS CD4(+ ) lymphocytes and CD56(+ ) ( NK cells ) predominated in the liver of infants with EHBA as compared with controls . The infiltrating cells exhibited marked proliferation ( CD71 expression ) and activation ( particularly LFA-1 but also CD25 expression ) . A smaller sub population of the cells also expressed VCAM and E-selectin . HLA-DR was strongly expressed on Kupffer cells and to a lesser extent on proliferating bile ducts and sinusoidal endothelium . Expression of the majority of markers was lower in the remnant bile duct tissue than in the liver of EHBA ( P < .05 ) with only HLA-DR and LFA-1 ( on infiltrating cells ) and ICAM ( on endothelium ) expressed strongly in the remnant bile duct tissue . Although quantitatively less pronounced , all of these immunohistochemical features also were noted in non-EHBA cholestatic liver tissue . A good outcome at 12 months was associated with lower CD68 ( macrophage ) expression in both the liver ( P < .05 ) and biliary tree ( P < .05 ) and with reduced expression of ICAM-1 ( P = .05 ) on infiltrating cells in the biliary remnant . CONCLUSIONS Immunohistochemical patterns of immune-mediated liver injury and inflammation were prevalent features at the time of portoenterostomy . They were neither exclusive to nor characteristic of EHBA . A reduction in the expression of the macrophage marker ( CD68 ) within the liver and biliary remnants and reduction of ICAM-1 expression on infiltrating cells in the biliary remnants appear to be associated with a better postoperative prognosis The objective of this study was to evaluate adjuvant corticosteroids after Kasai portoenterostomy for biliary atresia . The study consisted of a prospect i ve , 2‐center , double‐blind , r and omized , placebo‐controlled trial of post – Kasai portoenterostomy corticosteroids ( oral prednisolone : 2 mg/kg/day from day 7 to day 21 and 1 mg/kg/day from day 22 to day 28 ) . The data were compared with χ 2 or Mann‐Whitney tests , as appropriate . Seventy‐one postoperative infants with type 3 biliary atresia were r and omized to receive either oral prednisolone ( n = 36 ) or a placebo ( n = 37 ) . At 1 month , the median bilirubin level was lower in the steroid group ( 66 versus 92 μmol/L , P = 0.06 ) , but no difference was evident at 6 ( P = 0.56 ) or 12 ( P = 0.3 ) months . The proportion of infants with a normal bilirubin level ( < 20 μmol/L ) at 6 ( 47 % versus 49 % , P = 0.89 ) and 12 months ( 50 % versus 40 % , P = 0.35 ) was not significantly different . The need for transplantation by 6 ( 12 % versus 13 % , P = 0.99 ) and 12 months ( 26 % versus 35 % , P = 0.47 ) was not significantly different . The steroid effect was more pronounced in younger infants ( less than 70 days at Kasai portoenterostomy , n = 51 ) , with a reduced bilirubin level at 1 month ( 64 versus 117 μmol/L , P = 0.01 ) and with a greater proportion with a normal bilirubin level at 12 months ( 54 % versus 37 % , P = 0.22 ) . Conclusion : There was a beneficial effect on the rate of reduction of bilirubin in the early postoperative period ( specifically in infants less than 70 days old at surgery ) , but this steroid regimen did not reduce the need for liver transplantation . ( HEPATOLOGY 2007;46:1821–1827 . |
1,902 | 26,756,737 | Overdiagnosed women may be harmed by unnecessary procedures and treatments as well as by the burden of receiving a cancer diagnosis . | In 2009 , the U.S. Preventive Services Task Force ( USPSTF ) recommended biennial mammography screening for women aged 50 to 74 years ( 1 ) on the basis of evidence of benefits and harms ( 2 , 3 ) .
The USPSTF concluded that screening decisions for women aged 40 to 49 years should be based on individual considerations and that evidence was insufficient to assess benefits and harms for those aged 75 years or older ( 1 ) .
Although there is general consensus that mammography screening is beneficial for many women , benefits must be weighed against potential harms to determine the net effect of screening on individual women .
Determining the balance between benefits and harms is complicated by several important considerations that are unresolved , including defining and quantifying potential harms ; the optimal ages at which to begin and end routine screening ; the optimal screening intervals ; appropriate use of various imaging modalities , including supplemental technologies ; values and preferences of women in regards to screening ; and how all of these considerations vary depending on a woman 's risk for breast cancer .
This systematic review up date s evidence for the USPSTF on the harms of breast cancer screening , including false-positive mammography results , overdiagnosis , anxiety , pain during procedures , and radiation exposure , and how these adverse effects vary by age , risk factor , screening interval , and screening modality .
Overdiagnosis refers to women receiving a diagnosis of ductal carcinoma in situ ( DCIS ) or invasive breast cancer when they have abnormal lesions that are unlikely to become clinical ly evident during their lifetime in the absence of screening . | R and omised controlled trials have shown that the policy of mammographic screening confers a substantial and significant reduction in breast cancer mortality . This has often been accompanied , however , by an increase in breast cancer incidence , particularly during the early years of a screening programme , which has led to concerns about overdiagnosis , that is to say , the diagnosis of disease that , if left undetected and therefore untreated , would not become symptomatic . We used incidence data from two r and omised controlled trials of mammographic screening , the Swedish Two-county Trial and the Gothenburg Trial , to establish the timing and magnitude of any excess incidence of invasive disease and ductal carcinoma in situ ( DCIS ) in the study groups , to ascertain whether the excess incidence of DCIS reported early in a screening trial is balanced by a later deficit in invasive disease and provide explicit estimates of the rate of ' real ' and non-progressive ' overdiagnosed ' tumours from the study groups of the trials . We used a multistate model for overdiagnosis and used Markov Chain Monte Carlo methods to estimate the parameters . After taking into account the effect of lead time , we estimated that less than 5 % of cases diagnosed at prevalence screen and less than 1 % of cases diagnosed at incidence screens are being overdiagnosed . Overall , we estimate overdiagnosis to be around 1 % of all cases diagnosed in screened population s. These estimates are , however , subject to considerable uncertainty . Our results suggest that overdiagnosis in mammography screening is a minor phenomenon , but further studies with very large numbers are required for more precise estimation Background : The benefits and harms of population -wide mammography screening have been long debated . This study evaluated the impact of screening frequency and age range on breast cancer mortality reduction and overdiagnosis . Methods : We developed a Markov simulation model for the evaluation of mammography screening in a cohort of British women born in 1935–40 . Results : For triennial screening in women aged 47–73 , breast cancer mortality reduction and overdiagnosis was 18.1 % ( 95 % confidence interval : 17.3 % , 19.0 % ) and 5.6 % ( 5.1 % , 6.1 % ) , of all breast cancer deaths and diagnoses , respectively , from age 40 to 85 years . For annual screening in the same age range , estimates for both outcomes increased considerably to 35.0 % ( 34.2 % , 35.7 % ) and 7.6 % ( 7.1 % , 8.1 % ) , respectively . For the age extension of triennial screening from 50–70 to 47–73 , we estimated 5 ( 3 , 7 ) incremental breast cancer deaths avoided and 14 ( 9 , 19 ) incremental cases overdiagnosed per 10 000 women invited for screening . Conclusions : Estimates of mortality reduction and overdiagnosis were highly dependent on screening frequency , age range , and uptake , which may explain differences between some previous estimates obtained from r and omised trials and from service screening IMPORTANCE False-positive mammograms , a common occurrence in breast cancer screening programs , represent a potential screening harm that is currently being evaluated by the US Preventive Services Task Force . OBJECTIVE To measure the effect of false-positive mammograms on quality of life by measuring personal anxiety , health utility , and attitudes toward future screening . DESIGN , SETTING , AND PARTICIPANTS The Digital Mammographic Imaging Screening Trial ( DMIST ) quality -of-life sub study telephone survey was performed shortly after screening and 1 year later at 22 DMIST sites and included r and omly selected DMIST participants with positive and negative mammograms . EXPOSURE Mammogram requiring follow-up testing or referral without a cancer diagnosis . MAIN OUTCOMES AND MEASURES The 6- question short form of the Spielberger State-Trait Anxiety Inventory state scale ( STAI-6 ) and the EuroQol EQ-5D instrument with US scoring . Attitudes toward future screening as measured by women 's self-report of future intention to undergo mammographic screening and willingness to travel and stay overnight to undergo a hypothetical new type of mammography that would identify as many cancers with half the false-positive results . RESULTS Among 1450 eligible women invited to participate , 1226 ( 84.6 % ) were enrolled , with follow-up interviews obtained in 1028 ( 83.8 % ) . Anxiety was significantly higher for women with false-positive mammograms ( STAI-6 , 35.2 vs 32.7 ) , but health utility scores did not differ and there were no significant differences between groups at 1 year . Future screening intentions differed by group ( 25.7 % vs 14.2 % more likely in false-positive vs negative groups ) ; willingness to travel and stay overnight did not ( 9.9 % vs 10.5 % in false-positive vs negative groups ) . Future screening intention was significantly increased among women with false-positive mammograms ( odds ratio , 2.12 ; 95 % CI , 1.54 - 2.93 ) , younger age ( 2.78 ; 1.5 - 5.0 ) , and poorer health ( 1.63 ; 1.09 - 2.43 ) . Women 's anticipated high-level anxiety regarding future false-positive mammograms was associated with willingness to travel overnight ( odds ratio , 1.94 ; 95 % CI , 1.28 - 2.95 ) . CONCLUSIONS AND RELEVANCE False-positive mammograms were associated with increased short-term anxiety but not long-term anxiety , and there was no measurable health utility decrement . False-positive mammograms increased women 's intention to undergo future breast cancer screening and did not increase their stated willingness to travel to avoid a false-positive result . Our finding of time-limited harm after false-positive screening mammograms is relevant for clinicians who counsel women on mammographic screening and for screening guideline development groups Objective - To examine the psychological consequences at a number of stages in the screening process for women attending a screening mammography programme . Setting - A pilot mammographic screening programme in Melbourne , Australia . Method — The psychological consequences question naire ( PCQ ; a reliable and valid measure of the psychological consequences of screening mammography ) was used to measure the emotional , social , and physical functioning of women in a mammographic screening programme and a control community sample . A screening group ( in whom no abnormality was detected at initial screen ; n=142 ) had four measurements : at screening clinic ; before results were received ; one week after all-clear results were received ; and eight months after initial visit . The recall group ( who were recalled for further investigation which showed the detected abnormality to be benign ; n = 58 ) had measurements at the same points as the screening group and an additional measurement while waiting at the recall assessment clinic . A r and omly selected community control group ( n = 52 ) had measurements one week , two weeks , three weeks ; and eight months after consenting to participate . Results - Emotional , social , and physical functioning of women in the screening group did not change over time and at no point differed significantly from that of community controls . The profiles of emotional and physical dysfunction of women in the recall group differed significantly from those of the screening and control groups . The level of emotional and physical dysfunction in the recall group was highest while waiting at recall assessment clinic , and scores were still significantly higher than scores obtained at comparable times from screening and control groups one week after obtaining notification that there was no sign of cancer ( emotional P < 0·001 ; physical P < 0·05 ) . This difference had disappeared eight months after the screening visit , when the level of emotional and physical functioning was similar to that of the screening and control groups . Social dysfunction scores did not change significantly over time and were similar for all three groups . Conclusions - Given that up to 10 % of women are recalled for further investigations on first round screening , significant numbers of women may have psychological consequences . This speaks for the necessity for accurate reading of mammograms to minimise the false positive recall rate , and for counselling services to be available at recall assessment centres Objective To compare breast cancer incidence and mortality up to 25 years in women aged 40 - 59 who did or did not undergo mammography screening . Design Follow-up of r and omised screening trial by centre coordinators , the study ’s central office , and linkage to cancer registries and vital statistics data bases . Setting 15 screening centres in six Canadian provinces,1980 - 85 ( Nova Scotia , Quebec , Ontario , Manitoba , Alberta , and British Columbia ) . Participants 89 835 women , aged 40 - 59 , r and omly assigned to mammography ( five annual mammography screens ) or control ( no mammography ) . Interventions Women aged 40 - 49 in the mammography arm and all women aged 50 - 59 in both arms received annual physical breast examinations . Women aged 40 - 49 in the control arm received a single examination followed by usual care in the community . Main outcome measure Deaths from breast cancer . Results During the five year screening period , 666 invasive breast cancers were diagnosed in the mammography arm ( n=44 925 participants ) and 524 in the controls ( n=44 910 ) , and of these , 180 women in the mammography arm and 171 women in the control arm died of breast cancer during the 25 year follow-up period . The overall hazard ratio for death from breast cancer diagnosed during the screening period associated with mammography was 1.05 ( 95 % confidence interval 0.85 to 1.30 ) . The findings for women aged 40 - 49 and 50 - 59 were almost identical . During the entire study period , 3250 women in the mammography arm and 3133 in the control arm had a diagnosis of breast cancer , and 500 and 505 , respectively , died of breast cancer . Thus the cumulative mortality from breast cancer was similar between women in the mammography arm and in the control arm ( hazard ratio 0.99 , 95 % confidence interval 0.88 to 1.12 ) . After 15 years of follow-up a residual excess of 106 cancers was observed in the mammography arm , attributable to over-diagnosis . Conclusion Annual mammography in women aged 40 - 59 does not reduce mortality from breast cancer beyond that of physical examination or usual care when adjuvant therapy for breast cancer is freely available . Overall , 22 % ( 106/484 ) of screen detected invasive breast cancers were over-diagnosed , representing one over-diagnosed breast cancer for every 424 women who received mammography screening in the trial To assess how women regard having had a false positive mammogram screening exam , and the influence that this had on their quality of life , 126 such women were interviewed . Their responses were compared to those of 152 women r and omly selected among screenees with a negative exam . Eighteen months after the screening the reported prevalence of anxiety about breast cancer was 29 % among women with a false positive and 13 % among women with a negative screening mammogram ( P = 0.001 ) . Of 30 women biopsied , 8 ( 27 % ) had pain in the breast and 10 ( 33 % ) had reduced sexual sensitivity . A false positive mammogram was described by 7 ( 5 % ) of the women as the worst thing they ever had experienced . However , most women with a false positive result regarded this experience , in retrospect , as but one of many minor stressful experiences creating a temporary decrease in quality of life . They report the same quality of life today as women with negative screening results and 98 % would attend another screening . Even so , false positive results are a matter of concern , and efforts should be made to minimise this cost whenever a screening programme is conducted PURPOSE To assess cancer detection rates , false-positive rates before arbitration , positive predictive values for women recalled after arbitration , and the type of cancers detected with use of digital mammography alone and combined with tomo synthesis in a large prospect i ve screening trial . MATERIAL S AND METHODS A prospect i ve , reader- and modality-balanced screening study of participants undergoing combined mammography plus tomo synthesis , the results of which were read independently by four different radiologists , is under way . The study was approved by a regional ethics committee , and all participants provided written informed consent . The authors performed a preplanned interim analysis of results from 12,631 examinations interpreted by using mammography alone and mammography plus tomo synthesis from November 22 , 2010 , to December 31 , 2011 . Analyses were based on marginal log-linear models for binary data , accounting for correlated interpretations and adjusting for reader-specific performance levels by using a two-sided significance level of .0294 . RESULTS Detection rates , including those for invasive and in situ cancers , were 6.1 per 1000 examinations for mammography alone and 8.0 per 1000 examinations for mammography plus tomo synthesis ( 27 % increase , adjusted for reader ; P = .001 ) . False-positive rates before arbitration were 61.1 per 1000 examinations with mammography alone and 53.1 per 1000 examinations with mammography plus tomo synthesis ( 15 % decrease , adjusted for reader ; P < .001 ) . After arbitration , positive predictive values for recalled patients with cancers verified later were comparable ( 29.1 % and 28.5 % , respectively , with mammography alone and mammography plus tomo synthesis ; P = .72 ) . Twenty-five additional invasive cancers were detected with mammography plus tomo synthesis ( 40 % increase , adjusted for reader ; P < .001 ) . The mean interpretation time was 45 seconds for mammography alone and 91 seconds for mammography plus tomo synthesis ( P < .001 ) . CONCLUSION The use of mammography plus tomo synthesis in a screening environment result ed in a significantly higher cancer detection rate and enabled the detection of more invasive cancers . Clinical trial registration no. NCT01248546 Participation in breast cancer screening programmes often declines in the course of the programme . The purpose of the present study was to examine whether health education could diminish the amount of drop-outs between two screening rounds . The health education was tailored to women who previously underwent mammography . Based on the Elaboration Likelihood Model two versions of the tailored leaflet were made : a simple version and a version with additional peripheral cues . In an experimental study among 2961 women the effects of the tailored leaflets on reparticipation were tested against a st and ard leaflet . Re-participation rates were high ( > 90 % ) and did not differ between the 3 groups . No significant differences regarding beliefs about re-participating were found between the 3 groups . Results indicate that the tailored information leaflets did not enhance re-participation . Therefore , the required additional efforts and costs do not seem to be justified . The results of the study provide indications that less painful mammograms and friendly staff might improve re-participation Context Seven- and 10-year results of the Canadian National Breast Screening Study ( CNBSS ) showed no reduction in breast cancer mortality from five annual mammographies and breast examinations for 40- to 49-year-old women . Some authors have argued that longer follow-up would reveal important benefits . Contribution After 11 to 16 years , the cumulative rate ratios for mammography versus usual care were 0.97 ( 95 % CI , 0.74 to 1.27 ) for breast cancer mortality without adjustment for non study mammography and 1.06 ( CI , 0.80 to 1.40 ) with adjustment . Clinical Implication s The CNBSS suggests that screening 40- to 49-year-old women is unlikely to reduce breast cancer by 20 % or more . Controversy will persist because other studies suggest that screening causes small reductions in breast cancer mortality . The Editors The Canadian National Breast Screening Study -1 ( CNBSS-1 ) , an individually r and omized trial in women 40 to 49 years of age at study entry , evaluated the efficacy of annual mammography , breast physical examination , and instruction on breast self-examination in reducing breast cancer mortality ( 1 ) . The 7-year ( 2 ) and preliminary 10-year ( 3 ) mortality results were previously reported . At 7 years , 38 women in the mammography group and 28 women in the usual care group had died of breast cancer , for a rate ratio of 1.36 ( 95 % CI , 0.84 to 2.21 ) ( 2 ) . At 10 years , there were 82 breast cancer deaths in the mammography group and 72 in the usual care group ( rate ratio , 1.14 [ CI , 0.83 to 1.56 ] ) ( 3 ) . This article reports CNBSS-1 results after an average 13-year follow-up from study entry . Methods Patient Selection and Recruitment Participants were recruited through media publicity , personal invitation letters using population lists ( municipal registers and provincial health insurance registers ) , group mailings , and physicians ( 4 ) . Eligibility criteria were age 40 to 49 years , no previous diagnosis of breast cancer , not being pregnant , no mammography in the previous 12 months , and signed informed consent . The Human Experimentation Committee of the University of Toronto ( Toronto , Ontario , Canada ) and Human Experimentation Committees at 15 CNBSS collaborating centers approved the study . A total of 50 430 women age 40 to 49 years were enrolled from January 1980 through March 1985 . R and omization Before r and omization , all participants received an initial breast physical examination and instruction on breast self-examination . They were then immediately r and omly assigned to receive mammography and , thereafter , either annual screening with mammography and breast physical examination ( 25 214 women in the mammography group were available for analysis ) or usual care in the context of the Canadian health care system ( 25 216 women in the usual care group were available for analysis ) . Center coordinators r and omly assigned participants using prepared allocation lists , independent of breast physical examination findings . This sequence ensured that the conduct and interpretation of the breast physical examination would be unbiased by knowledge of whether mammography would follow . Intervention Screening Schedule In the mammography group , 62 % of women received five annual screenings . The remainder , recruited later , received four . Each screening examination comprised mammography , breast physical examination , and instruction and evaluation on breast self-examination . Women in the mammography group completed question naires at each rescreening visit . Women in the usual care group were not recalled for rescreening but were mailed annual question naires . We expected that these participants would continue their normal pattern of medical care as delivered through Canada 's universal health care coverage , including access to mammography for diagnosis . Study Procedures Two-view mammography was done on dedicated mammography units ( 5 ) , and second readers review ed mammograms deemed abnormal . Systematic audit procedures were used ( 6 ) . Nurses provided breast physical examination in 12 centers and physicians in 3 centers in Qubec ( 7 ) . These providers taught and evaluated breast self-examination while conducting their own examination ( 8) . If findings on breast physical examination or mammography were abnormal , participants were referred to a CNBSS review clinic . The study surgeon discussed mammography findings with the study radiologist , examined the participant , and decided whether further diagnostic procedures should be recommended to the woman 's physician . The woman 's physician determined whether and how to implement the study surgeon 's recommendations . Data Collection Protocol During the screening period , the center coordinators collected surgery and pathology reports for breast-related diagnostic and therapeutic procedures . The CNBSS pathologists review ed all slides . If the community and CNBSS pathologist disagreed , a panel of three to five CNBSS pathologists blindedly and independently review ed the slides . Extensive quality control procedures were used during data collection . After the screening centers closed in 1988 , the central CNBSS central office annually followed all women known to have breast cancer until 30 June 1996 , the cut-off for this analysis . Passive follow-up of all participants through linkage with the National Cancer Registry identified new diagnoses of breast cancer in study participants through 31 December 1993 . The central office collected pathology reports for postscreening cases of breast cancer . The community diagnosis was accepted for study purpose s. Family members responding to the annual mailed question naire identified deaths that occurred before completion of a participant 's screening schedule . Thereafter , women not known to have cancer were followed only through registry linkage ; their mammography experience was not traced . However , for women known to have breast cancer , attending physicians received annual requests for up date d clinical information , including death . Attending physicians , who received annual requests for information on women with breast cancer , reported deaths until 30 June 1996 . Linkage with the Canadian Mortality Data base at Statistics Canada ( including deaths in Canadians who resided in the United States at the time of death ) identified causes of death in the entire cohort until 31 December 1993 . The procedures used to verify deaths from breast cancer were described previously ( 2 ) . Investigative procedures were initiated for women dying with breast cancer ; those whose death certificates mentioned breast cancer ; and those whose cause of death was described as unknown , unknown primary , lung cancer , colon cancer , or liver cancer . The review ers were blinded to study group allocation . All other causes of death were accepted as certified . For the most recent record linkage , more stringent confidentiality requirements exercised by many hospitals hindered verification . Thus , of the breast cancer deaths reported in this paper , a panel review ed 67 % in the mammography group and 77 % in the usual care group . The remaining deaths are as reported on death certificates . Study Outcomes Death due to or probably due to breast cancer was the major study outcome . A previous report of the CNBBS-1 noted axillary node status , as assessed by community pathologists , through 7 years of follow-up ( 2 ) . Subsequently ( 1993 to 1997 ) , to achieve consistent reporting of tumor size , all available material for screening-detected cancer and cancer detected between screenings was re-collected from originating institutions and review ed by one of the CNBSS pathologists or a colleague . Slides were obtained for review for nearly 80 % of requested cases . For the current analysis , pathologists measured the size of small tumors as observed on the slide or the size of the invasive component for mixed invasive and in situ tumors . Statistical Analysis Sample Size The CNBSS-1 was planned to evaluate whether breast cancer mortality would decrease by 40 % in the mammography group compared with the usual care group after 5 years of follow-up , with a required sample size of 50 000 women ( = 0.05 ; power , 80 % ) ( 1 ) . At 5 years , however , too few women had died of breast cancer for the study to achieve the planned power . Thus , for the first report on breast cancer mortality , we extended follow-up to 7 years ( 2 ) . CNBSS Data base The data base includes records for 50 430 women , including demographic and risk factor variables and results of screening examinations , diagnostic and therapeutic procedures , pathology results , and causes of death . CNBSS Terminology The terms screen 1 , screen 2 , through screen 5 denote events associated with screening examinations in the mammography group . The initial breast physical examination received by the usual care group is called screen 1 . Screening-detected cancers are those diagnosed after a recommendation made by the study surgeon at the CNBSS review clinic . Interval cancers are cases of cancer that occurred less than 12 months after a screening examination at which no recommendation for diagnostic procedures was made . Incident cancers are cases of cancer that occurred more than 12 months after the previous CNBSS screening examination . Statistical Tests The statistical significance of differences in proportions was determined by using the chi-square test ( two-sided = 0.05 ) . For all observed-to-expected ratios , 95 % CIs were computed . Death rates were computed by using person-years based on stratification by quinquennium of age ; we assumed that all women not known to be dead are alive . Age was defined as age at entry . Because all eligible participants were included in the analysis and follow-up , this is an intention-to-treat analysis . Cox proportional-hazards regression was done to examine variables with the most significant independent influence on survival ( 9 ) , using the PHREG program in SAS software , version 6.12 ( SAS Institute , Inc. , Cary , North Carolina ) . Because the variable allocation to screening was our primary interest , it was The relevance of detection of ductal carcinoma in situ ( DCIS ) in a breast cancer screening programme , and the extent of overdiagnosis of non-progressive lesions , remains controversial . It was the purpose of this paper to estimate the incidence of non-progressive , ' overdiagnosed ' DCIS . We defined non-progressive DCIS ( DCIS(0 ) ) as DCIS which could not have progressed to invasive disease if left untreated . Progressive DCIS ( DCIS(1 ) ) was defined as DCIS which has the propensity to progress to invasive disease . We fitted a Markov process model of the incidence of progressive and non-progressive DCIS , the transition of the former to pre clinical invasive disease and the subsequent progression to clinical symptomatic cancer . We used data from the Swedish Two-County Trial and from service screening programmes in the UK , Netherl and s , Australia and the USA to estimate the incidence of progressive and non-progressive DCIS , and the detection rates of each at the first and subsequent screening . Average incidence of non-progressive DCIS was 1.11 per 100000 per year . Average incidence of progressive DCIS was 2.1 per 1000 per year . At prevalence screen , 37 % of DCIS cases were estimated to be non-progressive . A woman attending prevalence screen has a 19 times greater chance of having a progressive DCIS or an invasive tumour diagnosed than of having a non-progressive DCIS diagnosed . At incidence screen , only 4 % of DCIS cases were estimated to be non-progressive . A woman attending an incidence screen has a 166 times higher probability of having a progressive DCIS or invasive lesion diagnosed than of having a non-progressive DCIS diagnosed . There is an element of overdiagnosis of DCIS in breast cancer screening , but the phenomenon is small in both relative and absolute terms The aim was to investigate the psychological consequences of further investigation after breast cancer screening . Study participants include 509 women ( 61 % ) recalled due to suspicious findings on screening mammograms , and a matched control group of 285 women ( 68 % ) with normal mammograms . Psychological distress was prospect ively assessed with the Hospital Anxiety and Depression Scale ( HADS ) . 46 % of the women reported borderline or clinical ly significant anxiety prior to the recall visit . A few days after the visit , anxiety and depression had decreased significantly ( P<0.01 ) in women informed about normal or benign results at the recall clinic , while reported distress remained at relatively high levels in women referred to surgical biopsy . The results demonstrate the adverse short-term effect of a delay in receiving false-positive results , but do not indicate that the recall experience results in long-term anxiety or depression for a majority of women OBJECTIVE To evaluate women 's psychological responses to abnormal mammograms and the effect on mammography adherence . To identify psychological responses and other factors that predict mammography adherence in women with normal or abnormal mammograms . DESIGN Survey study with prospect i ve analysis of factors associated with mammography adherence . SETTING Health Maintenance Organization of Pennsylvania and New Jersey ( HMO PA/NJ ) . PATIENTS Study patients , members of HMO PA/NJ who were 50 years of age or older , and who had had mammography done 3 months earlier , included women with normal mammograms ( n = 121 ) , women with low-suspicion mammograms ( n = 119 ) , and women with high-suspicion mammograms ( n = 68 ) , but not women with breast cancer . MEASUREMENTS Psychological responses 3 months after mammography and adherence to subsequent annual mammography were assessed . MAIN RESULTS Women with high-suspicion mammograms had substantial mammography-related anxiety ( 47 % ) and worries about breast cancer ( 41 % ) . Such worries affected the moods ( 26 % ) and daily functioning ( 17 % ) of these women , despite diagnostic evaluation excluding malignancy . For each variable , a consistent trend ( P greater than 0.05 ) was seen with degree of mammogram abnormality . Sixty-eight percent of women with normal results , 78 % of women with low-suspicion results , and 74 % of women with high-suspicion results obtained their subsequent annual mammograms ( P greater than 0.05 ) . The number of previous mammograms ( odds ratio , 3.2 ; 95 % CI , 1.6 to 6.2 ) and the effect of the previous results on concerns about breast cancer ( odds ratio , 0.5 ; CI , 0.2 to 1.0 ) were independent predictors of adherence in logistic regression analyses ( P less than 0.05 ) . CONCLUSIONS A substantial proportion of women with suspicious mammograms have psychological difficulties , even after learning that they do not have cancer . Such sequelae do not appear to interfere with subsequent adherence OBJECTIVE We conducted a r and omized clinical trial to determine the impact on pain and image quality when breast cushions were used to pad the surfaces of the mammography equipment during film-screen mammography . METHODS We recruited a consecutive volunteer sample of 394 participants . Breast cushions were used for only one breast , with laterality and sequence of use assigned r and omly . Data collected from participants included demographic data , rating of pain from previous mammography , and rating of pain from present mammography using both a numeric rating scale and a visual analogue scale . Research assistants also collected breast compression and radiation exposure data . Radiologists were blinded to the laterality of cushion assignment while reading the mammograms and assessing image quality . RESULTS Participants were primarily white women ( 75.3 % ) , mean age 55.4 years . Most ( 94.4 % ) reported having previous mammography . Eight percent ( n = 32 ) of those surveyed had thought about skipping or delaying mammography because of the pain involved . The pain associated with mammography was significantly ( p < .001 ) less during oblique and craniocaudal views when breast cushions were used during the procedure . Retakes were required for 2 % of the 1576 views with the most common reason being positioning ( 53 % ) . CONCLUSION The use of breast cushions significantly reduced the pain during film-screen mammography . Image quality with the cushions was reduced in a very small subset of women probably due to the difficulty in positioning the breast without visual clues . More research needs to be done prior to the routine use of these cushions in clinical practice BACKGROUND Digital breast tomo synthesis with 3D images might overcome some of the limitations of conventional 2D mammography for detection of breast cancer . We investigated the effect of integrated 2D and 3D mammography in population breast-cancer screening . METHODS Screening with Tomo synthesis OR st and ard Mammography ( STORM ) was a prospect i ve comparative study . We recruited asymptomatic women aged 48 years or older who attended population -based breast-cancer screening through the Trento and Verona screening services ( Italy ) from August , 2011 , to June , 2012 . We did screen-reading in two sequential phases-2D only and integrated 2D and 3D mammography-yielding paired data for each screen . St and ard double-reading by breast radiologists determined whether to recall the participant based on positive mammography at either screen read . Outcomes were measured from final assessment or excision histology . Primary outcome measures were the number of detected cancers , the number of detected cancers per 1000 screens , the number and proportion of false positive recalls , and incremental cancer detection attributable to integrated 2D and 3D mammography . We compared paired binary data with McNemar 's test . FINDINGS 7292 women were screened ( median age 58 years [ IQR 54 - 63 ] ) . We detected 59 breast cancers ( including 52 invasive cancers ) in 57 women . Both 2D and integrated 2D and 3D screening detected 39 cancers . We detected 20 cancers with integrated 2D and 3D only versus none with 2D screening only ( p<0.0001 ) . Cancer detection rates were 5.3 cancers per 1000 screens ( 95 % CI 3.8 - 7.3 ) for 2D only , and 8.1 cancers per 1000 screens ( 6.2 - 10.4 ) for integrated 2D and 3D screening . The incremental cancer detection rate attributable to integrated 2D and 3D mammography was 2.7 cancers per 1000 screens ( 1.7 - 4.2 ) . 395 screens ( 5.5 % ; 95 % CI 5.0 - 6.0 ) result ed in false positive recalls : 181 at both screen reads , and 141 with 2D only versus 73 with integrated 2D and 3D screening ( p<0.0001 ) . We estimated that conditional recall ( positive integrated 2D and 3D mammography as a condition to recall ) could have reduced false positive recalls by 17.2 % ( 95 % CI 13.6 - 21.3 ) without missing any of the cancers detected in the study population . INTERPRETATION Integrated 2D and 3D mammography improves breast-cancer detection and has the potential to reduce false positive recalls . R and omised controlled trials are needed to compare integrated 2D and 3D mammography with 2D mammography for breast cancer screening . FUNDING National Breast Cancer Foundation , Australia ; National Health and Medical Research Council , Australia ; Hologic , USA ; Technologic , Italy The authors tested the hypothesis that giving women control over the compression portion of the mammography examination results in a less painful experience , greater overall patient satisfaction , and a radiographic image as good as that produced by means of technologist-controlled compression . One hundred nine women undergoing screening mammography at a hospital-based outpatient clinic were studied . Each underwent two-view , screen-film mammography performed in routine fashion except that , by r and om assignment , one breast was compressed by the technologist and the other breast , by the patient . Patient-controlled compression was significantly ( P = .003 ) less painful than technologist-controlled compression . Overall patient satisfaction ( 96 % [ 105 of 109 ] ) and willingness to repeat the experience were extremely high . The majority of images ( 93.5 % [ 202 of 216 ] ) were rated as having good to excellent compression . With minimal patient education , self-compression result ed in an image at least as good as that produced with technologist-applied compression . Further study of this technique is warranted Five community- design ed pilot projects were undertaken to reduce the time to diagnosis following an abnormal mammogram . One thous and five hundred and seventy-eight women with abnormal mammograms completed a self-administered question naire ( 71 % response ) which inquired about experiences and satisfaction with time delay from screening to diagnosis , the information received and support given by health professionals , and measures of anxiety and stress during this time interval . Four of the five pilot project initiatives shortened the time interval from screening to diagnosis , the greatest improvement occurring with facilitated referral from screening to diagnostic breast imaging . There was little difference among the pilot projects and control for most measures of client satisfaction and anxiety . Differences were found between biopsied and nonbiopsied women for several of these measures . Shortening the time to diagnosis positively influenced the client 's perception of unnecessary delay At mammography , strong compression of the breasts is required to reduce the radiation dose and to obtain radiographic images of high quality . In recent times the mass media have received a number of letters with complaints about the painfulness of the examination and an unsympathetic reception by the personnel . The aim of this study was to find out what effect information and a special manner of reception ( " reflection " ) had on the experience of pain at mammography . Reflection meant that the X-ray nurse , in an accepting manner , reflected the feelings and facts which the woman expressed . The study was performed as a 2 x 2 factorial design . One independent variable was a letter of information , with the two alternatives letter of information and no letter of information , and another was reflection , with the two alternatives reflection and no reflection . Seventy-six women were r and omly allocated to these four conditions . The letter of information stated why the examination was to be performed , how it is done and how it is usually experienced . The results showed that all women in all groups experienced relatively little pain . They considered that they were well received and were satisfied with the information . The difference between the groups was small . There was a tendency for those who were both received with reflection and were given a letter of information to be more satisfied with the examination as compared with the other women . A larger number of women in this former group than in the other groups stated reasons for their assessment . This result was significant . ( ABSTRACT TRUNCATED AT 250 WORDS PURPOSE To investigate whether informing patients about mammographic compression changed the anxiety and pain that they experience during mammography . MATERIAL S AND METHODS Five hundred and one patients were enrolled in the study . Two hundred and fifty seven ( 51.3 % ) were informed before the procedure by written forms explaining the necessity of compression . The remaining 244 ( 48.7 % ) did n't get any pre-procedural information . All participants completed demographic form and Spielberger 's State Anxiety Inventory while they were waiting for mammography . They marked the level of pain due to compression on a 100-mm visual analog scale ( VAS ) after the procedure . Chi square , Pearson 's correlation and Student 's t tests were used for statistical analyses . RESULTS We did n't find any significant difference between the anxiety scores of the informed ( 41.4+/-7.9 ) and uninformed ( 40.9+/-7.7 ) women , but the pain level was significantly lower in the informed group ( 16.5+/-22.4 ) than in the uninformed group ( 24.5+/-28.1 ) . There was no statistically significant relationship between the anxiety and pain levels . Women who had recently felt tense and nervous or had a fear of breast cancer diagnosis had higher anxiety levels . CONCLUSION Our data shows that informing patients about examination decreases the level of pain due to mammographic compression , but does not alter the anxiety level . The main cause of anxiety appears to be the fear of a malignant diagnosis . Any intervention to decrease this fear may increase the compliance rates for screening mammography BACKGROUND Screening for breast cancer with mammography in women aged 50 years or more has been shown to reduce mortality from breast cancer . However , the extent to which mammography contributes to the reduction of mortality in women who also undergo physical examination of the breasts is not known . This study was design ed to compare breast cancer mortality following annual screening consisting of two-view mammography and physical examination of the breasts with mortality following annual screening by physical examination only . Breast self-examination was taught to all participants . METHODS This trial r and omly and individually assigned 39 405 women aged 50 - 59 years , recruited from January 1980 through March 1985 , to one of the study arms . The women were followed by record linkage with the Canadian National Cancer Registry and National Mortality Data base to December 31 , 1993 , and by active follow-up of breast cancer patients to June 30 , 1996 . RESULTS R and omization achieved virtually equal distribution of demographic and breast cancer risk variables . At the first annual screen , 21 % of the cancers found by mammography alone ( in the mammography plus physical examination group ) were 20 mm or more in size compared with 46 % of those found by physical examination in the mammography plus physical examination group and 56 % in the physical examination-only group . The corresponding percentages for screens 2 - 5 were 10 % , 42 % , and 50 % , respectively . Screening detected 267 invasive breast cancers in the mammography plus physical examination group compared with 148 in the physical examination-only group . By December 31 , 1993 , 622 invasive and 71 in situ breast carcinomas were ascertained in the mammography plus physical examination group , and 610 and 16 were ascertained in the physical examination-only group . At 13-year follow-up , with 107 and 105 deaths from breast cancer in the respective groups , the cumulative rate ratio was 1.02 ( 95 % confidence interval = 0.78 - 1.33 ) . CONCLUSION In women aged 50 - 59 years , the addition of annual mammography screening to physical examination has no impact on breast cancer mortality Objectives – Firstly , to determine if attendance for second round mammography screening in those sent a tailored letter ( that is , making reference to their screening history ) is increased compared with those sent a st and ard letter ; secondly , to investigate the acceptability of tailored letters . Setting – North West Glasgow Breast Screening Centre . Methods – A r and omised controlled trial . Results – Overall attendance was unrelated to whether the women were sent a tailored or st and ard letter ; 60 % of those sent the st and ard letter attended ( 922/1531 ) compared with 62 % of those sent the tailored letter ( 956/1552 ) ( χ2 = 0·61 , P = 0·4 ) ( difference 2 % ; 95 % confidence interval − 2 % to 5 % ) . There were no significant differences in percentage attendance within each of the study subgroups : women who attended previously and received an all clear result , women who attended previously and received a false positive result , women who were invited previously and failed to attend , and women who were previously too young to be invited for screening . However , there was a statistically significant difference in percentage attendance between these four groups , independent of letter type ( χ2 = 510 , P<0·00001 ) . Although women found the letters acceptable and underst and able , they did not seem to pay close attention to the content . Conclusions – Tailoring invitation letters does not have a significant effect on uptake rates for breast screening and does not justify the additional workload required The aim of this prospect i ve study was to investigate associations of mammography pain and discomfort with sociodemographics , personal history and psychological and situational factors . Subjects were women with a negative screening finding ( n = 883 ) from a r and om sample of 50-year-old Finnish women attending their first breast cancer screening . Question naires were sent 1 month before the screening invitation and 2 months after screening . Sixty-one per cent reported painful and 59 % uncomfortable mammograms ( 4 % severely ) . Linear regression analyses showed that anticipation of pain and discomfort was the most powerful factor explaining pain and discomfort among women with earlier mammography . However , it had no effect among women without earlier mammography , for whom screening-related nervousness and perceptions of staff were crucial . Suggested interventions include better information before screening , a friendly screening atmosphere and empathetic , supportive staff behaviour , especially towards women having their first mammogram , encouraging them to feel more at ease and distracted from pain IMPORTANCE Mammography plays a key role in early breast cancer detection . Single-institution studies have shown that adding tomo synthesis to mammography increases cancer detection and reduces false-positive results . OBJECTIVE To determine if mammography combined with tomo synthesis is associated with better performance of breast screening programs in the United States . DESIGN , SETTING , AND PARTICIPANTS Retrospective analysis of screening performance metrics from 13 academic and nonacademic breast centers using mixed models adjusting for site as a r and om effect . EXPOSURES Period 1 : digital mammography screening examinations 1 year before tomo synthesis implementation ( start date s ranged from March 2010 to October 2011 through the date of tomo synthesis implementation ) ; period 2 : digital mammography plus tomo synthesis examinations from initiation of tomo synthesis screening ( March 2011 to October 2012 ) through December 31 , 2012 . MAIN OUTCOMES AND MEASURES Recall rate for additional imaging , cancer detection rate , and positive predictive values for recall and for biopsy . RESULTS A total of 454,850 examinations ( n=281,187 digital mammography ; n=173,663 digital mammography + tomo synthesis ) were evaluated . With digital mammography , 29,726 patients were recalled and 5056 biopsies result ed in cancer diagnosis in 1207 patients ( n=815 invasive ; n=392 in situ ) . With digital mammography + tomo synthesis , 15,541 patients were recalled and 3285 biopsies result ed in cancer diagnosis in 950 patients ( n=707 invasive ; n=243 in situ ) . Model-adjusted rates per 1000 screens were as follows : for recall rate , 107 ( 95 % CI , 89 - 124 ) with digital mammography vs 91 ( 95 % CI , 73 - 108 ) with digital mammography + tomo synthesis ; difference , -16 ( 95 % CI , -18 to -14 ; P < .001 ) ; for biopsies , 18.1 ( 95 % CI , 15.4 - 20.8 ) with digital mammography vs 19.3 ( 95 % CI , 16.6 - 22.1 ) with digital mammography + tomo synthesis ; difference , 1.3 ( 95 % CI , 0.4 - 2.1 ; P = .004 ) ; for cancer detection , 4.2 ( 95 % CI , 3.8 - 4.7 ) with digital mammography vs 5.4 ( 95 % CI , 4.9 - 6.0 ) with digital mammography + tomo synthesis ; difference , 1.2 ( 95 % CI , 0.8 - 1.6 ; P < .001 ) ; and for invasive cancer detection , 2.9 ( 95 % CI , 2.5 - 3.2 ) with digital mammography vs 4.1 ( 95 % CI , 3.7 - 4.5 ) with digital mammography + tomo synthesis ; difference , 1.2 ( 95 % CI , 0.8 - 1.6 ; P < .001 ) . The in situ cancer detection rate was 1.4 ( 95 % CI , 1.2 - 1.6 ) per 1000 screens with both methods . Adding tomo synthesis was associated with an increase in the positive predictive value for recall from 4.3 % to 6.4 % ( difference , 2.1 % ; 95 % CI , 1.7%-2.5 % ; P < .001 ) and for biopsy from 24.2 % to 29.2 % ( difference , 5.0 % ; 95 % CI , 3.0%-7.0 % ; P < .001 ) . CONCLUSIONS AND RELEVANCE Addition of tomo synthesis to digital mammography was associated with a decrease in recall rate and an increase in cancer detection rate . Further studies are needed to assess the relationship to clinical outcomes IMPORTANCE Controversy exists about the frequency women should undergo screening mammography and whether screening interval should vary according to risk factors beyond age . OBJECTIVE To compare the benefits and harms of screening mammography frequencies according to age , breast density , and postmenopausal hormone therapy ( HT ) use . DESIGN Prospect i ve cohort . SETTING Data collected January 1994 to December 2008 from mammography facilities in community practice that participate in the Breast Cancer Surveillance Consortium ( BCSC ) mammography registries . PARTICIPANTS Data were collected prospect ively on 11,474 women with breast cancer and 922,624 without breast cancer who underwent mammography at facilities that participate in the BCSC . MAIN OUTCOMES AND MEASURES We used logistic regression to calculate the odds of advanced stage ( IIb , III , or IV ) and large tumors ( > 20 mm in diameter ) and 10-year cumulative probability of a false-positive mammography result by screening frequency , age , breast density , and HT use . The main predictor was screening mammography interval . RESULTS Mammography biennially vs annually for women aged 50 to 74 years does not increase risk of tumors with advanced stage or large size regardless of women 's breast density or HT use . Among women aged 40 to 49 years with extremely dense breasts , biennial mammography vs annual is associated with increased risk of advanced-stage cancer ( odds ratio [ OR ] , 1.89 ; 95 % CI , 1.06 - 3.39 ) and large tumors ( OR , 2.39 ; 95 % CI , 1.37 - 4.18 ) . Cumulative probability of a false-positive mammography result was high among women undergoing annual mammography with extremely dense breasts who were either aged 40 to 49 years ( 65.5 % ) or used estrogen plus progestogen ( 65.8 % ) and was lower among women aged 50 to 74 years who underwent biennial or triennial mammography with scattered fibrogl and ular densities ( 30.7 % and 21.9 % , respectively ) or fatty breasts ( 17.4 % and 12.1 % , respectively ) . CONCLUSIONS AND RELEVANCE Women aged 50 to 74 years , even those with high breast density or HT use , who undergo biennial screening mammography have similar risk of advanced-stage disease and lower cumulative risk of false-positive results than those who undergo annual mammography . When deciding whether to undergo mammography , women aged 40 to 49 years who have extremely dense breasts should be informed that annual mammography may minimize their risk of advanced-stage disease but the cumulative risk of false-positive results is high |
1,903 | 20,823,763 | Thus , melatonin premedication is effective in ameliorating preoperative anxiety in adults , but its analgesic effects remain controversial in the perioperative period . | Melatonin possesses sedative , hypnotic , analgesic , antiinflammatory , antioxidative , and chronobiotic properties that distinguish it as an attractive alternative premedicant . | The effect of a single , oral bedtime dose of the benzodiazepine hypnotics flunitrazepam ( FR ; 2 mg ) , flurazepam ( FR ; 30 mg ) , and triazolam ( TR ; 0.5 mg ) on the sleep stages and the sleep EEG was investigated in eight healthy , young subjects . In comparison to the placebo night , all drugs reduced the percentage of stage 1 and REM sleep , increased stage 2 , and decreased the number of stage shifts . For FN and FR , some of these changes persisted in the postdrug night . All-night spectral analysis of the EEG showed a reduction of low-frequency activity ( 0.25 - 10.0 Hz ) in stages 2 , 3 + 4 and REM sleep , changes that persisted for all three drugs in the post-drug night . In the drug nights , activity in the spindle frequency range ( 11 - 14 Hz ) was enhanced particularly in stage 2 and 3 + 4 , activity in the high frequency range ( 17 - 25 Hz ) particularly in REM sleep and stage 1 . In the first third of the drug night , the depression of low-frequency activity in stage 2 was either absent ( FR ) or less prominent ( FN , TR ) than in the following part of the night . The results demonstrate that benzodiazepine hypnotics induce specific changes in the EEG spectra which reflect the immediate and residual drug effects more sensitively than conventional sleep scores We have evaluated the perioperative effects of melatonin with those of midazolam in 75 women in a prospect i ve , r and omized , double-blind , placebo-controlled study . Patients were given sublingual midazolam 15 mg , melatonin 5 mg or placebo , approximately 100 min before a st and ard anaesthetic . Sedation , anxiety and orientation were quantified before , and 10 , 30 , 60 and 90 min after premedication , and 15 , 30 , 60 and 90 min after admission to the recovery room . Psychomotor performance was evaluated at these times also , using the digit-symbol substitution test ( DSST ) and the Trieger dot test ( TDT ) . Patients who received premedication with either midazolam or melatonin had a significant decrease in anxiety levels and increase in levels of sedation before operation compared with controls . Midazolam produced the highest scores for sedation at 30 and 60 min after administration and significant psychomotor impairment in the preoperative period compared with melatonin or placebo . After operation , patients who received midazolam or melatonin premedication had increased levels of sedation at 30 min and impairment in performance on the DSST at 15 , 30 and 90 min compared with controls . There were no significant differences between the three groups for anxiety levels or TDT performance after operation . Amnesia was notable only in the midazolam group for one preoperative event ( entry into the operating room ) . Patient satisfaction was noted in the midazolam and melatonin groups only . We have demonstrated that melatonin can be used effectively for premedication of adult patients Postoperative pain can have a significant effect on patient recovery . An underst and ing of patient attitudes and concerns about postoperative pain is important for identifying ways health care professionals can improve postoperative care . To assess patients ’ postoperative pain experience and the status of acute pain management , we conducted a national study by using telephone question naires . A r and om sample of 250 adults who had undergone surgical procedures recently in the United States was obtained from National Family Opinion . Patients were asked about the severity of postsurgical pain , treatment , satisfaction with pain medication , patient education , and perceptions about postoperative pain and pain medications . Approximately 80 % of patients experienced acute pain after surgery . Of these patients , 86 % had moderate , severe , or extreme pain , with more patients experiencing pain after discharge than before discharge . Experiencing postoperative pain was the most common concern ( 59 % ) of patients . Almost 25 % of patients who received pain medications experienced adverse effects ; however , almost 90 % of them were satisfied with their pain medications . Approximately two thirds of patients reported that a health care professional talked with them about their pain . Despite an increased focus on pain management programs and the development of new st and ards for pain management , many patients continue to experience intense pain after surgery . Additional efforts are required to improve patients ’ postoperative pain experience The objective of the present study was to assess the toxicology of melatonin ( 10 mg ) , administered for 28 days to 40 volunteers r and omly assigned to groups receiving either melatonin ( N = 30 ) or placebo ( N = 10 ) in a double-blind fashion . The following measurements were performed : polysomnography ( PSG ) , laboratory examinations , including complete blood count , urinalysis , sodium , potassium and calcium levels , total protein levels , albumin , blood glucose , triglycerides , total cholesterol , high-density lipoprotein ( HDL ) , low-density lipoprotein ( LDL ) , and very low-density lipoprotein ( VLDL ) , urea , creatinine , uric acid , glutamic-oxalacetic transaminase ( GOT ) , glutamic-pyruvate transaminase ( GPT ) , bilirubin , alkaline phosphatase , gama-glutamic transaminase ( GGT ) , T3 , T4 , TSH , LH/FSH , cortisol , and melatonin serum concentrations . In addition , the Epworth Somnolence Scale ( ESS ) and a sleep diary ( SD ) were also applied to the volunteers 1 wk before each PSG . In addition , the volunteers were asked about possible side effects ( SE ) that appeared during the treatment . The study was carried out according to the following timetable : Visit 0 , filling out the term of consent and inclusion criteria ; Visit 1 , PSG , laboratory examinations , ESS , SD , melatonin serum concentrations ; Visit 2 , SD , melatonin serum concentrations , SE ; Visit 3 , melatonin serum concentrations , PSG , ESS , SE ; Visit 4 , laboratory examinations , SE , melatonin serum concentrations , SD ; and Visit 5 , PSG , ESS , SE . Analysis of the PSG showed a statistically significant reduction of stage 1 of sleep in the melatonin group . No other differences between the placebo and melatonin groups were obtained . In the present study we did not observe , according to the parameters analyzed , any toxicological effect that might compromise the use of melatonin at a dose of 10 mg for the period of time utilized in this study BACKGROUND : The effect of melatonin on the intraoperative requirements for IV anesthetics has not been documented . We studied the effect of melatonin premedication on the propofol and thiopental dose – response curves for abolition of responses to verbal comm and s and eyelash stimulation . METHODS : This prospect i ve , r and omized , double-blind study included 200 adults with ASA physical status I. Patients received either 0.2 mg/kg melatonin or a placebo orally for premedication ( n = 100 per group ) . Approximately 50 min later , subgroups of 10 melatonin and 10 placebo patients were administered various doses of propofol ( 0.5 , 1.0 , 1.5 , 2.0 , or 2.4 mg/kg ) or thiopental ( 2.0 , 3.0 , 4.0 , 5.0 , or 6.0 mg/kg ) for anesthetic induction . The ability of each patient to respond to the comm and , “ open your eyes , ” and the disappearance of the eyelash reflex were assessed 60 s after the end of the injection of propofol or thiopental . Dose – response curves were determined by probit analysis . RESULTS : Melatonin premedication decreased thiopental ED50 values for loss of response to verbal comm and and eyelash reflex from 3.4 mg/kg ( 95%confidence interval , 3.2–3.5 mg/kg ) and 3.7 mg/kg ( 3.5–3.9 mg/kg ) to 2.7 mg/kg ( 2.6–2.9 mg/kg ) and 2.6 mg/kg ( 2.5–2.7 mg/kg ) , respectively ( P < 0.05 ) . Corresponding propofol ED50 values decreased from 1.5 mg/kg ( 1.4–1.6 mg/kg ) and 1.6 mg/kg ( 1.5–1.7 mg/kg ) to 0.9 mg/kg ( 0.8–0.96 mg/kg ) and 0.9 mg/kg ( 0.8–0.95 mg/kg ) , respectively ( P < 0.05 ) . CONCLUSIONS : Melatonin premedication significantly decreased the doses of both propofol and thiopental required to induce anesthesia BACKGROUND Iletrospective studies fail to identify predictors of postoperative nausea and vomiting ( PONV ) . The authors prospect ively studied 17,638 consecutive out patients who had surgery to identify predictors . METHODS Data on medical conditions , anesthesia , surgery , and PONV were collected in the post-anesthesia care unit , in the ambulatory surgical unit , and in telephone interviews conducted 24 h after surgery . Multiple logistic regression with backward stepwise elimination was used to develop a predictive model An independent set of patients was used to vali date the model RESULTS Age ( younger or older ) , sex ( female or male ) , smoking status ( nonsmokers or smokers ) , previous PONV , type of anesthesia ( general or other ) , duration of anesthesia ( longer or shorter ) , and type of surgery ( plastic , orthopedic shoulder , or other ) were independent predictors of PONV . A 10-yr increase in age decreased the likelihood of PONV by 13 % . The risk for men was one third that for women . A 30-min increase in the duration of anesthesia increased the likelihood of PONV by 59 % . General anesthesia increased the likelihood of PONV 11 times compared with other types of anesthesia . Patients with plastic and orthopedic shoulder surgery had a sixfold increase in the risk for PONV . The model predicted PONV accurately and yielded an area under the receiver operating characteristic curve of 0.785+/-0.011 using an independent validation set . CONCLUSIONS A vali date d mathematical model is provided to calculate the risk of PONV in out patients having surgery . Knowing the factors that predict PONV will help anesthesiologists determine which patients will need antiemetic therapy Melatonin has been reported to reduce preoperative anxiety . We performed this study to compare preoperative anxiety in elderly patients receiving melatonin ( M ) or placebo ( P ) . Anxiety was measured in patients aged > 65 yr by a numerical rating scale ( range , 0–10 ) . Each patient was r and omized to receive M 10 mg or P orally : 71 patients were in group P and 67 in group M. The median ( quartiles ) anxiety level was 5 ( 2–8 ) before and 3 ( 1–7 ) 90 min after premedication in group M and 5 ( 3–6 ) and 3 ( 1–5 ) in group P , respectively . M and P reduce anxiety in elderly patients to a similar degree Midazolam ( 15 mg p.o . ) was compared with placebo and oxazepam ( 15 mg ) in 12 healthy volunteers and in seven patients suffering from sleep disorders in a single-blind cross-over study . Each treatment period lasted for seven days . The last two nights were spent in a sleep laboratory to evaluate the efficacy of the three compounds . The drugs were given to the patients every day and to the volunteers only on the recorded nights immediately before going to bed . The subjects rated their quality of sleep every morning after administration . Midazolam shortened ( P = 0.025 ) the sleep latency to first stage 2 ( t2 = 29 min ) compared with placebo ( t2 = 58.7 ) min and oxazepam ( t2 = 55.4 min ) in the group of patients ; in the group of volunteers t2 was shortened ( P = 0.05 ) only by midazolam ( t2 = 17.2 min ) compared with placebo ( t2 = 24.6 min ) . REM suppression was not found in the group of patients , while sleep stages 3 + 4 were slightly reduced . However , a suppression of REM by midazolam ( P = 0.025 ) and oxazepam ( P = 0.01 ) was observed in the volunteers compared with placebo . The effects of midazolam seemed to be related to its pharmacokinetics . The drug increased the amount of stage 3 + 4 ( P = 0.01 ) and suppressed REM ( P = 0.005 ) compared with oxazepam and placebo , only during the first 3 h , when it was measurable in plasma . Midazolam was rated by the patients more favourably than oxazepam ( P = 0.025 ) and placebo ( P = 0.05 ) . The volunteers noted no difference amongst the three treatments , but reported hangover effects after oxazepam BACKGROUND : Melatonin has anxiolytic and potential analgesic effects . In this study , we assessed the effects of melatonin premedication on pain , anxiety , intraocular pressure ( IOP ) , and operative conditions during cataract surgery under topical analgesia . METHODS : Forty patients undergoing cataract surgery under topical anesthesia were r and omly assigned into two groups ( 20 patients each ) to receive either melatonin 10 mg tablet ( melatonin group ) or placebo tablet ( control group ) as oral premedication 90 min before surgery . Anxiety scores , verbal pain scores , heart rate , mean arterial blood pressure , and IOP were recorded . In addition , the surgeon was asked to rate operating conditions . RESULTS : Melatonin significantly reduced the anxiety scores ( median , interquartile range ) from 5 , 3.5–6 to 3 , 2–3 after premedication and to 3 , 2–3.5 during surgery ( P = 0.04 and P = 0.005 compared with the placebo group , respectively ) . Perioperative verbal pain scores were significantly lower in the melatonin group with less intraoperative fentanyl requirement ( median , interquartile range ) compared with the control group , 0 , 0–32.5 vs 47.5 , 30–65 & mgr;g , respectively , P = 0.007 . Melatonin also decreased IOP ( mean ± sd ) significantly from 17.9 ± 0.9 to 14.2 ± 1.0 mm Hg after premedication and to 13.8 ± 1.1 mm Hg during surgery ( P < 0.001 ) . It also provided better quality of operative conditions . CONCLUSION : We concluded that oral melatonin premedication for patients undergoing cataract surgery under topical anesthesia provided anxiolytic effects , enhanced analgesia , and decreased IOP result ing in good operating conditions BACKGROUND : Melatonin has anxiolytic and potential analgesic effects . We assessed the efficacy of melatonin premedication in reducing tourniquet-related pain and improving analgesia in patients receiving IV regional anesthesia ( IVRA ) . METHODS : Forty patients undergoing elective h and surgery under IVRA were r and omly assigned into two groups ( 20 patients each ) to receive either melatonin 10 mg ( melatonin group ) or placebo ( control group ) as oral premedication . IVRA was achieved with lidocaine , 3 mg/kg , diluted with saline to a total volume of 40 mL. Anxiety scores , hemodynamic changes , sensory and motor block onset and recovery times , tourniquet pain , the quality of intraoperative anesthesia , time to first analgesic request , and 24 h analgesic requirements were recorded . RESULTS : After premedication , the anxiety scores were significantly reduced in the melatonin group ( P = 0.023 ) . During surgery , patients who received melatonin premedication had better tourniquet tolerance ( lower verbal pain scores at 30 , 40 , and 50 min after tourniquet inflation , P < 0.05 ) , lower rescue fentanyl requirements ( 15.6 ± 21.9 vs 45.7 ± 33.4 & mgr;g , P = 0.002 ) , longer time to the first postoperative analgesic request ( 145.4 ± 20.2 min vs 74.6 ± 12.8 , P < 0.001 ) and lower postoperative diclofenac consumption at 24 h ( 86.3 ± 27.5 mg vs 116.3 ± 38.3 mg , P = 0.007 ) compared with the control group . CONCLUSIONS : Melatonin is an effective premedication before IVRA since it reduced patient anxiety , decreased tourniquet-related pain , and improved perioperative analgesia We previously observed that low oral doses of melatonin given at noon increase blood melatonin concentrations to those normally occurring nocturnally and facilitate sleep onset , as assessed using an involuntary muscle relaxation test . In this study we examined the induction of polysomnographically recorded sleep by similar doses given later in the evening , close to the times of endogenous melatonin release and habitual sleep onset . Volunteers received the hormone ( oral doses of 0.3 or 1.0 mg ) or placebo at 6 , 8 , or 9 PM . Latencies to sleep onset , to stage 2 sleep , and to rapid eye movement ( REM ) sleep were measured polysomnographically . Either dose given at any of the three time points decreased sleep onset latency and latency to stage 2 sleep . Melatonin did not suppress REM sleep or delay its onset . Most volunteers could clearly distinguish between the effects of melatonin and those of placebo when the hormone was tested at 6 or 8 PM . Neither melatonin dose induced “ hangover ” effects , as assessed with mood and performance tests administered on the morning after treatment . These data provide new evidence that nocturnal melatonin secretion may be involved in physiologic sleep onset and that exogenous melatonin may be useful in treating insomnia UNLABELLED Recent evidence has demonstrated analgesic , anti-inflammatory , and anxiolytic properties of melatonin . Taking into account that higher anxiety makes the control of postoperative pain more difficult , one can hypothesize that melatonin anxiolytic and analgesic effects improve the control of postoperative pain . Thus , we conducted a r and omized , double-blind , placebo-controlled study with 59 patients undergoing abdominal hysterectomy to test the hypothesis that melatonin is as effective as clonidine and that both are more effective than placebo in reducing postoperative pain . Additionally , we compared their anxiolytic effects on postoperative pain . Patients were r and omly assigned to receive oral melatonin ( 5 mg ) ( n = 20 ) , clonidine ( 100 microg ) ( n = 19 ) , or placebo ( n = 20 ) orally . In addition to primary outcomes of pain intensity and analgesic consumption , secondary outcome measures included postoperative state anxiety . In anxious patients 6 hours after surgery , the number of patients needed to be to prevent moderate to intense pain during the first 24 hours after surgery was 1.52 ( 95 % CI , 1.14 to 6.02 ) and 1.64 ( 95 % CI , 1.29 to 5.93 ) , respectively , in the melatonin and clonidine groups compared with placebo . Also , the anxiolytic effect of melatonin and clonidine result ed in reduced postoperative morphine consumption by more than 30 % . However , in the mildly anxious , it was not observed the treatment effect on pain . PERSPECTIVES The preoperative anxiolysis with melatonin or clonidine reduced postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy . The effects these 2 drugs were equivalent and greater than with placebo Background and objective : To compare the perioperative effects of melatonin and midazolam given in premedication , on sedation , orientation , anxiety scores and psychomotor performance . Methods : Exogenous administration of melatonin not only facilitates the onset of sleep but also improves its quality . A prospect i ve , r and omized , double-blind , placebo-controlled study was performed in 66 patients undergoing laparoscopic cholecystectomy . Patients were given melatonin 5 mg , midazolam 15 mg or placebo , 90 min before anaesthesia , sublingually . Sedation , orientation and anxiety were quantified before ; 10 , 30 , 60 and 90 min after premedication ; and 15 , 30 , 60 and 90 min after admission to the recovery room . Neurocognitive performance was evaluated at these times , using the Trail Making A and B and Word Fluency tests . The differences between the groups were analysed by ANOVA . Two-way comparisons were performed by Scheffé analysis . Sedation and amnesia were analysed by the χ2 test . Results : Patients who received premedication with either melatonin or midazolam had a significant increase in sedation and decrease in anxiety before operation compared with controls . After operation , there was no difference in sedation scores of all groups . Whereas , 30 , 60 and 90 min after premedication the melatonin and midazolam groups exhibited a significantly poorer performance in Trail Making A and B tests compared with placebo , there were no significant differences among the groups in terms of neuropsychological performance after the operation . Amnesia was notable only in the midazolam group for one preoperative event . Conclusion : Melatonin premedication was associated with preoperative anxiolysis and sedation without postoperative impairment of psychomotor performance We design ed this prospect i ve , r and omized , double-blinded , placebo-controlled study to compare the perioperative effects of different doses of melatonin and midazolam . Doses of 0.05 , 0.1 , or 0.2 mg/kg sublingual midazolam or melatonin or placebo were given to 84 women , approximately 100 min before a st and ard anesthetic . Sedation , anxiety , and orientation were quantified before , 10 , 30 , 60 , and 90 min after premedication , and 15 , 30 , 60 , and 90 min after admission to the recovery room . Psychomotor performance of the patient was evaluated at these times also , by using the digit-symbol substitution test and Trieger dot test . Patients who received premedication with either midazolam or melatonin had a significant decrease in anxiety levels and increase in levels of sedation preoperatively compared with control subjects . Patients in the three midazolam groups experienced significant psychomotor impairment in the preoperative period compared with melatonin or placebo . After operation , patients who received 0.2 mg/kg midazolam premedication had increased levels of sedation at 90 min compared with 0.05 and 0.1 mg/kg melatonin groups . In addition , patients in the three midazolam groups had impairment of performance on the digit-symbol substitution test at all times compared with the 0.05 mg/kg melatonin group . Premedication with 0.05 mg/kg melatonin was associated with preoperative anxiolysis and sedation without impairment of cognitive and psychomotor skills or affecting the quality of recovery . Implication s Premedication with 0.05 mg/kg melatonin was associated with preoperative anxiolysis and sedation without impairment of cognitive and psychomotor skills or affecting the quality of recovery BACKGROUND : Melatonin has sedative , analgesic , antiinflammatory , antioxidative , and chronobiotic effects . We determined the impact of oral melatonin premedication on anxiolysis , analgesia , and the potency of the rest/activity circadian rhythm . METHODS : This r and omized , double-blind , placebo-controlled study included 33 patients , ASA physical status I – II , undergoing abdominal hysterectomy . Patients were r and omly assigned to receive either oral melatonin 5 mg ( n = 17 ) or placebo ( n = 16 ) the night before and 1 h before surgery . The analysis instruments were the Visual Analog Scale , the State-Trait Anxiety Inventory , and the actigraphy . RESULTS : The number of patients that needed to be treated to prevent one additional patient reporting high postoperative anxiety and moderate to intense pain in the first 24 postoperative hours was 2.53 ( 95 % CI , 1.41–12.22 ) and 2.20 ( 95 % CI , 1.26–8.58 ) , respectively . The number-needed-to-treat was 3 ( 95 % CI , 1.35–5.0 ) to prevent high postoperative anxiety in patients with moderate to intense pain , when compared with 7.5 ( 95 % CI , 1.36–∞ ) in the absence of pain or mild pain . Also , the treated patients required less morphine by patient-controlled analgesia , as assessed by repeated measures ANOVA ( F[1,31 ] = 6.05 , P = 0.02 ) . The rest/activity cycle , assessed by actigraphy , showed that the rhythmicity percentual of 24 h was higher in the intervention group in the first week after discharge ( [ 21.16 ± 8.90 ] versus placebo [ 14.00 ± 7.10 ] ; [ t = −2.41 , P = 0.02 ] ) . CONCLUSIONS : This finding suggested that preoperative melatonin produced clinical ly relevant anxiolytic and analgesic effects , especially in the first 24 postoperative hours . Also , it improved the recovery of the potency of the rest/activity circadian rhythm |
1,904 | 28,439,881 | The control group received either a flavanol-free product ( n = 26 treatment comparisons ) or a low-flavanol-containing cocoa powder ( range 6.4 to 88 mg flavanols ( mean = 55 mg , 13 treatment comparisons ; 259 mg , 1 trial).Meta-analyses of the 40 treatment comparisons involving 1804 mainly healthy participants revealed a small but statistically significant blood pressure-reducing effect of flavanol-rich cocoa products compared with control in trials of two to 18 weeks duration ( mean nine weeks):Mean difference systolic blood pressure ( SBP ) ( 95 % confidence interval ( CI ) : -1.76 ( -3.09 to -0.43 ) mmHg , P = 0.009 , n = 40 treatment comparisons , 1804 participants ; Mean difference diastolic blood pressure ( DBP ) ( 95 % CI ) : -1.76 ( -2.57 to -0.94 ) mmHg , P < 0.001 , n = 39 treatment comparisons , 1772 participants .Baseline blood pressure may play a role in the effect of cocoa on blood pressure .
While systolic blood pressure was reduced significantly by 4 mmHg in hypertensive people ( n = 9 treatment comparisons , 401 participants ) , and tended to be lowered in prehypertensive people ( n= 8 treatment comparisons , 340 participants ) , there was no significant difference in normotensive people ( n = 23 treatment comparisons , 1063 participants ) ; however , the test for subgroup differences was of borderline significance ( P = 0.08 ; I2 = 60 % ) , requiring further research to confirm the findings .Subgroup meta- analysis by blinding suggested a trend towards greater blood pressure reduction in unblinded trials compared to double-blinded trials , albeit statistically not significant .
Subgroup analysis by type of control ( flavanol-free versus low-flavanol control ) did not reveal a significant difference .
This review provides moderate- quality evidence that flavanol-rich chocolate and cocoa products cause a small ( 2 mmHg ) blood pressure-lowering effect in mainly healthy adults in the short term .
These findings are limited by the heterogeneity between trials , which could not be explained by prespecified subgroup analyses , including blinding , flavanol content of the control groups , age of participants , or study duration . | BACKGROUND High blood pressure is an important risk factor for cardiovascular disease , contributing to about 50 % of cardiovascular events worldwide and 37 % of cardiovascular-related deaths in Western population s. Epidemiological studies suggest that cocoa-rich products reduce the risk of cardiovascular disease .
Flavanols found in cocoa have been shown to increase the formation of endothelial nitric oxide which promotes vasodilation and therefore blood pressure reduction .
Here we up date previous meta-analyses on the effect of cocoa on blood pressure .
OBJECTIVES To assess the effects on blood pressure of chocolate or cocoa products versus low-flavanol products or placebo in adults with or without hypertension when consumed for two weeks or longer . | Evidence suggests that flavonoid-containing diets reduce cardiovascular risk , but the mechanisms responsible are unclear . In the present study , we sought to determine the effect of flavanol-rich cocoa on vascular function in individuals with CAD ( coronary artery disease ) . Forty subjects ( 61+/-8 years ; 30 male ) with CAD were recruited to a 6-week r and omized double-blind placebo-controlled study . Subjects consumed either a flavanol-rich chocolate bar and cocoa beverage daily ( total flavanols , 444 mg/day ) or matching isocaloric placebos daily ( total flavanols , 19.6 mg/day ) for 6 weeks . Brachial artery FMD ( flow-mediated dilation ) and SAC ( systemic arterial compliance ) were assessed at baseline , 90 min following the first beverage and after 3 and 6 weeks of daily consumption . Soluble cellular adhesion molecules and FBF ( forearm blood flow ) responses to ACh ( acetylcholine chloride ; 3 - 30 microg/min ) and SNP ( sodium nitroprusside ; 0.3 - 3 microg/min ) infusions , forearm ischaemia and isotonic forearm exercise were assessed at baseline and after 6 weeks . FMD , SAC and FBF responses did not differ between groups at baseline . No acute or chronic changes in FMD or SAC were seen in either group . No difference in soluble cellular adhesion molecules , FBF responses to ischaemia , exercise , SNP or ACh was seen in the group receiving flavanol-rich cocoa between baseline and 6 weeks . These data suggest that over a 6-week period , flavanol-rich cocoa does not modify vascular function in patients with established CAD AIMS Flavanol-rich chocolate ( FRC ) is beneficial for vascular and platelet function by increasing nitric oxide bioavailability and decreasing oxidative stress . Congestive heart failure ( CHF ) is characterized by impaired endothelial and increased platelet reactivity . As statins are ineffective in CHF , alternative therapies are a clinical need . We therefore investigated whether FRC might improve cardiovascular function in patients with CHF . METHODS AND RESULTS Twenty patients with CHF were enrolled in a double-blind , r and omized placebo-controlled trial , comparing the effect of commercially available FRC with cocoa-liquor-free control chocolate ( CC ) on endothelial and platelet function in the short term ( 2 h after ingestion of a chocolate bar ) and long term ( 4 weeks , two chocolate bars/day ) . Endothelial function was assessed non-invasively by flow-mediated vasodilatation of the brachial artery . Flow-mediated vasodilatation significantly improved from 4.98 ± 1.95 to 5.98 ± 2.32 % ( P = 0.045 and 0.02 for between-group changes ) 2h after intake of FRC to 6.86 ± 1.76 % after 4 weeks of daily intake ( P = 0.03 and 0.004 for between groups ) . No effect on endothelial-independent vasodilatation was observed . Platelet adhesion significantly decreased from 3.9 ± 1.3 to 3.0 ± 1.3 % ( P = 0.03 and 0.05 for between groups ) 2 h after FRC , an effect that was not sustained at 2 and 4 weeks . Cocoa-liquor-free CC had no effect , either on endothelial function or on platelet function . Blood pressure and heart rate did not change in either group . CONCLUSION Flavanol-rich chocolate acutely improves vascular function in patients with CHF . A sustained effect was seen after daily consumption over a 4-week period , even after 12 h abstinence . These beneficial effects were paralleled by an inhibition of platelet function in the presence of FRC only The consumption of cocoa and dark chocolate is associated with a lower risk of CVD , and improvements in endothelial function may mediate this relationship . Less is known about the effects of cocoa/chocolate on the augmentation index ( AI ) , a measure of vascular stiffness and vascular tone in the peripheral arterioles . We enrolled thirty middle-aged , overweight adults in a r and omised , placebo-controlled , 4-week , cross-over study . During the active treatment ( cocoa ) period , the participants consumed 37 g/d of dark chocolate and a sugar-free cocoa beverage ( total cocoa = 22 g/d , total flavanols ( TF ) = 814 mg/d ) . Colour-matched controls included a low-flavanol chocolate bar and a cocoa-free beverage with no added sugar ( TF = 3 mg/d ) . Treatments were matched for total fat , saturated fat , carbohydrates and protein . The cocoa treatment significantly increased the basal diameter and peak diameter of the brachial artery by 6 % ( + 2 mm ) and basal blood flow volume by 22 % . Substantial decreases in the AI , a measure of arterial stiffness , were observed in only women . Flow-mediated dilation and the reactive hyperaemia index remained unchanged . The consumption of cocoa had no effect on fasting blood measures , while the control treatment increased fasting insulin concentration and insulin resistance ( P= 0·01 ) . Fasting blood pressure ( BP ) remained unchanged , although the acute consumption of cocoa increased resting BP by 4 mmHg . In summary , the high-flavanol cocoa and dark chocolate treatment was associated with enhanced vasodilation in both conduit and resistance arteries and was accompanied by significant reductions in arterial stiffness in women Cocoa flavanol ( CF ) intake improves endothelial function in patients with cardiovascular risk factors and disease . We investigated the effects of CF on surrogate markers of cardiovascular health in low risk , healthy , middle-aged individuals without history , signs or symptoms of CVD . In a 1-month , open-label , one-armed pilot study , bi-daily ingestion of 450 mg of CF led to a time-dependent increase in endothelial function ( measured as flow-mediated vasodilation ( FMD ) ) that plateaued after 2 weeks . Subsequently , in a r and omised , controlled , double-masked , parallel-group dietary intervention trial ( Clinical trials.gov : NCT01799005 ) , 100 healthy , middle-aged ( 35–60 years ) men and women consumed either the CF-containing drink ( 450 mg ) or a nutrient-matched CF-free control bi-daily for 1 month . The primary end point was FMD . Secondary end points included plasma lipids and blood pressure , thus enabling the calculation of Framingham Risk Scores and pulse wave velocity . At 1 month , CF increased FMD over control by 1·2 % ( 95 % CI 1·0 , 1·4 % ) . CF decreased systolic and diastolic blood pressure by 4·4 mmHg ( 95 % CI 7·9 , 0·9 mmHg ) and 3·9 mmHg ( 95 % CI 6·7 , 0·9 mmHg ) , pulse wave velocity by 0·4 m/s ( 95 % CI 0·8 , 0·04 m/s ) , total cholesterol by 0·20 mmol/l ( 95 % CI 0·39 , 0·01 mmol/l ) and LDL-cholesterol by 0·17 mmol/l ( 95 % CI 0·32 , 0·02 mmol/l ) , whereas HDL-cholesterol increased by 0·10 mmol/l ( 95 % CI 0·04 , 0·17 mmol/l ) . By applying the Framingham Risk Score , CF predicted a significant lowering of 10-year risk for CHD , myocardial infa rct ion , CVD , death from CHD and CVD . In healthy individuals , regular CF intake improved accredited cardiovascular surrogates of cardiovascular risk , demonstrating that dietary flavanols have the potential to maintain cardiovascular health even in low-risk subjects Consumption of flavanol-rich dark chocolate ( DC ) has been shown to decrease blood pressure ( BP ) and insulin resistance in healthy subjects , suggesting similar benefits in patients with essential hypertension ( EH ) . Therefore , we tested the effect of DC on 24-hour ambulatory BP , flow-mediated dilation ( FMD ) , and oral glucose tolerance tests ( OGTTs ) in patients with EH . After a 7-day chocolate-free run-in phase , 20 never-treated , grade I patients with EH ( 10 males ; 43.7±7.8 years ) were r and omized to receive either 100 g per day DC ( containing 88 mg flavanols ) or 90 g per day flavanol-free white chocolate ( WC ) in an isocaloric manner for 15 days . After a second 7-day chocolate-free period , patients were crossed over to the other treatment . Noninvasive 24-hour ambulatory BP , FMD , OGTT , serum cholesterol , and markers of vascular inflammation were evaluated at the end of each treatment . The homeostasis model assessment of insulin resistance ( HOMA-IR ) , quantitative insulin sensitivity check index ( QUICKI ) , and insulin sensitivity index ( ISI ) were calculated from OGTT values . Ambulatory BP decreased after DC ( 24-hour systolic BP −11.9±7.7 mm Hg , P<0.0001 ; 24-hour diastolic BP −8.5±5.0 mm Hg , P<0.0001 ) but not WC . DC but not WC decreased HOMA-IR ( P<0.0001 ) , but it improved QUICKI , ISI , and FMD . DC also decreased serum LDL cholesterol ( from 3.4±0.5 to 3.0±0.6 mmol/L ; P<0.05 ) . In summary , DC decreased BP and serum LDL cholesterol , improved FMD , and ameliorated insulin sensitivity in hypertensives . These results suggest that , while balancing total calorie intake , flavanols from cocoa products may provide some cardiovascular benefit if included as part of a healthy diet for patients with EH To assess whether antioxidant , anti-inflammatory and other cardio-protective effects attributed to cocoa are achieved when regularly consuming moderate amounts of a flavanol-rich soluble cocoa product , a non-r and omized , controlled , crossover , free-living study was carried out in healthy ( n = 24 ; 25.9 ± 5.6 years ) and moderately hypercholesterolemic ( 200 - 240 mg dL(-1 ) ; n = 20 ; 30.0 ± 10.3 years ) volunteers . Participants consumed two servings per day ( 7.5 g per serving ) of a soluble cocoa product ( providing 45.3 mg flavanols per day ) in milk , which was compared with consuming only milk during a 4 week period . The effects on systolic and diastolic blood pressure and heart rate were determined , as well as on serum lipid and lipoprotein profiles , interleukins (IL)-1β , IL-6 , IL-8 , IL-10 , tumor necrosis factor-α ( TNF-α ) , monocyte chemoattractant protein-1 ( MCP-1 ) , vascular ( VCAM-1 ) and intercellular cell adhesion molecules ( ICAM-1 ) , serum malondialdehyde ( MDA ) , carbonyl groups ( CG ) , ferric reducing/antioxidant power ( FRAP ) , oxygen radical absorbance capacity ( ORAC ) , and free radical scavenging capacity ( ABTS ) . During the study , the volunteers ' diets and physical activity were also evaluated , as well as any changes in weight , skin folds , circumferences and related anthropometric parameters . Cocoa and certain polyphenol-rich fruits and vegetables and their derivatives were restricted . After consuming the cocoa product positive effects were observed such as an increase in serum HDL-C ( p < 0.001 ) and dietary fiber intake ( p = 0.050 ) , whereas IL-10 decreased ( p = 0.022 ) . Other cardiovascular-related biomarkers and anthropometric parameters were unaffected . We have therefore concluded that regular consumption of this cocoa product in a Spanish-Mediterranean diet may protect against cardiovascular disease in healthy and hypercholesterolemic subjects without producing any weight gain or other anthropometric changes Increased vascular stiffness , endothelial dysfunction , and isolated systolic hypertension are hallmarks of vascular aging . Regular cocoa flavanol ( CF ) intake can improve vascular function in healthy young and elderly at-risk individuals . However , the mechanisms underlying CF bioactivity remain largely unknown . We investigated the effects of CF intake on cardiovascular function in healthy young and elderly individuals without history , signs , or symptoms of cardiovascular disease by applying particular focus on functional endpoints relevant to cardiovascular aging . In a r and omized , controlled , double-masked , parallel-group dietary intervention trial , 22 young ( < 35 years ) and 20 elderly ( 50–80 year ) healthy , male non-smokers consumed either a CF-containing drink ( 450 mg CF ) or nutrient-matched , CF-free control drink bi-daily for 14 days . The primary endpoint was endothelial function as measured by flow-mediated vasodilation ( FMD ) . Secondary endpoints included cardiac output , vascular stiffness , conductance of conduit and resistance arteries , and perfusion in the microcirculation . Following 2 weeks of CF intake , FMD improved in young ( 6.1 ± 0.7 vs. 7.6 ± 0.7 % , p < 0.001 ) and elderly ( 4.9 ± 0.6 vs. 6.3 ± 0.9 % , p < 0.001 ) . Secondary outcomes demonstrated in both groups that CF intake decreased pulse wave velocity and lowered total peripheral resistance , and increased arteriolar and microvascular vasodilator capacity , red cell deformability , and diastolic blood pressure , while cardiac output remained affected . In the elderly , baseline systolic blood pressure was elevated , driven by an arterial-stiffness-related augmentation . CF intake decreased aortic augmentation index ( −9 % ) and thus systolic blood pressure ( −7 mmHg ; Clinical trials.gov : NCT01639781 ) . CF intake reverses age-related burden of cardiovascular risk in healthy elderly , highlighting the potential of dietary flavanols to maintain cardiovascular health Background : Sleep deprivation is a risk factor for cardiovascular disease . Cocoa flavonoids exert cardiovascular benefits and neuroprotection . Whether chocolate consumption may mitigate detrimental effects of sleep loss on cognitive performance and cardiovascular parameters has never been studied . Aim : We investigated the effects of flavanol-rich chocolate consumption on cognitive skills and cardiovascular parameters after sleep deprivation . Methods : Thirty-two healthy participants underwent two baseline sessions after one night of undisturbed sleep and two experimental sessions after one night of total sleep deprivation . Two hours before each testing session , participants were r and omly assigned to consume high or poor flavanol chocolate bars . During the tests were evaluated , the Psychomotor Vigilance Task and a working memory task , office SBP and DBP , flow-mediated dilation and pulse-wave velocity . Results : Sleep deprivation increased SBP/DBP . SBP/DBP and pulse pressure were lower after flavanol-rich treatment respect to flavanol-poor treatment ( SBP : 116.9 ± 1.6 vs. 120.8 ± 1.9 mmHg , respectively , P = 0.00005 ; DBP : 70.5 ± 1.2 vs. 72.3 ± 1.2 mmHg , respectively , P = 0.01 ; pulse pressure : 46.4 ± 1.3 vs. 48.4 ± 1.5 mmHg , P = 0.004 ) . Sleep deprivation impaired flow-mediated dilation ( 5.5 ± 0.5 vs. 6.5 ± 0.6 % , P = 0.02 ) , flavanol-rich , but not flavanol-poor chocolate counteracted this alteration ( flavanol-rich/flavanol-poor chocolate : 7.0 ± 0.6 vs. 5.0 ± 0.4 % , P = 0.000001 ) . Flavanol-rich chocolate mitigated the pulse-wave velocity increase ( P = 0.001 ) . Flavanol-rich chocolate preserved working memory accuracy in women after sleep deprivation . Flow-mediated dilation correlated with working memory performance accuracy in the sleep condition ( P = 0.04 ) . Conclusion : Flavanol-rich chocolate counteracted vascular impairment after sleep deprivation and restored working memory performance . Improvement in cognitive performance could be because of the effects of cocoa flavonoids on blood pressure and peripheral and central blood flow Abstract Aims Poor prognosis in chronic heart failure ( HF ) is linked to endothelial dysfunction for which there is no specific treatment currently available . Previous studies have shown reproducible improvements in endothelial function with cocoa flavanols , but the clinical benefit of this effect in chronic HF has yet to be determined . Therefore , the aim of this study was to assess the potential therapeutic value of a high dose of cocoa flavanols in patients with chronic HF , by using reductions in N‐terminal pro‐B‐type natriuretic peptide ( NT‐proBNP ) as an index of improved cardiac function . Methods and results Thirty‐two patients with chronic HF , stable on guideline ‐directed medical therapy , were r and omized to consume 50 g/day of high‐flavanol dark chocolate ( HFDC ; 1064 mg of flavanols/day ) or low‐flavanol dark chocolate ( LFDC ; 88 mg of flavanols/day ) for 4 weeks and then crossed over to consume the alternative dark chocolate for a further 4 weeks . Twenty‐four patients completed the study . After 4 weeks of HFDC , NT‐proBNP ( mean decrease % ± st and ard deviation ) was significantly reduced compared with baseline ( −44 ± 69 % ) , LFDC ( −33 ± 72 % ) , and follow‐up ( −41 ± 77 % ) values . HFDC also reduced diastolic blood pressure compared with values after LFDC ( −6.7 ± 10.1 mmHg ) . Conclusions Reductions in blood pressure and NT‐proBNP after HFDC indicate decreased vascular resistance result ing in reduced left ventricular afterload . These effects warrant further investigation in patients with chronic HF Numerous studies indicate that polyphenol-rich chocolate reduces fasting blood glucose , blood pressure ( BP ) and total cholesterol in healthy individuals and hypertensives with or without glucose intolerance . The aim of the present study was to investigate the effect of two doses of polyphenol-rich dark chocolate ( DC ) on fasting capillary whole blood glucose , total cholesterol and BP and to examine whether improvements in these parameters are associated with changes in adrenocorticoid excretion in overweight and obese individuals . The study used a r and omised , single-blind , cross-over design where fourteen overweight and obese subjects were r and omised to either take 20 g DC with 500 mg polyphenols then 20 g DC with 1000 mg polyphenols or vice-versa . Participants followed each diet for 2 weeks separated by a 1-week washout period . It was observed that the 500 mg polyphenol dose was equally effective in reducing fasting blood glucose levels , systolic BP ( SBP ) and diastolic BP ( DBP ) as the 1000 mg polyphenol dose suggesting that a saturation effect might occur with increasing dose of polyphenols . There was also a trend towards a reduction in urinary free cortisone levels with both groups although it did not reach statistical significance . No changes in anthropometrical measurements were seen . We suggest that more research is required to investigate the mechanism(s ) by which polyphenol-rich foods influence health BACKGROUND Studies suggest cardioprotective benefits of dark chocolate containing cocoa . OBJECTIVE This study examines the acute effects of solid dark chocolate and liquid cocoa intake on endothelial function and blood pressure in overweight adults . DESIGN R and omized , placebo-controlled , single-blind crossover trial of 45 healthy adults [ mean age : 53 y ; mean body mass index ( in kg/m(2 ) ) : 30 ] . In phase 1 , subjects were r and omly assigned to consume a solid dark chocolate bar ( containing 22 g cocoa powder ) or a cocoa-free placebo bar ( containing 0 g cocoa powder ) . In phase 2 , subjects were r and omly assigned to consume sugar-free cocoa ( containing 22 g cocoa powder ) , sugared cocoa ( containing 22 g cocoa powder ) , or a placebo ( containing 0 g cocoa powder ) . RESULTS Solid dark chocolate and liquid cocoa ingestion improved endothelial function ( measured as flow-mediated dilatation ) compared with placebo ( dark chocolate : 4.3 + /- 3.4 % compared with -1.8 + /- 3.3 % ; P < 0.001 ; sugar-free and sugared cocoa : 5.7 + /- 2.6 % and 2.0 + /- 1.8 % compared with -1.5 + /- 2.8 % ; P < 0.001 ) . Blood pressure decreased after the ingestion of dark chocolate and sugar-free cocoa compared with placebo ( dark chocolate : systolic , -3.2 + /- 5.8 mm Hg compared with 2.7 + /- 6.6 mm Hg ; P < 0.001 ; and diastolic , -1.4 + /- 3.9 mm Hg compared with 2.7 + /- 6.4 mm Hg ; P = 0.01 ; sugar-free cocoa : systolic , -2.1 + /- 7.0 mm Hg compared with 3.2 + /- 5.6 mm Hg ; P < 0.001 ; and diastolic : -1.2 + /- 8.7 mm Hg compared with 2.8 + /- 5.6 mm Hg ; P = 0.014 ) . Endothelial function improved significantly more with sugar-free than with regular cocoa ( 5.7 + /- 2.6 % compared with 2.0 + /- 1.8 % ; P < 0.001 ) . CONCLUSIONS The acute ingestion of both solid dark chocolate and liquid cocoa improved endothelial function and lowered blood pressure in overweight adults . Sugar content may attenuate these effects , and sugar-free preparations may augment them Previous studies with plant sterols ( PS ) and cocoa flavanols ( CF ) provide support for their dietary use in maintaining cardiovascular health . This double-blind , placebo-controlled , cross-over study evaluated the efficacy of daily consumption of a cocoa flavanol-containing dark chocolate bar with added PS on serum lipids , blood pressure , and other circulating cardiovascular health markers in a population with elevated serum cholesterol . We recruited 49 adults ( 32 women , 17 men ) with serum total cholesterol concentrations of 5.20 - 7.28 mmol/L and blood pressure of < or = 159/99 mm Hg . Following a 2-wk lead-in utilizing the AHA style diet , participants were r and omized into 2 groups and instructed to consume 2 cocoa flavanol-containing dark chocolate bars per day with ( 1.1 g sterol esters per bar ) or without PS . Each 419-kJ bar was nutrient-matched and contained approximately 180 mg CF . Participants consumed 1 bar 2 times per day for 4 wk then switched to the other bar for an additional 4 wk . Serum lipids and other cardiovascular markers were measured at baseline and after 4 and 8 wk . Blood pressure was measured every 2 wk . Regular consumption of the PS-containing chocolate bar result ed in reductions of 2.0 and 5.3 % in serum total and LDL cholesterol ( P < 0.05 ) , respectively . Consumption of CF also reduced systolic blood pressure at 8 wk ( -5.8 mm Hg ; P < 0.05 ) . Results indicate that regular consumption of chocolate bars containing PS and CF as part of a low-fat diet may support cardiovascular health by lowering cholesterol and improving blood pressure BACKGROUND Numerous studies indicate that flavanols may exert significant vascular protection because of their antioxidant properties and increased nitric oxide bioavailability . In turn , nitric oxide bioavailability deeply influences insulin-stimulated glucose uptake and vascular tone . Thus , flavanols may also exert positive metabolic and pressor effects . OBJECTIVE The objective was to compare the effects of either dark or white chocolate bars on blood pressure and glucose and insulin responses to an oral-glucose-tolerance test in healthy subjects . DESIGN After a 7-d cocoa-free run-in phase , 15 healthy subjects were r and omly assigned to receive for 15 d either 100 g dark chocolate bars , which contained approximately 500 mg polyphenols , or 90 g white chocolate bars , which presumably contained no polyphenols . Successively , subjects entered a further cocoa-free washout phase of 7 d and then were crossed over to the other condition . Oral-glucose-tolerance tests were performed at the end of each period to calculate the homeostasis model assessment of insulin resistance ( HOMA-IR ) and the quantitative insulin sensitivity check index ( QUICKI ) ; blood pressure was measured daily . RESULTS HOMA-IR was significantly lower after dark than after white chocolate ingestion ( 0.94 + /- 0.42 compared with 1.72 + /- 0.62 ; P < 0.001 ) , and QUICKI was significantly higher after dark than after white chocolate ingestion ( 0.398 + /- 0.039 compared with 0356 + /- 0.023 ; P = 0.001 ) . Although within normal values , systolic blood pressure was lower after dark than after white chocolate ingestion ( 107.5 + /- 8.6 compared with 113.9 + /- 8.4 mm Hg ; P < 0.05 ) . CONCLUSION Dark , but not white , chocolate decreases blood pressure and improves insulin sensitivity in healthy persons Flavanols from chocolate appear to increase nitric oxide bioavailability , protect vascular endothelium , and decrease cardiovascular disease ( CVD ) risk factors . We sought to test the effect of flavanol-rich dark chocolate ( FRDC ) on endothelial function , insulin sensitivity , beta-cell function , and blood pressure ( BP ) in hypertensive patients with impaired glucose tolerance ( IGT ) . After a run-in phase , 19 hypertensives with IGT ( 11 males , 8 females ; 44.8 + /- 8.0 y ) were r and omized to receive isocalorically either FRDC or flavanol-free white chocolate ( FFWC ) at 100 g/d for 15 d. After a wash-out period , patients were switched to the other treatment . Clinical and 24-h ambulatory BP was determined by sphygmometry and oscillometry , respectively , flow-mediated dilation ( FMD ) , oral glucose tolerance test , serum cholesterol and C-reactive protein , and plasma homocysteine were evaluated after each treatment phase . FRDC but not FFWC ingestion decreased insulin resistance ( homeostasis model assessment of insulin resistance ; P < 0.0001 ) and increased insulin sensitivity ( quantitative insulin sensitivity check index , insulin sensitivity index ( ISI ) , ISI(0 ) ; P < 0.05 ) and beta-cell function ( corrected insulin response CIR(120 ) ; P = 0.035 ) . Systolic ( S ) and diastolic ( D ) BP decreased ( P < 0.0001 ) after FRDC ( SBP , -3.82 + /- 2.40 mm Hg ; DBP , -3.92 + /- 1.98 mm Hg ; 24-h SBP , -4.52 + /- 3.94 mm Hg ; 24-h DBP , -4.17 + /- 3.29 mm Hg ) but not after FFWC . Further , FRDC increased FMD ( P < 0.0001 ) and decreased total cholesterol ( -6.5 % ; P < 0.0001 ) , and LDL cholesterol ( -7.5 % ; P < 0.0001 ) . Changes in insulin sensitivity ( Delta ISI - Delta FMD : r = 0.510 , P = 0.001 ; Delta QUICKI - Delta FMD : r = 0.502 , P = 0.001 ) and beta-cell function ( Delta CIR(120 ) - Delta FMD : r = 0.400 , P = 0.012 ) were directly correlated with increases in FMD and inversely correlated with decreases in BP ( Delta ISI - Delta 24-h SBP : r = -0.368 , P = 0.022 ; Delta ISI - Delta 24-h DBP r = -0.384 , P = 0.017 ) . Thus , FRDC ameliorated insulin sensitivity and beta-cell function , decreased BP , and increased FMD in IGT hypertensive patients . These findings suggest flavanol-rich , low-energy cocoa food products may have a positive impact on CVD risk factors BACKGROUND In recent years , there has been increased interest in the potential health-related benefits of antioxidant- and phytochemical-rich dark chocolate and cocoa . OBJECTIVE The objective of the study was to examine the short-term ( 6 wk ) effects of dark chocolate and cocoa on variables associated with neuropsychological functioning and cardiovascular health in healthy older adults . DESIGN A double-blind , placebo-controlled , fixed-dose , parallel-group clinical trial was used . Participants ( n = 101 ) were r and omly assigned to receive a 37-g dark chocolate bar and 8 ounces ( 237 mL ) of an artificially sweetened cocoa beverage or similar placebo products each day for 6 wk . RESULTS No significant group ( dark chocolate and cocoa or placebo)-by-trial ( baseline , midpoint , and end-of-treatment assessment s ) interactions were found for the neuropsychological , hematological , or blood pressure variables examined . In contrast , the midpoint and end-of-treatment mean pulse rate assessment s in the dark chocolate and cocoa group were significantly higher than those at baseline and significantly higher than the midpoint and end-of-treatment rates in the control group . Results of a follow-up question naire item on the treatment products that participants believed they had consumed during the trial showed that more than half of the participants in both groups correctly identified the products that they had ingested during the experiment . CONCLUSIONS This investigation failed to support the predicted beneficial effects of short-term dark chocolate and cocoa consumption on any of the neuropsychological or cardiovascular health-related variables included in this research . Consumption of dark chocolate and cocoa was , however , associated with significantly higher pulse rates at 3- and 6-wk treatment assessment BACKGROUND Dietary flavonoids may improve endothelial function and ultimately lead to beneficial cardiovascular effects . OBJECTIVE The objective was to assess whether pure dietary flavonoids can modulate nitric oxide and endothelin-1 production and thereby improve endothelial function . DESIGN A r and omized , placebo-controlled , crossover trial in 12 healthy men was conducted to compare the acute effects of the oral administration of 200 mg quercetin , (-)-epicatechin , or epigallocatechin gallate on nitric oxide , endothelin-1 , and oxidative stress after nitric oxide production was assessed via the measurement of plasma S-nitrosothiols and plasma and urinary nitrite and nitrate concentrations . The effects on oxidative stress were assessed by measuring plasma and urinary F(2)-isoprostanes . Plasma and urinary concentrations of quercetin , (-)-epicatechin , and epigallocatechin gallate were measured to establish the absorption of these flavonoids . RESULTS Relative to water ( control ) , quercetin and (-)-epicatechin result ed in a significant increase in plasma S-nitrosothiols , plasma nitrite , and urinary nitrate concentrations ( P < 0.05 ) , but not in plasma nitrate or urinary nitrite . Epigallocatechin gallate did not alter any of the measures of nitric oxide production . Quercetin and (-)-epicatechin result ed in a significant reduction in plasma endothelin-1 concentration ( P < 0.05 ) , but only quercetin significantly decreased the urinary endothelin-1 concentration . None of the 3 treatments significantly changed plasma or urinary F(2)-isoprostane concentrations . Significant increases in the circulating concentrations of the 3 flavonoids were observed ( P < 0.05 ) after the corresponding treatment . CONCLUSIONS Dietary flavonoids , such as quercetin and (-)-epicatechin , can augment nitric oxide status and reduce endothelin-1 concentrations and may thereby improve endothelial function BACKGROUND Flavonoids may be partly responsible for some health benefits , including antiinflammatory action and a decreased tendency for the blood to clot . An acute dose of flavanols and oligomeric procyanidins from cocoa powder inhibits platelet activation and function over 6 h in humans . OBJECTIVE This study sought to evaluate whether 28 d of supplementation with cocoa flavanols and related procyanidin oligomers would modulate human platelet reactivity and primary hemostasis and reduce oxidative markers in vivo . DESIGN Thirty-two healthy subjects were assigned to consume active ( 234 mg cocoa flavanols and procyanidins/d ) or placebo ( < or = 6 mg cocoa flavanols and procyanidins/d ) tablets in a blinded parallel- design ed study . Platelet function was determined by measuring platelet aggregation , ATP release , and expression of activation-dependent platelet antigens by using flow cytometry . Plasma was analyzed for oxidation markers and antioxidant status . RESULTS Plasma concentrations of epicatechin and catechin in the active group increased by 81 % and 28 % , respectively , during the intervention period . The active group had significantly lower P selectin expression and significantly lower ADP-induced aggregation and collagen-induced aggregation than did the placebo group . Plasma ascorbic acid concentrations were significantly higher in the active than in the placebo group ( P < 0.05 ) , whereas plasma oxidation markers and antioxidant status did not change in either group . CONCLUSIONS Cocoa flavanol and procyanidin supplementation for 28 d significantly increased plasma epicatechin and catechin concentrations and significantly decreased platelet function . These data support the results of acute studies that used higher doses of cocoa flavanols and procyanidins BACKGROUND Epidemiologic studies have suggested that flavonoid intake plays a critical role in the prevention of coronary heart disease . Because atherosclerosis is considered a low- grade inflammatory disease , some feeding trials have analyzed the effects of cocoa ( an important source of flavonoids ) on inflammatory biomarkers , but the results have been controversial . OBJECTIVE The objective was to evaluate the effects of chronic cocoa consumption on cellular and serum biomarkers related to atherosclerosis in high-risk patients . DESIGN Forty-two high-risk volunteers ( 19 men and 23 women ; mean + /- SD age : 69.7 + /- 11.5 y ) were included in a r and omized crossover feeding trial . All subjects received 40 g cocoa powder with 500 mL skim milk/d ( C+M ) or only 500 mL skim milk/d ( M ) for 4 wk . Before and after each intervention period , cellular and serum inflammatory biomarkers related to atherosclerosis were evaluated . RESULTS Adherence to the dietary protocol was excellent . No significant changes in the expression of adhesion molecules on T lymphocyte surfaces were found between the C+M and M groups . However , in monocytes , the expression of VLA-4 , CD40 , and CD36 was significantly lower ( P = 0.005 , 0.028 , and 0.001 , respectively ) after C+M intake than after M intake . In addition , serum concentrations of the soluble endothelium-derived adhesion molecules P-selectin and intercellular adhesion molecule-1 were significantly lower ( both P = 0.007 ) after C+M intake than after M intake . CONCLUSIONS These results suggest that the intake of cocoa polyphenols may modulate inflammatory mediators in patients at high risk of cardiovascular disease . These antiinflammatory effects may contribute to the overall benefits of cocoa consumption against atherosclerosis . This trial was registered in the Current Controlled Trials at London , International St and ard R and omized Controlled Trial Number , at controlled-trials.com as IS RCT N75176807 Flavanol-enriched chocolate consumption increases endothelium-dependent vasodilation . Most research so far has focused on flow-mediated dilation ( FMD ) only ; the effects on other factors relevant to endothelial health , such as inflammation and leukocyte adhesion , have hardly been addressed . We investigated whether consumption of regular dark chocolate also affects other markers of endothelial health , and whether chocolate enrichment with flavanols has additional benefits . In a r and omized double-blind crossover study , the effects of acute and of 4 wk daily consumption of high flavanol chocolate ( HFC ) and normal flavanol chocolate ( NFC ) on FMD , augmentation index ( AIX ) , leukocyte count , plasma cytokines , and leukocyte cell surface molecules in overweight men ( age 45 - 70 yr ) were investigated . Sensory profiles and motivation scores to eat chocolate were also collected . Findings showed that a 4 wk chocolate intake increased FMD by 1 % , which was paralleled by a decreased AIX of 1 % , decreased leukocyte cell count , decreased plasma sICAM1 and sICAM3 , and decreased leukocyte adhesion marker expression ( P<0.05 for time effect ) , with no difference between HFC and NFC consumption . Flavanol enrichment did affect taste and negatively affected motivation to consume chocolate . This study provides new insights on how chocolate affects endothelial health by demonstrating that chocolate consumption , besides improving vascular function , also lowers the adherence capacity of leukocytes in the circulation Background : Dark chocolate derived from the plant ( Theobroma cacao ) is a rich source of flavonoids . Cardioprotective effects including antioxidant properties , inhibition of platelet activity , and activation of endothelial nitric oxide synthase have been ascribed to the cocoa flavonoids . Objective : To investigate the effects of flavonoid-rich dark chocolate on endothelial function , measures of oxidative stress , blood lipids , and blood pressure in healthy adult subjects . Design : The study was a r and omized , double-blind , placebo-controlled design conducted over a 2 week period in 21 healthy adult subjects . Subjects were r and omly assigned to daily intake of high-flavonoid ( 213 mg procyanidins , 46 mg epicatechin ) or low-flavonoid dark chocolate bars ( 46 g , 1.6 oz ) . Results : High-flavonoid chocolate consumption improved endothelium-dependent flow-mediated dilation ( FMD ) of the brachial artery ( mean change = 1.3 ± 0.7 % ) as compared to low-flavonoid chocolate consumption ( mean change = −0.96 ± 0.5 % ) ( p = 0.024 ) . No significant differences were noted in the resistance to LDL oxidation , total antioxidant capacity , 8-isoprostanes , blood pressure , lipid parameters , body weight or body mass index ( BMI ) between the two groups . Plasma epicatechin concentrations were markedly increased at 2 weeks in the high-flavonoid group ( 204.4 ± 18.5 nmol/L , p ≤ 0.001 ) but not in the low-flavonoid group ( 17.5 ± 9 nmol/L , p = 0.99 ) . Conclusion : Flavonoid-rich dark chocolate improves endothelial function and is associated with an increase in plasma epicatechin concentrations in healthy adults . No changes in oxidative stress measures , lipid profiles , blood pressure , body weight or BMI were seen BACKGROUND The aim was to examine the effects of high-cocoa polyphenol-rich chocolate on lipid profiles , weight , blood pressure , glycemic control , and inflammation in individuals with Type 2 diabetes and hypertension . METHODS Sixty individuals [ 32 in dark chocolate group ( DCG ) and 28 in white chocolate group ( WCG ) ] with Type 2 diabetes on stable medication were enrolled in a r and omized , placebo-controlled double-blind study . Subjects were r and omized to consume 25 g DCG or WCG for 8 weeks . Changes in weight , blood pressure , glycemic control , lipid profile , and high sensitive C-reactive protein ( hsCRP ) were measured at the beginning and end of the intervention . This clinical trial was registered at the Iranian registry of clinical trials . RESULTS In DCC group , compared with baseline , serum levels of Apo A-1 ( P = 0.045 ) was increased and fasting blood sugar ( FBS ) ( P = 0.027 ) , hemoglobin A1c ( HbA1c ) ( P = 0.025 ) , Apo B ( P = 0.012 ) and Log of hsCRP ( P = 0.043 ) levels were decreased at the end of study . No changes were seen within the WCG in studied parameters . High polyphenol chocolate consumption compared to white chocolate result ed in significant decrease in of systolic ( −5.93 ± 6.25 vs. −1.07 ± 7.97 mmHg , P = 0.004 ) and diastolic blood pressure ( −6.4 ± 6.25 vs. 0.17 ± 7.9 mmHg , P = 0.002 ) , FBS ( −7.84 ± 19.15 vs. 4.00 ± 20.58 mg/dl , P = 0.019 ) over the course of 8 weeks of daily chocolate consumption neither weight nor body mass index and TG levels altered from baseline . CONCLUSION High polyphenol chocolate is effective in improving TG levels in hypertensive patients with diabetes and decreasing blood pressure and FBS without affecting weight , inflammatory markers , insulin resistance or glycemic control Flavanol consumption is favorably associated with cognitive function . We tested the hypothesis that dietary flavanols might improve cognitive function in subjects with mild cognitive impairment . We conducted a double-blind , parallel arm study in 90 elderly individuals with mild cognitive impairment r and omized to consume once daily for 8 weeks a drink containing ≈990 mg ( high flavanols ) , ≈520 mg ( intermediate flavanols ) , or ≈45 mg ( low flavanols ) of cocoa flavanols per day . Cognitive function was assessed by Mini Mental State Examination , Trail Making Test A and B , and verbal fluency test . At the end of the follow-up period , Mini Mental State Examination was similar in the 3 treatment groups ( P=0.13 ) . The time required to complete Trail Making Test A and Trail Making Test B was significantly ( P<0.05 ) lower in subjects assigned to high flavanols ( 38.10±10.94 and 104.10±28.73 seconds , respectively ) and intermediate flavanols ( 40.20±11.35 and 115.97±28.35 seconds , respectively ) in comparison with those assigned to low flavanols ( 52.60±17.97 and 139.23±43.02 seconds , respectively ) . Similarly , verbal fluency test score was significantly ( P<0.05 ) better in subjects assigned to high flavanols in comparison with those assigned to low flavanols ( 27.50±6.75 versus 22.30±8.09 words per 60 seconds ) . Insulin resistance , blood pressure , and lipid peroxidation also decreased among subjects in the high-flavanol and intermediate-flavanol groups . Changes of insulin resistance explained ≈40 % of composite z score variability through the study period ( partial r2=0.4013 ; P<0.0001 ) . To the best of our knowledge , this is the first dietary intervention study demonstrating that the regular consumption of cocoa flavanols might be effective in improving cognitive function in elderly subjects with mild cognitive impairment . This effect appears mediated in part by an improvement in insulin sensitivity Background Flavanol-rich chocolate and lycopene-rich tomato extract have attracted interest as potential alternative treatment options for hypertension , a known risk factor for cardiovascular morbidity and mortality . Treatment of prehypertension ( SBP 120–139/DBP 80–89 mmHg ) may forestall progression to hypertension . However , there has been only limited research into non-pharmacological treatment options for prehypertension . We investigated the effect of dark chocolate or tomato extract on blood pressure , and their acceptability as an ongoing treatment option in a prehypertensive population . Methods Our trial consisted of two phases : a r and omised controlled three-group-parallel trial over 12 weeks ( phase 1 ) followed by a crossover of the two active treatment arms over an additional 12-week period ( phase 2 ) . Group 1 received a 50 g daily dose of dark chocolate with 70 % cocoa containing 750 mg polyphenols , group 2 were allocated one tomato extract capsule containing 15 mg lycopene per day , and group 3 received one placebo capsule daily over 8 weeks followed by a 4-week washout period . In phase 2 the active treatment groups were crossed over to receive the alternative treatment . Median blood pressure , weight , and abdominal circumference were measured 4-weekly , and other characteristics including physical activity , general health , energy , mood , and acceptability of treatment were assessed by question naire at 0 , 8 and 20 weeks . We analysed changes over time using a linear mixed model , and one time point differences using Kruskal-Wallis , Fisher's-Exact , or t-tests . Results Thirty-six prehypertensive healthy adult volunteers completed the 6-month trial . Blood pressure changes over time within groups and between groups were not significant and independent of treatment . Weight and other characteristics did not change significantly during the trial . However , a marked difference in acceptability between the two treatment forms ( chocolate or capsule ) was revealed ( p < 0.0001 ) . Half of the participants allocated to the chocolate treatment found it hard to eat 50 g of dark chocolate every day and 20 % considered it an unacceptable long-term treatment option , whereas all participants found it easy and acceptable to take a capsule each day for blood pressure . Conclusion Our study did not find a blood pressure lowering effect of dark chocolate or tomato extract in a prehypertensive population . Practicability of chocolate as a long-term treatment option may be limited . Trial registration http://www.anzctr.org.au Identifier : The consumption of a diet rich in certain flavonoids , including the flavanol sub-class , has been associated with a reduced risk for vascular disease . We evaluated the effects of the regular consumption ( 14 d ) of a flavanol-containing milk chocolate ( FCMC ) or cocoa butter chocolate ( CBC ) on variables related to vascular disease risk , oxidative stress and physical activity . Twenty-eight free-living , young ( 18–20 years old ) male soccer players consumed daily 105 g of FCMC ( 168 mg of flavanols ) or CBC ( < 5 mg of flavanols ) , as part of their normal diet . The consumption of FCMC was significantly associated with a decrease in diastolic blood pressure ( -5 mm Hg ) , mean blood pressure ( -5 mm Hg ) , plasma cholesterol ( -11 % ) , LDL-cholesterol ( -15 % ) , malondialdehyde ( -12 % ) , urate ( -11 % ) and lactate dehydrogenase ( LDH ) activity ( -11 % ) , and an increase in vitamin E/cholesterol ( + 12 % ) . No relevant changes in these variables were associated with CBC consumption . No changes in the plasma levels of (-)-epicatechin were observed following analysis of fasting blood sample s. In conclusion , FCMC consumption was associated with changes in several variables often associated with cardiovascular health and oxidant stress . The presence of significant quantities of flavanols in FCMC is likely to have been one of the contributing factors to these results Background : Cocoa flavonoids exert beneficial vascular effects and reduce the risk of cardiovascular morbidity and mortality . Nevertheless , the involved mechanisms have not been clarified and no study has yet focused on the dose – response effects . Objectives : We aim ed to investigate the effects of different doses of cocoa flavonoids on flow-mediated dilation ( FMD ) , endothelin-1 ( ET-1 ) , pulse wave velocity ( PWV ) , and SBP and DBP . Design : According to a r and omized , double-blind , controlled , cross-over design , 20 healthy volunteers ( 1.5 % improvement in FMD in 20 individuals : 0.99 at alpha = 0.05 ) were assigned to receive either five treatments with daily intake of 10 g cocoa ( 0 , 80 , 200 , 500 and 800 mg cocoa flavonoids/day ) in five periods lasting 1 week each . Results : Cocoa dose-dependently increased FMD from 6.2 % ( control ) to 7.3 , 7.6 , 8.1 and 8.2 % after the different flavonoid doses , respectively ( P < 0.0001 ) . Compared with the control , even 80 mg cocoa flavonoids per day increased FMD ( P < 0.0001 ) . Cocoa dose-dependently decreased PWV ( P < 0.0001 ) . Cocoa intake decreased office blood pressure ( BP ) ( SBP : −4.8 ± 1.03 mmHg , P < 0.0001 ; DBP : −3.03 ± 1.07 mmHg , P = 0.0011 ) . With respect to control , cocoa ingestion decreased 24-h ( P = 0.05 ) and daytime ( P = 0.038 ) SBP , and 24-h ( P = 0.0064 ) , daytime ( P = 0.0088 ) and night-time ( P = 0.0352 ) pulse pressure . Compared with the control , cocoa dose-dependently decreased ET-1 levels [ from 17.1 ( control ) to 15.2 , 14.5 , 14.2 and 14.1 pg/ml , after the different flavonoid doses , respectively ( P for treatment < 0.05 ) ] . Compared with the control , significant changes were observed for all doses of flavonoids ( ET-1 ; P < 0.05 ) . Conclusion : Our study showed for the first time that cocoa dose-dependently improved FMD and decreased PWV and ET-1 also by ameliorating office and monitored BP . Our findings are clinical ly relevant , suggesting cocoa , with very low calorie intake , might be reasonably incorporated into a dietary approach , representing a consistent tool in cardiovascular prevention BACKGROUND Evidence from dietary intervention studies shows that the intake of flavanols and procyanidins can be beneficial for cardiovascular health . Nevertheless , there is a clear need for advancing our underst and ing with regard to safe amounts of intake for these bioactives . OBJECTIVE The aim was to investigate in healthy adults the effects of cocoa flavanol ( CF ) intake amount and intake duration on blood pressure , platelet function , metabolic variables , and potential adverse events ( AEs ) . DESIGN This investigation consisted of 2 parts . Part 1 was an open-label , intake-amount escalation study , in which 34 healthy adults ( aged 35 - 55 y ) consumed escalating amounts of CFs , ranging from 1000 to 2000 mg/d over 6 wk . Primary outcomes were blood pressure and platelet function , select metabolic variables , and the occurrence and severity of AEs . Secondary outcomes included plasma concentrations of CF-derived metabolites and methylxanthines . On the basis of the outcomes of study part 1 , and assessing the same outcome measures , part 2 of this investigation was a controlled , r and omized , double-masked , 2-parallel-arm dietary intervention study in which healthy participants ( aged 35 - 55 y ) were asked to consume for 12 consecutive weeks up to 2000 mg CFs/d ( n = 46 ) or a CF-free control ( n = 28 ) . RESULTS Daily intake of up to 2000 mg CFs/d for 12 wk was not associated with significant changes in blood pressure or platelet function compared with CF-free controls in normotensive , healthy individuals who exhibited a very low risk of cardiovascular disease . There were no clinical ly relevant changes in the metabolic variables assessed in either of the groups . AEs reported were classified as mild in severity and did not significantly differ between study arms . CONCLUSION The consumption of CFs in amounts up to 2000 mg/d for 12 wk was well tolerated in healthy men and women . This trial was registered at clinical trials.gov as NCT02447770 ( part 1 ) and NCT02447783 ( part 2 ) Impaired endothelial vasodilatation may contribute to the exaggerated blood pressure ( BP ) responses to exercise in individuals who are overweight/obese . The present study investigated whether consumption of cocoa flavanols , which improve endothelium-dependent flow-mediated dilatation ( FMD ) , can modify BP responsiveness to exercise . Twenty-one volunteers ( eight females and thirteen males , 54.9 ( se 2.2 ) years , BMI 31.6 ( se 0.8 ) kg/m2 , systolic BP 134 ( se 2 ) mmHg , diastolic BP ( DBP ) 87 ( se 2 ) mmHg ) were r and omised to consume single servings of either a high-flavanol ( HF , 701 mg ) or a low-flavanol ( LF , 22 mg ) cocoa beverage in a double-blind , cross-over design with 3 - 7-d washout between treatments . Two hours after cocoa consumption , FMD was measured , followed by continuous beat-to-beat assessment ( Finapres ) of BP before and during 10 min of cycling at 75 % of age-predicted maximum heart rate . Averaged data from two assessment s on each type of beverage were compared by analysis of covariance using pre-exercise BP as the covariate . Pre-exercise BP was similar after taking LF and HF ( 153 ( se 3)/88 ( se 3 ) v. 153 ( se 4)/87 ( se 2 ) mmHg , respectively , P>0.05 ) . However , the BP response to exercise ( area under BP curve ) was attenuated by HF compared with LF . BP increases were 68 % lower for DBP ( P = 0.03 ) and 14 % lower for mean BP ( P = 0.05 ) . FMD measurements were higher after taking HF than after taking LF ( 6.1 ( se 0.6 ) % v. 3.4 ( se 0.5 ) % , P < 0.001 ) . By facilitating vasodilation and attenuating exercise-induced increases in BP , cocoa flavanols may decrease cardiovascular risk and enhance the cardiovascular benefits of moderate intensity exercise in at-risk individuals Background Several studies have shown that cocoa and cocoa-containing foods have the potential to lower blood pressure and improve endothelial function . Most of the studies reporting the beneficial effects of dark chocolate on blood pressure have been short ( ≤ 4 weeks ) . The aim of the present 8-wks ( weeks ) study was to assess the effects of regular consumption of dark chocolate during a reduced snack consumption intervention on blood pressure and other cardiovascular risk factors in mildly hypertensive individuals . Design This was a r and omized , controlled , cross-over trial involving 22 adults ( 8 women , 14 men ) , aged 33–64 y , BMI 27.7 ± 3.7 kg/m2 with mild hypertension . During the intervention period ( 8-wks ) the participants reduced the intake of habitual snacks and replaced them with dark chocolate ( 49 g/day ) . In the control period , they only reduced the snacks without any added chocolate . Data ( blood lipid profile , glucose , insulin , 24 h blood pressure ) was collected in the beginning and end of both periods ( intervention and control ) , and some variables also in the run-in and run-out periods ( weight , body fat percentage , blood pressure , arterial stiffness index , diet and physical activity ) . Results Daily consumption of dark chocolate had no effects on 24 h blood pressure , resting blood pressure ( mean ± SD , pre 142 ± 11.5/89 ± 8.4 mmHg vs. post 142 ± 14.2/88 ± 9.4 mmHg in systolic and diastolic blood pressure , respectively ) or arterial stiffness ( mean ± SD , pre 7.68 ± 0.88 vs. post 7.76 ± 0.89).Weight was reduced by 1.0 ± 2.2 kg during the control ( reduced snack only ) period , but was unchanged while eating chocolate ( p < 0.027 between the treatments ) . Conclusion The data collected in this study indicates that inclusion of dark chocolate daily in the diet had no significant effects on blood pressure or other cardiovascular risk factors during a reduced snack period . Trial registration Clinical Trials.gov identifier Background and Aim . Cardiovascular risk is increased in women with menopause and metabolic syndrome . Aim of this study was to test the effect of a new supplement formula , combining cocoa polyphenols , myo-inositol , and soy isoflavones , on some biomarkers of cardiovascular risk in postmenopausal women with metabolic syndrome . Methods and Results . A total of 60 women were enrolled and r and omly assigned ( n = 30 per group ) to receive the supplement ( NRT : 30 mg of cocoa polyphenols , 80 mg of soy isoflavones , and 2 gr of myo-inositol ) , or placebo for 6 months . The study protocol included three visits ( baseline , 6 , and 12 months ) for the evaluation of glucose , triglycerides , and HDL-cholesterol ( HDL-C ) , adiponectin , visfatin , resistin , and bone-specific alkaline phosphatase ( bone-ALP ) . At 6 months , a significant difference between NRT and placebo was found for glucose ( 96 ± 7 versus 108 ± 10 mg/dL ) , triglycerides ( 145 ± 14 versus 165 ± 18 mg/dL ) , visfatin ( 2.8 ± 0.8 versus 3.7 ± 1.1 ng/mL ) , resistin ( 27 ± 7 versus 32 ± 8 µg/L ) , and b-ALP ( 19 ± 7 versus 15 ± 5 µg/mL ) . No difference in HDL-C concentrations nor in adiponectin levels between groups was reported at 6 months . Conclusions . The supplement used in this study improves most of the biomarkers linked to metabolic syndrome . This Trial is registered with NCT01400724 BACKGROUND Dark chocolate may have blood pressure-lowering properties . We conducted a prospect i ve r and omized open-label blinded end-point design trial to study a potential dose dependency of the presumed antihypertensive effect of dark chocolate by directly comparing low vs. higher doses of dark chocolate over the course of 3 months . METHODS We enrolled a total of 102 patients with prehypertension/stage 1 hypertension and established cardiovascular end-organ damage or diabetes mellitus . Patients were r and omly assigned to receive either 6 or 25 g/day of flavanol-rich dark chocolate for 3 months . The difference in 24-h mean blood pressure between groups was defined as the primary outcome measure . RESULTS Significant reductions in mean ambulatory 24-h blood pressure were observed between baseline and follow-up in both groups ( 6 g/day : -2.3 mm Hg , 95 % confidence interval -4.1 to -0.4 ; 25 g/day : -1.9 mm Hg , 95 % confidence interval -3.6 to -0.2 ) . There were no significant differences in blood pressure changes between groups . In the higher-dose group , a slight increase in body weight was noted ( 0.8 kg , 95 % confidence interval 0.06 to 1.6 ) . CONCLUSIONS The findings are consistent with the hypothesis that dark chocolate may be associated with a reduction in blood pressure ( BP ) . However , due to the lack of a control group , confounding may be possible and the results should be interpreted with caution BACKGROUND Essential hypertension is characterized by reciprocal relations between endothelial dysfunction and insulin resistance . Cocoa flavanols stimulate production of the vasodilator nitric oxide from vascular endothelium . OBJECTIVE The objective was to test the hypothesis that consumption of cocoa may simultaneously lower blood pressure , improve endothelial dysfunction , and ameliorate insulin resistance in subjects with essential hypertension . DESIGN We conducted a r and omized , placebo-controlled , double-blind , crossover trial of a flavanol-rich cocoa drink ( 150 mL twice a day , approximately 900 mg flavanols/d ) in individuals with essential hypertension ( n = 20 ) . Antihypertensive medications were discontinued before study enrollment . After a 7-d cocoa-free run-in period , cocoa or flavanol-poor placebo ( approximately 28 mg flavanols/d ) treatment for 2 wk was followed by a 1-wk washout and then crossover to the other treatment arm . Blood pressure was measured thrice weekly . At baseline and after each treatment period , we assessed insulin sensitivity ( hyperinsulinemic-isoglycemic glucose clamp ) and insulin-stimulated changes in brachial artery diameter and forearm skeletal muscle capillary recruitment ( Doppler ultrasound with or without microbubble contrast ) . RESULTS Cocoa treatment for 2 wk increased insulin-stimulated changes in brachial artery diameter when compared with placebo [ median percentage increase from baseline ( 25th-75th percentile ) : 8.3 ( 4.2 - 11.3 ) compared with 5.9 ( -0.3 to 9.6 ) ; P < 0.04 ] . Nevertheless , cocoa treatment did not significantly reduce blood pressure or improve insulin resistance and had no significant effects on skeletal muscle capillary recruitment , circulating plasma concentrations of adipocytokines , or endothelial adhesion molecules . CONCLUSIONS Daily consumption of flavanol-rich cocoa for 2 wk is not sufficient to reduce blood pressure or improve insulin resistance in human subjects with essential hypertension . This trial was registered at clinical trials.gov as NCT00099476 Cocoa supplementation has been associated with benefits to cardiovascular health . However , cocoa 's effects on cognition are less clear . A r and omized , placebo-controlled , double-blind clinical trial ( n = 40 , age M = 24.13 years , SD = 4.47 years ) was conducted to investigate the effects of both acute ( same-day ) and sub-chronic ( daily for four-weeks ) 250 mg cocoa supplementation on mood and mental fatigue , cognitive performance and cardiovascular functioning in young , healthy adults . Assessment involved repeated 10-min cycles of the Cognitive Dem and Battery ( CDB ) encompassing two serial subtraction tasks ( Serial Threes and Sevens ) , a Rapid Visual Information Processing task , and a mental fatigue scale over the course of half an hour . The Swinburne University Computerized Cognitive Assessment Battery ( SUCCAB ) was also completed to evaluate cognition . Cardiovascular function included measuring both peripheral and central blood pressure and cerebral blood flow . At the acute time point , consumption of cocoa significantly improved self-reported mental fatigue and performance on the Serial Sevens task in cycle one of the CDB . No other significant effects were found . This trial was registered with the Australian and New Zeal and Clinical Trial Registry ( Trial ID : ACTRN12613000626763 ) . Accessible via http://www.anzctr.org.au/Trial Search .aspx ? search Txt = ACTRN12613000626763&ddl Search = Registered CONTEXT Regular intake of cocoa-containing foods is linked to lower cardiovascular mortality in observational studies . Short-term interventions of at most 2 weeks indicate that high doses of cocoa can improve endothelial function and reduce blood pressure ( BP ) due to the action of the cocoa polyphenols , but the clinical effect of low habitual cocoa intake on BP and the underlying BP-lowering mechanisms are unclear . OBJECTIVE To determine effects of low doses of polyphenol-rich dark chocolate on BP . DESIGN , SETTING , AND PARTICIPANTS R and omized , controlled , investigator-blinded , parallel-group trial involving 44 adults aged 56 through 73 years ( 24 women , 20 men ) with untreated upper-range prehypertension or stage 1 hypertension without concomitant risk factors . The trial was conducted at a primary care clinic in Germany between January 2005 and December 2006 . INTERVENTION Participants were r and omly assigned to receive for 18 weeks either 6.3 g ( 30 kcal ) per day of dark chocolate containing 30 mg of polyphenols or matching polyphenol-free white chocolate . MAIN OUTCOME MEASURES Primary outcome measure was the change in BP after 18 weeks . Secondary outcome measures were changes in plasma markers of vasodilative nitric oxide ( S-nitrosoglutathione ) and oxidative stress ( 8-isoprostane ) , and bioavailability of cocoa polyphenols . RESULTS From baseline to 18 weeks , dark chocolate intake reduced mean ( SD ) systolic BP by -2.9 ( 1.6 ) mm Hg ( P < .001 ) and diastolic BP by -1.9 ( 1.0 ) mm Hg ( P < .001 ) without changes in body weight , plasma levels of lipids , glucose , and 8-isoprostane . Hypertension prevalence declined from 86 % to 68 % . The BP decrease was accompanied by a sustained increase of S-nitrosoglutathione by 0.23 ( 0.12 ) nmol/L ( P < .001 ) , and a dark chocolate dose result ed in the appearance of cocoa phenols in plasma . White chocolate intake caused no changes in BP or plasma biomarkers . CONCLUSIONS Data in this relatively small sample of otherwise healthy individuals with above-optimal BP indicate that inclusion of small amounts of polyphenol-rich dark chocolate as part of a usual diet efficiently reduced BP and improved formation of vasodilative nitric oxide . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00421499 Background — Dark chocolate has potent antioxidant properties . Coronary atherosclerosis is promoted by impaired endothelial function and increased platelet activation . Traditional risk factors , high oxidative stress , and reduced antioxidant defenses play a crucial role in the pathogenesis of atherosclerosis , particularly in transplanted hearts . Thus , flavonoid-rich dark chocolate holds the potential to have a beneficial impact on graft atherosclerosis . Methods and Results — We assessed the effect of flavonoid-rich dark chocolate compared with cocoa-free control chocolate on coronary vascular and platelet function in 22 heart transplant recipients in a double-blind , r and omized study . Coronary vasomotion was assessed with quantitative coronary angiography and cold pressor testing before and 2 hours after ingestion of 40 g of dark ( 70 % cocoa ) chocolate or control chocolate , respectively . Two hours after ingestion of flavonoid-rich dark chocolate , coronary artery diameter was increased significantly ( from 2.36±0.51 to 2.51±0.59 mm , P<0.01 ) , whereas it remained unchanged after control chocolate . Endothelium-dependent coronary vasomotion improved significantly after dark chocolate ( 4.5±11.4 % versus −4.3±11.7 % in the placebo group , P=0.01 ) . Platelet adhesion decreased from 4.9±1.1 % to 3.8±0.8 % ( P=0.04 ) in the dark chocolate group but remained unchanged in the control group . Conclusions — Dark chocolate induces coronary vasodilation , improves coronary vascular function , and decreases platelet adhesion 2 hours after consumption . These immediate beneficial effects were paralleled by a significant reduction of serum oxidative stress and were positively correlated with changes in serum epicatechin concentration Background Several r and omized clinical trials ( RCTs ) indicate that flavanol-rich chocolate has beneficial effects on flow-mediated dilation ( FMD ) and blood pressure ( BP ) . However , no RCTs have evaluated these outcomes in pregnant women . The objective of this 2-group , parallel , double-blind RCT was to examine the effects of flavanol-rich chocolate on FMD and BP in pregnant women with normal BP . Methods Forty-four healthy , pregnant women were r and omized to the high-flavanol ( n = 23 ) or low-flavanol ( n = 21 ) chocolate consumption for 12 weeks . At r and omization ( 0 , 60 , 120 and 180 min after a single 40-g dose of chocolate ) , 6 and 12 weeks after daily 20-g chocolate intake , we evaluated plasma concentrations of flavanols and theobromine , as well as the FMD and BP . Results Plasma epicatechin was significantly increased ( p < 0.001 ) 180 min after the consumption of 40-g high-flavanol chocolate compared to low-flavanol chocolate . Theobromine concentrations were significantly higher 180 min and 12 weeks after the intake of experimental chocolate or low-flavanol chocolate ( p < 0.001 ) . FMD was not different between the 2 groups at all pre-defined time periods . No other significant within-group or between-group changes were observed . Conclusion These results confirm the feasibility of a large-scale RCT comparing daily consumption of flavanol-rich chocolate to an equivalent placebo during pregnancy and demonstrate higher plasma epicatechin and theobromine concentration in the intervention group after acute ingestionTrial registration Clinical Trials.gov Identifier : Flavanol-rich cocoa products have been reported to lower blood pressure . It has been suggested that theobromine is partially responsible for this effect . We tested whether consumption of flavanol-rich cocoa drinks with natural or added theobromine could lower peripheral and central blood pressure . In a double-blind , placebo-controlled 3-period crossover trial we assigned 42 healthy individuals ( age 62±4.5 years ; 32 men ) with office blood pressure of 130 to 159 mm Hg/85 to 99 mm Hg and low added cardiovascular risk to a r and om treatment sequence of dairy drinks containing placebo , flavanol-rich cocoa with natural dose consisting of 106 mg of theobromine , or theobromine-enriched flavanol-rich cocoa with 979 mg of theobromine . Treatment duration was 3 weeks with a 2-week washout . The primary outcome was the difference in 24-hour ambulatory systolic blood pressure between placebo and active treatment after 3 weeks . The difference in central systolic blood pressure between placebo and active treatment was a secondary outcome . Treatment with theobromine-enriched cocoa result ed in a mean±SE of 3.2±1.1 mm Hg higher 24-hour ambulatory systolic blood pressure compared with placebo ( P<0.01 ) . In contrast , 2 hours after theobromine-enriched cocoa , laboratory peripheral systolic blood pressure was not different from placebo , whereas central systolic blood pressure was 4.3±1.4 mm Hg lower ( P=0.001 ) . Natural dose theobromine cocoa did not significantly change either 24-hour ambulatory or central systolic blood pressure compared with placebo . In conclusion , theobromine-enriched cocoa significantly increased 24-hour ambulatory systolic blood pressure while lowering central systolic blood pressure Introduction . The aim of this study was to assess the vascular benefits of dark chocolate in healthy and young individuals . Methods . A r and omized and controlled trial was carried out involving 60 healthy volunteers , r and omized into two groups : control group ( CG ; n = 30 ) and intervention group ( IG ; n = 30 ) . The IG ingested a daily dosage of 10 g of dark chocolate ( > 75 % cocoa ) for a month . Blood pressure ( BP ) , flow-mediated dilation ( FMD ) , arterial stiffness index ( ASI ) , aortic pulse wave velocity ( PWV ) , and pulse wave analysis ( PWA ) were assessed at baseline and one week after the one-month intervention period . Results . Arterial function improved after intervention in the IG , with PWV decreasing from 6.13 ± 0.41 m/s to 5.83 ± 0.53 m/s ( P = 0.02 ) , with no significant differences observed in the CG . A significant decrease in ASI ( 0.16 ± 0.01 to 0.13 ± 0.01 ; P < 0.001 ) and AiX ( −15.88 ± 10.75 to −22.57 ± 11.16 ; P = 0.07 ) was also depicted for the IG . Endothelial function improved in the IG , with the FMD increasing 9.31 % after the 1-month intervention ( P < 0.001 ) , with no significant variation in the CG . Conclusion . The daily ingestion of 10 g dark chocolate ( > 75 % cocoa ) during a month significantly improves vascular function in young and healthy individuals Flavonoids in cocoa and yerba mate have a beneficial role on inflammation and oxidative disorders . Their effect on HIV individuals has not been studied yet , despite the high cardiovascular risk of this population . This study investigated the role of cocoa and yerba mate consumption on oxidative and inflammatory biomarkers in HIV+ individuals . A cross-over , placebo-controlled , double-blind , r and omized clinical trial was conducted in 92 individuals on antiretroviral therapy for at least six months and at viral suppression . Participants were r and omized to receive either 65 g of chocolate or chocolate-placebo or 3 g of yerba mate or mate-placebo for 15 days each , alternating by a washout period of 15 days . At baseline , and at the end of each intervention regimen , data regarding anthropometry , inflammatory , oxidative and immunological parameters were collected . High-sensitivity C-reactive protein , fibrinogen , lipid profile , white blood cell profile and thiobarbituric acid reactive substances were assessed . There was a difference between mean concentrations of HDL-c ( ANOVA ; p ≤ 0.05 ) among the different regimens : dark chocolate , chocolate-placebo , yerba mate and mate-placebo . When a paired Student t-test was used for comparisons between mean HDL-c at baseline and after each regimen , the mean concentration of HDL-c was higher after supplementation with dark chocolate ( p = 0.008 ) Twenty-nine healthy volunteers aged 47–69 years old were r and omly assigned to a 28-day oral intake of different dark chocolate ( DC ) formulations . The main group received daily 30 g of proprietary lycopene-containing ( L-tug ) lycosome formulation of DC with enhanced bioavailability of cocoa flavanols . Two control groups daily consumed either 30 g of regular DC alone or along with 7 mg of lycopene , which corresponds to the amount of lycopene ingested with L-tug formulation . It was found that L-tug was more efficient in reducing diastolic blood pressure ( mean value of −6.22 mmHg , 95 % CI : 5.00 , 8.00 ) when compared with the regular DC group ( −3.00 mmHg , P < 0.05 ) or the group which ingested the DC and lycopene as two separate formulations ( mean reduction of −4 mmHg , 95 % CI : 2.47 , 6.00 , P = 0.0262 ) . Only marginal superiority for L-tug formulation in the reduction in systolic blood pressure was seen . However , the L-tug formulation was the only formulation of DC which affected serum lipids . There was a reduction in total cholesterol ( from median 228.00 mg/dL [ 95 % CI : 206.2 , 242.5 ] to 187.00 mg/dL [ 95 % CI : 166.2 , 202.2 , P < 0.05 ] ) with corresponding decline of low-density lipoprotein ( LDL ) cholesterol ( from a median of 166.00 mg/dL [ 95 % CI : 130.8 , 177.0 ] to 151.00 mg/dL [ 95 % CI : 122.8 , 167.4 ; P < 0.05 ] ) at the end of the intervention period . Similar decline was seen in serum triglycerides ( P < 0.05 ) . Serum high-density lipoprotein ( HDL ) cholesterol , glucose levels , and C-reactive protein ( CRP ) values remained statistically unchanged in all study groups throughout the intervention period . A superior biological activity of the L-tug lycosome formulation of DC extending beyond its antihypertensive effect to lipid-lowering ability opens up new possibilities for the use of DC for health purpose s helping to reduce daily caloric intake without compromising on the health benefits of DC consumption BACKGROUND Evidence from clinical studies has suggested that cocoa may increase high-density lipoprotein (HDL)-cholesterol concentrations . However , it is unclear whether this effect is attributable to flavonoids or theobromine , both of which are major cocoa components . OBJECTIVES We investigated whether pure theobromine increases serum HDL cholesterol and whether there is an interaction effect between theobromine and cocoa . DESIGN The study had a 2-center , double-blind , r and omized , placebo-controlled , full factorial parallel design . After a 2-wk run-in period , 152 healthy men and women ( aged 40 - 70 y ) were r and omly allocated to consume one 200-mL drink/d for 4 wk that contained 1 ) cocoa , which naturally provided 150 mg theobromine and 325 mg flavonoids [ cocoa intervention ( CC ) ] , 2 ) 850 mg pure theobromine [ theobromine intervention ( TB ) ] , 3 ) cocoa and added theobromine , which provided 1000 mg theobromine and 325 mg flavonoids [ theobromine and cocoa intervention ( TB+CC ) ] , or 4 ) neither cocoa nor theobromine ( placebo ) . Blood lipids and apolipoproteins were measured at the start and end of interventions . RESULTS In a 2-factor analysis , there was a significant main effect of the TB ( P < 0.0001 ) but not CC ( P = 0.1288 ) on HDL cholesterol but no significant interaction ( P = 0.3735 ) . The TB increased HDL-cholesterol concentrations by 0.16 mmol/L ( P < 0.0001 ) . Furthermore , there was a significant main effect of the TB on increasing apolipoprotein A-I ( P < 0.0001 ) and decreasing apolipoprotein B and LDL-cholesterol concentrations ( P < 0.02 ) . CONCLUSIONS Theobromine independently increased serum HDL-cholesterol concentrations by 0.16 mmol/L. The lack of significant cocoa and interaction effects suggested that theobromine may be the main ingredient responsible for the HDL cholesterol-raising effect . This trial was registered at clinical trials.gov as NCT01481389 Objectives There is previous epidemiological evidence that intake of polyphenol-rich foods has been associated with reduced cardiovascular disease risk . We aim ed to investigate the effect of increasing dietary polyphenol intake on microvascular function in hypertensive participants . Methods All participants completed a 4-week run-in phase , consuming < 2 portions of fruit and vegetables ( F&V ) daily and avoiding berries and dark chocolate . Subjects were then r and omised to continue with the low-polyphenol diet for 8 weeks or to consume a high-polyphenol diet of six portions F&V ( including one portion of berries/day and 50 g of dark chocolate ) . Endothelium-dependent ( acetylcholine , ACh ) and endothelium-independent ( sodium nitroprusside ) vasodilator responses were assessed by venous occlusion plethysmography . Compliance with the intervention was measured using food diaries and biochemical markers . Results Final analysis of the primary endpoint was conducted on 92 participants . Between-group comparison of change in maximum % response to ACh revealed a significant improvement in the high-polyphenol group ( p=0.02 ) . There was a significantly larger increase in vitamin C , carotenoids and epicatechin in the high-polyphenol group ( between-group difference p<0.001 ; p<0.001 ; p=0.008 , respectively ) . Conclusions This study has shown that increasing the polyphenol content of the diet via consumption of F&V , berries and dark chocolate results in a significant improvement in an established marker of cardiovascular risk in hypertensive participants . Trial registration number NCT01319786 BACKGROUND AND OBJECTIVES Hemodialysis ( HD ) per se entails vascular dysfunction in patients with ESRD . Endothelial dysfunction is a key step in atherosclerosis and is characterized by impaired flow-mediated dilation ( FMD ) . Interventional studies have shown that cocoa flavanol (CF)-rich supplements improve vascular function . Aim of this study was to investigate the effect of flavanol-rich bioactive food ingredients on acute and chronic HD-induced vascular dysfunction in ESRD . DESIGN , SETTING , PARTICIPANTS , & MEASUREMENTS We conducted a r and omized , double-blind , placebo-controlled trial from 2012 to 2013 . Fifty-seven participants were enrolled , ingested CF-rich beverages ( 900 mg CF per study day ) , and were compared with those ingesting CF-free placebo . This included ( 1 ) a baseline cross-over acute study to determine safety and efficacy of CF and ( 2 ) a subsequent chronic parallel group study with a 30-day follow-up period to study effects of CF on HD-mediated vascular dysfunction entailing ( 3 ) an acute sub study during HD in flavanol-naive patients and ( 4 ) an acute on chronic study during HD . Primary and secondary outcome measures included changes in FMD and hemodynamics . RESULTS CF ingestion was well tolerated . Acute ingestion improved FMD by 53 % ( 3.2±0.6 % to 4.8±0.9 % versus placebo , 3.2±0.7 % to 3.3±0.8 % ; P<0.001 ) , with no effects on BP or heart rate . A 30-day ingestion of CF led to an increase in baseline FMD by 18 % ( 3.4±0.9 % to 3.9±0.8 % versus placebo , 3.5±0.7 % to 3.5±0.7 % ; P<0.001 ) , with reduced diastolic BP ( 73±12 to 69±11 mmHg versus placebo , 70±11 to 73±13 mmHg ; P=0.03 ) and increased heart rate ( 70±12 to 74±13 bpm versus placebo , 75±15 to 74±13 bpm ; P=0.01 ) . No effects were observed for placebo . Acute ingestion of CF during HD alleviated HD-induced vascular dysfunction ( 3.4±0.9 % to 2.7±0.6 % versus placebo , 3.5±0.7 % to 2.0±0.6 % ; P<0.001 ) . This effect was sustained throughout the study ( acute on chronic , 3.9±0.9 % to 3.0±0.7 % versus placebo , 3.5±0.7 % to 2.2±0.6 ; P=0.01 ) . CONCLUSIONS Dietary CF ingestion mitigates acute HD-induced and chronic endothelial dysfunction in patients with ESRD and thus , improves vascular function in this high-risk population . Larger clinical trials are warranted to test whether this translates into an improved cardiovascular prognosis in patients with ESRD AIM to investigate the effect of consumption of dark chocolate 30 g/day for fifteen days on Nitric oxide ( NO ) serum levels and blood pressure in male and female employees with prehypertension . METHODS the study was a parallel r and omized clinical trial . A total of thirty-two subjects was divided into two groups using block r and omization . Sixteen subjects received 30 g/day dark chocolate and dietary counseling ( treatment group ) and the other 16 subjects received white chocolate 25 g/day and dietary counseling ( control group ) for fifteen days . Data collected in this study consisted of age , physical activity , body massa index , intake of energy , intake of sodium , and intake of polyphenol , NO serum levels and blood pressure . The measurement of NO serum levels was done in pre- and after- treatment , while blood pressure was assessed in pre- , during- and after- treatment . Statistical analysis was performed using independent t-test for normal distribution data and Mann-Whitney test for not normal distribution data , with the level of significancy of 5 % . RESULTS after 15 days treatment , NO serum level between treatment and control groups were significantly different 7.70 ± 3.84 vs 1.92(-0.79 ± 17.78 ) ( p=0.001 ) . Both groups had decreased systolic and diastolic blood pressure . Systolic blood pressure was different significantly between groups after treatment 120.64 ± 8.47 vs 131.19 ± 7.45 ( p=0.001 ) , while diastolic blood pressure was not significant 74.14 ± 6.30 vs 77.44 ± 10.29 ( p=0.308 ) . CONCLUSION in prehypertension subjects , dark chocolate 30 g/day increased NOx serum levels and decreased systolic blood pressure after 15 days of treatment OBJECTIVE The formation of reactive oxygen species ( ROS ) contributes to the pathogenesis and progression of several diseases . Polyphenols have been shown to be beneficial against ROS . The aim of this study was to evaluate the effects of a natural antioxidant ice cream on oxidative stress , vascular function , and physical performance . METHODS In this controlled , single-blind , crossover study , 14 healthy individuals were r and omized to consume 100 g of either antioxidant ice cream containing dark cocoa powder and hazelnut and green tea extracts or milk chocolate ice cream ( control ice cream ) . Participants were studied at baseline and 2 h after ingesting ice cream . Serum polyphenols , antioxidant status ( ferric-reducing ability of plasma [ FRAP ] ) , nitric oxide ( NOx ) bioavailability , markers of oxidative stress ( determination of reactive oxygen metabolites [ d-ROMs ] and hydrogen peroxide [ H2O2 ] ) , endothelium function ( flow-mediated dilation [ FMD ] and reactive hyperemia index [ RHI ] ) , and exercise tolerance ( stress test ) were assessed , and the double product was measured . RESULTS Serum polyphenols ( P < 0.001 ) , NOx ( P < 0.001 ) , FRAP ( P < 0.005 ) , FMD ( P < 0.001 ) , and RHI ( P < 0.05 ) increased significantly , oxidative stress decreased ( d-Roms , P < 0.001 ; H2O2 , P < 0.001 ) , and the double product ( P < 0.001 ) was improved only after antioxidant ice cream ingestion . No changes were found after control ice cream ingestion . CONCLUSIONS To our knowledge , this is the first study to demonstrate that a natural ice cream rich in polyphenols acutely improved vascular function and physical performance in healthy individuals through a reduction in oxidative stress Flavanol-rich dark chocolate consumption relates to lower risk of cardiovascular mortality , but underlying mechanisms are elusive . We investigated the effect of acute dark chocolate consumption on inflammatory measures before and after stress . Healthy men , aged 20 - 50years , were r and omly assigned to a single intake of either 50 g of flavanol-rich dark chocolate ( n=31 ) or 50 g of optically identical flavanol-free placebo-chocolate ( n=34 ) . Two hours after chocolate intake , both groups underwent the 15-min Trier Social Stress Test . We measured DNA-binding-activity of the pro-inflammatory transcription factor NF-κB ( NF-κB-BA ) in peripheral blood mononuclear cells , as well as plasma and whole blood mRNA levels of the pro-inflammatory cytokines IL-1β and IL-6 , and the anti-inflammatory cytokine IL-10 , prior to chocolate intake as well as before and several times after stress . We also repeatedly measured the flavanol epicatechin and the stress hormones epinephrine and cortisol in plasma and saliva , respectively . Compared to the placebo-chocolate-group , the dark-chocolate-group revealed a marginal increase in IL-10 mRNA prior to stress ( p=0.065 ) , and a significantly blunted stress reactivity of NF-κB-BA , IL-1β mRNA , and IL-6 mRNA ( p's⩽0.036 ) with higher epicatechin levels relating to lower pro-inflammatory stress reactivity ( p's⩽0.033 ) . Stress hormone changes to stress were controlled . None of the other measures showed a significant chocolate effect ( p's⩾0.19 ) . Our findings indicate that acute flavanol-rich dark chocolate exerts anti-inflammatory effects both by increasing mRNA expression of the anti-inflammatory cytokine IL-10 and by attenuating the intracellular pro-inflammatory stress response . This mechanism may add to beneficial effects of dark chocolate on cardiovascular health Endothelial dysfunction characterizes many disease states including sub clinical atherosclerosis . The consumption of flavanol-rich cocoa and cocoa-based products has been shown to improve endothelial function in both compromised and otherwise normal , healthy individuals when administered either acutely or over a period of several days , or weeks . Women experience increased risk for cardiovascular disease after menopause , which can be associated with endothelial dysfunction . Whether a flavanol-rich cocoa-based product can improve endothelial function in hypercholesterolemic postmenopausal women is not known . The purpose of the present study was to determine whether chronic dietary administration of flavanol-rich cocoa improves endothelial function and markers of cardiovascular health in hypercholesterolemic postmenopausal women . Thirty-two postmenopausal hypercholesterolemic women were r and omly assigned to consume a high-flavanol cocoa beverage ( high cocoa flavanols (CF)—446 mg of total flavanols ) , or a low-flavanol cocoa beverage ( low CF—43 mg of total flavanols ) for 6 weeks in a double-blind study ( n=16 per group ) . Endothelial function was determined by brachial artery-reactive hyperemia . Plasma was analyzed for lipids ( total cholesterol , high-density lipoprotein cholesterol , low-density lipoprotein cholesterol ) , hormones ( follicle-stimulating hormone ) , total nitrate/nitrite , activation of cellular adhesion markers ( vascular cell adhesion molecule 1 , intercellular adhesion molecule 1 , E-Selectin , P-Selectin ) , and platelet function and reactivity . Changes in these plasma markers were then correlated to brachial reactivity . Brachial artery hyperemic blood flow increased significantly by 76 % ( P<0.05 vs. baseline ) after the 6-week cocoa intervention in the high CF group , compared with 32 % in the low CF cocoa group ( P = ns vs. baseline ) . The 2.4-fold increase in hyperemic blood flow with high CF cocoa closely correlated ( r2=0.8 ) with a significant decrease ( 11 % ) in plasma levels of soluble vascular cell adhesion molecule-1 . Similar responses were not observed after chronic use of low CF . There were no significant differences between high and low CF in other biochemical markers and parameters measured . This study is the first to identify beneficial vascular effects of flavanol-rich cocoa consumption in hypercholesterolemic postmenopausal women . In addition , our results suggest that reductions in plasma soluble vascular cell adhesion molecule-1 after chronic consumption of a flavanol-rich cocoa may be mechanistically linked to improved vascular reactivity BACKGROUND In healthy participants , short-term flavan-3-ol and isoflavone intakes improve vascular function ; however , the potential combined benefit of these compounds on atherosclerosis progression remains unclear for those at elevated risk of cardiovascular disease . OBJECTIVE The objective was to examine whether combined isoflavone and flavan-3-ol intake alters vascular function in postmenopausal women with type 2 diabetes mellitus ( T2DM ) . DESIGN A double-blind , parallel- design , placebo-controlled 1-y trial was conducted in postmenopausal T2DM patients r and omly assigned to a split dose of 27 g flavonoid-enriched chocolate/d [ 850 mg flavan-3-ols ( 90 mg epicatechin ) + 100 mg isoflavones ( aglycone equivalents)/d ] or matched placebo . Intima-media thickness of the common carotid artery ( CCA-IMT ) , pulse wave velocity ( PWV ) , augmentation index , blood pressure ( BP ) , and vascular biomarkers were assessed . RESULTS A total of 93 patients completed the trial . Overall , the flavonoid intervention did not significantly change CCA-IMT , augmentation index , or BP , but pulse pressure variability improved ( flavonoid : -0.11 ± 0.07 mm Hg/min ; placebo : 0.10 ± 0.11 mm Hg/min ; P = 0.04 ) . In a subgroup with PWV data , net improvements were observed [ flavonoid ( n = 18 ) : -0.07 ± 0.38 m/s ; placebo ( n = 17 ) : 0.68 ± 0.25 m/s ; P = 0.01 ] , which equated to a 10 % CV risk reduction . Equol producers ( n = 17 ) had larger reductions in diastolic BP , mean arterial pressure , and PWV ( -2.24 ± 1.31 mm Hg , -1.24 ± 1.30 mm Hg , and -0.68 ± 0.40 m/s , respectively ; P < 0.01 ) compared with non-equol producers ( n = 30 ) . CONCLUSIONS Although the 1-y intervention did not change CCA-IMT or BP , clinical ly relevant improvements in arterial stiffness were observed ; equol producers were particularly responsive . Flavonoids may augment existing therapeutic strategies to reduce cardiovascular disease risk in postmenopausal T2DM patients , and longer studies are needed to examine the effects on atherosclerosis progression . This trial was registered at clinical trials.gov as NCT00677599 OBJECTIVES Our goal was to test feasibility and efficacy of a dietary intervention based on daily intake of flavanol-containing cocoa for improving vascular function of medicated diabetic patients . BACKGROUND Even in fully medicated diabetic patients , overall prognosis is unfavorable due to deteriorated cardiovascular function . Based on epidemiological data , diets rich in flavanols are associated with a reduced cardiovascular risk . METHODS In a feasibility study with 10 diabetic patients , we assessed vascular function as flow-mediated dilation ( FMD ) of the brachial artery , plasma levels of flavanol metabolites , and tolerability after an acute , single-dose ingestion of cocoa , containing increasing concentrations of flavanols ( 75 , 371 , and 963 mg ) . In a subsequent efficacy study , changes in vascular function in 41 medicated diabetic patients were assessed after a 30-day , thrice-daily dietary intervention with either flavanol-rich cocoa ( 321 mg flavanols per dose ) or a nutrient-matched control ( 25 mg flavanols per dose ) . Both studies were undertaken in a r and omized , double-masked fashion . Primary and secondary outcome measures included changes in FMD and plasma flavanol metabolites , respectively . RESULTS A single ingestion of flavanol-containing cocoa was dose-dependently associated with significant acute increases in circulating flavanols and FMD ( at 2 h : from 3.7 + /- 0.2 % to 5.5 + /- 0.4 % , p < 0.001 ) . A 30-day , thrice-daily consumption of flavanol-containing cocoa increased baseline FMD by 30 % ( p < 0.0001 ) , while acute increases of FMD upon ingestion of flavanol-containing cocoa continued to be manifest throughout the study . Treatment was well tolerated without evidence of tachyphylaxia . Endothelium-independent responses , blood pressure , heart rate , and glycemic control were unaffected . CONCLUSIONS Diets rich in flavanols reverse vascular dysfunction in diabetes , highlighting therapeutic potentials in cardiovascular disease BACKGROUND AND AIMS Epidemiological studies suggest that regular consumption of cocoa-containing products may confer cardiovascular protection , reducing the risk of coronary heart disease ( CHD ) . However , studies on the effects of cocoa on different cardiovascular risk factors are still scarce . The aim of this study was too evaluate the effects of chronic cocoa consumption on lipid profile , oxidized low-density lipoprotein ( oxLDL ) particles and plasma antioxidant vitamin concentrations in high-risk patients . METHODS AND RESULTS Forty-two high-risk volunteers ( 19 men and 23 women , mean age 69.7 ± 11.5 years ) were included in a r and omized , crossover feeding trial . All received 40 g of cocoa powder with 500 mL of skimmed milk/day(C + M ) or only 500 mL/day of skimmed milk ( M ) for 4 weeks in a r and om order . Before and after each intervention period , plasma lipids , oxLDL and antioxidant vitamin concentrations were measured , as well as urinary cocoa polyphenols metabolites derived from phase II and microbial metabolisms . Compared to M , C + M intervention increases HDLc [ 2.67 mg/dL ( 95 % confidence intervals , CI , 0.58 - 4.73 ; P = 0.008 ) ] and decreases oxLDL levels [ -12.3 U/L ( CI,-19.3 to -5.2;P = 0.001 ) ] . No changes between intervention groups were observed in vitamins B1 , B6 , B12 , C and E , or folic acid concentrations . In addition , subjects who showed higher increments in urinary cocoa polyphenol metabolites exhibited significant increases in HDLc and significant decreases in oxLDL levels ( P < 0.05 ; all ) . CONCLUSIONS Consumption of cocoa power with milk modulates the lipid profile in high-risk subjects for CHD . In addition , the relationship observed between the urinary excretion of cocoa polyphenol metabolites and plasma HDLc and oxLDL levels suggests a beneficial role for cocoa polyphenols in lipid metabolism BACKGROUND AND AIMS Cocoa flavanols are recognised by their favourable antioxidant and vascular effects . This study investigates the influence on health of the daily consumption of ready-to-eat meals supplemented with cocoa extract within a hypocaloric diet , on middle-aged overweight/obese subjects . METHODS AND RESULTS Fifty healthy male and female middle-aged volunteers [ 57.26 ± 5.24 years and body mass index ( BMI ) 30.59 ± 2.33 kg/m(2 ) ] were recruited to participate in a 4 week r and omised , parallel and double-blind study . After following 3 days on a low-polyphenol diet , 25 volunteers received meals supplemented with 1.4 g of cocoa extract ( 645.3 mg of polyphenols ) and the other 25 participants received control meals , within a 15 % energy restriction diet . On the 4th week of intervention individuals in both dietary groups improved ( p < 0.05 ) anthropometric , body composition , blood pressure and blood biochemical measurements . Oxidised LDL cholesterol ( oxLDL ) , showed a higher reduction ( p = 0.030 ) in the cocoa group . Moreover , myeloperoxidase ( MPO ) levels decreased only in the cocoa supplemented group ( p = 0.007 ) . Intercellular Adhesion Molecule-1 ( sICAM-1 ) decreased significantly in both groups , while Vascular Cell Adhesion Molecule-1 ( sVCAM-1 ) did not present differences after the 4 weeks of intervention . Interestingly , cocoa intake showed a different effect by gender , presenting more beneficial effects in men . CONCLUSIONS The consumption of cocoa extract as part of ready-to-eat meals and within a hypocaloric diet improved oxidative status ( oxLDL ) in middle-aged subjects , being most remarkable in males . REGISTRATION NUMBER Registered at www . clinical trials.gov ( NCT01596309 ) Consumption of flavanol-containing cocoa products has been shown to lower blood pressure ( BP ) , but the minimum dose required to reduce BP is not known . This study aim ed to examine the effect of three different doses of cocoa flavanols ( CF ) on 24-h mean arterial BP . Twenty four hour ambulatory BP ( 24-ABP ) monitoring was performed in 32 men and 20 postmenopausal women with untreated mild hypertension ( seated clinic BP > 130/85 and < 160/100 mm Hg ) . Participants were r and omized and instructed to consume daily a reconstituted cocoa beverage containing 33 , 372 , 712 or 1052 mg day−1 of CF for 6 weeks in a double-blind , parallel comparison . Seated clinic BP and 24-h ABP were measured at 0 , 3 and 6 weeks . Seated clinic BP did not change during the study period . There were significant reductions in 24-h systolic ( 5.3±5.1 mm Hg ; P=0.001 ) , diastolic ( 3±3.2 mm Hg ; P=0.002 ) and mean arterial BP ( 3.8±3.2 mm Hg ; P=0.0004 ) at the 1052 mg day−1 CF only . No reduction in BP was seen at any other dose . No evidence of dose – response was seen in this experiment . The highest dose of 1052 mg CF per day was found to significantly lower BP . These results support previous evidence for CF to lower BP , however more research is needed to establish the most effective dose and food matrix AIM In patients with coronary artery disease ( CAD ) , a J-curve relationship has been reported between blood pressure ( BP ) and future cardiovascular events . However , this is controversial . The purpose of the study was to determine the relationship between on-treatment BP and cardiovascular outcomes in patients with CAD . METHODS AND RESULTS We evaluated 10 001 patients with CAD and a low-density lipoprotein ( LDL ) cholesterol level < 130 mg/dL , r and omized to atorvastatin 80 vs. 10 mg , enrolled in the TNT trial . The post-baseline , time-dependent BPs [ systolic blood pressure ( SBP ) and diastolic blood pressure ( DBP ) ] were categorized into 10 mmHg increments . The primary outcome was a composite of death from coronary disease , non-fatal myocardial infa rct ion ( MI ) , resuscitated cardiac arrest , and fatal or non-fatal stroke . Among the 10 001 patients , 982 ( 9.82 % ) experienced a primary outcome at 4.9 years ( median ) of follow-up . The relationship between SBP or DBP and primary outcome followed a J-curve with increased event rates above and below the reference BP range , both unadjusted and adjusted ( for baseline covariates , treatment effect , and LDL levels ) . A time-dependent , non-linear , multivariate Cox proportional hazard model identified a nadir of 146.3/81.4 mmHg where the event rate was lowest . A similar non-linear relationship with a higher risk of events at lower pressures was found for most of the secondary outcomes of all-cause mortality , cardiovascular mortality , non-fatal MI , or angina . However , for the outcome of stroke , lower was better for SBP . CONCLUSION In patients with CAD , a low BP ( < 110 - 120/<60 - 70 mmHg ) portends an increased risk of future cardiovascular events ( except stroke ) OBJECTIVES In patients with coronary artery disease ( CAD ) medically managed according to currently accepted guidelines , we tested whether a 1-month dietary intervention with flavanol-containing cocoa leads to an improvement of endothelial dysfunction and whether this is associated with an enhanced number and function of circulating angiogenic cells ( CACs ) . BACKGROUND Dietary flavanols can improve endothelial dysfunction . The CACs , also termed endothelial progenitor cells , are critical for vascular repair and maintenance of endothelial function . METHODS In a r and omized , controlled , double-masked , cross-over trial , 16 CAD patients ( 64+/-3 years of age ) received a dietary high-flavanol intervention ( HiFI [ 375 mg ] ) and a macronutrient- and micronutrient-matched low-flavanol intervention ( LoFI [ 9 mg ] ) twice daily in r and om order over 30 days . RESULTS Endothelium-dependent vasomotor function , as measured by flow-mediated vasodilation of the brachial artery , improved by 47 % in the HiFI period compared with the LoFI period . After HiFI , the number of CD34+/KDR+-CACs , as measured by flow cytometry , increased 2.2-fold as compared with after LoFI . The CAC functions , as measured by the capacity to survive , differentiate , proliferate , and to migrate were not different between the groups . The HiFI led to a decrease in systolic blood pressure ( mean change over LoFI : -4.2+/-2.7 mm Hg ) , and increase in plasma nitrite level ( mean change over LoFI : 74+/-32 nM ) . Applying a mixed-effects linear regression model , the results demonstrated a significant increase in flow-mediated vasodilation and a decrease in systolic blood pressure with increasing levels of CD34+/KDR+-CACs . CONCLUSIONS Sustained improvements in endothelial dysfunction by regular dietary intake of flavanols are associated with mobilization of functional CACs . ( Effect of Cocoa Flavanols on Vascular Function in Optimally Treated Coronary Artery Disease Patients : Interaction Between Endothelial Progenitor Cells , Reactivity of Micro- and Macrocirculation ; NCT00553774 ) BACKGROUND Studies of cocoa suggest an array of cardiovascular benefits ; however , the effects of daily intake of sugar-free and sugar-sweetened cocoa beverages on endothelial function ( EF ) have yet to be established . METHODS 44 adults ( BMI 25 - 35 kg/m2 ) participated in a r and omized , controlled , crossover trial . Participants were r and omly assigned to a treatment sequence : sugar-free cocoa beverage , sugar-sweetened cocoa beverage , and sugar-sweetened cocoa-free placebo . Treatments were administered daily for 6 weeks , with a 4-week washout period . RESULTS Cocoa ingestion improved EF measured as flow-mediated dilation ( FMD ) compared to placebo ( sugar-free cocoa : change , 2.4 % [ 95 % CI , 1.5 to 3.2 ] vs. -0.8 % [ 95 % CI , -1.9 to 0.3 ] ; difference , 3.2 % [ 95 % CI , 1.8 to 4.6 ] ; p<0.001 and sugar-sweetened cocoa : change , 1.5 % [ 95 % CI , 0.6 to 2.4 ] vs. -0.8 % [ 95 % CI , -1.9 to 0.3 ] ; difference , 2.3 % [ 95 % CI , 0.9 to 3.7 ] ; p=0.002 ) . The magnitude of improvement in FMD after consumption of sugar-free versus sugar-sweetened cocoa was greater , but not significantly . Other biomarkers of cardiac risk did not change appreciably from baseline . BMI remained stable throughout the study . CONCLUSIONS Daily cocoa ingestion improves EF independently of other biomarkers of cardiac risk , and does not cause weight gain . Sugar-free preparations may further augment endothelial function Purpose Regular nut consumption reduces cardiovascular disease risk , partly from improvements to dietary quality . Examining how individuals make dietary changes when consuming nuts may reveal key behavioural eating patterns beneficial for the development of dietary interventions . We examined the effects of nuts in comparison with other energy-dense snacks on energy compensation , nutrient displacement , and food group patterns . Methods This was a 12-week r and omised , controlled , parallel study with four arms : ~1100 kJ/day for each of hazelnuts ( 42 g ) , chocolate ( 50 g ) , potato crisps ( 50 g ) , or no added snack food . Diet records , body composition , and physical activity were measured at baseline and week 12 , in 102 non-obese participants . Results Significant improvements in diet quality were observed in the hazelnut group , particularly when consumed as snacks . Intakes of monounsaturated fat ( MUFA ) and vitamin E were significantly higher ( all P < 0.05 ) , whereas saturated fat and carbohydrate were significantly lower ( both P ≤ 0.022 ) in the hazelnut group compared to the other groups . Partial energy compensation did not differ significantly between groups , but nutrient displacement values for MUFA and fibre differed significantly . Within the hazelnut group , there was nearly complete displacement for fibre , partial displacement for energy , protein , total fat , MUFA , PUFA , potassium , folate , and vitamin E , and overcompensation for carbohydrate and sugar . Conclusions Our results demonstrate that energy compensation occurs for all three intervention snacks in this non-obese population . Regular nut consumption significantly improves nutrient profiles compared to other snacks with changes occurring at the snack level |
1,905 | 29,949,587 | Compared with the No-KBI strategy , the KBI strategy reduced the incidence of side branch restenosis and increased the risk of main branch restenosis in the one-stent approach .
However , the clinical outcomes were similar between the KBI and No-KBI groups | The KBI ( kissing balloon inflation ) technique is considered the default strategy for the two-stent approach in real world practice .
Studies comparing KBI and No-KBI in patients undergoing the one-stent approach have reported conflicting results .
The meta- analysis was performed to compare the clinical outcomes of the KBI strategy and the No-KBI strategy for coronary bifurcation lesions in the one-stent approach . | BACKGROUND Rapamycin-eluting stents ( RES ) have been shown to reduce restenosis in many types of lesions . However , the ideal strategy for the treatment of coronary bifurcated lesions has not been established to date . This r and omized study compares 2 strategies for the RES treatment of bifurcation lesions : a simple approach ( stenting the main vessel and balloon dilatation for the side branch [ SB ] ) versus a complex approach ( stents for both vessels ) . METHODS To compare both strategies , a r and omized study was conducted in 91 patients with true coronary bifurcation lesions . All patients received an RES at the main vessel , covering the SB . Patients from group A ( n = 47 ) were assigned to balloon dilation of the involved SB ( simple strategy ) ; patients in group B ( n = 44 ) were r and omized to receive a second stent at the SB origin ( complex strategy ) . There were no differences between groups regarding baseline clinical and angiographic data . RESULTS Major adverse cardiac events occurred in 3 patients from group A ( 2 non-Q-wave myocardial infa rct ions and 1 target lesion revascularization ) . Six-month angiographic reevaluation was obtained in 80 patients ( 88 % ) . Restenosis of the main vessel was observed in 1 ( 2 % ) patient from group A and in 4 ( 10 % ) from group B. Restenosis of the SB appeared in 2 ( 5 % ) patients from group A and in 6 ( 15 % ) from group B. CONCLUSIONS Both strategies are effective in reducing the restenosis rate , with no differences in terms of clinical outcome . Elective SB stenting seems to provide no advantages over the simpler stent jail followed by SB balloon dilation OBJECTIVES This study sought to evaluate the optimal percutaneous coronary intervention techniques using drug-eluting stents for bifurcation coronary lesions . BACKGROUND The optimal bifurcation stenting technique needs to be evaluated . METHODS The trial included 2 r and omization studies separated by the presence of side branch ( SB ) stenosis for patients having non-left main bifurcation lesions . For 306 patients without SB stenosis , the routine final kissing balloon or leave-alone approaches were compared . Another r and omization study compared the crush or single-stent approaches for 419 patients with SB stenosis . RESULTS Between the routine final kissing balloon and leave-alone groups for nondiseased SB lesions , angiographic restenosis occurred in 17.9 % versus 9.3 % ( p=0.064 ) , comprising 15.1 % versus 3.7 % for the main branch ( p=0.004 ) and 2.8 % versus 5.6 % for the SB ( p=0.50 ) from 214 patients ( 69.9 % ) receiving 8-month angiographic follow-up . Incidence of major adverse cardiac events including death , myocardial infa rct ion , or target vessel revascularization over 1 year was 14.0 % versus 11.6 % between the routine final kissing balloon and leave-alone groups ( p=0.57 ) . In another r and omization study for diseased SB lesions , 28.2 % in the single-stent group received SB stents . From 300 patients ( 71.6 % ) receiving angiographic follow-up , between the crush and single-stent groups , angiographic restenosis rate was 8.4 % versus 11.0 % ( p=0.44 ) , comprising 5.2 % versus 4.8 % for the main branch ( p=0.90 ) and 3.9 % versus 8.3 % for the SB ( p=0.12 ) . One-year major adverse cardiac events rate between the crush and single-stent groups was 17.9 % versus 18.5 % ( p=0.84 ) . CONCLUSIONS Angiographic and clinical outcomes were excellent after percutaneous coronary intervention using drug-eluting stents with any stent technique for non-left main bifurcation lesions once the procedure was performed successfully We compared the myocardial ischemic burden of provisional and routine final kissing-balloon inflation ( FKI ) with the 1-stent strategy using a second-generation drug-eluting stent for coronary bifurcation lesions ( CBL ) . There are no established guidelines for side branch ( SB ) intervention after main vessel stenting . In total , 113 CBL patients were r and omized to receive different SB intervention strategies : provisional-FKI group ( n = 57 ; FKI only when SB flow was TIMI <3 ) and routine-FKI group ( n = 56 ; m and atory FKI with aggressive treatment until SB-residual stenosis < 50 % ) . Dipyridamole-stress myocardial perfusion scintigraphy with 99mTc was performed after 8 months . The regional summed-difference score ( r-SDS ) was calculated according to the coronary territory . The primary endpoint included target vessel ischemia ( TVI ; r-SDS ≥ 2 ) at 8 months , whereas the clinical primary endpoint was major adverse cardiovascular events ( MACE ) at 3 years . The percent ( % ) myocardial ischemia ( 100 × SDS/68 ) was also calculated . At 8 months , TVI was identified in 11 and 4 % in the provisional-FKI and routine-FKI groups , respectively ( p = 0.226 ) . SB-binary restenosis ( 48 vs. 4 % , p < 0.001 ) and myocardial ischemia at the SB territory ( 11 vs. 0 % , p = 0.030 ) were more common in the provisional-FKI group ; however , in TVI patients , % myocardial ischemia ( 4.12 ± 1.23 % vs. 3.68 ± 1.04 % ; p = 0.677 ) did not significantly differ . Moderate/severe ischemia ( > 10 % myocardial ischemia ) was not observed in the target vessel in either group . Long-term cumulative MACE were similar between the groups ( 9 vs. 14 % ; p = 0.358 ) . Provisional-FKI according to TIMI-SB flow grade led to similar and acceptable myocardial ischemia , in comparison with routine-FKI , which may contribute to the identical long-term follow-up Final kissing-balloon inflation is often recommended for percutaneous coronary intervention ( PCI ) of bifurcation lesions . However , r and omized trials focusing on kissing inflation have not confirmed its beneficial impact . We compared outcomes of kissing inflation for PCI of bifurcation lesions , explicitly stratifying results according to stenting strategy . Patients undergoing bifurcation PCI were retrospectively enrolled . Subjects receiving final kissing inflation were compared with those not undergoing kissing inflation , after stratification for a single-stent technique . The primary end point was the long-term rate of major adverse cardiac events ( MACE , i.e. , death , myocardial infa rct ion , or target lesion revascularization ( TLR ) ) . A total of 4314 patients were included : 1176 ( 27.3 % ) treated with a single stent and kissing inflation , 1637 ( 37.9 % ) with a single stent but no kissing , 1072 ( 24.8 % ) with two stents and kissing , and 429 ( 9.9 % ) with two stents but no kissing . At unadjusted analyses kissing was associated with fewer short-term MACE and deaths in the two-stent group , and with fewer long-term MACE , cardiac deaths , and side-branch TLR in the two-stent group ( all P < 0.05 ) . Conversely , kissing appeared detrimental after single stenting . However , after multivariable analyses , kissing no longer significantly affected the risk of adverse events , with the exception of the risk of side-branch TLR , which was lower in those receiving two stents and final kissing inflation ( hazard ratio = 0.52 , 95 % confidence interval 0.30–0.90 , P = 0.020 ) . Kissing inflation can be avoided in bifurcation lesions uneventfully treated with single-stent PCI . However , final kissing-balloon inflation appears beneficial in reducing the risk of side-branch repeat revascularization after using a two-stent strategy Background — It is unknown whether the preferred 1-stent bifurcation stenting approach with stenting of the main vessel ( MV ) and optional side branch stenting using drug-eluting stents should be finalized by a kissing balloon dilatation ( FKBD ) . Therefore , we compared strategies of MV stenting with and without FKBD . Methods and Results — We r and omized 477 patients with a bifurcation lesion to FKBD ( n=238 ) or no FKBD ( n=239 ) after MV stenting . The primary end point was major adverse cardiac events : cardiac death , non – procedure-related index lesion myocardial infa rct ion , target lesion revascularization , or stent thrombosis within 6 months . The 6-month major adverse cardiac event rates were 2.1 % and 2.5 % ( P=1.00 ) in the FKBD and no-FKBD groups , respectively . Procedure and fluoroscopy times were longer and more contrast media was needed in the FKBD group than in the no-FKBD group . Three hundred twenty-six patients had a quantitative coronary assessment . At 8 months , the rate of binary (re)stenosis in the entire bifurcation lesion ( MV and side branch ) was 11.0 % versus 17.3 % ( P=0.11 ) , in the MV was 3.1 % versus 2.5 % ( P=0.68 ) , and in the side branch was 7.9 % versus 15.4 % ( P=0.039 ) in the FKBD versus no-FKBD groups , respectively . In patients with true bifurcation lesions , the side branch restenosis rate was 7.6 % versus 20.0 % ( P=0.024 ) in the FKBD and no-FKBD groups , respectively . Conclusions — MV stenting strategies with and without FKBD were associated with similar clinical outcomes . FKBD reduced angiographic side branch (re)stenosis , especially in patients with true bifurcation lesions . The simple no-FKBD procedures result ed in reduced use of contrast media and shorter procedure and fluoroscopy times . Long-term data on stent thrombosis are needed . Clinical Trial Registration — URL : http:// clinical trials.gov . Unique identifier : NCT00914199 Background —Treatment of bifurcations is a complex problem . The clinical value of treating side branches is an unsolved problem in the field of interventional cardiology . Methods and Results —We initiated a prospect i ve r and omized controlled trial . One hundred and ten patients with bifurcations were r and omly assigned to 2 arms : Stenting of the main branch ( MB , Taxus-stent , paclitaxel-eluting stents ) and m and atory side branch ( SB ) percutaneous coronary intervention ( PCI ; kissing balloons ) with provisional SB stenting ( therapy A ) , or stenting of the MB ( paclitaxel-eluting stents ) with provisional SB-PCI only when the SB had a thrombolysis in myocardial infa rct ion flow < 2 ( therapy B ) . The primary end point was target lesion revascularization . The mean ages were 66.8 years ( A ) versus 65.1 years ( B , P=0.4 ) , 71.4 % ( A ) versus 77.8 % were men ( P=0.4 ) , patients with diabetes were present in 25.0 % versus 25.9 % ( P=0.9 ) . The MB was left anterior descending artery in 80.4 % versus 81.5 % ( A versus B , P=0.9 ) . The SB-PCI and kissing balloon-PCI were performed according to the study protocol in 82.1%/73.2 % versus 16.7%/13.0 % ( P<0.05 for both ) , while changing of the intended therapy was necessary in 17.9 % versus 16.7 % ( A versus B , P=0.9 ) . A final thrombolysis in myocardial infa rct ion flow 3 ( MB ) was reached in all patients ( groups A and B ) , final thrombolysis in myocardial infa rct ion flow 3 ( SB ) was observed in 96.4 % versus 88.9 % ( A versus B , P=0.3 ) . Radiation time ( min ) and contrast medium ( mL ) were 14.2/210 ( group A ) versus 7.8/151.6 ( group B ; P for both < 0.05 ) . Six month – follow up : major adverse cardiac events was 23.2 % ( A ) versus 24.1 % ( B , P=0.9 ) , target lesion revascularization was 17.9 % ( A ) versus 14.8 % ( B , P=0.7 ) , and late lumen loss ( MB ) was 0.2 mm ( A ) versus 0.3 mm ( B , P=0.5 ) . In group B , no PCI of the SB was done during follow up . Conclusion —A simple strategy using paclitaxel-eluting stents with only provisional SB-PCI may be of equal value to a more complex strategy with m and atory SB-PCI . Clinical Trial Registration —URL : http://www.controlled.trials.com . Unique identifier : IS RCT N22637771 OBJECTIVES The authors sought to compare conservative and aggressive strategies for provisional side branch ( SB ) intervention in coronary bifurcation lesions . BACKGROUND The optimal provisional approach for coronary bifurcation lesions has not been established . METHODS In this prospect i ve r and omized trial , 258 patients with a coronary bifurcation lesion treated with drug-eluting stents were r and omized to a conservative ( n = 128 ) or aggressive ( n = 130 ) SB intervention strategy . The criteria for SB intervention after main vessel stenting differed between the conservative and aggressive groups ; Thrombolysis In Myocardial Infa rct ion flow grade <3 versus diameter stenosis > 75 % for non-left main bifurcations and diameter stenosis > 75 % versus diameter stenosis > 50 % for left main bifurcations . The primary endpoint was target vessel failure ( cardiac death , myocardial infa rct ion , or target vessel revascularization ) at 12 months . RESULTS Left main bifurcation lesions were noted in 114 patients ( 44 % ) and true bifurcation lesions in 171 patients ( 66 % ) . SB ballooning after main vessel stenting and SB stenting after SB ballooning were performed less frequently in the conservative group than in the aggressive group ( 25.8 % vs. 68.5 % , p < 0.001 ; and 7.0 % vs. 30.0 % , p < 0.001 , respectively ) . The conservative strategy was associated with a lower incidence of procedure-related myocardial necrosis compared with the aggressive strategy ( 5.5 % vs. 17.7 % , p = 0.002 ) . At 12 months , the incidence of target vessel failure was similar in both groups ( 9.4 % in the conservative group vs. 9.2 % in the aggressive group , p = 0.97 ) . CONCLUSIONS Compared with the aggressive strategy , the conservative strategy for provisional SB intervention was associated with similar long-term clinical outcomes and a lower incidence of procedure-related myocardial necrosis . ( Optimal Strategy for Side Branch Stenting in Coronary Bifurcation Lesions [ SMART- STRATEGY ] ; NCT00794014 ) BACKGROUND The advantages of the final kissing balloon technique ( FKB ) in a provisional 1-stent approach are under debate . Long-term clinical outcomes remain unclear due to limited data . METHODS AND RESULTS Of 2,132 patients ( 2,502 lesions ) enrolled in the TAXUS Japan Postmarket Surveillance Study at 56 centers between July 2007 and December 2008 , patients having coronary bifurcation treated with a single cross-over stenting with FKB ( FKB-group : 132 patients /137 lesions ) were compared to those treated without FKB ( no-FKB-group : 121 patients /124 lesions ) . The no-FKB-group was also compared with non-bifurcation patients who had a single-stent implantation ( 814 patients /937 lesions ) . The primary outcome was MACE ( major adverse clinical events ) , defined as cardiac death , myocardial infa rct ion and target vessel revascularization ( TVR ) at 3 years . Higher late loss and binary restenosis were found in the main vessel ( MV ) of the FKB-group at the 9-month angiogram compared to the no-FKB-group . At 3 years , MACE was numerically higher ( 14.6 % vs. 6.9 % , P=0.07 ) and TVR was significantly higher ( 14.6 % vs. 5.9 % , P<0.05 ) in the FKB-group compared with the no-FKB-group . The rate of MACE ( 6.9 % vs. 10.4 % , P=0.34 ) and TVR ( 5.9 % vs. 7.7 % , P=0.57 ) were similar between the no-FKB and non-bifurcation patients . CONCLUSIONS In a 1-stent approach , FKB was associated with worse angiographic outcomes in the MV , and did not demonstrate any clinical benefit over the long-term follow-up period . Cross-over stenting without FKB showed similar clinical outcomes to patients without bifurcation OBJECTIVES We sought to assess the fate of stent (ST)-related side branches ( SB ) after coronary intervention in patients with in-ST restenosis . BACKGROUND In-ST restenosis constitutes a therapeutic challenge . Although the fate of lesion-related SB after conventional angioplasty or initial coronary stenting is well established , the outcome of ST-related SB in patients with in-ST restenosis undergoing repeat intervention is unknown . METHODS One hundred consecutive patients ( age 61 + /- 11 years , 22 women ) undergoing repeat intervention for in-ST restenosis ( 101 ST ) were prospect ively studied . Two hundred and twenty-six SB spanned by the ST were identified . The SB size , type , ostium involvement , location within the ST and take-off angle were evaluated . The SB TIMI ( Thrombolysis in Myocardial Infa rct ion trial ) flow grade was studied in detail before , during , immediately after the procedure , and at late angiography . RESULTS Occlusion ( TIMI flow grade = 0 ) was produced in 24 ( 10 % ) SB , whereas some degree of flow deterioration ( > or = 1 TIMI flow grade ) was observed in 57 SB ( 25 % ) . The SB occlusion was associated with non-Q wave myocardial infa rct ion in two patients ( both had large and diseased SB ) . Side-branch occlusion at the time of initial stenting ( RR [ relative risk ] 11.1 , 95 % CI [ confidence interval ] 3.5 - 35.5 , p < 0.001 ) , diabetes ( RR 3.5 , 95 % CI 1.1 - 10.5 , p = 0.02 ) , SB ostium involvement ( RR 5.0 , 95 % CI 1.4 - 17.2 , p = 0.004 ) , baseline SB TIMI flow grade <3 ( RR 5.5 , 95 % CI 1.7 - 18.1 , p = 0.005 ) , and restenosis length ( RR 1.05 95 % CI 1.01 - 1.11 , p = 0.03 ) were identified as independent predictors of SB occlusion . Late angiography in 19 initially occluded SB revealed that 17 ( 89 % ) were patent again . The long-term clinical event-free survival ( 81 % vs. 82 % at two years ) in patients with and without initial SB occlusion was similar . CONCLUSIONS Occlusion or flow deterioration of SB spanned by the ST is relatively common during repeat intervention for in-ST restenosis . Several factors ( mainly anatomic features ) are useful predictors of this event . However , most SB occlusions are clinical ly silent and frequently reappear at follow-up OBJECTIVES This study compared the long-term follow-up results of conservative versus aggressive strategies for provisional side branch ( SB ) intervention in coronary bifurcation lesions . BACKGROUND The appropriate criteria for provisional SB ballooning or stenting have not been established . METHODS A total of 258 patients with a large bifurcation lesion were r and omized to a conservative or aggressive SB intervention strategy . Different criteria applied for the initiation of SB intervention after main vessel stenting in the conservative and aggressive groups were Thrombolysis In Myocardial Infa rct ion flow grade lower than 3 versus a stenosis diameter > 75 % for non-left main bifurcations , and a stenosis diameter > 75 % versus a stenosis diameter > 50 % for left main bifurcations . The primary endpoint was target vessel failure ( TVF ) , defined as a composite of cardiac death , spontaneous myocardial infa rct ion , or target vessel revascularization at 3 years . RESULTS At 3 years , TVF occurred in 11.7 % of the conservative group versus 20.8 % of the aggressive group ( p = 0.049 ) . Although no significant differences were observed in the incidence of TVF between groups at 1 year ( 9.4 % vs. 9.2 % ; p = 0.97 ) , l and mark analysis between 1 and 3 years showed significantly less TVF in patients assigned to the conservative strategy ( 2.6 % vs. 12.7 % ; p = 0.004 ) . The crossover to the 2-stent technique was an independent predictor of TVF ( hazard ratio : 5.42 , 95 % confidence interval : 2.03 to 14.5 ; p < 0.001 ) . There was no interaction between left main bifurcation and treatment effects for TVF ( p for interaction = 0.8 ) . CONCLUSIONS A conservative strategy compared with an aggressive strategy for provisional SB intervention is associated with long-term benefits for patients with a large bifurcation lesion . ( Optimal Strategy for Side Branch Stenting in Coronary Bifurcation Lesion ; NCT00794014 ) |
1,906 | 31,450,966 | Aerobic exercise training significantly ( p < 0.001 ) reduced systolic and diastolic BP in each ethnic group .
Sub-analyses suggested somewhat larger reductions in systolic BP following aerobic training in hypertensive Africans compared with hypertensive Asians . | Background Exercise is key in the primary prevention and management of hypertension .
Yet , current exercise recommendations are predominantly based on meta-analyses involving population s of European descent .
Since blood pressure ( BP ) responses to pharmaceutical interventions are known to differ among ethnic groups , we aim ed to investigate the BP responses to exercise training in non-European descendants .
Purpose The aim of this study was to systematic ally summarize the available literature on the efficacy of exercise on BP in healthy adults ( age ≥18 years ) of African or Asian origin . | BACKGROUND Hypertension is the leading risk factor responsible for premature death worldwide , but its burden has shifted to low- and middle-income countries . Therefore , we studied hypertension and cardiovascular risk in the population of Suriname , a middle-income country with a predominantly urban population of African and Asian ancestry . METHODS A r and om sample of 1,800 noninstitutionalized men and women aged 18 - 70 years was selected to be interviewed at home and examined at the local hospital for cardiovascular risk factors , asymptomatic organ damage , and cardiovascular disease . RESULTS The 1,157 participants examined ( 37 % men ) were mainly of self-defined Asian ( 43 % ) or African ( 39 % ) ancestry , mean age 43 years ( SD 14 ) . The majority of the population ( 71 % ) had hypertension or prehypertension , respectively , 40 % and 31 % . Furthermore , 72 % was obese or overweight , while 63 % had diabetes or prediabetes . Only 1 % of the adult population had an optimal cardiovascular risk profile . Hypertension awareness , treatment , and control were respectively 68 % , 56 % , and 20 % . In line with this , 22 % of the adult population had asymptomatic organ damage , including increased arterial stiffness , left ventricular hypertrophy , microalbuminuria , or asymptomatic chronic kidney disease . CONCLUSIONS In this first extensive cardiovascular assessment in the general population of this middle-income Caribbean country , high prevalence of hypertension with inadequate levels of treatment and control was predominant . The findings emphasize the need for collaborative effort from national and international bodies to prioritize the implementation of affordable and sustainable public health programs that combat the escalating hypertension and cardiovascular risk factor burden OBJECTIVE We evaluated the effects of exercise on neurobehavioral function in healthy older people more than 75 years of age . DESIGN A r and omized controlled trial with 6-month follow-up was conducted . SETTING The study was performed in the rural town of Kahoku , Japan , the population of which is considered representative of the older population of Japan . PARTICIPANTS We studied 42 healthy volunteers ( 18 men and 24 women ; mean age , 79 years ( range 75 to 87 years ) ) who were r and omly assigned to one of two groups , exercise or control . INTERVENTION Subjects assigned to the exercise group were instructed to exercise for 60 minutes twice a week for 6 months . Subjects in the control group were not instructed to engage in an specific exercise regimen . MEASUREMENTS The following measurements were recorded for both groups at baseline and at 6-month follow-up : ( 1 ) Neurobehavioral function as determined by the following tests : Mini-Mental State Exam ( MMSE ) , Hasegawa Dementia Scale Revised ( HDSR ) , Visuospatial Cognitive Performance Test ( VCP-test ) , Button score , Up & Go test , and Functional Reach ; and ( 2 ) Body mass index and blood pressure . RESULTS The effects of exercise were shown in the Up & Go test , and Functional Reach ( ANOVA with repeated measures ) . CONCLUSION This study demonstrates the acceptability and effectiveness of exercise on neurobehavioral function , even in older people more than 75 years of age Background Both exercise training and diet are recommended to prevent and control hypertension and overweight/obesity . Purpose The purpose of this study was to determine the effectiveness of different 16-week aerobic exercise programmes with hypocaloric diet on blood pressure , body composition , cardiorespiratory fitness and pharmacological treatment . Methods Overweight/obese , sedentary participants ( n = 175 , aged 54.0 ± 8.2 years ) with hypertension were r and omly assigned into an attention control group ( physical activity recommendations ) or one of three supervised exercise groups ( 2 days/week : high-volume with 45 minutes of moderate-intensity continuous training ( MICT ) , high-volume and high-intensity interval training ( HIIT ) , alternating high and moderate intensities , and low-volume HIIT ( 20 minutes ) ) . All variables were assessed pre- and post-intervention . All participants received the same hypocaloric diet . Results Following the intervention , there was a significant reduction in blood pressure and body mass in all groups with no between-group differences for blood pressure . However , body mass was significantly less reduced in the attention control group compared with all exercise groups ( attention control –6.6 % , high-volume MICT –8.3 % , high-volume HIIT –9.7 % , low-volume HIIT –6.9 % ) . HIIT groups had significantly higher cardiorespiratory fitness than high-volume MICT , but there were no significant between-HIIT differences ( attention control 16.4 % , high-volume MICT 23.6 % , high-volume HIIT 36.7 % , low-volume HIIT 30.5 % ) . Medication was removed in 7.6 % and reduced in 37.7 % of the participants . Conclusions The combination of hypocaloric diet with supervised aerobic exercise 2 days/week offers an optimal non-pharmacological tool in the management of blood pressure , cardiorespiratory fitness and body composition in overweight/obese and sedentary individuals with hypertension . High-volume HIIT seems to be better for reducing body mass compared with low-volume HIIT . The exercise-induced improvement in cardiorespiratory fitness is intensity dependent with low-volume HIIT as a time-efficient method in this population . Clinical Trials.gov Registration : NCT02283047 Introduction : Several established tools are available to assess study quality and reporting of r and omized controlled trials ; however , these tools were design ed with clinical intervention trials in mind . In exercise training intervention trials some of the traditional study quality criteria , such as participant or research er blinding , are extremely difficult to implement . Methods : We developed the Tool for the assEssment of Study qualiTy and reporting in EXercise ( TESTEX ) – a study quality and reporting assessment tool , design ed specifically for use in exercise training studies . Our tool is a 15-point scale ( 5 points for study quality and 10 points for reporting ) and addresses previously unmentioned quality assessment criteria specific to exercise training studies . Results : There were no systematic differences between the summated TESTEX scores of each observer [ H(2 ) = 0.392 , P = 0.822 ] . There was a significant association between the summated TESTEX scores of the three observers , with almost perfect agreement between observers 1 and 2 [ intra-class correlation coefficient ( ICC ) = 0.93 , 95 % confidence interval ( CI ) 0.82–0.97 , P < 0.001 ] , observers 1 and 3 ( ICC = 0.96 , 95 % CI 0.89–0.98 , P < 0.001 ) and observers 2 and 3 ( ICC = 0.91 , 95 % CI 0.75–0.96 , P < 0.001 ) . Conclusions : The TESTEX scale is a new , reliable tool , specific to exercise scientists , that facilitates a comprehensive review of exercise training trials The effects of long-term aerobic exercise on endothelial function in patients with essential hypertension remain unclear . To determine whether endothelial function relating to forearm hemodynamics in these patients differs from normotensive subjects and whether endothelial function can be modified by continued physical exercise , we r and omized patients with essential hypertension into a group that engaged in 30 minutes of brisk walking 5 to 7 times weekly for 12 weeks ( n=20 ) or a group that underwent no activity modifications ( control group , n=7 ) . Forearm blood flow was measured using strain-gauge plethysmography during reactive hyperemia to test for endothelium-dependent vasodilation and after sublingual nitroglycerin administration to test endothelium-independent vasodilation . Forearm blood flow in hypertensive patients during reactive hyperemia was significantly less than that in normotensive subjects ( n=17 ) . Increases in forearm blood flow after nitroglycerin were similar between hypertensive and normotensive subjects . Exercise lowered mean blood pressure from 115.7+/-5.3 to 110.2+/-5.1 mm Hg ( P<0.01 ) and forearm vascular resistance from 25.6+/-3.2 to 23 . 2+/-2.8 mm Hg/mL per minute per 100 mL tissue ( P<0.01 ) ; no change occurred in controls . Basal forearm blood flow , body weight , and heart rate did not differ with exercise . After 12 weeks of exercise , maximal forearm blood flow response during reactive hyperemia increased significantly , from 38.4+/-4.6 to 47.1+/-4.9 mL/min per 100 mL tissue ( P<0.05 ) ; this increase was not seen in controls . Changes in forearm blood flow after sublingual nitroglycerin administration were similar before and after 12 weeks of exercise . Intra-arterial infusion of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine abolished the enhancement of reactive hyperemia induced by 12 weeks of exercise . These findings suggest that through increased release of nitric oxide , continued physical exercise alleviates impairment of reactive hyperemia in patients with essential hypertension Background —Reductions in the compliance of central arteries exert a number of adverse effects on cardiovascular function and disease risk . Endurance training is efficacious in increasing arterial compliance in healthy adults . We determined the effects of resistance training on carotid arterial compliance using the intervention study design . Methods and Results —Twenty-eight healthy men 20 to 38 years old were r and omly assigned to the intervention group ( n=14 ) and the control group ( n=14 ) . Control subjects were instructed not to alter their normal activity levels throughout the study period . Intervention subjects underwent 3 supervised resistance training sessions per week for 4 months and detraining for a subsequent 4 months . The resistance training increased maximal strength in all muscle groups tested ( P<0.001 ) . There were no significant differences in baseline arterial compliance and & bgr;-stiffness index between the intervention and control groups . In the intervention group , carotid arterial compliance decreased 19 % ( P<0.05 ) , and & bgr;-stiffness index increased 21 % ( P<0.01 ) after resistance training . These values returned completely to the baseline levels during the detraining period . Arterial compliance did not change in the control group . In both groups , there were no significant changes in brachial and carotid blood pressure , carotid intima-media thickness , lumen diameter , and femoral arterial compliance . Changes in carotid artery compliance were significantly and negatively related to corresponding changes in left ventricular mass index ( r=−0.56 , P<0.001 ) and left ventricular hypertrophy index ( r=−0.68 , P<0.001 ) . Conclusions —In marked contrast to the beneficial effect of regular aerobic exercise , several months of resistance training “ reduces ” central arterial compliance in healthy men BACKGROUND Lifestyle modification ( i.e. , regular physical activity and diet ) is effective in preventing the age-related increase in cardiovascular disease risks . Potential therapeutic effects of curcumin ( diferuloylmethane ) have been confirmed on various diseases , including cancer and Alzheimer 's disease , but the effects of curcumin have not been tested on central arterial hemodynamics . The aim of this pilot study was to test the hypothesis that the regular endurance exercise combined with daily curcumin ingestion lowers the age-related increase in left ventricular ( LV ) afterload to a greater extent than monotherapy with either intervention alone in postmenopausal women using a r and omized , double-blind , placebo-controlled , parallel manner . METHODS Forty-five women were r and omly assigned to four interventions : " placebo ingestion " ( n = 11 ) , " curcumin ingestion " ( n = 11 ) , " exercise training with placebo ingestion " ( n = 11 ) , or " exercise training with curcumin ingestion " ( n = 12 ) . Curcumin or placebo pills ( 150 mg/day ) were administered for 8 weeks . Aortic blood pressure ( BP ) and augmentation index ( AIx ) , an index of LV afterload , were evaluated by pulse wave analysis from tonometrically measured radial arterial pressure waveforms . RESULTS There were no significant differences in baseline hemodynamic variables among four groups . After the interventions , brachial systolic BP ( SBP ) significantly decreased in both exercise-trained groups ( P < 0.05 for both ) , whereas aortic SBP significantly decreased only in the combined-treatment ( e.g. , exercise and curcumin ) group ( P < 0.05 ) . Heart rate ( HR ) corrected aortic AIx significantly decreases only in the combined-treatment group . CONCLUSIONS These findings suggest that regular endurance exercise combined with daily curcumin ingestion may reduce LV afterload to a greater extent than monotherapy with either intervention alone in postmenopausal women Purpose Regular physical exercise is recommended for the prevention and treatment of cardiovascular disease . However , it is unclear whether the effects of exercise training on arterial stiffness are the same in older hypertensive individuals as those observed in older healthy subjects . The aim of this study was to compare the effects of exercise training on arterial stiffness between older hypertensive and healthy females . Methods Ninety-two females with untreated hypertension and 108 healthy females were r and omly assigned to either the control group or to participate in a 12-week training program . In the training groups , the subjects engaged in 90 min of training twice a week for 12 weeks . Each training program included recreational activities , six to eight resistance exercises for circuit training and chair-based exercise for the lower extremities . The systolic/diastolic blood pressure ( SBP/DBP ) and brachial to ankle pulse wave velocity ( baPWV ) were obtained in the supine position using an automatic pulse wave form analyzer . Results Compared with that observed in the control group , greater reductions in the baPWV and SBP/DBP were achieved in both training groups ( P < 0.05 ) . Furthermore , a significant difference in the delta baPWV values obtained before and after training was noted between the hypertensive ( −72.5 ± 8.1 cm s−1 ) and healthy females ( −131.5 ± 107.3 cm s−1 ) who participated in the training program ( P < 0.05 ) . Conclusions These data indicate that exercise training produces fewer improvements in arterial stiffness in older hypertensive females than in older healthy females Background : Resistance training has been increasingly incorporated into the overall exercise programme because of its effect on muscle strength , functional capacity and osteoporosis . High-intensity resistance training increases arterial stiffness . However , the effect of moderate-intensity resistance training on arterial stiffness is unknown . Objective : To determine whether 12 weeks of moderate-intensity resistance training increases arterial stiffness in middle-aged women . Methods : 35 middle-aged women ( age range 32 to 59 years ) volunteered to participate . The subjects were r and omly assigned to one of three groups : resistance training ( RT ) group , aerobic exercise training ( AET ) group or control group . The RT and AET groups performed 12 weeks of moderate-intensity resistance training or aerobic exercise training ( two days/week ) . Results : In the RT group , one-repetition maximum strength significantly increased after the intervention . Interestingly , aortic ( carotid – femoral ) pulse wave velocity ( PWV ; an index of arterial stiffness ) , and peripheral ( femoral – ankle ) PWV did not change with moderate-intensity resistance training . In contrast , in the AET group , carotid – femoral PWV significantly decreased after the intervention . Resistance training and aerobic exercise training did not affect blood pressure . Conclusions : This study found that moderate-intensity resistance training did not increase arterial stiffness in middle-aged women , which may have great importance for health promotion with resistance training Muscle contractions in normal resistance training are performed by eccentric ( ECC , lowering phase ) and concentric ( CON , lifting phase ) muscle contractions . However , the difference in effects of timing of muscle contraction during resistance training on arterial stiffness is unknown . This study investigated the effect of muscle contraction timing during resistance training on vascular function in healthy young adults . Thirty healthy men were r and omly assigned to group of resistance training with quick lifting and slow lowering ( ERT , n=10 ) , group of resistance training with slow lifting and quick lowering ( CRT , n=10 ) and sedentary groups ( SED , n=10 ) . The ERT and CRT groups underwent two supervised resistance-training sessions per week for 10 weeks . The ERT group performed the on set of 8–10 repetitions with 3 s ECC and 1 s CON muscle contractions . In contrast , the CRT group performed the on set of 8–10 repetitions with 1 s ECC and 3 s CON muscle contractions . Brachial – ankle pulse wave velocity ( baPWV ) after ERT did not change from baseline . In contrast , baPWV after CRT increased from baseline ( from 1049±37 to 1153±30 cm s−1 , P<0.05 ) . No significant changes in flow-mediated dilation were observed in the ERT and CRT groups . These values did not change in the SED group . These findings suggest that although both training does not deteriorate a vascular endothelial function , resistance training with quick lifting and slow lowering ( that is , ERT ) prevent the stiffening of arterial stiffness The concentration of high-density lipoprotein cholesterol ( HDL-C ) is inversely correlated with the risk of coronary heart disease . The effects of low-intensity aerobic training on serum HDL-C and other lipoprotein concentrations were examined in healthy elderly subjects . The subjects were r and omly assigned to two groups matched for sex , age , height , and weight . The training group ( n = 20 , 10 men and 10 women aged 67 + /- 4 years ) participated in a supervised physical exercise regimen using a bicycle ergometer at an intensity of 50 % estimated maximal oxygen consumption ( VO2max ) for 60 minutes two to four times per week for 5 months . In contrast , the control group ( n = 20 , 10 men and 10 women aged 68 + /- 4 years ) did not perform any particular physical training . The training protocol result ed in significant increases in the VO2max ( P < .05 ) , HDL-C , HDL2-C , and HDL2-C/HDL3-C ratio ( P < .01 ) . The change in HDL2-C ( r = .57 , P < .01 ) and HDL2-C/HDL3-C ( r = .63 , P < .01 ) was positively associated with an increase in the total exercise duration per week . In addition , the total weekly exercise duration also showed a significant positive relationship with HDL-C ( r = .75 , P < .01 ) , HDL2-C ( r = .81 , P < .01 ) , and HDL2-C/HDL3-C ( r = .71 , P < .01 ) after the training period . The changes in body weight and the VO2max were not significantly correlated with any lipid parameters . Low-intensity aerobic training may improve the profile of HDL-C and its subfractions in healthy elderly subjects . Also , the total exercise duration may be an important factor for improving HDL-C and HDL2-C in elderly subjects There is a dearth of reports on possible additive blood pressure (BP)-reducing effect of aerobic exercise on antihypertensive drug in humans . This study investigated the additive BP-reducing effect of aerobic exercise on BP in individuals with uncontrolled hypertension . In this 12-week double-blind study , 120 new-diagnosed individuals with mild-to-moderate hypertension were r and omized to receive coamilozide + 5/10 mg of amlodipine + aerobic dance or coamilozide + 5/10 mg of amlodipine alone . Forty-five and 43 participants in exercise and control groups , respectively , completed the 12-week intervention . Addition of aerobic exercise to antihypertensive drug therapy significantly reduced systolic BP ( 7.1 mm Hg [ 95 % confidence interval : 5.0 , 9.3 ] ; P < .001 ) and diastolic BP ( 1.7 mm Hg [ 95 % confidence interval : 0.4 , 3.0 ] ; P = .009 ) at 12 weeks . BP control rate differed significantly between exercise ( 53.9 % ) and control ( 35.3 % ) groups , P < .001 . Postintervention , proportion of participants in exercise group who had their number of antihypertensive drug reduced to one ( 20.3 % ) differed from that in control group ( 11.1 % ) ; ( χ(2 ) = 11.0 ; P = .001 ) . Combination of aerobic dance and antihypertensive drugs reduces number of antihypertensive drugs needed to achieve BP control and enhances BP control in individuals with hypertension on two antihypertensive drugs Interval training is effective for promoting aerobic capacity and general health . However , it involves repeated high-intensity activity , which could pose cardiovascular risks for the elderly or people who are less fit . We developed a transitory stimulation interval exercise ( TSIE ) in which the duration of strenuous exertion was reduced to 30 seconds at 75 % VO2max of intensity . This pilot study aims to explore the effects of this mode of exercise . Thirty women were r and omized and stratified into the TSIE group , the continuous moderate exercise ( CME ) group , or the no-exercise ( NE ) group . The two exercise groups performed exercises for 12 weeks . Significant positive changes were observed in the TSIE group compared with the NE group in the relative change ratio from baseline in body weight and VO2max , but no significant differences were observed between the CME group and the NE group . Glycated hemoglobin A1c ( HbA1c ) decreased significantly in both exercise groups compared with the NE group . Overall , there were few significant differences between the CME group and the TSIE group . There might not be any differences between the TSIE and the CME in a long term intervention with equalized training volumes Regular aerobic exercise can reduce blood pressure and is recommended as part of the lifestyle modification to reduce high blood pressure and cardiovascular risk . Hypertension itself , or/ and pharmacological treatment for hypertension is associated with adverse effects on some aspects of quality of life . This study was performed to evaluate the effects of regular endurance exercise training on quality of life and blood pressure . Patients with mild to moderate hypertension ( systolic blood pressure 140–180 or diastolic blood pressure 90–110 mm Hg ) were r and omized to a moderate‐intensity aerobic exercise group training for 3 sessions/week over 10 weeks or to a non‐exercising control group . Health‐related quality of life was assessed with the Short Form 36‐item Health Survey ( SF‐36 ) at baseline and after 6 and 10 weeks . In the 102 subjects ( 47 male , mean age 47 years ) who completed the study , reductions in blood pressure in the exercise group at 10 weeks ( − 13.1/− 6.3 mm Hg ) were significant ( P < 0.001 ) compared to baseline and to the control group ( − 1.5/+ 6.0 mm Hg ) . Unlike the control group , the exercise group showed an increase in exercise capacity from 8.2 ± 1.6 to 10.8 ± 2.2 METS ( P < 0.01 ) and showed higher scores on 7 out of 8 subscales ( P < 0.05 ) of the SF‐36 . Improvement in bodily pain and general health sub‐scores correlated with reduction in systolic blood pressure . Regular endurance training improves both blood pressure and quality of life in hypertensive patients and should be encouraged more widely Vascular endothelial cells produce nitric oxide ( NO ) , which is a potent vasodilator substance and is thought to have antiatherosclerotic properties . Therefore , it has also been proposed that NO may be useful to regulate vascular tonus and prevent progression of atherosclerosis . On the other h and , NO activity reduces with aging . We previously reported that the plasma nitrite/nitrate ( NOx : the stable end product of NO ) concentration was significantly increased by intense aerobic exercise training in healthy young humans . We hypothesized that lifestyle modification ( e.g. , even mild regular exercise training ) can increase NO production in previously sedentary older humans . We measured the plasma NOx concentration before and after a mild aerobic exercise training regimen ( cycling on a leg ergometer at 80 % ventilatory threshold for 30 min , 5 days/week ) for 3 months in elderly women . In addition , we assessed the plasma concentration of cyclic guanosine monophosphate ( cGMP ) , a second messenger of NO , in the same sample s. The individual ventilatory threshold increased significantly after the 3-month exercise training . The blood pressure at rest significantly decreased after exercise training . These results suggest that the 3-month exercise training in the older women produced favorable physiological effects . The plasma concentration of NOx significantly increased by the exercise training , and the plasma concentration of cGMP also increased by the exercise training . The present study suggests that even a mild regular aerobic-endurance exercise increases NO production in previously sedentary older humans , which may have beneficial effects ( i.e. , antihypertensive and antiatherosclerotic effects by endogenous NO ) on the cardiovascular system It has been suggested that resistance training ( RT ) increases arterial stiffness . The purpose of the present study was to clarify the effect of eccentric RT ( ERT ) and concentric RT ( CRT ) on arterial stiffness in female adults by an interventional study . In total , 29 healthy female subjects were r and omly assigned to either the ERT group ( n=10 ) , CRT group ( n=10 ) or sedentary ( SED ) group ( n=9 ) . The ERT and CRT groups performed resistance training three times a week for 8 weeks . We determined brachial blood pressure , brachial-ankle pulse wave velocity ( baPWV ) , carotid artery intimamedial thickness ( IMT ) and carotid arterial lumen diameter before and after training and after detraining . The before-training baPWV did not differ significantly among the three groups . After 8 weeks of RT , arterial stiffness in the CRT group was increased compared with the ERT and SED group ( P<0.05 ) . However , brachial blood pressure , baPWV , carotid IMT and carotid lumen diameter in the ERT and CRT groups were unchanged by RT for 8 weeks . Consequently , it was clarified that arterial stiffness was not changed by ERT for 8 weeks . This suggests that ERT may be effective as an exercise prescription for middle-aged and elderly adults Objective : Menopause is associated with increased arterial stiffness and reduced muscle strength . Combined resistance ( RE ) and endurance ( EE ) exercise training can decrease brachial-ankle pulse wave velocity ( baPWV ) , an index of arterial stiffness , in young men . We tested the hypothesis that combined circuit RE and EE training would improve baPWV , blood pressure ( BP ) , and muscle strength in postmenopausal women . Methods : Twenty-four postmenopausal women ( age 47 - 68 y ) were r and omly assigned to a " no exercise " control ( n = 12 ) or to combined exercise training ( EX ; n = 12 ) group . The EX group performed concurrent circuit RE training followed by EE training at 60 % of the predicted maximal heart rate ( HR ) 3 days per week . Brachial systolic BP , diastolic BP , mean arterial pressure , baPWV , HR , and dynamic and isometric muscle strength were measured before and after the 12-week study . Results : Mean ± SE baPWV ( −0.8 ± 0.2 meters/s ) , systolic BP ( −6.0 ± 1.9 mm Hg ) , diastolic BP ( −4.8 ± 1.7 mm Hg ) , HR ( −4.0 ± 1.0 beats/min ) , and mean arterial pressure ( −5.1 ± 1.6 mm Hg ) decreased ( P < 0.05 ) , whereas dynamic leg strength ( 5.1 ± 1.0 vs 0.6 ± 1.0 kg for the EX and control groups , respectively ) and isometric h and grip strength ( 2.8 ± 0.7 vs −0.6 ± 1.2 kg ) increased ( P < 0.05 ) in the EX group but not in the control group . Conclusions : Our findings indicate that a 12-week moderate-intensity combined circuit RE and EE training improves arterial stiffness , hemodynamics , and muscle strength in previously sedentary postmenopausal women . This study provides evidence that combined training may have important health implication s for the prevention of hypertension and frailty in postmenopausal women T blood pressure ( BP ) response to submaximal exercise may be especially important because of its relation to the future risk of hypertension and development of left ventricular hypertrophy.1–5 Exercise BP tends to be higher in African-American ( AA ) than in Caucasian ( C ) subjects,6 but lower in fit than unfit persons in the AA and C groups.7,8 In the Health Risk Factors Exercise Training and Genetics ( HERITAGE ) Family Study 9 submaximal BP was significantly reduced at both absolute ( 50 W ) and relative ( 60 % ) power outputs after exercise training . The decrease was greater in AA than C men and women , and in older than younger subjects . However , the specific effect in postmenopausal women was not evaluated . Considering postmenopausal AA women have a high incidence of hypertension10 and little is known about the effect of exercise training on resting and exercise BP in this population , the purpose of this study was to determine the resting and exercise BP responses to aerobic exercise training in C and AA postmenopausal women . • • • This was a r and omized , longitudinal , controlled trial examining the effects of a 6-month , moderate-tovigorous intensity , cardiovascular exercise training program on BP in C and AA postmenopausal women with normal and /or high normal BP . After undergoing baseline testing , women were r and omly assigned to exercise or control groups . The exercise groups participated in a 6-month supervised exercise program , whereas the control group was instructed to maintain their current lifestyle . Written informed consent was obtained from all volunteers ’ subjects before participation , and the study was approved by the University Medical Center Institutional Review Board . Sixty healthy sedentary postmenopausal women aged 45 to 70 years volunteered to serve as subjects . A postmenopausal subject was defined as one who had amenorrhea for 6 months or was aged 55 years with no bleeding for 6 months , and generally was in good health and was able to exercise at the rate described in our protocol ; this subject was also sedentary for a minimum of 6 months before participation . Sedentary was defined as no 1 day/week of aerobic exercise activity lasting 20 minutes . Subjects were excluded if they had moderate to severe hypertension ( defined as BP at rest 160/100 mm Hg at entry ) , diabetes , history of thyroid disease or use of thyroid medications , history of deep vein thrombosis , pulmonary embolism , cardiovascular disease , familial hypercoagulability , or if they were current cigarette smokers . Thirty-three C and 27 AA women were r and omly assigned to supervised aerobic exercise training ( C , n 17 ; AA , n 15 ) or nonexercise control ( C , n 16 ; AA , n 12 ) . Subjects visited the laboratory in the morning after a 12-hour fast , having refrained from physical activity for 24 hours . BP at rest was obtained through st and ard sphygmomanometry in the sitting position after 1 hour of rest in a quiet room with dim lighting . We measured BP in both arms , 3 times in each arm . The 3 BP determinations were made 2 minutes apart and the values were averaged to determine each subject ’s BP at rest . The subjects then performed a maximal exercise test using a modified Bruce protocol on a motorized treadmill with continuous electrocardiographic and gas analysis measurements ( Quinton Q-Plex , Bothell , Washington ) . Twelve-lead electrocardiograms , BP , and ratings of perceived exertion were recorded during the last minute of each exercise stage . Exercise BP was measured during grade d exercise testing through st and ard sphygmomanometry . The maximal ( or peak ) oxygen uptake was defined as the highest 20-second value attained provided 2 of the following criteria were met : the subject was within 10 beats/min of predicted maximal heart rate ; a plateau was reached in oxygen uptake with an increase in workload ( an increase of 2.0 ml/ kg/min ) ; ratings of perceived exertion were 18 ; and /or a respiratory exchange ratio was 1.05 . These procedures were performed at baseline and at the end of the 6-month study . After completion of the test , each subject was r and omly assigned to either the exercise or control group . The exercise training group entered the supervised exercise program and the control subjects were asked to maintain their current behavior throughout the 6-month study period . The aerobic exercise training consisted of 3 to 4 exercise sessions per week . Subjects were provided with Polar heart rate monitors ( Polar Electro Inc , Port Washington , New York ) to ensure and monitor adherence to the prescribed intensity . Exercise included treadmill walking/jogging , stationary cycling , and rowing . Intensity was prescribed at 70 % to 85 % of their measured maximal heart rate . Exercise duration was gradually increased during the first 8 weeks until subjects were exercising for 45 to 60 minutes/session , From the Exercise and Health Laboratory , Faculty of Human Movement , Technical University of Lisbon , Lisbon , Portugal ; Human Performance Laboratory , Medical Center , George Washington University , Washington , DC ; and Exercise Science Department , Syracuse University , Syracuse , New York . This study was supported by the American Heart Association , Washington , DC Affiliate , Washington , DC . Dr. Santa-Clara ’s address is : Faculdade de Motricidade Humana , Estrada da Costa , 1495 - 688 Cruz-Quebrada , Portugal . E-mail : [email protected] . Manuscript received August 26 , 2002 ; revised manuscript received and accepted January 7 , 2003 BACKGROUND The prevalence of hypertension and its cardiovascular complications is higher in African Americans than in whites . Interventions to control blood pressure in this population are particularly important . Regular exercise lowers blood pressure in patients with mild-to-moderate hypertension , but its effects in patients with severe hypertension have not been studied . We examined the effects of moderately intense exercise on blood pressure and left ventricular hypertrophy in African-American men with severe hypertension . METHODS We r and omly assigned 46 men 35 to 76 years of age to exercise plus antihypertensive medication ( 23 men ) or antihypertensive medication alone ( 23 men ) . A total of 18 men in the exercise group completed 16 weeks of exercise , and 14 completed 32 weeks of exercise , which was performed three times per week at 60 to 80 percent of the maximal heart rate . RESULTS After 16 weeks , mean ( + /- SD ) diastolic blood pressure had decreased from 88 + /- 7 to 83 + /- 8 mm Hg in the patients who exercised , whereas it had increased slightly , from 88 + /- 6 to 90 + /- 7 mm Hg , in those who did not exercise ( P = 0.002 ) . Diastolic blood pressure remained significantly lower after 32 weeks of exercise , even with substantial reductions in the dose of antihypertensive medication . In addition , the thickness of the interventricular septum ( P = 0.03 ) , the left ventricular mass ( P = 0.02 ) , and the mass index ( P = 0.04 ) had decreased significantly after 16 weeks in the patients who exercised , whereas there was no significant change in the nonexercisers . CONCLUSIONS Regular exercise reduced blood pressure and left ventricular hypertrophy in African-American men with severe hypertension Objective To determine the effects of exercise training on the blood pressure ( BP ) values of older adults , using home blood pressure measurement . Design R and omized controlled trial . Participants A total of thirty-nine free-living older adults ( including 19 men ) aged from 60–81 years with home systolic blood pressure > 120 mmHg and without significant cardiopulmonary-musculoskeletal disease , were r and omly allocated to either 25 weeks of exercise training ( exercise group ) or to a control program ( control group ) . Main outcome measurements Change in the 2-week averages of home systolic and diastolic blood pressure values measured with a vali date d automatic device before , during and after the intervention period . Results Compared with the control group , the exercise group showed a significant decrease in values for home systolic blood pressure ( maximum between-group difference = 7.7 mmHg , P = 0.003 ) and home diastolic blood pressure ( 4.2 mmHg , P = 0.001 ) . These changes were observed for both genders . Conclusions Exercise training was effective for older adults in lowering home blood pressure values . This is the first trial to demonstrate the usefulness of home blood pressure measurement in examining the effect of exercise training on blood pressure values Objective To investigate the effect of combined aerobic and resistance training ( CART ) on heart rate variability in sedentary , hypertensive women . Participants A total of twenty-eight hypertensive ( Stage 1 and 2 ) sedentary women ( Age 40.54 ± 4.2 yrs ; Height 155.14 ± 5.4 cm ; Weight 70.96 ± 10.2 kg ; BMI 29.6 ± 4.4 ; Duration of HTN : 6.43 ± 2.5 yrs ) were recruited for the study . Methods Participants were r and omly assigned to either the CART group that performed combined aerobic and resistance exercise of moderate intensity [ aerobic exercise 50–80 % of HRmax ( maximum heart rate ) and resistance exercises at 50–80 % of 1 Repetition Maximum ( RM ) ] , 5 times/week for 4 weeks , or to the control group that followed conventional treatment without any supervised exercise intervention . Main outcome measures Resting blood pressure was measured and st and ard heart rate variability ( HRV ) indices were calculated using time domain ( SDNN , pNN50 , RMSSD ) and frequency domain ( LFnu , HFnu , LF/HF and TP ) analysis . Results CART group demonstrated an increase in HFnu , TP , SDNN , and RMSSD , ( p < 0.05 ) along with a significant decrease in LFnu , LF/HF ratio , systolic blood pressure , and diastolic blood pressure ( p < 0.05 ) . Conclusion CART showed significant improvement in HRV parameters indicating vagal dominance in middle-aged hypertensive women . Therefore , exercise training in combined form ( aerobic and resistance ) may be incorporated in the management programs of the patients suffering from hypertension in order to augment improvement in their cardiac autonomic control Metabolic syndrome is associated with reductions in basal limb blood flow . Resistance training increasing muscle mass and strength increases basal limb blood flow . Low‐intensity resistance exercise with slow movement and tonic force generation ( LST ) has been proposed as one of the effective methods of resistance training increasing muscle mass and strength . The hypothesis that LST training increases basal femoral blood flow as well as traditional high‐intensity resistance training at normal speed ( HN ) was examined . Thirty‐six healthy young men without a history of regular resistance training were r and omly assigned to the LST [ ∼55–60 % one repetition maximum ( 1RM ) load , 3 s lifting and 3 s lowering with no relaxation phase , n = 12 ] , HN ( ∼85–90 % 1RM , 1 s lifting and 1 s lowering with 1 s relaxation , n = 12 ) or sedentary control ( CON , n = 12 ) groups . Participants in the training groups underwent two whole‐body training sessions per week for 13 weeks . Basal femoral blood flow increased significantly by + 18 % in LST and + 35 % in HN ( both P<0·05 ) , while there was no such change in CON . There were no significant differences between these increases induced by LST and HN , although the increase in LST corresponded to about half that in HN . In conclusion , not only resistance training in HN but in LST as well , were effective for increasing basal limb blood flow , and that this effect was evident even in healthy young men |
1,907 | 24,396,220 | Conclusion ] While the findings suggest the benefits of an AFO regarding gait velocity , the impact of this type of orthosis on cadence remains inconclusive . | [ Purpose ] The aim of the present study was to analyze the effect of an ankle-foot orthosis on gait variables ( velocity and cadence ) of stroke patients . | Objective : To compare the effect of the Chignon ankle-foot orthosis on gait versus a st and ard ankle-foot orthosis . Method : A multicentre r and omized study was conducted in seven rehabilitation centres . Hemiplegic patients were recruited after unilateral stroke lasting less than six months . Exclusion criteria were : impossibility to st and for 10 seconds ; ankle passive dorsiflexion < 5 degrees with knee flexed to 90 degrees ; triceps spasticity ≥3/4 on the Ashworth modified scale ; diseases that might impair active participation in the study . Thirteen patients were r and omized to the Chignon group and 15 to the control group . Included patients were given a st and ard ankle-foot orthosis or Chignon ankle-foot orthosis . The Chignon ankle-foot orthosis is an articulated double-stopped custom-made orthosis with elements to assist dorsiflexion and plantar flexion . Gait speed improvement ( ten-metre test ) , kinematic assessment , and functional scales were assessed . Results : Gain ratio of walking speed with the orthosis increased significantly more in the Chignon group than in the control group at day 0 ( 27.2 ± 36 % versus −0.8 ± 17 % ; P = 0.006 ) , day 30 ( 39.9 ± 19 % versus 7.5 ± 17 % ; P = 0.0004 ) and day 90 ( 44.6 ± 27 % versus 17.1 ± 0.3 % ; P = 0.04 ) . There was also a significant improvement in kinematic parameters and spasticity in the Chignon group . Conclusion : Early compensation of distal motor deficiency by the Chignon ankle-foot orthosis improves the immediate gait of hemiplegics more than the st and ard ankle-foot orthosis and seems to modify motor recovery processes in the legs after stroke Objective : To investigate the short- and long-term effects of dynamic ankle foot orthoses on functional ambulation activities in chronic hemiparetic patients . Design : R and omized controlled trial . Setting : University ’s neurological rehabilitation outpatient clinic and orthotics department . Subjects : Twenty-eight chronic hemiparetic patients of level 3–5 according to Functional Ambulation Classification and with a maximum spasticity level of 3 according to Modified Ashworth Scale , were r and omly assigned to the study and control groups . Interventions : The control group ( n = 14 ) was assessed with tennis shoes whereas the study group ( n = 14 ) was assessed initially with tennis shoes and after three months with dynamic ankle foot orthosis . Measures : Functional Reach , Timed Up and Go , Timed Up Stairs , Timed Down Stairs , gait velocity and Physiological Cost Index . Results : In the initial assessment no difference was found between the groups for any of the measured parameters ( P > 0.05 ) . After three months , intergroup comparisons while the patients in the study group were wearing dynamic ankle-foot orthosis showed a significant difference in favour of the study group for Timed Up Stairs 12.00 ( 10.21 ) seconds study versus 15.00 ( 7.29 ) seconds control group ; for gait velocity 0.99 ( 0.45 ) m/s study versus 0.72 ( 0.20 ) m/s control group and for Physiological Cost Index 0.12 ( 0.06 ) beats/min study versus 0.28 ( 0.13 ) beats/min control group ( P < 0.05 ) . No difference was found between the groups for Functional Reach , Timed Up and Go , Timed Down Stairs ( P > 0.05 ) . Conclusion : Chronic hemiparetic patients may benefit from using dynamic ankle-foot orthosis Objective : To examine the effects of an ankle-foot orthosis ( AFO ) on balance performance in patients with hemiparesis of short and long duration . Design : Within-subject r and om order of intervention , cross-sectional study design . Setting s : Medical centres and district hospitals . Subjects : Forty-two subjects with hemiparesis of short duration ( B = six months ) and 61 subjects of long duration ( = 12 months ) . Measurements : The balance and gait ability of subjects were evaluated both with an AFO and without . The static and dynamic balance activities were evaluated by the Balance Master System , whereas the functional balance was assessed with the Berg Balance Scale . The speed and cadence were also measured during a 10-metre walk . Paired t-test was used to determine the effect of the AFO . Results : In subjects with hemiparesis of short duration , we found that subjects wearing an AFO showed significant improvements in ( 1 ) weight-bearing distribution during quiet st and ing ( p / 0.042 , 95 % confidence interval ( CI ) 0.521 , 7.325 ) , ( 2 ) body sway during st and ing on foam surface with eyes open ( p / 0.020 , 95 % CI 0.020 , 0.680 ) and eyes closed ( p / 0.041 , 95 % CI 0.023 , 0.921 ) , ( 3 ) movement velocity during limit of stability test ( LOS ) / toward the affected side ( p / 0.037 , 95 % Cl / 0.978 , / 0.042 ) and nonaffected side ( p / 0.008 , 95 % CI / 2.223 , / 0.377 ) , ( 4 ) maximal excursion toward the affected side ( p / 0.042 , 95 % CI / 19.546,=0.071 ) , and ( 5 ) speed ( p / 0.028 , 95 % CI / 0.204 , / 0.017 ) and cadence ( p / 0.021 , 95 % CI / 22.983 , / 1.864 ) . Such effects were not observed in subjects with hemiparesis of long duration . Conclusions : For the subjects with hemiparesis of short duration , the AFO improves the symmetry in quiet and dynamic st and ing balances . It also increases speed and cadence . However , its effectiveness is minimal for patients of long duration OBJECTIVE To evaluate the kinematic features of rear-foot motion during gait in hemiplegic stroke patients , using anterior ankle-foot orthoses ( AFOs ) , posterior AFOs , and no orthotic assistance . DESIGN Crossover design with r and omization for the interventions . SETTING A rehabilitation center for adults with neurologic disorders . PARTICIPANTS Patients with hemiplegia due to stroke ( n=14 ) and able-bodied subjects ( n=11 ) . INTERVENTIONS Subjects with hemiplegia were measured walking under 3 conditions with r and omized sequences : ( 1 ) with an anterior AFO , ( 2 ) with a posterior AFO , and ( 3 ) without an AFO . Control subjects were measured walking without an AFO to provide a normative reference . MAIN OUTCOME MEASURES Rear-foot kinematic change in the sagittal , coronal , and transverse planes . RESULTS In the sagittal plane , compared with walking with an anterior AFO or without an AFO , the posterior AFO significantly decreased plantar flexion to neutral at initial heel contact ( P=.001 ) and the swing phase ( P<.001 ) , and increased dorsiflexion at the stance phase ( P=.002 ) . In the coronal plane , the anterior AFO significantly increased maximal eversion to neutral ( less inversion ) at the stance phase ( P=.025 ) , and decreased the maximal inversion angle at the swing phase when compared with using no AFO ( P=.005 ) . The posterior AFO also decreased the maximal inversion angle at the swing phase as compared with no AFO ( P=.005 ) . In the transverse plane , when compared with walking without an AFO , the anterior AFO and posterior AFO decreased the adduction angle significantly at initial heel contact ( P=.004 ) . CONCLUSIONS For poststroke hemiplegic gait , the posterior AFO is better than the anterior AFO in enhancing rear-foot dorsiflexion during a whole gait cycle . The anterior AFO decreases rear-foot inversion in both the stance and swing phases , and the posterior AFO decreases the rear-foot inversion in the swing phase when compared with using no AFO BACKGROUND Ankle-foot orthoses are often provided to improve walking in stroke patients , although the evidence of effects on walking and balance control is still inconsistent . This could be caused by a lack of insight into the influence of orthoses on the underlying impairments . These impairments can be assessed with dual plate posturography to determine the relative contribution of each lower limb to balance control and weight-bearing . This study examined the effects of ankle-foot orthoses on functional balance , static and dynamic weight-bearing asymmetry and dynamic balance control of the paretic and non-paretic lower limbs . METHODS Twenty stroke subjects ( time since stroke 5 - 127 months ) completed the study . Subjects were assessed with and without ankle-foot orthosis . Functional balance was assessed using the Berg Balance Scale , Timed Up & Go test , Timed Balance Test , 10-m walking test and Functional Ambulation Categories . Weight-bearing asymmetry and dynamic balance control were assessed with force plates on a movable platform . FINDINGS No significant effects of ankle-foot orthoses were found for weight-bearing asymmetry and dynamic balance control , but significant differences in favour of ankle-foot orthosis use were found for most functional tests . INTERPRETATION Although ankle-foot orthoses had no effect on weight-bearing asymmetry or dynamic balance contribution of the paretic lower limb , functional tests were performed significantly better with orthoses . Apparently , improvements at functional level can not be readily attributed to a greater contribution of the paretic lower limb to weight-bearing or balance control . This finding suggests that ankle-foot orthoses influence compensatory mechanisms Objective : Regaining walking ability is a major goal during the rehabilitation of stroke patients . To support this process an ankle-foot orthosis ( AFO ) is often prescribed . The aim of this study is to investigate the effect of an AFO on walking ability in chronic stroke patients . Design : Cross-over design with r and omization for the interventions . Methods : Twenty chronic stroke patients , wearing an AFO for at least six months , were included . Walking ability was operationalized as comfortable walking speed , scores on the timed up and go ( TUG ) test and stairs test . Patients were measured with and without their AFO , the sequence of which was r and omized . Additionally , subjective impressions of self-confidence and difficulty of the tasks were scored . Clinical ly relevant differences based on literature were defined for walking speed ( 20 cm/s ) , the TUG test ( 10 s ) . Gathered data were statistically analysed using a paired t-test . Results : The mean difference in favour of the AFO in walking speed was 4.8 cm/s ( 95 % CI 0.85–8.7 ) , in the TUG test 3.6 s ( 95 % CI 2.4 4.8 ) and in the stairs test 8.6 s ( 95 % CI 3.1 –14.1 ) . Sixty-five per cent of the patients experienced less difficulty and 70 % of the patients felt more self-confident while wearing the AFO . Conclusions : The effect of an AFO on walking ability is statistically significant , but compared with the a priori defined differences it is too small to be clinical ly relevant . The effect on self-confidence suggests that other factors might play an important role in the motivation to use an AFO |
1,908 | 20,143,206 | The results of this review were also positive for the active treatment regarding the secondary variables , which were represented by the number of patients with at least one RTI and the mean number of RTIs .
Conclusions This meta- analysis shows , as observed in several individual trials , that the population treated with OM-85 BV had significantly and consistently fewer cases of recurrent RTIs .
The data suggest that the effect is greater in patients at increased risk of recurrent RTIs | Background This study was conducted to assess the efficacy of OM-85 BV ( Broncho-Vaxom ) in the prevention of pediatric recurrent respiratory tract infections ( RTIs ) .
Available evidence suggests that defining recurrent RTIs as ≥3 infections per fall-winter semester is both medically and epidemiologically justified .
Therefore , this criterion was chosen as a primary endpoint . | The efficacy of Broncho-Vaxom/Imocur ( OM-85 BV ) , an orally administered lyophilized bacterial extract , for recurrent respiratory and ear , nose and throat ( ENT ) infections was evaluated in 116 children aged 6 months to 19 years by comparing its activity in 61 children with that of a placebo in 55 children . The study was r and omized , double-blind , and comprised a 90-day treatment period followed by a 90-day follow-up period without test drugs . Over the 180 days , 39.5 % of patients taking OM-85 BV remained free from infection compared with 16.5 % on placebo ( p less than 0.01 ) . 44 % on OM-85 BV did not need antibiotics compared with 23.5 % on placebo ( p less than 0.05 ) . These differences were even greater in the subgroup of children aged 6 years and less ( 34 vs. 3.5 % for the absence of infections , p less than 0.01 and 37 vs. 10 % for the need of antibiotics , p less than 0.05 ) . Tolerance to OM-85 BV was excellent , and laboratory investigations showed no abnormalities attributable to this product . This work confirms that the immunomodulator OM-85 BV is an effective immunotherapy for recurrent respiratory and ENT infections in children Using a cohort-based design and r and om enrollment , the relation of various risk factors to acute otitis media , respiratory infection and wheezy bronchitis was studied in 2512 children from the fetal period to the age of two years . The complex interrelations of the risk factors with each other were separated out by multivariate analysis , and the confounding effects of antenatal parameters were also st and ardized . Acute otitis media with effusion ( AOME ) , as demonstrated by myringotomy , was analyzed as a specific subgroup of acute otitis media ( AOM ) . Day care in local authority nursery was the major risk factor for both types of acute otitis media . The odds ratio ( OR ) for such children becoming ' otitis-prone ' ( greater than or equal to 3 episodes of AOME ) was 1.8 ( 95 % confidence interval , 1.4 - 2.2 ) . Short duration of breastfeeding involved another significant risk of recurrent respiratory infections and otitis media , the OR for AOME being 1.5 ( 1.1 - 2.0 ) and that for recurrent respiratory infection 1.3 ( 1.1 - 1.6 ) . Allergy and family day care were also significantly associated with infective parameters , but to a lesser extent . The risk factors for wheezy bronchitis were the same as for infections , indicating that wheezy bronchitis is closely related to infections In a 6-month placebo-controlled double-blind multicenter study in 230 patients with recurrent respiratory tract infections , the therapeutic efficacy of Broncho-Vaxom was demonstrated by comparing infection incidence and severity as well as antibacterial medication . Investigators and patients agreed that Broncho-Vaxom exerts a significantly greater protective effect than placebo . Reports of side effects were more frequent with placebo as compared to Broncho-Vaxom BACKGROUND Recurrent acute respiratory tract infections ( RARTIs ) in children are related to IgG subclass deficiencies . The aim of the trial was to evaluate the effect of OM-85 BV in the number of RARTIs as well as in the IgG subclass levels . METHODS This was a r and omized , double-blind , placebo-controlled clinical trial . Patients of ages three to six years , having three or more documented ARTIs during the last six months with subnormal IgG subclass levels were included . Patients took either one capsule of OM-85 BV ( 3.5 mg ) or placebo orally every day for ten consecutive days per month during three consecutive months . Patients were followed three further months without drug intake . IgG subclass levels were determined before and after treatment . RESULTS IgG4 levels diminished after the OM-85 BV treatment ( -3 [ -8.0 , -1.0 ] median difference [ 95 % CI ] p < 0.05 by Wilcoxon test ) . No other significant changes in IgG subclasses were observed . After six months the patients in the OM-85 BV group ( n = 20 ) experienced 2.8 1.4 ( mean SD ) ARTIs , while the patients in the placebo group ( n = 20 ) suffered 5.2 1.5 ARTIs ( -2.4 [ 3.3 , -1.5 ] mean difference [ 95 % CI ] p < 0.001 by Student 's t test ) . Three patients with OM-85 BV had gastrointestinal events related to drug administration , as well as three placebo patients . CONCLUSION This study demonstrated the clinical benefit of OM-85 BV in patients suffering from RARTIs and subnormal levels of IgG subclasses . This trial opens new perspectives in the research of the mechanism of action of OM-85 BV BACKGROUND Acute respiratory tract infections ( ARTIs ) are among the main causes of morbidity and mortality in children . The bacterial extract OM-85 BV has shown some protective effect for ARTIs in preschool children and a reduction in exacerbations of chronic bronchitis in adults . OBJECTIVES This trial reports results of a double-masked , placebo-controlled , parallel-group clinical study that assessed the efficacy and tolerability of OM-85 BV in the prevention of ARTIs in school girls living in an orphanage . METHODS Two hundred girls ( age range , 6 to 13 years ) living in an orphanage entered the trial . Participants were r and omly allocated to receive either OM-85 BV or placebo for 10 consecutive days a month for 3 consecutive months . Patients were followed up for 6 months , including the administration period . The trial began in September 1996 and finished in March 1997 . Primary end points were the type and number of infections . Secondary end points included when an infection occurred , time to clinical cure , severity of infection , absenteeism from school due to an ARTI , number of antibiotics or other drugs prescribed , and duration of concomitant drug treatment . RESULTS During the trial , patients in the OM-85 BV group experienced 143 ARTIs ( 135 upper ARTIs and 8 otitis episodes ) and patients in the placebo group experienced 299 ARTIs ( 273 upper ARTIs , 1 lower ARTI , and 25 otitis episodes ) . The median number of ARTIs was 1.0 ( 0.0 , 3.0 ; 5th percentile , 95th percentile ) in the OM-85 BV group compared with 3.0 ( 2.0 , 4.0 ; 5th percentile , 95th percentile ) in the placebo group . This difference was statistically significant ( P < 0.001 ) . Participants who received OM-85 BV also showed significantly better results ( P < 0.001 ) than participants who received placebo in terms of median duration of illness , median number of missed school days due to an ARTI , median number of antibiotic and drug courses , and median duration of concomitant treatment . There were significant differences ( P < 0.05 ) in severity of ARTIs during month 4 of the trial , with patients receiving OM-85 BV showing less severe ARTIs than patients receiving placebo and shorter mean time to clinical cure from the second month to the fourth month . No adverse events related to the trial medications were reported . CONCLUSIONS OM-85 BV had a preventive effect on ARTIs in the school girls , with a reduction in the antibiotic requirements and the duration of ARTIs . Future studies are needed to further explore the role of OM-85 BV in the prevention of ARTIs The role of repeated infections early in life in the development of childhood asthma and allergies has not been clarified . The aim of this study was to investigate the effect of repeated episodes of fever and antibiotic treatments during the first years of life on the prevalence of asthma , bronchial hyperresponsiveness ( BHR ) , and atopy at school age in a representative population . R and om sample s of schoolchildren aged 5 - 7 yrs ( n=7,545 ) and 9 - 11 yrs ( n=7,498 ) were studied using the International Study of Asthma and Allergies in Childhood ( ISAAC ) phase II protocol . To assess the prevalence of disease and early childhood exposures , parental question naires were administered ( response rates 82.2 % and 85.3 % , respectively ) . In addition , children underwent skin prick tests , hypertonic saline challenge and blood sampling for the measurement of serum immunoglobulin (Ig)E. Repeated episodes of fever and antibiotic treatment in early life were strongly associated with the prevalence of asthma ( odds ratio (OR)=7.95 ; 95 % confidence interval ( CI ) 6.02 - 10.50 ) and current wheeze at school age . Within asthmatic children the number of fever episodes and antibiotic courses were strongly inversely related to the prevalence of atopy ( OR=0.25 ; 95 % CI 0.11 - 0.54 for skin test reactivity ) and BHR ( OR=0.31 ; 95 % CI 0.10 - 0.92 ) . Furthermore , asthmatic children with recurrent early childhood infections were at a lower risk of being symptomatic at school age . When considering atopic and nonatopic asthmatic children separately , the highest risk of asthma with repeated early childhood infections was found for nonatopic asthma ( OR=24.29 ; 95 % Cl 11.86 - 49.76 ) . These findings suggest that a subgroup of children with a triggering or inducing of asthmatic symptoms through repeated early childhood infections exists within the " asthma syndrome " which has a better prognosis and is less related to the atopic phenotype A 6-month double-blind , prospect i ve , r and omized , placebo-controlled trial was conducted to establish the safety and efficacy of OM-85-BV in the treatment of subacute sinusitis and in the following prevention of the respiratory tract infections in 56 children from 18 months to 9 years of age . In the subacute phase of the sinusitis the patients were given one OM-85-BV capsule ( 3.5 mg of bacterial extracts ) ( n = 26 ) or placebo ( n = 30 ) , daily for ten days ; additionally both groups took amoxicillin/clavulanate 40/10 mg/kg daily in three divided doses for 21 days . For the following two months the patients took one OM-85-BV capsule or placebo , ten days a month . In the subacute phase the OM-85-BV group of patients improved sooner ( 5.56 + /- 4.98 vs 10 + /- 8.49 days ) and had a shorter convalescence ( 15.38 + /- 8.91 vs 20.28 + /- 7.17 days ) . During the six month follow-up the patients in the OM-85-BV group had a lower number of infections ( 1.56 + /- 0.3 vs 2.22 + /- 0.43 ) and required a lower number of drug treatments ( 1.47 + /- 0.32 vs 1.94 + /- 0.42 ) . One patient treated with OM-85-BV presented a mild rash which disappeared three days after the drug discontinuation . We conclude that OM-85-BV is safe at pediatric ages , as well as accelerates the cure and improvement of subacute sinusitis while it lowers the incidence of respiratory infections The effect of a bacterial extract orally administered to 20 children with recurrent infections of the upper respiratory tract , was investigated in a double-blind study . The composition of the peripheral blood mononuclear cells ( T and B-lymphocytes , monocytes ) and some of their biochemical properties ( 5'-nucleotidase , beta-N-acetyl-glucosaminidase and non-specific esterase ) were unaffected . In contrast , the allogeneic mixed lymphocyte reaction was significantly increased in patients treated with the bacterial extract . In the treated group the number of infectious episodes decreased significantly and the clinical response correlated positively with the mixed lymphocyte reaction . These findings suggest that the bacterial extract has the capacity of restoring depressed immune functions by acting through the gut-associated lymphoid tissue BACKGROUND Acute respiratory tract infections ( ARTIs ) are among the main causes of morbidity and mortality in children . The bacterial extract OM-85 BV ( bronchovaxom ) has shown protective effect for ARTIs on children . We report a double-blind , placebo-controlled , parallel , prospect i ve clinical trial to assess the safety and efficacy of two courses of OM-85 BV in the prevention of ARTIs in susceptible children during 12 months . METHODS Fifty-four susceptible children from 1 to 12 years of age living in the metropolitan area of Chihuahua City were selected . They were r and omized to receive either OM-85 BV or placebo ( one capsule a day for 10 days a month for 3 consecutive months ) at the beginning of the trial and 6 months later with the same schedule . Patients were followed up for 12 months , including the administration period . The trial began in July 1997 and ended in April 1999 . RESULTS The number ( mean + /- SD ) of ARTIs was 5.04 + /- 1.99 ( median , 5.0 ) in the OM-85 BV group vs 8.0 + /- 2.55 ( median , 8.0 ) in the placebo group , with a mean difference of - 2.96 ( 95 % confidence interval [ CI ] , - 4.22 to - 1.7 ) . The number of antibiotic courses was 2.46 + /- 2.08 ( median , 1.5 ) in the treatment group vs 4.46 + /- 2.08 ( median , 4.0 ) in the control group , a difference of - 2.0 ( 95 % CI , - 3.14 to - 0.86 ) . The total duration of ARTIs was 35.23 + /- 17.64 days ( median , 30.5 days ) in the OM-85 BV group vs 60.75 + /- 25.44 days ( median , 55.0 days ) in the placebo group , ie , a difference of - 25.52 days ( 95 % CI , - 37.56 to - 13.47 days ) , p < 0.001 by Student 's t test and Mann-Whitney U test for all the items . Four patients in the OM-85 BV group had five adverse events . Only one episode of skin rash was related to the medication intake . Six patients in the control group had six adverse events . CONCLUSIONS OM-85 BV had a preventive effect on ARTI in the susceptible children for 12 months with an important reduction on the antibiotic requirements and the number of days of suffering ARTIs A r and omized , double blind , placebo-controlled clinical trial was performed in 423 children attending day-care centers to assess whether stimulating nonspecific immunity would reduce the incidence of recurrent infections . The drug used for the trial ( Imocur ) is an extract obtained from eight different species of bacteria . At the end of the total follow-up period ( 3 months with treatment and 4.5 months without ) , the risk for > or = 4 episodes of upper respiratory infections was not significantly lower in the treated group than in the placebo group ( 26.7 % vs. 33.8 % , relative risk , 0.79 ; 95 % confidence interval , 0.59 to 1.06 ) . In an exploratory analysis limited to the 3-month treatment period , however , we observed a 48 % reduction in the risk of presenting > or = 3 episodes of upper respiratory infections : 9.5 % vs. 18.3 % , respectively , in the treatment group and the placebo group ( relative risk , 0.52 ; 95 % confidence interval , 0.31 to 0.86 ) . Similar results were found for the risk of > or = 1 episode of gastroenteritis . We also observed a strong correlation between the drug efficacy and age ; this observation is coherent with the underlying pathophysiologic model in which the immune system matures with age 94 children suffering from frequent infections of the respiratory tract and of the ear , nose and throat were treated under double-blind conditions with either a bacterial lysate ( n = 45 ) or a placebo ( n = 49 ) . During the 6 months of the trial both treatments brought about a significant decrease in the incidence and duration of these infections as well as in the duration of concomitant antibiotherapy in comparison to the corresponding prior 6-month reference period . As these positive results recorded under the bacterial lysate and the placebo could not be differentiated statistically , the influence of meteorological and epidemiological factors as well as of the age of the children is discussed Fifty-one children aged 4 - 12 years , presenting with an acute epidose of chronic rhinosinusitis , were treated for 6 months with either Broncho-Vaxom ( BV ; marketed in Yugoslavia under the trade mark of Broncho-Munal ) or placebo under double-blind r and omized conditions . The efficacy of BV was assessed on the basis of clinical symptoms ( cough , nasal discharge , congestion of nasal mucosa ) , number and duration of concomitant treatments ( antibiotics , secretolytics , antitussives ) , number and duration of acute episodes during the trial and serum IgA levels . In BV treated patients the incidence and duration of infectious episodes and the number and duration of concomitant treatments decreased significantly in comparison with the placebo group , and the clinical response correlated positively with an increase in the serum levels of IgA. The results of treatment of acute episodes of chronic rhinosinusitis in children demonstrated the curative and prophylactic efficacy of BV Recurrent upper respiratory tract infections in children have an important socioeconomic impact , with consequences on both the quality of life of the children , the possible medical sequelae and the inherent direct and indirect costs . The possibility to prevent these infections is limited in the absence of specific vaccines against microorganisms responsible for most of the respiratory tract infections ( i.e. respiratory syncitial virus , adenovirus , rhinovirus ) . Immunoactive bacterial extracts that stimulate the nonspecific component of the immune system may protect against a large variety of microorganisms that enter the body by the oral and respiratory pathway ; they may , therefore , play an important role with regard to this preventive action . OM-85 BV is an IBE that has been used in children who suffer from repeated infections to prevent the occurrence of new episodes ( secondary prevention ) . In this condition , the drug has been shown to be effective in protecting children against recurrent airway infections . Its use as a primary preventive agent to prevent the development of repeated infections in children attending day-care centers ( a very high-risk environment for repeated infections ) , however , did not show a similar efficacy . The risk of having > or = 4 episodes of upper respiratory tract infections over a period of 7.5 months was 26.7 % in the verum group and 33.8 % in the placebo group ( relative risk 0.79 , confidence interval 0.59 - 1.06 ] . In an exploratory analysis concentrating on the 3-month treatment period , however , a 48 % reduction of the risk of presenting > or = 3 episodes was observed . Furthermore , this exploratory analysis showed a strong correlation between drug efficacy and age of the children . ( ABSTRACT TRUNCATED AT 250 WORDS |
1,909 | 21,584,244 | Emerging evidence suggests that exercise has a positive impact on some physical determinants and on all functional ability outcomes reported in this systematic review .
Exercise programs that optimize the health of frail older adults seem to be different from those recommended for healthy older adults .
There was a paucity of evidence to characterize the most beneficial exercise program for this population .
However , multicomponent training interventions , of long duration ( ≥5 months ) , performed three times per week , for 30 - 45 minutes per session , generally had superior outcomes than other exercise programs .
In conclusion , structured exercise training seems to have a positive impact on frail older adults and may be used for the management of frailty | This systematic review examines the effectiveness of current exercise interventions for the management of frailty . | Background Fatigue or lack of interest can reduce the feasibility of intensive physical exercise in nursing home residents . Low-volume exercise interventions with similar training effects might be an alternative . The aim of this r and omised controlled trial was to investigate the feasibility of Whole Body Vibration ( WBV ) in institutionalised elderly , and its impact on functional capacity and muscle performance . Methods Twenty-four nursing home residents ( 15 female , 9 male ; mean age 77.5 ± 11.0 years ) were r and omised ( stratification for age , gender and ADL-category ) to 6 weeks static WBV exercise ( WBV+ , N = 13 ) or control ( only static exercise ; N = 11 ) . Outcome measures were exercise compliance , timed up- and -go , Tinetti-test , back scratch , chair sit- and -reach , h and grip strength and linear isokinetic leg extension . Results At baseline , WBV+ and control groups were similar for all outcome variables . Twenty-one participants completed the program and attended respectively 96 % and 86 % of the exercise sessions for the WBV+ and control groups . Training-induced changes in timed up- and -go and Tinetti-test were better for WBV+ compared to control ( p = 0.029 for timed up- and -go , p = 0.001 and p = 0.002 for Tinetti body balance and total score respectively ) . In an alternative analysis ( Worst Rank Score & Last Observation Carried Forward ) the differences in change remained significant on the Tinetti body balance and total score . No other significant differences in change between both groups were observed . Conclusion In nursing home residents with limited functional dependency , six weeks static WBV exercise is feasible , and is beneficial for balance and mobility . The supplementary benefit of WBV on muscle performance compared to classic exercise remains to be explored further The aims of this r and omised controlled trial were to determine if a high-intensity functional exercise program improves balance , gait ability , and lower-limb strength in older persons dependent in activities of daily living and if an intake of protein-enriched energy supplement immediately after the exercises increases the effects of the training . One hundred and ninety-one older persons dependent in activities of daily living , living in residential care facilities , and with a Mini-Mental State Examination ( MMSE ) score of ? 10 participated . They were r and omised to a high-intensity functional exercise program or a control activity , which included 29 sessions over 3 months , as well as to protein-enriched energy supplement or placebo . Berg Balance Scale , self-paced and maximum gait speed , and one-repetition maximum in lower-limb strength were followed-up at three and six months and analysed by 2 x 2 factorial ANCOVA , using the intention-to-treat principle . At three months , the exercise group had improved significantly in self-paced gait speed compared with the control group ( mean difference 0.04 m/s , p = 0.02 ) . At six months , there were significant improvements favouring the exercise group for Berg Balance Scale ( 1.9 points , p = 0.05 ) , self-paced gait speed ( 0.05 m/s , p = 0.009 ) , and lower-limb strength ( 10.8 kg , p = 0.03 ) . No interaction effects were seen between the exercise and nutrition interventions . In conclusion , a high-intensity functional exercise program has positive long-term effects in balance , gait ability , and lower-limb strength for older persons dependent in activities of daily living . An intake of protein-enriched energy supplement immediately after the exercises does not appear to increase the effects of the training Background : The knowledge concerning balance training actually lowering fall rates among frail older persons is limited . Objective : The aim of this study was to examine the effects of a 4-week individualized visual feedback-based balance training on the fall incidence during 1-year follow-up among frail older women living in residential care . Methods : Twenty-seven older women from 2 residential care homes were r and omized into exercise ( n = 20 ) and control ( n = 7 ) groups . Balance measurements were carried out before and after a 4-week training period and falls were monitored by monthly diaries for 1 year . An interview about fear of falling and physical activity was completed before and after the intervention and after the 1-year follow-up . Results : A positive effect of balance training on fall incidence was found . A dynamic Poisson regression model showed that during the follow-up the monthly risk of falling was decreased in the exercise group compared to controls ( risk ratio 0.398 , 95 % CI 0.174–0.911 , p = 0.029 ) . In addition , the exercise group reported a reduced fear of falling and increased physical activity after a training period but these changes declined during the follow-up period . Conclusion : Individualized visual feedback-based balance training was shown to be a promising method for fall prevention among frail older women . High compliance ( 97.5 % ) with the training program showed that carefully targeted training programs can be carried out among older people with health limitations Background and aims : The level of physical functioning ( PF ) late in life has , in recent years , been shown to be influenced by genetic factors . One of the most extensively studied genetic variants associated with PF and trainability is insertion/deletion ( I/D ) polymorphism in the gene encoding Angiotensin Converting Enzyme ( ACE ) . However , ACE studies have mainly been conducted among younger persons in excellent physical shape . In this study , we examine whether the level of PF , trainability , or rate-of-change are associated with the ACE genotype among the elderly . Methods : We used data from 4 r and omized training studies of elderly Danes ( N=203 ) . The measures of PF were self-report , maximal oxygen uptake , muscle strength , walking speed , and body composition . Results : Overall , a favorable change in the measures of PF was observed in training groups compared with control groups . However , within groups , neither pre- or post-training/control period levels of PF nor differences in pre- and post-levels were associated with the ACE genotype . Conclusions : On the basis of our r and omized studies , we could not detect any association between the ACE genotype and the level of PF or change , regardless of whether response to physical training or spontaneous changes was studied OBJECTIVES To determine the independent and combined effects of progressive resistance muscle strength training ( PRMST ) and megestrol acetate ( MA ) on strength , muscle mass , and function in older recuperative care patients . DESIGN Double-blind , r and omized , controlled intervention using a two-by-two factorial design and conducted between 1999 and 2001 . SETTING University-affiliated Department of Veterans Affairs hospital . PARTICIPANTS Twenty-nine patients ( mean age 79.4 + /- 7.4 , 90 % white ) aged 65 and older and had recent functional decline . INTERVENTIONS After r and omization to one of four treatment groups ( low-resistance exercises plus 800 mg per day of MA or a placebo or high-intensity PRMST plus 800 mg/d of MA or placebo ) , subjects received training and the drug or placebo for 12 weeks . MEASUREMENTS Change in muscle strength , mid-thigh muscle area , and aggregate functional performance score as assessed using analysis of covariance . RESULTS Five subjects withdrew from the study before its completion . Based on intent-to-treat analyses , subjects who received high-intensity PRMST and placebo experienced the greatest strength gains . The addition of MA was associated with worse outcomes than with high-intensity exercise training alone , especially with regard to the leg exercises . Post hoc analysis demonstrated that subjects who received high-intensity PRMST and placebo experienced significantly greater percentage increases in leg strength than subjects in either of the MA treatment groups ( P<.05 for each comparison ) . There was also a significant negative effect of MA on physical function . In general , subjects who received MA experienced a deterioration in aggregate physical function scores , whereas the remaining subjects improved ( -0.80+/-0.40 vs 0.48+/-0.41 , P=.04 ) . There was not a significant interaction between exercise and MA for any outcome . CONCLUSION High-intensity PRMST is a safe and well-tolerated exercise regimen for frail elderly patients . The addition of MA appears to blunt the beneficial effects of PRMST , result ing in less muscle strength and functional performance gains A decline in dietary intake due to inactivity and , consequently , development of a suboptimal nutritional status is a major problem in frail elderly people . However , benefits of micronutrient supplementation , all-round physical exercise or a combination of both on functional biochemical and hematologic indicators of nutritional and health status in frail elderly subjects have not been tested thoroughly . A 17-wk r and omized controlled trial was performed in 145 free-living frail elderly people ( 43 men , 102 women , mean age , 78 + /- 5.7 y ) . Based on a 2 x 2 factorial design , subjects were assigned to one of the following : 1 ) nutrient-dense foods , 2 ) exercise , 3 ) both ( 1 ) and ( 2 ) or 4 ) a control group . Foods were enriched with micronutrients , frequently characterized as deficient [ 25 - 100 % of the recommended daily allowance ( RDA ) ] in elderly people . Exercises focused on skill training , including strength , endurance , coordination and flexibility . Dietary intake , blood vitamin levels and nutritional and health indicators , including (pre)albumin , ferritin , transferrin , C-reactive protein , hemoglobin and lymphocytes were measured . At baseline , 28 % of the total population had an energy intake below 6.3 MJ , up to a maximum of 93 % having vitamin intakes below two thirds of the Dutch RDA . Individual deficiencies in blood at baseline ranged from 3 % for erythrocyte glutathione reductase-alpha to 39 % for 25-hydroxy vitamin D and 42 % for vitamin B-12 . These were corrected after 17 wk in the two groups receiving the nutrient-dense foods , whereas no significant changes were observed in the control or exercise group . Biochemical and hematologic indicators at baseline were within the reference ranges ( mean albumin , 46 g/L ; prealbumin , 0.25 g/L ; hemoglobin , 8.6 mmol/L ) and were not affected by any of the interventions . The long-term protective effects of nutrient supplementation and exercise , by maintaining optimal nutrient levels and thereby reducing the initial chance of developing critical biochemical values , require further investigation . Other indicative functional variables for suboptimal nutritional status , in addition to those currently selected , should also be explored BACKGROUND Frail elders are at risk of suboptimal micronutrient status , functional decline , and neurologic disorders . The influence of oral multimicronutrients in physiologic doses and of moderately intense physical exercise on homocysteine ( Hcy ) , methylmalonic acid ( MMA ) , and neurologic functioning have not yet been investigated . OBJECTIVE Our goal was to determine the effects of enriched foods and exercise on blood vitamins , Hcy , MMA , and neuropsychological functioning in the frail . DESIGN A 17-wk r and omized controlled intervention trial was used to study 1 ) enriched foods plus a social program , 2 ) regular foods plus exercise , 3 ) enriched foods plus exercise , and 4 ) regular foods plus a social program . Enriched foods contained multiple micronutrients ( 25 - 100 % of the Dutch recommended dietary allowances ) ; exercises focused on strength , coordination , flexibility , and endurance . Vitamin ( cobalamin , red blood cell folate , and pyridoxal 5'-phosphate ) , Hcy , and MMA concentrations were measured and 2 neuropsychological tests were conducted . RESULTS Vitamin concentrations were higher in the supplemented groups than in the unsupplemented groups ( P < 0.001 ; total n = 130 ) . Compared with baseline , cobalamin in the supplemented groups was increased by 22 % , plasma folate by 101 % , red blood cell folate by 87 % , and pyridoxal 5'-phosphate by 68 % . Concentrations in the unsupplemented groups changed by -2 % , -6 % , 1 % , and -13 % , respectively . Hcy decreased by 25 % and MMA by 30 % in the supplemented groups , compared with a small increase in Hcy ( 2 % ) and decrease in MMA ( 9 % ) in the unsupplemented groups . Exercise did not significantly affect vitamin , Hcy , or MMA concentrations . No significant effect of either intervention was observed on the neuropsychological tests . CONCLUSIONS The decrease in Hcy and MMA in frail elders confirms a sub clinical metabolic deficiency state . Enriched foods containing physiologic amounts of micronutrients have a beneficial effect on these metabolites . No effects of B vitamins on mental health were identified Fighting against inactivity and inadequate nutritional intake are of utmost importance in the elderly . To our knowledge , the few studies which have been performed were conducted for only a short period and the results do not permit formal conclusions to be drawn . We therefore tried to fill this gap in our knowledge by determining whether an intervention combining an acceptable progressive exercise programme and nutritional supplements would be feasible for a long-term period in the very frail elderly , and would bring about concomitant benefits in body composition and muscle power . Accordingly , this exercise and nutritional combination was assessed in the frail elderly in a 9-month r and omised trial with a factorial design . Fifty-seven elderly volunteers over 72 years , from sixteen retirement homes in Lyon , France participated in the study . Dietary supplements were compared with placebo , and physical exercise was compared with memory training . Main outcome measures were fat-free mass ( FFM ) and muscle power . FFM was determined by labelled water , and muscle power was measured by a leg-extensor machine . At 9 months , the compliance was 63 % for exercise sessions , and 54 % for nutritional supplements . In patients with dietary supplements , muscle power increased by 57 % at 3 months ( P=0.03 ) , and showed only a tendency at 9 months ; although FFM increased by 2.7 % at 9 months , the difference was not significant ( P=0.10 ) . Exercise did not improve muscle power at 9 months , but improved functional tests ( five-time-chair rise , P=0.01 ) . BMI increased with supplements ( + 3.65 % ) , but decreased with placebo ( -0.5 % ) at 9 months ( P=0.007 ) . A long-term combined intervention is feasible in frail elderly individuals with a good rate of compliance . Nutritional supplements and exercise may improve muscle function . Despite no significant results on FFM , due to the limited number of volunteers , combined intervention should be suggested to counteract muscle weakness in the frail elderly Background and aims : Home-based exercise is a viable solution for frail elderly individuals with difficulties in reaching exercise facilities outside home . The aim of this study was to determine the effects of a home-based video exercise program on physiological performance , functional capacity and health-related quality of life . Methods : Community-dwelling frail women ≥75 yrs , receiving public home care , were r and omized into a training group ( n=30 ) and a control group ( n=31 ) . Participants exercised for 26 minutes , three times per week for five months . Both groups received a bi-weekly telephone call . The effect of intervention was evaluated by the physical performance test , mobility-tiredness score , maximal isometric h and grip and biceps strength , lower limb explosive power , repeated chair rise ( 5 times ) , 10-m maximal walking-speed , semi-t and em balance , and health-related quality of life , as measured by EQ-5D and self-rated health . Results : Twenty-five participants ( 83 % ) in the training group and 28 ( 90 % ) in the control group completed the project . Adherence to the training protocol was on average 89.2 % . At follow-up , between-group analysis revealed a significant difference only in EQ-5D ( valued by time-trade-off tariffs ) , result ing from a significant decrease observed in the control group and a trend towards an increase in the training group ( p=0.082 ) . Significant within-group improvements , ranging from 8–35 % , were also observed for the physical performance test , mobility-tiredness score , h and grip , biceps strength , chair rise , and 10-m maximal walking-speed in the training group , and for walking-speed and self-rated health in the control group . Conclusions : These results suggest that home-based training for frail older women using an exercise video induces lasting health-related quality -of-life ( EQ-5D ) . In addition , a tendency towards improvements in physiological performance and functional capacity was observed BACKGROUND Physical activity programs in nursing homes typically consist of seated , range of motion ( ROM ) exercises , regardless of resident abilities . The Functional Fitness for Long-Term Care ( FFLTC ) Program was design ed not only to maintain ROM , but also to improve strength , balance , flexibility , mobility , and function . In addition , it was tailored to meet the needs of both high and low mobility residents . METHODS The feasibility and efficacy of the FFLTC Program were evaluated with 68 residents ( mean age 80 ) from five institutions . Persons were classified as low or high mobility and r and omized into either the FFLTC program or a seated ROM program . Classes were conducted in groups of 4 to 10 residents by trained facility staff for 45 minutes , three times per week . Assessment s at baseline and 4 months consisted of mobility , balance , gait , flexibility , functional capacity , and several upper and lower extremity strength measures . RESULTS Attendance averaged 86 % for the FFLTC and 79 % for the ROM classes . Four months of exercise led to significant improvements in mobility ( 16 % ) , balance ( 9 % ) , flexibility ( 36 % ) , knee ( 55 % ) , and hip ( 12 % ) strength for the FFLTC group . Shoulder strength was the only improvement found for the ROM group . The ROM group significantly deteriorated in some areas , particularly hip strength , mobility , and functional ability . CONCLUSIONS Institutionalized seniors , even those who are physically frail , incontinent and /or have mild dementia , can respond positively to a challenging exercise program . The FFLTC program demonstrated clear benefits over typical , seated ROM exercises . Moreover , with minimal training , the program can be safely delivered at low cost by institutional staff and volunteers OBJECTIVE To determine the safety and efficacy of an exercise protocol design ed to improve strength , mobility , and balance and to reduce subsequent falls in geriatric patients with a history of injurious falls . DESIGN A r and omized controlled 3-month intervention trial , with an additional 3-month follow-up . SETTING Out-patient geriatric rehabilitation unit . PARTICIPANTS Fifty-seven female geriatric patients ( mean age 82 + /- 4.8 years ; range 75 - 90 ) admitted to acute care or inpatient rehabilitation with a history of recurrent or injurious falls including patients with acute fall-related fracture . INTERVENTION Ambulatory training of strength , functional performance , and balance 3 times per week for 3 months . Patients of the control group attended a placebo group 3 times a week for 3 months . Both groups received an identical physiotherapeutic treatment 2 times a week , in which strengthening and balance training were excluded . MEASUREMENTS Strength , functional ability , motor function , psychological parameters , and fall rates were assessed by st and ardized protocol s at the beginning ( T1 ) and the end ( T2 ) of intervention . Patients were followed up for 3 months after the intervention ( T3 ) . RESULTS No training-related medical problems occurred in the study group . Forty-five patients ( 79 % ) completed all assessment s after the intervention and follow-up period . Adherence was excellent in both groups ( intervention 85.4 + /- 27.8 % vs control 84.2 + /- 29.3 % ) . The patients in the intervention group increased strength , functional motor performance , and balance significantly . Fall-related behavioral and emotional restrictions were reduced significantly . Improvements persisted during the 3-month follow-up with only moderate losses . For patients of the control group , no change in strength , functional performance , or emotional status could be documented during intervention and follow-up . Fall incidence was reduced nonsignificantly by 25 % in the intervention group compared with the control group ( RR:0.753 CI:0.455 - 1.245 ) . CONCLUSIONS Progressive resistance training and progressive functional training are safe and effective methods of increasing strength and functional performance and reducing fall-related behavioral and emotional restrictions during ambulant rehabilitation in frail , high-risk geriatric patients with a history of injurious falls OBJECTIVES To test the hypothesis that physical exercise induces an antiinflammatory response that is associated with reduced chronic activation of the tumor necrosis factor (TNF)-alpha system in frail elders and that the increase in muscle strength after resistance training is limited by systemic low- grade inflammation . DESIGN A 12-week controlled resistance-training study . SETTING Nursing homes in Copenhagen , Denmark . PARTICIPANTS Twenty-one frail nursing home residents aged 86 to 95 completed the study . INTERVENTION Ten participants were r and omized to a program of resistance training of knee extensors and flexors three times a week for 12 weeks ; the remaining 11 participants served as a control group who joined social activities supervised by an occupation therapist . MEASUREMENTS Muscle strength , plasma levels of TNF-alpha , soluble TNF receptor (sTNFR)-1 , and interleukin (IL)-6 were measured before and at the end of the intervention period . RESULTS The training program improved muscle strength but did not affect plasma levels of TNF-alpha and sTNFR-I or IL-6 . However , plasma levels of sTNFR-I at baseline were inversely correlated with the increase in muscle strength . CONCLUSION Low- grade activation of the TNF system could limit the increase in muscle strength after resistance training in the oldest old . Furthermore , data suggest that the antiinflammatory response induced by 12 weeks of resistance training is not sufficient to reduce chronic activation of the TNF system , but the small sample size limited this interpretation OBJECTIVES To determine the effects of moderate intensity group-exercise programs on falls , functional performance , and disability in older adults ; and to investigate the influence of frailty on these effects . DESIGN A 20-week , multicenter r and omized controlled trial , with 52-week follow-up . SETTING Fifteen homes for the elderly . PARTICIPANTS Two hundred seventy-eight men and women ( mean age + /- st and ard deviation , 85+/-6y ) . INTERVENTIONS Two exercise programs were r and omly distributed across 15 homes . The first program , functional walking ( FW ) , consisted of exercises related to daily mobility activities . In the second program , in balance ( IB ) , exercises were inspired by the principles of Tai Chi . Within each home participants were r and omly assigned to an intervention or a control group . Participants in the control groups were asked not to change their usual pattern of activities . The intervention groups followed a 20-week exercise program with 1 meeting a week during the first 4 weeks and 2 meetings a week during the remaining weeks . MAIN OUTCOME MEASURES Falls , Performance Oriented Mobility Assessment ( POMA ) , physical performance score , and the Groningen Activity Restriction Scale ( GARS ) ( measuring self-reported disability ) . RESULTS Fall incidence rate was higher in the FW group ( 3.3 falls/y ) compared with the IB ( 2.4 falls/y ) and control ( 2.5 falls/y ) groups , but this difference was not statistically significant . The risk of becoming a faller in the exercise groups increased significantly in the subgroup of participants who were classified as being frail ( hazard ratio [ HR ] = 2.95 ; 95 % confidence interval [ CI ] , 1.64 - 5.32 ) . For participants who were classified as being pre-frail , the risk of becoming a faller decreased ; this effect became significant after 11 weeks of training ( HR = .39 ; 95 % CI , .18-.88 ) . Participants in both exercise groups showed a small , but significant improvement in their POMA and physical performance scores . In the FW group , this held true for the GARS score as well . Post hoc analyses revealed that only the pre-frail participants improved their POMA and physical performance scores . CONCLUSIONS Fall-preventive moderate intensity group-exercise programs have positive effects on falling and physical performance in pre-frail , but not in frail elderly BACKGROUND Little is known about the natural course of frailty . We performed a prospect i ve study to determine the transition rates between frailty states and to evaluate the effect of the preceding frailty state on subsequent frailty transitions . METHODS We studied 754 community-living persons , aged 70 years or older , who were nondisabled in 4 essential activities of daily living . Frailty , assessed every 18 months for 54 months , was defined on the basis of weight loss , exhaustion , low physical activity , muscle weakness , and slow walking speed . Participants were classified as frail if they met 3 or more of these criteria , as prefrail if they met 1 or 2 of the criteria , and as nonfrail if they met none of the criteria . RESULTS Of the 754 participants , 434 ( 57.6 % ) had at least 1 transition between any 2 of the 3 frailty states during 54 months . The rates were 36.8 % , 21.5 % , and 9.2 % for 1 , 2 , and 3 transitions , respectively . During the 18-month intervals , transitions to states of greater frailty were more common ( rates up to 43.3 % ) than transitions to states of lesser frailty ( rates up to 23.0 % ) , and the probability of transitioning from being frail to nonfrail was very low ( rates , 0%-0.9 % ) , even during an extended period . The likelihood of transitioning between frailty states was highly dependent on one 's preceding frailty state . CONCLUSIONS Frailty among older persons is a dynamic process , characterized by frequent transitions between frailty states over time . Our findings suggest ample opportunity for the prevention and remediation of frailty OBJECTIVES To determine the effect of a 12-week intervention to improve the ability of disabled older adults to rise from a bed and from a chair . DESIGN Subjects were r and omly allocated to either a 12-week task-specific resistance-training intervention ( training in bed- and chair-rise subtasks , such as sliding forward to the edge of a chair with the addition of weights ) or a control flexibility intervention . SETTING Seven congregate housing facilities . PARTICIPANTS Congregate housing residents age 65 and older ( n = 161 , mean age 82 ) who reported requiring assistance ( such as from a person , equipment , or device ) in performing at least one of the following mobility-related activities of daily living : transferring , walking , bathing , and toileting . MEASUREMENTS At baseline , 6 weeks , and 12 weeks , subjects performed a series of bed- and chair-rise tasks where the rise task dem and varied according to height of the head of the bed , chair seat height , and use of h and s. Outcomes were able or unable to rise and , if able , the time taken to rise . Logistic regression for repeated measures was used to test for differences between tasks in the ability to rise . Following log transformation of rise time , a linear effects model was used to compare rise time between tasks . RESULTS Regarding the maximum total number of bed- and chair-rise tasks that could be successfully completed , a significant training effect was seen at 12 weeks ( P = .03 ) ; the training effect decreased as the total number of tasks increased . No statistically significant training effects were noted for rise ability according to individual tasks . Bed- and chair-rise time showed a significant training effect for each rise task , with analytic models suggesting a range of approximately 11 % to 20 % rise-time ( up to 1.5 seconds ) improvement in the training group over controls . Training effects were also noted in musculoskeletal capacities , particularly in trunk range of motion , strength , and balance . CONCLUSIONS Task-specific resistance training increased the overall ability and decreased the rise time required to perform a series of bed- and chair-rise tasks . The actual rise-time improvement was clinical ly small but may be useful over the long term . Future studies might consider adapting this exercise program and the focus on trunk function to a frailer cohort , such as in rehabilitation setting s. In these setting s , the less challenging rise tasks ( such as rising from an elevated chair ) and the ability to perform intermediate tasks ( such as hip bridging ) may become important intermediate rehabilitation goals OBJECTIVES To describe the development and implementation of a preventive , home-based physical therapy program ( PREHAB ) and to provide evidence for the safety and interrater reliability of the PREHAB protocol . DESIGN Demonstration study . SETTING General community . PARTICIPANTS Ninety-four physically frail , community-living persons , aged 75 years or older , who were r and omized to the PREHAB program in a clinical trial . INTERVENTIONS The PREHAB program built on the physical therapy component of 2 previous home-based protocol s. A total of 223 assessment items were linked to 28 possible interventions , including progressive balance and conditioning exercises , by using detailed algorithms and decisions rules that were automated on notebook computers . MAIN OUTCOMES MEASURES The percentages of participants who were eligible for and who completed each intervention , the extent of progress noted in the balance and conditioning exercises , adherence to the training program , and adverse events . RESULTS Participants who completed the PREHAB program and those who ended it prematurely received an average of 9.7 and 7.2 interventions during an average of 14.9 and 9.5 home visits , respectively . With few exceptions , the completion rate and interrater reliability for the specific interventions were high . Despite high self-reported adherence to the training program , the majority of participants did not advance beyond the initial Thera-B and level for the upper- and lower-extremity conditioning exercises , and only about a third advanced to the highest 2 levels of the balance exercises . Adverse events were no more common in the PREHAB group than in the educational control group . CONCLUSION Our results support the feasibility and safety of the PREHAB program , but also show the special challenges and pitfalls of such a strategy when it is implemented among persons of advanced age and physical frailty BACKGROUND Aging is associated with decline in both cell-mediated and humoral immunity and may contribute to increased incidence and severity of infections in frail elderly . Exercise , depending on intensity , has significant effects on the immune system . We conducted a r and omized , controlled clinical trial of a 32-week functionally oriented exercise program in frail elderly living in nursing homes and determined whether the exercise intervention was associated with a change in immune parameters in this frail elderly nursing home population . METHODS Nursing home residents were r and omly assigned to an intervention ( n = 94 ) and control group ( n = 96 ) . The intervention consisted of a functionally oriented endurance and resistance exercise training that was provided every 2 hours from 8:00 AM to 4:00 PM for 5 days a week for 8 months . Lymphocyte sub population s , including activation markers ( CD28 , CD25 , HLA-DR ) , in vitro proliferation , and soluble products of cytokine activity ( neopterin and sTNF-RII ) in serum were measured by taking blood sample s at baseline and after 8 weeks and 32 weeks of the intervention . RESULTS Exercise training did not induce changes in lymphocyte sub population s , activation markers ( CD28 , CD25 , HLA-DR ) , in vitro proliferation , and soluble products of cytokine activity ( neopterin and sTNF-RII ) in serum . CONCLUSIONS A 32-week exercise intervention did not bring about beneficial or detrimental effects on immune parameters in the frail elderly nursing home population and may explain why the intervention was not associated with a change in the incidence of infections in the intervention group compared with the control group OBJECTIVE To identify reasons for dropout and factors that may predict dropout from an exercise intervention aim ed at improving physical function in frail older persons . DESIGN / SETTING An 18-month r and omized controlled intervention in a community setting . The intervention comprised 2 groups : class-based and self-paced exercise . PARTICIPANTS 155 community-dwelling older persons , mean age 77.4 , with mildly to moderately compromised mobility . MEASUREMENTS The primary outcome measure was dropout . Dropouts were grouped as : D0 , dropout between baseline and 3-month assessment , and D3 , dropout after 3-month assessment . MEASUREMENTS Measurements of demographics , health , and physical performance included self-rated health , SF-36 , disease burden , adverse events , PPT-8 , MacArthur battery , 6-minute walk , and gait velocity . RESULTS There were 56 dropouts ( 36 % ) , 31 in first 3 months . Compared with retained subjects ( R ) , the D0 group had greater disease burden ( P = .011 ) , worse self-perceived physical health ( P = .014 ) , slower usual gait speed ( P = .001 ) , and walked a shorter distance over 6 minutes ( P<.001 ) . No differences were found between R and D3 . Multinomial logistic regression showed 6-minute walk ( P<.001 ) and usual gait velocity ( P<.001 ) were the strongest independent predictors of dropout . Controlling for all other variables , adverse events after r and omization and 6-minute walk distance were the strongest independent predictors of dropout , and self-paced exercise assignment increased the risk of dropout . CONCLUSIONS We observed baseline differences between early dropouts and retained subjects in disease burden , physical function , and endurance , suggesting that these factors at baseline may predict dropout . Improved underst and ing of factors that lead to and predict dropout could allow research ers to identify subjects at risk of dropout before r and omization . Assigning targeted retention techniques in accordance with these factors could result in decreased attrition in future studies . Therefore , the results of selective attrition of frailer subjects , such as decreased heterogeneity , restricted generalizability of study findings , and limited underst and ing of exercise effects in this population , would be avoided OBJECTIVES To evaluate a dynamic form of weighted vest exercise suitable for home use and design ed to enhance muscle power , balance , and mobility . DESIGN A single-blind , r and omized , controlled trial . SETTING Outpatient exercise research facility situated within an academic long-term care center . PARTICIPANTS Twenty-one community-dwelling women aged 70 and older with a Short Physical Performance Battery ( SPPB ) score between 4 and 10 ( out of 12 ) . INTERVENTIONS Subjects were r and omized into a progressive resistance-training program using weighted vests for resistance with exercises design ed to be specific to mobility tasks and have a component performed at the fastest possible velocity ( Increased Velocity Exercise Specific to Task ( InVEST ) , n=11 ) or a control exercise group ( control , n=10 ) , which performed slow-velocity , low-resistance exercise . Both groups exercised three times a week for 12 weeks . MEASUREMENTS Changes in muscle power , balance , and physical performance were compared . RESULTS In comparison to control group , InVEST group manifested significant improvements ( P<.05 ) in leg power across measurements obtained at 75 % to 90 % of the one-repetition maximum . Both groups demonstrated significant improvements in chair st and and SPPB score from baseline , and the InVEST group showed significant improvements in gait speed and chair st and from baseline ( P<.05 ) . InVEST produced significantly greater changes in chair st and time than control ( P<.05 ) . CONCLUSION InVEST training appears be an effective means of enhancing leg power and chair rise in this population and is worthy of further investigation as a means of enhancing balance and mobility BACKGROUND Progressive resistance exercise training ( PRT ) has been shown to increase muscle strength and fat-free mass ( FFM ) in elderly persons . Limited information is available regarding the effects of PRT on lean and fat mass in frail elderly persons . METHODS Ninety-one community-dwelling sedentary men and women , 78 years and older with physical frailty ( defined using st and ardized objective criteria ) were enrolled in a 9-month trial of exercise training ( ET ) . Physical frailty was defined as having 2 of the 3 following criteria : modified Physical Performance Test score between 18 and 32 , peak aerobic power between 10 and 18 ml/kg/min , or self-report of difficulty or assistance with two instrumental activities of daily living or one basic activity of daily living . Participants were r and omly assigned to either a control ( CTL ) group that performed a low intensity home exercise program or a supervised ET group that performed 3 months of low intensity exercise and 3 months of PRT . RESULTS After completion of PRT , ET participants had greater improvements than did CTL participants in maximal voluntary force production for knee extension ( mean Delta + 5.3 + /- 13 ft/lb vs + 1.1 + /- 11 ft/lb , p = .05 ) , measured using isokinetic dynamometry . Total body FFM ( measured using dual energy x-ray absorptiometry ) increased in the ET group , but not in the CTL group ( mean Delta + 0.84 + /- 1.4 kg vs + 0.01 + /- 1.5 kg , p = .005 ) . Total , trunk , intra-abdominal , and subcutaneous fat mass ( measured using dual energy x-ray absorptiometry and (1)H-magnetic resonance imaging ) did not change in response to PRT . CONCLUSIONS Three months of supervised PRT induced improvements in maximal voluntary thigh muscle strength and whole body FFM in frail , community-dwelling elderly women and men . This supervised exercise program may not be sufficient to reduce whole-body or intra-abdominal fat area in this population To determine the mechanisms underlying increased aerobic power in response to exercise training in octogenarians , we studied mildly frail elderly men and women r and omly assigned to an exercise group ( n = 22 ) who participated in a training program of 6 mo of physical therapy , strength training , and walking followed by 3 mo of more intense endurance exercise at 78 % of peak heart rate or a control sedentary group ( n = 24 ) . Peak O2 consumption ( V(O2 peak ) ) increased 14 % in the exercise group ( P < 0.0001 ) but decreased slightly in controls . Training induced 14 % increase ( P = 0.027 ) in peak exercise cardiac output ( Q ) , determined via acetylene re-breathing , and no change in arteriovenous O2 content difference . The increase in Q was mediated by increases in heart rate ( P = 0.009 ) and probably stroke volume ( P = 0.096 ) . Left ventricular stroke work also increased significantly . In the men , the increase in V(O2 peak ) was exclusively due to a large increase in peak Q ( 22 % ) . In the women , the gain in V(O2 peak ) was due to small increases in Q and O2 extraction from skeletal muscles . Pulse pressure normalized for stroke volume and arterial elastance during peak effort did not change with training . Controls showed no changes . The results suggest that , although frail octogenarians have a diminished capacity for improvement in aerobic power in response to exercise training , this adaptation is mediated mostly by an increase in Q during peak effort . Furthermore , Q likely plays a greater role in the adaptive increase in V(O2 peak ) in old men than old women Objective Although exercise therapy intervention for frail elderly people was not of great interest in the past , it has recently drawn attention as a method to prevent and improve conditions requiring care since the enforcement of the Long-Term Care Insurance Law and the revision of the long-term care insurance system . This r and omized controlled trial was performed to evaluate the effects of exercise therapy using the Takizawa Program . Methods In this r and omized controlled trial , we evaluated the effects of exercise therapy on the frail elderly , including those who need a high level of care , in terms of two factors : the range of motion and the functional independence measure . The subjects were 145 females admitted to special nursing homes for the elderly . They were stratified according to their care levels and r and omly assigned to either the exercise therapy intervention group or the control group . Results The range of motion values in the flexions of both shoulders , the right knee extension , and the dorsal flexions of both ankles significantly increased only in the exercise therapy intervention group . The functional independence measure score did not improve in the exercise therapy intervention group . Conclusion Exercise therapy should be used for the frail elderly requiring a high level of care Objective : To evaluate the specific effects of balance and gait exercises among frail elderly individuals . Design : A r and omized three-group parallel controlled study . Setting : Geriatric health services facility in Japan . Subjects : Thirty-four frail elderly subjects attending the care facility were r and omized into a control group , an exercise group with emphasis on balance or an exercise group with emphasis on gait re-education . Interventions : The two exercise groups received balance or gait exercise for 40 minutes , 2–3 times weekly , for 12 weeks . Main outcome measures : One Leg St and ing Test , Functional Reach Test , Manual Perturbation Test , Functional Balance Scale , Performance-Oriented Mobility Assessment , Timed ‘ Up and Go ’ Test and Stair Climbing/Descending Test . These assessment s were performed before and after 12-week intervention . Results : Comparison of the performance before and after intervention demonstrated significant improvement in One Leg St and ing Test , Functional Reach Test and Functional Balance Scale in the balance exercise group , and Functional Balance Scale , Timed ‘ Up and Go ’ Test and Stair Descending Test showed improvement in the gait exercise group . All test items showed no significant differences in the control groups . Among the three groups , the balance exercise group showed more significant improvement in Functional Balance Scale , and the gait exercise group showed more significant improvement in Performance-Oriented Mobility Assessment than the control group . The balance exercise group showed greater improvement in performance in Functional Reach Test than the gait exercise group . Conclusions : Balance exercises led to improvements in static balance function , and gait exercises result ed in improvements to dynamic balance and gait functions in the very frail elderly Objective : To examine the effects of 17 weeks of physical exercise and micronutrient supplementation on the psychological wellbeing of 139 independently living , frail , elderly subjects ( inactive , body mass index ≤25 or experiencing weight loss ) . Methods : Participants ( mean ( SD ) age 78.5 ( 5.7 ) ) were r and omly assigned to : ( a ) comprehensive , moderate intensity , group exercise ; ( b ) daily micronutrient enriched foods ( 25–100 % recommended daily amount ) ; ( c ) both ; ( d ) neither . A social programme and identical regular foods were offered as attention control and placebo . Results : At baseline , moderate to low but significant correlations were found between general wellbeing scores and physical fitness ( r = 0.28 ) , functional performance ( r = 0.37 ) , and blood concentrations of pyridoxine ( r = 0.20 ) , folate ( r = 0.25 ) , and vitamin D ( r = 0.23 ) ( all p values ≤0.02 ) , but not with physical activity levels and other blood vitamin concentrations . General wellbeing score and self rated health were not responsive to 17 weeks of exercise or nutritional intervention . Conclusion : Psychological wellbeing in frail elderly people was not responsive to 17 weeks of intervention with exercise and /or micronutrient enriched foods . The moderate but significant correlations between wellbeing and physical fitness and several blood vitamin concentrations at baseline suggest that changes in wellbeing may occur after long term interventions BACKGROUND Past studies suggest multidisciplinary interventions that include physical therapy ( PT ) can improve function of nursing home residents . This trial specifically evaluates effects of PT for frail long-stay nursing home residents . DESIGN R and omized , controlled trial . SETTING One academic nursing home and eight community nursing homes . PATIENTS A total of 194 elderly nursing home residents dependent in at least two activities of daily living residing in the nursing home for at least 3 months . INTERVENTIONS Patients were r and omized to individually tailored one-on-one PT sessions or friendly visits ( FVs ) three times a week for 4 months . Physical therapy included range-of-motion , strength , balance , transfer , and mobility exercises . MAIN OUTCOME MEASURES Performance-based physical function assessed by the Physical Disability Index ; self-perceived health status assessed with the Sickness Impact Profile ; observer-reported activities of daily living ; and falls . RESULTS Eighty-nine percent and 92 % of PT and FV sessions , respectively , were attended ; 5 % and 9 % of subjects dropped out in the PT group and FV group , respectively . Compared with the FV group , the PT group experienced no significant improvements in overall Physical Disability Index , Sickness Impact Profile , or activities of daily living scores . A 15.5 % improvement in the mobility subscale of the Physical Disability Index was seen ( 95 % confidence interval [ CI ] , 6.4 % to 24.7 % ) ; no benefits in range-of-motion , strength , or balance subscales were found . Compared with the FV group , the PT group used assistive devices for bed mobility tasks less often ( P = .06 ) and were less likely to use assistive devices and wheelchairs for locomotion ( P < .005 ) . There were 79 falls in the PT group vs 60 falls in the FV group ( P = .11 ) . Charge for the 4-month PT program was $ 1220 per subject ( 95 % CI , $ 412 to $ 1832 ) . CONCLUSION This st and ardized physical therapy program provided modest mobility benefits for very frail long-stay nursing home residents with physical disability due to multiple comorbid conditions BACKGROUND The purpose of this efficacy study was to measure the dose-response effect of a free weight-based resistance training program by comparing the effects of two training intensities ( low-moderate and high ) of the knee extensor ( KE ) muscles on muscle function , functional limitations , and self-reported disability . METHODS The authors conducted a single-blinded , r and omized , placebo-controlled trial . Twenty-two institutionalized elders ( mean age , 81.5 years ) were assigned to either high-intensity strength training ( HI ; n = 8) , low-moderate intensity strength training ( LI ; n = 6 ) , or weight-free placebo-control training ( PC ; n = 8) . The HI group trained at 80 % of their 1-repetition maximum and the LI group trained at 40 % . All groups performed 3 sets of 8 repetitions , 3 times per week for 10 weeks . Outcome measures included KE maximal strength , KE endurance , and functional performance as assessed by 6-minute walking , chair-rising , and stair-climbing tests , and by self-reported disability . RESULTS KE strength and endurance , stair-climbing power , and chair-rising time improved significantly in the HI and LI groups compared with the PC group . Six-minute walking distance improved significantly in the HI group but not in the LI group compared with the PC group . Changes observed in HI were significantly different from those observed in the LI group for KE strength and endurance and the 6-minute walking test , with a trend in the same direction for chair-rising and stair-climbing . Changes in strength were significantly related to changes in functional outcomes , explaining 37 % to 61 % of the variance . CONCLUSIONS These results show strong dose-response relationships between resistance training intensity and strength gains , and between strength gains and functional improvements after resistance training . Low-moderate intensity resistance training of the KE muscles may not be sufficiently robust from a physiologic perspective to achieve optimal improvement of functional performance . Supervised HI , free weight-based training for frail elders appears to be as safe as lower intensity training but is more effective physiologically and functionally OBJECTIVE To determine whether a home-based physical therapy ( PT ) program prevented decline in several higher-level measures of physical function among physically frail , community-living older persons . DESIGN R and omized controlled trial . SETTING General community . PARTICIPANTS Persons ( N=188 ) who were physically frail and aged 75 years or older . INTERVENTION A home-based PT program ( ie , prehabilitation ) that focused primarily on improving underlying impairments in physical capabilities . MAIN OUTCOME MEASURES Self-reported instrumental activities of daily living ( IADLs ) ; mobility , as determined by a modified version of the Performance Oriented Mobility Assessment ; timed rapid gait and timed chair st and s ; and integrated physical performance , as determined by a modified version of the Physical Performance Test , were assessed at baseline , 7 months , and 12 months . RESULTS As compared with participants in the educational control group , participants in the intervention group had reductions in IADL disability of 17.7 % at 7 months ( P=.036 ) and 12.0 % at 12 months ( P=.143 ) and had gains , ranging from 7.2 % to 15.6 % , in mobility and integrated physical performance at 7 and 12 months . CONCLUSIONS Our home-based prehabilitation program offered modest but consistent benefits for the prevention of decline in several higher-level measures of physical function OBJECTIVES To determine whether an intense tai chi exercise program could reduce fear of falling better than a wellness education ( WE ) program in older adults who had fallen previously and meet criteria for transitioning to frailty . DESIGN Cluster-r and omized , controlled trial of 48 weeks ' duration . SETTING Ten matched pairs of congregate living facilities in the greater Atlanta area . PARTICIPANTS Sample of 291 women and 20 men , aged 70 to 97 . MEASUREMENTS Activity-related fear of falling using the Activities-Specific Balance Confidence Scale ( ABC ) and the Fall Efficacy Scale at baseline and every 4 months for 1 year . Demographics , time to first fall and all subsequent falls , functional measures , Centers for Epidemiologic Studies Depression Scale , medication use , level of physical activity , comorbidities , and adherence to interventions . RESULTS Mean ABC was similar in both cohort groups at the time of r and omization but became significantly higher ( decreased fear ) in the tai chi cohort at 8 months ( 57.9 vs 49.0 , P<.001 ) and at study end ( 59.2 vs 47.9 , P<.001 ) . After adjusting for covariates , the mean ABC after 12 months of intervention was significantly greater in the tai chi group than in the WE group , with the differences increasing with time ( mean difference at 12 months=9.5 points , 95 % confidence interval=4.8 - 14.2 , P<.001 ) . CONCLUSION Tai chi led to a significantly greater reduction in fear of falling than a WE program in transitionally frail older adults . The mean percentage change in ABC scores widened between tai chi and WE participants over the trial period . Tai chi should be considered in any program design ed to reduce falling and fear of falling in transitionally frail older adults BACKGROUND Few data exist to evaluate whether Tai Chi ( TC ) training improves physical performance and hemodynamic outcomes more than a wellness education ( WE ) program does among older fallers transitioning to frailty . METHODS This 48-week r and omized clinical trial was provided at 10 matched pairs of congregate living facilities in the Atlanta metropolitan area to 291 women and 20 men , who were transitionally frail , > or=70 years old , and had fallen at least once within the past year . Pairs of facilities were r and omized to either TC exercise ( n = 158 ) or WE ( control ) interventions ( n = 153 ) over 48 weeks . Physical performance ( freely chosen gait speed , reach , chair-rises , 360 degrees turn , picking up an object from the floor , and single limb support ) and hemodynamic outcomes ( heart rate and blood pressure ) were obtained at baseline and after 4 , 8 , and 12 months . RESULTS Mean percent change ( baseline to 1 year ) for gait speed increased similarly in both cohorts ( TC : 9.1 % and WE : 8.2 % ; p = .78 ) . However , time to complete three chair-rises decreased 12.3 % for TC and increased 13.7 % for WE ( p = .006 ) . Baseline to 1 year mean percent change decreased among TC and increased within WE cohorts for : body mass index ( -2.3 % vs 1.8 % ; p < .0001 ) , systolic blood pressure ( -3.4 % vs 1.7 % ; p = .02 ) , and resting heart rate ( -5.9 % vs 4.6 % ; p < .0001 ) . CONCLUSIONS TC significantly improved chair-rise and cardiovascular performance . Because TC training reduced fall occurrences in this cohort , factors influencing functional and cardiovascular improvements may also favorably impact fall events When frail older people become acutely ill , they are at increased risk of further functional deterioration and rehabilitation is needed to restore functioning . The effects of an out-patient multicomponent training program including strength training after hospitalization were studied in a r and omized controlled trial . Sixty-eight women ( mean age 83.0 + /- 3.9 years ) who were hospitalized due to an acute illness and were mobility impaired at admission were r and omized into training ( N = 34 ) and home exercise ( N = 34 ) groups . Maximal voluntary isometric strength of knee extension and hip abduction , dynamic balance , and maximal walking speed were measured before and after the 10-week training period , and 3 and 9 months after the end of the intervention . After the intervention , significant improvements were observed in the training group compared to the home exercise group in the maximal voluntary isometric knee extension strength ( 20.8 % vs. 5.1 % , P= 0.009 ) , balance scale ( + 4.4 points vs. -1.3 points , P= 0.001 ) and walking speed ( + 0.12 m s-1 vs. -0.05 m s-1 , P= 0.022 ) . Effects on knee extension and hip abduction strength , balance and walking speed were observed 3 months later , and some effects on hip abduction strength ( 9.0 % vs. -11.8 % , P= 0.004 ) and mobility were still apparent even 9 months after the intervention We examined the hypothesis that physical activity will have favorable effects on measures of self-efficacy for a 400-m walk and satisfaction with physical functioning in older adults 70 + years of age who have deficits in mobility . We r and omized a total of 412 adults aged 70 - 89 years at elevated risk for mobility disability to either a physical activity or a successful aging educational control intervention for 12 months . Participants in the physical activity intervention had more favorable changes in both outcomes as a result of treatment than those in the successful aging intervention . Gender , age , and scores on a short physical performance battery did not moderate these effects . Physical activity is an effective means of intervening on self-efficacy and satisfaction with physical function in older adults with impaired lower extremity functioning . This is an important finding in light of the importance of these process variables in behavior change and quality of life Regular exercise is widely advocated for the young and middle-aged , but less is heard about its relevance to elderly people . This study reports the findings of a controlled trial of seated exercise in residents of local authority homes for the elderly . Forty-nine residents aged 64 - 91 years volunteered for the 7-month project , and participated in either twice-weekly exercise or reminiscence sessions . Primary outcome measures were postural sway , flexibility of the spine and knees , h and -grip strength and functional capacity . The average ( range of ) attendance at the exercise sessions was 91 % ( 64 - 100 % ) , and at the reminiscence sessions was 86 % ( 46 - 100 % ) . By the end of the project , the change observed in the exercise group was significantly different from that of the reminiscence group in terms of grip strength ( p < 0.02 ) , spinal flexion ( p < 0.001 ) , chair-to-st and time ( p < 0.001 ) , activities of daily living ( p < 0.05 ) , and self-rating of depression ( p < 0.01 ) . Even very elderly residents of old peoples homes can benefit from participation in regular seated exercise and improve their functional capacity Objective The purpose of this study was to investigate the effects of water exercise at a day service facility and the effects of water exercise frequency on health-related quality of life ( HRQL ) . Methods Participants ( n = 30 ) were r and omly separated into three groups : two indicating exercise frequency , at once-weekly or twice-weekly , and a control group . One-hour exercise intervention sessions were carried out once or twice a week , accordingly , for 24 weeks . The water exercise session comprised a warm-up on l and , activities of daily living ( ADL ) exercises , stretching , strength training , and relaxation in water . HRQL was evaluated using the Medical Outcomes Survey Short-Form 36 ( SF-36 ) question naire , and ADL disability was assessed using the Functional Independence Measure . Results Significant differences were found between pre- and 6 months in both the once- and twice-weekly groups in HRQL ( p < 0.05 ) . No significant difference was found among pre- , 3 months , and 6 months . The effect size between the once and twice groups was moderate in both the physical component summary ( 0.72 ) and mental component summary ( 0.75 ) at 3 months . ADL disability shows significant correlation with HRQL . Conclusion Water exercise intervention at a day service facility improved participants ’ HRQL for 6 months by improving exercise habits and ADL disability . Furthermore , the HRQL change differed according to exercise frequency : twice-weekly exercise showed more rapid improvement than once-weekly Background and aims : There are few studies published that combine the interventions of physical training and nutrition . The aim of the present study was to describe the impact of a physical and nutritional intervention program for frail community-dwelling elderly people over the age of 75 . Methods : Ninety-six community-dwelling elderly people ( 58 women ) were r and omized to four different groups : i ) a physical training program ( aerobic , muscle strength , balance ) , ii ) a nutritional intervention program ( individually targeted advice and group sessions ) , iii ) a combination of these interventions , and iv ) a control group . At baseline subjects were screened for physical performance such as muscle strength , balance , mobility and activities of daily living , as well as nutritional aspects such as energy intake , body weight and fat-free mass . These measurements were repeated immediately after the intervention , which lasted for 12 weeks , and after another 6 months . Results : The intention-to-treat analysis indicated significant improvements in lower-extremity muscle strength in both training groups compared with the nutrition group at 1st follow-up . There were small significant changes for some of the balance measurements in the training group without nutrition treatment . The nutrition intervention did not show any significant results . Conclusions : This study shows the positive effect on lower-extremity muscle strength directly after the intervention . Balance training most probably needs to be more individualized in order to be effective for frail elderly people . Further studies are needed , with larger sample sizes , to investigate the effects of these types of interventions before any further conclusions can be drawn PURPOSE Determine the independent and combined effects of progressive resistance muscle strength training ( PRMST ) and testosterone on strength , muscle mass , and function in hypogonadal elderly male recuperative care patients . METHODS Between 1999 and 2004 , 71 subjects ( mean age 78.2 + /- 6.4 yr , 86 % white ) were enrolled . After baseline one-repetition maximum ( 1RM ) strength testing and then r and omization to one of four treatment groups ( low-resistance ( 20 % of the 1RM ) exercises and weekly injections of either 100 mg of testosterone enanthate or placebo or high-intensity PRMST ( > or = 80 % 1RM ) and weekly injections ) , each subject received training and injections for 12 wk . RESULTS Ten subjects withdrew from the study before its completion . Based on intent-to-treat analyses , strength improved in all groups , but was greater with high-intensity PRMST compared with low-resistance exercise ( e.g. , leg press , ( mean + /- SE ) , 28 + /- 4 vs 13 + /- 4 % , P = 0.009 ) . Although testosterone led to significantly greater increases in midthigh cross-sectional muscle area compared with placebo ( 7.9 + /- 1.3 vs 2.4 + /- 1.4 % , P = 0.005 ) , it produced only a nonsignificant trend toward greater strength gains ( e.g. , leg press 25 + /- 4 vs 16 + /- 4 % , P = 0.144 ) . Change in aggregate functional performance score ( the sum of 4 functional performance test scores ) did not differ between the four intervention groups nor with high-intensity PRMST compared with low-resistance exercise ( 7 + /- 5 vs 15 + /- 5 % , P = 0.263 ) . There was not a significant interaction between exercise and testosterone for any outcome . CONCLUSION High-intensity PRMST is as safe and well tolerated as a similarly structured low-resistance exercise regimen for very frail elderly patients , but produces greater muscle strength improvements . The addition of testosterone leads to greater muscle size and a trend toward greater strength but did not produce a synergistic interaction with exercise . Neither intervention had a significant effect on functional performance AIM To determine if regular exercise classes , planned and supervised by a physiotherapist , improved physical function in a sample of frail institutionalised elderly . METHOD Weekly one hour and twice weekly 10 minute exercise classes were given by a physiotherapist , to a group of 34 residents who consented from r and omly selected rest homes . The study took place over a period of one year . At entry , 4 , 9 and 12 months the physical function was compared with the matched control group who received regular rest home activities , without physiotherapy input . The study used a sit st and test to measure change in physical function . This was indicated by recording ( a ) the time taken and ( b ) the h and assistance required to st and up . RESULTS Compared with the control group , the study group showed statistically significant improvement ( p < 0.05 ) in physical function as measured by sit st and time . The sit st and h and assistance test was found to be too insensitive to measure improvement or to differentiate between the two groups . The programme was enjoyable and had no health complications . CONCLUSION Regular exercise classes planned and supervised by a physiotherapist are safe and improve the physical functioning and daily activity levels of the frail , institutionalised elderly . They are a cost effective use of the physiotherapist 's limited time OBJECTIVE To determine if a program of intense Tai Chi exercise that has been shown to reduce the risk of falling in older adults improves postural control by altering the center of pressure ( COP ) trajectory during gait initiation . DESIGN Before-after trial . SETTING Biomechanics research laboratory . PARTICIPANTS Twenty-eight older adults transitioning to frailty who participated in either a 48-week intervention of intense Tai Chi training or a wellness education ( WE ) program . INTERVENTIONS Eight Tai Chi forms emphasizing trunk rotation , weight shifting , coordination , and narrowing of lower-extremity stance were taught twice weekly . WE program participants met once a week and received lectures focused on health . Main outcome measures The COP was recorded during gait initiation both before and after the 48-week intervention by using a forceplate sampling at 300 Hz . The COP trajectory was divided into 3 periods ( S1 , S2 , S3 ) by identifying 2 l and mark events . Displacement and average velocity of the COP trace in the anteroposterior ( x ) and mediolateral ( y ) directions , as well as smoothness , were calculated . RESULTS Tai Chi training increased the posterior displacement of the COP during S1 and improved the smoothness of the COP during S2 . CONCLUSIONS Tai Chi improved the mechanism by which forward momentum is generated and improved coordination during gait initiation , suggesting improvements in postural control OBJECTIVES Although deficits in skeletal muscle strength , gait , balance , and oxygen uptake are potentially reversible causes of frailty , the efficacy of exercise in reversing frailty in community-dwelling older adults has not been proven . The aim of this study was to determine the effects of intensive exercise training ( ET ) on measures of physical frailty in older community-dwelling men and women . DESIGN R and omized controlled trial . SETTING Medical school research center . PARTICIPANTS One hundred fifteen sedentary men and women ( mean age + /- st and ard deviation = 83 + /- 4 ) with mild to moderate physical frailty , as defined by two of the following three criteria : Modified Physical Performance Test ( modified PPT ) score between 18 and 32 , peak oxygen uptake ( VO2 peak ) between 10 and 18 mL/kg/min , and self-report of difficulty or assistance with one basic activity of daily living ( ADL ) , or two instrumental ADLs . INTERVENTION Participants were r and omly assigned to a control group that performed a 9-month low-intensity home exercise program ( control ) or an exercise-training program ( ET ) . The control intervention primarily consisted of flexibility exercises . ET began with 3 months of flexibility , light-resistance , and balance training . During the next 3 months , resistance training was added , and , during the next 3 months , endurance training was added . MEASUREMENTS Modified PPT score , VO2 peak , performance of ADLs as measured by the Older Americans Re sources and Services instrument , and the Functional Status Question naire ( FSQ ) . RESULTS ET result ed in significantly greater improvements than home exercise in three of the four primary outcome measures . Adjusted 95 % confidence bounds on the magnitude of improvement in the ET group compared with the control group were 1.0 to 5.2 points for the modified PPT score , 0.9 to 3.6 mL/kg/min for VO2 peak , and 1.6 to 4.9 points for the FSQ score . CONCLUSIONS Our results show that intensive ET can improve measures of physical function and pre clinical disability in older adults who have impairments in physical performance and oxygen uptake and are not taking hormone replacement therapy better than a low-intensity home exercise program Background and Purpose Tai chi , a Chinese exercise derived from martial arts , while gaining popularity as an intervention for reducing falls in older adults , also may improve health status . The purpose of this study was to determine whether intense tai chi ( TC ) exercise could improve perceived health status and self-rated health ( SRH ) more than wellness education ( WE ) for older adults who are transitionally frail . Subjects Study subjects were 269 women who were ≥70 years of age and who were recruited from 20 congregate independent senior living facilities . Methods Participants took part in a 48-week , single-blind , r and omized controlled trial . They were r and omly assigned to receive either TC or WE interventions . Participants were interviewed before r and omization and at 1 year regarding their perceived health status and SRH . Perceived health status was measured with the Sickness Impact Profile ( SIP ) . Results Compared with WE participants , TC participants reported significant improvements in the physical dimension and ambulation categories and borderline significant improvements in the body care and movement category of the SIP . Self-rated health did not change for either group . Discussion and Conclusion These findings suggest that older women who are transitionally frail and participate in intensive TC exercise demonstrate perceived health status benefits , most notably in ambulation OBJECTIVES This study determined the effect of enriched foods and all-around physical exercise on bone and body composition in frail elderly persons . METHODS A 17-week r and omized , controlled intervention trial , following a 2 x 2 factorial design --(1 ) enriched foods , ( 2 ) exercise , ( 3 ) both , or ( 4 ) neither -- was performed in 143 frail elderly persons ( aged 78.6 + /- 5.6 years ) . Foods were enriched with multiple micronutrients ; exercises focused on skill training , including strength , endurance , coordination , and flexibility . Main outcome parameters were bone and body composition . RESULTS Exercise preserved lean mass ( mean difference between exercisers and non-exercisers : 0.5 kg + /- 1.2 kg ; P < .02 ) . Groups receiving enriched food had slightly increased bone mineral density ( + 0.4 % ) , bone mass ( + 0.6 % ) , and bone calcium ( + 0.6 % ) compared with groups receiving non-enriched foods , in whom small decreases of 0.1 % , 0.2 % , and 0.4 % , respectively , were found . These groups differed in bone mineral density ( 0.006 + /- 0.020 g/cm2 ; P = .08 ) , total bone mass ( 19 + /- g ; P = .04 ) , and bone calcium ( 8 + /- 21 g ; P = .03 ) . CONCLUSIONS Foods containing a physiologic dose of micronutrients slightly increased bone density , mass , and calcium , whereas moderately intense exercise preserved lean body mass in frail elderly persons OBJECTIVES To determine whether an intense tai chi ( TC ) exercise program could reduce the risk of falls more than a wellness education ( WE ) program in older adults meeting criteria for transitioning to frailty . DESIGN R and omized , controlled trial of 48 weeks duration . SETTING Twenty congregate living facilities in the greater Atlanta area . PARTICIPANTS Sample of 291 women and 20 men aged 70 to 97 . MEASUREMENTS Demographics , time to first fall and all subsequent falls , functional measures , Sickness Impact Profile , Centers for Epidemiologic Studies -Depression Scale , Activities-specific Balance Confidence Scale , Falls Efficacy Scales , and adherence to interventions . RESULTS The risk ratio ( RR ) of falling was not statistically different in the TC group and the WE group ( RR=0.75 , 95 % confidence interval (CI)=0.52 - 1.08 ) , P=.13 ) . Over the 48 weeks of intervention , 46 % ( n=132 ) of the participants did not fall ; the percentage of participants that fell at least once was 47.6 % for the TC group and 60.3 % for the WE group . CONCLUSION TC did not reduce the RR of falling in transitionally frail , older adults , but the direction of effect observed in this study , together with positive findings seen previously in more-robust older adults , suggests that TC may be clinical ly important and should be evaluated further in this high-risk population OBJECTIVES To determine whether a 12-month program of group exercise can improve physical functioning and reduce the rate of falling in frail older people . DESIGN Cluster r and omized , controlled trial of 12 months duration . SETTING Retirement villages in Sydney and Wollongong , Australia . PARTICIPANTS Five hundred fifty-one people aged 62 to 95 ( mean+/-st and ard deviation=79.5+/-6.4 ) who were living in self- and intermediate-care retirement villages . MEASUREMENTS Accidental falls , choice stepping reaction time , 6-minute walk distance postural sway , leaning balance , simple reaction time , and lower-limb muscle strength . RESULTS Two hundred eighty subjects were r and omized to the weight-bearing group exercise ( GE ) intervention that was design ed to improve the ability of subjects to undertake activities for daily living . Subjects r and omized to the control arm ( n=271 ) attended flexibility and relaxation ( FR ) classes ( n=90 ) or did not participate in a group activity ( n=181 ) . In spite of the reduced precision of cluster r and omization , there were few differences in the baseline characteristics of the GE and combined control ( CC ) subjects , although the mean age of the GE group was higher than that of the CC group , and there were fewer men in the GE group . The mean number of classes attended was 39.4+/-28.7 for the GE subjects and 31.5+/-25.2 for the FR subjects . After adjusting for age and sex , there were 22 % fewer falls during the trial in the GE group than in the CC group ( incident rate ratio=0.78 , 95 % confidence interval (CI)=0.62 - 0.99 ) , and 31 % fewer falls in the 173 subjects who had fallen in the past year ( incident rate ratio=0.69 , 95 % CI=0.48 - 0.99 ) . At 6-month retest , the GE group performed significantly better than the CC group in tests of choice stepping reaction time , 6-minute walking distance , and simple reaction time requiring a h and press . The groups did not differ at retest in tests of strength , sway , or leaning balance . CONCLUSION These findings show that group exercise can prevent falls and maintain physical functioning in frail older people Background : Balance training programs have not shown consistent results among older adults , and it remains unclear how different training methods can be adapted to frail elderly people . Objective : The purpose of this study was to investigate the effects of a 4-week visual feedback-based balance training on the postural control of frail elderly women living in residential care homes . Methods : Elderly women of two residential care facilities were r and omized to an exercise group ( EG , n = 20 ) and to a control group ( CG , n = 7 ) . The EG participated in training sessions three times/week for 4 weeks . The exercises were carried out with a computerized force platform with visual feedback screen . The dimensions of balance function studied were st and ing body sway , dynamic weight shifting , and Berg Balance Scale performance . Results : The EG showed significant improvement in balance functions . The performance time in dynamic balance tests improved on average by 35.9 % compared with a 0.6 % increase in the CG ( p = 0.025–0.193 ) . The performance distance in these tests decreased on average by 28.2 % in the EG as compared with a 9.8 % decrease seen in the CG . The Berg Balance Scale performance improved by 6.9 % compared with a 0.7 % increase in the CG ( p = 0.003 ) . The st and ing balance tests in the more dem and ing st and ing positions showed improvements in the EG , whereas similar changes in the CG were not found . Conclusions : Our findings suggest that balance training based on visual feedback improves the balance control in frail elderly women living in residential care , also enhancing the performance of functional balancing tasks relevant to daily living . The subjects were motivated to participate in the training , as indicated by the high compliance ( 97.5 % ) with the program OBJECTIVE Reduced muscle mass and strength are characteristic findings of growth hormone deficiency ( GHD ) and aging . We evaluated measures of muscle strength , muscle fiber type , and cross sectional area in response to treatment with recombinant human growth hormone ( rhGH ) with or without a structured resistance exercise program in frail older subjects . DESIGN Placebo-controlled , r and omized , double blind trial . SETTING Outpatient clinical research center at an urban university-affiliated teaching hospital . PARTICIPANTS Thirty-one consenting older subjects ( mean age 71.3 + /- 4.5 years ) recruited as a subset of a larger project evaluating rhGH and exercise in older people , who underwent 62 quadricep-muscle biopsies . INTERVENTION R and om assignment to a 6-month course of one of four protocol s : rhGH administered subcutaneously daily at bedtime , rhGH and a structured resistance exercise program , structured resistance exercise with placebo injections , or placebo injections only . MEASUREMENTS Muscle biopsy specimens were obtained from the vastus lateralis muscle . Isokinetic dynamometry strength tests were used to monitor individual progress and to adjust the weights used in the exercise program . Serum insulin-like growth factor-I ( IGF-I ) was measured and body composition was measured using a Hologic QDR 1000W dual X-ray densitometer . RESULTS The administration of rhGH result ed in significant increase in circulating IGF-I levels in the individuals receiving rhGH treatment . Muscle strength increased significantly in both the rhGH/exercise ( + 55.6 % , P = .0004 ) as well as the exercise alone ( + 47.8 % , P = .0005 ) groups . There was a significant increase in the proportion of type 2 fibers between baseline and six months in the combined rhGH treated subjects versus those not receiving rhGH ( P = .027 ) . CONCLUSIONS Our results are encouraging in that they suggest an effect of growth hormone on a specific aging-correlated deficit . IGF-I was increased by administrating rhGH and muscle strength was increased by exercise . The administration of rhGH to frail older individuals in this study result ed in significant changes in the proportions of fiber types . Whether changes in fiber cross-sectional area or absolute number occur with long-term growth hormone administration requires further study Background and aims : Falls are particularly common among older people living in residential care facilities . The aim of this r and omized controlled trial was to evaluate the effectiveness of a high-intensify functional exercise program in reducing falls in residential care facilities . Methods : Participants comprised 191 older people , 139 women and 52 men , who were dependent in activities of daily ) living . Their mean±SD score on the Mini-Mental State Examination was 17.8±5.1 ( range 10–30 ) . Participants were r and omized to a high-intensity functional exercise program or a control activity , consisting of 29 sessions over 3 months . The fall rate and proportion of participants sustaining a fall were the outcome measures , subsequently analysed using negative binominal analysis and logistic regression analysis , respectively . Results : During the 6-month follow-up period , when all participants were compared , no statistically significant differences between groups were found for fall rate ( exercise group 3.6 falls per person years [ PY ] , control group 4.6 falls per PY ) , incidence rate ratio ( 95 % CI ) 0.82 ( 0.49−1.39 ) , p=0.46 , or the proportion of participants sustaining a fall ( exercise 53 % , control 51 % ) , odds ratio ( 95 % CI ) 0.95 ( 0.52−1.74 ) , p=0.86 . A subgroup interaction analysis revealed that , among participants who improved their balance during the intervention period , the exercise group had a lower fall rate than the control group ( exercise 2.7 falls per PY , control 5.9 falls per PY ) , incidence rate ratio ( 95 % CI ) 0.44 ( 0.21−0.91 ) , p=0.03 . Conclusions : In older people living in residential care facilities , a high-intensity functional exercise program may prevent falls among those who improve their balance OBJECTIVE The purpose of this pilot was to determine whether a strength and flexibility program in frail long-term care facility ( LTC ) residents would result in improved function . DESIGN A prospect i ve , r and omized , controlled , semicrossover trial was design ed with participants assigned either to group exercise ( EX ) or recreational therapy ( C ) . In the EX group , the intervention continued for 1 year . In the C group , recreation continued for 6 months ; these controls were then crossed over to the same exercise intervention as the EX group and followed for an additional 6 months . Functional outcomes were measured at baseline and 3 , 6 , 9 , and 12 months for both groups . SETTING A LTC facility , which included both assisted living ( AL ) and nursing home ( NH ) residents . PARTICIPANTS Twenty frail residents ( 5 from NH , 15 from AL ) aged 75 to 99 years at one LTC facility . INTERVENTION After r and om group assignment , the EX group met 1 hour three times per week . An exercise physiologist and LTC staff conducted sessions which included seated range of motion ( ROM ) exercises and strength training using simple equipment such as elastic resistance b and s ( therab and s ) and soft weights . The C group met three times per week and participated in activities such as painting during the first 6 months , before crossing over to exercise . MEASUREMENTS AND METHODS Objective measures of physical and cognitive function were obtained at baseline and 3 , 6 , 9 , and 12 months using the timed get-up- and -go test ( TUG ) , Berg balance scale , physical performance test ( PPT ) , and mini-mental status exam ( MMSE ) . Because we were interested in the impact of exercise on multiple endpoints and to protect the type I error rate , a global hypothesis test was used . RESULTS There was a significant overall impact across the four measures of the exercise intervention ( P = 0.013 ) . Exercise benefit as indicated by the difference between exercise and control conditions showed exercise decreased TUG by 18 seconds , which represents an effect size ( in st and ard deviation units ) of 0.50 , increased PPT scores by 1.3 , with effect size = 0.40 , increased Berg scores by 4.8 , with effect size of 0.32 , and increased MMSE by 3.1 , with effect size = 0.54 . Except for the Berg , 90 % confidence intervals on these exercise effects excluded 0 . CONCLUSION Frail elderly in a LTC facility were able to participate and benefit from a strength training program . The program was delivered with low-cost equipment by an exercise physiologist and LTC staff . The advantage of such a program is that it provides recreational and therapeutic benefits Elderly participants experiencing difficulty in chair rising and with a maximum knee-extensor torque below 87.5 N . m were r and omized to different versions of a strength-training program for the knee-extensors : to a high-guidance group ( HG ; two group sessions supervised by a physical therapist and one unsupervised home session per week , n = 17 ) , a medium-guidance group ( MG ; one supervised group session and two unsupervised home sessions per week , n = 16 ) , or a control group ( C ; no exercise , n = 16 ) . Maximal isometric knee strength increased more in HG than in C ( p = .03 ) and with increasing guidance ( p = .03 ) . The effect was mainly the result of participants with low initial strength . Walking speed increased more for HG than for C ( p = .02 ) and than for MG ( p = .06 ) . No statistically significant improvements were seen on other functional tests . In summary , the study shows a trend toward better results with more supervision , but more and larger studies are needed to confirm this Objective : To test the effect of two exercise regimes on health-related quality of life ( HRQoL ) and ambulatory capacity . Design : R and omized controlled trial . Subjects : Seventy-seven community-dwelling physically frail people over 75 years of age ( mean=81 , SD=4.5 ) . Interventions : Home training ( HT , N = 38 ) comprised twice daily functional balance and strength exercises and three group meetings . Combined training ( CT , N = 39 ) included group training twice weekly and the same home exercises . Interventions lasted 12 weeks . Physiotherapists ran both programmes . Home exercises were recorded daily . Main measures : HRQoL was assessed by SF-36 , and ambulatory capacity by walking speed and frequency and duration of outdoor walks . Results : Following intervention , CT improved the SF-36 mental health index significantly more than HT ( p = 0.01 ) . The SF-36 physical health index ( p = 0.002 ) and walking speed ( p = 0.02 ) demonstrated improvements , but no group differences . Six months after cessation of intervention there was still overall improvements on the mental health index ( p = 0.032 ) , borderline overall improvements on the physical health index ( p = 0.057 ) , higher weekly number of outdoor walks for the CT group than for the HT group ( p = 0.027 ) and an improved habitual walking speed in the CT group only ( p = 0.022 ) . Conclusions : HT improved HRQoL and walking speed , but additional group training gave larger benefits on mental health . Group training away from home may be beneficial for mental health and ambulatory capacity Objective : To evaluate effects of early intensive physiotherapy during acute illness on post hospitalization activity daily living autonomy ( ADL ) . Design : Prospect i ve r and omized controlled trial of intensive physiotherapy rehabilitation on day 1 to 2 after admission until clinical stability or usual care . Setting : acute care geriatric medicine ward . Patients : A total of 76 acutely ill patients , acutely bedridden or with reduced mobility but who were autonomous for mobility within the previous 3 months . Patients in palliative care or with limiting mobility pathology were excluded . Mean age was 85.4 ( SD 6.6 ) years . Measurements : At admission , at clinical stability and one month later : anthropometry , energy and protein intakes , h and grip strength , ADL scores , and baseline inflammatory parameters . An exploratory principal axis analysis was performed on the baseline characteristics and general linear models were used to explore the course of ADL and nutritional variables . Results : A 4-factor solution was found explaining 71.7 % of variance with a factor “ nutrition ” , a factor “ function ” ( 18.8 % of variance ) for ADL , h and grip strength , bedridden state , energy and protein intakes , serum albumin and C-reactive protein concentrations ; a factor “ strength ” and a fourth factor . During follow-up , dietary intakes , h and grip strength , and ADL scores improved but no changes occurred for anthropometric variables . Intervention was associated only with an increase in protein intake . Better improvement in ADL was found in intervention group when model was adjusted on “ function ” factor items . Conclusion : Physical intervention programs should be proposed according to nutritional intakes with the aim of preventing illness induced disability Although exercise is usually promoted for weight loss and better heart health , there is growing evidence that regular physical activity helps people preserve their mental ability . We describe the results of a pilot longitudinal study addressing the impact of a moderate intensity exercise program on behavioral problems of frail , elderly , demented patients living in nursing home . Overall , patients in the treatment group ( combination of aerobic/endurance activities , strength training , balance , and flexibility training ) showed a statistically significant reduction in the behavioral problems , such as w and ering , physical and verbal abuse , and in the sleep disorders . As a consequence , a significant reduction in the use of antipsychotic and hypnotic medications was observed in subjects of the treated group . In conclusion , our preliminary results suggest that engaging in regular physical activity , among other health benefits , may delay or prevent the onset of behavior problems in demented frail elderly people living in nursing home OBJECTIVES To determine the effectiveness of vitamin D and home-based quadriceps resistance exercise on reducing falls and improving the physical health of frail older people after hospital discharge . DESIGN Multicenter , r and omized , controlled trial with a factorial design . SETTING Five hospitals in Auckl and , New Zeal and , and Sydney , Australia . PARTICIPANTS Two hundred forty-three frail older people . INTERVENTIONS Patients were r and omized to receive a single dose of vitamin D ( calciferol , 300,000 IU ) or placebo tablets and 10 weeks of high-intensity home-based quadriceps resistance exercise or frequency-matched visits . MEASUREMENTS The primary endpoints were physical health according to the short-form health survey at 3 months and falls over 6 months . Physical performance and self-rated function were secondary endpoints . Assessment s took place in the participants ' homes at 3 and 6 months after r and omization and were performed by blinded assessors . RESULTS There was no effect of either intervention on physical health or falls , but patients in the exercise group were at increased risk of musculoskeletal injury ( risk ratio = 3.6 , 95 % confidence interval = 1.5 - 8.0 ) . Vitamin D supplementation did not improve physical performance , even in those who were vitamin D deficient ( < 12 ng/mL ) at baseline . CONCLUSION Neither vitamin D supplementation nor a home-based program of high-intensity quadriceps resistance exercise improved rehabilitation outcomes in frail older people after hospitalization . There was no effect of vitamin D on physical performance , and the exercises increased the risk of musculoskeletal injury . These findings do not support the routine use of these interventions at these dosages in the rehabilitation of frail older people The purpose of this study was to determine the influence of simple , progressive lower body exercise training , focusing on strength and power , on functional abilities in frail older adults . Twenty-five residents of a long-term care facility ( 75 - 94 yrs ) participated in this r and omized controlled trial of 10-wks duration . The exercise group ( Ex , n = 18 ) underwent simple , progressive lower body resistance exercises , specifically aim ed at improving muscle power , 3 times/wk ; the control subjects ( Con , n = 7 ) maintained their usual daily activities . Knee extensor strength and power were measured on an isokinetic dynamometer ( 180 degrees/s ) , and functional performance was assessed from a 6-m walk timed test , a 30-s chair st and , and an 8-ft up- and -go timed test , before and after the 10-wk intervention period . Significant increases were found in the Ex group for eccentric ( 44 % ) and concentric ( 60 % ) average power ( p < 0.05 ) , and improvements were seen on each functional test : the 8-foot up- and -go , chair st and , and walk time improved by 31 % , 66 % , and 33 % , respectively ( p < 0.05 ) . No significant change occurred in the Con group . In conclusion , simple progressive exercise training , even in the 10th decade , increases muscle power and is associated with an improved performance of functional activities using the trained muscles Background and aims : An acute illness may place older frail people at increased risk of losing independence in functional abilities . Physical exercise may reduce the risk by improving muscle strength and balance . However , the effects of physical training on functional abilities have not been studied among frail , very old people recovering from an acute illness . The aim of this study was to determine the effects of a group-based exercise program on their ability to carry out self-care ( ADL ) and instrumental activities ( IADL ) relevant to daily life after discharge from hospital . Methods : This r and omized controlled trial examined 68 community-dwelling women aged 75 years or older ( mean age 83.0 , SD 3.9 ) who were hospitalized due to an acute illness , and were mobility-impaired at admission . Participants were recruited from the geriatric ward of a primary -care health-center hospital , and were r and omized into group-based strength training ( n=34 ) and control ( n=34 ) groups . The 10-week group-based intervention included strength training and functional exercises . The control group received instructions for a home exercise training program , including functional exercises but no further encouragement to exercise . The level of independence in ADL and IADL was evaluated , using a 13-item scale with stepwise grading from fully independent to fully dependent . Measurements took place immediately before and after the intervention , and three and nine months later . Results : The intervention did not have any significant main effect ( p=0.407 ) , nor was there any significant interaction between follow-up time and intervention ( p=0.854 ) . Conclusions : The multi-component outpatient strength training program did not improve autonomy in expert-evaluated ADL/IADL functions OBJECTIVE To evaluate an exercise protocol design ed to improve strength and mobility , and to decrease injury risk factors in physically restrained nursing home residents . DESIGN A r and omized controlled trial . PARTICIPANTS Ninety-seven residents were r and omized into either exercise or control groups . Thirty-five exercise and 37 control group residents completed all post- assessment s after a 9-week trial . INTERVENTION Walking or wheelchair movement training was supplemented by rowing exercise three times per week . Practice in behaviors related to safe movement was provided incidental to the exercise . MEASUREMENT Endurance , speed , and injury risk measures relevant to walking , wheelchair propulsion , and st and ing were assessed by st and ardized protocol s. Rowing endurance , rowing range of motion , and h and grip strength measures were collected to assess the effect of the rowing component of the exercise protocol . RESULTS Fifty-four percent of the subjects who provided consent did not complete the protocol because of health status changes , lack of cooperation , or physical limitations that precluded exercise . The subjects who completed the exercise program showed significant improvement on injury risk and measures related to upper body strength ( h and grip strength , rowing endurance , wheelchair endurance , and speed ) . Measures related to lower body strength did not significantly improve . CONCLUSION Physically restrained residents are very frail , and it is difficult to implement a long-term exercise program with many residents because of the frailty . However , a substantial proportion of residents did cooperate well with the exercise program and showed improvement on measures correlated with decreased injury risk . The exercise program could be easily modified to include more lower body exercise , and the result ant protocol would be an important adjunct to restraint reduction programs The aim of this study was to analyze social welfare and healthcare costs and fall-related healthcare costs after a group-based exercise program . The 10-week exercise program , which started after discharge from the hospital , was design ed to improve physical fitness , mood , and functional abilities in frail elderly women . Sixty-eight acutely hospitalized and mobility-impaired women ( mean age 83.0 , SD 3.9 years ) were r and omized into either group-based ( intervention ) or home exercise ( control ) groups . Information on costs was collected during 1 year after hospital discharge . There were no differences between the intervention and control groups in the mean individual healthcare costs : 4381 euros ( SD 3829 euros ) vs 3539 euros ( SD 3967 euros ) , P=0.477 , in the social welfare costs : 3336 euros ( SD 4418 euros ) vs 4073 euros ( SD 5973 euros ) , P=0.770 , or in the fall-related healthcare costs : 996 euros ( SD 2612 euros ) vs 306 euros ( SD 915 ) , P=0.314 , respectively . This exercise intervention , which has earlier proved to be effective in improving physical fitness and mood , did not result in any financial savings in municipal costs . These results serve as a pilot study and further studies are needed to establish the cost-effectiveness of this exercise intervention for elderly people OBJECTIVE To examine the effects of 17-wk physical exercise and enriched foods on cellular immune response ( CIR ) in frail elderly . METHODS A total of 112 independently living , frail elderly men and women ( mean age 79.2 + /- 5.9 ) received : twice weekly comprehensive , moderate intensity , progressive group exercise ( group A , N = 26 ) ; daily enriched foods ( group B , N = 31 ) ; both ( group C , N = 29 ) ; or neither ( group D , N = 26 ) . Exercises focused on skills training . Foods were enriched with micronutrients with a high prevalence of deficiency in older people ( at 25 - 100 % the RDA ) . A social program and identical regular foods were offered as a control . CIR was measured by delayed-type hypersensitivity skin test response ( DTH ) against seven recall antigens expressed as the total number of positive responses and sum of diameters of all positive responses . RESULTS No independent or interactive effect of enriched foods was observed . Therefore , exercise ( groups A + C ) was compared with no exercise ( groups B + D ) . Nonexercising subjects showed an average decline of 0.5 responses compared with an unchanged responsiveness among exercising subjects ( difference = 0.5 , 95 % CI : 0.04 - 0.89 , P = 0.03 adjusted for baseline DTH , activity level , and micronutrient status ) . Nonexercising subjects had a larger decline in the sum of diameters of all positive responses than exercising subjects but the difference did not reach significance ( adjusted difference = 2.1 mm , 95 % CI:-1.0 - 4.8 ) . CONCLUSION Exercise may prevent or slow the age-related decline in immune response . Micronutrient enriched foods showed no effect . As infectious diseases can have debilitating or even fatal consequences for the elderly , prevention of the age-related decline in CIR could significantly improve their quality of life BACKGROUND Functional decline in physically frail , elderly persons is associated with substantial morbidity . It is uncertain whether such functional decline can be prevented . METHODS We r and omly assigned 188 persons 75 years of age or older who were physically frail and living at home to undergo a six-month , home-based intervention program that included physical therapy and that focused primarily on improving underlying impairments in physical abilities , including balance , muscle strength , ability to transfer from one position to another , and mobility , or to undergo an educational program ( as a control ) . The primary outcome was the change between base line and 3 , 7 , and 12 months in the score on a disability scale based on eight activities of daily living : walking , bathing , upper- and lower-body dressing , transferring from a chair , using the toilet , eating , and grooming . Scores on the scale ranged from 0 to 16 , with higher scores indicating more severe disability . RESULTS Participants in the intervention group had less functional decline over time , according to their disability scores , than participants in the control group . The disability scores in the intervention and control groups were 2.3 and 2.8 , respectively , at base line ; 2.0 and 3.6 at 7 months ( P=0.008 for the comparison between the groups in the change from base line ) ; and 2.7 and 4.2 at 12 months ( P=0.02 ) . The benefit of the intervention was observed among participants with moderate frailty but not those with severe frailty . The frequency of admission to a nursing home did not differ significantly between the intervention group and the control group ( 14 percent and 19 percent , respectively ; P=0.37 ) . CONCLUSIONS A home-based program targeting underlying impairments in physical abilities can reduce the progression of functional decline among physically frail , elderly persons who live at home OBJECTIVE To examine the effects of a 3-month low-intensity exercise program on physical frailty . DESIGN R and omized clinical trial . SETTING Regional tertiary-care hospital and academic medical center with an outpatient rehabilitation fitness center . PARTICIPANTS Eighty-four physically frail older adults ( mean age , 83 + /- 4 yrs ) . INTERVENTION Three-month low-intensity supervised exercise ( n = 48 ) versus unsupervised home-based flexibility activities ( n = 36 ) . MAIN OUTCOME MEASURES Physical performance test , measures of balance , strength , flexibility , coordination , speed of reaction , peripheral sensation . RESULTS Significant improvement was made by the exercise group on our primary indicator of frailty , a physical performance test ( PPT ) ( 29 + /- 4 vs 31 + /- 4 out of a possible 36 points ) , as well as many of the risk factors previously identified as contributors to frailty ; eg , reductions in flexibility , strength , gait speed , and poor balance . Although the home exercise control group showed increases in range of motion , the improvements in flexibility did not translate into improvements in physical performance capacity as assessed by the PPT . CONCLUSIONS Our results suggest that physical frailty is modifiable with a program of modest activities that can be performed by virtually all older adults . They also indicate that exercise programs consisting primarily of flexibility activities are not likely to reverse or attenuate physical frailty . Although results suggest that frailty is modifiable , it is not likely to be eliminated with exercise , and efforts should be directed toward preventing the condition Shimada H , Obuchi S , Furuna T , Suzuki T : New intervention program for preventing falls among frail elderly people : The effects of perturbed walking exercise using a bilateral separated treadmill . Am J Phys Med Rehabil 2004;83:493–499 . Objective : To determine the effects of a perturbed walking exercise using a bilateral separated treadmill in physically disabled elderly . Design : Participants of the study were 32 long-term care facility residents and out patients aged 66–98 yrs . Participants were r and omly assigned to a usual exercise group or to a treadmill exercise group . Perturbed gait exercise on a treadmill continued for 6 mos . Number of falls and time to first fall during a 6-mo period , balance and gait functions , and reaction time were evaluated before and after intervention . Results : The treadmill exercise group showed significant improvement in balance and reaction time when compared with the usual exercise group . Number of falls in the treadmill exercise group was 21 % lower than that in the usual exercise group . However , this difference was not significant . No significant differences were seen in time to first fall . Conclusions : Gait training with unexpected perturbation seems to have a beneficial impact on physical function in disabled elderly individuals . The results suggest that this program may be used as an exercise intervention to reduce falls in institutional setting BACKGROUND Strength loss is strongly associated with functional decline and is reversible with exercise . The effect of increased strength on function has not been clearly established . The purpose of this study was to determine whether strength gain is associated with improvement in physical performance and disability . METHODS One hundred functionally impaired community-dwelling men and women ( 77.6 + /- 7.6 yrs ) were tested at baseline and outcome for lower extremity strength , physical performance , and disability . After r and om group assignment , exercise participants received strengthening exercises in their homes three times a week for 10 weeks while control subjects continued their normal activities . Using multiple regression techniques , the relationship between strength gain and improvement in physical performance and disability was assessed , controlling for age , depression , and baseline strength . RESULTS A significant impact of strength gain on mobility skills ( p = .0009 ) was found . The impact of strength gain on chair rise performance was significant in participants who were more impaired ( p = .04 ) . Strength gain was associated with gain in gait speed ( p = .02 ) and in falls efficacy ( p = .05 ) , but not with other balance , endurance , or disability measures . CONCLUSIONS Lower extremity strength gain is associated with gains in chair rise performance , gait speed , and in mobility tasks such as gait , transfers , stooping , and stair climbing , but not with improved endurance , balance , or disability . Strength gain is also associated with improvement in confidence in mobility . Factors that may influence the ability of strength gain to affect function are initial level of frailty and specificity of exercise . These results support the idea that strength training is an intervention that can potentially improve physical health status in many frail elders OBJECTIVE To examine the effects of an exercise program and an enriched food regimen on physical functioning of frail elderly persons . DESIGN A 17-week r and omized , placebo-controlled trial . SETTING Community . PARTICIPANTS One hundred fifty-seven independently living frail elderly ( mean age , 78.7 + /- 5.6yr ) . INTERVENTION Thirty-nine subjects participated in a twice weekly group exercise design ed to improve daily functioning ; 39 subjects daily ate foods enriched with vitamins and minerals ( at 25%-100 % of the recommended daily allowances ) ; 42 subjects exercised and ate enriched foods ; and 37 subjects served as controls . Nonexercising groups followed a social program ; nonsupplement groups received the same food products without the micronutrients . MAIN OUTCOME MEASURES Functional performance based on 6 performance tests , physical fitness based on 7 fitness tests , and disabilities based on the self-reported ability to perform 16 daily activities . RESULTS Performance sum scores were significantly enhanced in trained ( + 8 % ) compared with nontrained subjects ( -8 % ) ( difference in change : 1.9 points , p < .001 , adjusted for baseline scores ) . Fitness sum scores were significantly enhanced as well ( + 3 % in trained vs -2 % in nontrained ) ( difference in change : 0.9 points , p = .05 , adjusted for baseline scores ) . No exercise effects on the disability score were observed . Consumption of enriched products did not affect performance , fitness , or disability scores . CONCLUSION Our comprehensive exercise program , design ed for widespread applicability , enhanced physical performance and fitness in a population of frail elderly . Daily consumption of micronutrient enriched foods showed no functional benefits within 17 weeks BACKGROUND Although disuse of skeletal muscle and undernutrition are often cited as potentially reversible causes of frailty in elderly people , the efficacy of interventions targeted specifically at these deficits has not been carefully studied . METHODS We conducted a r and omized , placebo-controlled trial comparing progressive resistance exercise training , multinutrient supplementation , both interventions , and neither in 100 frail nursing home residents over a 10-week period . RESULTS The mean ( + /- SE ) age of the 63 women and 37 men enrolled in the study was 87.1 + /- 0.6 years ( range , 72 to 98 ) ; 94 percent of the subjects completed the study . Muscle strength increased by 113 + /- 8 percent in the subjects who underwent exercise training , as compared with 3 + /- 9 percent in the nonexercising subjects ( P < 0.001 ) . Gait velocity increased by 11.8 + /- 3.8 percent in the exercisers but declined by 1.0 + /- 3.8 percent in the nonexercisers ( P = 0.02 ) . Stair-climbing power also improved in the exercisers as compared with the nonexercisers ( by 28.4 + /- 6.6 percent vs. 3.6 + /- 6.7 percent , P = 0.01 ) , as did the level of spontaneous physical activity . Cross-sectional thigh-muscle area increased by 2.7 + /- 1.8 percent in the exercisers but declined by 1.8 + /- 2.0 percent in the nonexercisers ( P = 0.11 ) . The nutritional supplement had no effect on any primary outcome measure . Total energy intake was significantly increased only in the exercising subjects who also received nutritional supplementation . CONCLUSIONS High-intensity resistance exercise training is a feasible and effective means of counteracting muscle weakness and physical frailty in very elderly people . In contrast , multi-nutrient supplementation without concomitant exercise does not reduce muscle weakness or physical frailty BACKGROUND Older people with somatic illnesses are at increased risk of depression . It is not known whether exercise alleviates depressive symptoms in frail , very old people recuperating from an acute illness . OBJECTIVE To determine the effects of a group-based exercise training program on mood . METHODS Sixty-eight women ( mean age 83.0 , SD 3.9 years ) who were hospitalized due to an acute illness , and were mobility impaired at admission , were r and omized into group-based 10-week strength training intervention ( N=34 ) and home exercise control ( N=34 ) groups . Twenty-four women in the training and 28 in the control group completed the follow-up . Measures of mood state with the Zung Self-Rating Depression Scale ( ZSDS ) were performed before and after the training intervention , and follow-up data was collected 3 and 9 months after the end of the intervention . RESULTS After the intervention , there was a significant improvement in mood in the intervention group compared to the home exercise control group : -3.1 ( SD 9.0 ) points vs + 1.3 ( SD 7.6 ) points ( p=0.048 ) and the positive effect was still apparent three months after the intervention ceased : -2.6 ( SD 7.7 ) points vs + 3.5 ( SD 9.7 ) points ( p=0.015 ) . Improvement of mood state at the first follow-up measurement was associated with the improvement in lower limb isometric muscle strength . CONCLUSIONS Group-based exercise program organized in the context of a Finnish health care organization improved mood in frail older women recuperating from an acute illness |
1,910 | 23,691,286 | The majority of studies failed to describe the specific strategies used in the delivery of the maintenance intervention , adherence to those strategies , and did not incorporate a maintenance phase process evaluation making it difficult to identify intervention characteristics associated with better weight loss maintenance .
However , the inclusion of cultural adaptations , particularly in studies with a mixed ethnicity/race sample , result ed in less % weight regain for African American women .
Studies with a formal maintenance intervention and weight management as the primary intervention focus reported more positive weight maintenance outcomes for African American women .
Nonetheless , our results present both the difficulty in weight loss and maintenance experienced by African American women in behavioral lifestyle interventions | null | null |
1,911 | 27,757,739 | A temporal pattern of the evolution of the illness was found .
In early sepsis , the median blood flow velocity ( Vm ) and pulsatility index ( PI ) increased , and the cerebral autoregulation ( CA ) remained unchanged .
In contrast , Vm normalization , PI reduction and CA impairment were found in later sepsis ( patients with severe sepsis or septic shock ) .
Cerebral haemodynamic is impaired in sepsis .
Modifications in cerebral blood flow may be consequence to the endothelial dysfunction of the microvasculature induced by the release of inflammatory mediators .
A better underst and ing of cerebral hemodynamics may improve the clinical management of patients with sepsis and , consequently , improve clinical outcomes | Cerebral microcirculation is gradually compromised during sepsis , with significant reductions in the function of capillaries and blood perfusion in small vessels .
Transcranial Doppler ultrasound ( TCD ) has been used to assess cerebral circulation in a typical clinical setting .
This study was to systematic ally review TCD studies , assess their method ological quality , and identify trends that can be associated with the temporal evolution of sepsis and its clinical outcome . | Introduction The pathophysiology of sepsis-associated delirium is not completely understood and the data on cerebral perfusion in sepsis are conflicting . We tested the hypothesis that cerebral perfusion and selected serum markers of inflammation and delirium differ in septic patients with and without sepsis-associated delirium . Methods We investigated 23 adult patients with sepsis , severe sepsis , or septic shock with an extracranial focus of infection and no history of intracranial pathology . Patients were investigated after stabilisation within 48 hours after admission to the intensive care unit . Sepsis-associated delirium was diagnosed using the confusion assessment method for the intensive care unit . Mean arterial pressure ( MAP ) , blood flow velocity ( FV ) in the middle cerebral artery using transcranial Doppler , and cerebral tissue oxygenation using near-infrared spectroscopy were monitored for 1 hour . An index of cerebrovascular autoregulation was calculated from MAP and FV data . C-reactive protein ( CRP ) , interleukin-6 ( IL-6 ) , S-100β , and cortisol were measured during each data acquisition . Results Data from 16 patients , of whom 12 had sepsis-associated delirium , were analysed . There were no significant correlations or associations between MAP , cerebral blood FV , or tissue oxygenation and sepsis-associated delirium . However , we found a significant association between sepsis-associated delirium and disturbed autoregulation ( P = 0.015 ) . IL-6 did not differ between patients with and without sepsis-associated delirium , but we found a significant association between elevated CRP ( P = 0.008 ) , S-100β ( P = 0.029 ) , and cortisol ( P = 0.011 ) and sepsis-associated delirium . Elevated CRP was significantly correlated with disturbed autoregulation ( Spearman rho = 0.62 , P = 0.010 ) . Conclusion In this small group of patients , cerebral perfusion assessed with transcranial Doppler and near-infrared spectroscopy did not differ between patients with and without sepsis-associated delirium . However , the state of autoregulation differed between the two groups . This may be due to inflammation impeding cerebrovascular endothelial function . Further investigations defining the role of S-100β and cortisol in the diagnosis of sepsis-associated delirium are warranted . Trial registration Clinical Trials.gov NCT00410111 Abstract . Objective : Perfusion abnormalities are an overall phenomenon in severe sepsis and septic shock , leading to organ dysfunction . We investigated whether carbon dioxide (CO2)-induced vasomotor reactivity ( VMR ) is impaired in septic patients , compared with values obtained outside sepsis . Design : Prospect i ve , clinical study . Setting : Six-bed neurologic critical care unit of a university hospital . Patients and participants : Eight consecutive patients with severe sepsis and septic shock . Measurements and results : CO2-reactivity was measured during and outside a period of severe sepsis or septic shock according to ACCP/SCCM criteria by means of transcranial Doppler sonography and near-infrared spectroscopy ( NIRS ) . VMR was calculated as the percentage change of cerebral blood flow velocity ( normalized CO2-reactivity , NCR ) and absolute changes in concentration of oxygenated hemoglobin , deoxygenated hemoglobin , total hemoglobin ( HbO2 , Hb , HbT ) and Hbdiff ( difference between HbO2 and Hb ) in µmol/l per 1 % increase in end-tidal CO2 ( CR-HbO2 , CR-Hb , CR-HbT , CR-Hbdiff ) . NCR and NIRS-reactivities were significantly reduced during severe sepsis and septic shock compared with values outside sepsis ( mean , SD , Wilcoxon ) : NCR 11.0 ( 7.1 ) versus 30.7 ( 13.0 ) , p<0.02 ; CR-HbO2 0.70 ( 0.61 ) versus 2.33 ( 1.11 ) , p<0.02 ; CR-Hb –0.17 ( 0.74 ) versus –1.42 ( 1.28 ) , p<0.04 ; CR-HbT 0.53 ( 0.48 ) versus 1.05 ( 0.40 ) , p<0.03 ; CR-Hbdiff 0.91 ( 1.33 ) versus 3.75 ( 2.33 ) , p<0.02 . This indicates a severely disturbed VMR . Conclusions : In the advent of a disturbed cerebral autoregulation , critical drops in blood pressure during sepsis are transferred directly into the vascular bed , leading to cerebral hypoperfusion . This mechanism might contribute to the pathogenesis of septic encephalopathy Introduction Pathophysiology of brain dysfunction due to sepsis remains poorly understood . Cerebral microcirculatory alterations may play a role ; however , experimental data are scarce . This study sought to investigate whether the cerebral microcirculation is altered in a clinical ly relevant animal model of septic shock . Methods Fifteen anesthetized , invasively monitored , and mechanically ventilated female sheep were allocated to a sham procedure ( n = 5 ) or sepsis ( n = 10 ) , in which peritonitis was induced by intra-abdominal injection of autologous faeces . Animals were observed until spontaneous death or for a maximum of 20 hours . In addition to global hemodynamic assessment , the microcirculation of the cerebral cortex was evaluated using Sidestream Dark-Field ( SDF ) videomicroscopy at baseline , 6 hours , 12 hours and at shock onset . At least five images of 20 seconds each from separate areas were recorded at each time point and stored under a r and om number to be analyzed , using a semi-quantitative method , by an investigator blinded to time and condition . Results All septic animals developed a hyperdynamic state associated with organ dysfunction and , ultimately , septic shock . In the septic animals , there was a progressive decrease in cerebral total perfused vessel density ( from 5.9 ± 0.9 at baseline to 4.8 ± 0.7 n/mm at shock onset , P = 0.009 ) , functional capillary density ( from 2.8 ± 0.4 to 2.1 ± 0.7 n/mm , P = 0.049 ) , the proportion of small perfused vessels ( from 95 ± 3 to 85 ± 8 % , P = 0.02 ) , and the total number of perfused capillaries ( from 22.7 ± 2.7 to 17.5 ± 5.2 n/mm , P = 0.04 ) . There were no significant changes in microcirculatory flow index over time . In sham animals , the cerebral microcirculation was unaltered during the study period . Conclusions In this model of peritonitis , the cerebral microcirculation was impaired during sepsis , with a significant reduction in perfused small vessels at the onset of septic shock . These alterations may play a role in the pathogenesis of septic encephalopathy Introduction The pathophysiology of sepsis-associated encephalopathy ( SAE ) is not entirely clear . One of the possible underlying mechanisms is the alteration of the cerebral microvascular function induced by the systemic inflammation . The aim of the present work was to test whether cerebral vasomotor-reactivity is impaired in patients with SAE . Methods Patients fulfilling the criteria of clinical sepsis and showing disturbance of consciousness of any severity were included ( n = 14 ) . Non-septic persons whithout previous diseases affecting cerebral vasoreactivity served as controls ( n = 20 ) . Transcranial Doppler blood flow velocities were measured at rest and at 5 , 10 , 15 and 20 minutes after intravenous administration of 15 mg/kgBW acetazolamide . The time course of the acetazolamide effect on cerebral blood flow velocity ( cerebrovascular reactivity , CVR ) and the maximal vasodilatory effect of acetazolemide ( cerebrovascular reserve capacity , CRC ) were compared among the groups . Results Absolute blood flow velocities after adminsitration of the vasodilator drug were higher among control subjects than in SAE . Assessment of the time-course of the vasomotor reaction showed that patients with SAE reacted slower to the vasodilatory stimulus than control persons . When assessing the maximal vasodilatory ability of the cerebral arterioles to acetazolamide during vasomotor testing , we found that patients with SAE reacted to a lesser extent to the drug than did control subjects ( CRC controls:46.2 ± 15.9 % , CRC SAE : 31,5 ± 15.8 % , P < 0.01 ) . Conclusions We conclude that cerebrovascular reactivity is impaired in patients with SAE . The clinical significance of this pathophysiological finding has to be assessed in further studies OBJECTIVE To determine whether the severity of septic encephalopathy is correlated with gram-negative bacteremia and mortality and whether there exists a single or combination of metabolic derangements(s ) that cause septic encephalopathy . DESIGN AND SETTING Prospect i ve case series in an academic medical center . PATIENTS Fifty patients selected according to clinical and laboratory criteria for severe sepsis . The criteria included temperature , heart rate , respiratory rate , and hypotension and /or signs of systemic hypoperfusion . MAIN OUTCOME MEASURES A single or combination of metabolic and laboratory derangements and organ failures , three different methods to grade the severity of septic encephalopathy , Acute Physiology and Chronic Health Evaluation II ( APACHE II ) scores , gram-negative bacteremia and infection , and mortality . RESULTS Encephalopathy was associated with an increase in mortality when grade d by the Glasgow Coma Score ; a score of 15 had 16 % mortality , 13 to 14 had 20 % , 9 to 12 had 50 % , and 3 to 8 had 63 % mortality ( P < .05 ) . Bacteremia was associated with encephalopathy ; 13 % of septic patients without encephalopathy vs 59 % of patients with encephalopathy had bacteremia ( P < .001 ) when grade d by altered mental status . Septic encephalopathic patients had elevated serum urea nitrogen and bilirubin levels , increased APACHE II scores , and a higher incidence of renal failure . CONCLUSIONS The severity of septic encephalopathy correlated with mortality , bacteremia , and renal and hepatic dysfunction . The Glasgow Coma Score is a useful tool for characterizing septic encephalopathy . Considerable variations can be found according to different criteria used to classify septic encephalopathy Objective To study the correlation between a dynamic index of cerebral autoregulation assessed with blood flow velocity ( FV ) using transcranial Doppler , and a tissue oxygenation index ( TOI ) recorded with near-infrared spectroscopy ( NIRS ) . Methods Twenty-three patients with sepsis , severe sepsis , or septic shock were monitored daily on up to four consecutive days . FV , TOI , and mean arterial blood pressure ( ABP ) were recorded for 60 min every day . An index of autoregulation ( Mx ) was calculated as the moving correlation coefficient between 10-s averaged values of FV and ABP over moving 5 min time-windows . The index Tox was evaluated as the correlation coefficient between TOI and ABP in the same way . The indices Mx and Tox , ABP and arterial partial pressure of CO2 were averaged for each patient . Results Synchronized slow waves , presenting with periods from 20 s to 2 min , were seen in the TOI and FV of most patients , with a reasonable coherence between the signals in this b and width ( coherence > 0.5 ) . The indices , Mx and Tox , demonstrated good correlation with each other ( R = 0.81 ; P < 0.0001 ) in the whole group of patients . Both indices showed a significant ( P < 0.05 ) tendency to indicate weaker autoregulation in the state of vasodilatation associated with greater values of arterial partial pressure of CO2 or lower values of ABP . Conclusion NIRS shows promise for the continuous assessment of cerebral autoregulation in adults INTRODUCTION The pathophysiology of sepsis-associated encephalopathy ( SAE ) is not entirely clear , but one of the possible underlying mechanisms is the alteration of the cerebral microvascular function . The aim of the present work was to test whether cerebral vasomotor reactivity is impaired in patients with severe sepsis . METHODS Patients fulfilling the criteria of clinical sepsis and showing at least 2 organ dysfunctions were included ( n = 16 ) . Nonseptic healthy persons without previous diseases affecting cerebral vasoreactivity served as controls ( n = 16 ) . Transcranial Doppler blood flow velocities were measured at rest and at 5 , 10 , 15 , and 20 minutes after intravenous administration of 15 mg/kg acetazolamide . The time course of the acetazolamide effect on cerebral blood flow velocity ( cerebrovascular reactivity [ CVR ] ) and the maximal vasodilatory effect of acetazolemide ( cerebrovascular reserve capacity [ CRC ] ) were compared among the groups . RESULTS Absolute blood flow velocities after administration of the vasodilator drug did not differ between control and septic patients . Assessment of the time course of the vasomotor reaction showed that patients with sepsis reacted in a similar fashion to the vasodilatory stimulus than control persons . When assessing the maximal vasodilatory ability of the cerebral arterioles to acetazolamide during vasomotor testing , we found that there was no difference in vasodilatory ability between septic and healthy subjects ( CRC controls , 54.8 % ± 11.1 % ; CRC sepsis-associated encephalopathy , 61.1 % ± 34.4 % ; P = .49 ) . CONCLUSIONS We conclude that cerebrovascular reactivity is not impaired in patients with severe sepsis . It is conceivable that cerebral vasoreactivity may be differently involved at different severity stages of the septic process Objectives To identify the neurologic complications of critical medical illnesses , and to assess their effect on mortality rates and on medical ICU and hospital lengths of stay . Design Prospect i ve clinical evaluation of all medical ICU admissions for 2 yrs . Setting A 14-bed , general medical intensive and coronary care unit in a large university hospital . Patients Patients ( n = 1,850 ) admitted to the hospital , of whom 92 were admitted for primarily neurologic problems . Of the remaining 1,758 patients , 217 ( 12.3 % ) experienced a neurologic complication . Interventions None . Measurements and Main Results Patients developing a neurologic complication while in the medical ICU demonstrated an increased risk of inhospital mortality when compared with patients who did not suffer such problems ( 45.7 % vs. 26.6 % ; p < .00001 ) . Patients with neurologic complications experienced 2.5-fold longer medical ICU stay times ( p < .001 ) and almost two-fold longer hospital stay times ( p < .001 ) . Metabolic encephalopathy , seizures , hypoxic-ischemic encephalopathy , and stroke were the most common complications . Sepsis was the most frequent cause of encephalopathy , and cerebrovascular lesions were the most common cause of seizures . Formal neurologic consulttions were requested in only 36 % of the patients . Conclusions Neurologic complications associated with increased mortality rates longer medical ICU and hospital lengths of st These conditions are probably underrecognis at present . ICUs have the potential to serve environments for neurologic teaching and search . ( Crit Care Med 1993 ; 21:98–103 |
1,912 | 27,358,442 | DATA ANALYSIS The results were mixed , but a partial influence of menu labeling on food choices was more frequent than an overall influence or no influence .
Menu labeling was more effective in cafeterias than in restaurants .
Qualitative information , such as healthy-food symbols and traffic-light labeling , was most effective in promoting healthy eating .
Calorie labeling in menus is not effective to promote healthier food choices . | CONTEXT Evidence that menu labeling influences food choices in real-life setting s is lacking .
Review s usually focus on calorie counts without addressing broader issues related to healthy eating . | BACKGROUND The federal menu labeling law will require chain restaurants to post caloric information on menus , but the impact of labeling is uncertain . PURPOSE The goal of the current study was to examine the effect of menu labeling on calories purchased , and secondarily , to assess self-reported awareness and use of labels . DESIGN Single-community pre-post-post cross-sectional study . Data were collected in 2008 - 2010 and analyzed in 2011 - 2012 . SETTING / PARTICIPANTS 50 sites from 10 chain restaurants in King County , Washington , selected through stratified , two-stage cluster r and om sampling . A total of 7325 customers participated . Eligibility criteria were : being an English speaker , aged ≥ 14 years , and having an itemized receipt . The study population was 59 % male , 76 % white non-Hispanic , and 53 % aged<40 years . INTERVENTION A regulation requiring chain restaurants to post calorie information on menus or menu boards was implemented . MAIN OUTCOME MEASURES Mean number of calories purchased . RESULTS No significant changes occurred between baseline and 4 - 6 months postregulation . Mean calories per purchase decreased from 908.5 to 870.4 at 18 months post-implementation ( 38 kcal , 95 % CI=-76.9 , 0.8 , p=0.06 ) in food chains and from 154.3 to 132.1 ( 22 kcal , 95 % CI=-35.8 , -8.5 , p=0.002 ) in coffee chains . Calories decreased in taco and coffee chains , but not in burger and s and wich establishments . They decreased more among women than men in coffee chains . Awareness of labels increased from 18.8 % to 61.7 % in food chains and from 4.4 % to 30.0 % in coffee chains ( both p<0.001 ) . Among customers seeing calorie information , the proportion using it ( about one third ) did not change substantially over time . After implementation , food chain customers using information purchased on average fewer calories compared to those seeing but not using ( difference=143.2 kcal , p<0.001 ) and those not seeing ( difference=135.5 kcal , p<0.001 ) such information . CONCLUSIONS Mean calories per purchase decreased 18 months after implementation of menu labeling in some restaurant chains and among women but not men This study investigated the effectiveness of labeling foods with the Choices nutrition logo on influencing cafeteria menu selection and the behavioral determinants of menu choices in work site cafeterias in the Netherl and s. A cluster r and omized controlled trial was conducted . Intervention cafeterias ( n=13 ) , where the Choices logo was used to promote healthier eating for a 3-week period , were compared with control cafeterias ( n=12 ) , which offered the same menu without the logo . Sales data were collected daily for 9 weeks , from March to May 2009 . In addition , employees from one intervention and one control company completed an online question naire at baseline and after the intervention ( n=368 ) in which the behavioral determinants of food choice ( ie , attitude , self-efficacy , and intention ) and logo use were measured . Generalized estimating equation analyses , χ² tests , t tests and linear regression analyses were performed . No nutritionally meaningful intervention effects were found in the sales of s and wiches , soups , snacks , fruit , and salads . Also , no significant differences in behavioral determinants were found . " Intention to eat healthier " and " paying attention to product information " were positively associated with self-reported consumption of foods with the Choices logo at lunch . The intervention did not have a significant effect on employees ' lunchtime food choices . Labeling healthy choices might be useful for health-conscious employees in the volitional phase of behavior change . Further research should focus on the possible health benefits of menu reformulation in the catering sector Objective Obesity is a pressing public health problem without proven population -wide solutions . Research ers sought to determine whether a city-m and ated policy requiring calorie labeling at fast food restaurants was associated with consumer awareness of labels , calories purchased and fast food restaurant visits . Design and Methods Difference-in-differences design , with data collected from consumers outside fast food restaurants and via a r and om digit dial telephone survey , before ( December 2009 ) and after ( June 2010 ) labeling in Philadelphia ( which implemented m and atory labeling ) and Baltimore ( matched comparison city ) . Measures included : self-reported use of calorie information , calories purchased determined via fast food receipts , and self-reported weekly fast-food visits . Results The consumer sample was predominantly Black ( 71 % ) , and high school educated ( 62 % ) . Post-labeling , 38 % of Philadelphia consumers noticed the calorie labels for a 33 percentage point ( p<.001 ) increase relative to Baltimore . Calories purchased and number of fast food visits did not change in either city over time . Conclusions While some consumer reports noticing and using calorie information , no population level changes were noted in calories purchased or fast food visits . Other controlled studies are needed to examine the longer term impact of labeling as it becomes national law The increase in the weight of American adults and children has been positively associated with the prevalence of the consumption of food-away-from-home . The objective was to assess the accuracy of cl aim ed nutritional information of foods purchased in contracted foodservices located on the campus of an institution of higher education . Fifty popular food items were r and omly collected from five main dining outlets located on a selected campus in the northeastern United States . The sampling was repeated three times on separate occasions for an aggregate total of 150 food sample s. The sample s were then weighed and assessed for nutrient composition ( protein , cholesterol , fiber , carbohydrates , total fat , calories , sugar , and sodium ) using nutrient analysis software . Results were compared with foodservices ' published nutrition information . Two group comparisons , cl aim ed and measured , were performed using the paired- sample t-test . Descriptive statistics were used as well . Among the nine nutritional values , six nutrients ( total fat , sodium , protein , fiber , cholesterol , and weight ) had more than 10 % positive average discrepancies between measured and cl aim ed values . Statistical significance of the variance was obtained in four of the eight categories of nutrient content : total fat , sodium , protein , and cholesterol ( P < .05 ) . Significance was also reached in the variance of actual portion weight compared to the published cl aims ( P < .001 ) . Significant differences of portion size ( weight ) , total fat , sodium , protein , and cholesterol were found among the sample d values and the foodservices ' published cl aims . The findings from this study raise the concern that if the actual nutritional information does not accurately reflect the declared values on menus , conclusions , decisions and actions based on posted information may not be valid We surveyed 7318 customers from 275 r and omly selected restaurants of 11 fast food chains . Participants purchased a mean of 827 calories , with 34 % purchasing 1000 calories or more . Unlike other chains , Subway posted calorie information at point of purchase and its patrons more often reported seeing calorie information than patrons of other chains ( 32 % vs 4 % ; P<.001 ) ; Subway patrons who saw calorie information purchased 52 fewer calories than did other Subway patrons ( P<.01 ) . Fast-food chains should display calorie information prominently at point of purchase , where it can be seen and used to inform purchases OBJECTIVE The present study is to describe , on the basis of recent Finnish population surveys , ( i ) the frequencies of school and worksite canteen use , ( ii ) the determinants of having a hot lunch during school or working hours and ( iii ) the associations of lunch eating patterns with food habits . SETTING The study summarises mainly basic reports and studies concerning catering services conducted in Finl and based on nationally representative population surveys . Design and subjectsCross-sectional study . The most important surveys cited in this paper are the School Health Promotion Study , the Work and the Working Conditions survey , the National FINDIET 2002 Study , and the Health Behavior and Health among Finnish Adult Population survey . RESULTS School lunch is eaten by on average 70 - 90 % of children aged 9 - 18 years . Of all employees , 30 % eat at a worksite canteen daily , whereas 30 % of men and 45 % of women eat packed lunches . Nationally representative cross-sectional population surveys show that the use of catering services is associated with more healthy food habits ; schoolchildren eating school meals and employees eating lunch at a worksite canteen tend to make food choices closer to nutritional recommendations as compared to those not using catering services to the same degree . CONCLUSIONS Some evidence exists that catering services in schools and worksites contribute to healthy eating habits in the population . In order to verify the positive role of catering services more scientific research with prospect i ve and intervention design studies will be needed OBJECTIVE To examine the influences of nutritional information and consumer characteristics on meal quality expectations , food selection and subsequent macronutrient intakes of consumers offered a reduced-fat option in a restaurant . DESIGN A target , full-fat ( FF ) main restaurant meal option was developed in a version substantially reduced in fat and energy ( RF ) . Restaurant patrons were r and omly placed into one of four treatment groups varying in provision of menu information about the target dish , and the actual version of that dish served ( if ordered ) . A full-fat blind ( FFB ) control group was given no nutritional information in the menu and was served the FF version . The other three groups were all served the modified RF version : ( i ) reduced-fat blind ( RFB ) , who were given no nutritional information ; ( ii ) reduced-fat informed ( RFI ) , who were given nutritional information ; and ( iii ) reduced-fat informed with details ( RFID ) , who were given the same nutritional information plus recipe modification details . Subjects rated their expected and actual liking , the pleasantness of taste , texture and appearance of the dish , how well the dish matched their expectations , and the likelihood of purchase again . Additional measures included the other dish selection s , sociodemographic and attitudinal information . SETTING A silver service ( training ) restaurant . SUBJECTS Members of the public ( n = 279 ) consuming meals in the restaurant . RESULTS The presence of nutritional information on the menu did not significantly increase subsequent intakes of energy and fat from the rest of the meal , and did not significantly influence sensory expectations or post-meal acceptance measures ( which also did not differ between the FF and RF versions ) . Consumer characteristics relating to fat reduction attitudes and behaviours were significantly related to the selection of different dishes . CONCLUSIONS Provision of RF alternatives in a restaurant can have significant positive dietary benefits . Menu nutritional information did not affect measures of meal acceptance . Further studies should identify which types of information formats might be most effective in enhancing the selection of ' healthy ' options This study assessed whether the inclusion of kilojoule labelling alone or accompanied by further nutrition information on menus led adults to select less energy-dense fast food meals . A between-subjects experimental design was used with online menu boards systematic ally varied to test the following labelling conditions : none ( control ) ; kilojoule ; kilojoule+percent daily intake ; kilojoule+traffic light ; and kilojoule+traffic light+percent daily intake . Respondents were 1294 adults aged 18 - 49 in Victoria , Australia who had purchased fast food in the last month and were r and omly assigned to conditions . Respondents in the no labelling condition selected meals with the highest mean energy content and those viewing the kilojoule and kilojoule+traffic light information selected meals with a significantly lower mean energy content , that constituted a reduction of around 500kJ ( 120kcal ) . Respondents most commonly reported using the traffic light labels in making their selection s. These findings provide support for the policy of disclosure of energy content on menus at restaurant chains . Given the magnitude of the reduction in energy density reported , and the prevalence of fast food consumption , this policy initiative has the potential to yield health benefits at the population level CONTEXT National recommendations for the prevention and treatment of obesity emphasize reducing energy intake . Foods purchased in restaurants provide approximately 35 % of the daily energy intake in US individuals but the accuracy of the energy contents listed for these foods is unknown . OBJECTIVE To examine the accuracy of stated energy contents of foods purchased in restaurants . DESIGN AND SETTING A vali date d bomb calorimetry technique was used to measure dietary energy in food from 42 restaurants , comprising 269 total food items and 242 unique foods . The restaurants and foods were r and omly selected from quick-serve and sit-down restaurants in Massachusetts , Arkansas , and Indiana between January and June 2010 . MAIN OUTCOME MEASURE The difference between restaurant-stated and laboratory-measured energy contents , which were corrected for st and ard metabolizable energy conversion factors . RESULTS The absolute stated energy contents were not significantly different from the absolute measured energy contents overall ( difference of 10 kcal/portion ; 95 % confidence interval [ CI ] , -15 to 34 kcal/portion ; P = .52 ) ; however , the stated energy contents of individual foods were variable relative to the measured energy contents . Of the 269 food items , 50 ( 19 % ) contained measured energy contents of at least 100 kcal/portion more than the stated energy contents . Of the 10 % of foods with the highest excess energy in the initial sampling , 13 of 17 were available for a second sampling . In the first analysis , these foods contained average measured energy contents of 289 kcal/portion ( 95 % CI , 186 to 392 kcal/portion ) more than the stated energy contents ; in the second analysis , these foods contained average measured energy contents of 258 kcal/portion ( 95 % CI , 154 to 361 kcal/portion ) more than the stated energy contents ( P < .001 for each vs 0 kcal/portion difference ) . In addition , foods with lower stated energy contents contained higher measured energy contents than stated , while foods with higher stated energy contents contained lower measured energy contents ( P < .001 ) . CONCLUSIONS Stated energy contents of restaurant foods were accurate overall . However , there was substantial inaccuracy for some individual foods , with understated energy contents for those with lower energy contents OBJECTIVES We examined the effect on food purchases of adding recommended calorie intake per day or per meal to the m and ated calorie information posted on chain restaurant menus . METHODS Before and after New York City implemented calorie posting on chain restaurant menus in 2008 , we provided daily , per-meal , or no calorie recommendations to r and omized subsets of adult lunchtime customers ( n = 1121 ) entering 2 McDonald 's restaurants , in Manhattan and Brooklyn , and collected receipts and survey responses as they exited . In linear and logistic regressions , with adjustment for gender , race , age , and day , we tested for simple differences in calories consumed and interactions between variables . RESULTS Posting calorie benchmarks had no direct impact , nor did it moderate the impact of calorie labels on food purchases . The recommendation appeared to promote a slight increase in calorie intake , attributable to increased purchases of higher-calorie entrées . CONCLUSIONS These results do not support the introduction of calorie recommendations as a means of enhancing the impact of posted calorie information or reducing the contribution of restaurant dining to the obesity epidemic |
1,913 | 17,054,241 | Tacrolimus is superior to cyclosporin in improving survival ( patient and graft ) and preventing acute rejection after liver transplantation , but it increases the risk of post-transplant diabetes . | BACKGROUND Most liver transplant recipients receive either cyclosporin or tacrolimus to prevent rejection .
Both drugs inhibit calcineurin phosphatase which is thought to be the mechanism of their anti-rejection effect and principle toxicities .
The drugs have different pharmacokinetic profiles and potencies .
Several r and omised clinical trials have compared cyclosporin and tacrolimus in liver transplant recipients , but it remains unclear which is superior .
OBJECTIVES To evaluate the beneficial and harmful effects of immunosuppression with cyclosporin versus tacrolimus for liver transplanted patients . | BACKGROUND The long-term complications of immunosuppressive therapy such as diabetes , hypercholesterolemia , and hypertension are a major source of morbidity in liver transplant recipients . In this prospect i ve , r and omized , open-label study we completely withdrew prednisone ( PRED ) 14 days after liver transplantation in an effort to decrease these metabolic complications . Patients were maintained on mycophenolate mofetil ( MMF ) in combination with either cyclosporine ( CsA ; Neoral formulation ) or tacrolimus ( TAC ) . Thus , we also were able to compare CsA to TAC in patients not receiving PRED with respect to efficacy , toxicity , and effect on posttransplant metabolic complications . METHODS A total of 71 patients were r and omized to receive either TAC-MMF ( n=35 ) or CsA-MMF ( n=36 ) after liver transplantation and were analyzed for patient and graft survival . Fifty-eight patients continued the immunosuppressive protocol for at least 6 months after transplantation and were analyzed for the incidence of acute rejection and the prevalence of diabetes , hypertension , and hypercholesterolemia . RESULTS The 6-month patient survival rates were 94.4 % for CsA-MMF and 88.6 % for TAC-MMF . Corresponding 6-month graft survival rates were 88.7 % and 85.71 % with no immunologic graft losses in either group . The incidence of biopsy-proven acute rejection was 46 % for CsA-MMF and 42.3 % for TAC-MMF . Six patients were converted from CsA to TAC ( four for recurrent rejection ) and seven patients were converted from TAC to CsA ( four for neurotoxicity ) . Only one patient ( in the TAC-MMF group ) developed new-onset posttransplant diabetes . In contrast , four of eight patients in the CsA-MMF group who were diabetic before transplant became nondiabetic in the first 3 months after transplant . The mean serum cholesterol level was significantly lower in the TAC-MMF group than in the CsA-MMF group ( 145.2+/-41.8 mg/dl and 190.3+/-62.2 , respectively ; P<0.001 ) and the incidence of hypertension was lower in the TAC-MMF group ( 12 % vs. 30.3 % in the CsA-MMF group , P<0.01 ) . Both groups had a lower incidence of metabolic complications compared with a historical group ( n=100 ) maintained on CsA and PRED ( 10 mg/day at 6 months ) . CONCLUSIONS MMF in combination with either TAC or CsA allows withdrawal of PRED 14 days after liver transplantation with a moderate rejection rate and no immunologic graft losses . Early PRED withdrawal decreases posttransplant diabetes , hypercholesterolemia , and hypertension , but patients maintained on TAC have lower serum cholesterol levels and a lower incidence of hypertension than CsA-treated patients BACKGROUND Results of studies in adult recipients of liver allograft suggest that tacrolimus is more efficacious than ciclosporin microemulsion in the prevention of acute rejection . We aim ed to compare these drugs in children undergoing liver transplantation . METHODS This 12-month multicentre , open-label , parallel-group , r and omised study compared a dual tacrolimus regimen ( tacrolimus/corticosteroids , n=93 ) with a triple ciclosporin microemulsion regimen ( ciclosporin microemulsion/corticosteroids/azathioprine , n=92 ) in children who had had liver transplants ( age < or = 16 years , bodyweight < or = 40 kg ) . Initial oral daily doses were 0.30 mg/kg for tacrolimus and 10 mg/kg for ciclosporin microemulsion . Primary endpoint was the incidence of and time to first histologically proven acute rejection . We excluded patients from analysis if they did not receive the study drug , or were given incorrect medication . Otherwise patients were analysed in accordance with their r and om treatment allocation , irrespective of whether they switched medication during the trial . FINDINGS Median age was 22 months ( IQR 9 - 56 ) in the tacrolimus group and 17 months ( 9 - 54 ) in the ciclosporin microemulsion group . We noted no difference between treatment groups with respect to patient survival ( 93.4 % vs 92.2 % ; p=0.77 ) or graft survival ( 92.3 % vs 85.4 % ; p=0.16 ) at month 12 after transplant . The acute rejection free rate at study end ( Kaplan-Meier method ) was 55.5 % for patients on tacrolimus and 40.2 % for patients on ciclosporin microemulsion ( p=0.0288 ) . The Kaplan-Meier estimate of patients free from corticosteroid-resistant acute rejection at study end was 94.0 % for tacrolimus-treated patients and 70.4 % for ciclosporin-microemulsion-treated patients ( p<0.0001 ) . Overall , incidence of adverse events did not differ between groups . INTERPRETATION Tacrolimus is a safe and effective treatment for the prevention of rejection after liver transplantation in children OBJECTIVES To analyze sources search ed in Cochrane review s , to determine the proportion of trials included in review s that are indexed in major data bases , and to compare the quality of these trials with those from other sources . METHODS All new systematic review s in the Cochrane Library , Issue1 2001 , that were restricted to r and omized controlled trials ( RCTs ) or quasi- RCTs were selected . The sources search ed in the review s were recorded , and the trials included were checked to see whether they were indexed in four major data bases . Trials not indexed were checked to determine how they could be identified . The quality of trials found in major data bases was compared with those found from other sources . RESULTS The range in the number of data bases search ed per review ranged between one and twenty-seven . The proportion of the trials in the four data bases were Cochrane Controlled Trials Register = 78.5 % , MEDLINE = 68.8 % , Embase = 65.0 % , and Science/Social Sciences Citation Index = 60.7 % . Search ing another twenty-six data bases after Cochrane Controlled Trials Register ( CCTR ) , MEDLINE , and Embase only found 2.4 % additional trials . There was no significant difference between trials found in the CCTR , MEDLINE , and Embase compared with other trials , with respect to adequate allocation concealment or sample size . CONCLUSIONS There was a large variation between review s in the exhaustiveness of the literature search es . CCTR was the single best source of RCTs . Additional data base search ing retrieved only a small percentage of extra trials . Contacting authors and manufacturers to find unpublished trials appeared to be a more effective method of obtaining the additional better quality trials BACKGROUND Calcineurin inhibitors are the most commonly used immunosuppressive drugs in liver transplantation , but the optimum initial immunosuppression regimen is not known . The aim of our study was to compare tacrolimus with microemulsified ciclosporin , in a regimen with st and ardised concomitant immunosuppressive therapy . METHODS In all liver transplant centres in the UK and Republic of Irel and , 606 patients undergoing a first orthotopic liver transplantation were r and omly assigned open-label tacrolimus or microemulsified ciclosporin . Primary outcome was the combined frequency ( whichever occurred first ) of death , retransplantation , or treatment failure for immunological reasons , analysed by intention to treat . FINDINGS 96 % of patients received the treatment allocated to them . The primary outcome was reached in 62 ( 21 % ) of 301 patients in the tacrolimus group versus 99 ( 32 % ) of 305 allocated microemulsified ciclosporin ( relative risk 0.63 [ 95 % CI 0.48 - 0.84 ] , p=0.001 ; time-to-event analysis log-rank test p=0.002 ) : deaths ( 50 [ 17 % ] vs 72 [ 24 % ] ) ; retransplantations ( 11 [ 4 % ] vs 31 [ 10 % ] ) treatment failure for immunological reasons ( 6 [ 2 % ] vs 12 [ 4 % ] ) . The relative risk for the composite outcome was in favour of tacrolimus . The main causes of death in both trial groups were sepsis and multiple organ failure ( 31 [ 10 % ] vs 30 [ 10 % ] ) , and the main cause for retransplantation was hepatic artery thrombosis ( 6 [ 2 % ] vs 17 [ 6 % ] ) . Renal dysfunction and the need for antihypertensive therapy were much the same in both groups . Tacrolimus was more diabetogenic . INTERPRETATION Clinical outcome at 1 year was better with tacrolimus-based immunosuppression than with microemulsified ciclosporin during the first year after liver transplantation . Tacrolimus should be the first choice of calcineurin inhibitor for patients receiving their first liver graft Abstract : Background : This is a 4‐yr follow‐up of a trial using mycophenolate mofetil ( MMF ) induction in orthotopic liver transplantation ( OLT ) . The goal of this study was to evaluate a multidrug approach that would reduce both early and long‐term morbidity related to immunosuppression while maintaining an acceptable freedom from rejection BACKGROUND Immunosuppression in patients with hepatitis C virus ( HCV ) following orthotopic liver transplantation can lead to significant increases in serum viral loads . Our aim was to analyze the effect of a r and omized study of two immunosuppressive agents ( tacrolimus vs. microemulsion cyclosporine ) on the outcome of HCV patients following orthotopic liver transplantation . METHODS From December 1995 to September 1996 , 50 adult patients transplanted for HCV cirrhosis were r and omly assigned to receive tacrolimus ( Prograf ) ( group 1 , 25 patients ) or microemulsion cyclosporine ( Neoral ) ( group 2 , 24 patients ) . All patients received alpha-interferon after transplantation , and the overall steroid doses were no different between the groups . Serum RNA levels were measured by signal amplification of Chiron . Biopsies were taken when transaminases were greater than 2x base line or when there was an inappropriate response to alterations in immunosuppression regimens . RESULTS There were more episodes of rejection in the Neoral group , but there were no differences in bacterial and viral infections , nor in the rate of HCV recurrence between the two groups . There were seven deaths in group 1 and eight in group 2 . Overall patient and graft survival rates in the Prograf and Neoral groups at 18 months were 72 and 68 % and 67 and 64 % , respectively . CONCLUSIONS ( a ) Both immunosuppression regimens had similar HCV recurrence rates ; ( b ) there were no differences in bacterial or opportunistic infections ; and ( c ) patient and graft survival was similar between the two groups Hepatitis C virus (HCV)-induced cirrhosis is the commonest indication for orthotopic liver transplantation , but HCV recurrence is nearly universal and may worsen patient / graft outcomes . The frequency and severity of HCV recurrence has apparently increased in recent years , raising concern about a possible role for newer immunosuppression regimens in this increase , including potentially tacrolimus . We r and omized 79 patients to receive tacrolimus or cyclosporine as primary immunosuppressant posttransplantation . A pathologist blinded to treatment review ed serial liver biopsies . Month 12 cumulative probabilities of histological hepatitis C recurrence for tacrolimus- and cyclosporine-treated patients were .38 and .54 ( P = .19 ) and failure / death were .25 and .28 , respectively ( P = .789 ) . Although cyclosporine-treated patients had significantly larger increases in median serum HCV RNA levels ( months 1 , 6 , and 12 ) , no significant differences were observed between the two treatment arms in histologically-diagnosed HCV recurrence / survival rates . In conclusion , choice of calcineurin inhibitors does not impact severity of recurrent HCV BACKGROUND Many reports of successful early withdrawal of regular maintenance steroids in transplant recipients have appeared in recent years . The question now arises whether , in the current age of powerful nonsteroidal immunosuppressants such as Neoral and Tacrolimus , routine administration of steroids posttransplant is necessary at all . This single center pilot study reports on the feasibility , safety , and efficacy of single agent immunosuppression " ab initio " with either Neoral or Tacrolimus , and no routine or maintenance steroids . METHODS A total of 64 adult patients receiving first liver grafts for a variety of indications were r and omized to receive either Neoral 5 mg/kg BDS or Tacrolimus 0.05 mg/kg BDS orally . Liver biopsies were performed on postoperative days 5 and 10 , and whenever else clinical ly indicated . Rejection episodes were treated with 1.0 g of Methylprednisolone daily for 3 consecutive days . A further episode of rejection after two courses of Methylprednisolone was considered to be monotherapy failure , and consequently other immunosuppressive agents , usually Prednisolone 1 mg/kg/day , was started on a regular basis , tapering slowly . RESULTS Actuarial 1 year survival was 85 % for Tacrolimus patients , and 78 % for Neoral patients ( P = NS ) , with 80 % for Tacrolimus and 73.5 % for Neoral at 30 months . Graft survival at 1 and 2.5 years was 73 and 62 % for Tacrolimus and Neoral , respectively ( P = NS ) . Two-thirds of patients in both groups showed biopsy evidence of acute cellular rejection . Rejection severity measured by a histological scoring system was similar for both patient groups . Additional longterm immunosuppressive therapy was necessary in 36 % of patients receiving Neoral , compared with 13 % of Tacrolimus patients ( P = NS ) . No graft was lost on account of acute or chronic rejection . Short-term pulse steroid therapy to treat acute rejection was necessary for 60 % of Tacrolimus patients and 40 % of Neoral patients . CONCLUSION Tacrolimus or Neoral monotherapy after liver transplantation provides adequate immunosuppression for 87 % of Tacrolimus patients and 64 % of Neoral patients . In this study , 33 % of patients in both groups showed no evidence of acute rejection , either clinical ly , biochemically or histologically , and were not exposed to steroids at any time . Evaluation of the long-term morbidity related to the side effects of the immunosuppressants given as monotherapy , for example , renal impairment and posttransplant lymphoproliferative disorder , and the effect on recurrent viral hepatitis in the graft , would be suitable areas for further study Corticosteroid therapy contributes significant toxicity to liver transplantation . The safety and efficacy of early steroid withdrawal were determined in patients treated with either tacrolimus or microemulsion cyclosporin A ( micro-CsA ) . The primary outcome was the proportion of patients who were steroid-free 1 year posttransplantation . From the seven Canadian adult liver transplant centers , 143 patients were r and omly allocated oral treatment with either tacrolimus ( n = 71 ) or micro-CsA ( n = 72 ) , together with corticosteroids and azathioprine . Eligibility criteria for steroid withdrawal included freedom from acute rejection for a minimum of 3 months , and prednisone < /=0.15 mg/kg/d . In eligible patients , the daily steroid dose was reduced by 2.5 mg each month until complete discontinuation was achieved . At 1 year after transplantation , 75 % of the tacrolimus patients and 63 % of the micro-CsA patients were steroid-free ( P = .20 ) . Of all of the patients who became eligible for steroid withdrawal , steroid discontinuation was achieved in over 80 % . One-year patient survival was 97 % with tacrolimus and 89 % with micro-CsA ( P = .052 ) . Graft survival was 97 % and 86 % , respectively ( P = .017 ) . The overall incidence of acute rejection during the first year was 35 % with tacrolimus and 43 % with micro-CsA ( P = .26 ) . There was no difference in survival , acute rejection , or rate of steroid withdrawal when adjusting for hepatitis C. All acute rejection episodes experienced during steroid withdrawal were steroid-responsive . Steroid-resistant rejection occurred in 5.6 % of the tacrolimus and 9.7 % of the micro-CsA patients . One patient , in the micro-CsA group , experienced refractory rejection . Chronic rejection was not observed in either group . The toxicity profiles were similar . Postoperative serum creatinine levels were similar , and dialysis was required in less than 10 % of patients in each group . Infectious complications were similar in both groups . Neurotoxicity was a serious adverse event in 13 % and 10 % of patients receiving tacrolimus and micro-CsA , respectively . Early steroid withdrawal is safe and effective after liver transplantation using either tacrolimus plus azathioprine or micro-CsA plus azathioprine immunoprophylaxis Liver transplant recipients administered gelatin ( GEL ) rather than human albumin solution ( HAS ) can become profoundly hypoalbuminemic in the early postoperative period and often have hepatic dysfunction at this time . The combined effect of these two abnormalities could be an increase in the unbound ( active ) concentration of low- extraction highly albumin-bound drugs , such as tacrolimus ( TAC ) . This may increase the efficacy and /or toxicity of such drugs . We prospect ively compared the clinical outcome of 69 de novo liver transplant recipients r and omized primarily to TAC or cyclosporine ( CYA ) and secondarily to HAS or GEL therapy during the first 14 days after liver transplantation . Antipyrine clearance on the 7th postoperative day was used as a measure of liver metabolic function . Serum albumin levels were significantly lower in both GEL arms than HAS arms during the first 14 days ( P < .001 ) . Although antipyrine clearance was similar in all four trial arms , it was intermediate between that found in historic healthy controls and patients with cirrhosis ( P < .0001 ) . Serum creatinine concentrations were significantly greater in the TAC plus GEL arm than the other three arms ( P < .001 ) . The linearized treated acute rejection rate was significantly greater in the TAC plus HAS arm than the other three arms ( relative risk , 2.02 ; 95 % confidence interval , 1.07 to 3.78 ; P = .03 ) . These data indicate that excess nephrotoxicity can occur with TAC in liver transplant recipients with impaired hepatic metabolism who are administered GEL . In addition , supplementary albumin may reduce the efficacy of TAC in liver transplant recipients at a time when the risk for rejection is greatest BACKGROUND Tacrolimus ( formerly FK506 ) was first used clinical ly in 1989 to successfully replace cyclosporine in hepatic transplant recipients who were experiencing intractable rejection or as the baseline drug from the time of operation . After extensive pilot experience , an institutional review board-m and ated clinical trial comparing cyclosporine with tacrolimus was performed . STUDY DESIGN From February 16 , 1990 to December 26 , 1991 , 154 patients were recruited . The competing drugs were combined with equal induction doses of prednisone in both arms of the study for the first 81 patients and with subsequently higher doses of prednisone in the remaining 35 patients who received cyclosporine and were entered into the trial . Drug crossover was permitted for lack of efficacy or adverse events . End points were rejection confirmed by biopsy and treatment failure leading to retransplantation or death . RESULTS Seventy-nine patients were r and omized to the tacrolimus arm and 75 to the cyclosporine arm during 1990 and 1991 . All patients were available for follow-up throughout the trial , which terminated on May 30 , 1995 . The mean duration of follow-up was four years . Patients r and omized to the tacrolimus arm were less likely to experience acute rejection than were those receiving cyclosporine , with 36.2 percent of the patients receiving tacrolimus and 16.8 percent of the patients receiving cyclosporine showing freedom from rejection at one year ( p = 0.003 , likelihood ratio test ) . Survival of patients over the course of the study was virtually the same in the two groups This is the first multicenter , r and omized , open-label study to compare the efficacy and safety of cyclosporine A microemulsion ( CsA-ME ) ( Neoral , Novartis , Basel , Switzerl and ) with C2 monitoring versus tacrolimus in de novo liver transplant recipients . Patients were stratified according to hepatitis C virus status and r and omized to receive CsA-ME ( n= 250 ) or tacrolimus ( n= 245 ) with steroids , with or without azathioprine . The primary endpoint was the incidence of biopsy-proven acute rejection ( BPAR ) at 3 months . Secondary endpoints included death or graft loss and safety evaluations at 6 months . The incidence of BPAR at 3 months was 26 % in the CsA-ME group and 24 % in the tacrolimus group ( not significant ) . At 6 months , 89 % of patients receiving CsA-ME and 88 % of patients receiving tacrolimus were alive with a functioning graft . Among the hepatitis C virus-positive patients , there was no difference in BPAR , but death or graft loss was more frequent in those receiving tacrolimus ( 15 % vs. 6 % , P < 0.05 ) . Diabetes mellitus ( 14 % vs. 7 % , P < 0.02 ) and diarrhea ( 29 % vs. 14 % , P < 0.001 ) were significantly more often reported in patients receiving tacrolimus . The incidence of hypertension was similar in both groups . At 6 months , the median total cholesterol was 4.7 mmol/L ( 2.9–7.4 mmol/L ) in the CsA-ME arm versus 4.3 mmol/L ( 2.5–6.4 mmol/L ) in the tacrolimus arm ; the median serum creatinine was 106 μmol/L ( 52–238 μmol/L ) in the CsA-ME arm versus 103 μmol/L ( 44–477 μmol/L ) in the tacrolimus arm . Efficacy is equivalent with CsA-ME using C2 monitoring or tacrolimus in liver transplant recipients . The incidence of adverse events is comparable except for a significantly higher incidence of diabetes mellitus and diarrhea in the tacrolimus group . Both agents are effective primary immunosuppressants in liver transplant recipients Cyclosporine ( CsA ) and tacrolimus ( FK506 ) have recently been reported to inhibit canalicular transport of bile acids in vitro and thereby possibly induce cholestasis . A relative reduction of chenodeoxycholic acid ( CDCA ) has been observed after liver transplantation when CsA is used as immunosuppressant . We tested the hypothesis that CsA induces cholestasis and reduces CDCA secretion as compared with treatment with monoclonal antibodies ( OKT3 ) , and that CsA differs from FK506 with regard to its effects on biliary lipid secretion . Bile flow , biliary lipid secretion rates , and biliary bile acid composition were determined during the first 10 days after transplantation in 29 liver transplant recipients . Two prospect i ve r and omized studies were performed that compared CsA and OKT3 and compared CsA- and FK506-based regimens . In study 1 , bile acid output averaged 0.75+/-0.15 micromol/min in the CsA I group and 0.54+/-0.11 micromol/min in the OKT3 group on postoperative day 1 . Bile flow and bile acid output then increased , and there was no significant difference between the two groups . The relative proportion of CDCA decreased to the same extent in both groups . In study 2 , mean bile acid outputs on postoperative day 1 were 0.57+/-0.26 micromol/min and 0.55+/-0.15 micromol/min in the CsA 2 and FK506 groups , respectively . The following increase in bile acid secretion was significantly larger in the FK506 group . After transplantation , the relative proportion of CDCA decreased with time in both groups , but the reduction was more rapid in the FK506 group . In conclusion , CsA did not inhibit bile secretion during short-term treatment after liver transplantation . Compared with patients given CsA-based treatment , patients with FK506-based treatment recovered bile secretion more rapidly There are several case reports in the literature that describe cardiac complications in the first few weeks after orthotopic liver transplantation ( OLT ) in patients receiving tacrolimus as their primary immunosuppressive therapy . In this study , we investigated the cardiac function of patients on tacrolimus ( T ) compared with those on cyclosporin ( C ) ( Neoral ; Novartis , Basel , Switzerl and ) immunosuppression , after OLT , in a prospect i ve r and omized trial . We r and omized 40 adult patients with cirrhosis to either T or C with azathioprine and prednisolone immunosuppression and followed up on them for 3 months after OLT . All had detailed clinical , biochemical , electrocardiographic and echocardiographic assessment s at regular intervals . Abnormalities in cardiac function were common after OLT and significant deterioration in left ventricular diastolic function was demonstrable up to 3 months in both patient groups . Cardiac function was similar in the T and C arms and no significant electrocardiographic differences were observed , although reduced heart rate variability ( HRV ) and higher mean serum brain natriuretic peptide ( BNP ) levels were identified in the T group . The percentage increase in posterior wall thickness was higher in the T group . Cardiac dysfunction as shown by worsening echocardiographic measures of left ventricular diastolic function and by clinical cardiac events is common in the first 3 months after OLT in patients with cirrhosis . HRV and BNP values in the T group were worse than in the C group , but this was not translated to an increase in cardiac clinical events in this study BACKGROUND The success of liver transplantation in this decade has become the stimulus to extend the donor and recipient pool . Reducing early posttransplant morbidity to maintain our success , as we exp and our frontiers , has led us to focus on balanced testing of multidrug immunosuppression regimens . METHODS A prospect i ve trial in orthotopic liver transplantation using Mycophenolate Mofetil and an identical steroid taper with r and omization of patients to Neoral ( N ) or Tacrolimus ( FK ) is the basis of this report . This was an intent-to-treat study design ed to compare the 6-month primary endpoints of rejection and infection and to compare the 6-month secondary endpoints of liver function , renal function , bone marrow function , hypertension , and serum cholesterol levels . RESULTS Ninety-seven patients completed the 6-month follow-up period ( N=49 , FK=48 ) . The actual 6-month patient and graft survival rates were 98 % and 94 % , respectively . There was no difference in the number of patients with rejection episodes ( N=11 , FK=8 ) ( P=0.61 ) . There were 24 infections ( 3 cytomegalovirus ) in the FK group and 30 infections ( 9 cytomegalovirus ) in the N group . The cholesterol levels at 6 months were not significantly different ( P=0.07 ) between the groups . The other secondary 6-month endpoints were not significantly different , except total bilirubin , which was lower in the FK arm ( P=0.02 ) . CONCLUSIONS The use of Mycophenolate Mofetil with N or FK and an identical steroid taper after orthotopic liver transplantation is associated with excellent graft and patient survival , and at 6 months , only 191 % of the patients experienced rejection , with a 48 % overall infection rate MYCOPHENOLATE mofetil ( MMF ) is an accepted immunosuppressive agent after kidney transplantation . Possible indications for MMF after liver transplantation include : ( 1 ) rejection therapy ; ( 2 ) reduction of cyclosporine or tacrolimus dosage in patients with nephro- , neuro- , or hepatotoxicity ; and ( 3 ) early steroid withdrawal . The potential role of additive MMF therapy in patients with HCV cirrhosis has been explored ; however , data concerning MMF induction or maintenance therapy are limited THE USE of cyclosporine ( CyA ) has greatly impacted the success of liver transplantation . FK 506 is a newly described immunosuppressive agent , with mechanisms of action similar to those of CyA , but more potent on a weight-to-weight basis . Pilot studies of FK 506 in primary liver transplantation have shown encouraging results .1 A r and omized trial using FK 506 with low-dose steroids ( LDS ) was compared to two different CyA regimens , one with LDS and the other with st and ard steroid therapy ( SST ) . The primary end point was to examine the incidence of rejection following liver transplantation , and to compare graft and patient survival rates after FK 506 with LDS , CyA with LDS , and CyA with SST |
1,914 | 27,925,386 | Treatment of patients with decompensated cirrhosis remains a great challenge .
In summary , treatment of HCV genotype 3 patients is improving rapidly , and this population may no longer be considered a difficult-to-treat subgroup in the near future | Treatment of hepatitis C virus ( HCV ) infection with genotype 3 remains a challenge .
The HCV elimination rate with direct-acting antivirals ( DAAs ) is lower than the values reported for other HCV genotypes .
In addition , genotype 3-infected patients have a higher risk of disease progression and hepatocellular carcinoma .
The aim of this study was to review the relevant literature concerning the treatment of HCV genotype 3 patients with interferon-free regimens . | OBJECTIVES To examine the safety and efficacy of ombitasvir and ABT-450 with ritonavir ( ABT-450/r ) ± ribavirin ( RBV ) in treatment-naïve , non-cirrhotic adults with chronic HCV genotype 1 - 3 infection . METHODS Patients in this open-label , exploratory , phase 2 , multicenter study received ombitasvir ( 25 mg QD ) and ABT-450/r ( 200/100 mg QD ) ± RBV for 12 weeks . Primary efficacy endpoint was HCV RNA < lower limit of quantitation ( LLOQ ) from week 4 through 12 . Sustained virologic response 12 weeks post-treatment ( SVR12 ) was a secondary endpoint . RESULTS Sixty-one patients were enrolled . Among genotype 1- , 2- , and 3-infected patients , respectively , HCV RNA was < LLOQ from week 4 through 12 in 10 ( 100 % ; 95 % CI 69 - 100 ) , 9 ( 90 % ; 56 - 100 ) , and 7 ( 70 % ; 35 - 93 ) receiving the RBV-containing regimen and 9 ( 90 % ; 56 - 100 ) , 8 ( 80 % ; 44 - 97 ) , and 2 ( 18 % ; 2 - 52 ) receiving the RBV-free regimen . Among genotype 1- , 2- , and 3-infected patients , respectively , SVR12 was achieved by 10 ( 100 % ) , 8 ( 80 % ) , and 5 ( 50 % ) receiving the RBV-containing regimen , and 6 ( 60 % ) , 6 ( 60 % ) , and 1 ( 9 % ) receiving the RBV-free regimen . The most common adverse events were fatigue , nausea , and headache . One patient discontinued due to an adverse event . CONCLUSIONS In this study , ombitasvir and ABT-450/r ± RBV regimens were generally well-tolerated . Sustained virologic response was achieved in most patients with HCV genotype 1 or 2 infection , but low SVR rates were observed in HCV genotype 3-infected patients BACKGROUND Sofosbuvir ( SOF ) is active against all hepatitis C virus ( HCV ) genotypes , and SOF-based therapies lead to high rates of sustained virologic response ( SVR ) . However , genotype 3 ( GT3 ) HCV remains a challenge with lower SVR rates reported , particularly in patients with cirrhosis . This study reports the effectiveness and safety of SOF-based therapy in patients with GT3 HCV treated in clinical practice . METHODS Hepatitis C Virus Therapeutic Registry and Research Network is an international , prospect i ve observational study evaluating patients treated in usual clinical practice . Patients with GT3 HCV were analyzed to assess predictors of treatment response and adverse events using descriptive statistics and multivariable logistic regression . RESULTS Treatment outcomes were available for 197 patients treated with SOF and ribavirin ( RBV ) , with or without peginterferon , including 54 % with cirrhosis and 49 % who failed prior therapy . Of 178 patients treated with SOF/RBV , 60 % achieved SVR at 12 weeks ( SVR12 ) , compared with 84 % of 19 patients treated with SOF/peginterferon/RBV . For patients treated with SOF/RBV , the SVR12 rate was 58 % in treatment-naive patients with cirrhosis , and 42 % in those with cirrhosis who failed prior therapy . In noncirrhotic patients , SVR12 rates were 89 % in treatment-naive and 88 % in treatment-experienced patients . After controlling for age and sex , absence of cirrhosis ( odds ratio [ OR ] , 6.4 ; 95 % confidence interval [ CI ] , 2.78 - 14.74 ) , albumin levels ≥3.2 g/dL ( OR , 12.48 ; 95 % CI , 3.86 - 40.33 ) , and platelet count > 10(5 ) cells/µL ( OR , 7.44 ; 95 % CI , 3.51 - 15.78 ) were associated with greater odds of SVR12 CONCLUSIONS : SVR rates were acceptable in patients with GT3 HCV without cirrhosis ; however , in those with cirrhosis , treatment with SOF/RBV was suboptimal , highlighting the need for new therapies for this population Treatment options for patients with hepatitis C virus ( HCV ) genotype 3 infection are limited , with the currently approved all-oral regimens requiring 24-week treatment and the addition of ribavirin ( RBV ) . This phase III study ( ALLY-3 ; http:// Clinical Trials.gov : NCT02032901 ) evaluated the 12-week regimen of daclatasvir ( DCV ; pangenotypic nonstructural protein [NS]5A inhibitor ) plus sofosbuvir ( SOF ; pangenotypic NS5B inhibitor ) in patients infected with genotype 3 . Patients were either treatment naïve ( n = 101 ) or treatment experienced ( n = 51 ) and received DCV 60 mg plus SOF 400 mg once-daily for 12 weeks . Co primary endpoints were the proportions of treatment-naïve and treatment-experienced patients achieving a sustained virological response ( SVR ) at post-treatment week 12 ( SVR12 ) . SVR12 rates were 90 % ( 91 of 101 ) and 86 % ( 44 of 51 ) in treatment-naïve and treatment-experienced patients , respectively ; no virological breakthrough was observed , and ≥99 % of patients had a virological response ( VR ) at the end of treatment . SVR12 rates were higher in patients without cirrhosis ( 96 % ; 105 of 109 ) than in those with cirrhosis ( 63 % ; 20 of 32 ) . Five of seven patients who previously failed treatment with an SOF-containing regimen and 2 of 2 who previously failed treatment with an alisporivir-containing regimen achieved SVR12 . Baseline characteristics , including gender , age , HCV-RNA levels , and interleukin-28B genotype , did not impact virological outcome . DCV plus SOF was well tolerated ; there were no adverse events ( AEs ) leading to discontinuation and only 1 serious AE on-treatment , which was unrelated to study medications . The few treatment-emergent grade 3/4 laboratory abnormalities that were observed were transient . Conclusion : A 12-week regimen of DCV plus SOF achieved SVR12 in 96 % of patients with genotype 3 infection without cirrhosis and was well tolerated . Additional evaluation to optimize efficacy in genotype 3–infected patients with cirrhosis is underway . ( Hepatology 2015;61:1127–1135 Abstract Background & Aims ABT‐530 is a next‐generation hepatitis C virus ( HCV ) NS5A inhibitor with potent pangenotypic antiviral activity in vitro . Paritaprevir is an NS3/4A protease inhibitor codosed with ritonavir that displays in vitro activity against HCV genotypes 1–4 and 6 . Methods Efficacy , pharmacokinetics and safety of ABT‐530 with paritaprevir/ritonavir and ribavirin were evaluated in this phase 2 , open‐label , multicentre study in treatment‐naïve non‐cirrhotic patients with genotype 3 infection . Ten patients , all genotype 3a , received 120 mg ABT‐530 and 150/100 mg paritaprevir/ritonavir once daily with ribavirin for 12 weeks . Results Nine ( 90 % ) patients achieved a sustained virological response at post‐treatment weeks 12 and 24 . One patient experienced virological failure at treatment week 6 . Sequence analyses for HCV variants in sample s from this patient identified A166S in NS3 at baseline and after breakthrough , as well as A30 K at baseline and linked S24F+M28K+A30 K variants in NS5A after breakthrough . Neither genotype 3 NS3 A166S nor NS5A A30 K variant confers any resistance to paritaprevir or ABT‐530 respectively . However , genotype 3 NS5A S24F+M28K+A30K‐linked variant confers a > 5000‐fold increase in ABT‐530 EC 50 relative to that of the wild‐type replicon . This patient 's ABT‐530 exposure was comparable to the cohort , while paritaprevir and ritonavir exposures were the lowest of all patients . No serious or severe adverse events and adverse events leading to early discontinuation were reported . Conclusions Results from this study show that ABT‐530 holds promise as part of a direct‐acting antiviral treatment regimen for HCV genotype 3 infection 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 Patients chronically infected with hepatitis C virus ( HCV ) genotype 2 or 3 for whom treatment with peginterferon is not an option , or who have not had a response to prior interferon treatment , currently have no approved treatment options . In phase 2 trials , regimens including the oral nucleotide polymerase inhibitor sofosbuvir have shown efficacy in patients with HCV genotype 2 or 3 infection . METHODS We conducted two r and omized , phase 3 studies involving patients with chronic HCV genotype 2 or 3 infection . In one trial , patients for whom treatment with peginterferon was not an option received oral sofosbuvir and ribavirin ( 207 patients ) or matching placebo ( 71 ) for 12 weeks . In a second trial , patients who had not had a response to prior interferon therapy received sofosbuvir and ribavirin for 12 weeks ( 103 patients ) or 16 weeks ( 98 ) . The primary end point was a sustained virologic response at 12 weeks after therapy . RESULTS Among patients for whom treatment with peginterferon was not an option , the rate of a sustained virologic response was 78 % ( 95 % confidence interval [ CI ] , 72 to 83 ) with sofosbuvir and ribavirin , as compared with 0 % with placebo ( P<0.001 ) . Among previously treated patients , the rate of response was 50 % with 12 weeks of treatment , as compared with 73 % with 16 weeks of treatment ( difference , -23 percentage points ; 95 % CI , -35 to -11 ; P<0.001 ) . In both studies , response rates were lower among patients with genotype 3 infection than among those with genotype 2 infection and , among patients with genotype 3 infection , lower among those with cirrhosis than among those without cirrhosis . The most common adverse events were headache , fatigue , nausea , and insomnia ; the overall rate of discontinuation of sofosbuvir was low ( 1 to 2 % ) . CONCLUSIONS In patients with HCV genotype 2 or 3 infection for whom treatment with peginterferon and ribavirin was not an option , 12 or 16 weeks of treatment with sofosbuvir and ribavirin was effective . Efficacy was increased among patients with HCV genotype 2 infection and those without cirrhosis . In previously treated patients with genotype 3 infection , 16 weeks of therapy was significantly more effective than 12 weeks . ( Funded by Gilead Sciences ; POSITRON and FUSION Clinical Trials.gov numbers , NCT01542788 and NCT01604850 , respectively . ) BACKGROUND & AIMS We conducted an open-label , r and omized , phase 3 trial to determine the efficacy and safety of sofosbuvir and ribavirin , with and without peginterferon-alfa , in treatment-experienced patients with cirrhosis and hepatitis C virus ( HCV ) genotype 2 infection and treatment-naïve or treatment-experienced patients with HCV genotype 3 infection . METHODS The study was conducted at 80 sites in Europe , North America , Australia , and New Zeal and Patients were r and omly assigned ( 1:1:1 ) to groups given sofosbuvir and ribavirin for 16 weeks ( n = 196 ) ; sofosbuvir and ribavirin for 24 weeks ( n = 199 ) ; or sofosbuvir , peginterferon-alfa , and ribavirin for 12 weeks ( n = 197 ) . The primary end point was the percentage of patients with HCV RNA < 15 IU/mL 12 weeks after stopping therapy ( sustained virologic response [ SVR12 ] ) . From October 2013 until April 2014 , we enrolled and treated 592 patients -48 with genotype 2 HCV and compensated cirrhosis who had not achieved SVR with previous treatments and 544 with genotype 3 HCV ( 279 treatment-naïve and 265 previously treated ) . Overall , 219 patients ( 37 % ) had compensated cirrhosis . The last post-treatment week 12 patient visit was in January 2015 . RESULTS Rates of SVR12 among patients with genotype 2 HCV were 87 % and 100 % , for those receiving 16 and 24 weeks of sofosbuvir and ribavirin , respectively , and 94 % for those receiving sofosbuvir , peginterferon , and ribavirin for 12 weeks . Rates of SVR12 among patients with genotype 3 HCV were 71 % and 84 % in those receiving 16 and 24 weeks of sofosbuvir and ribavirin , respectively , and 93 % in those receiving sofosbuvir , peginterferon , and ribavirin . On-treatment virologic failure occurred in 3 patients with HCV genotype 3a receiving sofosbuvir and ribavirin for 24 weeks . The most common adverse events were fatigue , headache , insomnia , and nausea . Overall , 1 % of patients discontinued treatment due to adverse events . CONCLUSIONS Among patients with genotype 3 HCV infection , including a large proportion of treatment-experienced patients with cirrhosis , the combination of sofosbuvir , peginterferon , and ribavirin for 12 weeks produces high rates of SVR . Treatment-experienced patients with cirrhosis and genotype 2 HCV infection had high rates of SVR in all groups . EudraCT ID 2013 - 002641 - 11 Patients with hepatitis C virus ( HCV ) genotype 3 infection , especially those with advanced liver disease , are a challenging population in urgent need of optimally effective therapies . The combination of daclatasvir ( DCV ; pangenotypic nonstructural protein 5A inhibitor ) and sofosbuvir ( SOF ; nucleotide nonstructural protein 5B inhibitor ) for 12 weeks previously showed high efficacy ( 96 % ) in noncirrhotic genotype 3 infection . The phase III ALLY‐3 + study ( N = 50 ) evaluated DCV‐SOF with ribavirin ( RBV ) in treatment‐naïve ( n = 13 ) or treatment‐experienced ( n = 37 ) genotype 3‐infected patients with advanced fibrosis ( n = 14 ) or compensated cirrhosis ( n = 36 ) . Patients were r and omized 1:1 to receive open‐label DCV‐SOF ( 60 + 400 mg daily ) with weight‐based RBV for 12 or 16 weeks . The primary endpoint was sustained virological response at post‐treatment week 12 ( SVR12 ) . SVR12 ( intention‐to‐treat ) was 90 % overall ( 45 of 50 ) : 88 % ( 21 of 24 ) in the 12‐week ( 91 % observed ) and 92 % ( 24 of 26 ) in the 16‐week group . All patients with advanced fibrosis achieved SVR12 . SVR12 in patients with cirrhosis was 86 % overall ( 31 of 36 ) : 83 % ( 15 of 18 ) in the 12‐week ( 88 % observed ) and 89 % ( 16 of 18 ) in the 16‐week group ; for treatment‐experienced patients with cirrhosis , these values were 87 % ( 26 of 30 ) , 88 % ( 14 of 16 ; 93 % observed ) , and 86 % ( 12 of 14 ) , respectively . One patient ( 12‐week group ) did not enter post‐treatment follow‐up ( death unrelated to treatment ) . There were 4 relapses ( 2 per group ) and no virological breakthroughs . The most common adverse events ( AEs ) were insomnia , fatigue , and headache . There were no discontinuations for AEs and no treatment‐related serious AEs . Conclusion : The all‐oral regimen of DCV‐SOF‐RBV was well tolerated and result ed in high and similar SVR12 after 12 or 16 weeks of treatment among genotype 3‐infected patients with advanced liver disease , irrespective of past HCV treatment experience . ( Hepatology 2016;63:1430‐1441 Context Options are needed when initial therapy fails for hepatitis C virus ( HCV ) infection . Contribution In a phase 2 trial , treatment-experienced patients with genotype 3 HCV infection who either did not have cirrhosis or had compensated cirrhosis , as well as patients with genotype 1 HCV infection that was unsuccessfully treated with a protease inhibitor plus peginterferon or ribavirin , received sofosbuvir plus 1 of 2 doses of velpatasvir with or without ribavirin . Sustained virologic response rates 12 weeks after treatment were high in all groups that received sofosbuvir plus 100 mg of velpatasvir . Treatment was well-tolerated . Caution The number of patients was small . Implication Larger trials of sofosbuvir plus velpatasvir are indicated for patients with HCV infection for whom initial therapy fails . Of the 6 hepatitis C virus ( HCV ) genotypes , 1 and 3 are the most common and account for approximately 46 % and 22 % of all global infections , respectively ( 1 ) . Chronic infection with genotype 1 HCV is most prevalent in the Americas , Europe , and China , and genotype 3 HCV infection is most prevalent in India , Pakistan , and Southeast Asia ( 1 ) . With the advent of direct-acting antiviral agents , effective interferon-free combination regimens are now available for most patients chronically infected with genotype 1 or 3 HCV ( 2 , 3 ) . However , some subgroups of patients do not achieve optimal rates of sustained virologic response ( SVR ) with existing 12-week regimensin particular , cirrhotic patients with genotype 1 or 3 HCV infection who previously received unsuccessful treatment of HCV infection ( 46 ) . These patients , who are at increased risk for progression to decompensated cirrhosis , hepatocellular carcinoma , and other liver complications , have a medical need for more effective and well-tolerated treatment ( 7 , 8) . Velpatasvir ( Gilead Sciences ) is a novel inhibitor of the HCV NS5A protein , which is involved in HCV replication , virion assembly , and modulation of host cellular response . Velpatasvir ( formerly GS-5816 ) has demonstrated potent pangenotypic antiviral activity in vitro ( 9 ) and in a 3-day monotherapy study in patients with genotype 1 , 2 , 3 , or 4 HCV infection ( 10 , 11 ) . Pharmacology studies showed no clinical ly important drug interactions between sofosbuvir and velpatasvir ( 12 ) . A recent phase 2 study demonstrated the safety and efficacy of 12 weeks of the combination of sofosbuvir and velpatasvir in treatment-naive patients with genotype 1 to 6 HCV infection , with rates of SVR at week 12 after treatment ( SVR12 ) of 93 % to 100 % ( 13 ) . We evaluated the antiviral activity , safety , and tolerability of sofosbuvir administered with 25 or 100 mg of velpatasvir with and without ribavirin for 12 weeks in treatment-experienced patients with genotype 1 or 3 HCV infection . Because previously treated patients have historically had a poorer response than treatment-naive patients , we chose to evaluate sofosbuvir plus velpatasvir with ribavirin , as well as sofosbuvir plus velpatasvir alone . Methods Design Overview This phase 2 , multicenter , r and omized , open-label study was conducted from June 2013 ( when the first patient was enrolled ) to August 2014 ( when the last patient completed follow-up ) . The study was originally design ed to enroll 2 cohorts of patients with chronic genotype 3 HCV infection who had not achieved SVR after previous therapy with an interferon-based regimenapproximately 100 patients without cirrhosis and 100 patients with compensated cirrhosis . Favorable results in treatment-naive patients with genotype 1 HCV infection in a phase 2 trial of similar design ( 13 ) prompted us to amend our protocol to enroll a third cohort of approximately 100 patients with chronic genotype 1 HCV infection who did not achieve SVR after previous therapy with an approved or experimental NS3/4A protease inhibitor in combination with peginterferon and ribavirin . Up to 50 % of patients with genotype 1 HCV infection could have compensated cirrhosis . The protocol was approved by the institutional ethics committees at all sites , and the study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki . Setting and Participants The study was conducted at 58 clinical sites : 7 in Australia , 2 in New Zeal and , and 49 in the United States . Some patients were recruited partly through a posting of study details on Clinical Trials.gov and others through referral by their treating physicians . Adults ( aged 18 years ) with HCV RNA levels greater than 10000 IU/mL were eligible . The HCV RNA genotype was determined by the central laboratory using the Versant HCV Genotype 2.0 Assay ( LiPA ) ( Siemens ) . If results were inconclusive , we used the TruGene HCV 5NC Genotyping Kit ( Siemens ) with the OpenGene DNA Sequencing System ( Siemens ) . The presence of cirrhosis was established by liver biopsy , a FibroTest score greater than 0.75 and an aspartate aminotransferaseplatelet ratio index greater than 2 during screening , or a FibroScan value greater than 12.5 kPa . Exclusion criteria were hepatic decompensation or co-infection with hepatitis B virus or HIV ; aminotransferase level more than 10 times the upper limit of normal ; direct bilirubin level more than 1.5 times the upper limit of normal ; platelet count less than 90109 cells/L ; hemoglobin A1c level greater than 8.5 % ; creatinine clearance rate less than 60 mL/min/1.73 m2 , as calculated by the CockcroftGault equation ; hemoglobin level less than 11 g/dL for female patients or less than 12 g/dL for male patients ; albumin level less than 454.55 mol/L ; and prothrombin time ( international normalized ratio ) greater than 1.5 times the upper limit of normal . To be eligible , patients must not have achieved SVR after previous treatment of HCV infection and must not have discontinued the previous regimen due to an adverse event . Patients with genotype 3 HCV infection with previous exposure to an approved or experimental HCV-specific direct-acting antiviral agent were excluded . Full eligibility criteria are listed in the study protocol ( Supplement ) . All patients provided written informed consent before screening . Supplement . Study Protocol R and omization and Interventions Three cohorts of eligible patients were enrolled : treatment-experienced patients with genotype 3 HCV infection without cirrhosis , treatment-experienced patients with genotype 3 HCV infection with compensated cirrhosis , and patients with genotype 1 HCV infection whose previous treatment with a protease inhibitor and interferon-based regimen was unsuccessful . Within each cohort , patients were r and omly assigned to 4 groups ( by a 1:1:1:1 ratio ) , each of which received 12 weeks of a single oral daily dose of 400 mg of sofosbuvir plus 25 mg of velpatasvir , 25 mg of velpatasvir with ribavirin , 100 mg of velpatasvir , or 100 mg of velpatasvir with ribavirin ( Figure ) . Velpatasvir was orally administered in single daily doses of either 25 or 100 mg . Ribavirin was administered orally in a divided daily dose determined by body weight : 1000 mg daily in patients weighing less than 75 kg and 1200 mg daily in patients weighing 75 kg or greater . Figure . Study flow diagram . Patients in groups 9 to 12 were enrolled after patients in groups 1 to 8 had completed the trial and were assessed for efficacy . HCV = hepatitis C virus ; RBV = ribavirin ; SOF = sofosbuvir ; VEL = velpatasvir . R and om assignment of patients was managed with an interactive Web-response system ( Bracket ) . A statistician employed by the sponsor ( L.H. ) generated the r and omization code using SAS , version 9.2 ( SAS Institute ) , which was vali date d by another statistician employed by the sponsor . The r and omization was stratified by cohort . Within cohort 3 ( patients with genotype 1 HCV infection ) , r and omization was stratified by genotype 1 subtype ( 1a or 1b ) and cirrhosis status ( presence or absence ) . Investigators ( Appendix ) , patients , and trial personnel were not blinded to treatment assignment . Outcomes and Follow-up The primary efficacy outcome measure was SVR12 , defined as a serum HCV RNA level below the lower limit of quantification ( LLOQ ) 12 weeks after completion of treatment . We measured HCV RNA levels with the Cobas TaqMan HCV Quantitative Test , v2.0 ( Roche Diagnostics ) , in combination with the High Pure System Viral Nucleic Acid Kit ( Roche Diagnostics ) , and used an LLOQ of 25 IU/mL. Secondary efficacy outcome measures included the proportion of patients with virologic failure , which was defined as either on-treatment virologic failure ( HCV RNA level at or above the LLOQ after 8 weeks of therapy , confirmed > 1 log10 increase in HCV RNA level from nadir , or confirmed HCV RNA level at or above the LLOQ after 2 consecutive HCV RNA levels less than the LLOQ ) or relapse ( HCV RNA level at or above the LLOQ during the posttreatment period or HCV RNA levels less than the LLOQ at the end of treatment ) . Other secondary efficacy outcome measures ( SVR4 , SVR24 , and HCV RNA levels less than the LLOQ by study visit and HCV RNA levels and change from baseline in HCV RNA levels through week 12 ) are not reported here . The primary safety outcome measure was any adverse event leading to permanent withdrawal of study drugs . Safety assessment s during treatment and up to 30 days after treatment included reports of adverse events , st and ard laboratory testing , 12-lead electrocardiography , assessment of vital signs , and symptom-driven physical examinations . Adverse events were coded using the Medical Dictionary for Regulatory Activities and grade d by severity by the investigator according to the Gilead Sciences Grading Scale for Severity of Adverse Events and Laboratory Abnormalities . Deep sequencing of the HCV NS5A and NS5B gene was done from pretreatment plasma sample s from all enrolled patients and from posttreatment sample s from all patients with virologic failure . The HCV NS5A and NS5B coding regions were amplified by DDL Diagnostic Laboratory ( Rijswijk , The Netherl and s ) with st and ard reverse IMPORTANCE Treatment of hepatitis C virus ( HCV ) infection in patients also infected with human immunodeficiency virus ( HIV ) has been limited due to drug interactions with antiretroviral therapies ( ARTs ) and the need to use interferon . OBJECTIVE To determine the rates of HCV eradication ( sustained virologic response [ SVR ] ) and adverse events in patients with HCV-HIV coinfection receiving sofosbuvir and ribavirin treatment . DESIGN , SETTING , AND PARTICIPANTS Open-label , nonr and omized , uncontrolled phase 3 trial conducted at 34 treatment centers in the United States and Puerto Rico ( August 2012-November 2013 ) evaluating treatment with sofosbuvir and ribavirin among patients with HCV genotypes 1 , 2 , or 3 and concurrent HIV . Patients were required to be receiving ART with HIV RNA values of 50 copies/mL or less and a CD4 T-cell count of more than 200 cells/μL or to have untreated HIV infection with a CD4 T-cell count of more than 500 cells/μL. Of the treatment-naive patients , 114 had HCV genotype 1 and 68 had HCV genotype 2 or 3 , and 41 treatment experienced participants who had been treated with peginterferon-ribavirin had HCV genotype 2 or 3 , for a total of 223 participants . INTERVENTIONS Treatment-naive patients with HCV genotype 2 or 3 received 400 mg of sofosbuvir and weight-based ribavirin for 12 weeks and treatment-naive patients with HCV genotype 1 and treatment-experienced patients with HCV genotype 2 or 3 received the same treatment for 24 weeks . MAIN OUTCOMES AND MEASURES The primary study outcome was the proportion of patients with SVR ( serum HCV < 25 copies/mL ) 12 weeks ( SVR12 ) after cessation of HCV therapy . RESULTS Among treatment-naive participants , 87 patients ( 76 % ) of 114 ( 95 % CI , 67%-84 % ) with genotype 1 , 23 patients ( 88 % ) of 26 with genotype 2 ( 95 % CI , 70%-985 ) , and 28 patients ( 67 % ) of 42 with genotype 3 ( 95 % CI , 51%-80 % ) achieved SVR12 . Among treatment-experienced participants , 22 patients ( 92 % ) of 24 with genotype 2 ( 95 % CI , 73%-99 % ) and 16 patients ( 94 % ) of 17 ( 95 % CI , 71%-100 % ) achieved SVR12 . The most common adverse events were fatigue , insomnia , headache , and nausea . Seven patients ( 3 % ) discontinued HCV treatment due to adverse events . No adverse effect on HIV disease or its treatment was observed . CONCLUSIONS AND RELEVANCE In this open-label , nonr and omized , uncontrolled study , patients with HIV who were coinfected with HCV genotype 1 , 2 , or 3 who received the oral , interferon-free combination of sofosbuvir and ribavirin for 12 or 24 weeks had high rates of SVR12 . Further studies of this oral regimen in diverse population s of coinfected patients are warranted . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01667731 BACKGROUND In clinical trials , treatment with a combination of the nucleotide polymerase inhibitor sofosbuvir and the antiviral drug ribavirin was associated with high response rates among patients with hepatitis C virus ( HCV ) genotype 2 infection , with lower response rates among patients with HCV genotype 3 infection . METHODS We conducted a study involving patients with HCV genotype 2 or 3 infection , some of whom had undergone previous treatment with an interferon-based regimen . We r and omly assigned 91 patients with HCV genotype 2 infection and 328 with HCV genotype 3 infection , in a 4:1 ratio , to receive sofosbuvir-ribavirin or placebo for 12 weeks . On the basis of emerging data from phase 3 trials indicating that patients with HCV genotype 3 infection had higher response rates when they were treated for 16 weeks , as compared with 12 weeks , the study was unblinded , treatment for all patients with genotype 3 infection was extended to 24 weeks , the placebo group was terminated , and the goals of the study were redefined to be descriptive and not include hypothesis testing . The primary end point was a sustained virologic response at 12 weeks after the end of therapy . RESULTS Of the 419 patients who were enrolled and treated , 21 % had cirrhosis and 58 % had received previous interferon-based treatment . The criterion for a sustained virologic response was met in 68 of 73 patients ( 93 % ; 95 % confidence interval [ CI ] , 85 to 98 ) with HCV genotype 2 infection who were treated for 12 weeks and in 213 of 250 patients ( 85 % ; 95 % CI , 80 to 89 ) with HCV genotype 3 infection who were treated for 24 weeks . Among patients with HCV genotype 3 infection , response rates were 91 % and 68 % among those without and those with cirrhosis , respectively . The most common adverse events were headache , fatigue , and pruritus . CONCLUSIONS Therapy with sofosbuvir-ribavirin for 12 weeks in patients with HCV genotype 2 infection and for 24 weeks in patients with HCV genotype 3 infection result ed in high rates of sustained virologic response . ( Funded by Gilead Sciences ; VALENCE Clinical Trials.gov number , NCT01682720 . ) Context Pangenotypic treatments for hepatitis C virus ( HCV ) infection would be useful worldwide . Contribution In a small , phase 2 , r and omized , open-label clinical trial , combination therapy consisting of sofosbuvir plus 1 of 2 doses of velpatasvir was studied in treatment-naive noncirrhotic patients infected with HCV genotypes 1 to 6 . Sustained virologic response rates at 12 weeks were high in all genotypes with 400 mg of sofosbuvir plus 100 mg of velpatasvir . No serious adverse events were noted . One death due to suicide occurred . Caution Few patients with genotype 4 , 5 , or 6 were included . Implication Velpatasvir may be a useful pangenotypic therapy for HCV infection and should be studied in larger clinical trials . Up to 150 million persons worldwide are chronically infected with hepatitis C virus ( HCV ) ( 1 ) . Chronic HCV infection causes slowly progressive liver fibrosis , which can lead to cirrhosis , hepatic decompensation , and hepatocellular carcinoma ( 2 , 3 ) . Chronic HCV infection is curable , as measured by the end point of sustained virologic response ( SVR ) , which is defined as undetectable HCV RNA 12 or 24 weeks after the end of treatment . For many years , however , HCV treatment regimens were based on recombinant interferon- , a poorly tolerated drug with moderate efficacy ( 4 ) . The recent advent of drugs that directly target HCV viral replication has revolutionized treatment of HCV infection . The first such direct-acting antiviral agents ( DAAs ) , the protease inhibitors telaprevir and boceprevir , were approved in combination with peginterferon and ribavirin in 2009 , but these regimens are no longer recommended ( 5 ) . With a second generation of DAAs , effective interferon-free treatment of HCV infection is now available . However , existing DAA combination regimens are not uniformly effective across the 6 HCV genotypes . The most effective regimens are for genotype 1 HCV , which accounts for approximately 46 % of infections worldwide ( 6 ) . Genotypes 2 and 3 HCV , the next most common genotypes , were historically grouped together in treatment guidelines , but recent studies have shown that infection with genotype 3 , especially in patients with cirrhosis , is more difficult to treat ( 7 , 8) . Many interferon-free combinations are now available for these and the other 3 HCV genotypes ( 9 , 10 ) , but clinicians must take into account the genotype and even the subtype as well as patterns of antiviral resistance in the choice of a regimen . The development of a single , short- duration regimen that is safe and effective in all HCV genotypes would greatly simplify treatment and would reduce the need for pretreatment testing and on-treatment monitoring . Sofosbuvir is a pangenotypic HCV NS5B polymerase inhibitor approved in the United States and other regions for the treatment of HCV infection ( 11 ) . Velpatasvir is a novel inhibitor of the HCV NS5A protein that has demonstrated pangenotypic antiviral activity in vitro ( 12 ) and in a 3-day monotherapy study in patients infected with genotypes 1 , 2 , 3 , and 4 HCV ( 13 ) . Drug interaction studies showed no clinical ly significant interactions between sofosbuvir and velpatasvir ( 14 ) , and both can be administered once daily ( 15 ) . The clinical potential of the combination of sofosbuvir and velpatasvir is suggested by their nonoverlapping viral targets , the proven success of sofosbuvir in combination with other NS5A inhibitors , and the in vitro potency of velpatasvir . We assessed the safety and efficacy of 8 or 12 weeks of velpatasvir coadministered with sofosbuvir . In addition , we examined the effect of adding ribavirin for patients receiving 8 weeks of treatment . Supplement . Original Version ( PDF ) Methods Study Overview Enrollment for this phase 2 , multicenter , r and omized , open-label study began on 22 August 2013 , and data collection for the primary efficacy end point was completed on 12 August 2014 ( Appendix Table ) . As originally design ed , the study consisted of 6 groups of treatment-naive patients receiving 12 weeks of treatment : approximately 50 patients with genotype 1 HCV infection ( groups 1 and 2 ) ; 50 with genotype 3 infection ( groups 3 and 4 ) ; and 50 with genotype 2 , 4 , 5 , or 6 infection ( groups 5 and 6 ) . Because interim analyses of results from these 6 groups ( part A ) indicated that patients with genotype 1 and 2 HCV infection achieved high rates of SVR at 12 weeks ( SVR12 ) , we amended the protocol to include part B , in which we evaluated 8 weeks of treatment with and without ribavirin in patients with genotype 1 infection ( groups 7 to 10 ) and genotype 2 infection ( groups 11 to 14 ) . Appendix Table . Reasons for Screen Failure Setting and Participants The study was conducted at 48 sites in the United States . Patients were recruited partly through a posting of study details on Clinical Trials.gov and partly through referral by their treating physicians . Treatment-naive noncirrhotic adults ( aged 18 years ) with HCV RNA levels greater than 10000 IU/mL were eligible . The HCV RNA genotype was determined by using the Siemens VERSANT HCV Genotype Assay , version 2 ( LiPA 2.0 ) , or , if results were inconclusive , the TRUGENE HCV 5'NC Genotyping Kit was used with the OpenGene DNA Sequencing System . Absence of cirrhosis was established by liver biopsy within 2 years of screening ; a FibroTest score of 0.48 or less and an aspartate aminotransferaseplatelet ratio index of 1 or less during screening ; or a Fibroscan score of 12.5 kPa or less within 6 months of baseline . Exclusion criteria were previous treatment for HCV infection , hepatic decompensation or co-infection with hepatitis B virus or HIV , aminotransferase levels greater than 10 times the upper limit of normal ( ULN ) , direct bilirubin level greater than 1.5 times the ULN , platelet count less than 90109 cells/L , hemoglobin A1c level greater than 8.5 % , creatinine clearance less than 60 mL/min ( as calculated by the CockcroftGault equation ) , hemoglobin level less than 110 g/L for female patients or less than 120 g/L for male patients , albumin level less than 30 g/L , and prothrombin time ( international normalized ratio ) greater than 1.5 times the ULN . All patients provided written informed consent before screening . The protocol was approved by institutional ethics committees at all study sites . The study was conducted in accordance with good clinical practice and the Declaration of Helsinki and was registered with Clinical Trials.gov ( NCT01858766 ) . R and omization and Interventions In part A , patients in each of the 3 HCV genotype categories were r and omly assigned in a 1:1 ratio to receive 25 or 100 mg of velpatasvir once daily for 12 weeks . All patients received 400 mg of sofosbuvir once daily . Patients with genotype 1 HCV infection were stratified by HCV subtype ( 1a vs. 1b ) . Patients in groups 5 and 6 were stratified by HCV genotype . In part B , patients in each of the 2 HCV genotype categories were r and omly assigned in a 1:1:1:1 ratio to receive 25 or 100 mg of velpatasvir once daily for 8 weeks or 25 or 100 mg of velpatasvir once daily plus ribavirin in a divided daily dose . All patients received 400 mg of sofosbuvir once daily for 8 weeks . Patients with genotype 1 HCV infection were stratified by HCV subtype ( 1a vs. 1b ) . Sofosbuvir was administered to all patients once daily in a 400-mg tablet . Velpatasvir was administered once daily in 25- or 100-mg tablets . Ribavirin was administered twice daily at a dose of 1000 mg/d ( three 200-mg tablets in the morning and two 200-mg tablets in the evening ) in patients with a total body weight less than 75 kg and 1200 mg/d ( three 200-mg tablets twice daily ) in those with a total body weight of 75 kg or greater ( 16 ) . Patient r and omization was managed by using an interactive Web response system ( Bracket ) . A statistician employed by the sponsor ( L.H. ) generated the r and omization code using a SAS program , which was vali date d by another statistician employed by the sponsor . R and omization was stratified by HCV genotype and used a block size of 4 . Investigators , patients , and trial personnel were not blinded to treatment assignments at any point . Outcomes and Follow-up The primary efficacy outcome measure was SVR12 , defined as a serum HCV RNA level below the lower limit of quantification ( LLOQ ) 12 weeks after completion of treatment . The HCV RNA concentration was measured using the Roche COBAS TaqMan HCV Test ( v2.0 ) with the High Pure System , with an LLOQ of 25 IU/mL. On-treatment virologic failure was defined as an HCV RNA level of at least 25 IU/mL after 8 weeks of therapy . Relapse was defined as an HCV RNA level of at least the LLOQ during the posttreatment follow-up in patients who achieved a level below the LLOQ by the end of treatment . Levels of HCV RNA were measured at posttreatment weeks 4 , 8 , 12 , and 24 . Deep sequencing of the HCV NS5A and NS5B genes was performed from pretreatment plasma sample s from all enrolled patients and from posttreatment sample s from all patients with virologic failure . NS5A resistance-associated variants ( RAVs ) were defined as changes from a genotype-specific reference sequence at amino acid positions 28 , 30 , 31 , 32 , 58 , 92 , and 93 . NS5B RAVs were defined as any change from the HCV reference sequence at positions 96 , 142 , 159 , 282 , 289 , 320 , and 321 . Statistical Analysis The analysis set for efficacy and safety included r and omly assigned patients who received at least 1 dose of the study drug . No inferential statistics or statistical comparisons were planned or conducted for efficacy or safety data . A 2-sided 95 % CI for the proportion of patients with SVR12 within treatment groups was calculated by using the ClopperPearson method , which provides the exact CI based on the binomial distribution rather than an approximation to the binomial distribution ( 17 ) . Patients with missing HCV RNA values for any reason at posttreatment week 12 and after were counted as treatment failures . No formal power or sample size calculations were used to determine group size . With a sample size of 25 patients in BACKGROUND The combination of daclatasvir , a hepatitis C virus ( HCV ) NS5A inhibitor , and the NS5B inhibitor sofosbuvir has shown efficacy in patients with HCV monoinfection . Data are lacking on the efficacy and safety of this combination in patients coinfected with human immunodeficiency virus type 1 ( HIV-1 ) . METHODS This was an open-label study involving 151 patients who had not received HCV treatment and 52 previously treated patients , all of whom were coinfected with HIV-1 . Previously untreated patients were r and omly assigned in a 2:1 ratio to receive either 12 weeks or 8 weeks of daclatasvir at a st and ard dose of 60 mg daily ( with dose adjustment for concomitant antiretroviral medications ) plus 400 mg of sofosbuvir daily . Previously treated patients were assigned to undergo 12 weeks of therapy at the same doses . The primary end point was a sustained virologic response at week 12 after the end of therapy among previously untreated patients with HCV genotype 1 who were treated for 12 weeks . RESULTS Patients had HCV genotypes 1 through 4 ( 83 % with genotype 1 ) , and 14 % had compensated cirrhosis ; 98 % were receiving antiretroviral therapy . Among patients with genotype 1 , a sustained virologic response was reported in 96.4 % ( 95 % confidence interval [ CI ] , 89.8 to 99.2 ) who were treated for 12 weeks and in 75.6 % ( 95 % CI , 59.7 to 87.6 ) who were treated for 8 weeks among previously untreated patients and in 97.7 % ( 95 % CI , 88.0 to 99.9 ) who were treated for 12 weeks among previously treated patients . Rates of sustained virologic response across all genotypes were 97.0 % ( 95 % CI , 91.6 to 99.4 ) , 76.0 % ( 95 % CI , 61.8 to 86.9 ) , and 98.1 % ( 95 % CI , 89.7 to 100 ) , respectively . The most common adverse events were fatigue , nausea , and headache . There were no study -drug discontinuations because of adverse events . HIV-1 suppression was not compromised . CONCLUSIONS Among previously untreated HIV-HCV coinfected patients receiving daclatasvir plus sofosbuvir for HCV infection , the rate of sustained virologic response across all genotypes was 97.0 % after 12 weeks of treatment and 76.0 % after 8 weeks . ( Funded by Bristol-Myers Squibb ; ALLY-2 Clinical Trials.gov number , NCT02032888 . ) BACKGROUND In phase 2 trials , the nucleotide polymerase inhibitor sofosbuvir was effective in previously untreated patients with chronic hepatitis C virus ( HCV ) genotype 1 , 2 , or 3 infection . METHODS We conducted two phase 3 studies in previously untreated patients with HCV infection . In a single-group , open-label study , we administered a 12-week regimen of sofosbuvir plus peginterferon alfa-2a and ribavirin in 327 patients with HCV genotype 1 , 4 , 5 , or 6 ( of whom 98 % had genotype 1 or 4 ) . In a noninferiority trial , 499 patients with HCV genotype 2 or 3 infection were r and omly assigned to receive sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa-2a plus ribavirin for 24 weeks . In the two studies , the primary end point was a sustained virologic response at 12 weeks after the end of therapy . RESULTS In the single-group study , a sustained virologic response was reported in 90 % of patients ( 95 % confidence interval , 87 to 93 ) . In the noninferiority trial , a sustained response was reported in 67 % of patients in both the sofosbuvir-ribavirin group and the peginterferon-ribavirin group . Response rates in the sofosbuvir-ribavirin group were lower among patients with genotype 3 infection than among those with genotype 2 infection ( 56 % vs. 97 % ) . Adverse events ( including fatigue , headache , nausea , and neutropenia ) were less common with sofosbuvir than with peginterferon . CONCLUSIONS In a single-group study of sofosbuvir combined with peginterferon-ribavirin , patients with predominantly genotype 1 or 4 HCV infection had a rate of sustained virologic response of 90 % at 12 weeks . In a noninferiority trial , patients with genotype 2 or 3 infection who received either sofosbuvir or peginterferon with ribavirin had nearly identical rates of response ( 67 % ) . Adverse events were less frequent with sofosbuvir than with peginterferon . ( Funded by Gilead Sciences ; FISSION and NEUTRINO Clinical Trials.gov numbers , NCT01497366 and NCT01641640 , respectively . ) BACKGROUND Although interferon-free regimens are approved for patients co-infected with HIV and genotype-2 or genotype-3 hepatitis C virus ( HCV ) , interferon-based regimens are still an option for those co-infected with HIV and HCV genotypes 1 or 4 . These regimens are limited by clinical ly significant toxic effects and drug interactions with antiretroviral therapy . We aim ed to assess the efficacy and safety of an interferon-free , all-oral regimen of sofosbuvir plus ribavirin in patients with HIV and HCV co-infection . METHODS We did this open-label , non-r and omised , uncontrolled , phase 3 study at 45 sites in seven European countries and Australia . We enrolled patients ( aged ≥18 years ) co-infected with stable HIV and chronic HCV genotypes 1 - 4 , including those with compensated cirrhosis . Once-daily sofosbuvir ( 400 mg ) plus twice-daily ribavirin ( 1000 mg in patients with bodyweights < 75 kg and 1200 mg in those with weights ≥75 kg ) was given for 24 weeks to all patients except treatment-naive patients with genotype-2 HCV , who received a 12-week regimen . The primary efficacy endpoint was sustained virological response 12 weeks after treatment . We did analysis by modified intention to treat . This study is registered with Clinical Trials.gov , number NCT01783678 . FINDINGS Between Feb 7 , 2013 , and July 29 , 2013 , we enrolled 275 eligible patients , of whom 262 ( 95 % ) completed treatment ; 274 patients were included in the final analysis . Overall rates of sustained virological response 12 weeks after treatment were 85 % ( 95 % CI 77 - 91 ) in patients with genotype-1 HCV , 88 % ( 69 - 98 ) in patients with genotype-2 HCV , 89 % ( 81 - 94 ) in patients with genotype-3 HCV , and 84 % ( 66 - 95 ) in patients with genotype-4 HCV . Response rates in treatment-naive patients with HCV genotypes 2 or 3 ( 89 % [ 95 % CI 67 - 99 ] and 91 % [ 81 - 97 ] , respectively ) were similar to those in treatment-experienced patients infected with those genotypes ( 83 % [ 36 - 100 ] and 86 % [ 73 - 94 ] , respectively ) . There was no emergence of sofosbuvir-resistance mutations in patients with HCV viral relapse . Six ( 2 % ) patients discontinued treatment because of adverse events . The most common adverse events were fatigue , insomnia , asthenia , and headache . Four ( 1 % ) patients had serious adverse events regarded as related to study treatment . Additionally , four ( 1 % ) patients receiving antiretroviral treatment had a transient HIV viral breakthrough ; however , none required changes in antiretroviral regimen . INTERPRETATION Sofosbuvir and ribavirin provided high rates of sustained virological response after 12 weeks of treatment in treatment-naive and treatment-experienced patients co-infected with HIV and HCV genotypes 1 - 4 . The characteristics of this interferon-free combination regimen make sofosbuvir plus ribavirin a useful treatment option for this patient population . FUNDING Gilead Sciences BACKGROUND In phase 2 trials , treatment with the combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir result ed in high rates of sustained virologic response in patients chronically infected with hepatitis C virus ( HCV ) genotype 2 or 3 . METHODS We conducted two r and omized , phase 3 , open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment , including patients with compensated cirrhosis . In one trial , patients with HCV genotype 2 were r and omly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir , in a once-daily , fixed-dose combination tablet ( 134 patients ) , or sofosbuvir plus weight-based ribavirin ( 132 patients ) for 12 weeks . In a second trial , patients with HCV genotype 3 were r and omly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir for 12 weeks ( 277 patients ) or sofosbuvir-ribavirin for 24 weeks ( 275 patients ) . The primary end point for the two trials was a sustained virologic response at 12 weeks after the end of therapy . RESULTS Among patients with HCV genotype 2 , the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 99 % ( 95 % confidence interval [ CI ] , 96 to 100 ) , which was superior to the rate of 94 % ( 95 % CI , 88 to 97 ) in the sofosbuvir-ribavirin group ( P=0.02 ) . Among patients with HCV genotype 3 , the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 95 % ( 95 % CI , 92 to 98 ) , which was superior to the rate of 80 % ( 95 % CI , 75 to 85 ) in the sofosbuvir-ribavirin group ( P<0.001 ) . The most common adverse events in the two studies were fatigue , headache , nausea , and insomnia . CONCLUSIONS Among patients with HCV genotype 2 or 3 with or without previous treatment , including those with compensated cirrhosis , 12 weeks of treatment with sofosbuvir-velpatasvir result ed in rates of sustained virologic response that were superior to those with st and ard treatment with sofosbuvir-ribavirin . ( Funded by Gilead Sciences ; ASTRAL-2 Clinical Trials.gov number , NCT02220998 ; and ASTRAL-3 , NCT02201953 . ) BACKGROUND As the population that is infected with the hepatitis C virus ( HCV ) ages , the number of patients with decompensated cirrhosis is expected to increase . METHODS We conducted a phase 3 , open-label study involving both previously treated and previously untreated patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis ( classified as Child-Pugh-Turcotte class B ) . Patients were r and omly assigned in a 1:1:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks , sofosbuvir-velpatasvir plus ribavirin for 12 weeks , or sofosbuvir-velpatasvir for 24 weeks . The primary end point was a sustained virologic response at 12 weeks after the end of therapy . RESULTS Of the 267 patients who received treatment , 78 % had HCV genotype 1 , 4 % genotype 2 , 15 % genotype 3 , 3 % genotype 4 , and less than 1 % genotype 6 ; no patients had genotype 5 . Overall rates of sustained virologic response were 83 % ( 95 % confidence interval [ CI ] , 74 to 90 ) among patients who received 12 weeks of sofosbuvir-velpatasvir , 94 % ( 95 % CI , 87 to 98 ) among those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin , and 86 % ( 95 % CI , 77 to 92 ) among those who received 24 weeks of sofosbuvir-velpatasvir . Post hoc analysis did not detect any significant differences in rates of sustained virologic response among the three study groups . Serious adverse events occurred in 19 % of patients who received 12 weeks of sofosbuvir-velpatasvir , 16 % of those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin , and 18 % of those who received 24 weeks of sofosbuvir-velpatasvir . The most common adverse events were fatigue ( 29 % ) , nausea ( 23 % ) , and headache ( 22 % ) in all patients and anemia ( 31 % ) in the patients receiving ribavirin . CONCLUSIONS Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks result ed in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis . ( Funded by Gilead Sciences ; ASTRAL-4 Clinical Trials.gov number , NCT02201901 . ) BACKGROUND & AIMS We performed a phase 2 clinical trial to evaluate the efficacy and safety of ledipasvir and sofosbuvir , with or without ribavirin , in patients infected with hepatitis C virus ( HCV ) genotype 3 or 6 . METHODS We performed an open-label study of 126 patients with HCV genotype 3 or 6 infections at 2 centers in New Zeal and from April 2013 through October 2014 . Subjects were assigned 1 of 4 groups that received 12 weeks of treatment . Previously untreated patients with HCV genotype 3 were r and omly assigned to groups given fixed-dose combination tablet of ledipasvir and sofosbuvir ( n = 25 ) or ledipasvir and sofosbuvir along with ribavirin ( n = 26 ) . Treatment-experienced patients with HCV genotype 3 ( n = 50 ) received ledipasvir and sofosbuvir and ribavirin . Treatment-naïve or treatment-experienced patients with HCV genotype 6 ( n = 25 ) received ledipasvir and sofosbuvir . The primary end point was the percentage of patients with HCV RNA ≤15 IU/mL 12 weeks after stopping therapy ( sustained virologic response at 12 weeks [ SVR12 ] ) . RESULTS Among treatment-naïve genotype 3 patients , 16 of 25 ( 64 % ) receiving ledipasvir and sofosbuvir alone achieved SVR12 compared with all 26 patients ( 100 % ) receiving ledipasvir and sofosbuvir and ribavirin . Among treatment-experienced patients with HCV genotype 3 , forty-one of fifty achieved an SVR12 ( 82 % ) . Among patients with HCV genotype 6 , the rate of SVR12 was 96 % ( 24 of 25 patients ) . The most common adverse events were headache , upper respiratory infection , and fatigue . One patient with HCV genotype 3 discontinued ledipasvir and sofosbuvir because of an adverse event ( diverticular perforation ) , which was not considered treatment related . CONCLUSIONS In an uncontrolled , open-label trial , high rates of SVR12 were achieved by patients with HCV genotype 3 infection who received 12 weeks of ledipasvir and sofosbuvir plus ribavirin , and by patients with HCV genotype 6 infection who received 12 weeks of sofosbuvir and ledipasvir without ribavirin . Current guidelines do not recommend the use of ledipasvir and sofosbuvir , with or without ribavirin , in patients with HCV genotype 3 infection . Clinical Trials.gov Number : NCT01826981 BACKGROUND & AIMS Studies are needed to determine the optimal regimen for patients with chronic hepatitis C virus ( HCV ) genotype 2 , 3 , 4 , or 6 infections whose prior course of antiviral therapy has failed , and the feasibility of shortening treatment duration . We performed a phase 2 study to determine the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir , the NS5A inhibitor velpatasvir , and the NS3/4A protease inhibitor GS-9857 in these patients . METHODS We performed a multicenter , open-label trial at 32 sites in the United States and 2 sites in New Zeal and from March 3 , 2015 to April 27 , 2015 . Our study included 128 treatment-naïve and treatment-experienced patients ( 1 with HCV genotype 1b ; 33 with HCV genotype 2 ; 74 with HCV genotype 3 ; 17 with genotype HCV 4 ; and 3 with HCV genotype 6 ) , with or without compensated cirrhosis . All patients received sofosbuvir-velpatasvir ( 400 mg/100 mg fixed-dose combination tablet ) and GS-9857 ( 100 mg ) once daily for 6 - 12 weeks . The primary end point was sustained virologic response 12 weeks after treatment ( SVR12 ) . RESULTS After 6 weeks of treatment , SVR12s were achieved by 88 % of treatment-naïve patients without cirrhosis ( 29 of 33 ; 95 % confidence interval , 72%-97 % ) . After 8 weeks of treatment , SVR12s were achieved by 93 % of treatment-naïve patients with cirrhosis ( 28 of 30 ; 95 % CI , 78%-99 % ) . After 12 weeks of treatment , SVR12s were achieved by all treatment-experienced patients without cirrhosis ( 36 of 36 ; 95 % CI , 90%-100 % ) and 97 % of treatment-experienced patients with cirrhosis ( 28 of 29 ; 95 % CI , 82%-100 % ) . The most common adverse events were headache , diarrhea , fatigue , and nausea . Three patients ( 1 % ) discontinued treatment due to adverse events . CONCLUSIONS In a phase 2 open-label trial , we found sofosbuvir-velpatasvir plus GS-9857 ( 8 weeks in treatment-naïve patients or 12 weeks in treatment-experienced patients ) to be safe and effective for patients with HCV genotype 2 , 3 , 4 , or 6 infections , with or without compensated cirrhosis . Clinical Trials.gov ID : NCT02378961 |
1,915 | 22,695,015 | The results do not support a preference for either approach | PURPOSE To determine the impact of secondary versus primary closure techniques on the frequency and severity of pain , facial swelling , trismus , infectious complications , and postoperative bleeding after impacted m and ibular third molar extraction . | The split-mouth design is a popular design in oral health research . In the most common split-mouth study , each of two treatments are r and omly assigned to either the right or left halves of the dentition . The attractiveness of the design is that it removes a lot of inter-individual variability from the estimates of the treatment effect . However , already about 20 years ago the pitfalls of the design have been reported in the oral health literature . Yet , many clinicians are not aware of the potential problems with the split-mouth design . Further , it is our experience that most statisticians are not even aware of the existence of this design . Since most of the critical remarks appeared in the oral health literature , we argue that it is necessary to introduce the split-mouth design to a statistical audience , so that both clinicians and statisticians clearly underst and the advantages , limitations , statistical considerations , and implication s of its use in clinical trials and advise them on its use in practice A prospect i ve r and omized crossover , within-patient , controlled study was performed in 26 healthy patients to test the effect of the prophylactic local use of gauze drain impregnated with chlortetracycline ( Aureomycin 3 % , Lederle ) ointment on postoperative alveolitis formation after surgical removal of 52 bilaterally impacted m and ibular third molars . The teeth were removed on two separate occasions ; on one side drain was inserted in the socket , and on the other side no drain treatment was used for control . The influence on postoperative pain , swelling , and mouth opening ability was investigated . The results indicated a statistically significant reduction ( P = 0.02 ) in the incidence of postoperative inflammatory complications , defined as postoperative alveolitis , from 35 % in the no-drain group to 4 % in the drain group . No statistically significant difference was found between the two treatment methods with regard to pain and mouth opening reduction . There was a significant difference between the drain and no-drain treatment with regard to swelling on the 1st postoperative day in favor of the no-drain method . It is concluded that insertion of a chlortetracycline-impregnated drain may be an effective method for reducing postoperative alveolitis formation but has no beneficial effect on pain , swelling , and mouth opening reduction after impacted m and ibular third-molar surgery PURPOSE To compare the effect of total and partial wound closure techniques on immediate postoperative tissue reactions and complications after m and ibular third molar surgery . PATIENTS AND METHODS This prospect i ve , r and omized , controlled study was carried out at the Department of Oral and Maxillofacial Surgery , National Hospital , Abuja , Nigeria . Patients were r and omly allocated to partial ( group I ) and total ( group II ) wound closure groups . Data were collected on pain , trismus , swelling , and complications experienced by the patients . Data analysis was carried out with SPSS software for Windows ( version 13.0 ; SPSS , Chicago , IL ) and GenStat ( Discovery Edition , 2005 ; VSN International Ltd , Hemel Hempstead , UK ) . RESULTS We studied 82 patients , consisting of 54 female and 28 male patients , with m and ibular third molar teeth impaction . There were 40 patients ( 48.8 % ) in group I and 42 patients ( 51.2 % ) in group II . A statistically significant reduction in facial swelling ( P = .001 ) was found in group I compared with group II , but no difference was recorded for pain and trismus . Group I presented with significant postoperative reactionary bleeding ( P = .007 ) , but no difference was recorded between the 2 groups regarding dry socket and socket infection . CONCLUSION The partial wound closure technique after third molar surgery was considered to be associated with more postoperative morbidity , in view of the distressing nature of reactionary bleeding that was found to be associated with it . However , patients should be adequately informed about the possibility of attendant facial swelling each time the technique of total wound closure is used PURPOSE Postoperative variables such as pain , swelling , and trismus after surgery of the impacted lower third molars are the main concerns of dental clinicians and surgeons . Many authors cl aim that the use of a drain could help control these variables . The purpose of this study was to evaluate the effect of the use of a tube drain in impacted lower third molar surgery . MATERIAL S AND METHODS Fifty-three patients of both genders with bilateral impacted lower third molars comprised our comparative study . The patients were divided into 2 groups : in the first the suture procedure was accomplished using a drain , and in the second the suture procedure was accomplished without a drain . The postoperative pain , swelling , and trismus were evaluated at 24 hours , 72 hours , 7 days , and 15 days . RESULTS In the group in which the drain was used , the control of the swelling variable was statistically significant at 24 and 72 hours ( P < .001 ) in comparison with the group in which the drain was not used . However , pain and trismus were not statistically significant at the evaluation period . CONCLUSION The use of the drain helps to control swelling . However , it had no effect on pain or trismus The aim of this prospect i ve r and omized study was to evaluate the effect of using a rubber drain on postoperative pain , swelling and trismus after lower third molar surgery . Of 100 patients with impacted lower third molars referred for surgical extraction , there were 40 males and 60 females , aged 18 - 40 years ( mean=26+/-6.2SD ) . The patients were r and omly divided into two equal groups . In the experimental group , a Penrose rubber drain was inserted into the extraction socket near the buccal fold after surgery and left for 72 h. The control group was selected using the same criteria and treated under the same surgical protocol as the experimental group , but without use of a rubber drain . Pain , swelling and trismus were evaluated at 24h , 72 h and 5 days postoperatively in both groups . The results of the study indicate that the use of a rubber drain reduces postoperative discomfort in the form of swelling and trismus after lower third molar surgery , but seems to have no effect on pain PURPOSE The aim of this study was to estimate the frequency of postoperative complications after m and ibular third molar ( M3 ) surgery and identify the risk indicators . PATIENTS AND METHODS This was a prospect i ve cohort study of a sample of subjects having at least 1 m and ibular M3 surgically extracted at a teaching hospital in Jordan . The predictor variables were categorized as patient , anatomic , and operative specific . The outcome variables were postoperative complications recorded as present or absent . Bivariate analyses were computed , then a multivariate logistic regression model was used to identify independent predictors for the common postoperative complications . RESULTS The study sample was comprised of 149 patients who had 245 extraction s. The mean age was 21.6 + /- 3.32 years ; 64.9 % were females . In the multivariate logistic regression model , age ( P = .033 , odds ratio [ OR ] = 1.178 ) , M3 side in relation to the h and edness of the operator ( P = .048 , OR = 4.078 ) , and lingual retraction ( P = .001 , OR = 11.293 ) were the variables found as independent predictors for alveolar osteitis . The level of impaction had a significant association with trismus , and operation time acted as an independent predictor for pain ( P < .001 , OR = 1.085 ) . CONCLUSION Postoperative morbidity increases with older age , deeper impaction , M3 side differing from the h and edness of the operator , and longer procedures BACKGROUND Swelling , pain and trismus are undesirable consequences of impacted m and ibular third-molar extraction . The authors conducted a study to evaluate the effectiveness of cryotherapy , the therapeutic use of cold , in reducing undesirable consequences after surgery . METHODS Fourteen patients aged 20 to 28 years comprised the sample . The authors extracted two impacted m and ibular third molars at different times from each patient . Immediately after surgery , the patient underwent cryotherapy on one side for 30 minutes every one and one-half hours for 48 hours when he or she was awake . The patient did not receive cryotherapy on the other side . The authors performed clinical examinations to measure trismus and swelling before surgery , immediately after surgery and 24 and 48 hours after surgery . RESULTS The authors compared both sides for differences in swelling , pain and trismus in each patient . The results showed significant statistical differences in two of the five points that were used to measure the swelling ( Wilcoxon nonparametric signed rank test of linear distances between the angle of the m and ible to the pogonion and to the tragus ) . They found statistical differences between the two sides in relation to the pain ; however , they found no significant differences in relation to trismus . CONCLUSIONS Cryotherapy was effective in reducing swelling and pain in this sample . Despite playing no role in the reduction of trismus , cryotherapy was effective in reducing swelling and pain in this sample , and the authors still recommend it be used . CLINICAL IMPLICATION S Cryotherapy is helpful after third-molar extraction . Further studies need to be conducted that use larger sample s of patients and other types of therapy , such as low-level laser therapy 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 Primary and secondary closure techniques after removal of impacted third molars were compared in terms of post-operative pain and swelling . Two hundred patients with impacted third molars were r and omly divided into two groups of 100 . Panoramic radiographs were taken to assess degree of eruption and angulation of third molars . Teeth were extracted , and in Group 1 the socket was closed by hermetically suturing the flap . In Group 2 a 5 - 6 mm wedge of mucosa adjacent to the second molar was removed to obtain secondary healing . Swelling and pain were evaluated for 7 days after surgery with the VAS scale . The statistical analysis ( * analysis of variance for repeated measures , P < 0.05 ) showed that pain was greater in Group 1 , although it decreased over time similarly in the two groups ( P = 0.081 , F(6,198 ) = 3.073 * ) . Swelling was significantly worse in Group 1 ( P < 0.001 , F(6,198 ) = 44.30 * ) . In Group 1 , dehiscence of the mucosa was present in 33 % of patients at day 7 , and 2 % showed signs of re-infection with suppurative alveolitis at 30 days . Pain and swelling were less severe with secondary healing than with primary healing The insertion of a small surgical tube drain with primary wound closure ( drain group ) was compared to a simple primary wound closure ( no drain group ) after removal of impacted third molars . Surgery was performed on 23 patients in a r and omized cross-over fashion . The operation time was found to be significantly longer and mouth opening significantly wider in the immediate postoperative period in the drain group subjects as compared to the no drain group ( P > or = 0.01 ) . There was no significant difference in the severity of pain between the two groups . Facial swelling was found to be significantly less in the drain group subjects ( P > or = 0.01 ) . The number of patients with wound breakdown , edema , and bleeding was found to be less in the drain group than in the no drain group . Thus , the postoperative problems , in general , were less in the small surgical drain group as compared to the no drain group Extraction of impacted m and ibular third molars is one of the most common procedures in the oral cavity and often is followed by pain , swelling , and post extraction alveolitis and trismus . It has been suggested that postoperative discomfort is in relation to the type of surgical wound healing . The aim of this study was to compare pain , swelling , and maximum mouth opening in two groups of patients with primary and secondary wound healing after impacted m and ibular third molar surgery . Thirty-two patients were enrolled in this study and r and omly divided into two equal groups , quantitatively and by gender . After the surgical procedures , 16 patients received primary wound closure , while the other 16 participants received secondary wound closure . A visual analog scale was used to collect pain data three days after the surgeries . A checklist was used to record data regarding swelling size and maximum mouth opening before , immediately following , three days after , and one week after surgery . Frequency tests and a t-test were used for statistical analysis and a P value of < 0.05 was considered to be statistically significant . Patients in the secondary wound healing group showed statistically significant lower discomfort regarding pain , swelling size , and maximal mouth opening compared to the primary wound healing group . The authors suggest the use of secondary wound healing closure to reduce postoperative complications such as pain , maximal mouth opening , and swelling size after impacted m and ibular third molar extraction PURPOSE Pain , swelling , and trismus are the most common complications associated with third molar surgery . Several methods of alleviation of these complications have been described . The effect of single and multiple suture techniques on these complications was compared in the present study . PATIENTS AND METHODS All consecutive patients 18 years of age or older who had been referred for surgical extraction of their impacted teeth between January and December 2007 at the maxillofacial unit of the Aminu Kano Teaching Hospital were recruited and r and omized into 2 groups . All selected participants underwent surgical extraction of their impacted teeth by the same surgeon under local anesthesia . The flaps in 1 group were closed by multiple sutures and those in the second group were closed by a single suture . Pain , swelling , and trismus were evaluated at postoperative days 1 , 2 , 3 , 5 , and 7 . Descriptive and comparative statistical analyses were performed , and the results are presented . Significance was set at P < .05 . RESULTS A total of 50 subjects participated in the present study . Both groups were comparable in terms of the age distribution ( multiple suture group , 26.0 ± 4.73 years ; single suture group , 25.8 ± 4.28 years , P = .755 ) , difficulty index ( multiple suture group , 5.0 ± 1.68 ; single suture group , 4.9 ± 4.79 ; P = .935 ) , duration of surgery ( multiple suture group , 29 . 7 ± 6.11 minutes ; single suture group , 30.0 ± 6.04 minutes ; P = .835 ) , and baseline parameters such as facial width ( multiple suture group , 10.0 ± 1.32 cm ; single suture group , 9.8 ± 0.37 cm ; P = .115 ) , mouth opening ( multiple suture group , 4.5 ± 1.32 cm , single suture group , 4.8 ± 0.26 cm ; P = .165 ) , and preoperative pain , which was 0 in both groups . Other comparable variables included impaction type ( P = .210 ) and indication for surgery ( P = .278 ) . A statistically significant difference was found in the level of pain at postoperative days 1 , 2 , and 3 ( P < .05 ) . A similar significant difference was found in swelling and trismus ( P < .05 ) . At days 5 and 7 , no significant differences were found between the 2 groups for all parameters of pain , swelling , and trismus ( P > .05 ) . CONCLUSION Our study had a comparable distribution of age , gender , and operative variables , such as the pattern of impaction , preoperative difficulty index , and operative time between patients undergoing the 2 methods of closure . With that , our results have shown that the single suture closure technique was better than the multiple suture technique with regard to postoperative pain , swelling , and trismus OBJECTIVE Surgical removal of impacted m and ibular third molars with primary wound closure may result in postoperative edema , facial swelling , pain , and restriction of mouth opening . The type of closure may be a cause of these complications . The aim of this study was to compare the effects of placement of a surgical tube drain before primary closure with the effects of primary closure alone after removal of fully impacted m and ibular third molars . METHOD AND MATERIAL S The study group included 13 patients aged 15 to 39 years with bilateral fully impacted m and ibular third molars . The insertion of a small surgical tube drain before primary closure ( drain group ) was compared to a simple primary closure procedure ( no drain group ) after removal of the impacted third molars in a r and omized crossover design . The duration of the operation was recorded . Patients were evaluated 1 , 2 , 3 , and 7 days postoperatively for facial swelling and trismus . RESULTS The facial swelling experienced by the drain group was significantly less than that experienced by the no drain group . The degree of trismus was greater in the no drain group than in the drain group , but the difference was not statistically significant . CONCLUSION Use of a surgical drain , especially after removal of fully impacted third molars , will reduce postoperative facial swelling OBJECTIVE The aim of this study was to describe demographic and clinical patterns of subjects hospitalized with complications associated with third molars ( M3 ) . STUDY DESIGN The investigation was design ed as a prospect i ve cohort study composed of subjects admitted to hospital for management of M3-associated complications . The predictor variable was " clinical status of the M3 " defined as ( A ) prophylactic M3 removal , ( B ) nonelective M3 removal , or ( C ) M3 present at the time of admission . Outcome variables were infection parameters , treatment costs , length of hospital stay , and days of disability . Postoperative complications ( A and B ) were compared to complications based on pericoronitis ( C ) . Complications due to prophylactic removal ( A ) were compared to those arising from pericoronitis or from the removal of symptomatic teeth ( B and C ) . RESULTS From January 2003 to December 2004 , 45 deep space infections , 6 m and ibular fractures , 2 lingual nerve injuries , 1 parapharyngeal tooth luxation , and 1 osteomyelitis were noticed . Fifteen complications result ed from prophylactic surgery ( A ) , 25 from nonelective removal ( B ) , and 15 from pericoronitis ( C ) . Direct treatment costs were 147,000 euro ( A : 42,000 euro ; B : 74,000 euro ; C : 31,000 euro ) . In 10 of the 15 patients of group C , deep space involvement result ed immediately from the first episode of pericoronitis . Neither clinical markers of infection nor economic parameters showed significant differences between the groups . CONCLUSION Within the catchment area of our institution , the majority of third molar-related hospitalizations result ed from diseased third molars or their removal |
1,916 | 28,347,797 | We found no compelling evidence suggesting that outcomes were bimodally distributed for any of the intervention groups .
Responder analysis would not meaningfully alter our interpretation of these data compared with the mean between group difference .
Our findings suggest that bimodal distribution of outcomes should not be assumed in interventions for spinal pain and do not support the automatic prioritization of responder analysis over the between group difference in the evaluation of treatment effectiveness for pain .
PERSPECTIVE Secondary analysis of clinical trials of nonsurgical interventions for spinal pain found no evidence for bimodally distributed outcomes .
The findings do not support the automatic prioritization of responder analyses over the average between group difference in the evaluation of treatment effectiveness for spinal pain | The presence of bimodal outcome distributions has been used as a justification for conducting responder analyses , in addition to , or in place of analyses of the mean between-group difference , in clinical trials and systematic review s of interventions for pain .
The aim of this study was to investigate the distribution of participants ' pain outcomes for evidence of bimodal distribution . | Abstract Whiplash‐associated disorders are common and incur considerable expense in social and economic terms . There are no known effective treatments for those people whose pain and disability persist beyond 3 months . We conducted a r and omized , assessor‐blinded , controlled trial at two centres in Australia . All participants received 3 advice sessions . In addition the experimental group participated in 12 exercise sessions over 6 weeks . Primary outcomes were pain intensity , pain bothersomeness and function measured at 6 weeks and 12 months . Exercise and advice was more effective than advice alone at 6 weeks for all primary outcomes but not at 12 months . The effect of exercise on the 0–10 pain intensity scale was −1.1 ( 95%CI −1.8 to −0.3 , p = 0.005 ) at 6 weeks and −0.2 ( 0.6 to −1.0 , p = 0.59 ) at 12 months ; on the bothersomeness scale the effect was −1.0 ( −1.9 to −0.2 , p = 0.003 ) at 6 weeks and 0.3 ( −0.6 to 1.3 , p = 0.48 ) at 12 months . The effect on function was 0.9 ( 0.3 to 1.6 , p = 0.006 ) at 6 weeks and 0.6 ( −0.1 to 1.4 , p = 0.10 ) at 12 months . High levels of baseline pain intensity were associated with greater treatment effects at 6 weeks and high levels of baseline disability were associated with greater treatment effects at 12 months . In the short‐term exercise and advice is slightly more effective than advice alone for people with persisting pain and disability following whiplash . Exercise is more effective for subjects with higher baseline pain and disability Background The evidence that exercise intervention is effective for treatment of chronic low back pain comes from trials that are not placebo-controlled . Objective The purpose of this study was to investigate the efficacy of motor control exercise for people with chronic low back pain . Design This was a r and omized , placebo-controlled trial . Setting The study was conducted in an outpatient physical therapy department in Australia . Patients The participants were 154 patients with chronic low back pain of more than 12 weeks ’ duration . Intervention Twelve sessions of motor control exercise ( ie , exercises design ed to improve function of specific muscles of the low back region and the control of posture and movement ) or placebo ( ie , detuned ultrasound therapy and detuned short-wave therapy ) were conducted over 8 weeks . Measurements Primary outcomes were pain intensity , activity ( measured by the Patient-Specific Functional Scale ) , and patient 's global impression of recovery measured at 2 months . Secondary outcomes were pain ; activity ( measured by the Patient-Specific Functional Scale ) ; patient 's global impression of recovery measured at 6 and 12 months ; activity limitation ( measured by the Rol and -Morris Disability Question naire ) at 2 , 6 , and 12 months ; and risk of persistent or recurrent pain at 12 months . Results The exercise intervention improved activity and patient 's global impression of recovery but did not clearly reduce pain at 2 months . The mean effect of exercise on activity ( measured by the Patient-Specific Functional Scale ) was 1.1 points ( 95 % confidence interval [CI]=0.3 to 1.8 ) , the mean effect on global impression of recovery was 1.5 points ( 95 % CI=0.4 to 2.5 ) , and the mean effect on pain was 0.9 points ( 95 % CI=−0.01 to 1.8 ) , all measured on 11-point scales . Secondary outcomes also favored motor control exercise . Limitation Clinicians could not be blinded to the intervention they provided . Conclusions Motor control exercise produced short-term improvements in global impression of recovery and activity , but not pain , for people with chronic low back pain . Most of the effects observed in the short term were maintained at the 6- and 12-month follow-ups In r and omized controlled trials , no single definition of response is ideal for all purpose s. We propose a method to present in a simple fashion the likelihood of response over a full range of response levels , which will facilitate a better underst and ing of clinical trial data . We present the technique called the cumulative proportion of responders analysis ( CPRA ) and its application to four pain clinical trial data sets as examples . The CPRA can be used to present the proportion of responders over the entire range of possible cut-off points as a graph . This allows the reader to compare treatment groups at any responder level that is valid for their patient population . Whether as a primary or secondary approach to a clinical trial of pain therapy , the display of data in a CPRA format may be useful in the underst and ing of results and applicability to patient care Background Reporting numbers needed to treat ( NNT ) improves interpretability of trial results . It is unusual that continuous outcomes are converted to numbers of individual responders to treatment ( i.e. , those who reach a particular threshold of change ) ; and deteriorations prevented are only rarely considered . We consider how numbers needed to treat can be derived from continuous outcomes ; illustrated with a worked example showing the methods and challenges . Methods We used data from the UK BEAM trial ( n = 1 , 334 ) of physical treatments for back pain ; originally reported as showing , at best , small to moderate benefits . Participants were r and omised to receive ' best care ' in general practice , the comparator treatment , or one of three manual and /or exercise treatments : ' best care ' plus manipulation , exercise , or manipulation followed by exercise . We used established consensus thresholds for improvement in Rol and -Morris disability question naire scores at three and twelve months to derive NNTs for improvements and for benefits ( improvements gained+deteriorations prevented ) . Results At three months , NNT estimates ranged from 5.1 ( 95 % CI 3.4 to 10.7 ) to 9.0 ( 5.0 to 45.5 ) for exercise , 5.0 ( 3.4 to 9.8 ) to 5.4 ( 3.8 to 9.9 ) for manipulation , and 3.3 ( 2.5 to 4.9 ) to 4.8 ( 3.5 to 7.8 ) for manipulation followed by exercise . Corresponding between-group mean differences in the Rol and -Morris disability question naire were 1.6 ( 0.8 to 2.3 ) , 1.4 ( 0.6 to 2.1 ) , and 1.9 ( 1.2 to 2.6 ) points . Conclusion In contrast to small mean differences originally reported , NNTs were small and could be attractive to clinicians , patients , and purchasers . NNTs can aid the interpretation of results of trials using continuous outcomes . Where possible , these should be reported alongside mean differences . Challenges remain in calculating NNTs for some continuous outcomes .Trial Registration UK BEAM trial registration : IS RCT N32683578 BACKGROUND Evidence suggests that brief physiotherapy programmes are as effective for acute whiplash-associated disorders as more comprehensive programmes ; however , whether this also holds true for chronic whiplash-associated disorders is unknown . We aim ed to estimate the effectiveness of a comprehensive exercise programme delivered by physiotherapists compared with advice in people with a chronic whiplash-associated disorder . METHODS PROMISE is a two group , pragmatic r and omised controlled trial in patients with chronic ( > 3 months and < 5 years ) grade 1 or 2 whiplash-associated disorder . Participants were r and omly assigned by a computer-generated r and omisation schedule to receive either the comprehensive exercise programme ( 20 sessions ) or advice ( one session and telephone support ) . Sealed opaque envelopes were used to conceal allocation . The primary outcome was pain intensity measured on a 0 - 10 scale . Outcomes were measured at baseline , 14 weeks , 6 months , and 12 months by a masked assessor . Analysis was by intention to treat , and treatment effects were calculated with linear mixed models . The trial is registered with the Australian New Zeal and Clinical Trials Registry , number ACTRN12609000825257 . FINDINGS 172 participants were allocated to either the comprehensive exercise programme ( n=86 ) or advice group ( n=86 ) ; 157 ( 91 % ) were followed up at 14 weeks , 145 ( 84 % ) at 6 months , and 150 ( 87 % ) at 12 months . A comprehensive exercise programme was not more effective than advice alone for pain reduction in the participants . At 14 weeks the treatment effect on a 0 - 10 pain scale was 0·0 ( 95 % CI -0·7 to 0·7 ) , at 6 months 0·2 ( -0·5 to 1·0 ) , and at 12 months -0·1 ( -0·8 to 0·6 ) . CNS hyperexcitability and symptoms of post-traumatic stress did not modify the effect of treatment . We recorded no serious adverse events . INTERPRETATION We have shown that simple advice is equally as effective as a more intense and comprehensive physiotherapy exercise programme . The need to identify effective and affordable strategies to prevent and treat acute through to chronic whiplash associated disorders is an important health priority . Future avenues of research might include improving underst and ing of the mechanisms responsible for persistent pain and disability , investigating the effectiveness and timing of drugs , and study of content and delivery of education and advice . FUNDING The National Health and Medical Research Council of Australia , Motor Accidents Authority of New South Wales , and Motor Accident Insurance Commission of Queensl and A post-hoc individual patient matching procedure was recently proposed within the context of parallel group r and omized clinical trials ( RCTs ) as a method for estimating treatment effect . In this paper , we consider a post-hoc individual patient matching problem within a parallel group RCT as a multi- objective decision-making problem focussing on the trade-off between the quality of individual matches and the overall percentage of matching . Using acute stroke trials as a context , we utilize exact optimization and simulation techniques to investigate a complex relationship between the overall percentage of individual post-hoc matching , the size of the respective RCT , and the quality of matching on variables highly prognostic for a good functional outcome after stroke , as well as the dispersion in these variables . It is empirically confirmed that a high percentage of individual post-hoc matching can only be achieved when the differences in prognostic baseline variables between individually matched subjects within the same pair are sufficiently large and that the unmatched subjects are qualitatively different to the matched ones . It is concluded that the post-hoc individual matching as a technique for treatment effect estimation in parallel-group RCTs should be exercised with caution because of its propensity to introduce significant bias and reduce validity . If used with appropriate caution and thorough evaluation , this approach can complement other viable alternative approaches for estimating the treatment effect Abstract Practice guidelines recommend various types of exercise and manipulative therapy for chronic back pain but there have been few head‐to‐head comparisons of these interventions . We conducted a r and omized controlled trial to compare effects of general exercise , motor control exercise and manipulative therapy on function and perceived effect of intervention in patients with chronic back pain . Two hundred and forty adults with non‐specific low back pain ⩾3 months were allocated to groups that received 8 weeks of general exercise , motor control exercise or spinal manipulative therapy . General exercise included strengthening , stretching and aerobic exercises . Motor control exercise involved retraining specific trunk muscles using ultrasound feedback . Spinal manipulative therapy included joint mobilization and manipulation . Primary outcomes were patient‐specific function ( PSFS , 3–30 ) and global perceived effect ( GPE , −5 to 5 ) at 8 weeks . These outcomes were also measured at 6 and 12 months . Follow‐up was 93 % at 8 weeks and 88 % at 6 and 12 months . The motor control exercise group had slightly better outcomes than the general exercise group at 8 weeks ( between‐group difference : PSFS 2.9 , 95 % CI : 0.9–4.8 ; GPE 1.7 , 95 % CI : 0.9–2.4 ) , as did the spinal manipulative therapy group ( PSFS 2.3 , 95 % CI : 0.4–4.2 ; GPE 1.2 , 95 % CI : 0.4–2.0 ) . The groups had similar outcomes at 6 and 12 months . Motor control exercise and spinal manipulative therapy produce slightly better short‐term function and perceptions of effect than general exercise , but not better medium or long‐term effects , in patients with chronic non‐specific back pain Background Low back pain is a highly prevalent and disabling condition worldwide . Clinical guidelines for the management of patients with acute low back pain recommend first-line treatment consisting of advice , reassurance and simple analgesics . Exercise is also commonly prescribed to these patients . The primary aim of this study was to evaluate the short-term effect of adding the McKenzie method to the first-line care of patients with acute low back pain . Methods A multi-centre r and omized controlled trial with a 3-month follow-up was conducted between September 2005 and June 2008 . Patients seeking care for acute non-specific low back pain from primary care medical practice s were screened . Eligible participants were assigned to receive a treatment programme based on the McKenzie method and first-line care ( advice , reassurance and time-contingent acetaminophen ) or first-line care alone , for 3 weeks . Primary outcome measures included pain ( 0 - 10 Numeric Rating Scale ) over the first seven days , pain at 1 week , pain at 3 weeks and global perceived effect ( -5 to 5 scale ) at 3 weeks . Treatment effects were estimated using linear mixed models . Results One hundred and forty-eight participants were r and omized into study groups , of whom 138 ( 93 % ) completed the last follow-up . The addition of the McKenzie method to first-line care produced statistically significant but small reductions in pain when compared to first-line care alone : mean of -0.4 points ( 95 % confidence interval , -0.8 to -0.1 ) at 1 week , -0.7 points ( 95 % confidence interval , -1.2 to -0.1 ) at 3 weeks , and -0.3 points ( 95 % confidence interval , -0.5 to -0.0 ) over the first 7 days . Patients receiving the McKenzie method did not show additional effects on global perceived effect , disability , function or on the risk of persistent symptoms . These patients sought less additional health care than those receiving only first-line care ( P = 0.002 ) . Conclusions When added to the currently recommended first-line care of acute low back pain , a treatment programme based on the McKenzie method does not produce appreciable additional short-term improvements in pain , disability , function or global perceived effect . However , the McKenzie method seems to reduce health utilization although it does not reduce patient 's risk of developing persistent symptoms . Trial Registration Australian New Zeal and Clinical Trials Registry : & 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 Objective . Pain is a patient-important outcome , but current reporting in r and omized controlled trials and systematic review s is often suboptimal , impeding clinical interpretation and decision making . Methods . A working group at the 2014 Outcome Measures in Rheumatology ( OMERACT 12 ) was convened to provide guidance for reporting treatment effects regarding pain for individual studies and systematic review s. Results For individual trials , authors should report , in addition to mean change , the proportion of patients achieving 1 or more thresholds of improvement from baseline pain ( e.g. , ≥ 20 % , ≥ 30 % , ≥ 50 % ) , achievement of a desirable pain state ( e.g. , no worse than mild pain ) , and /or a combination of change and state . Effects on pain should be accompanied by other patient-important outcomes to facilitate interpretation . When pooling data for meta analysis , authors should consider converting all continuous measures for pain to a 100 mm visual analog scale ( VAS ) for pain and use the established , minimally important difference ( MID ) of 10 mm , and the conventionally used , appreciably important differences of 20 mm , 30 mm , and 50 mm , to facilitate interpretation . Effects ≤ 0.5 units suggest a small or very small effect . To further increase interpretability , the pooled estimate on the VAS should also be transformed to a binary outcome and expressed as a relative risk and risk difference . This transformation can be achieved by calculating the probability of experiencing a treatment effect greater than the MID and the thresholds for appreciably important differences in pain reduction in the control and intervention groups . Conclusion . Presentation of relative effects regarding pain will facilitate interpretation of treatment effects Background Motor control exercises to improve control and coordination of trunk muscles and grade d activity under the principles of cognitive-behavioral therapy are 2 commonly used exercise therapies , yet there is little evidence to support the use of one intervention over the other . Objective The objective of this study was to compare the effectiveness of motor control exercises and grade d activity for patients with chronic nonspecific low back pain . Design This study was a prospect ively registered r and omized controlled trial with outcome assessment and statistical analyses conducted blind to group . Setting The study was conducted in primary care setting s. Patients The participants were 172 patients with chronic ( > 12 weeks ) nonspecific low back pain . Interventions Patients were r and omly assigned to receive either motor control exercises or grade d activity . There was no attempt to subclassify patients to match them to a treatment . Patients in both groups received 14 sessions of individualized , supervised exercise therapy . Measurements Primary outcomes were average pain over the previous week ( numeric rating scale ) and function ( Patient-Specific Functional Scale ) ; secondary outcomes were disability ( 24-item Rol and -Morris Disability Question naire ) , global impression of change ( Global Perceived Effect Scale ) , and quality of life ( 36-Item Short-Form Health Survey question naire [ SF-36 ] ) . Outcome measures were collected at baseline and at 2 , 6 , and 12 months after intervention . Results A linear mixed models analysis showed that there were no significant differences between treatment groups at any of the time points for any of the outcomes studied . For example , the effect for pain at 2 months was 0.0 ( −0.7 to 0.8 ) . Limitations Clinicians could not be blinded to the interventions . Conclusion The results of this study suggest that motor control exercises and grade d activity have similar effects for patients with chronic nonspecific low back pain 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 There has been a recent increase in research evaluating treatment-based subgroups of non-specific low back pain . The aim of these sub-classification schemes is to identify subgroups of patients who will respond preferentially to one treatment as opposed to another . Our article provides accessible guidance on to how to interpret this research and determine its implication s for clinical practice . We propose that studies evaluating treatment-based subgroups can be interpreted in the context of a three-stage process : ( 1 ) hypothesis generation-proposal of clinical features to define subgroups ; ( 2 ) hypothesis testing-a r and omised controlled trial ( RCT ) to test that subgroup membership modifies the effect of a treatment ; and ( 3 ) replication-another RCT to confirm the results of stage 2 and ensure that findings hold beyond the specific original conditions . At this point , the bulk of research evidence in defining subgroups of patients with low back pain is in the hypothesis generation stage ; no classification system is supported by sufficient evidence to recommend implementation into clinical practice BACKGROUND We aim ed to investigate whether the addition of non-steroidal anti-inflammatory drugs or spinal manipulative therapy , or both , would result in faster recovery for patients with acute low back pain receiving recommended first-line care . METHODS 240 patients with acute low back pain who had seen their general practitioner and had been given advice and paracetamol were r and omly allocated to one of four groups in our community-based study : diclofenac 50 mg twice daily and placebo manipulative therapy ( n=60 ) ; spinal manipulative therapy and placebo drug ( n=60 ) ; diclofenac 50 mg twice daily and spinal manipulative therapy ( n=60 ) ; or double placebo ( n=60 ) . The primary outcome was days to recovery from pain assessed by survival curves ( log-rank test ) in an intention-to-treat analysis . This trial was registered with the Australian Clinical Trials Registry , ACTRN012605000036617 . FINDINGS Neither diclofenac nor spinal manipulative therapy appreciably reduced the number of days until recovery compared with placebo drug or placebo manipulative therapy ( diclofenac hazard ratio 1.09 , 95 % CI 0.84 - 1.42 , p=0.516 ; spinal manipulative therapy hazard ratio 1.01 , 95 % CI 0.77 - 1.31 , p=0.955 ) . 237 patients ( 99 % ) either recovered or were censored 12 weeks after r and omisation . 22 patients had possible adverse reactions including gastrointestinal disturbances , dizziness , and heart palpitations . Half of these patients were in the active diclofenac group , the other half were taking placebo . One patient taking active diclofenac had a suspected hypersensitivity reaction and ceased treatment . INTERPRETATION Patients with acute low back pain receiving recommended first-line care do not recover more quickly with the addition of diclofenac or spinal manipulative therapy |
1,917 | 28,503,070 | Although data for erlotinib plus bevacizumab came from a single Phase 2 study , the results of the NMA suggest that adding bevacizumab to erlotinib may be a promising approach to improving the outcomes achieved with EGFR-TKI monotherapy in patients with advanced EGFR+ NSCLC | INTRODUCTION The introduction of epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR-TKIs ) has improved the outlook for patients with advanced non-small-cell lung cancer ( NSCLC ) with EGFR+ mutations .
However , most patients develop resistance , with the result that median progression-free survival ( PFS ) iŝ12 months .
Combining EGFR-TKIs with other agents , such as bevacizumab , is a promising approach to prolonging remission .
This systematic review and network meta- analysis ( NMA ) were undertaken to assess available evidence regarding the benefits of first-line combination therapy involving EGFR-TKIs in patients with advanced NSCLC . | The aim of this study was to evaluate the safety and effectiveness of erlotinib plus DC/CIK in maintenance therapy of advanced non – small cell lung cancer . After 4 cycles of the 2-drug regimen treatment with platinum , the 54 patients with non – small cell lung cancer in phase IIIb or IV reached stable or beyond stable stages . The patients were then r and omly divided into 2 groups . One group was treated with erlotinib therapy ( erlotinib group ) , and the other was treated with DC/CIK plus erlotinib ( DC/CIK plus erlotinib group ) . The progression-free survival of the erlotinib group and the DC/CIK plus erlotinib group was 3.98 months ( 95 % CI , 3.56–4.40 ) and 5.02 months ( 95 % CI , 4.32–5.72 ) ( P=0.002 ) , respectively . The median overall survival of the erlotinib group and the DC/CIK plus erlotinib group was 9.9 months ( 95 % CI , 9.1–10.6 ) and 10.5 months ( 95 % CI , 9.6–11.4 ) ( P=0.29 ) , respectively . The levels of CD3 + , CD4 + , and CD8 + were significantly different before and after the treatment in the DC/CIK plus erlotinib group , but not in the erlotinib group . There was no significant difference in toxicity between the 2 groups . In conclusion , there was no statistically significant difference in overall survival between DC/CIK plus erlotinib and erlotinib as maintenance therapy . DC/CIK plus erlotinib was well tolerated with a manageable safety profile BACKGROUND The phase III , r and omized , open-label ENSURE study ( NCT01342965 ) evaluated first-line erlotinib versus gemcitabine/cisplatin ( GP ) in patients from China , Malaysia and the Philippines with epidermal growth factor receptor ( EGFR ) mutation-positive non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients ≥18 years old with histologically/cytologically confirmed stage IIIB/IV EGFR mutation-positive NSCLC and Eastern Cooperative Oncology Group performance status 0 - 2 were r and omized 1:1 to receive erlotinib ( oral ; 150 mg once daily until progression/unacceptable toxicity ) or GP [ G 1250 mg/m(2 ) i.v . days 1 and 8 ( 3-weekly cycle ) ; P 75 mg/m(2 ) i.v . day 1 , ( 3-weekly cycle ) for up to four cycles ] . Primary end point : investigator-assessed progression-free survival ( PFS ) . Other end points include objective response rate ( ORR ) , overall survival ( OS ) , and safety . RESULTS A total of 217 patients were r and omized : 110 to erlotinib and 107 to GP . Investigator-assessed median PFS was 11.0 months versus 5.5 months , erlotinib versus GP , respectively [ hazard ratio ( HR ) , 0.34 , 95 % confidence interval ( CI ) 0.22 - 0.51 ; log-rank P < 0.0001 ] . Independent Review Committee-assessed median PFS was consistent ( HR , 0.42 ) . Median OS was 26.3 versus 25.5 months , erlotinib versus GP , respectively ( HR , 0.91 , 95 % CI 0.63 - 1.31 ; log-rank P = .607 ) . ORR was 62.7 % for erlotinib and 33.6 % for GP . Treatment-related serious adverse events ( AEs ) occurred in 2.7 % versus 10.6 % of erlotinib and GP patients , respectively . The most common grade ≥3 AEs were rash ( 6.4 % ) with erlotinib , and neutropenia ( 25.0 % ) , leukopenia ( 14.4 % ) , and anemia ( 12.5 % ) with GP . CONCLUSION These analyses demonstrate that first-line erlotinib provides a statistically significant improvement in PFS versus GP in Asian patients with EGFR mutation-positive NSCLC ( NCT01342965 ) BACKGROUND The OPTIMAL study found that erlotinib improved progression-free survival ( PFS ) versus st and ard chemotherapy in Chinese patients with advanced EGFR mutation-positive non-small-cell lung cancer ( NSCLC ) . This report describes the quality of life ( QoL ) and up date d PFS analyses from this study . PATIENTS AND METHODS Chinese patients ≥ 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR ( exon 19 deletion or exon 21 L858R point mutation ) received erlotinib ( 150 mg/day ; n = 82 ) or gemcitabine-carboplatin ( n = 72 ) . The primary efficacy end point was PFS ; QoL was assessed using the Functional Assessment of Cancer Therapy-Lung ( FACT-L ) question naire , Trial Outcome Index ( TOI ) and Lung Cancer Subscale ( LCS ) . RESULTS Patients receiving erlotinib experienced clinical ly relevant improvements in QoL compared with the chemotherapy group in total FACT-L , TOI and LCS ( P < 0.0001 for all scales ) . Erlotinib scored better than chemotherapy for all FACT-L subscales from baseline to cycles 2 and 4 ( non-significant ) . In the up date d analysis , PFS was significantly longer for erlotinib than chemotherapy ( median PFS 13.7 versus 4.6 months ; HR = 0.164 , 95 % CI = 0.105 - 0.256 ; P < 0.0001 ) , which was similar to the previously reported primary analysis . CONCLUSION Erlotinib improves QoL compared with st and ard chemotherapy in the first-line treatment of patients with EGFR mutation-positive advanced NSCLC AIM This analysis investigates incidence and time course of rash in the EURTAC study . MATERIAL S & METHODS Patients with EGFR mutation-positive non-small-cell lung cancer were r and omized 1:1 to receive once daily erlotinib or 3-weekly cycles of chemotherapy . RESULTS Of the 86 erlotinib-treated patients , 71 reported rash . Median time to first rash appearance was 0.7 months . Most patients ( n = 65 ) had the same or lower grade rash at final assessment compared with initial assessment . Of the 21 patients with decreased rash grade between initial and final assessment s , 61.9 % received no erlotinib dose modification , 42.8 % had no concomitant rash treatment . CONCLUSION Most rash cases were mild , occurred within 1 month of erlotinib treatment , and rapidly improved without the need for erlotinib dose alterations BACKGROUND The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer ( NSCLC ) . We aim ed to compare the efficacy and safety of afatinib and gefitinib in this setting . METHODS This multicentre , international , open-label , exploratory , r and omised controlled phase 2B trial ( LUX-Lung 7 ) was done at 64 centres in 13 countries . Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation ( exon 19 deletion or Leu858Arg ) were r and omly assigned ( 1:1 ) to receive afatinib ( 40 mg per day ) or gefitinib ( 250 mg per day ) until disease progression , or beyond if deemed beneficial by the investigator . R and omisation , stratified by EGFR mutation type and status of brain metastases , was done central ly using a vali date d number generating system implemented via an interactive voice or web-based response system with a block size of four . Clinicians and patients were not masked to treatment allocation ; independent review of tumour response was done in a blinded manner . Co primary endpoints were progression-free survival by independent central review , time-to-treatment failure , and overall survival . Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug . This ongoing study is registered with Clinical Trials.gov , number NCT01466660 . FINDINGS Between Dec 13 , 2011 , and Aug 8 , 2013 , 319 patients were r and omly assigned ( 160 to afatinib and 159 to gefitinib ) . Median follow-up was 27·3 months ( IQR 15·3 - 33·9 ) . Progression-free survival ( median 11·0 months [ 95 % CI 10·6 - 12·9 ] with afatinib vs 10·9 months [ 9·1 - 11·5 ] with gefitinib ; hazard ratio [ HR ] 0·73 [ 95 % CI 0·57 - 0·95 ] , p=0·017 ) and time-to-treatment failure ( median 13·7 months [ 95 % CI 11·9 - 15·0 ] with afatinib vs 11·5 months [ 10·1 - 13·1 ] with gefitinib ; HR 0·73 [ 95 % CI 0·58 - 0·92 ] , p=0·0073 ) were significantly longer with afatinib than with gefitinib . Overall survival data are not mature . The most common treatment-related grade 3 or 4 adverse events were diarrhoea ( 20 [ 13 % ] of 160 patients given afatinib vs two [ 1 % ] of 159 given gefitinib ) and rash or acne ( 15 [ 9 % ] patients given afatinib vs five [ 3 % ] of those given gefitinib ) and liver enzyme elevations ( no patients given afatinib vs 14 [ 9 % ] of those given gefitinib ) . Serious treatment-related adverse events occurred in 17 ( 11 % ) patients in the afatinib group and seven ( 4 % ) in the gefitinib group . Ten ( 6 % ) patients in each group discontinued treatment due to drug-related adverse events . 15 ( 9 % ) fatal adverse events occurred in the afatinib group and ten ( 6 % ) in the gefitinib group . All but one of these deaths were considered unrelated to treatment ; one patient in the gefitinib group died from drug-related hepatic and renal failure . INTERPRETATION Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib , with a manageable tolerability profile . These data are potentially important for clinical decision making in this patient population . FUNDING Boehringer Ingelheim BACKGROUND Bevacizumab and erlotinib target different tumour growth pathways with little overlap in their toxic-effect profiles . On the basis of promising results from a phase 1/2 trial assessing safety and activity of erlotinib plus bevacizumab for recurrent or refractory non-small-cell lung cancer ( NSCLC ) , we aim ed to assess efficacy and safety of this combination in a phase 3 trial . METHODS In our double-blind , placebo-controlled , r and omised phase 3 trial ( BeTa ) , we enrolled patients with recurrent or refractory NSCLC who presented to 177 study sites in 12 countries after failure of first-line treatment . Patients were r and omly allocated in a one-to-one ratio to receive erlotinib plus bevacizumab ( bevacizumab group ) or erlotinib plus placebo ( control group ) according to a computer-generated r and omisation sequence by use of an interactive voice response system . The primary endpoint was overall survival in all enrolled patients . Patients , study staff , and investigators were masked to treatment assignment . We assessed safety by calculation of incidence of adverse events and tissue was collected for biomarker analyses . This trial is registered with Clinical Trials.gov , number NCT00130728 . FINDINGS Overall survival did not differ between 317 controls and 319 patients in the bevacizumab group ( hazard ratio [ HR ] 0·97 , 95 % CI 0·80 - 1·18 , p=0·7583 ) . Median overall survival was 9·3 months ( IQR 4·1 - 21·6 ) for patients in the bevacizumab group compared with 9·2 months ( 3·8 - 20·2 ) for controls . Progression-free survival seemed to be longer in the bevacizumab group ( 3·4 months [ 1·4 - 8·4 ] ) than in the control group ( 1·7 months [ 1·3 - 4·1 ] ; HR 0·62 , 95 % CI 0·52 - 0·75 ) and objective response rate suggested some clinical activity of bevacizumab and erlotinib . However , these secondary endpoint differences could not be defined as significant because the study prespecified that the primary endpoint had to be significant before testing of secondary endpoints could be done , to control type I error rate . In the bevacizumab group , 130 ( 42 % ) of 313 patients with safety data had a serious adverse event , compared with 114 ( 36 % ) controls . There were 20 ( 6 % ) grade 5 adverse events , including two arterial thromboembolic events , in the bevacizumab group , and 14 ( 4 % ) in the control group . INTERPRETATION Addition of bevacizumab to erlotinib does not improve survival in patients with recurrent or refractory NSCLC . FUNDING Genentech BACKGROUND The OPTIMAL study was the first study to compare efficacy and tolerability of the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor ( TKI ) erlotinib , versus st and ard chemotherapy in first-line treatment of patients with EGFR mutation-positive advanced non-small-cell lung cancer ( NSCLC ) . Findings from final overall survival ( OS ) analysis and assessment of post- study treatment impact are presented . PATIENTS AND METHODS Of 165 r and omised patients , 82 received erlotinib and 72 gemcitabine plus carboplatin . Final OS analyses were conducted when 70 % of deaths had occurred in the intent-to-treat population . Subgroup OS was analysed by Cox proportional hazards model and included r and omisation stratification factors and post- study treatments . RESULTS Median OS was similar between the erlotinib ( 22.8 months ) and chemotherapy ( 27.2 months ) arms with no significant between-group differences in the overall population [ hazard ratio ( HR ) , 1.19 ; 95 % confidence interval ( CI ) 0.83 - 1.71 ; P = 0.2663 ] , the exon 19 deletion sub population ( HR , 1.52 ; 95 % CI 0.91 - 2.52 ; P = 0.1037 ) or the exon 21 L858 mutation sub population ( HR , 0.92 ; 95 % CI 0.55 - 1.54 ; P = 0.7392 ) . More patients in the erlotinib arm versus the chemotherapy arm did not receive any post- study treatment ( 36.6 % versus 22.2 % ) . Patients who received sequential combination of EGFR-TKI and chemotherapy had significantly improved OS compared with those who received EGFR-TKI or chemotherapy only ( 29.7 versus 20.7 or 11.2 months , respectively ; P < 0.0001 ) . OS was significantly shorter in patients who did not receive post- study treatments compared with those who received subsequent treatments in both arms . CONCLUSION The significant OS benefit observed in patients treated with EGFR-TKI emphasises its contribution to improving survival of EGFR mutant NSCLC patients , suggesting that erlotinib should be considered st and ard first-line treatment of EGFR mutant patients and EGFR-TKI treatment following first-line therapy also brings significant benefits to those patients . CLINICAL TRIALSGOV IDENTIFIER NCT00874419 BACKGROUND With use of EGFR tyrosine-kinase inhibitor monotherapy for patients with activating EGFR mutation-positive non-small-cell lung cancer ( NSCLC ) , median progression-free survival has been extended to about 12 months . Nevertheless , new strategies are needed to further extend progression-free survival and overall survival with acceptable toxicity and tolerability for this population . We aim ed to compare the efficacy and safety of the combination of erlotinib and bevacizumab compared with erlotinib alone in patients with non-squamous NSCLC with activating EGFR mutation-positive disease . METHODS In this open-label , r and omised , multicentre , phase 2 study , patients from 30 centres across Japan with stage IIIB/IV or recurrent non-squamous NSCLC with activating EGFR mutations , Eastern Cooperative Oncology Group performance status 0 or 1 , and no previous chemotherapy for advanced disease received erlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day monotherapy as a first-line therapy until disease progression or unacceptable toxicity . The primary endpoint was progression-free survival , as determined by an independent review committee . R and omisation was done with a dynamic allocation method , and the analysis used a modified intention-to-treat approach , including all patients who received at least one dose of study treatment and had tumour assessment at least once after r and omisation . This study is registered with the Japan Pharmaceutical Information Center , number JapicCTI-111390 . FINDINGS Between Feb 21 , 2011 , and March 5 , 2012 , 154 patients were enrolled . 77 were r and omly assigned to receive erlotinib and bevacizumab and 77 to erlotinib alone , of whom 75 patients in the erlotinib plus bevacizumab group and 77 in the erlotinib alone group were included in the efficacy analyses . Median progression-free survival was 16·0 months ( 95 % CI 13·9 - 18·1 ) with erlotinib plus bevacizumab and 9·7 months ( 5·7 - 11·1 ) with erlotinib alone ( hazard ratio 0·54 , 95 % CI 0·36 - 0·79 ; log-rank test p=0·0015 ) . The most common grade 3 or worse adverse events were rash ( 19 [ 25 % ] patients in the erlotinib plus bevacizumab group vs 15 [ 19 % ] patients in the erlotinib alone group ) , hypertension ( 45 [ 60 % ] vs eight [ 10 % ] ) , and proteinuria ( six [ 8 % ] vs none ) . Serious adverse events occurred at a similar frequency in both groups ( 18 [ 24 % ] patients in the erlotinib plus bevacizumab group and 19 [ 25 % ] patients in the erlotinib alone group ) . INTERPRETATION Erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC . Further investigation of the regimen is warranted . FUNDING Chugai Pharmaceutical Co BACKGROUND NEJ002 study , comparing gefitinib with carboplatin ( CBDCA ) and paclitaxel ( PTX ; Taxol ) as the first-line treatment for advanced non-small cell lung cancer ( NSCLC ) harboring an epidermal growth factor receptor ( EGFR ) mutation , previously reported superiority of gefitinib over CBDCA/PTX on progression-free survival ( PFS ) . Subsequent analysis was carried out mainly regarding overall survival ( OS ) . MATERIAL S AND METHODS For all 228 patients in NEJ002 , survival data were up date d in December , 2010 . Detailed information regarding subsequent chemotherapy after the protocol treatment was also assessed retrospectively and the impact of some key drugs on OS was evaluated . RESULTS The median survival time ( MST ) was 27.7 months for the gefitinib group , and was 26.6 months for the CBDCA/PTX group ( HR , 0.887 ; P=0.483 ) . The OS of patients who received platinum throughout their treatment ( n=186 ) was not statistically different from that of patients who never received platinum ( n=40 ) . The MST of patients treated with gefitinib , platinum , and pemetrexed ( PEM ) or docetaxel ( DOC , Taxotere ; n=76 ) was around 3 years . CONCLUSIONS No significant difference in OS was observed between gefitinib and CBDCA/PTX in the NEJ002 study , probably due to a high crossover use of gefitinib in the CBDCA/PTX group . Considering the many benefits and the risk of missing an opportunity to use the most effective agent for EGFR-mutated NSCLC , the first-line gefitinib is strongly recommended BACKGROUND Activating mutations in EGFR are important markers of response to tyrosine kinase inhibitor ( TKI ) therapy in non-small-cell lung cancer ( NSCLC ) . The OPTIMAL study compared efficacy and tolerability of the TKI erlotinib versus st and ard chemotherapy in the first-line treatment of patients with advanced EGFR mutation-positive NSCLC . METHODS We undertook an open-label , r and omised , phase 3 trial at 22 centres in China . Patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR ( exon 19 deletion or exon 21 L858R point mutation ) received either oral erlotinib ( 150 mg/day ) until disease progression or unacceptable toxic effects , or up to four cycles of gemcitabine plus carboplatin . Patients were r and omly assigned ( 1:1 ) with a minimisation procedure and were stratified according to EGFR mutation type , histological subtype ( adenocarcinoma vs non-adenocarcinoma ) , and smoking status . The primary outcome was progression-free survival , analysed in patients with confirmed disease who received at least one dose of study treatment . The trial is registered at Clinical Trials.gov , number NCT00874419 , and has completed enrolment ; patients are still in follow-up . FINDINGS 83 patients were r and omly assigned to receive erlotinib and 82 to receive gemcitabine plus carboplatin ; 82 in the erlotinib group and 72 in the chemotherapy group were included in analysis of the primary endpoint . Median progression-free survival was significantly longer in erlotinib-treated patients than in those on chemotherapy ( 13.1 [ 95 % CI 10.58 - 16.53 ] vs 4.6 [ 4.21 - 5.42 ] months ; hazard ratio 0.16 , 95 % CI 0.10 - 0.26 ; p<0.0001 ) . Chemotherapy was associated with more grade 3 or 4 toxic effects than was erlotinib ( including neutropenia in 30 [ 42 % ] of 72 patients and thrombocytopenia in 29 [ 40 % ] patients on chemotherapy vs no patients with either event on erlotinib ) ; the most common grade 3 or 4 toxic effects with erlotinib were increased alanine aminotransferase concentrations ( three [ 4 % ] of 83 patients ) and skin rash ( two [ 2 % ] patients ) . Chemotherapy was also associated with increased treatment-related serious adverse events ( ten [ 14 % ] of 72 patients [ decreased platelet count , n=8 ; decreased neutrophil count , n=1 ; hepatic dysfunction , n=1 ] vs two [ 2 % ] of 83 patients [ both hepatic dysfunction ] ) . INTERPRETATION Compared with st and ard chemotherapy , erlotinib conferred a significant progression-free survival benefit in patients with advanced EGFR mutation-positive NSCLC and was associated with more favourable tolerability . These findings suggest that erlotinib is important for first-line treatment of patients with advanced EGFR mutation-positive NSCLC . FUNDING F Hoffmann-La Roche Ltd ( China ) ; Science and Technology Commission of Shanghai Municipality Background The results of R and omized Controlled Trials ( RCTs ) on time-to-event outcomes that are usually reported are median time to events and Cox Hazard Ratio . These do not constitute the sufficient statistics required for meta- analysis or cost-effectiveness analysis , and their use in secondary analyses requires strong assumptions that may not have been adequately tested . In order to enhance the quality of secondary data analyses , we propose a method which derives from the published Kaplan Meier survival curves a close approximation to the original individual patient time-to-event data from which they were generated . Methods We develop an algorithm that maps from digitised curves back to KM data by finding numerical solutions to the inverted KM equations , using where available information on number of events and numbers at risk . The reproducibility and accuracy of survival probabilities , median survival times and hazard ratios based on reconstructed KM data was assessed by comparing published statistics ( survival probabilities , medians and hazard ratios ) with statistics based on repeated reconstructions by multiple observers . Results The validation exercise established there was no material systematic error and that there was a high degree of reproducibility for all statistics . Accuracy was excellent for survival probabilities and medians , for hazard ratios reasonable accuracy can only be obtained if at least numbers at risk or total number of events are reported . Conclusion The algorithm is a reliable tool for meta- analysis and cost-effectiveness analyses of RCTs reporting time-to-event data . It is recommended that all RCTs should report information on numbers at risk and total number of events alongside KM curves BACKGROUND Non-small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor ( EGFR ) is highly responsive to EGFR tyrosine kinase inhibitors such as gefitinib , but little is known about how its efficacy and safety profile compares with that of st and ard chemotherapy . METHODS We r and omly assigned 230 patients with metastatic , non-small-cell lung cancer and EGFR mutations who had not previously received chemotherapy to receive gefitinib or carboplatin-paclitaxel . The primary end point was progression-free survival ; secondary end points included overall survival , response rate , and toxic effects . RESULTS In the planned interim analysis of data for the first 200 patients , progression-free survival was significantly longer in the gefitinib group than in the st and ard-chemotherapy group ( hazard ratio for death or disease progression with gefitinib , 0.36 ; P<0.001 ) , result ing in early termination of the study . The gefitinib group had a significantly longer median progression-free survival ( 10.8 months , vs. 5.4 months in the chemotherapy group ; hazard ratio , 0.30 ; 95 % confidence interval , 0.22 to 0.41 ; P<0.001 ) , as well as a higher response rate ( 73.7 % vs. 30.7 % , P<0.001 ) . The median overall survival was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group ( P=0.31 ) . The most common adverse events in the gefitinib group were rash ( 71.1 % ) and elevated aminotransferase levels ( 55.3 % ) , and in the chemotherapy group , neutropenia ( 77.0 % ) , anemia ( 64.6 % ) , appetite loss ( 56.6 % ) , and sensory neuropathy ( 54.9 % ) . One patient receiving gefitinib died from interstitial lung disease . CONCLUSIONS First-line gefitinib for patients with advanced non-small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival , with acceptable toxicity , as compared with st and ard chemotherapy . ( UMIN-CTR number , C000000376 . Introduction : In the phase III , LUX-Lung 6 trial , afatinib prolonged progression-free survival ( PFS ) versus cisplatin/gemcitabine in Asian patients with epidermal growth factor receptor ( EGFR ) mutation-positive non – small-cell lung cancer ( NSCLC ) . This article provides detailed assessment s of patient-reported outcomes ( PROs ) , a LUX-Lung 6 secondary end point , and explores the relationship between PFS and health-related quality of life ( QoL ) in these patients . Methods : Patients ( n = 364 ) were r and omized ( 2:1 ) to oral afatinib ( 40 mg/day ) or up to six cycles of cisplatin/gemcitabine ( 21-day cycle ; cisplatin 75 mg/m2 [ d1 ] ; gemcitabine 1000 mg/m2 [ d1,8 ] ) . QoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Question naire and its lung cancer-specific module . The relationship between PFS ( investigator assessment and independent review ) and QoL was evaluated using analysis of covariance and a longitudinal model . Results : More patients treated with afatinib versus cisplatin/gemcitabine showed improvements in global health status/QoL ( p < 0.0001 ) and physical ( p < 0.0001 ) , role ( p = 0.013 ) , and social ( p < 0.001 ) functioning scales . Delayed symptom deterioration and better QoL over time was also observed with afatinib . QoL measured before tumor assessment was considerably poorer for patients with progression than those without progression , with significant differences in mean scores at multiple assessment time points . Results from the longitudinal analysis consistently demonstrated a significant negative impact of progression on QoL ( p < 0.0001 ) . Conclusion : Afatinib improved PFS and PROs versus chemotherapy in EGFR mutation-positive NSCLC patients . Progression was associated with statistically significant worsening in QoL measured before tumor assessment , underscoring the value of PFS as a clinical ly relevant end point BACKGROUND Erlotinib has been shown to improve progression-free survival compared with chemotherapy when given as first-line treatment for Asian patients with non-small-cell lung cancer ( NSCLC ) with activating EGFR mutations . We aim ed to assess the safety and efficacy of erlotinib compared with st and ard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC . METHODS We undertook the open-label , r and omised phase 3 EURTAC trial at 42 hospitals in France , Italy , and Spain . Eligible participants were adults ( > 18 years ) with NSCLC and EGFR mutations ( exon 19 deletion or L858R mutation in exon 21 ) with no history of chemotherapy for metastatic disease ( neoadjuvant or adjuvant chemotherapy ending ≥ 6 months before study entry was allowed ) . We r and omly allocated participants ( 1:1 ) according to a computer-generated allocation schedule to receive oral erlotinib 150 mg per day or 3 week cycles of st and ard intravenous chemotherapy of cisplatin 75 mg/m(2 ) on day 1 plus docetaxel ( 75 mg/m(2 ) on day 1 ) or gemcitabine ( 1250 mg/m(2 ) on days 1 and 8) . Carboplatin ( AUC 6 with docetaxel 75 mg/m(2 ) or AUC 5 with gemcitabine 1000 mg/m(2 ) ) was allowed in patients unable to have cisplatin . Patients were stratified by EGFR mutation type and Eastern Cooperative Oncology Group performance status ( 0 vs 1 vs 2 ) . The primary endpoint was progression-free survival ( PFS ) in the intention-to-treat population . We assessed safety in all patients who received study drug ( ≥ 1 dose ) . This study is registered with Clinical Trials.gov , number NCT00446225 . FINDINGS Between Feb 15 , 2007 , and Jan 4 , 2011 , 174 patients with EGFR mutations were enrolled . One patient received treatment before r and omisation and was thus withdrawn from the study ; of the remaining patients , 86 were r and omly assigned to receive erlotinib and 87 to receive st and ard chemotherapy . The preplanned interim analysis showed that the study met its primary endpoint ; enrolment was halted , and full evaluation of the results was recommended . At data cutoff ( Jan 26 , 2011 ) , median PFS was 9·7 months ( 95 % CI 8·4 - 12·3 ) in the erlotinib group , compared with 5·2 months ( 4·5 - 5·8 ) in the st and ard chemotherapy group ( hazard ratio 0·37 , 95 % CI 0·25 - 0·54 ; p < 0·0001 ) . Main grade 3 or 4 toxicities were rash ( 11 [ 13 % ] of 84 patients given erlotinib vs none of 82 patients in the chemotherapy group ) , neutropenia ( none vs 18 [ 22 % ] ) , anaemia ( one [ 1 % ] vs three [ 4 % ] ) , and increased amino-transferase concentrations ( two [ 2 % ] vs 0 ) . Five ( 6 % ) patients on erlotinib had treatment-related severe adverse events compared with 16 patients ( 20 % ) on chemotherapy . One patient in the erlotinib group and two in the st and ard chemotherapy group died from treatment-related causes . INTERPRETATION Our findings strengthen the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors . FUNDING Spanish Lung Cancer Group , Roche Farma , Hoffmann-La Roche , and Red Temática de Investigacion Cooperativa en Cancer BACKGROUND The first-line combination of an epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitor ( TKI ) and platinum-based doublet chemotherapy has not been sufficiently evaluated for patients with EGFR-mutant non-small cell lung cancer ( NSCLC ) . This r and omized phase II study was design ed to select a combination regimen for phase III evaluation . PATIENTS AND METHODS Chemotherapy-naïve patients with advanced non-squamous , EGFR-mutant NSCLC were r and omly assigned to receive either a concurrent or a sequential alternating regimen with gefitinib ( 250 mg ) and carboplatin/pemetrexed [ area under the curve ( AUC ) = 6 and 500 mg/m(2 ) ; 3-weekly ] . The primary end point was progression-free survival ( PFS ) . Secondary end points were overall survival ( OS ) , response , and safety . RESULTS All 80 patients enrolled were eligible and assessable for efficacy ( 41 and 39 patients in the concurrent and sequential alternating regimen groups , respectively ) . Median PFS was 18.3 months for the concurrent regimen and 15.3 months for the sequential alternating regimen [ hazard ratio ( HR ) 0.71 ( 0.42 - 1.20 ) , P = 0.20 ] . Although OS data are immature ( 16 and 24 death events ) , median survival times were 41.9 and 30.7 months in the concurrent and sequential alternating regimen groups , respectively [ HR 0.51 ( 0.26 - 0.99 ) ; P = 0.042 ] . Response rates were similar in both groups ( 87.8 % and 84.6 % ) . Hematological and non-hematological adverse events were common and reversible ; interstitial lung disease was neither frequent nor fatal ( two cases in each group ; 5 % of all patients ) . CONCLUSION This is the first r and omized study to investigate the efficacy of combinational EGFR-TKI and chemotherapy in the EGFR-mutated setting . Both regimens had promising efficacy with predictable toxicities , although concurrent regimens might provide better OS . The concurrent regimen was chosen to compare with gefitinib monotherapy in our ongoing phase III study . CLINICAL TRIALS REGISTRATION University Hospital Medical Information Network ( UMIN ) Clinical Trial Registry ( UMIN C000002789 ) BACKGROUND Patients with non-small-cell lung cancer harbouring mutations in the epidermal growth factor receptor ( EGFR ) gene respond well to the EGFR-specific tyrosine kinase inhibitor gefitinib . However , whether gefitinib is better than st and ard platinum doublet chemotherapy in patients selected by EGFR mutation is uncertain . METHODS We did an open label , phase 3 study ( WJTOG3405 ) with recruitment between March 31 , 2006 , and June 22 , 2009 , at 36 centres in Japan . 177 chemotherapy-naive patients aged 75 years or younger and diagnosed with stage IIIB/IV non-small-cell lung cancer or postoperative recurrence harbouring EGFR mutations ( either the exon 19 deletion or L858R point mutation ) were r and omly assigned , using a minimisation technique , to receive either gefitinib ( 250 mg/day orally ; n=88 ) or cisplatin ( 80 mg/m(2 ) , intravenously ) plus docetaxel ( 60 mg/m(2 ) , intravenously ; n=89 ) , administered every 21 days for three to six cycles . The primary endpoint was progression-free survival . Survival analysis was done with the modified intention-to-treat population . This study is registered with UMIN ( University Hospital Medical Information Network in Japan ) , number 000000539 . FINDINGS Five patients were excluded ( two patients were found to have thyroid and colon cancer after r and omisation , one patient had an exon 18 mutation , one patient had insufficient consent , and one patient showed acute allergic reaction to docetaxel ) . Thus , 172 patients ( 86 in each group ) were included in the survival analyses . The gefitinib group had significantly longer progression-free survival compared with the cisplatin plus docetaxel goup , with a median progression-free survival time of 9.2 months ( 95 % CI 8.0 - 13.9 ) versus 6.3 months ( 5.8 - 7.8 ; HR 0.489 , 95 % CI 0.336 - 0.710 , log-rank p<0.0001 ) . Myelosuppression , alopecia , and fatigue were more frequent in the cisplatin plus docetaxel group , but skin toxicity , liver dysfunction , and diarrhoea were more frequent in the gefitinib group . Two patients in the gefitinib group developed interstitial lung disease ( incidence 2.3 % ) , one of whom died . INTERPRETATION Patients with lung cancer who are selected by EGFR mutations have longer progression-free survival if they are treated with gefitinib than if they are treated with cisplatin plus docetaxel . FUNDING West Japan Oncology Group ( WJOG ) : a non-profit organisation supported by unrestricted donations from several pharmaceutical companies PURPOSE This multicenter , r and omized , open-label , phase II study ( JO19907 ) compared the efficacy and safety of first-line carboplatin-paclitaxel ( CP ) alone with bevacizumab-CP in Japanese patients with advanced non-squamous non-small-cell lung cancer ( NSCLC ) . METHODS Chemonaïve patients with stage IIIB , IV or recurrent non-squamous NSCLC were eligible for participation . Patients were r and omly assigned in a 2:1 ratio to receive bevacizumab-CP or CP alone . Chemotherapy was repeated for up to 6 cycles or until disease progression or unacceptable toxicity . Bevacizumab recipients who completed ≥3 cycles of chemotherapy could continue bevacizumab as monotherapy until disease progression or unacceptable toxicity . The primary endpoint was progression-free survival ( PFS ) . RESULTS After confirming the tolerability of bevacizumab-CP in a small number of patients , 180 patients were recruited , of whom 121 were assigned to bevacizumab-CP and 59 to CP alone . Hazard ratio ( HR ) for PFS was 0.61 with bevacizumab-CP versus CP alone ( p=0.0090 ; median 6.9 versus 5.9 months ) . Objective response rate was significantly higher with bevacizumab-CP than with CP alone ( 60.7 % versus 31.0 % ; p=0.0013 ) . Median overall survival was > 22 months in both treatment groups ( HR 0.99 ; p=0.9526 ) . No new safety signals were detected . CONCLUSION Study JO19907 met its primary endpoint , demonstrating that the addition of bevacizumab to first-line CP significantly improves PFS in Japanese patients with advanced non-squamous NSCLC . This prolonged PFS by bevacizumab did not translate into OS benefit with the extremely longer underlying survival compared to historical data . No new safety signals were identified in this population . ( Japan Pharmaceutical Information Center [ JAPIC ] registration number : CTI-060338 ) BACKGROUND The EGFR T790 M mutation is the most common mechanism of drug resistance to epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors in patients who have lung cancer with an EGFR mutation ( EGFR-mutated lung cancer ) . In pre clinical models , the EGFR inhibitor AZD9291 has been shown to be effective against both EGFR tyrosine kinase inhibitor-sensitizing and T790 M resistance mutations . METHODS We administered AZD9291 at doses of 20 to 240 mg once daily in patients with advanced lung cancer who had radiologically documented disease progression after previous treatment with EGFR tyrosine kinase inhibitors . The study included dose-escalation cohorts and dose-expansion cohorts . In the expansion cohorts , pre study tumor biopsies were required for central determination of EGFR T790 M status . Patients were assessed for safety , pharmacokinetics , and efficacy . RESULTS A total of 253 patients were treated . Among 31 patients enrolled in the dose-escalation cohorts , no dose-limiting toxic effects occurred at the doses evaluated . An additional 222 patients were treated in five expansion cohorts . The most common all-cause adverse events were diarrhea , rash , nausea , and decreased appetite . The overall objective tumor response rate was 51 % ( 95 % confidence interval [ CI ] , 45 to 58 ) . Among 127 patients with central ly confirmed EGFR T790 M who could be evaluated for response , the response rate was 61 % ( 95 % CI , 52 to 70 ) . In contrast , among 61 patients without central ly detectable EGFR T790 M who could be evaluated for response , the response rate was 21 % ( 95 % CI , 12 to 34 ) . The median progression-free survival was 9.6 months ( 95 % CI , 8.3 to not reached ) in EGFR T790M-positive patients and 2.8 months ( 95 % CI , 2.1 to 4.3 ) in EGFR T790M-negative patients . CONCLUSIONS AZD9291 was highly active in patients with lung cancer with the EGFR T790 M mutation who had had disease progression during prior therapy with EGFR tyrosine kinase inhibitors . ( Funded by AstraZeneca ; Clinical Trials.gov number , NCT01802632 . ) BACKGROUND Afatinib-an oral irreversible ErbB family blocker-improves progression-free survival compared with pemetrexed and cisplatin for first-line treatment of patients with EGFR mutation-positive advanced non-small-cell lung cancer ( NSCLC ) . We compared afatinib with gemcitabine and cisplatin-a chemotherapy regimen widely used in Asia-for first-line treatment of Asian patients with EGFR mutation-positive advanced NSCLC . METHODS This open-label , r and omised phase 3 trial was done at 36 centres in China , Thail and , and South Korea . After central testing for EGFR mutations , treatment-naive patients ( stage IIIB or IV cancer [ American Joint Committee on Cancer version 6 ] , performance status 0 - 1 ) were r and omly assigned ( 2:1 ) to receive either oral afatinib ( 40 mg per day ) or intravenous gemcitabine 1000 mg/m(2 ) on day 1 and day 8 plus cisplatin 75 mg/m(2 ) on day 1 of a 3-week schedule for up to six cycles . R and omisation was done central ly with a r and om number-generating system and an interactive internet and voice-response system . R and omisation was stratified by EGFR mutation ( Leu858Arg , exon 19 deletions , or other ; block size three ) . Clinicians and patients were not masked to treatment assignment , but the independent central imaging review group were . Treatment continued until disease progression , intolerable toxic effects , or withdrawal of consent . The primary endpoint was progression-free survival assessed by independent central review ( intention-to-treat population ) . This study is registered with Clinical Trials.gov , NCT01121393 . FINDINGS 910 patients were screened and 364 were r and omly assigned ( 242 to afatinib , 122 to gemcitabine and cisplatin ) . Median progression-free survival was significantly longer in the afatinib group ( 11·0 months , 95 % CI 9·7 - 13·7 ) than in the gemcitabine and cisplatin group ( 5·6 months , 5·1 - 6·7 ; hazard ratio 0·28 , 95 % CI 0·20 - 0·39 ; p<0·0001 ) . The most common treatment-related grade 3 or 4 adverse events in the afatinib group were rash or acne ( 35 [ 14·6 % ] of 239 patients ) , diarrhoea ( 13 [ 5·4 % ] ) , and stomatitis or mucositis ( 13 [ 5·4 % ] ) , compared with neutropenia ( 30 [ 26·5 % ] of 113 patients ) , vomiting ( 22 [ 19·5 % ] ) , and leucopenia ( 17 [ 15·0 % ] ) in the gemcitabine and cisplatin group . Treatment-related serious adverse events occurred in 15 ( 6·3 % ) patients in the afatinib group and nine ( 8·0 % ) patients in the gemcitabine and cisplatin group . INTERPRETATION First-line afatinib significantly improves progression-free survival with a tolerable and manageable safety profile in Asian patients with EGFR mutation-positive advanced lung NSCLC . Afatinib should be considered as a first-line treatment option for this patient population . FUNDING Boehringer Ingelheim PURPOSE Patient-reported symptoms and health-related quality of life ( QoL ) benefits were investigated in a r and omized , phase III trial of afatinib or cisplatin/pemetrexed . PATIENTS AND METHODS Three hundred forty-five patients with advanced epidermal growth factor receptor ( EGFR ) mutation-positive lung adenocarcinoma were r and omly assigned 2:1 to afatinib 40 mg per day or up to six cycles of cisplatin/pemetrexed . Lung cancer symptoms and health-related QoL were assessed every 21 days until progression using the European Organisation for Research and Treatment of Cancer Quality of Life Question naire C30 and Lung Cancer-13 question naires . Analyses of cough , dyspnea , and pain were preplanned , including percentage of patients who improved on therapy , time to deterioration of symptoms , and change in symptoms over time . RESULTS Question naire compliance was high . Compared with chemotherapy , afatinib significantly delayed the time to deterioration for cough ( hazard ratio [ HR ] , 0.60 ; 95 % CI , 0.41 to 0.87 ; P = .007 ) and dyspnea ( HR , 0.68 ; 95 % CI , 0.50 to 0.93 ; P = .015 ) , but not pain ( HR , 0.83 ; 95 % CI , 0.62 to 1.10 ; P = .19 ) . More patients on afatinib ( 64 % ) versus chemotherapy ( 50 % ) experienced improvements in dyspnea scores ( P = .010 ) . Differences in mean scores over time significantly favored afatinib over chemotherapy for cough ( P < .001 ) and dyspnea ( P < .001 ) . Afatinib showed significantly better mean scores over time in global health status/QoL ( P = .015 ) and physical ( P < .001 ) , role ( P = .004 ) , and cognitive ( P = .007 ) functioning compared with chemotherapy . Fatigue and nausea were worse with chemotherapy , whereas diarrhea , dysphagia , and sore mouth were worse with afatinib ( all P < .01 ) . CONCLUSION In patients with lung adenocarcinoma with EGFR mutations , first-line afatinib was associated with better control of cough and dyspnea compared with chemotherapy , although diarrhea , dysphagia , and sore mouth were worse . Global health status/QoL was also improved over time with afatinib compared with chemotherapy ABSTRACT Aim : Overall survival ( OS ) as an endpoint in trials of first-line therapy is challenging due to the effect of post- study therapy ( PST ) . OS benefit may not be observed despite a clear benefit in progression-free survival . This exploratory analysis of the first-line EURTAC study assesses the effect of erlotinib on OS , using two statistical models to control for second-line ( 2L ) PST use . Methods : Patients with EGFR mutation-positive non-small-cell lung cancer were r and omised to receive once-daily erlotinib ( E ) or 4–6 cycles of chemotherapy ( C ) . OS , calculated from date of r and omisation to death , was assessed by Kaplan – Meier methodology . In this analysis , two statistical methods controlled for 2L PST use ; method 1 : the original Cox proportional hazard model was used , with OS censored at the time of 2L PST initiation , to evaluate OS only when patients were not receiving 2L PST ; method 2 : a Cox model adjusting for 2L PST exposure in the OS analyses where ‘ 2L PST exposure ’ was incorporated as a time-dependent covariate ( allowing for differential effects for E and C ) . Results : Baseline characteristics were balanced between the arms ( E , n = 86 ; C , n = 88 ) . In the protocol -specified analysis ( data cut-off 11 April 2012 ) , the hazard ratio ( HR ) for OS was 0.92 ( 95 % CI 0.63–1.35 , p = 0.68 ; median OS 22.9 vs 19.6 months for E vs C ) . When adjusted for baseline factors ( age , gender , ECOG PS , smoking history and EGFR mutation type ) , the HR was 0.86 ( 95 % CI 0.58–1.27 ) . A total of 58 % of patients received 2L PST ( tyrosine-kinase inhibitors : 31 % E , 58 % C ; platinum compounds : 44 % E , 5 % C ; antimetabolites : 48 % E , 19 % C ) . Median time to initiation of 2L PST from time of disease progression ( n = 102 ) was 0.85 months for E and 0.36 months for C. Using method 1 , the HR was 0.68 ( 95 % CI 0.37–1.25 , p = 0.21 ; median OS was not reached with E vs 20.8 months with C ) . The adjusted HR was 0.63 ( 95 % CI 0.34–1.19 ) . Using method 2 , the HR was 0.69 ( 95 % CI 0.38–1.26 ) , with an adjusted HR of 0.65 ( 95 % CI 0.35–1.20 ) . Conclusions : These exploratory results suggest a trend towards a survival benefit for first-line E vs C , which was previously unobserved due to the confounding factor of non-r and omised 2L PST use . Disclosure : L.F. Leon : Stock ownership : Yes , Genentech/Roche , Employee Stock Options Advisory board : No Board of directors : No Corporate sponsored research : Yes , Genentech/Roche , Employee Other substantive relationships : Yes , Genentech/Roche , Employee ; A. Golsorkhi : Stock ownership : Yes , Genentech/Roche , Employee Stock Options Advisory board : No Board of directors : No Corporate sponsored research : Yes , Genentech/Roche , Employee Other substantive relationships : Yes , Genentech/Roche , Employee ; S. Liu : Stock ownership : Yes , Genentech/Roche , Employee Stock Options Advisory board : No Board of directors : No Corporate sponsored research : Yes , Genentech/Roche , Employee Other substantive relationships : Yes , Genentech/Roche , Employee ; A. Drozdowskyj : Stock ownership : No Advisory board : No Board of directors : No Corporate sponsored research : No Other substantive relationships : Yes , Statistical Consultant for Roche . All other authors have declared no conflicts of interest |
1,918 | 25,886,390 | Many immigrants lacked adequate knowledge of aetiology , symptoms , transmission risk factors , prevention strategies , and treatment , of hepatitis HBV and HCV .
Ethnicity , gender , better education , higher income , and English proficiency influenced variations in levels and forms of knowledge .
Conclusion Immigrants are vulnerable to HBV and HCV , and risk life-threatening complications from these infections because of poor knowledge and help-seeking behaviour . | Background Hepatitis B and C ( HBV , HCV ) infections are associated with high morbidity and mortality .
Many countries with traditionally low prevalence ( such as UK ) are now planning interventions ( screening , vaccination , and treatment ) of high-risk immigrants from countries with high prevalence .
This review aim ed to synthesis e the evidence on immigrants ’ knowledge of HBV and HCV that might influence the uptake of clinical interventions .
We aim ed to identify qualitative and quantitative studies that investigated knowledge of HBV and HCV among immigrants from high endemic areas to low endemic areas . | BACKGROUND Vietnamese have higher liver cancer rates than any other racial/ethnic group in the United States . Approximately 80 % of liver cancers are etiologically associated with hepatitis B virus ( HBV ) infection , which is endemic in Southeast Asia . METHODS A telephone survey of r and omly selected Vietnamese households ( n = 75 ) was conducted during 1998 to examine HBV knowledge among Seattle 's Vietnamese community . The question naire included items related to the transmission of HBV , the possible sequelae of infection , and disease prevention . RESULTS The response rate was 70 % among reachable and eligible households . Prior to being provided with a description of the disease , two thirds of our respondents had heard of HBV infection . Less than 60 % knew that asymptomatic individuals can transmit the disease to others . Most thought that HBV infection can cause liver cancer ( 63 % ) and death ( 80 % ) . However , only a minority knew that infection can be lifelong ( 38 % ) and incurable ( 22 % ) . Finally , 28 % had never heard of the HBV vaccine . There were significant associations between knowledge and educational level as well as home ownership . CONCLUSIONS The findings suggest that Vietnamese immigrants have low levels of knowledge about HBV infection , and indicate a need for targeted educational interventions aim ed at reducing HBV-related liver cancer mortality BACKGROUND & AIMS Little is known about the HCV prevalence in non-Western migrant population s. To determine whether targeted HCV screening and prevention programs for migrants are needed , we examined HCV prevalence and determinants among non-Western , Western migrants , and the native Dutch population in the Netherl and s. METHODS Data were obtained from four surveys : ( 1 ) 3895 heterosexual visitors recruited during biannual surveys at the STI-clinic Amsterdam , 2007 - 2009 ; ( 2 ) r and om sample of 4563 pregnant women in Amsterdam , 2003 ; ( 3 ) population -based r and om sample of 1309 inhabitants of Amsterdam , 2004 ; ( 4 ) population -based r and om sample of 4428 people living in the Netherl and s , 2006 - 2007 . Characteristics associated with HCV-positivity were examined and phylogenetic analysis was used to obtain insight in the geographical origin of HCV strains . RESULTS HCV seroprevalence in the four surveys was low ( 0.3 - 0.6 % ) . In total 4860/14,195 ( 34 % ) were non-Western and 9329/14,195 ( 66 % ) Western participants ( including Dutch ) . First-generation non-Western migrants were more likely to be HCV-positive ( 0.7 - 2.3 % ) than Western participants ( 0.1 - 0.4 % ) . Except for survey 3 , second-generation non-Western migrants had a lower HCV prevalence than first-generation migrants , comparable to Western migrants and the Dutch population . Phylogenetic analysis showed that the majority of the HCV-positive , first-generation non-Western non-European migrants were infected with endemic strains which are rarely observed in Europe . CONCLUSIONS First-generation non-Western migrants are at increased risk for HCV . Phylogenetic analysis suggests that transmission likely took place in the country of origin , causing introduction but no further transmission of endemic HCV strains in the Netherl and s. HCV screening and prevention programs should target first-generation , but not second-generation , non-Western migrants This study examines mortality patterns among Canadian immigrants , including both refugees and non-refugees , 1980–1998 . Records of a stratified r and om sample of Canadian immigrants l and ing between 1980–1990 ( N = 369,936 ) were probabilistically linked to mortality data ( 1980–1998 ) . Mortality rates among immigrants were compared to those of the general Canadian population , stratifying by age , sex , immigration category , region of birth and time in Canada . Multivariate analysis examined mortality risks for various immigrant subgroups . Although immigrants presented lower all-cause mortality than the general Canadian population ( SMR between 0.34 and 0.58 ) , some cause-specific mortality rates were elevated among immigrants , including mortality from stroke , diabetes , infectious diseases ( AIDS and hepatitis among certain subgroups ) , and certain cancers ( liver and nasopharynx ) . Mortality rates differed by region of birth , and were higher among refugees than other immigrants . These results support the need to consider the heterogeneity of immigrant population s and vulnerable subgroups when developing targeted interventions BACKGROUND Liver cancer , a significant health problem in Chinese , can be controlled through HBV blood testing , vaccination , and community education about HBV . The PRECEDE framework has been very helpful in identifying factors associated with health practice s. OBJECTIVES The objective was to identify factors associated with HBV testing in Chinese Canadians , using the PRECEDE framework . METHODS Five hundred and thirty-three r and omly selected Chinese Canadian adults were interviewed about HBV blood testing practice s. Factors were grouped as predisposing , reinforcing and enabling . RESULTS Fifty-five percent had received HBV blood testing . Several predisposing factors , all reinforcing factors and one enabling factor were associated with HBV testing in bivariate analysis . A physician 's recommendation for testing was the strongest factor associated with testing in multiple logistic regression analysis ( OR=4.4 , p<0.0001 ) . INTERPRETATION Many Chinese Canadian adults in Vancouver have not been tested for HBV . Continuing educational efforts are needed and the PRECEDE framework can inform the development of health education interventions Southeast Asians have higher liver cancer rates than any other racial/ethnic group in the US . Approximately 80 percent of liver cancers are etiologically associated with hepatitis B virus ( HBV ) infection which is endemic in Southeast Asia . An in-person survey of Cambodian women ( n = 320 ) was conducted in Seattle , Washington , during 1999 . The question naire included items about HBV knowledge , beliefs , and practice s. Prior to being provided with a description of the disease , only about one-half ( 56 percent ) of our respondents had heard of HBV infection . Less than one-quarter ( 23 percent ) of the study group thought that asymptomatic individuals can transmit the disease to others . Most thought that HBV infection can cause liver cancer ( 54 percent ) and death ( 72 percent ) . However , a minority thought that infection can be lifelong ( 24 percent ) and incurable ( 15 percent ) . Only 38 percent reported they had been serologically tested for HBV . Finally , of those who had been tested and thought they were susceptible , two-thirds ( 67 percent ) had not been vaccinated . Lower levels of education were associated with lower levels of HBV knowledge and serologic testing . Our findings suggest that Cambodian immigrants have low levels of HBV knowledge , serologic testing , and vaccination ; and demonstrate a need for targeted educational interventions aim ed at reducing HBV-related liver cancer mortality among Southeast Asian communities |
1,919 | 18,333,924 | AND RECOMMENDATIONS Isolated performance of capillary refill assessment is of limited value and no nursing interventions rely solely on this measure .
Future research should be directed toward evaluation and comparative analyses of alternate methods of evaluating peripheral perfusion | PURPOSE A research roundtable was held in an urban community hospital in the United States to determine the strength , usefulness , and feasibility of empirical and clinical evidence evaluated in a systematic review assessing capillary refill .
APPROACH The roundtable was undertaken to provide an additional dimension for the development of a best- practice guideline . | STUDY OBJECTIVES To evaluate whether the capillary refill test can correctly differentiate between hypovolemic and euvolemic emergency department patients . DESIGN A prospect i ve , nonr and omized , nonblinded time series . SETTING The orthostatic and hypotensive patients were seen in a university hospital ED with 44,000 visits per year . Blood donors were studied in the hospital 's blood donor center . TYPE OF PARTICIPANTS Thirty-two adult ED patients who presented with a history suggestive of hypovolemia and either abnormal orthostatic vital signs ( 19 ) or frank hypotension ( 13 ) , and 47 volunteer blood donors who ranged in age from 19 to 83 participated . INTERVENTIONS Capillary refill was measured before rehydration in the ED subjects and , in the donor group , before and after a 450-mL blood donation . MEASUREMENTS Sensitivity , specificity , accuracy , and positive and negative predictive values were calculated . Analyses were stratified by age , sex , and study group . MAIN RESULTS For the blood donor group , mean capillary refill time before donation was 1.4 seconds and after donation was 1.1 seconds . Mean capillary refill time for the orthostatic group was 1.9 seconds and for the hypotensive group was 2.8 seconds . When scored with age-sex specific upper limits of normal , the sensitivity of capillary refill in identifying hypovolemic patients was 6 % for the 450-mL blood loss group , 26 % for the orthostatic group , and 46 % for the hypotensive group . The accuracy of capillary refill in a patient with a 50 % prior probability of hypovolemia is 64 % . Orthostatic vital signs were found to be more sensitive and specific than capillary refill in detecting the 450-mL blood loss . CONCLUSION Capillary refill does not appear to be a useful test for detecting mild-to-moderate hypovolemia in adults Background : The research -to- practice gap is at the heart of the problem in the underuse of nondrug complementary methods to manage postoperative pain . Purpose : To show how the six steps of the Collaborative Research Utilization ( CRU ) model can be used to translate research into practice , using an example of nondrug pain management protocol s. Methods : The CRU model was used to translate empirically tested nondrug interventions for surgical pain management enhancement into cost-effective , easy-to-use , best- practice nursing interventions , using tailored patient teaching . Results : The preliminary findings of the sub study in the context of the CRU model are reported . Discussion : The CRU model was successful in changing patients ' knowledge , attitudes , and use of nondrug interventions for pain management . Further research is needed in heterogeneous population s. Organization receptivity to research and a well-integrated computerized documentation system for cueing clinicians ' pain management practice s are key for effectiveness of change It is not uncommon for a decade to pass between the time a research problem is identified and the time that research -based solutions are translated into st and ards for care . This quasi-experimental study demonstrated the effectiveness of a collaborative research utilization model directed towards the transfer of specific research -based knowledge ( pain assessment ) into practice for the purpose of helping to solve pain management problems . At the same time , nurses who participated in the model significantly improved their competency in research utilization and their attitudes towards research when compared to a control group who did not participate in the model Objective Peripheral perfusion in critically ill patients frequently is assessed by use of clinical signs . Recently , the pulse oximetry signal has been suggested to reflect changes in peripheral perfusion . A peripheral perfusion index based on analysis of the pulse oximetry signal has been implemented in monitoring systems as an index of peripheral perfusion . No data on the variation of this index in the normal population are available , and clinical application of this variable in critically ill patients has not been reported . We therefore studied the variation of the peripheral perfusion index in healthy adults and related it to the central -to-toe temperature difference and capillary refill time in critically ill patients after changes in clinical signs of peripheral perfusion . Design Prospect i ve study . Setting University-affiliated teaching hospital . Patients One hundred eight healthy adult volunteers and 37 adult critically ill patients . Interventions None . Measurements and Main Results Capillary refill time , peripheral perfusion index , and arterial oxygen saturation were measured in healthy adults ( group 1 ) . Capillary refill time , peripheral perfusion index , arterial oxygen saturation , central -to-toe temperature difference , and hemodynamic variables were measured in critically ill patients ( group 2 ) during different peripheral perfusion profiles . Poor peripheral perfusion was defined as a capillary refill time > 2 secs and central -to-toe temperature difference ≥7 ° C . Peripheral perfusion index and arterial oxygen saturation were measured by using the Philips Medical Systems Viridia/56S monitor . In group 1 , measurements were made before and after a meal . In group 2 , two measurements were made , with the second measurement taken when the peripheral perfusion profile had changed . A total of 216 measurements were carried out in group 1 . The distribution of the peripheral perfusion index was skewed and values ranged from 0.3 to 10.0 , median 1.4 ( inner quartile range , 0.7–3.0 ) . Seventy-four measurements were carried out in group 2 . A significant correlation between the peripheral perfusion index and the core-to-toe temperature difference was found ( R2= .52;p < .001 ) . A cutoff peripheral perfusion index value of 1.4 ( calculated by constructing a receiver operating characteristic curve ) best reflected the presence of poor peripheral perfusion in critically ill patients . Changes in peripheral perfusion index and changes in core-to-toe temperature difference correlated significantly ( R = .52 , p < .001 ) . Conclusions The peripheral perfusion index distribution in the normal population is highly skewed . Changes in the peripheral perfusion index reflect changes in the core-to-toe temperature difference . Therefore , peripheral perfusion index measurements can be used to monitor peripheral perfusion in critically ill patients The influence of gender , local temperature , and systemic blood pressure on human capillary pressure is unknown . Finger nail fold capillary pressure was therefore directly measured in 74 healthy supine volunteers ( 40 female ) at midaxillary level . Capillary pressure was lower in women than in men ( 15.9 + /- 3.0 vs. 18.2 + /- 2.3 mmHg ; P = 0.001 ) , particularly in premenopausal women , but was not related to systolic , diastolic , or mean blood pressure . Capillary pulse pressure amplitude was related to skin temperature , an effect more marked in women ( P = 0.003 ) . There was a significant association between skin temperature and the time taken for the systolic pressure rise to reach the capillary , in women only ( r = -0.69 , P < 0.001 ) . Increasing age reduced the high-frequency waves in the pressure waveform [ 2nd harmonic percentage of fundamental : r = -0.52 and P = 0.002 ( women ) , r = -0.52 and P = 0.004 ( men ) ] . Thus mean capillary pressure and the pressure waveform may be influenced by gender , age , and skin temperature , illustrating the necessity to adequately match control groups during assessment s of capillary pressure pathophysiology |
1,920 | 24,999,427 | Bulimia nervosa ( BN ) received the most attention in the treatment literature , with cognitive behavioural therapy ( CBT ) and antidepressants the most common interventions .
For anorexia nervosa ( AN ) , family based therapy ( FBT ) was the most studied . | Eating disorders often develop during adolescence and young adulthood , and are associated with significant psychological and physical burden .
Identifying evidence -based interventions is critical and there is need to take stock of the extant literature , to inform clinical practice regarding well- research ed interventions and to direct future research agendas by identifying gaps in the evidence base .
Aim To investigate and quantify the nature and distribution of existing high- quality research on the prevention and treatment of eating disorders in young people using evidence mapping methodology . | CONTEXT Antidepressant medication is frequently prescribed for patients with anorexia nervosa . OBJECTIVE To determine whether fluoxetine can promote recovery and prolong time-to-relapse among patients with anorexia nervosa following weight restoration . DESIGN , SETTING , AND PARTICIPANTS R and omized , double-blind , placebo-controlled trial . From January 2000 until May 2005 , 93 patients with anorexia nervosa received intensive inpatient or day-program treatment at the New York State Psychiatric Institute or Toronto General Hospital . Participants regained weight to a minimum body mass index ( calculated as weight in kilograms divided by the square of height in meters ) of 19.0 and were then eligible to participate in the r and omized phase of the trial . INTERVENTIONS Participants were r and omly assigned to receive fluoxetine or placebo and were treated for up to 1 year as out patients in double-blind fashion . All patients also received individual cognitive behavioral therapy . MAIN OUTCOME MEASURES The primary outcome measures were time-to-relapse and the proportion of patients successfully completing 1 year of treatment . RESULTS Forty-nine patients were assigned to fluoxetine and 44 to placebo . Similar percentages of patients assigned to fluoxetine and to placebo maintained a body mass index of at least 18.5 and remained in the study for 52 weeks ( fluoxetine , 26.5 % ; placebo , 31.5 % ; P = .57 ) . In a Cox proportional hazards analysis , with prer and omization body mass index , site , and diagnostic subtype as covariates , there was no significant difference between fluoxetine and placebo in time-to-relapse ( hazard ratio , 1.12 ; 95 % CI , 0.65 - 2.01 ; P = .64 ) . CONCLUSIONS This study failed to demonstrate any benefit from fluoxetine in the treatment of patients with anorexia nervosa following weight restoration . Future efforts should focus on developing new models to underst and the persistence of this illness and on exploring new psychological and pharmacological treatment approaches . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00288574 Women who were referred with an eating disorder ( ED ) were compared with a matched normal control group to answer the following questions : What are the frequencies of anxiety disorders in cases of anorexia and bulimia nervosa diagnosed according to DSM-IV criteria ? Are anxiety disorders significantly more frequent among women with an eating disorder than among women from the community ? We assessed the frequencies of six specific anxiety disorders among 271 women with a current diagnosis of anorexia or bulimia nervosa and 271 controls , using the Mini-International Neuropsychiatric Interview , French DSM-IV version . A lifetime comorbidity with at least one anxiety disorder was found in 71 % of both the anorexic and the bulimic subjects , significantly higher than the percentage of controls with an anxiety disorder . The prevalence was significantly higher in the eating disorder groups than in controls for most types of anxiety disorder , and between 41.8 and 53.3 % of comorbid cases had an anxiety disorder preceding the onset of the eating disorder . Anxiety disorders are significantly more frequent in subjects with eating disorders than in volunteers from the community , a finding that has important etiological and therapeutic implication OBJECTIVE The aim of this study was to compare two maintenance treatment conditions for weight-restored anorexia nervosa ( AN ) : individual cognitive behavior therapy ( CBT ) and maintenance treatment as usual ( MTAU ) . METHOD This study was a nonr and omized clinical trial . The participants were 88 patients with AN who had achieved a minimum body mass index ( BMI ) of 19.5 and control of binge eating and purging symptoms after completing a specialized hospital-based program . Forty-six patients received 1 year of manualized individual CBT and 42 were in an assessment -only control condition ( i.e. , MTAU ) for 1 year . This condition was intended to mirror follow-up care as usual . Participants in both the conditions were assessed at 3-month intervals during the 1-year study . The main outcome variable was time to relapse . RESULTS When relapse was defined as a BMI < or= 17.5 for 3 months or the resumption of regular binge eating and /or purging behavior for 3 months , time to relapse was significantly longer in the CBT condition when compared with MTAU . At 1 year , 65 % of the CBT group and 34 % of the MTAU group had not relapsed . DISCUSSION The current findings provide preliminary evidence that CBT may be helpful in improving outcome and preventing relapse in weight-restored AN Background This study compared the best available treatment for bulimia nervosa , cognitive – behavioural therapy ( CBT ) augmented by fluoxetine if indicated , with a stepped-care treatment approach in order to enhance treatment effectiveness . Aims To establish the relative effectiveness of these two approaches . Method This was a r and omised trial conducted at four clinical centres ( Clinical trials.gov registration number : NCT00733525 ) . A total of 293 participants with bulimia nervosa were r and omised to one of two treatment conditions : manual-based CBT delivered in an individual therapy format involving 20 sessions over 18 weeks and participants who were predicted to be non-responders after 6 sessions of CBT had fluoxetine added to treatment ; or a stepped-care approach that began with supervised self-help , with the addition of fluoxetine in participants who were predicted to be non-responders after six sessions , followed by CBT for those who failed to achieve abstinence with self-help and medication management . Results Both in the intent-to-treat and completer sample s , there were no differences between the two treatment conditions in inducing recovery ( no binge eating or purging behaviours for 28 days ) or remission ( no longer meeting DSM – IV criteria ) . At the end of 1-year follow-up , the stepped-care condition was significantly superior to CBT . Conclusions Therapist-assisted self-help was an effective first-level treatment in the stepped-care sequence , and the full sequence was more effective than CBT suggesting that treatment is enhanced with a more individualised approach OBJECTIVE To date no trial has focused on the treatment of adolescents with bulimia nervosa . The aim of this study was to compare the efficacy and cost-effectiveness of family therapy and cognitive behavior therapy ( CBT ) guided self-care in adolescents with bulimia nervosa or eating disorder not otherwise specified . METHOD Eighty-five adolescents with bulimia nervosa or eating disorder not otherwise specified were recruited from eating disorder services in the United Kingdom . Participants were r and omly assigned to family therapy for bulimia nervosa or individual CBT guided self-care supported by a health professional . The primary outcome measures were abstinence from binge-eating and vomiting , as assessed by interview at end of treatment ( 6 months ) and again at 12 months . Secondary outcome measures included other bulimic symptoms and cost of care . RESULTS Of the 85 study participants , 41 were assigned to family therapy and 44 to CBT guided self-care . At 6 months , bingeing had undergone a significantly greater reduction in the guided self-care group than in the family therapy group ; however , this difference disappeared at 12 months . There were no other differences between groups in behavioral or attitudinal eating disorder symptoms . The direct cost of treatment was lower for guided self-care than for family therapy . The two treatments did not differ in other cost categories . CONCLUSIONS Compared with family therapy , CBT guided self-care has the slight advantage of offering a more rapid reduction of bingeing , lower cost , and greater acceptability for adolescents with bulimia or eating disorder not otherwise specified OBJECTIVE To collect nationally representative epidemiological data on early-onset eating disorders ( EOEDs ) in children . DESIGN Prospect i ve , active surveillance using the Australian Paediatric Surveillance Unit with key informant design . SETTING Child health specialists in Australia ( July 2002 to June 2005 ) . PATIENTS Incident cases of EOEDs in children aged 5 - 13 years . MAIN OUTCOME MEASURES Disease rates , demographic characteristics , clinical features and complications , hospitalisation , psychological comorbidity , and concordance of clinical features with Diagnostic and statistical manual of mental disorders , fourth edition ( DSM-IV ) criteria . RESULTS We identified 101 children aged 5 - 13 years with EOEDs ( median age , 12.2 years ; range , 5.5 - 13.9 years ) , of whom one in four were boys . Most were hospitalised ( 78 % ) , and the mean duration of hospitalisation was 24.7 days ( range , 1 - 75 days ) . More than 70 % of in patients were admitted to specialised eating disorder units in paediatric teaching hospitals . Among in patients , 37 % met DSM-IV diagnostic criteria for anorexia nervosa ; although 61 % had life-threatening complications of malnutrition , only 51 % met weight criteria . Psychological symptoms were similar to those in adults with anorexia nervosa : 67 % of in patients met both psychological diagnostic criteria for anorexia nervosa ( fear of weight gain/fatness and misperception of body shape ) . Of 19 postmenarchal girls , 18 had secondary amenorrhoea . Nasogastric feeding was used in 58 % of in patients , and 34 % received psychotropic medications . CONCLUSIONS This is the first prospect i ve national study of EOEDs . It demonstrates the limitations of applying DSM-IV diagnostic criteria for anorexia nervosa to young children ; the high proportion of boys affected by EOEDs ; and the significant psychological comorbidity and high frequency of hospitalisation associated with EOEDs . Potentially life-threatening medical complications are common at presentation , suggesting possible missed diagnoses and a need for education of health professionals . The study underlines the severity of EOEDs and the need for joint medical and psychiatric specialist management CONTEXT Evidence d-based treatment trials for adolescents with bulimia nervosa are largely absent . OBJECTIVE To evaluate the relative efficacy of family-based treatment ( FBT ) and supportive psychotherapy ( SPT ) for adolescents with bulimia nervosa . DESIGN R and omized controlled trial . SETTING The University of Chicago from April 1 , 2001 , through June 30 , 2006 . PARTICIPANTS Eighty patients , aged 12 to 19 years , with a DSM-IV diagnosis of bulimia nervosa or a strict definition of partial bulimia nervosa . INTERVENTIONS Twenty outpatient visits over 6 months of FBT or SPT . Participants were followed up at 6 months posttreatment . MAIN OUTCOME MEASURES Abstinence from binge- and -purge episodes as measured by the Eating Disorder Examination . Secondary outcome measures were Eating Disorder Examination binge- and -purge frequency and Eating Disorder Examination subscale scores . RESULTS Forty-one patients were assigned to FBT and 39 to SPT . Categorical outcomes at posttreatment demonstrated that significantly more patients receiving FBT ( 16 [ 39 % ] ) were binge- and -purge abstinent compared with those receiving SPT ( 7 [ 18 % ] ) ( P = .049 ) . Somewhat fewer patients were abstinent at the 6-month follow-up ; however , the difference was statistically in favor of FBT vs SPT ( 12 patients [ 29 % ] vs 4 patients [ 10 % ] ; P = .05 ) . Secondary outcome assessment , based on r and om regression analysis , revealed main effects in favor of FBT on all measures of eating pathological features ( P = .003 to P = .03 for all ) . CONCLUSIONS Family-based treatment showed a clinical and statistical advantage over SPT at posttreatment and at 6-month follow-up . Reduction in core bulimic symptoms was also more immediate for patients receiving FBT vs SPT Recently hospitalized bipolar , manic patients ( N = 53 ) were r and omly assigned to a 9-month , manual-based , family-focused psychoeducational therapy ( n = 28 ) or to an individually focused patient treatment ( n = 25 ) . All patients received concurrent treatment with mood-stabilizing medications . Structured follow-up assessment s were conducted at 3-month intervals for a 1-year period ofactive treatment and a 1-year period of posttreatment follow-up . Compared with patients in individual therapy , those in family-focused treatment were less likely to be rehospitalized during the 2-year study period . Patients in family treatment also experienced fewer mood disorder relapses over the 2 years , although they did not differ from patients in individual treatment in their likelihood of a first relapse . Results suggest that family psychoeducational treatment is a useful adjunct to pharmacotherapy in decreasing the risk of relapse and hospitalization frequently associated with bipolar disorder Recovered recurrently depressed patients were r and omized to treatment as usual ( TAU ) or TAU plus mindfulness-based cognitive therapy ( MBCT ) . Replicating previous findings , MBCT reduced relapse from 78 % to 36 % in 55 patients with 3 or more previous episodes ; but in 18 patients with only 2 ( recent ) episodes corresponding figures were 20 % and 50 % . MBCT was most effective in preventing relapses not preceded by life events . Relapses were more often associated with significant life events in the 2-episode group . This group also reported less childhood adversity and later first depression onset than the 3-or-more-episode group , suggesting that these groups represented distinct population s. MBCT is an effective and efficient way to prevent relapse/recurrence in recovered depressed patients with 3 or more previous episodes This study evaluated mindfulness-based cognitive therapy ( MBCT ) , a group intervention design ed to train recovered recurrently depressed patients to disengage from dysphoria-activated depressogenic thinking that may mediate relapse/recurrence . Recovered recurrently depressed patients ( n = 145 ) were r and omized to continue with treatment as usual or , in addition , to receive MBCT . Relapse/recurrence to major depression was assessed over a 60-week study period . For patients with 3 or more previous episodes of depression ( 77 % of the sample ) , MBCT significantly reduced risk of relapse/recurrence . For patients with only 2 previous episodes , MBCT did not reduce relapse/recurrence . MBCT offers a promising cost-efficient psychological approach to preventing relapse/recurrence in recovered recurrently depressed patients OBJECTIVE The aims of this study were to evaluate whether a single session of motivational enhancement therapy ( MET ) would increase participant readiness to change , improve the efficacy of self-help treatment for binge eaters , and improve participant compliance with the self-help manual . METHOD Participants with bulimia nervosa or binge eating disorder were r and omly assigned either to attend a 1-hr MET session prior to receiving the self-help manual ( n = 45 ) or to receive the self-help manual only ( n = 45 ) . Participants were followed for 4 months for assessment of self-reported eating disorder outcome and compliance . RESULTS The MET intervention result ed in increased readiness to change for binge eating compared with the self-help-only ( SH ) condition . Few differences were found between the MET condition and the SH condition for changes in eating attitudes and frequency of binge eating and compensatory behaviors . No significant effects were found for compliance . DISCUSSION This research adds to the literature regarding the use of brief motivational interventions to enhance readiness for change in population s with eating disorders OBJECTIVE The purpose of this study was to assess the primary methods used by psychotherapists in treating individuals with eating disorders and to determine the extent to which certain empirically supported psychotherapies ( i.e. , cognitive behavioral therapy [ CBT ] and interpersonal psychotherapy [ IPT ] ) are used in clinical setting s. METHOD Surveys developed for this study were sent to 500 psychologists r and omly selected from a list of all licensed doctoral-level psychologists in an upper midwestern state . RESULTS Despite the findings that CBT techniques were reported to be frequently used , most respondents identified something other than CBT or IPT as their primary theoretical approach . In addition , the majority of respondents indicated not having received training in the use of manual-based , empirically supported treatment approaches for working with individuals with eating disorders , although most reported a desire to obtain such training . CONCLUSIONS Although commonly referred to as the " treatments of choice " in research literature , manual-based , empirically supported approaches to working with individuals with eating disorders has not received adequate dissemination OBJECTIVE This study provides what the authors believe is the first empirical evaluation of cognitive behavior therapy as a posthospitalization treatment for anorexia nervosa in adults . METHOD After hospitalization , 33 patients with DSM-IV anorexia nervosa were r and omly assigned to 1 year of outpatient cognitive behavior therapy or nutritional counseling . RESULTS The group receiving nutritional counseling relapsed significantly earlier and at a higher rate than the group receiving cognitive behavior therapy ( 53 % versus 22 % ) . The overall treatment failure rate ( relapse and dropping out combined ) was significantly lower for cognitive behavior therapy ( 22 % ) than for nutritional counseling ( 73 % ) . The criteria for " good outcome " were met by significantly more of the patients receiving cognitive behavior therapy ( 44 % ) than nutritional counseling ( 7 % ) . CONCLUSIONS Cognitive behavior therapy was significantly more effective than nutritional counseling in improving outcome and preventing relapse . To the authors ' knowledge , these data provide the first empirical documentation of the efficacy of any psychotherapy , and cognitive behavior therapy in particular , in posthospitalization care and relapse prevention of adult anorexia nervosa Background : The treatment of binge eating disorder ( BED ) is still the object of debate . In the present study , the effectiveness of antidepressant drugs ( fluoxetine – FLX – 60 mg/day , fluvoxamine – FLV –300 mg/day ) , cognitive-behavioural therapy ( CBT ) and combined treatments ( CBT + FLX , CBT + FLV ) has been evaluated in a r and omized , clinical trial . Results at the end of the active treatment ( in the 24th week ) and 1-year follow-up outcomes have been evaluated . Methods : One hundred eight ( 44 M , 64 F ) BED patients were r and omly assigned to either CBT , FLX ( 60 mg/day ) , FLV ( 300 mg/day ) , CBT + FLX or CBT + FLV , for 24 weeks . At the beginning ( T0 ) , at the end ( T1 ) of treatment and after 1 year ( T2 ) , body mass index ( BMI ) and eating attitude and behaviours ( by EDE 12.0D ) were assessed . Results : At T1 , BMI and EDE scores were significantly reduced in CBT , CBT + FLX and CBT + FLV , but not in the FLX and FLV treatment groups . In the CBT + FLV group , a greater ( p < 0.05 ) reduction of EDE total scores was observed , when compared to CBT + FLX or CBT treatment groups . At T2 , BMI was significantly higher than at T1 , but still significantly lower than at T0 in the CBT , CBT + FLX and CBT + FLV groups , while EDE scores remained unchanged from T1 in all treatment groups . Conclusions : CBT was more effective than FLX or FLV in the treatment of BED . The addition of FLX to CBT does not seem to provide any clear advantage , while the addition of FLV could enhance the effects of CBT on eating behaviours . Modifications of eating behaviours are maintained at the 1-year follow-up , although the lost weight was partly regained BACKGROUND Anorexia nervosa is an often chronic disorder with high morbidity and mortality . Many people relapse after weight restoration . This study was design ed to determine whether a selective serotonin reuptake inhibitor would improve outcome and reduce relapse after weight restoration by contributing to maintenance of a healthy normal weight and a reduction of symptoms . METHODS We administered a double-blind placebo-controlled trial of fluoxetine to 35 patients with restricting-type anorexia nervosa . Anorexics were r and omly assigned to fluoxetine ( n = 16 ) or a placebo ( n = 19 ) after inpatient weight gain and then were observed as out patients for 1 year . RESULTS Ten of 16 ( 63 % ) subjects remained on fluoxetine for a year , whereas only three of 19 ( 16 % ) remained on the placebo for a year ( p = .006 ) . Those subjects remaining on fluoxetine for a year had reduced relapse as determined by a significant increase in weight and reduction in symptoms . CONCLUSIONS This study offers preliminary evidence that fluoxetine may be useful in improving outcome and preventing relapse of patients with anorexia nervosa after weight restoration BACKGROUND The aim of this study was to evaluate the effectiveness of a stepped care approach to the treatment of bulimia nervosa : a self-care manual followed , if necessary , by a course of attenuated cognitive behavioural treatment ( CBT ) in comparison with st and ard CBT . METHOD One hundred and ten patients , presenting at a tertiary referral centre with ICD-10 bulimia nervosa or atypical bulimia nervosa , were r and omly assigned to one of two treatment conditions ; a ) a sequential treatment group : 8 weeks with a self-care manual followed by up to eight sessions of CBT ( if still symptomatic ) or b ) 16 sessions of CBT . RESULTS Bulimic symptoms improved significantly in both groups with no significant differences between the two groups on any of the measures at the end of treatment or at 18 months follow-up . At end of treatment 30 % ( 95 % CI : 18 - 46 % ) of the sequential group and 30 % ( 95 % CI : 17 - 47 % ) of the st and ard treatment group were free from all bulimic symptoms . Sixteen of those in the sequential group improved significantly with self-care and did not require additional treatment . The median number of sessions taken by the sequential group was three ( 95 % CI : 0 - 6 ) . At 18 months follow-up 40 % ( 95 % CI : 23 - 59 % ) of the sequential group and 41 % ( 95 % CI : 25 - 59 % ) of the CBT group were symptom free . CONCLUSIONS A sequential approach to the treatment of bulimia may be as effective as st and ard CBT and can considerably reduce the amount of therapist contact required OBJECTIVE To assess the long-term course of recovery and relapse and predictors of outcome in anorexia nervosa . METHOD A naturalistic , longitudinal prospect i ve design was used to assess recovery and relapse in patients ascertained through a university-based specialty treatment program . Patients were assessed semiannually for 5 years and annually thereafter over 10 - 15 years from the time of their index admission . Recovery was defined in terms of varying levels of symptom remission maintained for no fewer than 8 consecutive weeks . RESULTS Nearly 30 % of patients had relapses following hospital discharge , prior to clinical recovery . However , most patients were weight recovered and menstruating regularly by the end of follow-up , with nearly 76 % of the cohort meeting criteria for full recovery . Relapse after recovery was relatively uncommon . Of note , time to recovery was protracted , ranging from 57 - 79 months depending on definition of recovery . Among restrictors at intake , nearly 30 % developed binge eating , occurring within 5 years of intake . A variety of predictors of chronic outcome and binge eating were identified . There were no deaths in the cohort . CONCLUSION The course of anorexia nervosa is protracted . Predictors of outcome are surprisingly few , but those identified are in keeping with previous accounts . The intensive treatment received by these patients may account for the lower levels of morbidity and mortality when considered in relation to other reports in the follow-up literature Behavioral family systems therapy ( BFST ) was compared with ego-oriented individual therapy ( EOIT ) in a controlled , r and om-assignment investigation involving 22 young adolescents with anorexia nervosa . Each adolescent and her parents received approximately 16 months of outpatient therapy along with a common medical and dietary regimen . BFST emphasized parental control over eating and weight gain , coupled with cognitive restructuring and problem-solving communication training . EOIT emphasized building ego strength , adolescent autonomy , and insight into the emotional blocks to eating . BFST produced greater change on body-mass index than did EOIT , but both treatments produced comparable improvements on eating attitudes , body shape dissatisfaction , interoceptive awareness , depression/internalizing psychopathology , and eating-related family conflict . The implication s of these results for the clinician who treats adolescents with anorexia nervosa are discussed . J Dev Behav Pediatr 15:111–116 , 1994 . Index terms : anorexia nervosa , adolescents , family therapy , individual therapy Technological advancements allow new approaches to psychotherapy via electronic media . The eating disorder literature currently contains no studies on internet intervention in anorexia nervosa ( AN ) . This study presents a RCT on an internet-based relapse prevention program ( RP ) over nine months after inpatient treatment for AN . The sample comprised 258 women , r and omized to the RP or treatment as usual ( TAU ) . Expert- and self-ratings were evaluated by intent-to-treat analyses . Concerning age , age at onset and comorbidity , both groups were comparable at r and omization . During the RP , the intervention group gained weight while the TAU group had minimal weight loss . RP completers gained significantly more body weight than patients in the TAU condition . Group-by-time comparisons for eating-related cognitions and behaviors and general psychopathology showed a significantly more favorable course in the RP program for " sexual anxieties " and " bulimic symptoms " ( interview ) , and " maturity fears " and " social insecurity " ( EDI-2 ) . General psychopathology showed no significant group-by-time interaction . Important factors for successful relapse prevention were adherence to the intervention protocol and increased spontaneity . Considering the unfavorable course and chronicity of anorexia nervosa ( AN ) , internet-based relapse prevention in AN following inpatient treatment appears a promising approach . Future internet-based programs may be further improved and enhanced OBJECTIVE To assess the course and outcome of anorexia nervosa ( AN ) and bulimia nervosa ( BN ) at a median of 90 months of follow-up in a large cohort of women with eating disorders . METHOD A prospect i ve , naturalistic , longitudinal design was used to map the course of AN and BN in 246 women . Follow-up data are presented in terms of full and partial recovery , predictors of time to recovery , and rates and predictors of relapse . RESULTS The full recovery rate of women with BN was significantly higher than that of women with AN , with 74 % of those with BN and 33 % of those with AN achieving full recovery by a median of 90 months of follow-up . Intake diagnosis of AN was the strongest predictor of worse outcome . No predictors of recovery emerged among bulimic subjects . Eighty-three percent of women with AN and 99 % of those with BN achieved partial recovery . Approximately one third of both women with AN and women with BN relapsed after full recovery . No predictors of relapse emerged . CONCLUSIONS The findings suggest that the course of AN is characterized by high rates of partial recovery and low rates of full recovery , while the course of BN is characterized by higher rates of both partial and full recovery OBJECTIVE The authors sought to evaluate patterns and predictors of relapse among women with eating disorders . METHOD Interviews were conducted biannually to annually to assess symptoms of eating disorders , axis I disorders , treatment , and psychosocial function on a weekly basis for women diagnosed with anorexia nervosa ( N=136 ) or bulimia nervosa ( N=110 ) and prospect ively followed for 9 years . At the last follow-up , 229 ( 93 % ) of the subjects had been retained in the study group . RESULTS Relapse occurred in 36 % of the women with anorexia nervosa and 35 % of the women with bulimia nervosa . Women with intake diagnoses of anorexia nervosa , restricting subtype , tended to develop bulimic symptoms during relapse , whereas women with intake diagnoses of anorexia nervosa , binge-purge subtype , or bulimia nervosa tended to return to bulimic patterns during relapse . Greater body image disturbance contributed to a risk of relapse in both eating disorders , and worse psychosocial function increased the risk of relapse in bulimia nervosa . CONCLUSIONS These results may explain the long-term efficacy of interpersonal therapy for bulimia nervosa and suggest that focused body image work during relapse prevention may enhance long-term recovery from eating disorders |
1,921 | 15,674,954 | No statistical differences were observed between CABG and stenting for meta- analysis of mortality or AMI , but there was heterogeneity .
Composite cardiac event and revascularisation rates were lower for CABG than for stents .
CABG is associated with reduced rates of major adverse cardiac events , mostly driven by reduced repeat revascularisation .
Research on real-world patient population or patient level data meta-analyses may identify risk factors and groupings who may benefit most from one strategy over the other | BACKGROUND Coronary artery bypass graft surgery ( CABG ) replaces obstructed vessels with ones from other parts of the body .
Alternatively , obstructions are remodelled using catheter-based techniques such as percutaneous coronary angioplasty with the use of stents .
Though less invasive , stenting techniques are limited by the re-narrowing of treated vessels ( restenosis ) .
We examined evidence on cardiac-related outcomes occurring after CABG or stenting , with implication s for re source use , re source allocation and informing patient choice .
OBJECTIVES To examine evidence from r and omised controlled trials ( RCTs ) on benefit of stents or CABG in reducing cardiac events in people with stable angina or acute coronary syndrome ( ACS ) . | BACKGROUND The recent recognition that coronary-artery stenting has improved the short- and long-term outcomes of patients treated with angioplasty has made it necessary to reevaluate the relative benefits of bypass surgery and percutaneous interventions in patients with multivessel disease . METHODS A total of 1205 patients were r and omly assigned to undergo stent implantation or bypass surgery when a cardiac surgeon and an interventional cardiologist agreed that the same extent of revascularization could be achieved by either technique . The primary clinical end point was freedom from major adverse cardiac and cerebrovascular events at one year . The costs of hospital re sources used were also determined . RESULTS At one year , there was no significant difference between the two groups in terms of the rates of death , stroke , or myocardial infa rct ion . Among patients who survived without a stroke or a myocardial infa rct ion , 16.8 percent of those in the stenting group underwent a second revascularization , as compared with 3.5 percent of those in the surgery group . The rate of event-free survival at one year was 73.8 percent among the patients who received stents and 87.8 percent among those who underwent bypass surgery ( P<0.001 by the log-rank test ) . The costs for the initial procedure were $ 4,212 less for patients assigned to stenting than for those assigned to bypass surgery , but this difference was reduced during follow-up because of the increased need for repeated revascularization ; after one year , the net difference in favor of stenting was estimated to be $ 2,973 per patient . CONCLUSION As measured one year after the procedure , coronary stenting for multivessel disease is less expensive than bypass surgery and offers the same degree of protection against death , stroke , and myocardial infa rct ion . However , stenting is associated with a greater need for repeated revascularization Background —This investigation compares the results of contemporary percutaneous coronary intervention ( PCI ) with st and ard balloon angioplasty among patients with multivessel coronary disease . Patients having balloon angioplasty in the Bypass Angioplasty Revascularization Investigation ( BARI ) and those within the Dynamic Registry meeting BARI eligibility criteria were studied . Methods and Results — Clinical features and in-hospital and 1-year outcomes of 857 BARI-eligible patients in the Dynamic Registry ( contemporary PCI ) were compared with the 904 r and omized patients who underwent percutaneous transluminal coronary angioplasty in BARI . Compared with BARI patients , Registry patients had fewer lesions attempted ( 1.53 versus 2.56 , P = 0.001 ) , more frequent single-vessel PCI ( 76 % versus 33 % , P < 0.001 ) , greater use of intracoronary stents ( 76 % versus 1 % , P < 0.001 ) , and GP IIb/IIIa receptor antagonist ( 24 % versus 0 % , P < 0.001 ) . Angiographic success was achieved more often among Registry patients ( 91 % versus 72 % , P < 0.001 ) , whereas abrupt closure ( 1.5 % versus 9.5 % , P < 0.001 ) and in-hospital coronary artery bypass graft ( CABG ) ( 1.9 % versus 10.2 % , P < 0.001 ) and myocardial infa rct ion ( 0.8 % versus 2.1 % , P = 0.025 ) were less common . No differences were observed in either in-hospital or 1-year death , but 1-year death/myocardial infa rct ion was lower in the Registry . Registry patients had lower 1-year rates of subsequent CABG ( 8.6 % versus 22.7 % , P < 0.001 ) and PCI ( 12.4 % versus 22.5 % , P < 0.001 ) . By multivariate analysis , contemporary PCI was independently associated with reduced risk for in-hospital CABG , 1-year CABG , and 1-year PCI . Conclusions —Among patients with multivessel disease , contemporary PCI result ed in safer and more durable revascularization . These results support the role of PCI for selected patients with multivessel coronary artery disease OBJECTIVES To compare the clinical - and cost-effectiveness of minimally invasive direct coronary artery bypass grafting ( MIDCAB ) and percutaneous transluminal coronary angioplasty ( PTCA ) with or without stenting in patients with single-vessel disease of the left anterior descending coronary artery ( LAD ) . DESIGN Multi-centre r and omised trial without blinding . The computer-generated sequence of r and omised assignments was stratified by centre , allocated participants in blocks and was concealed using a central ised telephone facility . SETTING Four tertiary cardiothoracic surgery centres in Engl and . PARTICIPANTS Patients with ischaemic heart disease with at least 50 % proximal stenosis of the LAD , suitable for either PTCA or MIDCAB , and with no significant disease in another vessel . INTERVENTIONS Patients r and omised to PTCA had local anaesthetic and underwent PTCA according to the method preferred by the operator carrying out the procedure . Patients r and omised to MIDCAB had general anaesthetic . The chest was opened through an 8 - 10-cm left anterior thoracotomy . The ribs were retracted and the left internal thoracic artery ( LITA ) harvested . The pericardium was opened in the line of the LAD to confirm the feasibility of operation . The distal LITA was anastomosed end-to-side to an arteriotomy in the LAD . All operators were experienced in carrying out MIDCAB . MAIN OUTCOME MEASURES The primary outcome measure was survival free from cardiac-related events . Relevant events were death , myocardial infa rct ion , repeat coronary revascularisation and recurrence of symptomatic angina or clinical signs of ischaemia during an exercise tolerance test at annual follow-up . Secondary outcome measures were complications , functional outcome , disease-specific and generic quality of life , health and social services re source use and their costs . RESULTS A total of 12,828 consecutive patients undergoing an angiogram were logged at participating centres from November 1999 to December 2001 . Of the 1091 patients with proximal stenosis of the LAD , 127 were eligible and consented to take part ; 100 were r and omised and the remaining 27 consented to follow-up . All r and omised participants were included in an intention-to-treat analysis of survival free from cardiac-related events , which found a non-significant benefit from MIDCAB . Cumulative hazard rates at 12 months were estimated to be 7.1 and 9.2 % for MIDCAB and PTCA , respectively . There were no important differences between MIDCAB and PTCA with respect to angina symptoms or disease-specific or generic quality of life . The total NHS procedure costs were 1648 British pounds and 946 British pounds for MIDCAB and PTCA , respectively . The costs of re sources used during 1 year of follow-up were 1033 British pounds and 843 British pounds , respectively . CONCLUSIONS The study found no evidence that MIDCAB was more effective than PTCA . The procedure costs of MIDCAB were observed to be considerably higher than those of PTCA . Given these findings , it is unlikely that MIDCAB represents a cost-effective use of re sources in the reference population . Recent advances in cardiac surgery mean that surgeons now tend to carry out off-pump bypass grafting via a sternotomy instead of MIDCAB . At the same time , cardiologists are treating more patients with multi-vessel disease by PTCA . Future primary research should focus on this comparison . Other small trials of PTCA versus MIDCAB have now finished and a more conclusive answer to the original objective could be provided by a systematic review Purpose : To compare percutaneous coronary intervention ( PCI ) using stent implantation versus coronary artery bypass graft ( CABG ) in patients with multiple vessel disease with involvement of the proximal left anterior descending coronary artery ( LAD ) . Methods : 230 patients with multiple vessel disease and severe stenosis of the proximal LAD ( 113 with PCI , 117 with CABG ) . They were a cohort of patients from the r and omised ERACI ( Argentine r and omized trial of percutaneous transluminal coronary angioplasty versus coronary artery bypass surgery in multivessel disease ) II study . Results : Both groups had similar baseline characteristics . There were no significant differences in 30 day major adverse cardiac events ( death , myocardial infa rct ion , stroke , and repeat procedures ) between the strategies ( PCI 2.7 % v CABG 7.6 % , p = 0.18 ) . There were no significant differences in survival ( PCI 96.4 % v CABG 95 % , p = 0.98 ) and survival with freedom from myocardial infa rct ion ( PCI 92 % v CABG 89 % , p = 0.94 ) at 41.5 ( 6 ) months ’ follow up . However , freedom from new revascularisation procedures ( CABG 96.6 % v PCI 73 % , p = 0.0002 ) and frequency of angina ( CABG 9.4 % v PCI 22 % , p = 0.025 ) were superior in the CABG group . Conclusion : Patients with multivessel disease and significant disease of the proximal LAD r and omly assigned in the ERACI II trial to PCI or CABG had similar survival and survival with freedom from myocardial infa rct ion at long term follow up . Repeat revascularisation procedures were higher in the PCI group Background —Our aims were to compare coronary artery bypass grafting ( CABG ) and stenting for the treatment of diabetic patients with multivessel coronary disease enrolled in the Arterial Revascularization Therapy Study ( ARTS ) trial and to determine the costs of these 2 treatment strategies . Methods and Results — Patients ( n=1205 ) were r and omly assigned to stent implantation ( n=600 ; diabetic , 112 ) or CABG ( n=605 ; diabetic , 96 ) . Costs per patient were calculated as the product of each patient ’s use of re sources and the corresponding unit costs . Baseline characteristics were similar between the groups . At 1 year , diabetic patients treated with stenting had the lowest event-free survival rate ( 63.4 % ) because of a higher incidence of repeat revascularization compared with both diabetic patients treated with CABG ( 84.4 % , P < 0.001 ) and nondiabetic patients treated with stents ( 76.2 % , P = 0.04 ) . Conversely , diabetic and nondiabetic patients experienced similar 1-year event-free survival rates when treated with CABG ( 84.4 % and 88.4 % ) . The total 1-year costs for stenting and CABG in diabetic patients were $ 12 855 and $ 16 585 ( P < 0.001 ) and in the nondiabetic groups , $ 10 164 for stenting and $ 13 082 for surgery . Conclusions —Multivessel diabetic patients treated with stenting had a worse 1-year outcome than patients assigned to CABG or nondiabetics treated with stenting . The strategy of stenting was less costly than CABG , however , regardless of diabetic status Background —Earlier reports have shown that the outcome of balloon angioplasty or bypass surgery in unstable angina is less favorable than in stable angina . Recent improvements in percutaneous treatment ( stent implantation ) and bypass surgery ( arterial grafts ) warrant reevaluation of the relative merits of either technique in treatment of unstable angina . Methods and Results —Seven hundred fifty-five patients with stable angina were r and omly assigned to coronary stenting ( 374 ) or bypass surgery ( 381 ) , and 450 patients with unstable angina were r and omly assigned to coronary stenting ( 226 ) or bypass surgery ( 224 ) . All patients had multivessel disease considered to be equally treatable by either technique . Freedom from major adverse events , including death , myocardial infa rct ion , and cerebrovascular events , at 1 year was not different in unstable patients ( 91.2 % versus 88.9 % ) and stable patients ( 90.4 % versus 92.6 % ) treated , respectively , with coronary stenting or bypass surgery . Freedom from repeat revascularization at 1 year was similar in unstable and stable angina treated with stenting ( 79.2 % versus 78.9 % ) or bypass surgery ( 96.3 % versus 96 % ) but was significantly higher in both unstable and stable patients treated with stenting ( 16.8 % versus 16.9 % ) compared with bypass surgery ( 3.6 % versus 3.5 % ) . Neither the difference in costs between stented or bypassed stable or unstable angina ( $ 2594 versus $ 3627 ) nor the cost-effectiveness was significantly different at 1 year . Conclusions —There was no difference in rates of death , myocardial infa rct ion , and cerebrovascular event at 1 year in patients with unstable angina and multivessel disease treated with either stented angioplasty or bypass surgery compared with patients with stable angina . The rate of repeat revascularization of both unstable and stable angina was significantly higher in patients with stents OBJECTIVE The recent appreciation that stenting has improved the short- and long-term outcomes of patients treated with coronary angioplasty has made it imperative to reconsider the comparison between surgery and percutaneous interventions in patients with multivessel disease . METHODS One thous and two hundred five patients were r and omly assigned to undergo bypass surgery or angioplasty with stent implantation when there was consensus between the cardiac surgeon and interventional cardiologist as to equivalent treatability . The primary clinical end point was freedom from major adverse cardiac and cerebrovascular events at 1 year . Major adverse cardiac and cerebrovascular events at 2 years constituted a secondary end point . RESULTS At 2 years , 89.6 % of the surgical group and 89.2 % of the stent group were free from death , stroke , and myocardial infa rct ion ( log-rank test P = .65 ) . Among patients who survived without stroke or myocardial infa rct ion , 19.7 % in the stent group underwent a second revascularization , as compared with 4.8 % in the surgical group ( P < .001 ) . At 2 years , 84.8 % of the surgical group and 69.5 % of the stent group were event-free survivors ( log-rank test P < .001 ) , and 87.2 % in the surgical cohort and 79.6 % in the stent group were angina-free survivors ( P = .001 ) . In the diabetes subgroup , 82.3 % of the surgical group and 56.3 % of the stent group were free from any events after 2 years ( log-rank test P < .001 ) . CONCLUSION The difference in outcome between surgery and stenting observed at 1 year in patients with multivessel disease remained essentially unchanged at 2 years . Stenting was associated with a greater need for repeat revascularization . In view of the relatively greater difference in outcome in patients with diabetes , surgery clearly seems to be the preferable form of treatment for these patients BACKGROUND Percutaneous coronary angioplasty ( PTCA ) and stent implantation have become the first-line intervention for patients with isolated proximal LAD-lesions . Minimally invasive direct coronary artery bypass surgery ( MIDCAB ) has recently been developed to reduce surgical invasiveness for single LAD revascularization . This study focus on the question whether MIDCAB could be an alternative treatment for isolated proximal LAD lesions . METHODS Starting in 1996 , MIDCAB was performed in 618 patients . Angiography was performed before discharge and repeated after 6 months at follow-up examination . In an ongoing r and omized trial 150 patients with an indication for treatment of a LAD lesion have been included to compare the mid-term outcome after PTCA ( n=79 ) vs. MIDCAB ( n=71 ) . RESULTS In 618 MIDCAB procedures 30-day mortality was 0.6 % , perioperative myocardial infa rct ion rate was 1.6 % . The conversion rate to sternotomy was 3.4 % . The learning curve was demonstrated by a patency rate of 96.0 % in 1997 , 98.0 % in 1998 and 99.1 % in 1999 , respectively . At 6 months patency rate was 94.4 % in 1997 and 97.0 % in 1998 . The rate of severe stenosis > 75 % dropped from 5.4 % in 1997 to 3.4 % in 1998 . The over all rate of re interventions was 5.6 % . The preliminary result of the r and omized trial revealed a difference in the number of perioperative adverse events , 11.4 % in the MIDCAB group vs. 6.3 % in the PTCA group ( P<0.05 ) . At 6 months follow-up 88 . 7 % of the MIDCAB patients were free from angina vs. 58.2 % of the PTCA patients ( P<0.02 ) . Restenosis and a positive stress test was diagnosed in 27.9 % of the PTCA patients vs. 8.4 % of the MIDCAB patients ( P<0.02 ) . Reintervention was necessary in 27.9 % of the patients after PTCA vs. 8.4 % of the patients after MIDCAB . CONCLUSION MIDCAB is a safe and effective but technically dem and ing procedure . Perioperative adverse events may be expected , but early as well as mid-term patency rate are good . When compared to PTCA , the freedom from angina and the need for additional revascularization procedures after 6 months is statistically better for patients having MIDCAB surgery . Thus , MIDCAB is considered a valuable alternative for isolated proximal high grade LAD lesions Background —Functional status and quality of life are important outcomes in the evaluation of revascularization approaches for symptomatic coronary artery disease . Few data are available regarding the comparative improvement in disease-specific health status after CABG versus percutaneous coronary intervention ( PCI ) in the era of coronary stenting . Methods and Results —Cardiac-specific health status was evaluated at baseline and at 6 and 12 months after intervention with the Seattle Angina Question naire ( SAQ ) in patients r and omized to stent-assisted PCI ( n=488 ) versus CABG ( n=500 ) in the Stent or Surgery trial . Scores for physical limitation , angina frequency , and quality of life improved significantly for both treatment groups at 6 months ( range of improvement from 13.6 to 34.7 points ) and 12 months ( 14.3 to 38.2 points ; all P < 0.001 ) . CABG patients had greater improvement than those assigned to PCI , although the magnitude of the difference decreased over time ( difference at 6 months , 4.03 to 6.48 points ; 12 months , 2.05 to 2.93 points ) . A component of this reduction is accounted for by PCI-arm patients who required repeat intervention . Differences between treatment groups were greatest for the 6-month angina frequency scores ( difference=6.48 points ; 95 % CI 3.96 to 8.99 ) . Overall , treatment satisfaction was high and did not differ significantly between groups . Conclusions —Both CABG and stent-assisted PCI dramatically improved cardiac-related health status in patients with multivessel disease at 6- and 12-month follow-up . During the first postprocedure year , patients ’ angina burden and physical limitations were alleviated to a greater extent with CABG Background — Outcomes after percutaneous coronary intervention ( PCI ) have been documented extensively in clinical trials and single-center series , but few data exist on the clinical and economic outcomes after PCI in an unselected population . Methods and Results —We used the Medicare St and ard Analytic File to identify all initial PCI procedures performed in 1998 among a r and om sample of 5 % of all Medicare beneficiaries ≥65 years of age . These patients ( n=9868 ) were followed up for 1 year after PCI to identify clinical outcomes , medical re source use , and costs . Between 1 month and 1 year after PCI , 16.9 % of patients required ≥1 repeat revascularization procedures . Mean 1-year medical care costs increased 5-fold among patients with repeat revascularization compared with those without ( $ 26 186 versus $ 5344 ; P < 0.001 ) . After adjustment for baseline differences , the independent cost of repeat revascularization was $ 19 074 ( 95 % CI , 18 440 to 19 707 ) . Assuming from previous studies that 85 % of repeat revascularization procedures over the first year of follow-up are attributable to restenosis , the estimated clinical restenosis rate was 14.4 % , and the 1-year economic burden of restenosis to the healthcare system was $ 2747 per initial PCI procedure . Conclusions —Among unselected elderly patients undergoing PCI , repeat revascularization occurs in ≈14 % and increases 1-year healthcare costs by > $ 19 000 per occurrence . These findings have important implication s for the cost-effectiveness of new treatments that substantially reduce restenosis Background —The primary results of Arterial Revascularization Therapy Study reported a greater need for repeated revascularization after percutaneous coronary intervention with stenting ( PCI ) . However , PCI was less expensive than coronary artery bypass grafting ( CABG ) and offered the same degree of protection against death , stroke , and myocardial infa rct ion . Methods and Results — Patients with multivessel disease ( n=1205 ) were r and omly assigned to either CABG or PCI and followed up for up to 3 years . Survival rates without stroke or myocardial infa rct ion were similar in each group at 1 year and 3 years ( 90.5 % versus 91.4 % for PCI versus CABG at 1 year and 87.2 % versus 88.4 % for PCI versus CABG at 3 years ) . However , the respective repeat revascularization rates were 21.2 % and 26.7 % at 1 and 3 years in patients allocated to PCI , compared with 3.8 % and 6.6 % in patients allocated to CABG ( P < 0.0001 ) . Diabetes ( P < 0.0009 ) and maximal pressure for stent deployment ( P < 0.002 ) are the strongest independent predictors of events at 3 years after PCI , whereas left anterior descending coronary artery grafting ( P < 0.006 ) is the best predictor of event-free survival at 3 years after CABG . The incremental cost of surgery compared with PCI for an event-free patient was 19 257 & OV0556 ; at 1 year but decreased to 10 492 & OV0556 ; at 3 years . It remained at 142 391 & OV0556 ; at 3 years when revascularization procedures were excluded in the efficacy end point , however . Conclusions —Three-year survival rates without stroke and myocardial infa rct ion are identical in both groups , and the cost/benefit ratio of stenting is determined primarily by the increasing need for revascularization in the PCI group OBJECTIVES The objective of this study was to compare the long-term outcome of patients with an isolated high- grade stenosis of the left anterior descending ( LAD ) coronary artery r and omized to percutaneous transluminal coronary angioplasty with stenting ( PCI , stenting ) or to off-pump coronary artery bypass grafting ( surgery ) . METHODS Patients with an isolated high- grade stenosis ( American College of Cardiology/American Heart Association classification type B2/C ) of the proximal LAD were r and omly assigned to stenting ( n=51 ) or to surgery ( n=51 ) and were followed for 3 - 5 years ( mean 4 years ) . Primary composite endpoint was freedom from major adverse cardiac and cerebrovascular events ( MACCEs ) , including cardiac death , myocardial infa rct ion , stroke and repeat target vessel revascularization . Secondary endpoints were angina pectoris status and need for anti-anginal medication at follow-up . Analysis was by intention to treat . RESULTS MACCEs occurred in 27.5 % after stenting and 9.8 % after surgery ( P=0.02 ; absolute risk reduction 17.7 % ) . Freedom from angina pectoris was 67 % after stenting and 85 % after surgery ( P=0.036 ) . Need for anti-anginal medication was significantly lower after surgery compared to stenting ( P=0.002 ) . CONCLUSION Patients with an isolated high- grade lesion of the proximal LAD have a significantly better 4-year clinical outcome after off-pump coronary bypass grafting than after PCI Between January 1991 and September 1997 , in the Cardiovascular Surgery Department of the Institute of Cardiology of Jagiellonian University Medical School , 23 patients underwent emergency CABG due to acute myocardial ischaemia in result of failed PTCA . Over the same period of time invasive cardiologists performed 1883 PTCAs out of which 23 ( 1.2 % ) were emergency cardiosurgical procedures , and in 38 patients , stents were implanted in the damaged coronary arteries . The patients ' age ranged from 37 to 67 years ( median 52.2 ) . In all patients good left ventricular function was preserved , median ejection fraction being 64 % . Two patients required IABP to support left ventricular function . 1 - 4 bypass grafts were implanted ( median 1.9 per patient ) . In one patient , internal mammary artery was collected and then implanted into anterior interventricular branch . The most common complication was myocardial infa rct ion which occurred in 12 patients ( 52 % ) . In ten patients low output was observed postoperatively . One operated patient ( a female died ( 4.3 % ) . The mean time of hospitalization was 11 days . Emergency myocardial revascularisation procedures performed after failed PTCA , bring higher risk of mortality and dangerous postoperative complications BACKGROUND Percutaneous revascularization is a well-accepted method of treatment for a single left anterior descending coronary artery ( LAD ) stenosis . With the introduction of primary stenting , it has become the treatment of choice for a LAD lesion . In the last few years however , the introduction of minimally invasive cardiac surgery , video-assisted left internal thoracic artery ( LITA ) harvesting , and robotic surgery have raised the question as to whether minimally invasive surgical revascularization would be competitive with percutaneous coronary interventions in cases of single-vessel stenoses . METHODS A group of 100 patients with Canadian Cardiovascular Society class II to IV , and angiographically confirmed single critical stenosis of the LAD ( type A or B ) , were treated with direct primary stenting ( group 1 , n = 50 ) , or with endoscopic atraumatic coronary artery bypass grafting ( group 2 , n = 50 ) . RESULTS All patients in a group 1 , obtained a very good angiographic and clinical effect . No acute postoperative complications were noted at 1 month of follow-up . However , at 1 month of follow-up , 3 patients ( 6 % ) developed restenosis of the LAD , and at 6 months follow-up , 6 patients ( 12 % ) , developed restenosis of the LAD . In these cases , repeated percutaneous coronary interventions of the target vessel were successfully performed . In group 2 , very good operative results were observed . In 1 and 6 months of follow-up , all patients remained asymptomatic . Critical stenosis of the left internal thoracic artery-LAD anastomosis was angiographically documented in 1 case ( 2 % ) . This patient was successfully treated with balloon angioplasty . CONCLUSIONS The study results document the superiority of endoscopic atraumatic coronary artery bypass grafting over direct primary stenting in LAD revascularization , along with the slightly higher costs of the surgical procedure OBJECTIVE To determine current outcomes of percutaneous transluminal coronary angioplasty ( PTCA ) and coronary artery bypass grafting ( CABG ) . DESIGN The Scottish coronary revascularisation register provided prospect ively collected data on case mix and in-hospital complications for all revascularisation procedures between April 1997 and March 1999 ( 4775 PTCA ; 5115 CABG ) . Linkage to routine hospital discharge and death data provided follow up information on survival and repeat revascularisation . RESULTS Stents were used in 51 % of PTCA procedures . CABG patients were older , had more severe coronary disease , and had greater comorbidity . PTCA was more likely to be undertaken as an urgent or emergency procedure . Perioperative death and urgent surgery followed 0.3 % and 0.6 % of PTCA procedures , respectively . Case fatality rates were higher following CABG , with 6.7 % dead within two years compared with 3.4 % following PTCA . PTCA was more often followed by readmission for ischaemic heart disease , repeat angiography , or revascularisation : 22.8 % of patients had repeat revascularisation within two years , compared with 1.8 % following CABG . CONCLUSIONS The severity of coronary heart disease was greater than in previously published registry studies and r and omised trials . Despite this , overall survival figures were comparable and repeat revascularisation rates lower , particularly following PTCA . Perioperative death and urgent surgery following PTCA were also lower . These favourable outcomes may be attributable , in part , to increased use of bail out and elective stenting The rising costs of health care have forced policy makers to make choices , and new treatments are increasingly assessed in terms of the balance between additional costs and additional effects . The recent recognition that stenting has a major and long-lasting effect enhancing balloon PTCA procedure has made it imperative to compare in patients with multivessel disease the st and ard surgical procedure with multiple stenting in a large scale multinational and multicentre approach ( 19 countries , 68 sites ) . Selection and inclusion of patients is based on a consensus of the cardiac surgeon and interventional cardiologist on equal ' treatability ' of patients by both techniques with analysis of clinical follow-up ( event-free survival ) on the short ( 30 day ) , medium ( 1 year ) , and long-term ( 3 and 5 year ) with analysis of cost-effectiveness and quality of life ( EuroQol and SF-36 ) . Of the entire trial , the primary null hypothesis which needs to be rejected is that there will be no difference in event-free survival or effectiveness ( E ) , at 1 year and also that the direct and indirect costs ( C ) per event-free year are not different between surgery or stenting . For this to become significant with a power of 90 % one needs 1200 patients . Between April 97 and June 98 , 1205 patients have been r and omized with a monthly recruitment of 83 patients . Expected costs , effects and cost-effectiveness ratio ( CE ratio ) are : Stent high costs 2 VDStent high costs 3 VDStent low costs 2 VDStent low costs 3 VDCABG costs (C)$19.297$24.566$16.638$20.456$21.350 effects (E)81%81%81%81%88 % CE ratio$23.876$30.397$20.586$25.322$24.348 Clinical ly , stenting is not expected to be more effective than CABG , but should be cost effective in both the 2- and 3-VD group when using the lower cost estimate and in the 2 VD group when using the higher cost assumptions OBJECTIVE The purpose of this study was to compare percutaneous transluminal coronary revascularization ( PTCR ) employing stent implantation to conventional coronary artery bypass graft surgery ( CABG ) in symptomatic patients with multivessel coronary artery disease . BACKGROUND Previous r and omized studies comparing balloon angioplasty versus CABG have demonstrated equivalent safety results . However , CABG was associated with significantly fewer repeat revascularization procedures . METHODS A total of 2,759 patients with coronary artery disease were screened at seven clinical sites , and 450 patients were r and omly assigned to undergo either PTCR ( 225 patients ) or CABG ( 225 patients ) . Only patients with multivessel disease and indication for revascularization were enrolled . RESULTS Both groups had similar clinical demographics : unstable angina in 92 % ; 38 % were older than 65 years , and 23 % had a history of peripheral vascular disease . During the first 30 days , PTCR patients had lower major adverse events ( death , myocardial infa rct ion , repeat revascularization procedures and stroke ) compared with CABG patients ( 3.6 % vs. 12.3 % , p = 0.002 ) . Death occurred in 0.9 % of PTCR patients versus 5.7 % in CABG patients , p < 0.013 , and Q myocardial infa rct ion ( MI ) occurred in 0.9 % PTCR versus 5.7 % of CABG patients , p < 0.013 . At follow-up ( mean 18.5 + /- 6.4 months ) , survival was 96.9 % in PTCR versus 92.5 % in CABG , p < 0.017 . Freedom from MI was also better in PTCR compared to CABG patients ( 97.7 % vs. 93.4 % , p < 0.017 ) . Requirements for new revascularization procedures were higher in PTCR than in CABG patients ( 16.8 % vs. 4.8 % , p < 0.002 ) . CONCLUSIONS In this selected high-risk group of patients with multivessel disease , PTCR with stent implantation showed better survival and freedom from MI than did conventional surgery . Repeat revascularization procedures were higher in the PTCR group BACKGROUND The immediate and long-term outcomes of reoperative coronary artery bypass surgery ( CABG ) ( n = 1561 ) and catheter-based coronary intervention ( angioplasty ) ( n = 2613 ) were compared in patients from Emory University Hospitals who had previous CABG . METHODS AND RESULTS The surgical and angioplasty procedures and statistical methods were st and ard . Data were collected prospect ively and entered into a computerized data base . Followup was by letter , telephone , or additional events result ing in readmission . In the angioplasty group , 2.9 % required in-hospital CABG . Hospital mortality was 1.2 % after angioplasty versus 6.8 % after repeat CABG ( P < .0001 ) . Recurrent angina was noted frequently at about 4 years and was more common after angioplasty . One- , 5- , and 10-year mortalities were 11 % , 24 % , and 49 % after CABG versus 6 % , 22 % , and 38 % after angioplasty . Survival corrected for baseline differences did not vary with the choice of procedure . There were more additional procedures after angioplasty . Patients undergoing angioplasty may be divided into those with procedures only in native coronary arteries ( n = 1545 ) , only in vein grafts ( n = 869 ) , and a mixture ( n = 199 ) , with respective 10 year survivals of 66 % , 56 % , and 65 % ( P < .0001 ) . CONCLUSIONS These patients have a high incidence of events both in-hospital and in the long term . Although initial mortality was higher after CABG , after baseline differences were accounted for , there was no difference in the long term . Patients more frequently have additional procedures after angioplasty . Choice of therapy should consider clinical and angiographic suitability and patient preference Information on the relative benefit of coronary artery bypass grafting ( CABG ) versus stent-assisted percutaneous coronary intervention ( PCI ) for improvement of cardiac-related health status in women and how it compares with men is limited . The Stent or Surgery trial compared r and omly assigned CABG and stent-assisted PCI in 206 women and 782 men with multivessel disease . We examined longitudinal changes at 6 and 12 months from baseline by gender and treatment in 3 subscales of the Seattle Angina Question naire ( SAQ ) : physical limitation , angina frequency , and quality of life . At the time of revascularization , women were older , more severely ill , and tended to have lower SAQ scores than men . At 6 months , SAQ scores after both procedures improved significantly in both genders , with greater improvement achieved with CABG . After adjustment for other factors , in men , CABG was associated with a 54.7 % greater improvement in physical limitation compared with PCI , 31.3 % greater improvement in angina frequency , and 18.3 % greater improvement in quality of life . In women , these relative differences were 11.6 % , 43.2 % , and 39.3 % , respectively . At 1 year , men continued to show greater improvement with CABG in all 3 dimensions ( 50.6 % , 19.7 % , and 15.3 % , respectively ) , but in women the relative differences decreased substantially ( 1.6 % , 11.1 % , and 0.6 % , respectively ) due to a greater later improvement after PCI ( p = 0.049 for the interaction among treatment , gender , and follow-up for the quality of life domain ) . Although CABG may be superior to PCI in men , in women , at 1 year after intervention , both procedures appear equally effective BACKGROUND Stents are now used in the majority of percutaneous coronary revascularization procedures . It is not clear whether the higher initial cost of stenting is later repaid by reducing costly complications and repeat revascularization procedures , especially for patients with multivessel disease . METHODS To project the long-term costs of using coronary stents , angioplasty , or bypass surgery to treat patients with multivessel coronary artery disease , we developed a decision model based on the outcomes documented in the Bypass Angioplasty Revascularization Investigation ( BARI ) r and omized trial of coronary artery bypass grafting ( CABG ) and percutaneous transluminal coronary angioplasty ( PTCA ) . We studied 2 clinical strategies : provisional stenting of suboptimal PTCA results and primary stenting of all angiographically eligible lesions . The cost of CABG was also up date d to reflect contemporary practice . RESULTS Provisional stenting had lower projected costs over a 4-year period than either traditional PTCA ( -$1742 , or -3.4 % ) or contemporary CABG ( -$832 , or -1.7 % ) , mostly because of reductions in emergency CABG after PTCA . In contrast , primary stenting had higher projected costs over a 4-year period than either PTCA ( + $ 333 , or + 0 . 7 % ) or contemporary CABG ( + $ 1243 , or + 2.5 % ) , mainly because of the higher initial procedure costs . These results were not substantially altered when we systematic ally varied the key parameters of the models in 1-way and 2-way sensitivity analyses . CONCLUSIONS A primary stenting strategy in patients with multivessel disease has higher projected long-term costs than CABG . In contrast , a provisional stenting strategy in multivessel disease has lower projected costs than either PTCA or CABG BACKGROUND Patients with multivessel coronary artery disease are c and i date s for either angioplasty and stenting or coronary artery bypass grafting . A prospect i ve r and omized study design ed to compare the both methods included only a minority of the eligible patients . OBJECTIVE To compare coronary artery bypass grafting to angioplasty plus stenting in patients with multivessel disease who declined r and omization to a multicenter study ( the ARTS ) . METHODS During 1997 - 98 we prospect ively followed 96 consecutive patients who were eligible according to the ARTS criteria but refused r and omization . Of these patients , 50 underwent angioplasty + stenting and 46 underwent coronary bypass surgery . We compared the incidence of major adverse cardiac and cerebral events , chest pain recurrence , quality of life and procedural cost during the first 6 months . RESULTS All procedures were completed successfully without mortality or cerebral events . The rate of Q-wave myocardial infa rct ion was 2 % in the AS group vs. 0 % in the CABG group ( not significant ) . Minor complications occurred in 7 patients ( 14 % ) in the AS group and in 21 patients ( 45 % ) in the CABG group ( P < 0.01 ) . At 6 months follow-up the incidence of major cardiac and cerebral events was similar in both groups ( 11 % and 4 % in the AS and CABG groups respectively , P = NS ) . Seventeen patients ( 36 % ) in the AS group required repeat revascularization compared to only 3 ( 7 % ) in the CABG group ( P = 0.002 ) . Nevertheless , quality of life was better , hospitalization was shorter and the cost was lower during the first 6 months after angioplasty . CONCLUSION Angioplasty with stenting compared to coronary bypass surgery in patients with multivessel disease result ed in similar short-term major complications . However , 36 % of patients undergoing angioplasty may need further revascularization procedures during the first 6 months OBJECTIVES We sought to assess the relationship between completeness of revascularization and adverse events at one year in the ARTS ( Arterial Revascularization Therapies Study ) trial . BACKGROUND There is uncertainty to what extent degree of completeness of revascularization , using up-to- date techniques , influences medium-term outcome . METHODS After consensus between surgeon and cardiologist regarding the potential for equivalence in the completeness of revascularization , 1,205 patients with multivessel disease were r and omly assigned to either bypass surgery or stent implantation . All baseline and procedural angiograms and surgical case-record forms were central ly assessed for completeness of revascularization . RESULTS Of 1,205 patients r and omized , 1,172 underwent the assigned treatment . Complete data for review were available in 1,143 patients ( 97.5 % ) . Complete revascularization was achieved in 84.1 % of the surgically treated patients and 70.5 % of the angioplasty patients ( p < 0.001 ) . After one year , the stented angioplasty patients with incomplete revascularization showed a significantly lower event-free survival than stented patients with complete revascularization ( i.e. , freedom from death , myocardial infa rct ion , cerebrovascular accident and repeat revascularization ) ( 69.4 % vs. 76.6 % ; p < 0.05 ) . This difference was due to a higher incidence of subsequent bypass procedures ( 10.0 % vs. 2.0 % ; p < 0.05 ) . Conversely , at one year , bypass surgery patients with incomplete revascularization showed only a marginally lower event-free survival rate than those with complete revascularization ( 87.8 % vs. 89.9 % ) . CONCLUSIONS Complete revascularization was more frequently accomplished by bypass surgery than by stent implantation . One year after bypass , there was no significant difference in event-free survival between surgically treated patients with complete revascularization and those with incomplete revascularization , but patients r and omized to stenting with incomplete revascularization had a greater need for subsequent bypass surgery The Octopus Study consists of two multicenter r and omized clinical trials in which coronary artery bypass grafting on the beating heart ( off-pump CABG ) using the Utrecht Octopus Method is compared to intracoronary stent implantation and conventional CABG . The primary endpoint in the comparison of off-pump CABG versus stent implantation ( OctoStent Trial ) is medical effectiveness ( i.e. , absence of reintervention and major adverse cardiac and cerebrovascular events at 1 year after treatment ) . The primary endpoint in the comparison of off-pump CABG versus conventional CABG ( OctoPump Trial ) is cerebral safety ( i.e. , absence of cognitive deficits and cerebrovascular events at 3 months after treatment ) . Secondary endpoints in both trials include presence and severity of angina , quality of life , exercise capacity , and cost-effectiveness . A total of 560 patients will be enrolled . A r and om sample of 210 patients will undergo repeat angiography at 1 year to assess angiographic restenosis rate and graft patency . Including 1-year follow-up , the study will last for 3 years . Control Clin Trials 2000;21:595 - OBJECTIVES This study was done to identify the best treatment for an isolated high- grade stenosis of the proximal left anterior descending coronary artery ( LAD ) . BACKGROUND Percutaneous transluminal coronary angioplasty with stenting ( PCI ) and off-pump coronary artery bypass grafting ( surgery ) are used to treat single-vessel disease of a high- grade stenosis of the proximal LAD . Midterm results of both treatments are compared in this prospect i ve r and omized study . METHODS In a single-center prospect i ve trial , we r and omly assigned 102 patients with a high- grade stenosis of the proximal LAD ( American College of Cardiology/American Heart Association classification type B2 or C ) to PCI ( n = 51 ) or surgery ( n = 51 ) . Primary composite end point was freedom from Major Adverse Cardiac and Cerebrovascular Events ( MACCE ) at follow-up , including death , myocardial infa rct ion , cerebrovascular accident , and repeat target vessel revascularization ( TVR ) . Secondary end points were angina pectoris class and need for antianginal medication at follow-up . Analysis was by intention-to-treat ( ITT ) and received treatment ( RT ) . RESULTS Mean follow-up time was three years ( 90 % midrange , two to four years ) . Incidence of MACCE was 23.5 % after PCI and 9.8 % after surgery ; p = 0.07 ITT ( 24.1 % vs. 8.3 % ; p = 0.04 RT ) . After surgery a significantly lower angina pectoris class ( p = 0.02 ) and need for antianginal medication ( p = 0.01 ) was found compared to PCI . Target vessel revascularization was 15.7 % after PCI and 4.1 % after surgery ( p = 0.09 ) . CONCLUSIONS At three-year follow-up ( range , two to four years ) , a trend in favor of surgery is observed in regard to MACCE-free survival with a significantly lower angina pectoris status and significantly lower need for antianginal medication BACKGROUND Coronary-stent placement is a new technique in which a balloon-exp and able , stainless-steel , slotted tube is implanted at the site of a coronary stenosis . The purpose of this study was to compare the effects of stent placement and st and ard balloon angioplasty on angiographically detected restenosis and clinical outcomes . METHODS We r and omly assigned 410 patients with symptomatic coronary disease to elective placement of a Palmaz-Schatz stent or to st and ard balloon angioplasty . Coronary angiography was performed at base line , immediately after the procedure , and six months later . RESULTS The patients who underwent stenting had a higher rate of procedural success than those who underwent st and ard balloon angioplasty ( 96.1 percent vs. 89.6 percent , P = 0.011 ) , a larger immediate increase in the diameter of the lumen ( 1.72 + /- 0.46 vs. 1.23 + /- 0.48 mm , P < 0.001 ) , and a larger luminal diameter immediately after the procedure ( 2.49 + /- 0.43 vs. 1.99 + /- 0.47 mm , P < 0.001 ) . At six months , the patients with stented lesions continued to have a larger luminal diameter ( 1.74 + /- 0.60 vs. 1.56 + /- 0.65 mm , P = 0.007 ) and a lower rate of restenosis ( 31.6 percent vs. 42.1 percent , P = 0.046 ) than those treated with balloon angioplasty . There were no coronary events ( death ; myocardial infa rct ion ; coronary-artery bypass surgery ; vessel closure , including stent thrombosis ; or repeated angioplasty ) in 80.5 percent of the patients in the stent group and 76.2 percent of those in the angioplasty group ( P = 0.16 ) . Revascularization of the original target lesion because of recurrent myocardial ischemia was performed less frequently in the stent group than in the angioplasty group ( 10.2 percent vs. 15.4 percent , P = 0.06 ) . CONCLUSIONS In selected patients , placement of an intracoronary stent , as compared with balloon angioplasty , results in an improved rate of procedural success , a lower rate of angiographically detected restenosis , a similar rate of clinical events after six months , and a less frequent need for revascularization of the original coronary lesion BACKGROUND Balloon-exp and able coronary-artery stents were developed to prevent coronary restenosis after coronary angioplasty . These devices hold coronary vessels open at sites that have been dilated . However , it is unknown whether stenting improves long-term angiographic and clinical outcomes as compared with st and ard balloon angioplasty . METHODS A total of 520 patients with stable angina and a single coronary-artery lesion were r and omly assigned to either stent implantation ( 262 patients ) or st and ard balloon angioplasty ( 258 patients ) . The primary clinical end points were death , the occurrence of a cerebrovascular accident , myocardial infa rct ion , the need for coronary-artery bypass surgery , or a second percutaneous intervention involving the previously treated lesion , either at the time of the initial procedure or during the subsequent seven months . The primary angiographic end point was the minimal luminal diameter at follow-up , as determined by quantitative coronary angiography . RESULTS After exclusions , 52 patients in the stent group ( 20 percent ) and 76 patients in the angioplasty group ( 30 percent ) reached a primary clinical end point ( relative risk , 0.68 ; 95 percent confidence interval , 0.50 to 0.92 ; P = 0.02 ) . The difference in clinical -event rates was explained mainly by a reduced need for a second coronary angioplasty in the stent group ( relative risk , 0.58 ; 95 percent confidence interval , 0.40 to 0.85 ; P = 0.005 ) . The mean ( + /- SD ) minimal luminal diameters immediately after the procedure were 2.48 + /- 0.39 mm in the stent group and 2.05 + /- 0.33 mm in the angioplasty group ; at follow-up , the diameters were 1.82 + /- 0.64 mm in the stent group and 1.73 + /- 0.55 mm in the angioplasty group ( P = 0.09 ) , which correspond to rates of restenosis ( diameter of stenosis , > or = 50 percent ) of 22 and 32 percent , respectively ( P = 0.02 ) . Peripheral vascular complications necessitating surgery , blood transfusion , or both were more frequent after stenting than after balloon angioplasty ( 13.5 vs. 3.1 percent , P < 0.001 ) . The mean hospital stay was significantly longer in the stent group than in the angioplasty group ( 8.5 vs. 3.1 days , P < 0.001 ) . CONCLUSIONS Over seven months of follow-up , the clinical and angiographic outcomes were better in patients who received a stent than in those who received st and ard coronary angioplasty . However , this benefit was achieved at the cost of a significantly higher risk of vascular complications at the access site and a longer hospital stay OBJECTIVE We sought to compare minimally invasive coronary artery bypass grafting ( surgical intervention ) with percutaneous transluminal coronary angioplasty with primary stenting ( stenting ) in patients having an isolated high- grade stenosis ( American College of Cardiology/American Heart Association classification type B2 or C ) of the proximal left anterior descending coronary artery . At 6 months , both procedures were compared on the basis of quantitative angiography and clinical outcome . METHODS Both treatments were compared in a single-center , prospect i ve , r and omized study . The primary end point of this study was quantitative angiographic outcome at 6 months . The secondary end point was 6-month clinical outcome . Statistical analysis was performed in accordance with the intention-to-treat principle . RESULTS From March 1997 to September 1999 , patients with angina pectoris caused by an isolated high- grade stenosis of the proximal left anterior descending coronary artery were r and omly assigned to surgical intervention ( n = 51 ) or stenting ( n = 51 ) . At 6 months , quantitative coronary angiography showed an anastomotic stenosis rate of 4 % after surgical intervention and a restenosis rate of 29 % after stenting ( P < .001 ) . Periprocedural events did not significantly differ between surgical intervention and stenting . After surgical intervention , 2 patients died ; no patients died after stenting . After 6 months , no significant difference was found for major adverse cardiac or cerebral events and need for repeat target vessel revascularization . After 6 months , return of angina pectoris , physical work capacity , and use of antianginal drugs did not significantly differ between treatments . CONCLUSIONS After 6 months , surgical intervention had a significantly better angiographic outcome than stenting in patients with an isolated high- grade stenosis of the proximal left anterior descending coronary artery . Clinical outcome did not significantly differ between treatments BACKGROUND : The rising costs of healthcare have forced policy makers to make choices , and new treatments are increasingly assessed in terms of the balance between additional costs and additional effects . The recent recognition that stenting has a major and long-lasting effect enhancing balloon PTCA procedure has made it imperative to compare in patients with multivessel disease the st and ard surgical procedure with multiple stenting in a large-scale multinational and multicenter approach ( 19 countries , 68 sites ) . METHODS : Selection and inclusion of patients is based on a consensus of the cardiac surgeon and interventional cardiologist on equal ' treatability ' of patients by both techniques with analysis of clinical follow-up ( event-free survival ) on the short ( 30 days ) , medium ( 1 year ) , and long term ( 3 and 5 years ) with analysis of cost-effectiveness and quality of life ( EuroQol and SF-36 ) . Of the entire trial , the primary null hypothesis which needs to be rejected is that there will be no difference in event-free survival or effectiveness ( E ) , at 1 year and also that the direct and indirect costs ( C ) per event-free year are not different between surgery or stenting . For this to become significant with a power of 90 % requires 1200 patients . Between April 97 and June 98 , 1205 patients have been r and omized with a monthly recruitment of 83 patients ; the one year follow-up will thus be completed in June 1999 . Expected costs , effects and cost-effectiveness ratio ( CE ratio ) for stents are : Stent : high-cost estimate , 2 vessel disease ( C 3 $ 19,297 , E 3 81 % , CE ratio 3 $ 23,876 ) ; 3 vessel disease ( C 3 $ 24,566 , E 3 81 % , CE ratio 3 $ 30,397 ) low-cost estimate , 2 vessel disease ( C 3 $ 16,638 , E 3 81 % , CE ratio 3 $ 20,586 ) ; 3 vessel disease ( C 3 $ 20,456 , E 3 81 % , CE ratio 3 $ 25,322 ) Compared with CABG ( C 3 $ 21,350 , E 3 88 % , CE ratio 3 $ 24,348 ) CONCLUSION : Clinical ly , stenting is not expected to be more effective than CABG , but should be cost-effective in both the 2- and 3-vessel disease groups when using the lower-cost estimate and in the 2 vessel group when using the higher-cost assumptions . ( Int J PURPOSE Patients who develop recurrent myocardial ischemia after coronary artery bypass graft ( CABG ) surgery are often referred for percutaneous coronary interventions . The objective of this study was to evaluate the changing demographic and clinical characteristics , and procedural and long-term outcomes , in patients with prior CABG referred for percutaneous coronary interventions during a 20-year period . METHODS We prospect ively collected data on patients who underwent coronary interventional procedures following CABG surgery . We compared angiographic and procedural success , and long-term event-free survival , among patients who had procedures from 1979 to 1989 ( n = 393 ) , from 1990 to 1994 ( n = 811 ) , and from 1995 to 1998 ( n = 937 ) . RESULTS Patients in the 1995 to 1998 cohort were older , had a lower mean left ventricular ejection fraction , and were more likely to have diabetes , hypertension , and hyperlipidemia , but less likely to smoke . They were more likely to have treatment of complex lesions , including vein graft lesions , and had more prior CABG surgeries . More patients received intracoronary stents in 1995 to 1998 . Both angiographic success rates ( 78 % from 1979 to 1989 , 88 % from 1990 to 1994 , and 91 % from 1995 to 1998 , P < 0.0001 ) and procedural success rates ( 78 % , 86 % , and 91 % , P < 0.0001 ) improved with time . Long-term mortality was greater in the pre-1990 group ( relative risk = 1.8 , 95 % confidence interval : 1.3 to 2.4 ) and 1990 to 1994 group ( relative risk = 1.7 , 95 % confidence interval : 1.3 to 2.2 ) compared with the 1995 to 1998 group , as were the likelihoods of repeat revascularization and recurrent severe angina . CONCLUSION Although the demographic and clinical characteristics of patients who underwent percutaneous intervention following CABG surgery indicate that they are at increasingly greater risk of adverse cardiac events , success rates and long-term survival have improved with time . The rates of recurrent severe angina as well as of subsequent revascularization have also decreased , probably as a result of improvements in technique and greater use of stents and adjunctive medications The ' Stent or Surgery ' trial ( SoS ) is a r and omized controlled trial to compare coronary artery bypass grafting with percutaneous transluminal coronary angioplasty and primary stent implantation in patients with multi-vessel coronary artery disease . This is a multicentre , multinational venture involving over 40 centres in 12 countries throughout Europe and Canada . Eligible and consenting patients will be r and omly allocated , in equal proportions , to open revascularization by CABG or by PTCA with the primary implantation of intracoronary stents . The trial design is pragmatic and imposes few protocol restrictions in patient selection , surgical and intervention techniques or adjunctive medication schedules . The rationale and design of the trial are discussed , including important sub- studies , examining quality of life , neuropsychological outcome , cost and cost benefit Background —Stenting improves cardiac outcome in comparison with balloon angioplasty . Compared with conventional surgery , off-pump bypass surgery on the beating heart without cardiopulmonary bypass may reduce morbidity , hospital stay , and costs . The purpose , therefore , was to compare cardiac outcome , quality of life , and cost-effectiveness 1 year after stenting and after off-pump surgery . Methods and Results — Patients referred for angioplasty ( n=280 ) were r and omly assigned to stenting ( n=138 ) or off-pump bypass surgery . At 1 year , survival free from stroke , myocardial infa rct ion , and repeat revascularization was 85.5 % after stenting and 91.5 % after off-pump surgery ( relative risk , 0.93 ; 95 % CI , 0.86 to 1.02 ) . Freedom from angina was 78.3 % after stenting and 87.0 % after off-pump surgery ( P = 0.06 ) . Quality -adjusted lifetime was 0.82 year after stenting and 0.79 year after off-pump surgery ( P = 0.09 ) . Hospital stay after the initial procedure was 1.43 and 5.77 days , respectively ( P < 0.01 ) . Stenting reduced overall costs by $ 2933 ( 26.2 % ) per patient ( $ 8276 versus $ 11 209 ; P < 0.01 ) . Stenting was more cost-effective in 95 % of the bootstrap estimates . Conclusions —At 1 year , stenting was more cost-effective than off-pump surgery while maintaining comparable cardiac outcome and quality of life . Stenting rather than off-pump surgery , therefore , can be recommended as a first-choice revascularization strategy in selected patients BACKGROUND The Arterial Revascularization Therapies Study was a multicenter , r and omized trial design ed to compare percutaneous coronary intervention with stenting versus coronary artery bypass graft surgery in 1,205 patients with multivessel coronary artery disease . The most appropriate type of treatment for these patients is still a matter of considerable debate . OBJECTIVES To evaluate the clinical characteristics of patients enrolled in the ARTS trial in Israel in comparison to those worldwide , and to assess the 1 year outcome in these patients . METHODS Between April 1997 and June 1998 , a total of 1,205 patients with multivessel coronary artery disease , who were considered to be equally treatable with both modalities , were r and omized to either stenting ( n = 600 ) or CABG ( n = 605 ) at 67 centers around the world . In Israel , 53 patients at four participating medical centers were r and omized to either PCI with stents ( n = 27 ) or CABG ( n = 26 ) . RESULTS Clinical and angiographic characteristics were similar in the two groups , except for a significantly higher incidence of diabetic patients in Israel who were r and omized to CABG , compared to those worldwide ( 35 % vs. 16 % , P = 0.01 ) . Also , there were more patients with unstable angina in Israel ( 63 vs. 37 % , P = 0.006 ) . At 1 year follow-up , overall mortality and cerebrovascular accident rates were similar between the two groups and equivalent to results obtained around the world . There was a significantly higher incidence of myocardial infa rct ion rates in patients r and omized to stenting in Israel compared to patients worldwide ( 7.4 vs. 5.3 % , P = 0.01 ) or to patients r and omized to CABG in Israel ( 7.4 vs. 0 % , P = 0.006 ) . Similar to the overall ARTS results , there was a higher incidence of repeat revascularization procedures in patients assigned to the PCI with stenting arm ( 22.2 vs. 3.8 % , P = 0.004 ) compared to those r and omized to CABG , respectively . CONCLUSIONS The results of this analysis of the Israeli ARTS population indicate that coronary stenting and bypass surgery yield similar findings with regard to mortality and stroke and are comparable to those obtained in the whole study group . Likewise , coronary stenting was associated with an increased incidence of repeat revascularization procedures as compared to CABG . However , patients in Israel r and omized to stenting had a higher rate of myocardial infa rct ion as compared to the overall results and to patients who underwent CABG in Israel . The present analysis provides important data for the safety and efficacy of either stenting or bypass surgery in treating patients with multivessel disease in Israel OBJECTIVES We sought to compare survival after coronary artery bypass graft ( CABG ) and percutaneous transluminal coronary angioplasty ( PTCA ) in high-risk anatomic subsets . BACKGROUND Compared with medical therapy , CABG decreases mortality in patients with three-vessel disease and two-vessel disease involving the proximal left anterior descending artery ( LAD ) , particularly if left ventricular ( LV ) dysfunction is present . How survival after PTCA and CABG compares in these high-risk anatomic subsets is unknown . METHODS In the Bypass Angioplasty Revascularization Investigation ( BARI ) , 1,829 patients with multivessel disease were r and omized to an initial strategy of PTCA or CABG between 1988 and 1991 . Stents and IIb/IIIa inhibitors were not utilized . Since patients in BARI with diabetes mellitus had greater survival with CABG , separate analyses of patients without diabetes were performed . RESULTS Seven-year survival among patients with three-vessel disease undergoing PTCA and CABG ( n = 754 ) was 79 % versus 84 % ( p = 0.06 ) , respectively , and 85 % versus 87 % ( p = 0.36 ) when only non-diabetics ( n = 592 ) were analyzed . In patients with three-vessel disease and reduced LV function ( ejection fraction < 50 % ) , seven-year survival was 70 % versus 74 % ( p = 0.6 ) in all PTCA and CABG patients ( n = 176 ) , and 82 % versus 73 % ( p = 0.29 ) among non-diabetic patients ( n = 124 ) . Seven-year survival was 87 % versus 84 % ( p = 0.9 ) in all PTCA and CABG patients ( including diabetics ) with two-vessel disease involving the proximal LAD ( n = 352 ) , and 78 % versus 71 % ( p = 0.7 ) in patients with two-vessel disease involving the proximal LAD with reduced LV function ( n = 72 ) . CONCLUSION In high-risk anatomic subsets in which survival is prolonged by CABG versus medical therapy , revascularization by PTCA and CABG yielded equivalent survival over seven years |
1,922 | 23,072,265 | This systematic review found that although reflexology has been shown to have an effect on selected hemodynamic variables , the lack of method ological control for nonspecific general massage effects means that there is little convincing evidence at this time to suggest the existence of a specific treatment-related hemodynamic effect .
Furthermore , the review found that few studies of reflexology controlled for nonspecific effects in order to isolate any specific active component , despite the hemodynamic cl aim being a key part of the therapeutic value of reflexology . | OBJECTIVES Reflexology cl aims that the feet are representative of the body and that massage to specific points of the feet increases blood supply to " mapped " organs in the body .
This review provides the first systematic evaluation of existing reflexology r and omized controlled trials ( RCTs ) to determine whether there is any evidence to suggest the existence of a reflexology treatment-related hemodynamic effect ; to examine whether reflexology research ers used study design s that systematic ally controlled for nonspecific effects in order to isolate this specific component ; and to highlight some of the method ological challenges that need to be overcome to demonstrate specific and beneficial hemodynamic effects . | AIM The objective of this study was to determine whether reflexology has an impact on the quality of life of patients in the palliative stage of cancer . METHOD Twelve patients in the palliative stage of cancer with various tumour types were r and omised into two groups . They were r and omly assigned to receive either reflexology or placebo reflexology . All participants completed a linear analogue self- assessment scale relating to quality of life . All participants then received three sessions of either reflexology or placebo reflexology . The same person , a qualified reflexologist , provided the interventions for both groups . The participants were not aware of which intervention they were receiving . All participants then completed a second linear analogue self- assessment scale relating to quality of life . RESULTS All participants felt that their quality of life had improved , even those who had received the placebo treatment . The reflexology group , however , reported more benefit than the placebo group . There was a significant difference ( p = 0.004 ) between the reflexology group and the placebo group . CONCLUSION This study showed that reflexology does have an impact on the quality of life of patients in the palliative stage of cancer It is known that many patients with obstructive pulmonary diseases use a number of complementary and alternative medicines ( CAM ) . There has been a great deal of interest into the CAM recently , with the House of Lords select committee for science and technology 's report suggesting r and omised-controlled trials are the best means of research ing the area . There is very little research into the effects of reflexology specifically on the effects it has on COPD . As such a r and omised-controlled trial was set up to examine the effects of reflexology treatments on COPD . Results were qualitative and quantitative and showed that there are a number of areas of possible benefit for patients with COPD , but a larger scale study with a longer time frame is needed for a full evaluation of these effects Many specialist palliative care services are under pressure to provide therapies such as aromatherapy , acupuncture or reflexology either by paid staff or volunteers . The evidence to justify the provision of such treatment , however , remains largely anecdotal as controlled clinical trials are difficult to design . Reflexology involves the application of pressure to ` reflex ’ areas of the h and s or feet with the intention of producing specific effects elsewhere in the body . The reflexologist palpates tender or painful areas that , it is suggested , indicate functional imbalance . As well as treatment of specific conditions , it is suggested that reflexology can relax the patient , which may aid selfhealing and prevention of disease . We have therefore conducted a pilot study with a r and omized controlled design to compare reflexology with simple foot massage Integrative therapies such as massage have gained support as interventions that improve the overall patient experience during hospitalization . Cardiac surgery patients undergo long procedures and commonly have postoperative back and shoulder pain , anxiety , and tension . Given the promising effects of massage therapy for alleviation of pain , tension , and anxiety , we studied the efficacy and feasibility of massage therapy delivered in the postoperative cardiovascular surgery setting . Patients were r and omized to receive a massage or to have quiet relaxation time ( control ) . In total , 113 patients completed the study ( massage , n=62 ; control , n=51 ) . Patients receiving massage therapy had significantly decreased pain , anxiety , and tension . Patients were highly satisfied with the intervention , and no major barriers to implementing massage therapy were identified . Massage therapy may be an important component of the healing experience for patients after cardiovascular surgery The study aim ed to compare the effects of facial massage with that of foot massage on sleep induction and vital signs of healthy adults and to test a methodology that could be used by a lone research er in such a study . A r and omised within-group crossover pilot study of six healthy female volunteers was conducted . The interventions were a 20min foot and a 20min facial massage using peach-kernel base oil Prunus persica . A drop in systolic blood pressure of 8.5mmHg was recorded immediately after facial massage compared to that of 1mmHg recorded after foot massage . Both treatments were equally effective in reducing subjective levels of alertness during the interventions , with face massage marginally better at producing subjective sleepiness . A lone research er using these methods would be able objective ly to measure vital signs before and after interventions , but not during ; and would be able subjectively to measure sleep induction in non-sleep-laboratory context BACKGROUND Irritable bowel syndrome ( IBS ) is a significant problem for primary care , as treatment options are limited and it can frequently develop into a chronic condition . Complementary and alternative medicine , including reflexology , is being turned to increasingly in an attempt to manage symptoms . There are currently no studies which address the effectiveness of reflexology for IBS . Despite this , it continues to be advocated and used . AIM To provide the first evidence on the effectiveness of reflexology in the management of the core defining symptoms of IBS . DESIGN OF STUDY A single-blind trial carried out in primary care setting s. SETTING Thirty-four participants diagnosed with IBS on the basis of the Rome Criteria . METHOD Participants were allocated to receive either a reflexology foot massage or a non-reflexology foot massage control group . RESULTS On none of the three symptoms monitored -- abdominal pain , constipation/diarrhoea , and abdominal distention -- was there a statistically or clinical ly significant difference between reflexology and control groups . CONCLUSION On the basis of these results there is nothing to suggest that reflexology produces any specific benefit for patients with IBS . There is currently no evidence to support its use . However this was one ( relatively ) small scale study ; further research that , for example , assesses the impact of therapist ( professional and lay ) versus therapy , is still needed OBJECTIVE This experimental , repeated- measures , crossover design study with nursing home residents examined the efficacy of reflexology in individuals with mild-to-moderate stage dementia . Specifically , the study tested whether a weekly reflexology intervention contributed to the resident outcomes of reduced physiologic distress , reduced pain , and improved affect . SETTING The study was conducted at a large nursing home in suburban Philadelphia . SAMPLE The sample included 21 nursing home residents with mild-to-moderate stage dementia r and omly assigned to two groups . INTERVENTIONS The first group received 4 weeks of weekly reflexology treatments followed by 4 weeks of a control condition of friendly visits . The second group received 4 weeks of friendly visits followed by 4 weeks of weekly reflexology . OUTCOME MEASURES The primary efficacy endpoint was reduction of physiologic distress as measured by salivary alpha-amylase . The secondary outcomes were observed pain ( Checklist of Nonverbal Pain Indicators ) and observed affect ( Apparent Affect Rating Scale ) . RESULTS The findings demonstrate that when receiving the reflexology treatment condition , as compared to the control condition , the residents demonstrated significant reduction in observed pain and salivary alpha-amylase . No adverse events were recorded during the study period . CONCLUSIONS This study provides preliminary support for the efficacy of reflexology as a treatment of stress in nursing home residents with mild-to-moderate stage dementia OBJECTIVE To determine whether foot reflexology , a complementary therapy , has an effect greater than sham reflexology on induction of ovulation . DESIGN Sham-controlled r and omized trial with patients and statistician blinded . SETTING Infertility clinic in Plymouth , United Kingdom . PATIENT(S ) Forty-eight women attending the clinic with anovulation . INTERVENTION(S ) Women were r and omized to receive eight sessions of either genuine foot reflexology or sham reflexology with gentle massage over 10 weeks . MAIN OUTCOME MEASURE(S ) The primary outcome was ovulation detected by serum progesterone level of > 30 nmol/L during the study period . RESULT ( S ) Twenty-six patients were r and omized to genuine reflexology and 22 to sham ( one r and omized patient was withdrawn ) . Patients remained blinded throughout the trial . The rate of ovulation during true reflexology was 11 out of 26 ( 42 % ) , and during sham reflexology it was 10 out of 22 ( 46 % ) . Pregnancy rates were 4 out of 26 in the true group and 2 out of 22 in the control group . Because of recruitment difficulties , the required sample size of 104 women was not achieved . CONCLUSION ( S ) Patient blinding of reflexology studies is feasible . Although this study was too small to reach a definitive conclusion on the specific effect of foot reflexology , the results suggest that any effect on ovulation would not be clinical ly relevant . Sham reflexology may have a beneficial general effect , which this study was not design ed to detect OBJECTIVE To evaluate the effect of reflexology on symptoms of multiple sclerosis ( MS ) in a r and omized , sham-controlled clinical trial . METHODS Seventy-one MS patients were r and omized to either study or control group , to receive an 11-week treatment . Reflexology treatment included manual pressure on specific points in the feet and massage of the calf area . The control group received nonspecific massage of the calf area . The intensity of paresthesias , urinary symptoms , muscle strength and spasticity was assessed in a masked fashion at the beginning of the study , after 1.5 months of treatment , end of study and at three months of follow-up . RESULTS Fifty-three patients completed this study . Significant improvement in the differences in mean scores of paresthesias ( P = 0.01 ) , urinary symptoms ( P = 0.03 ) and spasticity ( P = 0.03 ) was detected in the reflexology group . Improvement with borderline significance was observed in the differences in mean scores of muscle strength between the reflexology group and the controls ( P = 0.06 ) . The improvement in the intensity of paresthesias remained significant at three months of follow-up ( P = 0.04 ) . CONCLUSIONS Specific reflexology treatment was of benefit in alleviating motor ; sensory and urinary symptoms in MS patients OBJECTIVE An influence on organ-associated blood flow is considered as a possible mechanism of action of reflex zone massage of the feet ( FRZM ) therapy . In the present study we investigated whether changes in intestinal blood flow can be achieved by FRZM . MATERIAL AND METHODS 32 healthy adults ( 19 women and 13 men ) were r and omly assigned to the treatment or the placebo group . Subjects of the treatment group received foot massage on the zones assigned to the intestines and those of the placebo group received massage on zones unrelated to the intestines . Before , during and after FRZM , the blood flow velocity , the peak systolic and the end diastolic velocities in the superior mesenteric artery as well as the resistive index as a parameter of vascular resistance were calculated . RESULTS During FRZM , in the subjects of the treatment group there was a significant reduction in the resistive index ( p = 0.021 ) , suggesting an increase in the blood flow in the superior mesenteric artery and the subordinate vascular system . In contrast , there were no significant changes in the resistive index in the subjects of the placebo group . CONCLUSION The reduction in the resistive index observed in the treatment group supports the assumption that FRZM improves blood flow in the organs considered to be associated with the specific foot zones , at least during the therapy process Objective : To determine whether reflexology therapy — the application of manual pressure to reflex points on the ears , h and s , and feet that somatotopically correspond to specific areas of the body — can significantly reduce premenstrual symptoms compared to placebo treatment . Methods : Thirty-five women who complained of previous distress with premenstrual syndrome ( PMS ) were r and omly assigned to be treated by ear , h and , and foot reflexology or to receive placebo reflexology . All subjects completed a daily diary , which monitored 38 premenstrual symptoms on a four-point scale . Somatic and psychological indicators of premenstrual distress were recorded each day for 2 months before treatment , for 2 months during reflexology , and for 2 months afterward . The reflexology sessions for both groups were provided by a trained reflexology therapist once a week for 8 weeks , and lasted 30 minutes each . Results : Analysis of variance for repeated measures demonstrated a significantly greater decrease in premenstrual symptoms for the women given true reflexology treatment than for the women in the placebo group . Conclusion : These clinical findings support the use of ear , h and , and foot reflexology for the treatment of PMS Critical care can be considered to be a stressful environment at both physiological and psychological levels for patients . In this article , a research study in which a five-minute foot massage was offered to 25 patients ( 68 sessions in total ) as a stress-reduction intervention is described . A quasi-experimental repeated measures design was used to collect data before , during and after the intervention . Physiological data ( heart rate , mean arterial blood pressure , respirations and peripheral oxygen saturation ) were obtained from the patient bedside monitoring system . Repeated measures analysis of variance indicated there was no significant effect from the intervention on peripheral oxygen saturation . However , a significant decrease in heart rate , blood pressure and respirations was observed during the foot massage intervention . Results indicated foot massage had the potential effect of increasing relaxation as evidence d by physiological changes during the brief intervention administered to critically ill patients in intensive care Objective Clinical experience suggests that reflexology may have beneficial effects on the symptoms occurring in menopausal women , particularly psychological symptoms . This study aims to examine that effect rigorously BACKGROUND Because of the widely presumed association between heart disease and psychological wellbeing , the use of so-called ' complementary ' therapies as adjuncts to conventional treatment modalities have been the subject of considerable debate . The present study arose from an attempt to identify a safe and effective therapeutic intervention to promote wellbe ing , which could be practicably delivered by nurses to patients in the postoperative recovery period following coronary artery bypass graft ( CABG ) surgery . Aim . To investigate the impact of foot massage and guided relaxation on the wellbeing of patients who had undergone CABG surgery . METHOD Twenty-five subjects were r and omly assigned to either a control or one of two intervention groups . Psychological and physical variables were measured immediately before and after the intervention . A discharge question naire was also administered . RESULTS No significant differences between physiological parameters were found . There was a significant effect of the intervention on the calm scores ( ANOVA , P=0.014 ) . Dunnett 's multiple comparison showed that this was attributable to increased calm among the massage group . Although not significant the guided relaxation group also reported substantially higher levels of calm than control . There was a clear ( nonsignificant ) trend across all psychological variables for both foot massage and , to a lesser extent , guided relaxation to improve psychological wellbeing . Both interventions were well received by the subjects . CONCLUSIONS These interventions appear to be effective , noninvasive techniques for promoting psychological wellbeing in this patient group . Further investigation is indicated Many asthma patients seek alternative or adjunctive therapies . One such modality is reflexology , whereby finger pressure is applied to certain parts of the body . The aim of the study was to examine the popular cl aim that reflexology treatment benefits bronchial asthma . Ten weeks of active or simulated ( placebo ) reflexology given by an experienced reflexologist , were compared in an otherwise blind , controlled trial of 20 + 20 out patients with asthma . Objective lung function tests ( peak flow morning and evening , and weekly spirometry at the clinic ) did not change . Subjective scores ( describing symptoms , beta2-inhalations and quality of life ) and also bronchial sensitivity to histamine improved on both regimens , but no differences were found between groups receiving active or placebo reflexology . However , a trend in favour of reflexology became significant when a supplementary analysis of symptom diaries was carried out . It was accompanied by a significant pattern compatible with subconscious unblinding , in that patients tended to guess which treatment they had been receiving . No evidence was found that reflexology has a specific effect on asthma beyond placebo influence The aim of this study was to examine whether foot reflexology has beneficial effects on patients with idiopathic detrusor overactivity . One hundred and nine women with symptomatic idiopathic detrusor overactivity were r and omized into either foot reflexology treatment group or nonspecific foot massage control group . The primary outcome measure was the change in the diurnal micturition frequency . There was significant change in the number of daytime frequency in the reflexology group when compared with the massage group ( −1.90 vs −0.55 , p = 0.029 ) . There was also a decrease in the 24-h micturition frequency in both groups , but the change was not statistically significant ( −2.80 vs −1.04 p = 0.055 ) . In the reflexology group , more patients believed to have received “ true ” reflexology ( 88.9 vs 67.4 % , p = 0.012 ) . This reflects the difficulty of blinding in trials of reflexology . Larger scale studies with a better- design ed control group and an improved blinding are required to examine if reflexology is effective in improving patients ’ overall outcome OBJECTIVE The current study was design ed as a pilot study for a r and omised controlled trial to investigate the effectiveness of reflexology in the management of low back pain ( LBP ) . MATERIAL S AND METHODS Participants suffering non-specific LBP were recruited and r and omised into either a reflexology or a sham group . Patients and outcome assessor were blinded to group allocation . Each patient received either a 40 min reflexology treatment or sham treatment ( according to group allocation ) once per week for six consecutive weeks . The primary outcome measure was pain ( visual analogue scale ) , secondary outcome measures were the McGill pain question naire , Rol and -Morris disability question naire , and SF-36 health survey . Outcome measures were performed at baseline , week 6 , week 12 and week 18 . RESULTS VAS scores for pain reduced in the treatment group by a median value of 2.5 cm , with minimal change in the sham group ( 0.2 cm ) . Secondary outcome measures produced an improvement in both groups ( McGill pain question naire : 18 points in the reflexology group and 11.5 points in the sham group ) . Results indicate that reflexology may have a positive effect on LBP . CONCLUSION Reflexology appears to offer promise as a treatment in the management of LBP ; however , an adequately powered trial is required before any more definitive pronouncements are possible Swedish massage technique includes mechanically activated muscular tissue and also skin , tendons , fascias , and connected tissue , which indirectly regulates the tonus of the autonomous nervous system . This study set out to examine the effects of Swedish massage on blood pressure . Healthy males were given massage treatment at the Karolinska Hospital , Stockholm , Sweden . Treatment was over a 12-week period divided into three parts , each consisting of 4 weeks . Two treatment periods contained massage treatment either on back , neck and chest ( BNC ) , or leg , arm and face ( LAF ) , with an in between washout period . The first treatment period with massage decreased systolic blood pressure directly after treatment ( BNC : P<0.005 , LAF : P<0.01 ) , but no significant changes were seen in diastolic blood pressure . In the second period , BNC massage decreased systolic ( P<0.005 ) and diastolic ( P<0.005 ) blood pressure whereas LAF massage ( P<0.05 ) increased systolic blood pressure . Swedish massage on the BNC result ed in a minor decrease in blood pressure possibly due to sympathetic inhibition . It may be suggested that massage may be tried as a complementary therapy in patients suffering from increased blood pressure due to stress AIM Our purpose was to pilot test whether reflexology may reduce anxiety in patients undergoing Coronary Artery Bypass Graft Surgery in Icel and . BACKGROUND Nurses need to study the effects of complementary therapies in general and particularly those that may be beneficial to decrease patients ' anxiety . It has been assumed that reflexology lessens anxiety , but research is needed to substantiate such expectations . DESIGN A pilot study using r and omized design with experimental and control groups . METHODS Nine patients were recruited and r and omly assigned into groups with five patients assigned into an experimental group receiving reflexology for 30 minutes and four patients into control group which rested for 30 minutes . Anxiety and physiological variables were measured pre- and post-reflexology sessions once a day over five days . RESULTS The anxiety scores were lower for patients in the control group on all measures . Systolic blood pressure lowered significantly more in the control group than in the treatment group . No significant changes were observed for other variables . Patients ' comments and responses overwhelmingly suggested increased well-being due to both experimental and control intervention . CONCLUSION This study showed little evidence to support reflexology as a mean of reducing anxiety in CABG patients . Several method ological problems were identified that need to be considered further . RELEVANCE TO CLINICAL PRACTICE It is suggested that reflexology should be tailored to individual needs and research methods used that allow for capturing its holistic nature . Further scholarly work is warranted to explore several method ological issues in study ing complementary therapies in a highly complex treatment situation Using colour Doppler sonography blood flow changes of the right kidney during foot reflexology were determined in a placebo-controlled , double-blind , r and omised study . 32 healthy young adults ( 17 women , 15 men ) were r and omly assigned to the verum or placebo group . The verum group received foot reflexology at zones corresponding to the right kidney , the placebo group was treated on other foot zones . Before , during and after foot reflexology the blood flow of three vessels of the right kidney was measured using colour Doppler sonography . Systolic peak velocity and end diastolic peak velocity were measured in cm/s , and the resistive index , a parameter of the vascular resistance , was calculated . The resistive index in the verum group showed a highly significant decrease ( p < /= 0.001 ) during and an increase ( p = 0.001 ) after foot reflexology . There was no difference between men and women and no difference between smokers and non-smokers . Verum and placebo group significantly differed concerning alterations of the resistive index both between the measuring points before versus during foot reflexology ( p = 0.002 ) and those during versus after foot reflexology ( p = 0.031 ) . The significant decrease of the resistive index during foot reflexology in the verum group indicates a decrease of flow resistance in renal vessels and an increase of renal blood flow . These findings support the hypothesis that organ-associated foot reflexology is effective in changing renal blood flow during therapy |
1,923 | 16,215,368 | CONCLUSIONS Ventilator-associated pneumonia occurs in a considerable proportion of patients undergoing mechanical ventilation and is associated with substantial morbidity , a two-fold mortality rate , and excess cost . | BACKGROUND Ventilator-associated pneumonia ( VAP ) is the most common nosocomial infection in critically ill patients .
The clinical and economic consequences of VAP are unclear , with a broad range of values reported in the literature OBJECTIVE To perform a systematic review to determine the incidence of VAP and its attributable mortality rate , length of stay , and costs . | Objective To determine the attributable cost of ventilator-associated pneumonia from a hospital-based cost perspective , after adjusting for potential confounders . Design Patients admitted between January 19 , 1998 , and December 31 , 1999 , were followed prospect ively for the occurrence of ventilator-associated pneumonia . Hospital costs were defined by using the hospital cost accounting data base . Setting The medical and surgical intensive care units at a suburban , tertiary care hospital . Patients Patients requiring > 24 hrs of mechanical ventilation . Interventions None . Measurements and Main Results We measured occurrence of ventilator-associated pneumonia , in-hospital mortality rate , total intensive care unit ( ICU ) and hospital lengths of stay ( LOS ) , and total hospital cost per patient . Ventilator-associated pneumonia occurred in 127 of 819 patients ( 15.5 % ) . Compared with uninfected , ventilated patients , patients with ventilator-associated pneumonia had a higher Acute Physiology and Chronic Health Evaluation II score on admission ( p < .001 ) and were more likely to require multiple intubations ( p < .001 ) , hemodialysis ( p < .001 ) , tracheostomy ( p < .001 ) , central venous catheters ( p < .001 ) , and corticosteroids ( p < .001 ) . Patients with ventilator-associated pneumonia were more likely to be bacteremic during their ICU stay ( 36 [ 28 % ] vs. 22 [3%];p < .001 ) . Patients with ventilator-associated pneumonia had significantly higher unadjusted ICU LOS ( 26 vs. 4 days;p < .001 ) , hospital LOS ( 38 vs. 13 days;p < .001 ) , mortality rate ( 64 [ 50 % ] vs. 237 [34%];p < .001 ) , and hospital costs ( $ 70,568 vs. $ 21,620 , p < .001 ) . Multiple linear regression , controlling for other factors that may affect costs , estimated the attributable cost of ventilator-associated pneumonia to be $ 11,897 ( 95 % confidence interval = $ 5,265–$26,214;p < .001 ) . Conclusions Patients with ventilator-associated pneumonia had significantly longer ICU and hospital LOS , with higher crude hospital cost and mortality rate compared with uninfected patients . After we adjusted for underlying severity of illness , the attributable cost of ventilator-associated pneumonia was approximately $ 11,897 Objective : To evaluate the effect of a method of Selective Decontamination of the Digestive Tract ( SDD ) on colonization , nosocomial infection ( NI ) , bacterial resistance , mortality and economic costs . Design : R and omized , double blind , placebo controlled study . Setting : Polyvalent intensive care unit ( ICU ) of a tertiary care hospital with 27 beds . Patients : 101 patients with > 3 days of mechanical ventilation and > 5 days of stay , without infection at the start of the study . 47 belonged to the Treated Group ( TG ) and 54 to the Placebo Group ( PG ) . Interventions : The TG was given Cefotaxime i.v . ( 6 g/day ) for the first four days and an association of Polymyxin E , Tobramycin and Amphothericin B at the oropharyngeal and gastrointestinal level throughout the whole stay . Results : In the TG , colonization by gram-negative agents at oropharyngeal , tracheal and gastrointestinal level fell significantly . There was a significant drop in the overall , respiratory and urinary NI ( 26 % vs 63%,p<0.001 ; 15 % vs 46%,p<0.001 ; 9 % vs 31%,p<0.01 ) . The overall mortality and NI related mortality was less in the TG ( 21 % vs 44%,p<0.05 ; 2 % vs 20%,p<0.01 ) . The economic costs , mechanical ventilation time and length of stay were similar . The percentage of bacterial isolations resistant to Cefotaxime and Tobramycin was greater in the TG ( 38 % vs 15 % and 38 % vs 9%,p<0.001 ) . Conclusions : colonization by gram-negative bacilli , NI and the mortality related to it can be modified by SDD . Continuous bacteriological surveillance is necessary BACKGROUND The purpose of this study was to compare the performance of heat and moisture exchanger filters with heated humidifying systems in the mechanical ventilator circuit on the incidence of ventilator-associated pneumonia ( VAP ) and bacterial colonization . METHOD Two hundred and forty-three consecutive patients who required mechanical ventilation for 48 hours or more in the adult intensive care unit were r and omized to either a heat and moisture exchanger ( HME ) or a heated humidifying breathing circuit . RESULTS The VAP rate among the group with HME was 11.4 % ; the rate among the group with heated humidifying system ( HHS ) was 15.8 % . The difference was not statistically significant . Approximately 68 % of the patients in the HME group had no pathogen isolated compared with 50 % of the patients in the HHS group . This difference was statistically significant ( P = .006 ) . However , the distribution of the pathogens among those patients who had the isolated pathogens was mostly identical in the 2 groups . CONCLUSION Even though the study did not find HME to be significantly advantageous over the HHS , in as much as VAP rate is concerned , other advantages such as reduced nurses workload , reduced financial cost , and better safety made HME a more favorable device for use in our adult intensive care unit STUDY OBJECTIVE To determine the cost-effectiveness of continuous subglottic suctioning ( CSS ) as a strategy to decrease the incidence of ventilator-associated pneumonia ( VAP ) . DESIGN Decision-model analysis of the cost and efficacy of endotracheal tubes that allow CSS at preventing VAP . The primary outcome was cases of VAP averted . Model estimates were based on data from published prospect i ve trials of CSS and other prospect i ve studies of the incidence of VAP . SETTING AND PATIENTS Hypothetical cohort of 100 patients requiring nonelective endotracheal intubation and management in an ICU . INTERVENTIONS In the model , patients were managed with either traditional endotracheal tubes ( ETs ) or ETs capable of CSS . MEASUREMENTS AND MAIN RESULTS The marginal cost-effectiveness of CSS was calculated as the savings result ing from cases of VAP averted minus the additional costs of CSS-ETs , and expressed as cost ( or savings ) per episode of VAP prevented . Sensitivity analysis of the impact of the major clinical inputs on the cost-effectiveness was performed . The base case assumed that the incidence of VAP in patients requiring > 72 h of mechanical ventilation ( MV ) was 25 % , that CSS-ETs had no impact on patients requiring MV for < 72 h , and that CSS-ETs result ed in a relative risk reduction of VAP of 30 % . Despite the higher costs of ETs capable of CSS , this tactic yielded a net savings of $ 4,992 per case of VAP prevented . For sensitivity analysis , model inputs were adjusted by 50 % individually and then simultaneously . This demonstrated the model to be only moderately sensitive to the calculated cost of VAP . With the relative risk reduction at 50 % of the base-case estimate , CSS result ed in $ 1,924 saved per case of VAP prevented . When all variables were skewed against CSS , total outlays were trivial ( approximately $ 14 per patient in the cohort ) . CONCLUSIONS CSS represents a strategy for the prevention of VAP that may result in savings . Further studies are warranted to confirm the efficacy of CSS Risk factors for the development of ventilator-associated pneumonia ( VAP ) , as identified in epidemiological studies , have provided a basis for testable interventions in r and omized trials . We describe how these results have influenced patient treatment . Single interventions in patients undergoing intubation have focused on either reducing aspiration of oropharyngeal secretions , modulation of colonization ( in either the oropharynx , the stomach , or the whole digestive tract ) , use of systemic antimicrobial prophylaxis , or ventilator circuit changes . More recently , multiple simultaneously implemented interventions have been used . In general , routine measures to decrease oropharyngeal aspiration and antibiotic-containing prevention strategies appear to be the most effective , and the latter were associated with improved rates of patient survival in recent trials . These benefits must be balanced against the widespread fear of emergence of antibiotic resistance . In hospital setting s with low baseline levels of antibiotic resistance , however , the benefits to patient outcome may outweigh this fear of resistance . In setting s with high levels of antibiotic resistance , combined approaches of non-antibiotic using strategies and education programs might be most beneficial STUDY OBJECTIVE To compare the clinical outcomes of critically ill patients developing early-onset nosocomial pneumonia ( NP ; ie , within 96 h of ICU admission ) and late-onset NP ( ie , occurring after 96 h of ICU admission ) . DESIGN Prospect i ve cohort study . SETTING A medical ICU and a surgical ICU from a university-affiliated urban teaching hospital . PATIENTS Between July 1997 and November 1998 , 3 , 668 patients were prospect ively evaluated . INTERVENTION Prospect i ve patient surveillance and data collection . RESULTS Four hundred twenty patients ( 11.5 % ) developed NP . Early-onset NP was observed in 235 patients ( 56.0 % ) , whereas 185 patients ( 44.0 % ) developed late-onset NP . Among patients with early onset NP , 114 patients ( 48 . 5 % ) spent at least 24 h in the hospital prior to ICU admission , compared to 57 patients ( 30.8 % ) with late-onset NP ( p = 0.001 ) . One hundred eighty-three patients ( 77.9 % ) with early-onset NP received antibiotics prior to the development of NP , as compared to 162 patients ( 87.6 % ) with late-onset NP ( p = 0.010 ) . The most common pathogens associated with early-onset NP were Pseudomonas aeruginosa ( 25.1 % ) , oxacillin-sensitive Staphylococcus aureus ( OSSA ; 17.9 % ) , oxacillin-resistant S aureus ( ORSA ; 17.9 % ) , and Enterobacter species ( 10.2 % ) . P aeruginosa ( 38.4 % ) , ORSA ( 21.1 % ) , Stenotrophomonas maltophilia ( 11.4 % ) , OSSA ( 10.8 % ) , and Enterobacter species ( 10.3 % ) were the most common pathogens associated with late-onset NP . The ICU length of stay was significantly longer for patients with early-onset NP ( 10.3 + /- 8.3 days ; p < 0.001 ) and late-onset NP ( 21 . 0 + /- 13.7 days ; p < 0.001 ) , as compared to patients without NP ( 3.5 + /- 3.2 days ) . Hospital mortality was significantly greater for patients with early-onset NP ( 37.9 % ; p = 0.001 ) and late-onset NP ( 41.1 % ; p = 0.001 ) compared to patients without NP ( 13.1 % ) . CONCLUSIONS Both early-onset and late-onset NP are associated with increased hospital mortality rates and prolonged lengths of stay . The pathogens associated with NP were similar for both groups . This may be due , in part , to the prior hospitalization and use of antibiotics in many patients developing early-onset NP . These data suggest that P aeruginosa and ORSA can be important pathogens associated with early-onset NP in the ICU setting . Additionally , clinicians should be aware of the common microorganisms associated with both early-onset NP and late-onset NP in their hospitals in order to avoid the administration of inadequate antimicrobial treatment Nosocomial pneumonia is the leading cause of death among all hospital-acquired infections [ 1 ] . The estimated incidence of nosocomial pneumonia in intensive care units ranges from 10 % to 65 % ; most studies [ 2 - 6 ] show case fatality rates of more than 20 % . Ventilator-associated pneumonia specifically refers to nosocomial pneumonia that develops in a mechanically ventilated patient and that was not present at the time of airway intubation [ 7 ] . Various clinical risk factors have been associated with an increased incidence of ventilator-associated pneumonia , either because they predispose the patient to bacterial colonization of the oropharynx and stomach ( for example , the administration of antacids or histamine-2-receptor antagonists ) or because they facilitate aspiration of contaminated contents from these sites ( for example , supine positioning ) [ 1 , 2 , 8 , 9 ] . Craven and colleagues [ 10 ] first showed that the frequency of ventilator circuit changes also influences the incidence of ventilator-associated pneumonia . They found that changing circuits every 24 rather than every 48 hours was independently associated with the occurrence of nosocomial pneumonia [ 10 ] . This association has been attributed to increased manipulation of the patient , the endotracheal tube , and the ventilator circuit , which results in increased aspiration of contaminated tubing condensate or upper airway secretions [ 10 , 11 ] . More recently , several groups of investigators have found that ventilator circuits can be used safely for more than 48 hours without increasing the incidence of nosocomial pneumonia [ 12 - 16 ] . However , because of limitations in the design of these studies and the small number of patients prospect ively examined , the Centers for Disease Control and Prevention has given no clear recommendation for the maximum length of time that ventilator circuits can safely be left in place during prolonged mechanical ventilation [ 17 ] . This has result ed in the development of ambiguous guidelines about the frequency with which ventilator circuits should be changed [ 18 , 19 ] and in a call for well- design ed investigations to resolve this issue [ 20 ] . We did a r and omized , controlled trial to compare the effect and cost-efficacy of routine and no routine ventilator circuit changes in patients having prolonged mechanical ventilation . Our main goals were to determine 1 ) the incidence and outcome of ventilator-associated pneumonia in patients receiving scheduled ventilator circuit changes and 2 ) whether this incidence was increased in patients whose ventilator circuits remained unchanged . Methods Study Location and Patients The study was conducted at two university-affiliated teaching hospitals : Barnes Hospital ( 900 beds ) and Jewish Hospital ( 450 beds ) . During a 7-month period ( June 1994 to December 1994 ) , all patients receiving mechanical ventilation in the intensive care units of these hospitals ( surgical , trauma , medical , cardiothoracic , and neurosurgical units at Barnes Hospital ; surgical , medical , and cardiothoracic units at Jewish Hospital ) were potentially eligible for this investigation . Patients were entered into the trial if they were older than 18 years and had received mechanical ventilation for more than 5 days . Mechanical ventilation for more than 5 days was predetermined , on the basis of our previous experience at these institutions [ 2 , 21 ] , to be necessary so that a more homogeneous cohort of patients requiring prolonged mechanical ventilation could be accrued . Patients were excluded if they were likely to be extubated within 24 hours of r and omization , if they had transferred from other hospitals and had already received mechanical ventilation for more than 24 hours , if they had had lung transplantation , or if they had active hemoptysis . Barnes Hospital and Jewish Hospital share the same respiratory therapy and infection control departments . The study was approved by the Washington University School of Medicine Human Studies Committee and the Institutional Review Board of Jewish Hospital . Both waived the requirement for informed consent because this study was a quality assessment of two low-risk practice s already in clinical use . Study Design Patients were r and omly assigned to receive no routine ventilator circuit changes or circuit changes every 7 days within 24 hours of meeting eligibility criteria . A schedule of changing ventilator circuits every 7 days was selected on the basis of available clinical data [ 12 - 16 ] and our survey of 16 regional medical centers ( DM Baker . Unpublished communication ) . Stratification according to hospital site was done before r and omization to control for differences in patient population s and health care personnel . R and omization within each hospital was done using opaque , sealed envelopes , which were opened at the time each patient was enrolled in the study . For the purpose s of this investigation , ventilator circuits were defined to include gas delivery tubing , humidifier water reservoirs , water traps , and medication delivery devices ( such as metered-dose inhaler chambers or adapters ) . Ventilator circuits could be changed at any time , at the discretion of individual care providers ( physicians , nurses , and respiratory therapists ) , secondary to a mechanical failure of the ventilator circuit ( such as an air leak ) or visible soil ( such as that result ing from hemoptysis or aspirated emesis ) . Scheduled ventilator circuit changes were done during the evening or night shifts to minimize the identification of individual patient group assignments to blinded investigators . All nonscheduled circuit changes were done when an appropriate indication for the circuit change ( that is , a mechanical defect or soil ) was identified . Patients transferred to the operating room for a surgical procedure ( such as tracheotomy ) or to diagnostic radiology received the same mechanical ventilator and circuit when they returned to the intensive care unit . The ventilators used for this study included Siemens Servo 900C ( Siemens-Elema Ventilator Systems , Schaumburg , Illinois ) , Puritan-Bennett 700 Series ( Puritan-Bennett Corporation , Carlsbad , California ) , and Bird 8400 Series ventilators ( Bird Products Corporation , Palm Springs , California ) . All ventilators were equipped with wick-type humidifiers ( Concha Therm III Plus , Hudson Respiratory Care , Inc. , Temecula , California ) filled with sterile irrigation water . All ventilator circuits were disposable ( Hudson Respiratory Care , Inc. , model 1613 ) and equipped with Y connectors . Each ventilator circuit had an attached trap for the collection of tubing condensate ( Marquest Medical Products , Inc. , Englewood , Colorado ) . As per our st and ard procedure , all ventilator circuits were monitored at least every 2 hours and water traps were emptied when full . Data Collection For all study patients , the following characteristics were prospect ively recorded by one of the investigators : age , sex , diagnosis at hospital admission , indication for mechanical ventilation , Premorbid Lifestyle score , the ratio of arterial blood oxygen tension to the concentration of inspired oxygen ( Pao 2 : Fio 2 ) , severity of illness based on APACHE II ( Acute Physiology and Chronic Health Evaluation [ 22 ] ) scores , the Organ System Failure Index , and the occurrence of a witnessed aspiration event . Specific processes of medical care examined to assess risk factors for ventilator-associated pneumonia were the administration of antacids or histamine-2-receptor antagonists , pharmacologic aerosol treatments during mechanical ventilation ( such as bronchodilators , antibiotics , and mucolytics ) , fiberoptic bronchoscopy , surgical tracheostomy , and the number of ventilator circuit changes done and the indications for those changes ( scheduled according to the study protocol , soil , or mechanical defect ) . Two of the investigators made daily rounds in the intensive care units of each hospital to identify eligible patients . Patients entered into the study were prospect ively followed for the occurrence of ventilator-associated pneumonia until they were successfully weaned from mechanical ventilation , were discharged from the hospital , or died . All patients suspected by these investigators of having ventilator-associated pneumonia were prospect ively and independently review ed by another investigator who was blinded to the patient 's treatment group assignment . The diagnosis of ventilator-associated pneumonia was strictly based on the predetermined criteria described below . Patients could not be entered into the study more than once during the same hospitalization , and only the first episode of ventilator-associated pneumonia was evaluated . In addition to the occurrence of ventilator-associated pneumonia , secondary outcomes assessed included the length of hospitalization , the duration of mechanical ventilation , hospital mortality , and mortality directly attributed to ventilator-associated pneumonia . All study variables were recorded in data collection books maintained at each of the participating hospitals . Definitions All definitions were selected prospect ively as part of the original study design . The Premorbid Lifestyle score was used as previously defined [ 23 ] : Zero indicated that the patient was employed without restriction ; 1 indicated that the patient was independent , fully ambulatory , not employed , or employed with restriction ; 2 indicated that the patient had restricted activities , could live alone and get out of the house to do basic necessities , or had severely limited exercise ability ; 3 indicated that the patient was housebound , could not get out of the house unassisted , could not live alone , or could not do heavy chores ; and 4 indicated that the patient was bed- or chairbound . We calculated APACHE II scores on the basis of clinical data available from the 24-hour period before study enrollment ( day 5 of mechanical ventilation ) . The Organ System Failure Index was modified from that used by Rubin and coworkers [ 24 ] . One point was given for Objective : To evaluate the attributable mortality associated with late-onset nosocomial pneumonia ( LOP ) while taking into account the severity at admission , the evolution of the patients during the first 4 days after admission to the ICU and the appropriateness of initial empiric antibiotic treatment . Design : Multicenter cohort study with prospect i ve st and ardization of diagnostic interventions when nosocomial pneumonia develops . Setting : Medical and surgical ICUs of four university-affiliated teaching hospitals . Patients : Seven hundred sixty-four consecutive patients requiring ICU hospitalization for at least 4 days . Main outcome measures : The clinical and biological data as well as the therapeutic data and the outcome were prospect ively recorded from the day of admission to ICU discharge . Simplified Acute Physiologic Score ( SAPS II ) and Logistic Organ Dysfunction ( LOD ) score were collected and computed within the first 4 calendar days of ICU admission . Variables associated with the outcome were selected using a stepwise Cox model . The time to acquisition of the first LOP was then introduced in the final model as a time-dependent covariate . The analysis was stratified by ICU center . Finally , as initial antibiotic therapy could have an impact on the increased risk of death induced by LOP , the Cox model was applied again introducing LOP immediately adequately treated and LOP not immediately adequately treated as two different time-dependent covariates . Results : Late-onset pneumonia developed in 89 patients ( 12 % ) . A McCabe score of more than 1 , SAPS II score and increases in SAPS between days 1 and 2 , days 2 and 3 , and days 3 and 4 were significantly associated with an increased risk of death . When the time to acquisition of the first episode of LOP was introduced into the Cox model , the LOP occurrence was associated with increased mortality , even adjusted over the selected prognostic parameters and after stratification by center ( hazard ratio (HR)=1.53 , 95 % CI 1.02–2.3 , p=0.04 ) . When LOP immediately adequately treated and LOP not immediately adequately treated were separately introduced into the Cox model , inappropriately treated LOP remained significantly associated with an increased risk of mortality ( HR=1.69 , 95 % CI 1.08–2.65 , p=0.022 ) , whereas appropriately treated LOP did not ( HR=1.44 , 95 % CI 0.75–2.76 , p=0.27 ) . Conclusion : These data suggest that , in addition to severity scores , the underlying medical conditions and the evolution of severity within the first 4 days in ICU , late-onset pneumonia independently contribute to ICU patient mortality when empirical antibiotic treatment is not immediately appropriate Patients admitted during the study period to the Sharp Memorial Hospital intensive-care units who required mechanical ventilation were followed prospect ively ; 15 ( 10.4 % ) of 145 acquired ventilator-associated pneumonia ( VAP ) . Duration of prior oral or nasal intubation and H2 receptor antagonists use were longer among patients who developed VAP than among those who did not . Prior cefazolin use was associated with a higher rate of VAP ( 11 of 63 [ 17 % ] versus 4 of 82 [ 5 % ] , P = .01 ) Nosocomial pneumonia develops in 0.5 to 1 patient per 100 hospital admissions and is associated with high morbidity and mortality [ 1 , 2 ] . Mechanically ventilated patients have a high risk for developing nosocomial pneumonia ; indeed , ventilator-associated pneumonia has a cumulative incidence ranging from 18 % to 60 % , and it was found in more than 70 % of patients who died of acute lung injury [ 3 - 6 ] . Nosocomial pneumonia is frequently caused by gram-negative bacilli and usually results from aspiration of bacteria from the colonized oropharynx [ 7 - 9 ] . Colonization of the pharynx by gram-negative bacilli [ 9 - 12 ] is associated with chronic illness and previous use of antibiotic agents and endotracheal intubation ; in the pathogenesis of ventilator-associated pneumonia , the relation between chronic aspiration of colonized secretions through a tracheal cuff and the development of pneumonia is well established [ 13 , 14 ] . Several strategies , such as infection-control measures ( for example , h and -washing ) [ 15 , 16 ] , preservation of a normal gastric pH , or topical administration of a nonabsorbable antibiotic combination ( selective digestive decontamination ) have been recommended to decrease the incidence of ventilator-associated pneumonia [ 17 - 19 ] . However , further investigation is required to define the role of selective digestive decontamination in selected patients in intensive care units ; in addition , there is considerable concern about the risk for selection of resistant strains . Recently , two studies suggested the possibility of preventing the chronic aspiration of subglottic secretions either by changes in body position [ 20 ] or by manual intermittent aspiration of subglottic secretions [ 21 ] , two alternative approaches for preventing ventilator-associated pneumonia . We evaluated the usefulness of continuous aspiration of subglottic secretions in the prevention of ventilator-associated pneumonia in a medicalsurgical intensive care unit . Methods Patients All patients admitted to the intensive care unit of the Sabadell Hospital from June 1990 to March 1993 who required intubation and were expected to receive mechanical ventilation for at least 72 hours were eligible for study . The intubation could be done either in the intensive care unit or in the emergency department . Patients were excluded if they were intubated in other areas of the hospital , if they carried a tracheostomy tube , or if they developed a pneumonia or died during the first 72 hours of mechanical ventilation . Study was considered complete when a patient was extubated , when a tracheostomy was done , when a patient died , or when ventilator-associated pneumonia was diagnosed . The follow-up period consisted of the patient 's remaining stay in the intensive care unit . All patients were intubated with the same type of endotracheal tube ( Hi-Lo Evac ; Mallinckrodt Laboratories , Athlone , Irel and ) , which incorporates a dorsal separate lumen ending into the subglottic area by creating a large elliptical dorsal opening above the cuff for aspiration of subglottic secretions ( Figure 1 ) . The size of each endotracheal tube was selected by the attending physician ; after intubation , the correct position of endotracheal tube was verified by a roentgenogram of the chest . Figure 1 . Diagram of continuous aspiration of subglottic secretions . Patients were r and omly assigned to receive continuous aspiration through the additional lumen from the endotracheal tube ( case- patients ) or to receive st and ard treatment in which the additional lumen remained closed ( control patients ) . Intra-cuff pressure was monitored every 4 hours ( Mallinckrodt GmbH , Mallinckrodt Laboratories , Neunkirchen-Seelscheid , Germany ) and was kept above 20 mm Hg . Subglottic drainage was continuous , and secretions were collected in a mucous collector ( Mocstrap ; Proclinics , Barcelona , Spain ) . The amount of secretions obtained daily was also recorded . If subglottic drainage was negative , the permeability was checked every 4 hours by injecting sterile saline serum into the evacuation lumen . All patients received stress ulcer prophylaxis with sucralfate . We did not use a selective decontamination regimen or antibiotic prophylaxis . The study protocol was review ed and approved by the hospital 's institutional review board for human studies . Data Collection and Definitions We prospect ively recorded each patient 's demographic characteristics , diagnosis at admission , and underlying diseases . The Acute Physiology and Chronic Health Evaluation ( APACHE ) II scoring system of Knaus and colleagues [ 22 ] was used to assess the severity of an acute illness . Several risk factors for ventilator-associated pneumonia were recorded , such as continuous sedation , previous surgery , multiple trauma , structural or pharmacologic coma ( score of 8 according to the Glasgow coma scale [ 23 ] ) , and use of muscle relaxants and antibiotic treatment during the intensive care unit stay . Ventilator-associated pneumonia was suspected in patients who met the following criteria after 72 hours of mechanical ventilation : fever ( body temperature 38.3 C ) , leukocytosis ( > 12 000 leukocytes/mm3 ) or leukopenia ( < 4000 leukocytes/mm3 ) , purulent secretions , and the presence of new and persistent pulmonary infiltrates . The diagnosis of pneumonia was confirmed by a positive protected specimen brush culture containing 103 colony-forming units (CFU)/mL or more , a positive bronchoalveolar lavage culture with 104 CFU/mL or more , or by a good clinical response to antibiotic agents . Additional criteria were the absence of a diagnosis other than pneumonia and pathologic findings consistent with pneumonia in patients who died and in whom autopsy was authorized . Ventilator-associated pneumonia was histologically diagnosed when foci of consolidation with intense polymorphonuclear leukocyte accumulation in the bronchioles and alveolar spaces were observed . Roentgenograms of the chest were interpreted by a radiologist who had no knowledge of patients ' treatment groups . Crude mortality rates included all deaths that occurred in the intensive care unit in patients with ventilator-associated pneumonia . Death was considered attributable to the pulmonary infection if the patient died before having any objective response to antimicrobial therapy or if the pulmonary infection was considered a contributing factor to death in patients with additional conditions . We used the definitions described by Knaus and colleagues [ 22 ] to define the underlying diseases . We considered previous surgery when a surgical procedure had been done within the present admission to the hospital and considered previous antibiotic treatment when a patient was receiving antibiotic agents at r and omization . Bacteriologic Examination In patients in whom ventilator-associated pneumonia was suspected , bronchoscopy was done while they were being ventilated with an Fio 2 of 1.0 and without positive end-expiratory pressure . All patients received midazolam as a sedative and atracurium as a relaxant while the bronchoscopy was done . The fiberoptic bronchoscope ( Olympus BF 20 ; Olympus Corp. , Tokyo , Japan ) was passed into the trachea through the endotracheal tube by a special connector ( Unimed Ltd. , Shaftesbury , United Kingdom ) and was advanced under visual control to the bronchial orifice of the abnormal lobe . The telescoping plugged catheter ( TAG Medical , Bobigny Cedex , France ) was inserted through the inner suction channel and was advanced to a wedged peripheral position . Airway secretions were obtained using a previously described technique [ 24 ] . For a bronchoalveolar lavage , the bronchoscope was sustained in a wedged position , and lavage was done with three 50-mL aliquots of sterile isotonic saline . The bronchoscope was then removed , and ventilation with an Fio 2 of 1.0 was continued for 15 minutes . After the protected specimen brush was transected into a sterile vial containing 1 mL of sterile lactate Ringer 's solution , the vial was vigorously agitated for at least 60 seconds to suspend all the material from the brush . Specimens were immediately sent to the laboratory for quantitative cultures . Aliquots of 0.01 mL were then taken from the original suspension and inoculated into blood agar , chocolate agar , anaerobic kanamicin blood agar , anaerobic blood agar , MacConkey agar , buffered charcoal yeast extract agar , and Sabouraud media . One 0.001-mL aliquot was also inoculated into chocolate agar media . Culture plates were incubated at 37 C under adequate aerobic and anaerobic conditions ; all plates except for the Sabouraud plates were evaluated for growth at 24 and 48 hours . For the protected specimen brush , bacterial counts of 103 CFU/mL or greater were used as the cutoff point to diagnose pneumonia . Two serial 10-fold dilutions were then done on the recovered bronchoalveolar lavage fluid , and 0.01-mL aliquots of the original suspension and each dilution were placed onto plates in the same way as for the protected specimen brush sample . All protected specimen brush and bronchoalveolar lavage fluid isolates were identified by st and ard laboratory techniques [ 25 ] . Two blood cultures were done simultaneously in all patients , as were pleural fluid cultures if present . Surveillance cultures for aerobic microorganisms in the subglottic secretions were obtained from patients in the continuous aspiration group and were repeated every 5 days until ventilator-associated pneumonia developed or until patients were extubated or died . Statistical Analysis We compared the characteristics of the two groups using the Student t-test or Mann-Whitney test for continuous variables and the chi-square test or Fisher exact test for categorical variables . We defined the cumulative incidence as the number of events divided by the number of patients and estimated risk ratios and 95 % CIs [ 26 ] . The incidence rate was defined as the number of events divided by the number of days the patient was at risk because of the presence of an endotracheal tube . We compared OBJECTIVE To determine whether selective decontamination of the digestive tract using oral and nonabsorbable antimicrobial agents and parenteral cefotaxime prevents infection in critically ill patients . DESIGN R and omized , controlled trial without blinding . SETTING Surgical trauma and medical intensive care units in a tertiary referral hospital . PATIENTS One hundred fifty patients admitted to surgical trauma and medical intensive care units during a 3-year interval , whose condition suggested a prolonged stay ( greater than 3 days ) . INTERVENTION Patients were r and omly allocated to an experimental group ( n = 75 ) that received cefotaxime , 1 g intravenously every 8 hours for the first 3 days only , and oral , nonabsorbable antibiotics ( gentamicin , polymyxin , and nystatin by oral paste and oral liquid ) for the entire stay in the intensive care unit . Control patients ( n = 75 ) received usual care . MEASUREMENTS The number of infections , total hospital days , and deaths , as well as the number of days in intensive care unit , were recorded . RESULTS Control patients experienced more infections ( 36 compared with 12 , P = 0.04 ) , including bacteremias ( 14 compared with 4 , P = 0.05 ) and pulmonary infections ( 14 compared with 4 , P = 0.03 ) . Although total hospital days , days in intensive care , and the overall death rate all were lower in the treatment group , these differences were not statistically significant . Clinical ly important complications of selective decontamination of the digestive tract were not encountered . CONCLUSIONS Selective decontamination of the digestive tract decreases subsequent infection rates , especially by gram-negative bacilli , in selected patients during long-term stays in the intensive care unit STUDY OBJECTIVE To determine whether the development of late-onset ventilator-associated pneumonia ( VAP ) is associated with an increased risk of hospital mortality . DESIGN Prospect i ve cohort study . SETTING ICUs of two university-affiliated teaching hospitals . PATIENTS Three hundred fourteen patients admitted to an ICU who required mechanical ventilation for greater than 5 days . INTERVENTIONS Prospect i ve patient surveillance and data collection . MEASUREMENTS The primary outcome measures were the development of late-onset VAP ( ie , occurring > 96 h after intubation ) and hospital mortality . RESULTS Late-onset VAP was observed in 87 patients ( 27.7 % ) . Thirty-four ( 39.1 % ) patients with late-onset VAP died during hospitalization compared with 85 patients ( 37.4 % ) without late-onset VAP ( relative risk , 1.04 ; 95 % confidence interval [ CI ] , 0.76 to 1.43 ) . Twenty patients ( 6.4 % ) developed late-onset VAP due to a " high-risk " pathogen ( ie , Pseudomonas aeruginosa , Acinetobacter sp , Xanthomonas maltophilia ) with an associated mortality rate of 65 % . Stepwise logistic regression analysis identified five variables as independent risk factors for hospital mortality ( p < 0.05 ) : an organ system failure index of 3 or greater ( adjusted odds ratio [ AOR ] , 3.4 ; 95 % CI , 2.0 to 5.8 ; p < 0.001 ) , having a nonsurgical diagnosis ( AOR , 2.1 ; 95 % CI , 1.3 to 3.6 ; p = 0.002 ) , a premorbid lifestyle score of 2 or greater ( AOR , 1.8 ; 95 % CI , 1.1 to 2.9 ; p = 0.015 ) , acquiring late-onset VAP due to a " high-risk " pathogen ( AOR , 3.4 ; 95 % CI , 1.2 to 10.0 ; p = 0.025 ) , and having received antacids or histamine type-2 receptor antagonists ( AOR , 1.7 ; 95 % CI , 1.0 to 2.9 ; p = 0.034 ) . Additionally , we found the occurrence of late-onset VAP due to high-risk pathogens to be the most important predictor of hospital mortality among patients developing VAP ( AOR , 5.4 ; 95 % CI , 2.8 to 10.3 ; p = 0.009 ) . CONCLUSIONS Nosocomial pneumonia due to certain high-risk microorganisms is an independent risk factor for hospital mortality among patients requiring prolonged mechanical ventilation . We suggest that future investigations of late-onset VAP stratify patient outcomes according to the distribution of high-risk pathogens when reporting their results Background Mechanical ventilator circuits are commonly changed at 48-h intervals . This frequency may be unnecessary because ventilator-associated pneumonia often results from aspiration of pharyngeal secretions and not from the ventilator circuit . We compared the ventilator-associated pneumonia rates and costs associated with 48-h and 7-day circuit changes . Methods Ventilator circuits were changed at 48-h intervals during the control period ( November 1992 to April 1993 ) and at 7-day intervals during the study period ( June 1993 to November 1993 ) . Nosocomial pneumonias were prospect ively identified using the criteria of the Centers for Disease Control and Prevention . The annual cost difference of changing circuits at 48-h and 7-day intervals was calculated using the distribution of ventilator days for the control and study periods . Results There were 1,708 patients , 9,858 ventilator days , and a pneumonia rate of 9.64 per 1,000 ventilator days in the control group ( 48-h circuit changes ) . There were 1,715 patients , 9,160 ventilator days , and 8.62 pneumonias per 1,000 ventilator days when circuits were changed at 1-week intervals ( study group ) . Using a logistic regression model , there were significantly greater odds of developing a ventilator-associated pneumonia in surgical patients ( odds ratio 1.77 , P = 0.02 ) and patients in critical care units ( odds ratio 1.54 , P = 0.05 ) , but no significant risk of ventilator-associated pneumonia in patients in whom circuits were changed at 1-week intervals ( odds ratio 0.82 , P = 0.22 ) . Changing circuits at 7-day intervals result ed in a 76.6 % ( $ 111,530 ) reduction in the annual cost for material s and salaries . Conclusions We found no difference in pneumonia rates with ventilator circuit changes at 48-h and 7-day intervals . Ventilator circuits can be safely changed at weekly intervals , result ing in large cost savings Circuits on mechanical ventilators with cascade humidifiers are routinely changed every day or every other day , although humidifying cascades have been considered unlikely to increase the risk of respiratory infection because they do not generate aerosols . Moreover , changing ventilator tubings every 24 rather than every 48 h increases the risk of ventilator-associated pneumonia . To study the effects of ventilator circuit changes on the rate of nosocomial pneumonia and on patient and circuit colonization , 73 consecutive patients requiring continuous mechanical ventilation for more than 48 h were r and omly assigned to either ventilator circuit changes every 48 h ( Group 1 , n = 38 ) or no change ( Group 2 , n = 35 ) . Patients dying or being weaned before 96 h were not analyzed ( Group 1 n = 3 ; Group 2 n = 7 ; leaving Group 1 n = 35 and Group 2 n = 28 ; p = 0.13 ) . Ventilator-associated pneumonia was defined as the occurrence during mechanical ventilation or within 48 h after weaning of a new and persistent infiltrate on chest X-ray , purulent tracheal secretions , and a positive culture of a protected brush specimen ( greater than or equal to 10(3 ) cfu/ml ) . Bacterial colonization was assessed every 48 h by quantitative cultures of pharyngeal swab , tracheal aspirate , humidifying cascade , and expiratory tubing trap . The two groups were similar in terms of age , indication for and duration of ventilation , and severity of illness . ( ABSTRACT TRUNCATED AT 250 WORDS OBJECTIVE To compare the degree of bacterial circuit colonization , frequency of ventilator-associated pneumonia ( VAP ) , character of respiratory secretions , rewarming of hypothermic patients , disposable costs , and air flow resistance in intensive care patients ventilated using either a heat and moisture exchanger ( HME ) or hot water ( HW ) humidifier circuit . DESIGN A prospect i ve , r and omized blinded trial of patients in the intensive care unit undergoing mechanical ventilation . SETTING A metropolitan teaching hospital . PATIENTS One hundred sixteen patients undergoing mechanical ventilation for a minimum period of 48 hrs were enrolled . INTERVENTIONS Patients were r and omized to three ventilation groups using a ) an HW circuit with a 2-day circuit change ( n = 41 ) ; or b ) a bacterial-viral filtering HME in the circuit , with either a 2-day ( n = 42 ) ; or c ) a 4-day circuit change ( n = 33 ) . MEASUREMENTS AND MAIN RESULTS Circuit colonization was assessed using quantitative culture of washings taken from the circuit tubing and semiquantitative culture of swabs from the Y connectors . Sixty-seven percent of HW circuits became contaminated compared with 12 % in the two HME groups ( p < .0001 ) . Median colony counts were lower in the HME groups ( p < .0001 ) . If circuits at first circuit change were contaminated in the HW group , 89 % of subsequent circuit changes became contaminated compared with 0 % and 25 % for the 2- and 4-day HME groups , respectively . The frequency of VAP , the time to resolution of admission hypothermia , and the volume and fluidity of secretions were similar for all groups . The resistance of the HME after 24 hrs of use was < 0.025 cm H2O/L at gas flows of 40 L/min . HME use result ed in a cost reduction of $ 1.48 (Australian)/day . CONCLUSIONS Circuits with a bacterial-viral filtering HME are less readily colonized by bacteria . Contamination is a r and om event . Humidification technique has no influence on the frequency rate of VAP , the effectiveness of rewarming , nor the character of the respiratory secretions . Breathing resistance is generally low and disposable costs are reduced when an HME is used The objective of this r and omized study was to compare the occurrence of nosocomial pneumonia in nasotracheally intubated patients who were r and omly allocated either to a systematic search of sinusitis by CT scan ( study group ) or not ( control group ) . A total of 399 patients were included : 272 male and 127 female ; mean age , 61 + /- 17 yr ; SAPS : 12.6 + /- 4.9 . The study group consisted of 199 patients and the control group consisted of 200 . In the study group , sinus CT scans were performed in case of fever at Days 4 and 8 and then every 7 d. Nosocomial sinusitis was defined as follows : fever of > /= 38 degrees C , radiographic ( sinusal air-fluid level or opacification on CT scan ) signs , and presence of purulent aspirate from the involved sinus puncture with > /= 10(3 ) cfu/ml . Patients with sinusitis received sinus lavage and intravenously administered antibiotics . In the study group , 80 patients experienced nosocomial sinusitis . In the control group , no patient was treated for a sinusitis . Ventilator-associated bronchopneumonia ( VAP ) was observed in 88 patients : 37 in the study group ( 1 mo Kaplan-Meier estimate , 34 % ) versus 51 in the control group ( 1 mo Kaplan-Meier estimate , 47 % ) ; ( p = 0.02 , log-rank test ; relative risk [ RR ] = 0.61 ; 95 % confidence interval [ CI ] , 0.40 to 0.93 ) . Two months overall mortality was estimated at 36 % in the study group versus 46 % in the control group ( p = 0.03 , log-rank test ; RR = 0.71 ; 95 % CI , 0.52 to 0.97 ) . We conclude that the occurrence of VAP in patients undergoing prolonged mechanical ventilation via a nasotracheal intubation can be prevented by the systematic search and treatment of nosocomial sinusitis . The effect on mortality should be confirmed BACKGROUND Critically ill patients who require mechanical ventilation are at increased risk for gastrointestinal bleeding from stress ulcers . There are conflicting data on the effect of histamine H2-receptor antagonists and the cytoprotective agent sucralfate on rates of gastrointestinal bleeding , ventilator-associated pneumonia , and mortality . METHODS In a multicenter , r and omized , blinded , placebo-controlled trial , we compared sucralfate with the H2-receptor antagonist ranitidine for the prevention of upper gastrointestinal bleeding in 1200 patients who required mechanical ventilation . Patients received either nasogastric sucralfate suspension ( 1 g every six hours ) and an intravenous placebo or intravenous ranitidine ( 50 mg every eight hours ) and a nasogastric placebo . RESULTS The patients in the two groups had similar base-line characteristics . Clinical ly important gastrointestinal bleeding developed in 10 of 596 ( 1.7 percent ) of the patients receiving ranitidine , as compared with 23 of 604 ( 3.8 percent ) of those receiving sucralfate ( relative risk , 0.44 ; 95 percent confidence interval , 0.21 to 0.92 ; P=0.02 ) . In the ranitidine group , 114 of 596 patients ( 19.1 percent ) had ventilator-associated pneumonia , as compared with 98 of 604 ( 16.2 percent ) in the sucralfate group ( relative risk , 1.18 ; 95 percent confidence interval , 0.92 to 1.51 ; P=0.19 ) . There was no significant difference between the groups in mortality in the intensive care unit ( ICU ) ( 23.5 percent in the ranitidine group and 22.9 percent in the sucralfate group ) or the duration of the stay in the ICU ( median , nine days in both groups ) . CONCLUSIONS Among critically ill patients requiring mechanical ventilation , those receiving ranitidine had a significantly lower rate of clinical ly important gastrointestinal bleeding than those treated with sucralfate . There were no significant differences in the rates of ventilator-associated pneumonia , the duration of the stay in the ICU , or mortality BACKGROUND Reduction of potential pathogens by selective intestinal decontamination has been proposed to improve intensive care . Despite large scientific interest in this method , little is known about its benefit in homogeneous trauma population s. METHODS In a prospect i ve , controlled study , we enrolled non-infected trauma patients ( age over 18 years , mechanical ventilation > or = 48 hours , intensive care for more than 3 days ) who primarily were admitted to our university medical center . We r and omized patients to be treated with two different topical regimens ( polymyxin , tobramycin , and amphotericin ( PTA ) or polymyxin , ciprofloxin , amphotericin ( PCA ) ) or the carrier only ( placebo ) , administered four times daily both to the oropharynx and to the gastrointestinal tract . All patients received intravenous ciprofloxacin ( 200 mg , bd ) for 4 days . FINDINGS Of 357 enrolled patients , 310 ( age 38.0 + /- 16.5 years , Injury Severity Score 35.2 + /- 12.7 ) met all inclusion criteria . Selective decontamination successfully reduced intestinal bacterial colonization . However , we did not identify significant differences between groups regarding pneumonia ( PTA 47.5 % , PCA 39.0 % , placebo 45.3 % ) , sepsis ( PTA 47.5 % , PCA 37.8 % , placebo 42.6 % ) , multiple organ failure ( PTA 56.3 % ; PCA 52.4 % , placebo 58.1 % ) , and death ( PTA 11.3 % , PCA 12.2 % , placebo 10.8 % ) . Total costs per patient were highest with the PTA regimen . CONCLUSIONS We found no benefit of selective decontamination in trauma patients . Apparently , bacterial overgrowth in the intestinal tract is not the sole link between trauma , sepsis , and organ failure The purpose of the study was to examine risk factors for nosocomial pneumonia in the surgical and medical/respiratory intensive care unit ( ICU ) population s. In a public teaching hospital , all cases of nosocomial pneumonia in the surgical and medical/respiratory ICUs ( n = 20 , respectively ) were identified by prospect i ve surveillance during a 5-yr period from 1987 - 1991 . Each group of ICU cases was compared with 40 ICU control patients who did not acquire pneumonia , and analyzed for 25 potential risk factors . Surgical ICU patients were found to have consistently higher rates of nosocomial pneumonia than medical ICU patients ( RR = 2.2 ) . The strongest predictor for nosocomial pneumonia in both the surgical and medical/respiratory ICU groups was found to be prolonged mechanical ventilation ( > 1 d ) result ing in a 12-fold increase in risk over nonventilated patients . APACHE III score was found to be predictive of nosocomial pneumonia in the surgical ICU population , but not in the medical/respiratory ICU population . We conclude that certain groups deserve special attention for infection control intervention . Surgical ICU patients with high APACHE scores and receiving prolonged mechanical ventilation may be at the greatest risk of acquiring nosocomial pneumonia of all hospitalized patients BACKGROUND Risk factors for nosocomial pneumonia , such as gastro-oesophageal reflux and subsequent aspiration , can be reduced by semirecumbent body position in intensive-care patients . The objective of this study was to assess whether the incidence of nosocomial pneumonia can also be reduced by this measure . METHODS This trial was stopped after the planned interim analysis . 86 intubated and mechanically ventilated patients of one medical and one respiratory intensive-care unit at a tertiary-care university hospital were r and omly assigned to semirecumbent ( n=39 ) or supine ( n=47 ) body position . The frequency of clinical ly suspected and microbiologically confirmed nosocomial pneumonia ( clinical plus quantitative bacteriological criteria ) was assessed in both groups . Body position was analysed together with known risk factors for nosocomial pneumonia . FINDINGS The frequency of clinical ly suspected nosocomial pneumonia was lower in the semirecumbent group than in the supine group ( three of 39 [ 8 % ] vs 16 of 47 [ 34 % ] ; 95 % CI for difference 10.0 - 42.0 , p=0.003 ) . This was also true for microbiologically confirmed pneumonia ( semirecumbent 2/39 [ 5 % ] vs supine 11/47 [ 23 % ] ; 4.2 - 31.8 , p=0.018 ) . Supine body position ( odds ratio 6.8 [ 1.7 - 26.7 ] , p=0.006 ) and enteral nutrition ( 5.7 [ 1.5 - 22.8 ] , p=0.013 ) were independent risk factors for nosocomial pneumonia and the frequency was highest for patients receiving enteral nutrition in the supine body position ( 14/28 , 50 % ) . Mechanical ventilation for 7 days or more ( 10.9 [ 3.0 - 40.4 ] , p=0.001 ) and a Glasgow coma scale score of less than 9 were additional risk factors . INTERPRETATION The semirecumbent body position reduces frequency and risk of nosocomial pneumonia , especially in patients who receive enteral nutrition . The risk of nosocomial pneumonia is increased by long- duration mechanical ventilation and decreased consciousness STUDY OBJECTIVES To prospect ively identify the occurrence of ventilator-associated pneumonia ( VAP ) in a community hospital , and to determine the risk factors for VAP and the influence of VAP on patient outcomes in a nonteaching institution . DESIGN Prospect i ve cohort study . SETTING A medical ICU and a surgical ICU in a 500-bed private community nonteaching hospital : Missouri Baptist Hospital . PATIENTS Between March 1998 and December 1999 , all patients receiving mechanical ventilation who were admitted to the ICU setting were prospect ively evaluated . INTERVENTION Prospect i ve patient surveillance and data collection . RESULTS During a 22-month period , 3,171 patients were admitted to the medical and surgical ICUs . Eight hundred eighty patients ( 27.8 % ) received mechanical ventilation . VAP developed in 132 patients ( 15.0 % ) receiving mechanical ventilation . Three hundred one patients ( 34.2 % ) who received mechanical ventilation died during hospitalization . Logistic regression analysis demonstrated that tracheostomy ( adjusted odds ratio [ AOR ] , 6.71 ; 95 % confidence interval [ CI ] , 3.91 to 11.50 ; p < 0.001 ) , multiple central venous line insertions ( AOR , 4.20 ; 95 % CI , 2.72 to 6.48 ; p < 0.001 ) , reintubation ( AOR , 2.88 ; 95 % CI , 1.78 to 4.66 ; p < 0.001 ) , and the use of antacids ( AOR , 2.81 ; 95 % CI , 1.19 to 6.64 ; p = 0.019 ) were independently associated with the development of VAP . The hospital mortality of patients with VAP was significantly greater than the mortality of patients without VAP ( 45.5 % vs 32.2 % , respectively ; p = 0.004 ) . The occurrence of bacteremia , compromised immune system , higher APACHE ( acute physiology and chronic health evaluation ) II scores , and older age were identified as independent predictors of hospital mortality . CONCLUSIONS These data suggest that VAP is a common nosocomial infection in the community hospital setting . The risk factors for the development of VAP and risk factors for hospital mortality in a community hospital are similar to those identified from university-affiliated hospitals . These risk factors can potentially be employed to develop local strategies for the prevention of VAP . CLINICAL IMPLICATION S ICU clinicians should be aware of the risk factors associated with the development of VAP and the impact of VAP on clinical outcomes . More importantly , they should cooperate in the development of local multidisciplinary strategies aim ed at the prevention of VAP and other nosocomial infections BACKGROUND Appropriate and timely antibiotic therapy to treat pneumonia in trauma patients is extremely important . We evaluated the incidence and microbiology of pneumonia stratified by days postadmission and risk factors . METHODS Prospect i ve data were collected on 714 trauma patients admitted to the intensive care unit over a 1-year period . Pneumonia was classified as community acquired ( CAP ) ( < or = 3 days ) , early nosocomial ( ENP ) ( 4 - 6 days ) , or late nosocomial ( LNP ) ( > or = 7 days ) . In addition , pneumonia was classified as CAP only , nosocomial only ( NI ) , or combination ( CAP and NI , or ENP and LNP ) pneumonia . Strict institutional guidelines were followed for diagnosis . RESULTS One hundred eighty-two patients ( 25 % ) were diagnosed with 204 pneumonias over the study period . One hundred twenty-five ( 61 % ) of these pneumonias were ventilator associated . Staphylococcus aureus and Haemophilus influenzae were the most common pathogens isolated . Twenty-one percent of patients with CAP acquired an LNP ( p < 0.025 ) , in which Pseudomonas was the most common organism . Haemophilus caused LNP in 12 % of patients . Cancer ( p < 0.01 ) , liver failure ( p < 0.05 ) , and age ( p < 0.01 ) were predictive of nontypical pathogens in patients with CAP and ENP ( p < 0.05 ) . Obesity was most predictive of increased ventilator days ( p < 0.001 ) and intensive care unit length of stay ( p < 0.001 ) . Increased age , alcohol abuse , and field airway were most predictive of mortality . CONCLUSION Unanticipated pathogens were isolated in each class of pneumonia . The clinician must be aware of significant risk factors that may predispose patients to pathogens that are not ordinarily covered with st and ard antibiotic therapy Secondary pneumonia in patients requiring mechanical ventilation has a high morbidity and mortality . Diagnosis is difficult and treatment failure common ; therefore , preventive measures are important . In a double-blind , placebo-controlled trial , we evaluated selective decontamination of the oropharynx with polymyxin B sulfate , neomycin sulfate , and vancomycin hydrochloride ( PNV ) in 52 patients requiring mechanical ventilation during a 3- to 34-day period ( mean , 10 days ) . Either PNV or placebo was administered six times daily in the oropharynx . During the first 12 days of intubation , tracheobronchial colonization by gram-negative bacteria and Staphylococcus aureus , as well as pneumonia , occurred less frequently in the PNV than in the placebo group ( 16 % vs 78 % ; P less than .0001 ) . Hospital mortality was not different , but systemic antibiotics were prescribed less often in the PNV group and no resistant microorganism emerged . In these critically ill patients , topical oropharyngeal antibiotic application lowered the rate of ventilator-associated pneumonia by a factor of 5 , probably by interrupting the stomach-to-trachea route of infection , and decreased the requirement for intravenous antibiotics Cases of ventilator-associated pneumonia ( VAP ) were investigated in a cardiothoracic surgery postoperative intensive care unit between 1 January 1999 and 31 December 1999 . A total of 1716 patients who had undergone cardiothoracic operations and admitted to the intensive care unit ( ICU ) were included in the study . Patient- and laboratory-based prospect i ve surveillance of VAP was done along with other hospital-acquired infections . During the study period a total of 26 585 patient-days with 2708 ventilator-days were recorded . Forty-six cases of VAP occurred in 36 of 1716 patients who had undergone cardiothoracic operations ( 2.09 % , 1.3 episodes of pneumonia per patient ) . The ventilator utilization rate at our institution was 0.10 . There were 16.4 VAPs per 1000 ventilation days . Thirty-eight percent of VAP were caused by Gram-negative enteric rods , 34 % by Pseudomonas aeruginosa , and 17 % by Staphylococcus aureus . VAP was polymicrobial in 9 % of cases . No causative micro-organism was identified in 2 % of cases . The same bacteria were isolated in both blood and endotracheal aspirate cultures in 10 of 46 pneumonia cases ( 22 % ) . The crude mortality rate of VAP was calculated as 30 BACKGROUND H2-receptor antagonists are commonly used for stress ulcer prophylaxis on intensive care units . However , there is evidence that via the route of an elevated gastric pH , followed by bacterial overgrowth and subsequent tracheal aspiration , pneumonia could occur . In line with this assumption total gastrectomized patients should develop a very high incidence of pneumonia , which is actually not the case . We therefore formulated the hypothesis that stress ulcer prophylaxis with H2-receptor antagonists does not lead to an increased pneumonia rate . METHODS A total of 158 patients with mechanical ventilation > or = 48 hours of a surgical intensive care unit were r and omized to the following groups : A , placebo ( n = 57 ) ; B , pirenzepine ( 3 x 10 mg intravenously , n = 44 ) ; and C , ranitidine ( 3 x 50 mg intravenously , n = 57 ) . RESULTS The pneumonia rate in ranitidine- , pirenzepine- , and placebo-treated patients is 10 of 57 , 10 of 44 , and 12 of 57 , respectively . CONCLUSIONS Pneumonia rate is not adversely affected by H2-receptor antagonists in stress ulcer prophylaxis Intensive care patients are at risk for bleeding from stress ulcers of the upper gastrointestinal tract [ 1 ] . Despite the decline of this complication over the last two decades [ 2 ] , certain patients , such as those requiring prolonged mechanical ventilation , remain at high risk and may benefit from stress ulcer prophylaxis [ 1 , 3 - 5 ] . Over the last few years , studies have shown that agents that raise the gastric pH may promote proliferation of bacteria in the stomach , particularly gram-negative bacilli that may originate in the duodenum [ 6 - 10 ] . Passive esophageal reflux and microaspiration of the gastric content along the endotracheal tube may lead to the colonization of the trachea and then to pneumonia [ 6 , 7 , 10 - 18 ] . Thus , concerns have arisen that the risk for nosocomial pneumonia may outweigh the benefit of stress ulcer prophylaxis when agents raising the gastric pH are used . Sucralfate is a complex salt of sucrose sulfate and aluminum hydroxide that appears to be as effective as antacids or histamine-2 ( H2 ) antagonists for stress ulcer prophylaxis [ 2 , 19 , 20 ] but by mechanisms of action that do not result in clinical ly relevant gastric pH modification . Several studies have documented that gastric colonization is less frequent and of a lesser magnitude in ventilated patients treated with this agent compared with antacids or H2-antagonists [ 8 , 21 - 23 ] . However , whether this would result in a decreased risk for nosocomial pneumonia is controversial [ 18 , 24 ] because a reduction was found in some [ 21 - 23 , 25 ] but not all [ 17 , 21 - 23 , 25 - 29 ] comparative studies . Method ologic differences among these studies might explain these conflicting findings [ 18 ] . For example , small numbers of patients for analysis [ 17 , 26 ] , low risk for pneumonia in the study patients [ 27 , 28 ] , periods of observation that were too brief [ 28 ] , insufficient dosages of the agents that raise pH [ 27 , 29 ] , and wide use of enteral feeding [ 17 ] might account for the absence of reduction in the incidence of pneumonia noted in some studies . On the other h and , differences in the distribution of the base-line characteristics among the patients [ 22 , 23 ] , the grouping of patients receiving antacids and H2-antagonists , and analysis of subgroups of patients not r and omly assigned to a treatment group [ 21 , 25 ] may have biased the studies in which sucralfate was associated with lower rates of pneumonia . In addition , in two of these latter studies , the reduction of pneumonia developing in patients treated with sucralfate compared with other treatment did not reach the usual 0.05 level of significance [ 21 , 23 ] . Furthermore , previous studies did not distinguish between pneumonia occurring early or late after intubation . This may be important because it is likely that early-onset pneumonia may be related to the introduction of bacteria in the trachea at the time of intubation [ 30 - 32 ] , a process that is not expected to be influenced by the type of anti-stress ulcer prophylaxis . Therefore , we compared three anti-stress ulcer prophylaxis regimens ( antacid , ranitidine , and sucralfate ) in a large group of ventilated patients for the occurrence of bacterial colonization , early and late-onset nosocomial pneumonia , and overt gastrointestinal bleeding . Methods Patients The Centre Hospitalier Universitaire Vaudois is a 1100-bed hospital serving both as a municipal facility and a tertiary referral center . During a 2-year period ( January 1989 to January 1991 ) , all patients admitted to the adult medical and surgical intensive care units who were receiving mechanical ventilation and had a nasogastric tube in place were eligible for the study . Exclusion criteria were as follows : active upper gastrointestinal bleeding ; treatment with antacids , H2-blockers , or sucralfate during the preceding 48 hours ; creatinine levels greater than 200 mol/L ; esogastric surgery ; cardiac surgery ; or organ transplantations . Patients likely to be extubated within 24 hours were also excluded . At intubation , patients were stratified into five categories according to the following underlying conditions : trauma ( surgical intensive care unit ) , intervention after surgery ( surgical intensive care unit ) , cardiac disease ( medical intensive care unit ) , pulmonary disease ( medical intensive care unit ) , and other medical conditions [ medical intensive care unit ] . R and omization was done using a r and om permutable table to generate a r and om treatment list . Treatment regimens were included in opaque , sealed envelopes . The patients were assigned to one of the following anti-stress ulcer prophylactic regimens : 1 ) antacid , a hospital-made suspension containing 5.4 % aluminum hydroxide and 1.5 % magnesium hydroxide with a buffer capacity of 1.2 mEq/mL , administered every 2 hoursthe st and ard dose of 20 mL was doubled if the gastric pH ( tested with pH-indicator strips [ Merck and Co. , Darmstadt , Germany ] before each administration ) was less than 4.0 ; 2 ) ranitidine ( Zantac , Glaxo , Bern , Switzerl and ) administered as a continuous intravenous infusion of 150 mg/d [ 100 mg/d if the blood creatinine level was between 150 and 200 mol/L ] ; or 3 ) sucralfate ( Ulcogant , Merck and Co. , Zurich , Switzerl and ) administered every 4 hours as 1 gram of suspension diluted in 20 mL of sterile water . After antacid or sucralfate was administered , the nasogastric tube was flushed with 10 mL of sterile water and clamped for 30 minutes . Each prophylactic regimen was continued until extubation unless interrupted earlier for any of the following predetermined reasons : an increase of the blood creatinine level to more than 200 mol/L , removal of the nasogastric tube , moribund state , discharge from the intensive care units , or side effects likely to be related to the stress ulcer regimen . Data Collection and Definitions For all eligible patients , demographic characteristics , diagnosis , underlying diseases , physical signs , laboratory tests , and medications were recorded prospect ively by one of the investigators . However , only patients eventually intubated for more than 24 hours were followed and included in the final analysis . Glasgow coma and Acute Physiology and Chronic Health Evaluation ( APACHE II ) scoring systems were used to assess the severity of the acute illness [ 33 ] . The adult respiratory distress syndrome was defined by the following criteria : acute bilateral diffuse pulmonary infiltrates and severe hypoxemia without evidence of cardiogenic edema [ 34 ] . Gastric aspirates were examined for the macroscopic presence of blood ( coffee ground material or fresh blood ) . The severity of gastric hemorrhage was assessed by clinical criteria ( physical signs , blood transfusion requirements , and outcome ) . Chest radiographs were obtained on a daily basis or more often if clinical ly indicated . They were interpreted by a pneumologist who had knowledge of all relevant data except for the patient 's stress ulcer prophylactic regimen , gastric pH , or colonization data . Criteria for the diagnosis of ventilator-associated pneumonia were predetermined and derived from those of Salata and colleagues [ 35 ] : presence of a new or progressive infiltrate on the chest radiograph consistent with pneumonia , without other obvious cause , and associated with conditions A or B or both , defined as follows . Condition A refers to any of the following findings : pleural fluid or blood culture positive for an organism also isolated in the tracheal aspirate , radiographic cavitation , or histopathologic evidence of pneumonia . Condition B includes at least two of the following : tracheal aspirates with more than 25 leukocytes per low-power field ( x 100 ) on a Gram stain , new leukocytosis defined as a leukocyte count greater than 10 109/L with an increase of at least 25 % over baseline , or body temperature greater than 38.5 C with an increase of at least 1 C above baseline . The latter two criteria were considered only when other causes for these findings were excluded . Pneumonia was considered to be caused by a pathogen when it was cultured in high counts as the sole or predominant microorganism in the tracheal aspirate culture . Using the criteria of Langer and colleagues [ 30 ] , early-onset and late-onset pneumonia were diagnosed if they occurred during the first 4 days of or 4 days after the initiation of mechanical ventilation , respectively . Consequently , only patients observed for more than 4 days could be evaluated for the development of late-onset pneumonia . A second episode of pneumonia was diagnosed when it was clearly temporally distinct from the first episode and when it involved other areas of the lungs . Pneumonia was attributed to a given anti-stress ulcer prophylactic regimen if it developed during treatment or within 2 days after extubation or treatment interruption . Death was considered to be directly related to nosocomial pneumonia when it occurred during the episode and when no other major contributing cause was present . Bacteriologic Investigations and pH Measurements Gastric and tracheal aspirates and oropharyngeal swabs were obtained twice daily and cultured quantitatively ( gastric juice ) or semi-quantitatively in aerobic conditions . Aerobic bacteria were identified by st and ard microbiologic methods . Cultures for Chlamydia species , Legionella pneumophila , or Mycoplasma pneumoniae were not done . Blood or pleural fluid cultures were ordered by the primary care physician according to the clinical situation . Gastric pH was measured twice a day using a pH meter ( except in 11 patients for whom values were derived only from pH-indicator strips [ Merck and Co. ] ) . A cut-off value of 4.0 for median pH was chosen for further analysis within the three treatment groups because it has been shown to be a critical value for the growth of gram-negative bacilli in the stomach [ 6 , 7 , 25 ] . Colonization was defined by the presence of one microorganism at a given site on at least two occasions . A patient was considered to have gastric colonization with high counts when quantitative culture of at least one Objective To assess the frequency of and the reasons for changing empiric antibiotics during the treatment of pnnumonia acquired in the intensive care unit ( ICU ) . Design A prospect i ve multicenter study of 1 year 's duration . Setting Medical and surgical ICUs in 30 hospitals all over Spain . Patients Of a total of 16872 patients initially enrolled into the study , 530 patients developed 565 episodes of pneumonia after admission to the ICU . Results Empiric antibiotics were administered in 490 ( 86.7 % ) of the 565 episodes of pneumonia . The antimicrobials most frequently used were amikacin in 120 case , tobramycin in 110 , ceftazidime in 96 , and cefotaxime in 96 . Monotherapy was indicated in 135 ( 27.6 % ) of the 490 episodes , a combination of two antibiotics in 306 episodes ( 62.4 % ) , and a combination of three antibiotics in 49 episodes ( 10 % ) . The empiric antibiotic treatment was modified in 214 ( 43.7 % ) cases because of isolation of a microorganism not covered by treatment in 133 ( 62.1 % ) cases , lack of clinical response in 77 ( 36 % ) , and development of resistance in 14 ( 6.6 % ) . Individual factors associated with modification of empiric treatment identified in the multivariate analysis were microorganism not covered ( relative risk ( RR ) ) 22.02 ; 95 % confidence interval ( CI ) 11.54 to 42.60;p<0.0001 ) , administration of more than one antimicrobial ( RR 1.29 ; 95 % CI 1.02 to 1.65;p=0.0018 ) attributable mortability was 16.2 % Epidemiologic studies of nosocomial bacterial pneumonia in patients requiring mechanical ventilation have been limited because of the poor reliability of diagnosis procedures in this setting . To determine prognostic and descriptive factors of ventilator-associated ( V-A ) pneumonia , we prospect ively studied 567 patients who had been receiving mechanical ventilation for more than 3 days in our unit . Fiberoptic bronchoscopy using a protected specimen brush ( PSB ) was performed on each patient suspected of having pneumonia because of the presence of a new pulmonary infiltrate and purulent tracheal secretions . The diagnosis of V-A pneumonia was retained only if PSB specimens yielded greater than 10(3 ) cfu/ml of at least one microorganism , unless this result was established to be a false positive result on follow-up . V-A pneumonia developed in 49 patients for a total of 52 episodes ( 9 % ) . The actuarial risk of V-A pneumonia was 6.5 % at 10 days , 19 % at 20 days , and 28 % at 30 days of ventilation . Patients with pneumonia were significantly older ( 65 versus 57 yr of age , p less than 0.01 ) and more frequently had severe underlying illnesses ( 24 versus 10 % , p less than 0.01 ) than did patients without pneumonia . A total of 84 microorganisms ( 51 gram-negative and 33 gram-positive ) were isolated in significant concentrations from PSB specimens . Pseudomonas aeruginosa and Staphylococcus aureus were involved in 31 and 33 % of these pneumonias , respectively . Forty percent of all specimens yielded a polymicrobial flora with more than one potential pathogen . ( ABSTRACT TRUNCATED AT 250 WORDS Objective To study the effects of pharmacologically increasing gastric pH on gastric colonization and the development of pneumonia in intubated critically ill patients . Design R and omized , controlled trial . Setting Medical ICU in a university hospital . Patients Thirty-four tracheotomized patients with tetanus . Interventions Sixteen patients received iv ranitidine to increase gastric pH > 4 ( ranitidine group ) , while 18 patients received no prophylaxis for upper gastrointestinal bleeding ( control group ) . Measurements and Main Results Mean gastric pH was higher in the ranitidine group ( median 4.7 , range 3.6 to 6.1 ) than in the control group ( median 2.1 , range 1.2 to 4.9 ; p < .05 ) . Gastric colonization occurred in 15 ( 94 % ) of 16 patients who received ranitidine , 2 days ( median ; range 1 to 5 ) after intubation ; gastric colonization also occurred in all control patients ( median 4 days , range 1 to 9 ; p < .05 ) . Pneumonia occurred in 13 ( 81 % ) of 16 patients who received ranitidine , 3 days ( median , range 1 to 5 ) after intubation and in nine ( 50 % ) of 18 control patients ( p < .01 ) 5 days after tracheal intubation ( median , range 3 to 14 ; p < .01 ) . Prior gastric colonization by the pathogen that caused pneumonia was demonstrable in nine ( 56 % ) of 16 patients who received ranitidine vs. eight ( 44 % ) of 18 control patients ( p > .05 ) . The risk for developing pneumonia in the ranitidine-treated group was highest in the first 4 days after tracheal intubation . There was no difference in the frequency of upper gastrointestinal hemorrhage in the two groups . Conclusions Pharmacologically increasing gastric pH increases the risk for developing pneumonia in intubated critically ill patients . The pneumonia occurs earlier than in untreated control patients . ( Crit Care Med 1992 ; 20:590–593 To determine if there is a difference in nosocomial pneumonia frequency rate in mechanically ventilated trauma patients treated with sucralfate vs. ranitidine for stress ulcer prophylaxis . Design : Prospect i ve , r and omized trial . Setting : A 640-bed urban teaching hospital and trauma center . Patients : Ninety-two mechanically ventilated trauma patients . Interventions : Thirty-nine patients received sucralfate and 44 patients received intravenous ranitidine for stress ulcer prophylaxis ; nine patients were excluded from the study for protocol breaks . Measurements and Main Results : The study population was severely injured and critically ill . The Trauma Score averaged 11.3 , the Injury Severity Score averaged 27.7 , and the Acute Physiology and Chronic Health Evaluation ( APACHE ) score averaged 18.1 . There were no significant differences in demographics , mechanisms of injury , Trauma Score , Injury Severity Score , APACHE score , length of hospital stay , length of surgical intensive care unit stay , or duration of endotracheal intubation between the sucralfate and ranitidine groups . Eleven ( 13.2 % ) patients developed nosocomial pneumonia : six ( 15.4 % ) of 39 patients in the sucralfate group and five ( 11.4 % ) of 44 patients in the ranitidine group ; these numbers were not significantly different ( x2 = 0.0226 , p = .8805 ) . There were no episodes of significant upper gastrointestinal bleeding . Six patients died during hospitalization , all secondary to severe head injury and none with pneumonia . Conclusions : There was no statistically significant difference in pneumonia rate in mechanically ventilated trauma patients receiving stress ulcer prophylaxis with sucralfate vs. ranitidine . ( Crit Care Med 1993 ; 21:1856–1862 STUDY OBJECTIVE To determine the safety and cost-effectiveness of mechanical ventilation with an extended-use hygroscopic condenser humidifier ( Duration ; Nellcor Puritan-Bennett ; Eden Prairie , Minn ) compared with mechanical ventilation with heated-water humidification . DESIGN Prospect i ve r and omized clinical trial . SETTING Medical and surgical ICUs of Barnes-Jewish Hospital , St. Louis , a university-affiliated teaching hospital . PATIENTS Three hundred ten consecutive qualified patients undergoing mechanical ventilation . INTERVENTIONS Patients requiring mechanical ventilation were r and omly assigned to receive humidification with either an extended-use hygroscopic condenser humidifier ( for up to the first 7 days of mechanical ventilation ) or heated-water humidification . MEASUREMENTS Occurrence of ventilator-associated pneumonia , endotracheal tube occlusion , duration of mechanical ventilation , lengths of intensive care and hospitalization , acquired multiorgan dysfunction , and hospital mortality . RESULTS One hundred sixty-three patients were r and omly assigned to receive humidification with an extended-use hygroscopic condenser humidifier , and 147 patients were r and omly assigned to receive heated-water humidification . The two groups were similar at the time of r and omization with regard to demographic characteristics , ICU admission diagnoses , and severity of illness . Risk factors for the development of ventilator-associated pneumonia were also similar during the study period for both treatment groups . Ventilator-associated pneumonia was seen in 15 ( 9.2 % ) patients receiving humidification with an extended-use hygroscopic condenser humidifier and in 15 ( 10.2 % ) patients receiving heated-water humidification ( relative risk , 0.90 ; 95 % confidence interval=0.46 to 1.78 ; p=0.766 ) . No statistically significant differences for hospital mortality , duration of mechanical ventilation , lengths of stay in the hospital ICU , or acquired organ system derangements were found between the two treatment groups . No episode of endotracheal tube occlusion occurred during the study period in either treatment group . The total cost of providing humidification was $ 2,605 for patients receiving a hygroscopic condenser humidifier compared with $ 5,625 for patients receiving heated-water humidification . CONCLUSION Our findings suggest that the initial application of an extended-use hygroscopic condenser humidifier is a safe and more cost-effective method of providing humidification to patients requiring mechanical ventilation compared with heated-water humidification A prospect i ve cohort study was performed to determine the prolongation of stay and the extra costs incurred due to the occurrence of ventilator-associated pneumonia in intensive care unit patients . Over a 16-month period a sample of 270 consecutive adult patients from a large university anesthesiological intensive care unit requiring ventilation therapy for more than 24 hours was analyzed . A matching procedure using multiple control patients without pneumonia per infected patient ( = case ) was employed . Of 78 cases 21 ( 26.9 % ) died and were excluded from the matching procedure as well as 23 ( 29.5 % ) for whom suitable controls could not be found . The maximum number of controls per case was five . The mean added stay was calculated to be 10.13 days and the extra costs attributable to the prolongation of stay were 14,253 German Marks ( US$ 8,800 ) per patient , demonstrating considerable added stay and costs due to ventilator-associated pneumonia acquired during intensive care . However , it should be taken into account that the calculations for excess stay and costs are based on a subset of rather ill patients and thus can not generally apply to all ventilated patients and that cases were excluded which could not be matched Background Enteral feeding provides nutrients for patients who require endotracheal tubes and mechanical ventilation . There is a presumed increase in the risk of ventilator-associated pneumonia ( VAP ) with tube feeding . This has stimulated the development of procedures for duodenal intubation and small intestinal ( SI ) feeding as primary prophylaxes to prevent VAP . Objective To investigate the rate of VAP and adequacy of nutrient delivery with gastric ( G ) vs. SI feeding . Design A prospect i ve , r and omized , controlled trial . Setting A medical intensive care unit of a county hospital . Patients A total of 44 endotracheally intubated , mechanically ventilated patients requiring enteral nutrition . Intervention Subjects were r and omized to receive enteral nutrition via G or SI feeding . Protocol s directed the placement of the feeding tube and the infusion of enteral nutrition and defined the radiographic and clinical criteria for a diagnosis of VAP . Measurements and Outcomes The incidence of VAP and the adequacy of nutritional supplementation were prospect ively followed . The relative risk of VAP with SI was 1.1 ( 95 % confidence interval 0.96–2.44 ) compared with G. The SI group received a greater percentage of their caloric requirements ( SI 69 ± 7 % vs. G 47 ± 7 % , mean ± sem , p < .05 ) . Mortality did not differ between G ( 26 ± 9 % ) and SI ( 24 ± 10 , p = .86 ) . Conclusions There is no clear difference in the incidence of VAP in SI compared with G enteral nutrition . Patients given feeding into the SI do receive higher calorie and protein intakes Abstract A prospect i ve study was conducted to determine the incidence , risk factors and pathogens of ventilator-associated pneumonia ( VAP ) in 198 patients requiring mechanical ventilation for more than 48 hours . VAP occurred in 67 ( 33.8 % ) patients . Risk factors associated with VAP were admission APACHE II score > 20 ( odds ratio [ OR ] 4.77 , 95 % confidence interval [ CI ] 2.04–11.27 , P<0.001 ) , mechanical ventilation > 10 days ( OR 44.4 , 95 % CI 2.16–26.7 , P<0.0001 ) , ICU length of stay > 10 days ( OR 9.4 , 95 % CI 3.55–25.65 , P<0.0001 ) , and admission PaO2/FiO2 ratio < 200 mmHg ( OR 3.4 , 95 % CI 1.00–11.41 , P<0.05 ) . Logistic regression analysis showed a relationship between VAP and length of stay in ICU , duration of fever and presence of catheter-related infection . The pathogens isolated were predominantly gram-negative bacteria ( 83.2 % ) , with a high proportion of Acinetobacter spp . ( 35 % ) resistant to commonly used antimicrobial agents . The mortality rate was not influenced by VAP Nosocomial pneumonia is a frequent complication of prolonged mechanical ventilation [ 1 - 3 ] . Oropharyngeal and gastric colonization , because of potentially pathogenic microorganisms and their subsequent aspiration to the lower airways , play a substantial role in the pathogenesis of ventilator-associated nosocomial pneumonia [ 4 , 5 ] . Selective digestive decontamination has been widely used as a prophylactic regimen for ventilator-associated nosocomial pneumonia . The first to describe this complication , Stoutenbeek and colleagues [ 6 ] suggested that the best combination for preventing nosocomial pneumonia was the use of topical nonabsorbable antibiotics in the oropharynx and stomach together with systemic antibiotics . Most studies have shown a substantial decrease in the carriage of gram-negative bacilli of the upper and lower airways and also in the incidence of nosocomial pneumonia [ 7 , 8 ] , and a few studies have shown a substantial decrease in the overall mortality rate [ 9 - 11 ] . Several important considerations in most of the studies still make selective digestive decontamination a controversial issue . First , several studies were not r and omized or used historical controls [ 6 , 12 - 19 ] . Second , most of the r and omized studies used only nonspecific methods to diagnose nosocomial pneumonia [ 9 , 11 , 20 - 28 ] . Finally , despite the apparent decrease in the incidence of nosocomial pneumonia , mortality did not change in most of the studies [ 12 - 28 ] , including two recent r and omized and double-blind studies [ 29 , 30 ] of a large population sample of patients in an intensive care unit . We did a r and omized , double-blind study of selective digestive decontamination in a general population of patients requiring mechanical ventilation . The main end points of this study were to assess the effect of selective digestive decontamination in decreasing nosocomial pneumonia and mortality . Additional end points of this study were to determine the effect of selective digestive decontamination on the morbidity ( length of stay and duration of mechanical ventilation ) and the mortality rate . Methods Patients The study was done in the Respiratory Intensive Care Unit of the Hospital Clinic of Barcelona , Spain , a 1000-bed teaching hospital , during a period of 12 months . All mechanically ventilated patients admitted to the respiratory intensive care unit and expected to remain intubated for more than 3 days were included in the study . The only exclusion criterion was the presence of immunosuppression ( human immunodeficiency virus [ HIV ] infection , HIV-related diseases , patients who received transplants , and patients treated with antineoplastic chemotherapy ) . Patients who were extubated or who died before receiving 72 hours of selective digestive decontamination or placebo were also excluded from the analysis . Study Design Patients were r and omly allocated to either the selective digestive decontamination or the placebo group . The r and omization was done using a computer-generated table , and the patients were enrolled consecutively . Severity of illness was evaluated by means of the Simplified Acute Physiologic Score after r and omization . The authors of the study were blinded in the recovery of the results . The study ended after extubation or death of the patient in the intensive care unit . Administration of Antibiotics After sample s for the bacteriologic assessment were obtained , antibiotics were administered for selective digestive decontamination . An aqueous suspension of 10 mL containing polymyxin E , 100 mg ( Dumex ; Dumex Limited , Denmark ) ; tobramycin , 80 mg ( Tobradistin ; Dista SA , Madrid , Spain ) ; and amphotericin B , 500 mg ( Fungizona ; Squibb Industria Farmaceutica SA , Madrid ) was administered through a nasogastric tube to patients in the selective digestive decontamination group . Carboxymethyl-cellulose with pectin and with gelatin ( 0.5 mL , Orabase ; Drogfesa , Mollet del Valles , Spain ) containing polymyxin E , tobramycin , and amphotericin B , at 2 % concentration , was applied four times a day . In the placebo group , an aqueous suspension of Maxipro ( Scientific Hospital Supplies Limited , Liverpool , United Kingdom ) and Orabase , both colored with tartrazine , were administered through the nasogastric tube and in the oropharynx at the same dosage as for patients who received selective digestive decontamination . Systemic Antibiotic and Stress Ulcer Prophylaxis Patients were treated with 2 g of intravenous cefotaxime four times a day ( Primafen , Hoechst Iberica SA , Barcelona , Spain ) for the first 4 days of mechanical ventilation if they did not have infection on admission . Infected patients who were admitted to the intensive care unit received other parenteral antibiotics according to clinical decisions . Prophylaxis for stress ulcers was done using 1 g of sucralfate every 4 hours ( Urbal ; Merck-Igoda SA , Mollet del Valles ) through a nasogastric tube , except in patients with paralytic ileus or with upper gastrointestinal bleeding , who were treated with 50 mg of intravenous ranitidine , four times a day ( Zantac ; Glaxo SA-Allen Farmaceutica SA , Madrid ) . Bacteriologic Assessment Endotracheal aspirates , pharyngeal swabs , and gastric juice sample s were obtained three times a week for quantitative cultures . Endotracheal aspirate sample s were obtained by means of sterile tubes ( Mocstrap ; Productes Clinics , SA , La Llagosta , Barcelona ) . Sample s obtained were diluted and homogenized in distilled water to 1/2 concentration using a vortex-style shaker ( Reax 2000 ; Heidolph , Germany ) and were rediluted in distilled water to 1/20 and 1/200 concentrations . Pharyngeal swabs were obtained using sterile swabs with Amies transport media ( Eurotubo ; Industrias Aulabor SA , Barcelona ) , were homogenized in 1 mL of distilled water , and were diluted to concentrations of 1/10 , 1/102 , and 1/103 . Gastric juice sample s were obtained by aspiration through a nasogastric tube using a sterile feeding syringe . The pH was determined in all the sample s using paper indicators ( Acilit , pH 0 to 6 and Spezialindikator , pH 6.5 to 10 ; Merck , Darmstadt , Germany ) . The sample s were homogenized using a vortex-style shaker and were diluted in distilled water to concentrations of 1/10 and 1/100 . All sample s were plated on the following agar media : blood ; chocolate ; McConkey-2 ; buffered , charcoal , and yeast extract ( BCYEa ) ; Sabouraud-dextrose ; Sabouraud with nalidixic acid ; and blood with nalidixic acid . If negative , the plates were discarded after 5 days of testing for aerobic bacteria , after 10 days of testing for Legionella and anaerobic bacteria , and after 4 weeks of testing for fungi . If positive , counts of colony-forming units per milliliter and identification using st and ard methods [ 31 ] were done for the microorganisms . Definitions Potentially pathogenic microorganisms were defined [ 32 ] as those causing infection in a person with impaired defense mechanisms . They can be classified into community microorganisms , which cause infections in previously healthy persons with intact carriage defense , and nosocomial microorganisms , which cause infections in persons with impaired carriage defense . Colonization was defined as the isolation of the same strain of a potentially pathogenic microorganism from at least two consecutive surveillance sample s in any concentration . The clinical diagnosis of pneumonia was based on the presence of all of the following criteria : new or progressive pulmonary radiologic infiltrate or both for 48 hours or more , purulent tracheal secretions , temperature of 38.5 C or more , and leukocytosis ( 12 109/L ) or leukopenia ( 4 109/L ) . The diagnosis of pneumonia was confirmed by the isolation of a potentially pathogenic microorganism in a protected specimen brush sample in concentrations of 103 CFU/mL or more or in a bronchoalveolar lavage sampling in concentrations of 104 CFU/mL or more [ 33 ] . We defined definite pneumonia when all the clinical criteria and one bacteriologic criterion were present or by the presence of histologic signs of pneumonia at autopsy . Probable pneumonia was defined when only clinical criteria were present . Primary endogenous pneumonia was diagnosed when pneumonia developed within the first 4 days of mechanical ventilation and when etiologic microorganisms were isolated previously or concomitantly in pharyngeal swabs or in gastric juice . Secondary endogenous pneumonia was pneumonia that developed after the fourth day of mechanical ventilation . Exogenous pneumonia was diagnosed when the etiologic microorganism was not isolated in pharyngeal swabs or in gastric juice before the development of pneumonia . Community flora was defined as the isolation of normal buccal flora ( Neisseria species , Streptococcus viridans , among others ) , Streptococcus pneumoniae , or Haemophilus influenzae . A catheter-related infection was diagnosed when inflammatory signs occurred in a catheterized blood vessel together with a temperature of 38.3 C or more , irrespective of the isolation of a potentially pathogenic microorganism in the culture of the removed catheter . Likewise , this diagnosis was considered if the fever improved within 12 hours after removing the catheter . A urinary tract infection was diagnosed after fresh-voided catheter urine containing five or more leukocytes per high-power light-microscopic field were identified and a potentially pathogenic microorganism was isolated in urine culture in concentrations of 105 CFU/mL or more . A wound infection was diagnosed if purulent secretions from wounds occurred with signs of inflammation and the isolation of a potentially pathogenic microorganism in concentrations of 105 CFU/mL or more from the purulent wound secretions . Septicemia was diagnosed if clinical signs of systemic infection occurred , such as fever , leukocytosis , increased percentage of b and forms , and metabolic acidosis , combined with a positive blood culture . Multiple organ system failure was defined as three or more organ systems failing for more than 2 consecutive days . The objective of this study was to verify the incidence of nosocomial pneumonia in intubated and extended mechanically ventilated patients having endotracheal suctioning by an open vs. closed suction method aim ing to decrease nosocomial pneumonia . Twenty-four ( 51.1 % ) patients received open-tracheal suction and 23 ( 48.9 % ) received closed-tracheal suction . The inclusion criteria were : surgical and medical patients older than 13 years , undergoing mechanical ventilation for more than 48 hours . Additional data were gathered using the Acute Physiology and Chronic Health Evaluation II , and details on smoking , alcoholism , diabetes mellitus , renal failure , previous lung disease , and previous use of antibiotics , steroids , H2 antagonists and antacids . Among the 24 patients having open-tracheal suction , 11 developed nosocomial pneumonia while of the 23 patients undergoing closed-tracheal suction , seven developed infection ( P = 0.278 ) . Risk factors for nosocomial pneumonia were not significantly different between the two groups . In the final logistical regression model the following variables remained : groups ( open and closed ) [ odds ratio ( OR ) = 0.014 ; confidence interval ( CI ) = 0.001 - 0.416 ; P = 0.014 ] and use of prior antibiotics ( OR = 2.297 ; CI = 1.244 - 4.242 ; P = 0.008 ) . Use of a closed suction system did not decrease the incidence of nosocomial pneumonia when compared with the open system . The exogenous risk factors were the most important for acquiring this infection Inspired gases must be warmed and humidified during mechanical ventilation . In a prospect i ve r and omized study we compared the performance of a heated humidifier ( HH ) ( Draegger Aquaport ) and a heat and moisture exchanger ( HME ) ( Pall Filter BB 2215 ) . A total of 116 patients requiring mechanical ventilation ( Servo 900C Siemens ) were enrolled into the study and were r and omly assigned to 2 groups . Patients in group I were ventilated with a traditional breathing circuit with HH and patients in group II using a simplified circuit with HME . Pre-existing and hospital acquired atelectasis and pneumonia , occurrence of endotracheal tube ( ET ) occlusion and ventilatory parameters ( respiratory rate , tidal volume ) were studied . No statistical difference was found between groups for each parameter except the greater frequency of ET occlusions in the II group ( 0/61 vs 9/55 ) ( p=0.0008 ) . Pall Filter ( PF ) , a hydrophobic filter , humidifies the dry gases from the condensed water which is put down on the HME surfaces during cooling of saturated expired gases . This purely physical property is linked to the magnitude of the thermic gradient between the expired pried gase and the ambiant temperture . Performance impairment of PF in our study might be due to high ambiant temperature in the intensive care unit ( usually around 28 ° C ) which reduces thermic gradient and water exchanges . We conclude that efficiency of PF may be weak in some conditions of ambiant temperature OBJECTIVE To study the effect of subglottic secretions drainage on the incidence of ventilator-associated pneumonia ( VAP ) in patients receiving mechanical ventilation . DESIGN A r and omized clinical trial . SETTING A 12-bed general ICU . PATIENTS One hundred fifty patients with an expected duration of mechanical ventilation > 72 h were enrolled in the study . INTERVENTION Patients were r and omly assigned to receive either an endotracheal tube for intermittent subglottic secretions drainage or a st and ard endotracheal tube . OUTCOME MEASUREMENTS Incidence of VAP , duration of mechanical ventilation , length of ICU stay , length of hospital stay , and mortality . RESULTS Seventy-five patients were r and omized to subglottic secretion drainage , and 75 patients were r and omized to the control group . The two groups were similar at the time of r and omization with respect to demographic characteristics and severity of illness . VAP was seen in 3 patients ( 4 % ) receiving suction secretion drainage and in 12 patients ( 16 % ) in the control group ( relative risk , 0.22 ; 95 % confidence interval , 0.06 to 0.81 ; p = 0.014 ) . The other outcome measures were not significantly different between the two groups . CONCLUSION Intermittent subglottic secretion drainage reduces the incidence of VAP in patients receiving mechanical ventilation OBJECTIVE To determine the risk of acquiring ventilator-associated pneumonia ( VAP ) and the impact on costs when extending ventilator circuit change intervals beyond 2 days to 7 and 30 days . DESIGN Prospect i ve 4-year review of mechanically ventilated patients . SETTING The respiratory and medical ICUs of an 800-bed tertiary teaching Veterans Affairs hospital . PATIENTS All adult patients receiving mechanical ventilation from January 1991 through December 1994 . INTERVENTIONS Ventilator circuits with active heated water humidifiers were changed at 2-day intervals during a 2-year control period , followed by 7-day and 30-day intervals ( for 1 year each ) . Heated wire circuits were adopted with the 30-day interval . The rate of VAP per 1,000 ventilator days was calculated for each circuit change interval group . Survival analysis was used to model VAP with ventilator circuit change to determine risk . RESULTS During the study period , 637 patients received mechanical ventilation . During the 2 years with 2-day change intervals , the VAP per 1,000 ventilator days was 11.88 ( n=343 ) , compared with 3.34 ( n=137 ) and 6.28 ( n=157 ) for 7-day and 30-day change intervals , respectively . The risk of acquiring a VAP for those with a circuit change every 2 days was significantly greater ( relative risk , 3.1 ; p=0.0004 ; 95 % confidence interval , 1.662 , 5.812 ) than those with the 7- and 30-day circuit changes . Extending circuit change intervals reduced supply and labor costs averaging $ 4,231/yr for each ventilator in use . CONCLUSIONS Circuit change intervals of 7 and 30 days have lower risks for VAP than the 2-day intervals , yielding substantial reductions in morbidity as well labor and supply costs Objective To evaluate the mortality rate attributable to nosocomial ventilator-associated pneumonia in an intensive care unit . Design Prospect i ve , matched , risk-adjusted cohort study . Setting A 18-bed adult medical-surgical intensive care unit in a 1,100-bed regional and teaching hospital in France . Patients From January 1 , 1996 , to April 30 , 1999 , 135 patients who developed nosocomial pneumonia were matched with 135 control patients without nosocomial pneumonia . Interventions None . Measurements and Main Results Nosocomial pneumonia was identified on the basis of results of distal bronchial sample s. The matching process was conducted according to the following primary criteria : cause of admission , indication for ventilatory support , immunologic status , cardiac status , probability of death ( ±5 % ) , Glasgow Coma Scale score ( ±2 points ) , age ( ±7 yrs ) , and duration of exposure to risk . When possible , case and control patients were matched according to five secondary criteria : respiratory and alcoholism status before admission , diagnosis categories , surgical procedure or not , and gender . The mortality rates were compared between case and control patients by using the Kaplan-Meier estimate and the log-rank test . The influence of nosocomial pneumonia on mortality rate then was tested by adjusting for the secondary criteria and other possible confounding factors by using the Cox proportional-hazards model . The matching process was successful for 1,080 of 1,080 primary criteria . The crude intensive care unit mortality rate was higher in patients with nosocomial pneumonia than in control patients ( 41 vs. 14%;p < .0001 ) . In actuarial survival analysis , the probability of intensive care unit death was higher in the case patients ( odds ratio = 2.7 , 95 % confidence interval = 1.8–3.1 , p = .028 ) . After adjustment , the occurrence of nosocomial pneumonia remained an independent risk factor of death ( odds ratio = 2.1 , 95 % confidence interval = 1.2–3.6 , p = .008 ) . Nosocomial pneumonia attributable to multiresistant microorganisms was significantly associated with death ( odds ratio = 2.6 , 95 % confidence interval = 1.1–5.8 , p = .02 ) . The length of intensive care unit stay was higher in case than in control patients ( 31 ± 19 vs. 26 ± 17 days , p < .0001 ) . Conclusions Nosocomial pneumonia is independently associated with death in the intensive care unit . In addition , it increases the length of intensive care unit stay Continuous enteral feeding ( CEF ) has been associated with decreased gastric acidity , thereby stimulating gastric colonization and ventilator-associated pneumonia ( VAP ) . Intermittent enteral feeding ( IEF ) could induce a temporary increase in gastric acidity and decrease the risk of VAP . We studied the influence of IEF ( 18 h/d ) and CEF ( 24 h/d ) on gastric and oropharyngeal colonization . Sixty patients were r and omized to receive either IEF or CEF , and continuous intragastric pH monitoring was performed in 50 patients . Median intragastric pH levels were similar before enteral feeding was instituted ( pH 2.5 for CEF and pH 2.4 for IEF ) , and median pH values increased slightly after institution of nutrition ( NS ) . In patients receiving IEF , median pH decreased from 3.5 to 2.2 ( p = 0.0002 ) when enteral feeding was discontinued . However , despite this , 80 % of the patients in both study groups were colonized in the stomach after 7 d in study . In addition , colonization rates of the oropharynx and trachea , the incidence of VAP , and mortality were similar in both study groups . IEF was less well tolerated than CEF . We conclude that almost all patients receiving enteral feeding are colonized in the stomach with gram-negative bacteria . IEF result ed in a slight decrease in intragastric pH without influencing rates of colonization and infection of the respiratory tract UNLABELLED This study evaluates the effects of sucralfate and antacids on intragastric acidity , colonization of stomach , oropharynx and trachea , and the incidence of ventilator-associated pneumonia ( VAP ) in mechanically ventilated patients in intensive care units . We conducted a prospect i ve r and omized double-blind trial in which patients were stratified on initial gastric pH. Intragastric acidity was measured with computerized , continuous intragastric monitoring . The diagnosis of VAP was established with protected specimen brush and /or bronchoalveolar lavage . The study included consecutive eligible patients with mechanical ventilation and nasogastric tube . INTERVENTIONS After stratification on initial intragastric pH into two groups , patients from both groups were r and omly assigned to receive either antacids ( a suspension of aluminum hydroxide and magnesium hydroxide ) , 30 mL every 4 h , or sucralfate , 1 g every 4 h. Continuous intragastric pH monitoring was performed in 112 patients ( 58 antacids , 54 sucralfate ) . Using predetermined criteria , colonization of stomach , oropharynx , and trachea , and the incidence of VAP were assessed . Altogether , 141 patients were included ( 74 receiving antacids , 67 sucralfate ) and continuous intragastric pH monitoring was performed in 112 patients , with a mean of 75 h per patient . The median pH and the percentage of time with a pH < 4.0 were calculated from each measurement . No significant differences in median pH values ( 4.7 + /- 2.2 and 4.5 + /- 2.0 for antacids and sucralfate , respectively ) were observed . Median pH values were higher in patients with gastric bacterial colonization than in noncolonized patients ( 5.5 + /- 2.1 and 3.3 + /- 2.0 , p < 0.01 ) , but colonization of oropharynx and trachea was not related to intragastric acidity . Thirty-one patients ( 22 % ) developed VAP , with a similar incidence in both treatment groups . In addition , antibiotic use , duration of hospitalization , and mortality rates were similar in both groups . Enteral feeding did not change intragastric acidity significantly but increased gastric colonization with Enterobacteriaceae , without influencing oropharyngeal and tracheal colonization . Antacids and sucralfate had a similar effect on intragastric acidity , colonization rates , and incidence of VAP . Intragastric acidity influenced gastric colonization but not colonization of the upper respiratory tract or the incidence of VAP . Therefore , it is unlikely that the gastropulmonary route is important for the development of VAP Objective : To compare the frequency of stress erosions and ulcers in critically ill adult patients treated with either sucralfate or placebo . Design : Prospect i ve , r and omized study . Setting : Intensive care unit in a university hospital . Patients : Twenty‐six adult patients . All patients were mechanically ventilated and were at risk of developing stress ulceration . Interventions : Patients were r and omized to receive either sucralfate ( 2 g every 8 hrs ) ( group 1 ) via the nasogastric tube ( flushed with 10 mL of sterile water ) or 20 mL of sterile water every 8 hrs ( group 2 ) via the nasogastric tube . Measurements and Main Results : At the time of intensive care unit admission , the frequency of stress ( acute ) erosions ( as assessed with the endoscope ) was 21.7 % . No ulcers were detected . By day 3 , the frequency had increased to 37.5 % in group 1 and 88.9 % in group 2 . Mucosal deterioration was more likely in the patients treated with placebo ( water ) ( p < .05 ) . In total , seven patients developed acute ulceration in group 2 compared with only one patient in group 1 ( p < .05 ) . The frequency of gastric colonization with aerobic Gram‐negative bacilli was 25.6 % in group 1 and 28.6 % in group 2 . Only one retro grade nosocomial pneumonia developed ( group 1 ) . Conclusion : Based on our findings , we strongly recommend the adoption of sucralfate as opposed to no prophylaxis in the prevention of acute upper gastrointestinal ulceration . ( Crit Care Med 1994 ; 22:1949–1954 Objective To determine the influence of using different denominators on risk estimates of ventilator-associated pneumonia ( VAP ) . Design and setting Prospect i ve cohort study in the medical ICU of a large teaching hospital . Patients All consecutive patients admitted for more than 48 h between October 1995 and November 1997 . Measurements and results We recorded all ICU-acquired infections using modified CDC criteria . VAP rates were reported per 1,000 patient-days , patient-days at risk , ventilator-days , and ventilator-days at risk . Of the 1,068 patients admitted , VAP developed in 106 ( 23.5 % ) of those mechanically ventilated . The incidence of the first episode of VAP was 22.8 per 1,000 patient-days ( 95 % CI 18.7–27.6 ) , 29.6 per 1,000 patient-days at risk ( 24.2–35.8 ) , 35.7 per 1,000 ventilator-days ( 29.2–43.2 ) , and 44.0 per 1,000 ventilator-days at risk ( 36.0–53.2 ) . When considering all episodes of VAP ( n=127 ) , infection rates were 27.3 episodes per 1,000 ICU patient-days ( 95 % CI 22.6–32.1 ) and 42.8 episodes per 1,000 ventilator-days ( 35.3–50.2 ) . Conclusions The method of reporting VAP rates has a significant impact on risk estimates . Accordingly , clinicians and hospital management in charge of patient-care policies should be aware of how to read and compare nosocomial infection rates OBJECTIVE To compare the incidence of nosocomial pneumonia in critically injured patients r and omized to one of three stress ulcer prophylaxis regimens . DESIGN Prospect i ve , r and omized clinical trial . METHODS Mechanically ventilated patients admitted to the trauma intensive care unit of a Level I trauma center received sucralfate , antacid , or ranitidine . MEASUREMENTS AND MAIN RESULTS Two hundred forty-two patients were r and omized : sucralfate , n = 80 ; antacid , n = 82 ; and ranitidine , n = 80 . There was no statistically significant difference in pneumonia rates among the treatment groups ( p = 0.875 ) . Pneumonia occurred more frequently in patients with gram-negative retro grade colonization from stomach to trachea ( p = 0.02 ) , but this accounted for only 13 % of all pneumonias in the study population . The death rate in patients with pneumonia was not statistically different among the three groups . Although 20 % developed overt gastrointestinal bleeding , no episode was clinical ly significant . Mean gastric pH was > 4 in 95 % of the study population , including 88 % of patients receiving sucralfate . The death rate in the antacid group was significantly higher ( p = 0.046 ) but not because of increased gastrointestinal bleeding or pneumonia . CONCLUSIONS Our results show no difference in the incidence of nosocomial pneumonia in mechanically ventilated trauma patients during the first 4 days of stress ulcer prophylaxis with sucralfate , antacid , or ranitidine . There is a trend toward decreased pneumonia in the sucralfate group after study day 4 . Even after controlling for injury severity , the mortality rate in the antacid group was significantly higher ; the reasons for this are unknown Closed suction catheters ( CSC ) for removal of bronchial secretions in intubated patients have been used in intensive care units ( ICU ) for many years . Manufacturers still recommend daily changes of the catheter in order to reduce the incidence of ventilator associated pneumonia ( VAP ) . There is , however , a lack of clinical evidence to support this recommendation . The objective of this study was therefore to compare the incidence of VAP in patients who receive either 24 hourly or 48 hourly changes of the CSC . Eligible patients were r and omised to one of the two groups to receive either a 24 hourly change ( n = 53 ) or a 48 hourly change ( n = 48 ) of the CSC . Sputum specimens were sent second daily for quantitative culture . Chest x-rays ( CXR ) and white blood cell counts were attended daily . A VAP was diagnosed according to previously established criteria . A second set of modified criteria were also used to conduct a further analysis of the results . Of the 158 patients r and omised , 101 completed the study . These patients had a mean age of 65 years and a mean APACHE II score of 28.2 in the first 24 hours of the study . The average duration in the trial was 10 days . The two groups were comparable in terms of demographic features . There were no reported cases of VAP in either group using the criteria originally selected in the study design . Using a modified criteria to diagnose VAP there were 10 ( 19 % ) patients with VAP in the 24 hour group and 13 ( 27 % ) in the 48 hour group . The incidence of VAP between the two groups was not statistically different ( p = 0.35 ) . To conclude , there was no difference in the incidence of VAP between the two groups studied . Based on previous studies conducted by Quirke and Kollef and the experience of our study we have changed our clinical practice to a 48 hour change of the CSC . We would , however , suggest further study or a meta- analysis of the available literature before a recommendation is made OBJECTIVE Ventilator-associated pneumonia ( VAP ) complicates the course of up to 24 % of intubated patients . Data from the Middle East are scarce . The objective of this study was to evaluate the incidence , microbiology , and antimicrobial susceptibility patterns of isolated microorganisms in VAP in a developing country . DESIGN Prospect i ve observational cohort study . SETTING The American University of Beirut Medical Center , a tertiary-care center that serves as a major referral center for Lebanon and neighboring countries . PATIENTS All patients admitted to the intensive care and respiratory care units from March to September 2001 , and who had been receiving mechanical ventilation for at least 48 hours , were included in the study . Results of sample s su bmi tted for culture were recorded and antimicrobial susceptibility testing of isolated pathogens was performed . RESULTS Seventy patients were entered into the study . The incidence of VAP was 47 % . Gram-negative bacilli accounted for 83 % of all isolates . The most commonly identified organism was Acinetobacter anitratus , followed by Pseudomonas aeruginosa . Fifty percent of all gram-negative bacterial isolates were classified as antibiotic resistant . Compared with patients without VAP , patients with VAP remained intubated for a longer period and stayed in the intensive care unit longer . VAP was not associated with an increased mortality rate . CONCLUSION Compared with other studies , the results from this referral center in Lebanon indicate a higher incidence of VAP and a high prevalence of resistant organisms . These data are relevant because they direct the choice of empiric antibiotic therapy for VAP INTRODUCTION Ventilator-associated pneumonia ( VAP ) is the most common nosocomial infection among intensive care unit ( ICU ) patients . OBJECTIVE Prospect ively identify the factors associated with development of VAP and examine the incidence of VAP . SUBJECTS Over a 6-month period we had 175 patients who required mechanical ventilation for longer than 24 hours . RESULTS VAP occurred in 56 patients ( 32 % ) . Stepwise logistic regression analysis identified 5 factors independently associated with VAP ( p < 0.05 ) : bronchoscopy ( adjusted odds ratio [ AOR ] = 2.95 ; 95 % confidence interval [ CI ] , 1.1 - 8.3 ; p = 0.036 ) ; tube thoracostomy ( AOR = 2.78 ; 95 % CI , 1.1 - 6.6 ; p = 0.023 ) ; tracheostomy ( AOR = 3.56 ; 95 % CI , 1.7 - 8.4 ; p = 0.002 ) ; Acute Physiology and Chronic Health Evaluation ( APACHE II ) score > /= 18 ( AOR = 2.33 ; 95 % CI , 1.1 - 5.1 ; p = 0.033 ) ; and enteral feeding ( AOR = 2.89 ; 95 % CI , 1.3 - 7.7 ; p = 0.026 ) . The duration of mechanical ventilation was longer among patients who developed VAP ( p < 0.001 ) . VAP was not associated with the cause of ICU admission . CONCLUSIONS VAP is a common infection and certain interventions might affect the incidence of VAP . ICU clinicians should be aware of the risk factors for VAP , which could prove useful in identifying patients at high risk for VAP and modifying patient care to minimize the risk of VAP , such as avoiding unnecessary bronchoscopy or modulating enteral feeding OBJECTIVES To evaluate the impact of risk factors on the development of stress-related upper gastrointestinal bleeding in severe head injury patients r and omized to treatment with a 6.25 mg/hr continuous ranitidine infusion or placebo . DESIGN Prospect i ve , multicenter , r and omized , double-blind , placebo-controlled , parallel-group study . SETTING Ten intensive care units in the United States . PATIENTS Patients with severe head injury , defined as having a Glasgow Coma Score of < or = 10 , were eligible for enrollment . INTERVENTIONS Ranitidine 6.25 mg/hr or saline placebo was administered by continuous infusion for a maximum of 5 days . MEASUREMENTS AND MAIN RESULTS Patients were evaluated every 8 hrs for the presence of stress-related upper gastrointestinal bleeding . Bleeding developed in 15 ( 19 % ) of 81 placebo-treated patients vs. three ( 3 % ) of 86 ranitidine-treated patients ( p = .002 ) . None of the individual risk factors had a significant effect on bleeding frequency . No bleeding occurred in the four patients with one risk factor . Placebo bleeding rates in patients with 2 , 3 to 5 , and > 5 risk factors were 20 % , 20 % , and 18 % , respectively . For the ranitidine-treated patients , bleeding was reported in 0 % , 5 % , and 0 % in the 2 , 3 to 5 , and > 5 risk factor subgroups , respectively . Pneumonia occurred in 19 % of the placebo-treated patients vs. 14 % in the ranitidine treatment group . CONCLUSIONS The full risk to develop stress-related upper gastrointestinal bleeding was realized when two risk factors were present concomitantly . The presence of additional risk factors did not increase the occurrence of bleeding . A continuous infusion of ranitidine at 6.25 mg/hr provided significant protection from bleeding , regardless of the number of risk factors present UNLABELLED Colonization of the intestinal tract has been assumed to be important in the pathogenesis of ventilator-associated pneumonia ( VAP ) , but relative impacts of oropharyngeal , gastric , or intestinal colonization have not been eluci date d. Our aim was to prevent VAP by modulation of oropharyngeal colonization , without influencing gastric and intestinal colonization and without systemic prophylaxis . In a prospect i ve , r and omized , placebo-controlled , double-blind study , 87 patients received topical antimicrobial prophylaxis ( gentamicin/ colistin/vancomycin 2 % in Orabase , every 6 h ) in the oropharynx and 139 patients , divided over two control groups , received placebo ( 78 patients were studied in the presence of patients receiving topical prophylaxis [ control group A ] and 61 patients were studied in an intensive care unit where no topical prophylaxis was used [ control group B ] ) . Baseline characteristics were comparable in all three groups . Topical prophylaxis eradicated colonization present on admission in oropharynx ( 75 % in study group versus 0 % in control group A [ p < 0.00001 ] and 9 % in control group B patients [ p < 0.00001 ] ) and in trachea ( 52 % versus 22 % in A [ p = 0.03 ] and 7 % in B [ p = 0.004 ] ) . Moreover , topical prophylaxis prevented acquired oropharyngeal colonization ( 10 % versus 59 % in A [ p < 0.00001 ] and 63 % in B [ p < 0.00001 ] ) . Colonization rates in stomach and intestine were not affected . Incidences of VAP were 10 % in study patients , 31 % in Group A , and 23 % in Group B patients ( p = 0.001 and p = 0.04 , respectively ) . This was not associated with shorter duration s of ventilation or ICU stay or better survival . Oropharyngeal colonization is of paramount importance in the pathogenesis of VAP , and a targeted approach to prevent colonization at this site is a very effective method of infection prevention . KEYWORDS cross infection , prevention and control ; respiration , artificial , adverse effects ; antibiotics , administration and dosage infection control methods ; pneumonia , etiology , prevention and control ; intubation , intratracheal , adverse BACKGROUND Ventilator-associated pneumonia is the leading nosocomial infection in critically ill patients . The frequency of ventilator-associated pneumonia caused by multidrug-resistant bacteria has increased in recent years , and these pathogens cause most of the deaths attributable to pneumonia . The authors , therefore , evaluated factors associated with selected multidrug-resistant ventilator-associated pneumonia in critical care patients . METHODS The authors prospect ively recorded potential risk factors at the time of intensive care unit admission . An endotracheal aspirate was obtained in all patients who met clinical criteria for pneumonia . Patients were considered to have ventilator-associated pneumonia only when they met the clinical criteria and aspirate culture was positive for bacteria 48 h or more after initiation of mechanical ventilation . Pediatric patients were excluded . Adult patients with ventilator-associated pneumonia were first grouped as " early-onset " ( < 5 days ) and " late-onset , " determined by episodes of ventilator-associated pneumonia , and then , assigned to four groups based on the bacteria cultured from their tracheal aspirates : Pseudomonas aeruginosa , Acinetobacter baumanii , methicillin-resistant staphylococci , and all others . The first three bacteria were considered to be multidrug resistant , whereas the others were considered to be antibiotic susceptible . Potential risk factors were evaluated with use of univariate statistics and multivariate regression . RESULTS Among 486 consecutive patients admitted during the study , 260 adults underwent mechanical ventilation for more than 48 h. Eighty-one patients ( 31 % ) experienced 99 episodes of ventilator-associated pneumonia , including Pseudomonas(33 episodes ) , methicillin-resistant staphylococci ( 17 episodes ) , Acinetobacter(9 episodes ) , and nonresistant bacteria ( 40 episodes ) . Sixty-six of these episodes were early onset and 33 episodes were late onset . Logistic regression analysis identified three factors significantly associated with early-onset ventilator-associated pneumonia caused by any one of the multidrug-resistant bacterial strains : emergency intubation ( odds ratio , 6.4 ; 95 % confidence interval , 2.0 - 20.2 ) , aspiration ( odds ratio , 12.7 ; 95 % confidence interval , 2.4 - 64.6 ) , and Glasgow coma score of 9 or less ( odds ratio , 3.9 ; 95 % confidence interval , 1.3 - 11.3 ) . A. baumanii-related pneumonia cases were found to be significantly associated with two of these factors : aspiration ( odds ratio , 14.2 ; 95 % confidence interval , 1.5 - 133.8 ) and Glasgow coma score ( odds ratio , 6.0 ; 95 % confidence interval , 1.1 - 32.6 ) . CONCLUSIONS The authors recommend that patients undergoing emergency intubation or aspiration or who have a Glasgow coma score of 9 or less be monitored especially closely for early-onset multidrug-resistant pneumonia . The occurrence of aspiration and a Glasgow coma score of 9 or less are especially associated with pneumonia caused by A. baumanii To evaluate the attributable morbidity and mortality of ventilator-associated pneumonia ( VAP ) in intensive care unit ( ICU ) patients , we conducted a prospect i ve , matched cohort study . Patients expected to be ventilated for > 48 h were prospect ively followed for the development of VAP . To determine the excess ICU stay and mortality attributable to VAP , we matched patients with VAP to patients who did not develop clinical ly suspected pneumonia . We also conducted sensitivity analyses to examine the effect of different population s , onset of pneumonia , diagnostic criteria , causative organisms , and adequacy of empiric treatment on the outcome of VAP . One hundred and seventy-seven patients developed VAP . As compared with matched patients who did not develop VAP , patients with VAP stayed in the ICU for 4.3 d ( 95 % confidence interval [ CI ] : 1.5 to 7 . 0 d ) longer and had a trend toward an increase in risk of death ( absolute risk increase : 5.8 % ; 95 % CI : -2.4 to 14.0 d ; relative risk ( RR ) increase : 32.3 % ; 95 % CI : -20.6 to 85.1 % ) . The attributable ICU length of stay was longer for medical than for surgical patients ( 6 . 5 versus 0.7 d , p < 0.004 ) , and for patients infected with " high risk " organisms as compared with " low risk " organisms ( 9.1 d versus 2.9 d ) . The attributable mortality was higher for medical patients than for surgical patients ( RR increase of 65 % versus -27.3 % , p = 0 . 04 ) . Results were similar for three different VAP diagnostic criteria . We conclude that VAP prolongs ICU length of stay and may increase the risk of death in critically ill patients . The attributable risk of VAP appears to vary with patient population and infecting organism PURPOSE To compare the performance of an in-line heat moisture exchanging filter ( HMEF ) ( Pall BB-100 ; Pall Corporation ; East Hills , NY ) to a conventional heated wire humidifier ( H-wH ) ( Marquest Medical Products Inc. , Englewood , Colo ) in the mechanical ventilator circuit on the incidence of ventilator-associated pneumonia ( VAP ) and the rate of endotracheal tube occlusion . METHODS This report describes a prospect i ve , r and omized trial of 280 consecutive trauma patients in a 20-bed trauma ICU ( TICU ) . All intubated patients not ventilated elsewhere in the medical center prior to their TICU admission were r and omized to either an in-line HMEF or a H-wH in the breathing circuit . Ventilator circuits were changed routinely every 7 days , and closed system suction catheters were changed every 3 days . HMEFs were changed every 24 h , or more frequently if necessary . A specific endotracheal tube suction and lavage protocol was not employed . Patients were dropped from the HMEF group if the filter was changed more than three times a day or the patient was placed on a regimen of ultra high-frequency ventilation . The Centers for Disease Control and Prevention ( CDC ) criteria for diagnosis of pneumonia were used ; early-onset , community-acquired pneumonia was defined if CDC criteria were met in < or =3 days , and late-onset , hospital-acquired pneumonia was defined if criteria were met in > 3 days . Laboratory and chest radiograph interpretation were blinded . RESULTS The patient ages ranged from 15 to 95 years in the HMEF group and 16 to 87 years in the H-wH group ( p = not significant ) , with a mean age of 46 years and 48 years , respectively . The male to female ratio ranged between 78 to 82%/22 to 18 % , respectively , and 55 % of all admissions were related to blunt trauma , 40 % secondary to penetrating trauma , and 5 % to major burns . There was no difference in Injury Severity Score ( ISS ) between the two groups . Moreover , there was no significant difference in mean ISS among those who did not develop pneumonia and those patients who developed either early-onset , community-acquired or late-onset , hospital-acquired pneumonia . The HMEF nosocomial VAP rate was 6 % compared to 16 % for the H-wH group ( p<0.05 ) , and total ventilator circuit costs ( per group ) were reduced . There were no differences in duration of ventilation ( mean+/-SD ) if the patient did not develop pneumonia or if the patient developed an early-onset , community-acquired or a late-onset , hospital-acquired pneumonia . Moreover , total TICU days were reduced in the HMEF group . In addition , the incidence of partial endotracheal tube occlusion was not significantly different between the H-wH and the HMEF groups . CONCLUSIONS The HMEF used in this study reduced the incidence of late-onset , hospital-acquired VAP , but not early-onset , community-acquired VAP , compared to the conventional H-wH circuit . This was associated with a significant reduction in total ICU stay . Disposable ventilator circuit costs in the HMEF group were reduced compared to the H-wH group in whom circuit changes occurred at 7-day intervals . CLINICAL IMPLICATION S The use of the HMEF is a cost-effective clinical practice associated with fewer late-onset , hospital-acquired VAPs , and should result in improved re source allocation and utilization OBJECTIVE To assess the effect on the rate of ventilator-associated pneumonia ( VAP ) of decreasing the frequency of ventilator circuit changes from three times to once per week . DESIGN Prospect i ve , r and omized trial . SETTING Medical intensive care unit ( MICU ) , a 12-bed , critical-care internal medicine unit , and neurosciences intensive care unit ( NICU ) , a 21-bed , predominantly adult neurosurgical unit , of an urban university hospital . PATIENTS All 447 patients requiring mechanical ventilation during October 1992 through June 1993 . INTERVENTION Patients were allocated r and omly on the basis of permanent medical record numbers : those with odd numbers had circuits changed three times per week , those with even numbers once per week . Intensive-care-unit surveillance was conducted in accordance with definitions and methods of the National Nosocomial Infections Surveillance System . RESULTS In the MICU , the one-change-per-week group had a VAP rate of 7.3 per 1,000 ventilator days , versus 5.9 for the three-per-week group ( P = .6 ) . In the NICU , the one-change-per-week group had a rate of 12.2 per 1,000 ventilator days , versus 12.6 for the three-per-week group ( P = .9 ) . Considering patients in both units ventilated for no more than 7 days , the one-change-per-week group had a VAP rate of 5.9 per 1,000 ventilator days , versus 9.0 per 1,000 for the three-changes-per-week group ( odds ratio [ OR ] , 0.65 ; 95 % confidence interval [ CI95 ] , 0.25 to 1.69 ) . Including patients in the two units maintained on mechanical ventilation for more than 7 days , the one-change-per-week group had a VAP rate of 13.2 per 1,000 ventilator days , versus 9.6 per 1,000 for the three-changes-per-week group ( OR , 1.37 ; CI95 , 0.71 to 2.65 ) . CONCLUSIONS Decreasing the frequency of ventilator circuit changes from three times to once per week had no adverse effect on the overall rate of VAP . Less frequent ventilator circuit changes may decrease the incidence of VAP among patients ventilated for no more than 1 week . However , the incidence of VAP may be higher among patients with once weekly circuit changes ventilated for more than 1 week Objective : To determine the influence of selective oropharyngeal decontamination ( SOD ) on the rate of colonization and infection of the respiratory tract in intensive care patients requiring mechanical ventilation for more than 4 days . A financial assessment was also performed . Design : R and omized , prospect i ve , controlled study using amphotericin B , colistin sulfate ( polymyxin E ) , and tobramycin applied to the oropharynx and systemic cefotaxime prophylaxis . Setting : Anesthesiology intensive care unit ( ICU ) of a 1500-bed hospital . Patients : A total of 88 patients admitted as emergencies and intubated within less than 24 h were enrolled . Fifty- eight patients received SOD and 30 patients served as controls . R and omization was in the proportion of 2 : 1 study patients to controls . Interventions : Microbiological sample s from the oropharynx and other infected sites were taken at the time of admission , then twice a week and after extubation . Measurements and results : With the use of SOD , colonization was significantly reduced . Furthermore , the infection rate decreased from 77 % in the controls to 22 % in the study patients . Staphylococcus aureus was the main potential pathogen causing colonization and pneumonia . Number of days in the ICU , duration of ventilation , and mortality were not significantly decreased . The total cost of antibiotics was reduced . Development of resistance was not observed . Conclusions : The use of SOD significantly reduced the colonization and pneumonia and the total charge for antibiotics . The length of stay in the ICU , duration of ventilation , and mortality were similar . No resistance was observed . Staphylococcus aureus was selected by SOD in some patients and the clinical relevance needs further observation One hundred and twenty consecutive episodes of nosocomial pneumonia ( NP ) in 118 nonneutropenic adults admitted to a 1,000-bed teaching hospital were studied in order to investigate the prognosis and risk factors . The overall fatality rate was 36.6 percent . The identification of a " high-risk " microorganism ( Pseudomonas aeruginosa , Enterobacteriaceae , and other Gram-negative bacilli , Streptococcus faecalis , Staphylococcus aureus , C and ida sp , Aspergillus sp , and episodes of polymicrobial pneumonia ) , bilateral involvement on chest x-ray examination , the presence of respiratory failure , inappropriate antibiotic therapy , and age older than 60 years or an underlying condition ultimately or rapidly fatal were those factors selected by a stepforward logistic regression analysis as independently worsening the prognosis . A series of variables frequently quoted as predisposing to NP was determined to be either present or absent in the same 120 cases of NP and in an equal number of r and omly selected control subjects . After adjusting for confounding , factors significantly predisposing to NP were tracheal intubation , depressed level of consciousness , underlying chronic lung disease , thoracic or upper abdominal surgery , prior episode of a large volume aspiration , and age older than 70 years . Since some of the factors influencing the risk or the prognosis of NP are amenable to medical intervention , a percentage of NP might be prevented and its prognosis can be improved All episodes of ventilator-associated pneumonia ( VAP ) caused by Staphylococcus aureus were prospect ively analyzed for a 30-mo period . Methicillin-sensitive S. aureus ( MSSA ) was isolated in 38 episodes and methicillin-resistant S. aureus ( MRSA ) in 11 others . The two groups were similar regarding sex , severity of underlying diseases , prior surgery , and presence of renal failure , diabetes , cardiopathy , and coma . MRSA-infected persons were more likely to have received steroids before developing infection ( relative risk [ RR ] = 3.45 , 95 % confidence interval [ CI ] = 1.38 - 8.59 ) , to have been ventilated > 6 d ( RR = 2.03 , 95 % CI = 1.36 - 3.03 ) , to have been older than 25 yr ( RR = 1.50 , 95 % CI = 1.09 - 2.06 ) , and to have had preceding chronic obstructive pulmonary disease ( RR = 2.76 , 95 % CI = 0.89 - 8.56 ) than MSSA-infected patients . MSSA-infected persons were more likely than MRSA-infected patients to have cranioencephalic trauma ( RR = 1.94 , 95 % CI = 1.22 - 3.09 ) . All patients with MRSA VAP had previously received antibiotics , compared with only 21.1 % of those with MSSA infection ( p < 0.000001 ) . The incidence of empyema was similar in both groups ; nevertheless , the presence of bacteremia and septic shock was more frequent in the MRSA group . Finally , mortality directly related to pneumonia was significantly higher among patients with MRSA episodes ( RR = 20.72 , 95 % CI = 2.78 - 154.35 ) . This analysis was repeated for monomicrobial episodes , and the difference remained statistically significant . We conclude that MRSA and MSSA strains infect patients with different demographic profiles ; previous antibiotic therapy is the most important risk factor for developing MRSA infection . ( ABSTRACT TRUNCATED AT 250 WORDS OBJECTIVE To define the influence of prior antibiotic use on the etiology and mortality of ventilator-associated pneumonia ( VAP ) . SETTING A university hospital medical-surgical ICU . DESIGN Prospect i ve clinical study . METHODS Over a 35-month period , we prospect ively studied 129 consecutive episodes of VAP . Etiologic diagnosis was established using a protected specimen brush and quantitative culture techniques . We examined prognostic factors by univariate and multivariate analyses using a statistical software package ( SPSS ) . RESULTS The rate of VAP caused by Gram-positive cocci or Haemophilus influenzae was statistically lower ( p < 0.05 ) in the patients who had received antibiotics previously , while the rate of VAP caused by Pseudomonas aeruginosa was statistically higher ( p < 0.01 ) . Patients died of causes directly related to the infection in 18 ( 14.0 percent ) episodes , P aeruginosa being isolated in 9 of these fatal cases . Indeed , we found that 27.7 percent ( 15/54 ) of patients who had received prior antimicrobial therapy before the onset of pneumonia died , compared with only 4.0 percent ( 3/75 ) of those who did not . In the univariate analysis , the variables significantly associated with attributable mortality were age older than 45 years , use of corticosteroids , presence of shock , hospital day of VAP over 9 , antecedent COPD , and a prior antibiotic use . A step-forward logistic regression analysis defined only prior antibiotic use ( p < 0.0001 , OR = 9.2 ) as significantly influencing the risk of death from VAP . The same result was obtained when severity was included in the model . However , prior antibiotic use entirely dropped out as a significant risk factor when the etiologic agent was included in the regression equation . CONCLUSIONS Distribution of infecting microorganisms responsible for VAP differs in patients who received prior antimicrobial therapy , and this factor determines a higher mortality rate . We suggest a restrictive antibiotic policy in mechanically ventilated patients with the purpose of reducing the risk of death from VAP BACKGROUND An earlier r and omized , controlled trial showed that weekly or as-needed ( as opposed to daily ) changes of in-line suction catheters were associated with substantial cost savings , without a higher rate of ventilator-associated pneumonia ( VAP ) . To examine the impact of decreasing the frequency of in-line suction catheter changes in our medical intensive care unit , we conducted an observational study , comparing the catheter costs and frequency of VAP during ( 1 ) a control period , during which in-line suction catheters were changed daily , and ( 2 ) a treatment period , during which the catheters were changed every 7 days or sooner if needed , for mechanical failure or soilage . METHODS All adult patients admitted to our 18-bed medical intensive care unit were evaluated for the 3-month interval 1 year prior to the practice change ( May through July 1998 ) and for the 3 months after implementing the new policy ( May through July 1999 ) . To avoid bias related to usual seasonal variation in VAP frequency , we also determined ( via medical records ) the VAP rate during May through July 1997 . The occurrence of VAP was ascertained by an infection control practitioner , using criteria established by the Centers for Disease Control and applied in a st and ard fashion . The VAP rate was calculated as the mean number of VAPs per 100 ventilator-days for each 3-month interval . Use of ventilators , humidifiers , and non-heated-wire , disposable circuits was uniform during the study , as were policies regarding humidity , temperature setting s , and frequency of routine ventilator circuit changes . RESULTS During the control period 146 patients accounted for 1,075 ventilator-days and there were 2 VAPs ( 0.19 VAPs per 100 ventilator-days ) . During the treatment period 143 patients accounted for 1,167 ventilator-days and there were no VAPs . The mean + /- SD duration of in-line suction catheter use during the treatment period was 3.8 + /- 0.8 days , and 51 % of the patients had the same catheter in place for > 3 days ( range 4 - 9 days ) . The actual cost of catheters used during the treatment period was lower than during the control period ( $ 1,330 vs $ 6,026 ) , predicting annual catheter cost savings of $ 18,782 . CONCLUSIONS We conclude that ( 1 ) a policy of weekly ( vs daily ) change of in-line suction catheter is associated with substantial cost savings , with no significant increase in the frequency of VAP , and ( 2 ) to the extent that these findings confirm the results of prior studies they support a policy of changing in-line suction catheters weekly rather than daily The objective of this study was to assess the effect of a novel regimen of antibiotic prophylaxis on the incidence of lower respiratory tract infection in patients requiring prolonged ( at least five days ) mechanical ventilation . The design was a controlled , prospect i ve , r and omized trial , with blinded comparison of the groups regarding the incidence of respiratory tract infection in an intensive care unit of a university hospital . After determination of the APACHE II score for severity of disease , 88 patients were r and omly divided in three groups . Twenty-four of these patients did not complete five days of mechanical ventilation , and eight were withdrawn for other reasons . Fifty-six patients ( 18 in group 1 , 21 in group 2 , 17 in group 3 ) completed the study . Patients in both control groups 1 and 2 did not receive antibiotic prophylaxis , but the two groups differed in the antibiotic policy in case of infection . Patients in group 3 received antibiotic prophylaxis consisting of norfloxacin , polymyxin E , and amphotericin B , applied topically in oropharynx and stomach from time of ICU admission until extubation , and intravenous cefotaxime 500 mg three times a day during the first five days of admission . In both control groups , about 90 percent of the patients acquired microbial colonization of oropharynx or stomach . In group 3 , only 12 percent and 24 percent of the patients acquired colonization of oropharynx and stomach , respectively ( p less than 0.001 ) . This result ed in a reduction of the incidence of lower respiratory tract infection ( 78 percent in group 1 , 62 percent in group 2 , 6 percent in group 3 [ p = 0.0001 ] ) . The regimen of antibiotic prophylaxis studied prevented respiratory tract infection in mechanically ventilated patients . Antibiotic prophylaxis should be considered in all patients expected to require prolonged mechanical ventilation OBJECTIVE To evaluate the efficacy of two regimens of selective decontamination of the digestive tract in mechanically ventilated patients . DESIGN Prospect i ve , r and omized , concurrent trial . SETTING Multidisciplinary intensive care unit ( ICU ) in a 1,800-bed university hospital . PATIENTS Consecutive patients ( n = 660 ) who were likely to require mechanical ventilation for at least 48 hrs were r and omized to one of three groups : conventional antibiotic regimen ( control group A ) ; oral and enteral ofloxacin-amphotericin B ( group B ) ; and oral and enteral polymyxin E-tobramycin-amphotericin B ( group C ) . Both treatment groups received systemic antibiotics for 4 days ( ofloxacin in group B and cefotaxime in group C ) . INTERVENTIONS Patients were r and omized to receive st and ard treatment ( control group A , n = 220 ) , selective decontamination regimen B ( group B , n = 220 ) , and selective decontamination regimen C ( group C , n = 220 ) . After early deaths and exclusions from the study , 185 controls ( group A ) and 193 ( group B)/200 ( group C ) selective decontamination regimen patients were available for analysis . MEASUREMENTS AND MAIN RESULTS Measurements included colonization and primary / secondary infection rate , ICU mortality rate , emergence of antibiotic resistance , length of ICU stay , and antimicrobial agent costs . The study duration was 19 months . The patient groups were fully comparable for age , diagnostic category , and severity of illness . One third of patients in each group suffered a nosocomial infection at the time of admission . There was a significant difference between treatment group B and control group A in the number of infected patients ( odds ratio of 0.42 , 95 % confidence interval of 0.27 to 0.64 ) , secondary lower respiratory tract infection ( odds ratio of 0.47 , 95 % confidence interval of 0.26 to 0.82 ) , and urinary tract infection ( odds ratio of 0.47 , 95 % confidence interval of 0.27 to 0.81 ) . Significantly more Gram-positive bacteremias occurred in treatment group C vs. group A ( odds ratio of 1.22 , 95 % confidence interval 0.72 to 2.08 ) . Infection at the time of admission proved to be the most significant risk factor for subsequent infection in control and both treatment groups . ICU mortality rate was almost identical ( group A 16.8 % , group B 17.6 % , and group C 15.5 % ) and was not significantly related to primary or secondary infection . Increased antimicrobial resistance was recorded in both treatment groups : tobramycin-resistant enterobacteriaceae ( group C 48 % vs. group A 14 % , p < .01 ) , ofloxacin-resistant enterobacteriaceae ( group B 50 % vs. group A 11 % , p < .02 ) , ofloxacin-resistant nonfermenters ( group B 81 % vs. group A 52 % , p < .02 ) , and methicillin-resistant Staphylococcus aureus ( group C 83 % vs. group A 55 % , p < .05 ) . Antimicrobial agent costs were comparable in control and group C patients ; one third less was spent for group B patients . CONCLUSIONS In cases of high colonization and infection rates at the time of ICU admission , the preventive benefit of selective decontamination is highly debatable . Emergence of multiple antibiotic-resistant microorganisms creates a clinical problem and a definite change in the ecology of environmental , colonizing , and infecting bacteria . The selection of multiple antibiotic-resistant Gram-positive cocci is particularly hazardous . No beneficial effect on survival is observed . Moreover , selective decontamination adds substantially to the cost of ICU care The aim of this study was to assess , in a selected population , the effects of selective decontamination of the digestive tract on colonization of the oropharynx , trachea , stomach and rectum , and on the infection rate . An economical assessment was also performed . Design : A prospect i ve , double-blind , r and omized , placebo-controlled , dual-center trial . Setting : Two neurosurgical intensive care units . Patients : A total of 191 comatose patients admitted emergently and intubated within < 24 hrs were enrolled . Of these patients , 68 were excluded because they either died , got an early infection , or were extubated within the first 5 days . A total of 123 patients were analyzed : 63 treated and 60 placebo patients . Interventions : Topical antibiotics ( tobramycin , polymyxin E , amphotericin B ) were applied in the oropharynx and in the stomach . Vanco-mycin was added in the oropharyngeal paste . Placebo patients received the same regimen ( i.e. , a suspension of fluid and a paste ) but without antibiotics . No parenteral antibiotics were given during the study period . Measurements and Main Results : Broncho-pneumonia episodes were diagnosed with protected specimen brush or plugged telescoping catheter and other infections were diagnosed according to the Center for Disease Control of Atlanta criteria . Antibiotic costs and cost per survivor were calculated . Selective decontamination of the digestive tract significantly reduced Gram-negative bacilli colonization as well as the number of episodes of bronchopneumonia , urinary tract infections , and sinusitis . Despite the addition of vancomycin , Staphylococcus aureus remained the main potential pathogen causing tracheal colonization and subsequent bronchopneumonia . The reduction in bronchopneumonia rate was observed in head-trauma patients only . We were able to show that : a ) the trachea was the main reservoir of microorganisms responsible for pneumonia ; b ) pneumonia developed after tracheal colonization . Total charges for antibiotics were 2.8 times higher in the treated group than in the placebo group ; in calculating the cost per survivor , selective decontamination of the digestive tract might be beneficial due to the reduced length of stay . Conclusions : Selective decontamination of the digestive tract is an effective technique in reducing infectious morbidity in comatose neurosurgical patients . Because of its cost , this technique should be used only in selected population s. ( Crit Care Med 1993 ; 21:1466–1473 Objective To determine the frequency , etiology , and risk factors of ventilator-associated pneumonia ( VAP ) and purulent tracheobronchitis ( TBX ) in patients who have undergone heart surgery . To study the predictive role of systematic surveillance cultures . Design Prospect i ve study . Setting Heart surgery intensive care unit . Patients Intubated heart surgical patients . Interventions Systematic tracheal aspirate and protected brush catheter cultures of all intubated patients . Measurements and Main Results Studied were the frequency of lower respiratory tract infection in ventilated patients and the role of surveillance cultures . The frequency of VAP was 7.87 % ( 34.5 per 1,000 days of mechanical ventilation ) , and the criteria for purulent tracheobronchitis was fulfilled by 8.15 % of patients ( 31.13 per 1,000 days of mechanical ventilation ) . After multivariate analysis , the variables independently associated with the development of respiratory tract infection were central nervous system disorder ( relative risk [ RR ] = 4.7 ) , ulcer disease ( RR = 3.6 ) , New York Heart Association score ≥3 ( RR = 4 ) , need for mechanical circulatory support ( RR = 6.8 ) , duration of mechanical ventilation > 96 hrs ( RR = 12.3 ) , and reintubation ( RR = 63.7 ) . Mortality in our study was as follows : VAP patients , 57.1 % ; purulent tracheobronchitis patients , 20.7 % ; colonized patients , 11.5 % ; and noncolonized patients , 1.6 % . Regular surveillance cultures were taken from all ventilated patients to assess the anticipative value of the cultures in predicting respiratory tract infection . A total of 1,626 respiratory surveillance sample s were obtained . Surveillance cultures effectively predicted only one episode of VAP and one of tracheobronchitis . Conclusions Patients undergoing heart surgery have a high frequency of VAP . VAP is associated with a poor prognosis . In this study , surveillance cultures failed as an anticipative diagnostic method Objective To examine the characteristics , prognostic factors , and outcome of patients with severe hospital-acquired pneumonia admitted to the ICU . Design and setting Prospect i ve observational clinical study in two medical-surgical ICUs with 16 and 20 beds Patients and participants During a 7-year period all hospitalized patients requiring admission to either ICU for hospital-acquired pneumonia were followed up . Measurements and results We diagnosed 96 episodes of severe hospital-acquired pneumonia , and in 67 cases a causal diagnosis was made . Most episodes were late-onset pneumonia . Gram-negative micro-organisms were isolated in 51 % of episodes diagnosed , and Pseudomonas aeruginosa was the most frequent pathogen isolated ( 24 % ) . Clearly significant variations happened between hospitals , particularly affecting the incidence of Aspergillus spp . and Legionella pneumophila . Forty-nine patients developed septic shock ( 51 % ) . Fifty-one patients died ( 53 % ) . Aspergillosis and pneumonia due to P. aeruginosa were associated with the highest mortality . Septic shock ( OR : 14.27 ) and chronic obstructive pulmonary disease ( OR : 6.11 ) were independently associated with a poor prognosis . Conclusions Patients with severe hospital-acquired pneumonia admitted to the ICU present high mortality . The presence of septic shock and chronic obstructive pulmonary disease in conjunction with specific microorganisms are associated with a poor prognosis . Local epidemiological data combined with a patient-based approach may allow a more accurate therapy decision making This prospect i ve study was conducted to evaluate the risk of nosocomial pneumonia when changing heat and moisture exchangers every 48 hours in 1996 instead of every 24 hours in 1995 for patients needing continuous mechanical ventilation . Medical and surgical patients in the two periods did not differ in terms of demographic characteristics and markers of acute or underlying illnesses . The incidence density of nosocomial pneumonia was not different in the two groups . Extended heat and moisture exchanger use reduces circuit manipulation and cost BACKGROUND This study sought to compare 2 strategies for the administration of enteral feeding to mechanically ventilated medical patients . METHODS The prospect i ve , controlled , clinical trial was carried out in a medical intensive care unit ( 19 beds ) in a university-affiliated , urban teaching hospital . Between May 1999 and December 2000 , 150 patients were enrolled . Patients were scheduled to receive their estimated total daily enteral nutritional requirements on either day 1 ( early-feeding group ) or day 5 ( late-feeding group ) of mechanical ventilation . Patients in the late-feeding group were also scheduled to receive 20 % of their estimated daily enteral nutritional requirements during the first 4 days of mechanical ventilation . RESULTS Seventy-five ( 50 % ) consecutive eligible patients were entered into the early-feeding group and 75 ( 50 % ) patients were enrolled in the late-feeding group . During the 5 five days of mechanical ventilation , the total intake of calories ( 2370 + /- 2000 kcal versus 629 + /- 575 kcal ; p < .001 ) and protein ( 93.6 + /- 77.2 g versus 26.7 + /- 26.6 g ; p < .001 ) were statistically greater for patients in the early-feeding group . Patients in the early-feeding group had statistically greater incidences of ventilator-associated pneumonia ( 49.3 % versus 30.7 % ; p = .020 ) and diarrhea associated with Clostridium difficile infection ( 13.3 % versus 4.0 % ; p = .042 ) . The early-feeding group also had statistically longer intensive care unit ( 13.6 + /- 14.2 days versus 9.8 + /- 7.4 days ; p = .043 ) and hospital lengths of stay ( 22.9 + /- 19.7 days versus 16.7 + /- 12.5 days ; p = .023 ) compared with patients in the late-feeding group . No statistical difference in hospital mortality was observed between patients in the early-feeding and late-feeding groups ( 20.0 % versus 26.7 % ; p = .334 ) . CONCLUSIONS The administration of more aggressive early enteral nutrition to mechanically ventilated medical patients is associated with greater infectious complications and prolonged lengths of stay in the hospital . Clinicians must balance the potential for complications result ing from early enteral feeding with the expected benefits of such therapy In comatose patients admitted to an ICU , particularly those with head injury , the incidence of early onset pneumonia is exceedingly high . We performed an open , prospect i ve , r and omized , and controlled clinical trial aim ing at the reduction of the incidence of ventilator-associated pneumonia in head-injured patients and patients with stroke requiring mechanical ventilation . One hundred patients were included because of head injury or coma caused by medical stroke and with Glasgow coma scores < or = 12 and mechanical ventilation > 72 h. Patients eligible for the study ( n = 50 ) received cefuroxime intravenously ( two 1,500-mg doses 12 h apart after intubation ) ( the cefuroxime group ) and 50 patients not receiving cefuroxime formed the control group . In the former group patients did not receive any other antibiotics before the end-point determination , whereas in the latter , 17 patients received prophylactic antibiotics as prescribed by the attending physician . The global incidence of microbiologically confirmed pneumonia was 37 % ( n = 37 ) ; 12 ( 24 % ) belonged to the cefuroxime group , and 25 ( 50 % ) belonged to the control group ( p = 0.007 ) . Early-onset pneumonia accounted for 70 % of all the pneumonia episodes ( n = 26 ) , eight ( 67 % ) belonging to the cefuroxime group , and 18 ( 72 % ) belonging to the control group ( p = 0.02 ) . In the control group , four of 17 ( 23 % ) patients receiving prior antibiotics developed pneumonia , whereas 21 of 33 ( 64 % ) patients who did not receive antibiotics developed pneumonia ( p = 0.016 ) . The multivariate analysis revealed that the duration of mechanical ventilation ( per each day ) was an independent risk factor significantly associated to the development of pneumonia . Furthermore , the use of cefuroxime and /or prior antibiotics in the control group , before the pneumonia episode , had a protective effect against its development . No differences were found with regard to mortality and morbidity when comparing the study population with the control group . Nevertheless , when comparing patients with pneumonia ( from both study and control groups ) with those without it , there was a decrease in total hospital stay ( 35 + /- 13 versus 25 + /- 14 d , p = 0.048 ) and ICU stay ( 20 + /- 11 versus 11 + /- 7 d , p = 0.001 ) . The study demonstrated that the administration of two single high doses 1,500 mg each of cefuroxime after the intubation of patients comatose because of head injury or medical stroke is an effective prophylactic strategy to decrease the incidence of ventilator-associated pneumonia STUDY OBJECTIVES To determine whether the application of continuous aspiration of subglottic secretions ( CASS ) is associated with a decreased incidence of ventilator-associated pneumonia ( VAP ) . DESIGN Prospect i ve clinical trial . SETTING Cardiothoracic ICU ( CTICU ) of Barnes-Jewish Hospital , St. Louis , a university-affiliated teaching hospital . PATIENTS Three hundred forty-three patients undergoing cardiac surgery and requiring mechanical ventilation in the CTICU . INTERVENTIONS Patients were assigned to receive either CASS , using a specially design ed endotracheal tube ( Hi-Lo Evac ; Mallinckrodt Inc ; Athlone , Irel and ) , or routine postoperative medical care without CASS . RESULTS One hundred sixty patients were assigned to receive CASS , and 183 were assigned to receive routine postoperative medical care without CASS . The two groups were similar at the time of r and omization with regard to demographic characteristics , surgical procedures performed , and severity of illness . Risk factors for the development of VAP were also similar during the study period for both treatment groups . VAP was seen in 8 patients ( 5.0 % ) receiving CASS and in 15 patients ( 8 . 2 % ) receiving routine postoperative medical care without CASS ( relative risk , 0.61 % ; 95 % confidence interval , 0.27 to 1.40 ; p = 0 . 238 ) . Episodes of VAP occurred statistically later among patients receiving CASS ( [ mean + /- SD ] 5.6 + /- 2.3 days ) than among patients who did not receive CASS ( 2.9 + /- 1.2 days ) ; ( p = 0.006 ) . No statistically significant differences for hospital mortality , overall duration of mechanical ventilation , lengths of stay in the hospital or CTICU , or acquired organ system derangements were found between the two treatment groups . No complications related to CASS were observed in the intervention group . CONCLUSIONS Our findings suggest that CASS can be safely administered to patients undergoing cardiac surgery . The occurrence of VAP can be significantly delayed among patients undergoing cardiac surgery using this simple-to-apply technique Chronic microaspiration through a tracheal cuff is the main culprit in the penetration and colonization of the lower respiratory tract . A total of 145 patients intubated for more than 3 days were r and omly assigned to a double nosocomial pneumonia ( NP ) prevention : 1-Prevention of aspiration by hourly subglottic secretion drainage ( SSD ) with a specific endotracheal tube ( HI-LO Evac tube , Mallinckrodt ) ; 2-Prevention of gastric colonization using either sucralfate or antacids . Four r and om groups were defined , similar in age and severity of illness . Subglottic secretion drainage treatment was associated with : a ) a twice lower incidence of NP ( no-SSD : 29.1 % , SSD : 13 % ) ; b ) a prolonged time of onset of NP ( no-SSD : 8.3±5 days , SSD : 16.2±11 days ) ; c ) a decrease in the colonization rate from admission to end-point day in tracheal aspirates ( no-SSD:+21.3 % , SSD:+6.6 % ) and in subglottic secretions ( no-SSD:+33.4 % , SSD:+2.1 % ) . Sucralfate was not associated with a significantly lower incidence of NP ( antacids : 23.6 % , sucralfate : 17.8 % ) , but with a lower increase in the colonization rate in subglottic and gastric aspirates , from admission to end-point day STUDY OBJECTIVE To evaluate the safety of a combined heat and moisture exchanger filter ( HMEF ) for the conditioning of inspired gas in long-term mechanical ventilation ( MV ) . DESIGN R and omized controlled trial . SETTING Medical ICU in a large teaching hospital . PATIENTS One hundred fifteen consecutive patients who required > or = 48 h of MV . INTERVENTIONS Patients were r and omized at intubation time ( day 1 ) to receive inspired gas conditioned either by a water-bath humidifier heated at 32 degrees C ( HWBH ) or by an HMEF ( Hygroster ; DAR ; Mir and ola , Italy ) . MEASUREMENTS AND MAIN RESULTS The two study groups were comparable in terms of primary pathologic condition at the time of hospital admission , disease severity as measured by the Simplified Acute Physiology Score , and ICU mortality . They did not differ with respect to ventilator days per patient ( mean + /- SD : HMEF , 7.6 + /- 6.5 ; HWBH , 7.8 + /- 5.8 ) , incidence of endotracheal tube obstruction ( HMEF , 0/59 ; HWBH , 1/56 ) , and incidence of hypothermic episodes ( HMEF , five ; HWBH , two ) . In 41 patients receiving MV for > or = 5 days , the morphologic integrity of respiratory epithelium was evaluated on day 1 and day 5 , using a cytologic examination of tracheal aspirate smears . The state of ciliated epithelium was scored on a scale from 0 ( poorest integrity ) to 1,200 ( maximum integrity ) , according to a well-described method . In both patient groups , the scores slightly but significantly decreased from day 1 to day 5 ( mean + /- SD : HWBH , from 787 + /- 104 to 745 + /- 88 ; HMEF , from 813 + /- 79 to 739 + /- 62 ; p < 0.01 for both groups ) ; there were no statistically significant differences between groups . CONCLUSIONS These data indicate acceptable safety of HMEFs of the type used in the present study for long-term mechanical ventilation OBJECTIVES To identify factors associated with the development of ventilator-associated pneumonia ( VAP ) and to examine the incidence of VAP in different intensive care unit ( ICU ) population s. DESIGN An inception cohort study . SETTING Barnes Hospital , St Louis , Mo , an academic tertiary care center . PATIENTS OR OTHER PARTICIPANTS A total of 277 consecutive patients required mechanical ventilation for longer than 24 hours from a medical ICU ( 75 patients ) , surgical ICU ( 100 patients ) , or cardiothoracic ICU ( 102 patients ) . INTERVENTIONS Prospect i ve patient surveillance and data collection . MAIN OUTCOME MEASURES Ventilator-associated pneumonia and ICU mortality . RESULTS Ventilator-associated pneumonia occurred in 43 patients ( 15.5 % ) . Stepwise logistic regression analysis identified four factors to be independently associated with VAP ( P < .05 ) : an organ system failure index of 3 or greater ( adjusted odds ratio [ AOR ] = 10.2 ; 95 % confidence interval [ CI ] , 4.5 to 23 ; P < .001 ) ; patient age of 60 years or older ( AOR = 5.1 ; 95 % CI , 1.9 to 14.1 ; P = .002 ) ; prior administration of antibiotics ( AOR = 3.1 ; 95 % CI , 1.4 to 6.9 ; P = .004 ) ; and supine head positioning during the first 24 hours of mechanical ventilation ( AOR = 2.9 ; 95 % CI , 1.3 to 6.8 ; P = .013 ) . Ventilator-associated pneumonia occurred more often in cardiothoracic patients ( 21.6 % ) compared with medical patients ( 9.3 % ) ( P = .03 ) . Patients with VAP also had a higher mortality ( 37.2 % ) than those without VAP ( 8.5 % ) ( P < .001 ) . An organ system failure index of 3 or greater ( AOR = 16.1 ; 95 % CI , 6.1 to 42 ; P < .001 ) , a premorbid lifestyle score of 2 or greater ( AOR = 3.1 ; 95 % CI , 1.3 to 7.3 ; P = .012 ) , and supine head positioning during the first 24 hours of mechanical ventilation ( AOR = 3.1 ; 95 % CI , 1.2 to 7.8 ; P = .016 ) were independently associated with mortality . CONCLUSIONS These data suggest potential interventions that might affect the incidence of VAP or outcome associated with VAP . Additionally , they indicate that different ICU population s may have different incidences of VAP OBJECTIVE To determine the impact of histamine2 (H2)-receptor antagonist use on the occurrence of infectious complications in severely injured patients . SUMMARY BACKGROUND DATA Some previous studies suggest an increased risk of nosocomial pneumonia associated with the use of H2-receptor blockade in critically ill patients , but other investigations suggest an immune-enhancing effect of H2-receptor antagonists . The purpose of this study was to determine whether H2-receptor antagonist use affects the overall incidence of infectious complications . METHODS Patients enrolled in a r and omized trial comparing ranitidine with sucralfate for gastritis prophylaxis were examined for all infectious complications during their hospitalization . Data on the occurrence of pneumonia were prospect ively collected , and other infectious complications were retrospectively obtained from the medical record . The relative risk of infectious complications associated with ranitidine use and total infectious complications were analyzed . RESULTS Of 98 patients included , the charts of 96 were available for review . Sucralfate was given to 47 , and 49 received ranitidine . Demographic factors were similar between the groups . Ranitidine use was associated with a 1.5-fold increased risk of developing any infectious complication ( 37 of 47 vs. 26 of 47 ; 95 % confidence interval , 1.04 to 2.28 ) . Infectious complications totaled 128 in the ranitidine-treated group and 50 in the sucralfate-treated group ( p = 0.0014 ) . These differences remained after excluding catheter-related infections ( p = 0.0042 ) and secondary bacteremia ( p = 0.0046 ) . CONCLUSIONS Ranitidine use in severely injured patients is associated with a statistically significant increase in overall infectious complications when compared with sucralfate . These results indicate that ranitidine should be avoided where possible in the prophylaxis of stress gastritis The contribution of ventilator circuit bacterial contamination to the occurrence of ventilator-associated pneumonia remains controversial . In a previous study , we found that the incidence of pneumonia was identical with ventilator circuit changes every 48 h and with no ventilator circuit changes . The present study prospect ively assessed whether keeping ventilator circuits clean with a heat and moisture exchanger exhibiting antimicrobial barrier properties affects patient colonization and the incidence of nosocomial pneumonia in patients receiving mechanical ventilation for more than 48 h. Consecutive patients were r and omly allocated to humidification with either a heat and moisture exchanger ( Group 1 , n = 61 ) or a heated humidifier ( Group 2 , n = 70 ) . In both groups , no circuit changes were performed throughout ventilatory support . Duration of mechanical ventilation was identical in both groups ( 10 + /- 8.6 d ( range : 2 to 47 ) in Group 1 and 12.5 + /- 14.2 d [ range : 2 to 85 ] in Group 2 ) . The incidence of pneumonia ( positive quantitative culture of protected brush specimen ) was similar in both groups ( 6/61 and 8/70 in Groups 1 and 2 , respectively ; p = 0.8 ) , as was duration of ventilation prior to pneumonia ( 9 + /- 5.9 versus 8.2 + /- 5.7 d ; p = 0.8 ) . Ventilator tubing contamination was considerably reduced with the use of a heat and moisture exchanger . In contrast , bacterial colonization of the pharynx and trachea was identical in both groups . These results suggest that circuit colonization plays little or no role in the occurrence of ventilator-associated pneumonia , provided usual maintenance pre caution s are applied . ( ABSTRACT TRUNCATED AT 250 WORDS Objective To examine the physiologic consequences and costs associated with two methods of endotracheal suctioning : closed vs. open . Design A prospect i ve , r and omized , controlled study . Setting An eight-bed trauma intensive care unit ( ICU ) in a 460-bed level I trauma center . Patients The study included 35 trauma/general surgery patients ( 16 in the open suction group , 19 in the closed suction group ) who were treated with a total of 276 suctioning procedures ( 127 open , 149 closed ) . Measurements and Main Results Physiologic data collected after hyperoxygenation , immediately after suctioning , and 30 sees after suctioning , were compared with baseline values . Open endotracheal suctioning result ed in significant increases in mean arterial pressure throughout the suctioning procedure . Both methods result ed in increased mean heart rates . However , 30 sees after the procedure , the open-suction method was associated with a significantly higher mean heart rate than was the closed method . Closed suctioning was associated with significantly fewer dysrhythmias . Arterial oxygen saturation and systemic venous oxygen saturation decreased with open suctioning . In contrast , arterial oxygen saturation and systemic venous oxygen saturation increased with the closed suction method . There was no difference between the two methods in the occurrence of nosocomial pneumonia . Open endotracheal suctioning cost 1.88 more per patient per day and required more nursing time . Conclusions The closed suction method result ed in significantly fewer physiologic disturbances . Closed suctioning appears to be an effective and cost-efficient method of endotracheal suctioning that is associated with fewer suction-induced complications . ( Crit Care Med 1994 ; 22:658–666 BACKGROUND Selective decontamination of the digestive tract with topical nonabsorbable antibiotics has been reported to prevent nosocomial infections in patients receiving mechanical ventilation , and the procedure is used widely in Europe . However , it is unclear whether selective decontamination improves survival . METHODS We conducted a r and omized , double-blind multicenter study in which 445 patients receiving mechanical ventilation in 15 intensive care units were given either prophylactic nonabsorbable antibiotics ( n = 220 ) or a placebo ( n = 225 ) . Topical antibiotics ( tobramycin , colistin sulfate , and amphotericin B ) or a placebo was administered through a nasogastric tube and applied to the oropharynx throughout the period of ventilation . The main end points were the mortality rate in the intensive care unit and within 60 days of r and omization . RESULTS A total of 142 patients died in the intensive care unit ; 75 ( 34 percent ) in the treatment group and 67 ( 30 percent ) in the placebo group ( P = 0.37 ) . Mortality within 60 days of r and omization was similar in the two groups ( P = 0.40 ) , even after adjustment for factors that were either unbalanced or individually predictive of survival in the two groups ( P = 0.70 ) . Pneumonia developed in 59 patients ( 13 percent ) in the intensive care unit within 30 days of enrollment in the study ( 33 in the placebo group and 26 in the treatment group , P = 0.42 ) . Pneumonia acquired in the intensive care unit and due to gram-negative bacilli was less frequent ( P = 0.01 ) in the treatment group than in the placebo group . The total charges for antibiotics were 2.2 times higher in the treatment group . CONCLUSIONS Selective decontamination of the digestive tract does not improve survival among patients receiving mechanical ventilation in the intensive care unit , although it substantially increases the cost of their care Nosocomial infection is a major problem in intensive therapy units ( ITUs ) and a significant cause of mortality . Selective decontamination of the digestive tract ( SDD ) has been advocated as a means to reduce ITU morbidity and mortality . Ninety-one patients in a general ITU underwent SDD , consisting of topical polymyxin E , tobramycin and amphotericin B administered throughout the unit stay together with parenteral ceftazidime for the first three days , and were compared with 84 historical and 92 contemporaneous control patients who were treated conventionally . Twenty-seven historical and 32 contemporaneous control patients developed unit-acquired infections , in comparison with only three patients in the SDD group ( P less than 0.01 ) . Mortality in the SDD group ( 36 % ) was not significantly different from that in the other two groups ( historical control 40 % , contemporaneous control 43 % ) . Screening specimens revealed a significantly higher rate of colonization with resistant Acinetobacter spp . in the contemporaneous control than in the other two groups of patients ; infection caused by resistant bacteria did not occur . SDD did not lead to a significant reduction in the use of systemically-administered antibiotics when compared with either control group . SDD may be used selectively in an ITU without ill effects on those patients not receiving SDD ; nevertheless , microbiological monitoring is needed to detect emergence of resistant bacteria in the unit Patients entering intensive care units ( ICUs ) routinely receive prophylaxis against stress-related gastrointestinal hemorrhage . The rationale for this approach is based on reports of reductions in bleeding rates among patients receiving prophylaxis with antacids [ 1 , 2 ] , histamine-2 (H2)-receptor antagonists [ 3 - 5 ] , or sucralfate [ 6 , 7 ] . However , the benefit of prophylaxis is uncertain because no study has shown that prophylaxis reduces mortality rates . Further , current literature suggests a decreasing value for stress-related gastritis prophylaxis for patients entering the ICU as a result of improved ICU care [ 8 , 9 ] . For example , critically ill neurosurgical patients requiring mechanical ventilation are considered to be at substantial risk for severe bleeding from stress-related gastritis [ 10 , 11 ] . A recent study of these patients , however , did not show clinical ly relevant upper gastrointestinal bleeding among patients not receiving prophylaxis [ 12 ] . Cook and associates [ 13 ] examined the risk factors for gastrointestinal bleeding in patients entering the ICU . The incidence of clinical ly important gastrointestinal bleeding was only 0.1 % for patients without respiratory failure or coagulopathy , whereas patients with one or both of these risk factors had a 3.7 % incidence of substantial hemorrhage . These observations suggest that most patients entering the ICU will not benefit from prophylaxis for stress-related gastritis . Whether prophylaxis can reduce the incidence of bleeding for patients at high risk was not investigated in that study . In addition to the issue of efficacy , concerns exist regarding the safety of prophylaxis . Specifically , investigators suggest that some regimens may be associated with an increased incidence of nosocomial pneumonia [ 7 , 14 , 15 ] . If the risk for stress-related hemorrhage is so low that prophylaxis benefits few patients and if prophylaxis increases the risk for concomitant illness , then the role of prophylaxis for stress-related bleeding should be reevaluated . We completed a r and omized , controlled , blinded study to determine the role of prophylaxis for stress-related gastritis for patients entering a medical ICU . Our specific goals were to determine the incidence and outcome of clinical ly important stress-related hemorrhage for patients in a medical ICU and the safety and efficacy of cimetidine and sucralfate prophylaxis . Methods Study Patients Henry Ford Hospital , a 900-bed tertiary-care teaching institution , has 28 adult medical ICU beds , excluding those in the coronary care unit . All patients 18 years or older who were admitted to the medical ICU between 1 February and 25 November 1992 were screened for study eligibility . Exclusion criteria were 1 ) expected stay of 24 hours or less ; 2 ) evidence of gastrointestinal bleeding ( hematemesis , vomiting of coffee grounds , hematochezia , or melena ) at the time of admission to the ICU ; 3 ) treatment with antacids , H2-receptor antagonists , sucralfate , or omeprazole during the 24 hours before entering the ICU ; 4 ) use of nonsteroidal anti-inflammatory agents , systemic anticoagulants , or thrombolytic agents during the 7 previous days ; 5 ) surgery requiring general anesthesia during the previous 2 weeks ; 6 ) closed head injury or clinical evidence for increased intracranial pressure ; 7 ) grade 4 hepatic encephalopathy ; 8) esophageal or gastric surgery in the previous year ; 9 ) history of gastrointestinal bleeding during the previous year ; and 10 ) pregnancy or lactatation . Patients with several ICU admissions during the study period were r and omly assigned to a therapy protocol only once . This protocol was review ed and approved by the Henry Ford Hospital Institutional Review Board . Informed consent was obtained from the patient or from legally authorized representatives when the patient could not provide consent . Therapy R and om assignment to one of the two study treatments or control group and commencement of therapy occurred within 6 hours of ICU admission . R and omization was by sealed envelope using the permuted block design [ 16 ] . Control patients did not receive antacids , sucralfate , omeprazole , or H2-receptor antagonists . Patients assigned to receive sucralfate were given 1 g of the medication orally or as a suspension through the nasogastric tube every 6 hours . The nasogastric tube was clamped for 1 hour after sucralfate administration . Patients receiving cimetidine were given a 300-mg intravenous loading dose followed by continuous intravenous infusion according to the creatinine clearance : more than 50 mL/min , 900 mg/d ; 20 to 50 mL/min , 600 mg/d ; and less than 20 mL/min , 300 mg/d . The cimetidine dose was titrated to maintain gastric pH 4.0 . If two consecutive gastric pH values were less than 4.0 , the dose was increased by the following amounts based on creatinine clearance : 300 mg/d , 200 mg/d , and 100 mg/d . The maximum allowable cimetidine doses for the patients grouped by renal function were 2400 mg/d , 1600 mg/d , and 800 mg/d . Nasogastric tubes were not required as part of the protocol , but gastric pH was checked every 2 hours for patients with these tubes ( using S/P pH Indicator Strips , Baxter Health Care , McGaw Park , Illinois ) . Substantial gastrointestinal hemorrhage required the presence of any of the following : 1 ) persistent hematemesis ( red blood or guaiac-positive coffee grounds ) that did not clear with 1.5 L saline lavage ; 2 ) 3-point decrease in hematocrit during 24 hours accompanied by red blood or guaiac-positive coffee grounds material that cleared with lavage , or melena , or three guaiac-positive stools without evidence of lower gastrointestinal bleed ; and 3 ) any unexplained 6-point decrease in hematocrit during a 48-hour period . This last criterion was added as a safety measure because some patients would not receive prophylaxis . Data Collection On admission to the ICU , the following data were collected : age ; sex ; admission diagnoses ; APACHE II score [ 17 ] ; vital signs ; result of chest roentgenogram ; arterial blood gases ; and hematologic , biochemical , and coagulation laboratory values . Data collected daily during the ICU stay included vital signs , fluid intake and output , presence of blood in the stool or nasogastric aspirate , hematocrit value , serum creatinine concentration , coagulation values ( prothrombin time , partial thromboplastin time , and platelet count ) , results of chest roentgenogram , gastric pH values , signs and symptoms of gastrointestinal hemorrhage , number of units of packed red blood cells transfused , medications , volume of total parenteral or enteral nutrition , and possible adverse drug reactions [ 18 - 20 ] . Possible central nervous system reactions to cimetidine were defined as anxiety , confusion , delirium , depression , hallucination , headache , or somnolence [ 21 ] . The presence of putative risk factors for stress-related hemorrhage [ 22 - 24 ] was recorded at entry into the study and daily during the ICU stay ( Table 1 ) . Table 1 . Definitions of Risk Factors for Stress-Related Hemorrhage Outcomes The primary study end point was substantial hemorrhage from stress gastritis . Information regarding hematocrit , Hemoccult status of stool and nasogastric aspirate , and volume status was presented daily to two investigators ( RF and RSB ) who were blinded to therapy . These investigators determined whether patients satisfied the criteria for substantial hemorrhage . All patients who met the criteria received endoscopy within the next 24 hours performed by one of the two investigators . Treatment was considered to have failed only in patients who were diagnosed with stress-related hemorrhage by the endoscopy . After diagnosis of stress-related hemorrhage , the patients ' study medication was stopped and they were treated with continuous intravenous infusion of cimetidine and with blood transfusions , if necessary . This treatment protocol is the st and ard in our medical ICU . Adverse drug reactions were recorded , and the Adverse Drug Reaction Probability score was calculated [ 26 ] . In the appropriate clinical situation , patients were rechallenged with the same medication within 24 hours . If the study medication was discontinued , prophylaxis was continued at the discretion of the primary physician . Nosocomial Pneumonia Diagnosis of nosocomial pneumonia in the medical ICU required all of the following : 1 ) chest roentgenogram obtained 72 hours or more after ICU admission that showed a new and persistent infiltrate ; 2 ) fever , leukocytosis , or both ; 3 ) purulent tracheobronchial secretions ; 4 ) Gram-stained sputum showing more than 25 polymorphonuclear leukocytes and fewer than 10 squamous epithelial cells per low-power field ; and 5 ) recovery of an accepted nosocomial pathogen from sputum culture . Additional end points were total transfusion requirement , recurring hemorrhage , duration of hospitalization , death in the ICU , and outcome of hospitalization ( death or discharge ) . Statistical Analysis We estimated sample size to provide 80 % power to detect a 75 % reduction in bleeding rate , that is , a 12 % bleeding rate for the control group compared with a 3 % rate in either of the two treatment groups . We used an value of 0.05 ( two-tailed ) adjusted for the comparison of the control group with each of the prophylaxis groups . As a result of these assumptions , 160 patients were needed in each of the three groups . Results are expressed as mean SD , or median and interquartile range for lengths of stay . We compared baseline differences using chi-square tests and analysis of variance [ 27 ] . The primary data analysis compared the incidence of bleeding and death between the control group and each of the prophylaxis groups . We confirmed the results of these tests with more detailed analysis using Cox regression [ 28 ] . Differences in incidence are expressed as relative risks , with their corresponding 95 % CIs . To compare lengths of stay , we calculated median differences and 95 % CIs [ 29 ] . Safety and Quality Assurance To guarantee patient safety , an independent monitoring Objective To compare the frequency of acute stress ulceration and secondary pneumonia caused by aerobic Gram-negative bacilli in ICU patients treated with either sucralfate or ranitidine . Design Prospect i ve , r and omized study . Setting ICU , university hospital . Patients Sixty adult patients who were mechanically ventilated and at risk of developing stress ulceration . InterventionThe patients were r and omized to receive either sucralfate ( 1 g every 6 hrs ) via the nasogastric tube or iv ranitidine ( 50 mg every 6 hrs ) . If the gastric pH was < 3.5 in the latter group , 30 mL of 0.3 M sodium citrate was given via the nasogastric tube . Measurements and Main Results On admission , the frequency rate of erosion/ulceration ( assessed with the endoscope ) was 13.5 % . After 4 days , this rate had increased to 18 % in sucralfate-treated patients and 36 % in ranitidine-treated patients ( NS ) . Mean gastric pH was more alkaline in the ranitidine-treated patients ( 5.50 ) compared with the sucralfate-treated patients ( 4.26 ) ( p < .01 ) . This pH permitted a higher occurrence rate of gastric colonization by aerobic Gram-negative bacilli in ranitidine-treated patients ( 64.3 % ) compared with sucralfate-treated patients ( 23.8 % ) ( p < .01 ) . Retro grade bacterial colonization from the stomach to oropharynx and trachea occurred more frequently in ranitidine-treated patients compared with sucralfate-treated patients . Ultimately , the occurrence rate of pneumonia was greater in the ranitidine-treated ( 35.7 % ) than in the sucralfate-treated patients ( 10.3 % ) ( p < .05 ) . Conclusion Based on our findings , we recommend the adoption of sucralfate for routine prophylaxis against stress ulceration . ( Crit Care Med 1991 ; 19:1491 The purpose of this study was to determine the safety and cost-effectiveness of not routinely changing in-line suction catheters for patients requiring mechanical ventilation . Patients were r and omly assigned to receive either no routine in-line suction catheter changes ( n = 258 ) or in-line suction catheter changes every 24 h ( n = 263 ) . The main outcome measure was the incidence of ventilator-associated pneumonia . Other outcomes evaluated included hospital mortality , acquired organ system derangements , duration of mechanical ventilation , lengths of intensive care and hospital stay , and the cost for in-line suction catheters . Ventilator-associated pneumonia was seen in 38 patients ( 14.7 % ) receiving no routine in-line suction catheter changes and in 39 patients ( 14.8 % ) receiving in-line suction catheter changes every 24 h ( relative risk , 0.99 ; 95 % CI , 0.66 to 1.50 ) . No statistically significant differences for hospital mortality , lengths of stay , the number of acquired organ system derangements , death in patients with ventilator-associated pneumonia , or mortality directly attributed to ventilator-associated pneumonia were found between the two treatment groups . Patients receiving in-line suction catheter changes every 24 h had 1,224 catheter changes costing a total of $ 11,016 ; patients receiving no routine in-line suction catheter changes had a total of 93 catheter changes costing $ 837 . Our findings suggest that the elimination of routine in-line suction catheter changes is safe and can reduce the costs associated with providing mechanical ventilation A r and omized , double-blind , placebo-controlled trial of selective decontamination of the oropharynx and gastrointestinal tract was conducted on 61 intubated patients in a medical-surgical intensive care unit ( ICU ) to determine the impact on nosocomial pneumonia , other infections , and emergence of colonization or infection with antibiotic-resistant bacteria . Over 8 months , 30 patients received an oral paste and solution containing polymyxin , gentamicin , and nystatin ; 31 patients received a placebo paste and solution . At study entry , patients in both groups were seriously ill ( mean acute physiologic score , 27.2 ) , frequently had pulmonary infiltrates ( 73.8 % ) , and were likely to be receiving systemic antibiotics ( 86.9 % ) . There were no differences between study patients and control patients in these characteristics or in frequency of any nosocomial infection ( 50 % vs. 55 % ) , nosocomial pneumonia ( 27 % vs. 26 % ) , febrile days ( 2.3 vs. 2.0 ) , duration of antibiotic therapy ( 14.0 vs. 13.4 ) , or mortality rates ( 37 % vs. 48 % ) . There was no difference in infections caused by antibiotic-resistant gram-negative bacilli , although a trend towards more frequent infection with gentamicin-resistant enterococci was found for study patients . Selective decontamination did not appear to be effective in our very ill medical-surgical ICU patients , although the number of patients in our trial was sufficient to detect only a 50 % or greater reduction in pneumonia rates STUDY OBJECTIVE To determine whether patient transport out of the ICU is associated with an increased risk of developing ventilator-associated pneumonia . DESIGN Prospect i ve cohort study . SETTING ICUs of Barnes-Jewish Hospital , a university-affiliated teaching hospital . PATIENTS Five hundred twenty-one ICU patients requiring mechanical ventilation for > 12 h. INTERVENTION Prospect i ve patient surveillance and data collection . MEASUREMENTS AND RESULTS The primary outcome measure was the development of ventilator-associated pneumonia . A total of 273 ( 52.4 % ) mechanically ventilated patients required at least one transport out of the ICU while 248 ( 47.6 % ) patients did not undergo transport . Sixty-six ( 24.2 % ) of the transported patients developed ventilator-associated pneumonia compared with 11 ( 4.4 % ) patients in the group not undergoing transport ( relative risk=5.5 ; 95 % confidence interval [CI]=2.9 to 10.1 ; p<0.001 ) . Multiple logistic regression analysis demonstrated that a preceding episode of transport out of the ICU was independently associated with the development of ventilator-associated pneumonia ( adjusted odds ratio=3.8 ; 95 % CI=2.6 to 5.5 ; p<0.001 ) . Other variables independently associated with the development of ventilator-associated pneumonia included reintubation , presence of a tracheostomy , administration of aerosols , and male gender . CONCLUSIONS We conclude that patient transport out of the ICU is associated with an increased risk for the development of ventilator-associated pneumonia |
1,924 | 26,922,293 | The results of the present paper support the use of NAC in the prevention of CIN in patients undergoing CAG±PCI . | BACKGROUND There have been a myriad of studies investigating the effectiveness of N-acetylcysteine ( NAC ) in the prevention of contrast induced nephropathy ( CIN ) in patients undergoing coronary angiography ( CAG ) with or without percutaneous coronary intervention ( PCI ) .
However the consensus is still out about the effectiveness of NAC pre-treatment due to vastly mixed results amongst the literature .
OBJECTIVES The aim of this study was to conduct a meta- analysis and trial sequential analysis to determine the effects of pre-operative NAC in lowering the incidence of CIN in patients undergoing CAG and /or PCI . | Background : Pharmacokinetic data suggests that the intravenous form of n‐acetylcysteine ( NAC ) may be more effective than the oral formulation in preventing contrast induced nephropathy ( CIN ) . NAC owing to its anti‐oxidant properties might be beneficial for patients with acute coronary syndromes ( ACS ) who are at increased risk for CIN . The aim of this prospect i ve r and omized , single‐center , double‐blind , placebo controlled trial ( NCT00939913 ) was to assess the effect of high‐dose intravenous NAC on CIN in ACS patients undergoing coronary angiography and /or percutaneous coronary intervention ( PCI ) . Methods : We r and omized 398 ACS patients scheduled for diagnostic angiography ± PCI to an intravenous regimen of high‐dose NAC ( 1,200 mg bolus followed by 200 mg/hr for 24 hr ; n = 206 ) or placebo ( n = 192 ) . The primary end‐point was incidence of CIN defined as an increase in serum creatinine concentration ≥25 % above the baseline level within 72 hr of the administration of intravenous contrast . Results : There was no difference found for the primary end point with CIN in 16 % of the NAC group and in 13 % of the placebo group ( p = 0.40 ) . Change in serum cystatin‐C , a sensitive marker for renal function , was 0.046 ± 0.204 in the NAC group and 0.002 ± 0.260 in the control group ( p = 0.07 ) . Conclusion : In ACS patients undergoing angiography ± PCI , high‐dose intravenous NAC failed to reduce the incidence of CIN . © 2011 Wiley Periodicals , BACKGROUND Contrast-induced nephropathy ( CIN ) is a leading cause of acute renal failure and affects mortality and morbidity . We investigated the efficacy of prophylactic intravenous ( IV ) N-acetylcysteine ( NAC ) and hydration for the prevention of CIN in patients with mild to moderate renal dysfunction who are undergoing coronary angiography and /or percutaneous coronary intervention ( PCI ) . METHODS A total of 220 patients who had mild to moderate renal dysfunction with serum creatinine ( SCr ) ≥ 1.1mg/dL or creatinine clearance ≤ 60 mL/min were r and omized in 3 groups : 80 patients were assigned to IV NAC plus high-dose hydration with normal saline , 80 patients to only high-dose hydration with normal saline and 60 patients to st and ard hydration with normal saline ( control group ) . The primary end point was the alteration of SCr level . The secondary end point was the development of CIN after the procedure . RESULTS SCr levels changed the least in the NAC plus high-hydration group ( P=0.004 ) . The rate of the CIN in the NAC plus high-dose hydration group was also lower than the high-dose hydration group ( P=0.006 ) . No significant differences in the primary and secondary end points were found between high-dose hydration and control group . CONCLUSION The results of this study suggest that NAC plus high-dose hydration was superior to high-dose hydration alone as well as st and ard hydration for the protection of renal functions in patients with mild to moderate renal dysfunction who are undergoing coronary angiography and /or PCI . High-dose hydration without NAC was not better than st and ard hydration alone OBJECTIVES Prophylactic acetylcysteine along with hydration seems to be better than hydration alone in preventing the reduction in renal function induced by a contrast dye . BACKGROUND Contrast media can lead to acute renal failure that may occasionally require hemodialysis . METHODS One hundred eighty-three consecutive patients with impairment of renal function , undergoing coronary and /or peripheral angiography and /or angioplasty , were r and omly assigned to receive 0.45 % saline intravenously and acetylcysteine ( 600 mg orally twice daily ; group A , n = 92 ) or 0.45 % saline intravenously alone ( group B , n = 91 ) before and after nonionic , low-osmolality contrast dye administration . RESULTS The baseline serum creatinine concentrations were similar ( 1.5 + /- 0.4 mg/dl in group A vs. 1.5 + /- 0.4 mg/dl in group B ; p = 0.37 ) . An increase of > or = 25 % in the baseline creatinine level 48 h after the procedure occurred in 6 ( 6.5 % ) of 92 patients in group A and in 10 ( 11 % ) of 91 patients in group B ( p = 0.22 ) . In the subgroup with a low ( < 140 ml ) contrast dose , renal function deterioration occurred in 5 ( 8.5 % ) of 60 patients in group B and in 0 of 60 patients in group A ( p = 0.02 ; odds ratio [ OR ] 0.44 , 95 % confidence interval [ CI ] 0.35 to 0.54 ) . In the subgroup with a high contrast dose , no difference was found ( 5/31 vs. 6/32 patients , p = 0.78 ) . By multivariate analysis , the amount of contrast agent , but not the treatment strategy , was a predictor of the occurrence of contrast dye-associated nephrotoxicity ( OR 2.58 , 95 % CI 1.1 to 4.9 ; p = 0.035 ) . CONCLUSIONS In patients with reduced renal function undergoing angiography and /or angioplasty , the amount of contrast agent , but not the administration of prophylactic acetylcysteine , was a predictor of renal function deterioration . Prophylactic acetylcysteine might provide better protection than hydration alone , only when a small volume of contrast agent is used BACKGROUND Contrast-induced nephropathy ( CIN ) after cardiac catheterization is common in patients with preexisting renal dysfunction . Studies of oral acetylcysteine to prevent CIN have produced conflicting results . Intravenous N-acetylcysteine ( NAC ) has logistic advantages in this setting . The objective of this study was to evaluate , in a blinded , r and omized , placebo-controlled fashion , whether intravenous NAC reduced CIN in the setting of cardiac catheterization in patients with preexisting renal insufficiency . METHODS Patients with renal dysfunction undergoing cardiac catheterization were r and omly assigned to intravenous NAC 500 mg immediately before the procedure or placebo . All patients received isotonic saline ( 200 mL ) beforeh and , followed by 1.5 mL/kg per hour for 6 hours , unless contraindicated . Exclusion criteria included acute renal failure , creatinine > 400 micromol/L , concurrent dialysis , unstable clinical status , and prior NAC use . Baseline creatinine was obtained immediately before the procedure and repeated 2 to 8 days later . The primary end point was the occurrence of CIN defined as a reduction in creatinine clearance from baseline of > 5 mL/min ( Cockcroft-Gault formula ) . RESULTS The study was terminated early because of a determination of futility by the Data Safety Monitoring Committee after enrollment of 487 patients . The median baseline creatinine clearance was 44 mL/min ( interquartile range , 33 , 55 ) . Median contrast received was 120 mL ( interquartile range , 80 , 175 ) . Baseline characteristics were similar in the two groups . Altogether , 98 ( 22.0 % ) subjects had the primary end point : 23.3 % in the NAC group and 20.7 % in the placebo arm ( P = .57 ) . CONCLUSIONS In this large , r and omized trial , enrolling a high-risk group of patients with impaired renal function , intravenous NAC was ineffective in preventing CIN OBJECTIVES The aim of this r and omized , single-blind , controlled trial was to assess N-acetylcysteine effects on contrast-induced nephropathy and reperfusion injury in ST-segment elevation myocardial infa rct ion patients undergoing primary angioplasty with moderate contrast volumes . BACKGROUND High-dose N-acetylcysteine reduced the incidence of contrast-induced nephropathy in patients with high contrast volumes and reduced reperfusion injury in animal trials . METHODS Patients undergoing primary angioplasty were r and omized to either high-dose N-acetylcysteine ( 2 x 1,200 mg/day for 48 h ; n = 126 ) or placebo plus optimal hydration ( n = 125 ) . The 2 primary end points were : 1 ) the occurrence of > 25 % increase in serum creatinine level < 72 h after r and omization ; and 2 ) a reduction in reperfusion injury measured as myocardial salvage index by magnetic resonance imaging . RESULTS The median volume of an iso-osmolar contrast agent during angiography was 180 ml ( interquartile range [ IQR ] 140 to 230 ml ) in the N-acetylcysteine and 160 ml ( IQR 120 to 220 ml ) in the placebo group ( p = 0.20 ) . The primary end point contrast-induced nephropathy occurred in 14 % of the N-acetylcysteine group and in 20 % of the placebo group ( p = 0.28 ) . The myocardial salvage index was also not different between both treatment groups ( 43.5 ; IQR 25.4 to 71.9 vs. 51.5 ; IQR 29.5 to 75.3 ; p = 0.36 ) . Activated oxygen protein products and oxidized low-density lipoprotein as markers for oxidative stress were reduced by as much as 20 % in the N-acetylcysteine group ( p < 0.05 ) , whereas no change was evident in the placebo group . CONCLUSIONS High-dose intravenous N-acetylcysteine reduces oxidative stress . However , it does not provide an additional clinical benefit to placebo with respect to CIN and myocardial reperfusion injury in nonselected patients undergoing angioplasty with moderate doses of contrast medium and optimal hydration . ( Myocardial Salvage and Contrast Dye Induced Nephropathy Reduction by N-Acetylcysteine [ LIPSIA-N-ACC ] ; NCT00463749 ) CONTEXT The antioxidant acetylcysteine prevents acute contrast nephrotoxicity in patients with impaired renal function who undergo computed tomography scanning . However , its role in coronary angiography is unclear . OBJECTIVE To determine whether oral acetylcysteine prevents acute deterioration in renal function in patients with moderate renal insufficiency who undergo elective coronary angiography . DESIGN AND SETTING Prospect i ve , r and omized , double-blind , placebo-controlled trial conducted from May 2000 to December 2001 at the Grantham Hospital at the University of Hong Kong . PARTICIPANTS Two hundred Chinese patients aged mean ( SD ) 68 ( 6.5 ) years with stable moderate renal insufficiency ( creatinine clearance < 60 mL/min [ 1.00 mL/s ] ) who were undergoing elective coronary angiography with or without intervention . INTERVENTION Participants were r and omly assigned to receive oral acetylcysteine(600 mg twice per day ; n = 102 ) or matching placebo tablets ( n = 98 ) on the day before and the day of angiography . All patients received low-osmolality contrast agent . MAIN OUTCOME MEASURES Occurrence of more than a 25 % increase in serum creatinine level within 48 hours after contrast administration ; change in creatinine clearance and serum creatinine level . RESULTS Twelve control patients ( 12 % ) and 4 acetylcysteine patients ( 4 % ) developed a more than 25 % increase in serum creatinine level within 48 hours after contrast administration ( relative risk , 0.32 ; 95 % confidence interval [ CI ] , 0.10 - 0.96 ; P = .03 ) . Serum creatinine was lower in the acetylcysteine group ( 1.22 mg/dL [ 107.8 micromol/L ] ; 95 % CI , 1.11 - 1.33 mg/dL vs 1.38 mg/dL [ 122.9 micromol/L ] ; 95 % CI , 1.27 - 1.49 mg/dL ; P = .006 ) during the first 48 hours after angiography . Acetylcysteine treatment significantly increased creatinine clearance from 44.8 mL/min ( 0.75 mL/s ) ( 95 % CI , 42.7 - 47.6 mL/min ) to 58.9 mL/min ( 0.98 mL/s ) ( 95 % CI , 55.6 - 62.3 mL/min ) 2 days after the contrast administration ( P<.001 ) . The increase was not significant in the control group ( from 42.1 to 44.1 mL/min [ 0.70 to 0.74 mL/s ] ; P = .15 ) . The benefit of acetylcysteine was consistent among various patient subgroups and persistent for at least 7 days . There were no major treatment-related adverse events . CONCLUSION Acetylcysteine protects patients with moderate chronic renal insufficiency from contrast-induced deterioration in renal function after coronary angiographic procedures , with minimal adverse effects and at a low cost Background Patients with diabetes mellitus ( DM ) and chronic kidney disease ( CKD ) constitute to be a high-risk population for the development of contrast-induced nephropathy ( CIN ) , in which the incidence of CIN is estimated to be as high as 50 % . We performed this trial to assess the efficacy of N-acetylcysteine ( NAC ) in the prevention of this complication . Methods In a prospect i ve , double-blind , placebo controlled , r and omized clinical trial , we studied 90 patients undergoing elective diagnostic coronary angiography with DM and CKD ( serum creatinine ≥ 1.5 mg/dL for men and ≥ 1.4 mg/dL for women ) . The patients were r and omly assigned to receive either oral NAC ( 600 mg BID , starting 24 h before the procedure ) or placebo , in adjunct to hydration . Serum creatinine was measured prior to and 48 h after coronary angiography . The primary end-point was the occurrence of CIN , defined as an increase in serum creatinine ≥ 0.5 mg/dL ( 44.2 μmol/L ) or ≥ 25 % above baseline at 48 h after exposure to contrast medium . Results Complete data on the outcomes were available on 87 patients , 45 of whom had received NAC . There were no significant differences between the NAC and placebo groups in baseline characteristics , amount of hydration , or type and volume of contrast used , except in gender ( male/female , 20/25 and 34/11 , respectively ; P = 0.005 ) and the use of statins ( 62.2 % and 37.8 % , respectively ; P = 0.034 ) . CIN occurred in 5 out of 45 ( 11.1 % ) patients in the NAC group and 6 out of 42 ( 14.3 % ) patients in the placebo group ( P = 0.656 ) . Conclusion There was no detectable benefit for the prophylactic administration of oral NAC over an aggressive hydration protocol in patients with DM and CKD.Trial registration STUDY OBJECTIVE To determine the incidence of cardiovascular and renal toxicity of a nonionic contrast agent when used for cardiac catheterization , and to assess the value of electrolytes and urinalysis results as predictors of nephropathy induced by a contrast agent . STUDY DESIGN Nonr and omized trial using a criterion st and ard and a cohort analytic study with a 48-hour follow-up . SETTING Referral-based university hospital . PATIENTS Convenience sample of patients having diagnostic cardiac catheterization . Renal function and clinical status were evaluated at baseline in 1,144 patients ; at 24 hours in 1,077 ( 94 % ) ; and at 48 hours in 663 ( 57 % ) . INTERVENTIONS After patients received saline for hydration , coronary angiography and left ventriculography were done with iopamidol ( average dose , 203 + /- 56 cc ) . MEASUREMENTS AND MAIN RESULTS The definite and possible incidence of major acute cardiovascular complications from nonionic contrast media was 0.2 % and 0.7 % , respectively . The mean serum creatinine level increased 11.5 mumol/L from baseline at 24 hours ( P less than 0.0001 ) and 16.8 mumol/L from baseline at 48 hours ( P less than 0.0001 ) . Results in a r and omly selected training sample were studied to determine predictors of a rise in serum creatinine of 44.2 mumol/L or more . The baseline serum creatinine level and age were significant predictors of renal injury , but hypertension , diabetes mellitus , congestive heart failure , vascular disease , the volume of contrast agent injected or baseline values of urinary variables did not predict nephrotoxicity . In an independent validation sample , only the baseline serum creatinine level was confirmed as a predictor of nephrotoxicity , whereas age was not . A model that predicted contrast-induced nephropathy by the serum creatinine level showed an exponential increase in the risk for nephrotoxicity if the baseline level was 106.1 mumol/L or higher . CONCLUSIONS Patients have a small but significant rise in serum creatinine after cardiac catheterization with a nonionic contrast agent . Baseline renal insufficiency is the only confirmed predictor of nonionic contrast-induced nephrotoxicity BACKGROUND Several protective therapies have been developed to prevent contrast-induced nephropathy ( CIN ) . We aim ed to investigate the efficacy of sodium bicarbonate by comparing 2 other regimens , including combination of N-acetylcysteine ( NAC ) plus sodium chloride and sodium chloride alone , to prevent CIN in patients undergoing cardiovascular procedures . METHODS We prospect ively enrolled 264 patients who were scheduled for cardiovascular procedures and had a baseline creatinine level > 1.2 mg/dL. The patients were assigned 1 of 3 prophylactic regimens : infusion of sodium bicarbonate , sodium chloride , sodium chloride plus oral NAC ( 600 mg bid ) . Contrast-induced nephropathy was defined as an increase in serum creatinine level > 25 % or 0.5 mg/dL after 48 hours . RESULTS There were no significant differences among groups regarding baseline demographic properties and nephropathy risk factors . The change in creatinine clearance was significantly better in the sodium bicarbonate group than other 2 groups ( P = .007 ) . The incidence of CIN was significantly lower in the sodium bicarbonate group ( 4.5 % ) compared with sodium chloride alone ( 13.6 % , P = .036 ) and tended to be lower than in the combination group ( 12.5 % , P = .059 ) . After adjusting the Mehran nephropathy risk score , the risk of CIN significantly reduced with sodium bicarbonate compared with sodium chloride alone ( adjusted risk ratio 0.29 , P = .043 ) . CONCLUSIONS Hydration with sodium bicarbonate provides better protection against CIN than the sodium chloride infusion does alone . Combination therapy of NAC plus sodium chloride did not offer additional benefit over hydration with sodium chloride alone Background —Contrast-induced nephropathy ( CIN ) is a serious condition in patients with ST-segment – elevation myocardial infa rct ion treated with primary percutaneous coronary intervention . We compared the risk of acute CIN and the influence of preventive strategies in patients with ST-segment – elevation myocardial infa rct ion undergoing primary percutaneous coronary intervention . Methods and Results —A total of 720 patients were r and omized in the Prevention of Contrast-induced Nephropathy in Patients With ST-Segment Elevation Myocardial Infa rct ion Undergoing Primary Percutaneous Coronary Intervention ( CINSTEMI ) trial . Patients were r and omly assigned in a 1:1:1:1 ratio to receive hydration with sodium chloride together with 1 of 4 prophylactic regimes ( 1 ) N-acetylcysteine ( NAC ) , ( 2 ) sodium bicarbonate ( NaHCO3 ) infusion , ( 3 ) NAC in combination with NaHCO3 , or ( 4 ) hydration with sodium chloride infusion alone . Patients in cardiogenic shock were excluded . Acute CIN was defined as an increase in serum creatinine concentration > 25 % from the baseline value within a 3-day period . Overall , CIN occurred in 141 ( 21.9 % ) patients . The prevention treatment with NAC , NaHCO3 , or the combined NAC and NaHCO3 did not reduce the rate of CIN significantly compared with hydration with intravenous sodium chloride infusion alone ( 20.1 % versus 20.1 % versus 20.8 % versus 26.5 % ; P = NS ) . However , an increase in serum creatinine > 25 % from the baseline value to 30 day was significantly lower in patients treated with combined NAC and NaHCO3 ( 18.7 % versus 19.1 % versus 9.2 % versus 21.3 % ; P=0.033 ) . Conclusions —Treatment with NAC or NaHCO3 did not reduce the rate of acute CIN significantly . Combined treatment with NAC and NaHCO3 may reduce the risk of renal dysfunction after 30 days . Clinical Trial Registration —URL : http://www . clinical trials.gov . Unique identifier : NCT01160627 OBJECTIVES This study was design ed to test a rapid protocol of intravenous acetylcysteine for prevention of radiocontrast-induced nephropathy ( RCIN ) . BACKGROUND Oral acetylcysteine ( NAC ) may provide better prophylaxis against RCIN than intravenous ( i.v . ) hydration alone . Current protocol s preclude prophylaxis of same-day or emergency patients owing to the need for prolonged pretreatment . METHODS We prospect ively r and omized 80 patients with stable renal dysfunction undergoing cardiac catheterization/intervention to a rapid protocol of i.v . NAC ( 150 mg/kg in 500 ml N/saline over 30 min immediately before contrast followed by 50 mg/kg in 500 ml N/saline over 4 h , n = 41 , 67 + /- 10 years , 90 % men ) or i.v . hydration ( 1 ml/kg/h N/saline for 12 h pre- and post-contrast , n = 39 , 71 + /- 8.8 years , 85 % men ) . RESULTS Radiocontrast-induced nephropathy occurred in 2 of the 41 patients in the NAC group ( 5 % ) and in 8 of the 39 patients in the hydration group ( 21 % ; p = 0.045 ; relative risk : 0.28 ; 95 % confidence interval 0.08 to 0.98 ) . In the NAC group , mean serum creatinine fell from 1.85 + /- 0.59 to 1.77 + /- 0.73 and 1.79 + /- 0.73 mg/dl 48 h and four days post-contrast ( p = 0.02 and 0.023 vs. baseline , respectively ) . In the hydration group , serum creatinine increased from 1.75 + /- 0.41 to 1.81 + /- 0.6 48 h and 1.80 + /- 0.50 mg/dl four days post-contrast ( p = 0.99 and 0.23 , respectively ) . NAC infusion was ceased after the bolus in three patients ( 7 % ) due to flushing , itching , or a transient rash . CONCLUSIONS Administration of i.v . NAC should be considered in all patients at risk of RCIN before contrast exposure when time constraints preclude adequate oral prophylaxis , provided the patient is able to tolerate this degree of volume loading BACKGROUND Contrast-induced nephropathy ( CIN ) continues to be a common cause of acute renal failure in high-risk patients undergoing radiocontrast studies . However , there is still a lack of consensus regarding the most effective measures to prevent CIN . METHODS ONE HUNDRED EIGHTEEN PATIENTS WITH DIABETES MELLITUS AND /OR RENAL INSUFFICIENCY , SCHEDULED FOR CORONARY ANGIOGRAPHY OR INTERVENTION , WERE R AND OMLY ASSIGNED TO ONE OF FOUR TREATMENT GROUPS : intravenous ( IV ) 0.9 % NaCl alone , IV 0.9 % NaCl plus N-acetylcysteine ( NAC ) , IV 0.9 % sodium bicarbonate ( NaHCO(3 ) ) alone or IV 0.9 % NaHCO(3 ) plus NAC . All patients received IV hydration as a preprocedure bolus and as maintenance . Iso-osmolar contrast was used in all patients . CIN was defined as an increase of greater than 25 % in the serum creatinine concentration from baseline to 72 h. RESULTS The overall incidence of CIN was 6 % . There was no statistically significant difference in the incidence of CIN among the groups . There was a CIN incidence of 7 % in the NaCl only group , 5 % in the NaCl/NAC group , 11 % in the NaHCO(3 ) only group and 4 % in the NaHCO(3)/NAC group ( P=0.86 ) . The maximum increase in serum creatinine was 14.14±12.38 μmol/L in the NaHCO(3 ) group , 10.60±29.14 μmol/L in the NaCl only group , 9.72±13.26 μmol/L in the NaCl/NAC group and 0.177±15.91 μmol/L for the NaHCO(3)/NAC group ( P=0.0792 ) . CONCLUSION CIN in high-risk patients may be effectively minimized solely through the use of an aggressive hydration protocol and an iso-osmolar contrast agent . The addition of NaHCO(3 ) and /or NAC did not have an effect on the incidence of CIN Despite myriad improvements in the care of hospitalized patients , a decline in renal function remains a common event . Renal function in 4,622 consecutive patients admitted to the medical and surgical services of an urban tertiary care hospital was followed up prospect ively from the time of admission . Some degree of renal insufficiency developed in 7.2 % of patients . Decreased renal perfusion , medications , surgery , and radiographic contrast media were the most common causes of hospital-acquired renal insufficiency ( HARI ) . The overall mortality rate was 19.4 % and was similar among patients for all causes of renal insufficiency , except sepsis . For patients with a greater than 3.0-mg/dL increase in serum creatinine level , the mortality rate was 37.8 % . As shown by previous investigators , age and preexisting renal insufficiency were risk factors for HARI . Women and blacks had less hospital-acquired renal failure . The increasing acuity of hospital admissions has been accompanied by a greater incidence of acute renal insufficiency in patients admitted to hospitals . There is a trend toward better survival in patients with a severe deterioration in renal function Objective : To evaluate oral N-acetylcysteine in the prevention of contrast induced nephropathy ( CIN ) in patients at low to moderate risk undergoing cardiac catheterisation with ionic low osmolality contrast medium . Methods : In a multicentre double blind clinical trial 156 patients undergoing coronary angiography or percutaneous coronary intervention with serum creatinine ⩾ 106.08 μmol/l or creatinine clearance < 50 ml/min or diabetes mellitus were r and omly assigned to receive N-acetylcysteine 600 mg orally twice daily for two days or placebo . Only low osmolality ionic contrast medium was used . Results : Sixteen patients developed CIN , defined as an increase of 44.2 μmol/l in creatinine in 48 hours : eight of 77 patients ( 10.4 % ) in the N-acetylcysteine group and eight of 79 patients ( 10.1 % ) in the placebo group ( p = 1.00 ) . The mean ( SD ) change in serum creatinine was similar in both groups : 7.96 ( 35.36 ) μmol/l in the N-acetylcysteine group and 6.19 ( 25.64 ) μmol/l in the placebo group ( p = 0.67 ) . No difference was observed in the change in endogenous creatinine clearance ( −0.54 ( 10.4 ) ml/min v –2.52 ( 12.3 ) ml/min , N-acetylcysteine and placebo , respectively , p = 0.28 ) . Conclusion : Oral N-acetylcysteine did not prevent CIN in patients at low to moderate risk undergoing cardiac catheterisation with ionic low osmolality contrast medium AIMS Prophylactic administration of N-acetylcysteine ( NAC ) ( 600 mg orally twice daily ) , along with hydration , prevents contrast agent-associated nephrotoxicity ( CAN ) induced by a low dose of non-ionic , low-osmolality contrast dye . We tested whether a double dose of NAC is more effective to prevent CAN . METHODS AND RESULTS Two-hundred-twenty-four consecutive patients with chronic renal insufficiency ( creatinine level > or = 1.5mg/dl and /or creatinine clearance < 60ml/min ) , referred to our institution for coronary and /or peripheral procedures , were r and omly assigned to receive 0.45 % saline intravenously and NAC at the st and ard dose ( 600 mg orally twice daily ; SD Group ; n=110 ) or at a double dose ( 1200 mg orally twice daily ; DD Group ; n=114 ) before and after a non-ionic , low-osmolality contrast dye administration . Increase of at least 0.5mg/dl of the creatinine concentration 48h after the procedure occurred in 12/109 patients ( 11 % ) in the SD Group and 4/114 patients ( 3.5 % ) in the DD Group ( P=0.038 ; OR=0.29 ; 95 % CI=0.09 - 0.94 ) . In the subgroup with low ( < 140ml , or contrast ratio < = 1 ) contrast dose , no significant difference in renal function deterioration occurred between the 2 groups . In the subgroup with high ( > or = 140ml , or contrast ratio > 1 ) contrast dose , the event was significantly more frequent in the SD Group . Conclusions Double dose of NAC seems to be more effective than the st and ard dose in preventing CAN , especially with high volumes of non-ionic , low-osmolality contrast agent OBJECTIVE Contrast-induced renal dysfunction is an iatrogenic complication that occurs more frequently in patients with preexisting renal dysfunction . A prospect i ve , double-blind , r and omized , placebo , controlled trial was completed to assess the efficacy of N-acetylcysteine in decreasing the incidence of contrast-induced renal dysfunction in patients with an acute coronary syndrome and renal insufficiency who underwent coronary angiography with or without percutaneous coronary intervention . METHODS With similar intravenous hydration protocol s , 20 patients received N-acetylcysteine ( treatment group ) and 20 patients received placebo ( control group ) in a twice per day dosing regimen with one dose before and three doses after contrast media exposure . RESULTS The two groups were similar at baseline on demographic and clinical characteristics , and preexisting renal insufficiency . Contrast-induced renal dysfunction , defined as an increase in serum creatinine greater than 44 micromol/L ( .5 mg/dL ) and /or 25 % above baseline within 48 hours , occurred in 7.5 % of the cohort , with 2.5 % in the treatment group , and 5 % in the control group , for an absolute difference of 2.5 % . There was no difference in serum creatinine or creatinine clearance at 24 hours or at 48 hours between the treatment and control groups . CONCLUSION These results suggest that this cohort gained no added protection to renal function with the use of N-acetylcysteine BACKGROUND Few studies that have assessed the effect of abbreviated oral N-acetylcysteine ( NAC ) regimens in radiocontrast-induced nephropathy ( RCIN ) yield mixed results . OBJECTIVE To evaluate the renoprotective effect of high periprocedural oral doses ( HPOD ) of NAC in patients with chronic renal impairment undergoing a same-day angiography . METHODS Sixty one patients with renal impaired function scheduled to undergo a same-day angiography were r and omly assigned to NAC 1200 mg orally 3 hours before and 3 after the procedure , or a placebo . All patients received 0.9 % saline intravenous . RCIN was defined as an increase in SCC > 0.5 mg/dl 48 hours after the procedure . RESULTS The mean baseline SCC for all patients was 1.44 + /- 0.42 mg/dl . A significant difference in SCC change at 48 hours after the angiography was found ( -0.07 mg/dl NAC , 0.09 mg/dl placebo , P = 0.04 ) . RCIN occurred in 1 ( 3 % ) patient of NAC group and in 2 ( 7.1 % ) patients of placebo group ( P = 0.59 ) . Adverse effects were similar in both groups . CONCLUSIONS In patients with mild renal impairment patients undergoing angiographic procedures , HPOD of NAC were more effective than placebo in preventing SCC change 48 hours . A non significant benefit in RCIN incidence was found Objective Contrast medium-induced nephropathy ( CIN ) is a well-known complication of coronary angiographic procedures , especially in patients treated with primary angioplasty . To prevent CIN , we examined using a local application of N-acetylcysteine ( NAC ) for the prevention of CIN during primary angioplasty . We hypothesized that a local application of NAC into the renal arteries would provide the benefit of a higher local concentration , lower first-pass metabolism , and faster efficacy . To evaluate the effects of NAC by the intrarenal route , we performed a prospect i ve , r and omized clinical study in patients with acute myocardial infa rct ion treated with primary angioplasty . Methods Participants were 312 patients with ST-segment elevation myocardial infa rct ion undergoing primary angiography . Eligible patients were r and omly assigned to receive intravenous NAC , intrarenal NAC , or placebo . Results Overall , CIN occurred in 74 ( 23.7 % ) of the 312 patients . The rate of CIN was 25 % in the intravenous NAC group , 22.9 % in the intrarenal NAC group , and 23.2 % in the placebo group , with no significant effect seen for either treatment ( P=0.64 ) . We did find a significant correlation between CIN and ejection fraction ( P=0.05 ) and baseline renal function ( P=0.01 ) . Conclusion Both intrarenal and intravenous applications of NAC failed to show any benefit over placebo in the prevention of CIN . This result shows that NAC application does not have any prophylactic effect , dose dependent or otherwise , on CIN , as previously reported . Our results suggest that more attention should be paid to optimize hemodynamic variables for the prevention of CIN BACKGROUND Patients with diabetes mellitus ( DM ) are at increased risk of contrast-associated nephropathy irrespective of their baseline creatinine ( Cr ) . We tested the efficacy of N-acetylcysteine ( NAC ) relative to hydration in unselected patients ( irrespective of baseline Cr ) with DM . METHODS We conducted a r and omized open-label study comparing hydration alone ( combined oral and rapid intravenous hydration , n = 69 ) to NAC plus hydration ( similar hydration protocol plus NAC 600 mg BID x 4 doses , n = 68 ) in diabetic patients ( mean age 65 + /- 10 years , 65 % men ) undergoing elective coronary angiography . The primary end point was the mean change in serum Cr measured up to 96 hours postangiography . RESULTS Baseline Cr was 1.14 + /- 0.43 mg/dL ( Cr > or = 1.3 mg/dL in 37 subjects ) . Baseline characteristics including blood urea nitrogen , Cr , and contrast volume were similar between the 2 groups . The mean Cr change in the NAC group was 0.14 + /- 0.47 versus 0.08 + /- 0.11 mg/dL in the hydration only group ( P = NS ) . Contrast-associated nephropathy , defined as a > or = 0.5 mg/dL increase in Cr , was significantly more common in the NAC group , 9.2 % versus 1.4 % , P = .043 . Similar results were found in the subgroup of participants with either an increased baseline serum Cr ( > or = 1.3 mg/dL ) or in those receiving high contrast volumes ( > 100 mL ) . CONCLUSIONS N-Acetylcysteine provides no benefit over an aggressive hydration protocol in patients with DM undergoing coronary angiography OBJECTIVES We examined oral N-acetylcysteine effects on contrast-induced nephropathy ( CIN ) and clinical events in patients undergoing primary angioplasty for acute myocardial infa rct ion . BACKGROUND Recent studies have reported that N-acetylcysteine reduces CIN and improves the clinical outcome in patients undergoing primary angioplasty . However , additional investigations are warranted to further support these findings . METHODS We r and omly assigned 76 patients undergoing primary angioplasty into two groups : 38 patients were assigned to N-acetylcysteine ( NAC , 705 mg orally administration before and 12 , 24 , 36 hours after primary angioplasty ) , and 38 patients to placebo . CIN was defined as an increase in the serum creatinine concentration of 25 percent or more from baseline value within the 72-hour period after primary angioplasty . RESULTS CIN occurred in 7 patients ( 9.2 % ) . In the NAC group , the incidence of CIN tended to be lower than in the placebo group ( NAC ; 2/38 ; 5.3 % vs. Placebo ; 5/38 ; 13.2 % , p=0.21 ) . The composite endpoints such as death , acute renal failure requiring temporary renal replacement therapy , or need for mechanical ventilation did not occur in either group . CONCLUSION While N-acetylcysteine might have the possibility to reduce the incidence of contrast-induced nephropathy in patients undergoing primary angioplasty for acute myocardial infa rct ion , the in-hospital mortality and morbidity were not significantly different between the two groups Contrast induced nephropathy ( CIN ) , an acute decline in renal function after the administration of intravenous contrast in the absence of other causes , is the third leading cause of acute renal failure in hospitalized patients . Antioxidant N-acetylcysteine prevents acute contrast nephrotoxicity in patients with impaired renal function who underwent coronary angiography ( CAG ) and percutaneous coronary intervention ( PCI ) . Hydration is the cornerstone in preventing CIN . N-acetylcysteine has additive preventive affect . We compared N-acetylcysteine plus hydration with hydration alone in preventing CIN . Patients were assigned to receive either premedication with hydration with normal saline ( 1ml/kg/hour-12 hour before and 12 hour after CAG and intravenous PCI ) alone or to receive both hydration and oral N acetylcysteine ( 600 mg bid for 2 days , starting day before CAG and PCI ) . Main out come was occurrence of ≥25 % or ≥0.5mg/dl increase in serum creatinine level within 24 to 48 hours after contrast administration ; change in creatinine clearance and serum creatinine level . Six patients ( 12 % ) of hydration group i.e. Group A and none of the patients of N-acetylcysteine All group i.e. Group B develop CIN ( p=0.012 ) . Baseline serum creatinine level was slightly higher in N-acetylcysteine group than hydration group ( 1.52±0.32 and 1.44±0.22 ) . After 24 hours of CAG and PCI serum creatinine level lower than base line in N-acetylcysteine group but slightly higher than base line in hydration group ( 1.42±0.39 and 1.51±0.38 ) . Difference in serum creatinine in both the groups were statistically significant ( p=0.006 in N-acetylcysteine group and p=0.029 in hydration group ) . Creatinine clearance rate significantly improved in N-acetylcysteine group after coronary intervention . In conclusion , N-acetylcysteine and hydration prevent CIN better than hydration alone in high risk patients BACKGROUND AND HYPOTHESIS Several studies have utilized low-dose regimens of N-acetylcysteine ( NAC ) for 48 hours to prevent contrast-induced nephropathy ( CIN ) after cardiac catheterization ( cath ) and percutaneous coronary intervention ( PCI ) . A lengthy pretreatment period with NAC may not be feasible in urgent situations . The purpose of this study was to assess the efficacy of an abbreviated , higher dose regimen of NAC for the prevention of CIN after elective and urgent coronary angiography ( cath ) and /or percutaneous coronary intervention ( PCI ) . METHODS We prospect ively evaluated 80 patients referred for elective or urgent cath and /or PCI with stable chronic renal insufficiency ( creatinine clearance < 50 cc/min ) . Patients were r and omized to : NAC 1000 mg PO 1 hour before cath/PCI and 4 hours later , or placebo . All patients received hydration ( 0.9 % saline ) before and after cath/PCI ( minimum total volume > or = 1500 mL ) . CIN was defined as an increase of Cr > or = 0.5 mg/dL or > or = 25 % 48 hours after cath/PCI . RESULTS CIN occurred in 3 of 36 ( 8 % ) patients of the NAC group vs. 11 of 44 ( 25 % ) in the placebo group ( P = 0.051 ; OR 3.7 , 95 % CI 0.94 - 14.4 ) . Serum creatinine ( mean + /- SD ) remained stable in the NAC group after cath/PCI ( 2.02 + /- 0.56 vs. 2.10 + /- 0.81 mg/dL ; P = 0.34 ) , but increased after cath/PCI in the placebo group ( 1.93 + /- 0.53 vs. 2.10 + /- 0.74 mg/dL ; P < 0.01 ) . CONCLUSIONS An abbreviated , higher dose regimen of NAC prevents the rise of serum creatinine 48 hours after cath/PCI , and may prevent CIN after cath/PCI BACKGROUND Antioxidant drugs such as N-acetylcysteine ( NAC ) and ascorbic acid have been evaluated in interventional studies to prevent contrast-induced nephropathy ( CIN ) , however , there are limited data on comparing either or both , with background of st and ard intravenous saline hydration versus the st and ard intravenous saline hydration alone in preventing CIN . METHODS We conducted a single-center r and omized trial among patients undergoing coronary angiography or percutaneous coronary intervention who had serum creatinine ≥ 1.3 mg/dL or were on diabetes mellitus medication . Eligible patients were r and omly assigned to one of the following 4 groups : ( 1 ) NAC , ( 2 ) ascorbic acid , ( 3 ) combination of both drugs , and ( 4 ) control group . Additionally , all the groups received the st and ard intravenous saline hydration . Creatinine was measured 4 - 5 days after procedure . RESULTS A total of 243 patients were r and omized ; 62 to NAC , 57 to ascorbic acid , 58 to both drugs , and 66 to placebo . The development of 0.5 mg/dL absolute increase of serum creatinine , 25 % relative decrease of creatinine clearance , or either ( CIN ) were measured in the ascorbic acid group ( 3.6 % for all ) , NAC group ( 6.8 % , 3.4 % , 8.5 % , respectively ) , combined group ( 5.5 % , 5.5 % , 9.1 % , respectively ) , and control group ( 6.2 % , 6.2 % , 7.7 % , respectively ) . None of these differences were significant ( P = 0.896 for serum creatinine , P = 0.863 for creatinine clearance , and P = 0.684 for CIN ) . CONCLUSIONS In a cohort of patients at risk of developing CIN , we could not detect any significant benefit of the use of ascorbic acid , NAC , or a combination of both drugs over the st and ard hydration regimen in preventing CIN Background This study aim ed to observe the preventive potential of different hydration solutions on contrast-induced nephropathy ( CIN ) after percutaneous coronary intervention . Methods We initially screened 627 patients who were admitted to the Division of Cardiology , Beijing Anzhen Hospital between October 2010 and October 2011 . The research subjects were r and omly divided into four groups and were given : normal physiological saline ( PS ) , sodium bicarbonate ( SB ) , oral administration of PS + N-acetylcysteine ( NAC ) ( PS + NAC ) , or oral administration of SB + NAC ( SB + NAC ) . These patients were administered a hypotonic nonionic contrast agent , and the incidence of CIN in each group was observed . Results The total incidence rate of CIN was 4.47 % , while the CIN incidence rates in the PS group , the SB group , the PS + NAC group and the SB + NAC group were 3.11 , 5.03 , 4.46 and 5.33 % , respectively . The differences between these groups were not statistically significant ( P = 0.238 ) , and for patients with diabetes and /or renal dysfunction , the incidence rates of CIN among the four groups did not show statistically significant differences ( P = 0.238 , 0.156 , 0.287 ) . Conclusion Use of PS , SB , and NAC caused no significant reduction in the incidence of CIN , but in high-risk patients with diabetes and /or renal dysfunction , SB + NAC might be superior to the application of isotonic crystalloid solution BACKGROUND The effect of N-acetylcysteine ( NAC ) to prevent contrast nephropathy ( CN ) in patients with moderate to severe renal insufficiency undergoing coronary angiography or interventions is not clear . METHODS This is a prospect i ve , open-label , r and omized , controlled trial . Ninety-one consecutive patients with a serum creatinine level of 1.69 to 4.52 mg/dL ( 149 to 400 micromol/L ) undergoing coronary procedures were recruited and r and omly assigned to administration of either oral NAC , 400 mg , thrice daily the day before and day of the contrast procedure ( the NAC group ) or no drug ( the control group ) . Serum creatinine was measured before and 48 hours after contrast exposure . The primary end point of this study was the development of CN , defined as an increase in serum creatinine concentration of 0.5 mg/dL or greater ( > or = 44 micromol/L ) or a reduction in estimated glomerular filtration rate ( GFR ) of 25 % or greater of the baseline value 48 hours after the procedure . RESULTS There were no significant differences between the 2 groups ( 46 patients , NAC group ; 45 patients , control group ) in baseline characteristics or mean volume of contrast agent administered . Six patients ( 13.3 % ) in the control group and 8 patients ( 17.4 % ) in the NAC group developed CN ( P = 0.8 ) . Serum creatinine levels increased from 2.27 + /- 0.54 to 2.45 + /- 0.65 mg/dL ( 201 + /- 48 to 217 + /- 57 micromol/L ; P = 0.003 ) in the NAC group and 2.37 + /- 0.61 to 2.40 + /- 0.70 mg/dL ( 210 + /- 54 to 212 + /- 62 micromol/L ; P = 0.6 ) in the control group . The increase in serum creatinine levels between the 2 groups had no difference ( P = 0.7 ) . Estimated GFR decreased from 30.3 + /- 8.4 to 28.1 + /- 8.4 mL/min ( P = 0.01 ) in the NAC group and 28.4 + /- 8.6 to 27.5 + /- 8.8 mL/min ( P = 0.3 ) in the control group . The decline in estimated GFR between the 2 groups had no difference ( P = 0.7 ) . CONCLUSION In the current study , oral NAC had no effect on the prevention of CN in patents with moderate to severe renal insufficiency undergoing coronary angiography or interventions . However , the sample size of our present study is small . Our findings highlight the need for a large-scale , r and omized , controlled trial to determine the exact beneficial effect of NAC OBJECTIVE The purpose of this study was to assess the effect of i.v . administration of N-acetylcysteine ( NAC ) on serum levels of creatinine and cystatin C , two markers of renal function , in patients with renal insufficiency who undergo emergency contrast-enhanced CT . SUBJECTS AND METHODS Eighty-seven adult patients with renal insufficiency who underwent emergency CT were r and omized to two groups . In the first group , in addition to hydration , patients received a 900-mg injection of NAC 1 hour before and another immediately after injection of iodine contrast medium . Patients in the second group received hydration only . Serum levels of creatinine and cystatin C were measured at admission and on days 2 and 4 after CT . Nephrotoxicity was defined as a 25 % or greater increase in serum creatinine or cystatin C concentration from baseline value . RESULTS A 25 % or greater increase in serum creatinine concentration was found in nine ( 21 % ) of 43 patients in the control group and in two ( 5 % ) of 44 patients in the NAC group ( p = 0.026 ) . A 25 % or greater increase in serum cystatin C concentration was found in nine ( 22 % ) of 40 patients in the control group and in seven ( 17 % ) of 41 patients in the NAC group ( p = 0.59 ) . CONCLUSION On the basis of serum creatinine concentration only , i.v . administration of NAC appears protective against the nephrotoxicity of contrast medium . No effect is found when serum cystatin C concentration is used to assess renal function . The effect of NAC on serum creatinine level remains unclear and may not be related to a renoprotective action BACKGROUND Contrast nephropathy ( CN ) is a common cause of renal dysfunction after cardiac angiography . Recently , N-acetylcysteine ( NAC ) has been found to reduce the risk of CN after CT imaging with contrast enhancement . The purpose of the current study was to evaluate the efficacy of NAC for the prevention of CN in the setting of cardiac angiography . METHODS Eligible patients were those undergoing cardiac angiography with serum creatinine>1.7 mg/dL. Patients were r and omized to one of two groups : Group 1 , IV hydration and NAC , 1200 mg one hour before angiography , and a second dose 3 hours after ; Group 2 , IV hydration and placebo . CN was defined as an increase of 0.5 mg/dL in serum creatinine . RESULTS Seventy-nine patients completed the study . There were no significant differences between the groups in baseline characteristics , duration of angiography , mean volume of dye infused or mean IV hydration . Contrast nephropathy developed in 24.0 % of subjects , 26.3 % NAC , and 22.0 % placebo ( P = NS ) . Among subjects with diabetes mellitus , there was no significant difference in the rate of CN between the groups ( 42.1 % NAC , 27.8 % placebo ; P = 0.09 ) . The independent predictors of CN risk were diabetes mellitus and preexisting chronic renal insufficiency . CONCLUSIONS NAC was not effective for the prevention of CN after cardiac angiography Radiographic contrast agents can cause acute decrease in renal functions . It is thought that anti-oxidant acetylcysteine can prevent contrast nephropathy . Fifty patients planned to undergo elective diagnostic coronary angiography with serum creatinine values above 1.3 mg/dL were included in the study . Acetylcysteine was given orally at a dose of 600 mg twice daily , on the day before and on the day of administration of contrast agent in the acetylcysteine group ( n = 25 ) . Acetylcysteine was not given to the control group ( n = 25 ) . Saline ( 0.9 % ) was given intravenously at a rate of 1 mL/kg/h for 12 hours before and 12 hours after administration of contrast agent . Contrast nephropathy was detected in 3 of 25 patients ( 12 % ) in the acetylcysteine group and 2 of 25 patients ( 8 % ) in the control group ( P > 0.05 ) . Contrast nephropathy was developed in 2 of 4 patients ( 50 % ) with baseline serum creatinine concentrations above 2.5 mg/dL , whereas it was developed in only 3 of 46 patients ( 6.5 % ) with baseline serum creatinine concentrations below 2.5 mg/dL ( P = 0.04 ) . It was detected that in patients planned to undergo elective diagnostic coronary angiography with renal dysfunction , oral acetylcysteine and hydration before the procedure was not more effective than hydration alone in the prevention of contrast nephropathy . High baseline serum creatinine values were detected as a risk factor for development of contrast nephropathy BACKGROUND Contrast-induced acute kidney injury ( CI-AKI ) is a serious complication of procedures requiring contrast media associated with rising costs , prolonged hospitalization , and increased mortality . The aim of this study was to assess whether prophylactic administration of st and ard dosages of intravenous N-acetylcysteine or ascorbic acid reduce the incidence of CI-AKI in patients with chronic renal insufficiency undergoing elective cardiac catheterization . METHODS In a single-center , prospect i ve , r and omized , double-blind , placebo-controlled trial , the preventive effects of N-acetylcysteine and ascorbic acid were evaluated in 520 patients with chronically impaired renal function ( serum creatinine ≥1.3 mg/dL ) undergoing elective cardiac catheterization . The study drugs ( 600 mg N-acetylcysteine , 500 mg ascorbic acid , placebo ) were administered intravenously twice ( at 24 hours and 1 hour before the procedure ) . Serum creatinine , estimated glomerular filtration rate ( eGFR ) and serum urea were assessed at baseline and at 24 hours and 72 hours after contrast media exposure . CI-AKI was defined as a postangiographical increase in serum creatinine ≥0.5 mg/dL. Results . The incidence of CI-AKI was 27.6 % in the N-acetylcysteine group ( P=.20 vs placebo group ) and in 24.5 % in the ascorbic acid group ( P=.11 vs placebo group ) . CI-AKI occurred in 32.1 % of the placebo group . CONCLUSIONS St and ard doses of N-acetylcysteine and ascorbic acid did not prevent CI-AKI in patients at high risk undergoing cardiac catheterization with non-ionic , low-osmolality contrast agent The objective of this study was to compare the efficacy of N‐acetylcysteine ( NAC ) , fenoldopam , and saline in preventing radiocontrast‐induced nephropathy ( RCIN ) in high‐risk patients undergoing cardiovascular procedures . We prospect ively enrolled 123 patients who were scheduled for cardiovascular procedures and had a baseline creatinine > 1.6 mg/dl or creatinine clearance of < 60 ml/min . Patients were r and omly assigned to receive either saline ( 0.45 % normal saline at 1 cc/kg ) for 12 hr before and 12 hr after the procedure , or fenoldopam ( 0.1 μg/kg/min ) plus saline for 4 hr prior and 4 hr after the procedure , or NAC orally ( 600 mg ) plus saline every 12 hr for 24 hr prior and 24 hr after the procedure . All the patients received low‐osmolality nonionic contrast . RCIN was defined as an increase in creatinine level > 0.5 mg/dl after 48 hr . The incidence of RCIN was 17.7 % in the NAC group , 15.3 % in the saline group , and 15.7 % in the fenoldopam group ( P = 0.919 ) . Of the 20 patients who developed RCIN , 2 required dialysis . Serum creatinine decreased after 48 hr ( vs. baseline ) in 38 % patients in the NAC group , 18 % in the fenoldopam group , and 15 % in the saline group . In patients with chronic renal insufficiency , NAC or fenoldopam offered no additional benefit over hydration with saline in preventing RCIN . Cathet Cardiovasc Intervent 2002;57:279–283 . © 2002 Wiley‐Liss , OBJECTIVES We sought to evaluate the efficacy of the antioxidant acetylcysteine in limiting the nephrotoxicity after coronary procedures . BACKGROUND The increasingly frequent use of contrast-enhanced imaging for diagnosis or intervention in patients with coronary artery disease has generated concern about the avoidance of contrast-induced nephrotoxicity ( CIN ) . Reactive oxygen species have been shown to cause CIN . METHODS We prospect ively studied 121 patients with chronic renal insufficiency ( mean [ + /-SD ] serum creatinine concentration 2.8 + /- 0.8 mg/dl ) who underwent a coronary procedure . Patients were r and omly assigned to receive either acetylcysteine ( 400 mg orally twice daily ) and 0.45 % saline intravenously , before and after injection of the contrast agent , or placebo and 0.45 % saline . Serum creatinine and blood urea nitrogen were measured before , 48 h and 7 days after the coronary procedure . RESULTS Seventeen ( 14 % ) of the 121 patients had an increase in their serum creatinine concentration of at least 0.5 mg/dl at 48 h after administration of the contrast agent : 2 ( 3.3 % ) of the 60 patients in the acetylcysteine group and 15 ( 24.6 % ) of the 61 patients in the control group ( p < 0.001 ) . In the acetylcysteine group , the mean serum creatinine concentration decreased significantly from 2.8 + /- 0.8 to 2.5 + /- 1.0 mg/dl ( p < 0.01 ) at 48 h after injection of the contrast medium , whereas in the control group , the mean serum creatinine concentration increased significantly from 2.8 + /- 0.8 to 3.1 + /- 1.0 mg/dl ( p < 0.01 ) . CONCLUSIONS Prophylactic oral administration of the antioxidant acetylcysteine , along with hydration , reduces the acute renal damage induced by a contrast agent in patients with chronic renal insufficiency undergoing a coronary procedure NAC reduces the risk of postcardiac catheterization nephropathy in patients with chronic renal insufficiency and decreased ejection fraction . Thus , it should be considered as routine prophylaxis in patients with chronic renal insufficiency undergoing cardiac catheterization Contrast medium-induced nephropathy ( CIN ) is a serious complication with increasing frequency and an unfavorable prognosis . Previous analyses of surrogate parameters have suggested beneficial effects of hemodialysis that are assessed in this r and omized clinical trial . We performed a prospect i ve single-center trial in 424 consecutive patients with serum creatinine concentrations between 1.3- 3.5 mg/dl who underwent elective coronary angiography . Patients were r and omized to one of three treatment strategies with all patients receiving pre- and postprocedural hydration : One group received no additional therapy , patients in the second group were hemodialyzed once , and the third group received oral N-acetylcysteine . The frequency of CIN ( defined as an increase in serum creatinine > or=0.5 mg/dl ) from 48 to 72 h after catheterization was 6.1 % in the hydration-only group , 15.9 % with hemodialysis treatment , and 5.3 % in the N-ACC group ( intention-to-treat analysis ; P=0.008 ) . There were no differences between the treatment groups with regard to increased ( > or=0.5 mg/dl ) serum creatinine concentrations after 30 - 60 days ( 4.8 % , 5.1 % , and 3.1 % , respectively ; P=0.700 ) . Analyses of long-term follow-up ( range 63 to 1316 days ) by Cox regressions models of the study groups found quite similar survival rates ( P=0.500 ) . In contrast to other ( retrospective ) studies , long-term survival of patients with vs those without CIN within 72 h was not different , but patients who still had elevated creatinine concentrations at 30 - 60 days suffered from a markedly higher 2-year mortality ( 46 % vs 17 % , P=0.002 ) . In conclusion , hemodialysis in addition to hydration therapy for the prevention of CIN provided no evidence for any outcome benefit but evidence for probable harm . Increased creatinine concentrations at 30 - 60 days , but not within 72 h , were associated with markedly reduced long-term survival BACKGROUND Contrast-induced nephropathy ( CIN ) after coronary angiography is associated with increased morbidity and mortality rates . Preliminary studies with N-acetylcysteine ( NAC ) have found conflicting results in the prevention of CIN in patients undergoing coronary angiography . This study was design ed to evaluate the efficacy and safety of NAC in the prevention of CIN in patients undergoing coronary angiography . METHODS This study was prospect i ve , r and omized , double-blind , and placebo-controlled . Patients referred for elective coronary angiography with a baseline creatinine clearance level < 50 mL/min and serum creatinine > 1.2 mg/dL were r and omly assigned to 1500 mg NAC or placebo , starting the evening before angiography and given every 12 hours for 4 doses . The primary study end point was the development of CIN , which was defined as an increase of > 0.5 mg/dL or an increase of > or = 25 % in serum creatinine over baseline within 48 hours of angiography . Secondary end points included changes in serum creatinine and blood urea nitrogen , requirement of dialysis , side effects of study medication , hospital length of stay , and hospital charges . RESULTS CIN occurred in 8.2 % ( 4/49 ) of patients taking NAC and 6.4 % ( 3/47 ) of patients taking placebo . Changes in BUN and serum creatinine from baseline were not significantly different in the two treatment groups . Baseline BUN and volume of contrast were the only independent predictors of CIN . More patients with diabetes had development of CIN ( 5/43 ; 12 % ) compared with nondiabetic patients ( 2/52 ; 4 % ) , but the difference was not significant ( P = .15 ) . The incidence of CIN in diabetic patients was not different in the two treatment groups . No patient with development of CIN required dialysis . Side effects ( mostly gastrointestinal ) occurred in 16 % of patients taking NAC and in none of the patients taking placebo . Length of stay and hospital charges were not different between the treatment groups . CONCLUSIONS In patients with reduced renal function undergoing elective coronary angiography , NAC does not reduce the risk of CIN BACKGROUND Studies evaluating the role of N-acetylcysteine in patients undergoing coronary angiography have yielded inconsistent data . Less is known about patients with normal renal function at baseline . METHODS Prospect i ve , double-blind , placebo-controlled trial to determine the benefits of intravenous N-acetylcysteine as an adjunct to hydration in this kind of population . Patients were r and omly assigned to receive either N-acetylcysteine ( 600 mg twice daily ) or placebo , in addition to 0.45 % intravenous saline . The primary end point was development of contrast-induced nephropathy , defined as an acute increase in the serum creatinine concentration > or = 0.5 mg/dl and /or > 25 % increase above baseline level at 48 h after contrast dosing . RESULTS A total of 216 patients were studied : N-acetylcysteine = 107 and placebo = 109 . Treatment groups were similar with respect to baseline clinical characteristics . Overall incidence of contrast-induced nephropathy was 10.2 % , 10.3 % in the N-acetylcysteine group and 10.1 % in the placebo group . Furthermore , no significant differences were observed when considering the non-diabetic population , although there was a trend towards a protective effect of N-acetylcysteine in the subgroup of 47 patients with both hypertension and diabetes . There were no significant changes in serum urea nitrogen concentrations . The incidence of in-hospital adverse clinical events was low : no patient with contrast-induced nephropathy required dialysis , the median Coronary Unit stay was 4.5 vs. 4 days , and the mortality rate was 2.8 % vs. 4.6 % in the N-acetylcysteine and placebo groups , respectively ( p = NS ) . CONCLUSIONS The prophylactic administration of intravenous N-acetylcysteine provides no additional benefit to saline hydration in high-risk coronary patients with normal renal function BACKGROUND Contrast agents used in angiography procedures for patients with cardiovascular disease are known to cause contrast-induced nephropathy ( CIN ) , which may be partially due to the production of nephrotoxic oxygen-free radicals . It is uncertain whether administration of intravenous ( IV ) anti-oxidant , N-acetylcysteine ( NAC ) , can prevent reduction in renal function and whether this is a cost-effective approach . METHODS Sixty-five day-only patients with renal impairment ( mean serum creatinine concentration 0.16+/-0.03 mmol/l ) due to undergo coronary or peripheral angiography and /or stenting were r and omly assigned to IV NAC 300 or 600 mg immediately before and after the procedure or IV fluid alone . RESULTS Of the 60 patients with complete data , none had acute CIN ( increase in serum creatinine concentration > or = 0.044 mmol/l , 48 h after administration of contrast agent ) . Eight patients ( 13 % ) have demonstrated an increase in their serum creatinine concentration > or = 0.044 mmol/l 30 days after administration of contrast agent : 2/19 ( 11 % ) in the control group , 2/21 ( 10 % ) in the 600 mg NAC group and 4/20 ( 20 % ) the 300 mg NAC group ( p = 0.66 ) . The mean volumes of contrast agent used and prehydration given for each of the three groups did not differ significantly ( p > 0.83 ) . There was significant improvement in creatinine clearance within each group from baseline to 30 days ( p < or = 0.03 ) , but no significant difference between the groups at 48 h and 30 days ( p > or = 0.43 ) . Considering the cost of NAC and its administration , we estimate that this would translate to a saving of dollar 26,637 per annum . CONCLUSION For day-stay patients with mild-to-moderate chronic renal impairment undergoing angiography and /or intervention , prehydration alone is less complicated and more cost-effective than a combination of IV NAC ( at doses used ) and hydration Contrast-induced nephropathy is the third most common cause of acute renal failure in hospitalized patients . The purpose of this study was to compare three supportive treatments for prevention of contrast-induced nephropathy in high-risk patients undergoing coronary angiography . In this r and omized clinical trial study , 150 patients with at least one risk factor , such as , congestive heart failure , history of diabetes mellitus , age>65 years or renal failure were r and omly assigned to three equal groups : First group ( Sodium ( Na ) bicarbonate infusion ) , second group [ ( N-Acetylcysteine (NAC)+Sodium Chloride ( Nacl ) ] , third group ( Nacl ) . Angiography was performed with 350 mgI/mL of Iohexol ( Omnipaque ) . Serum creatinine ( Cr ) , blood blood urea nitrogen ( BUN ) , and urine pH were measured at the start of angiography and 48 hours later . The three groups had no significant difference in demographic characteristics or other risk factors before intervention ( P>0.05 ) . Forty eight hours after exposure , the Cr level increased significantly in the Nacl group ( P=0.039 ) , while these changes were not significant in the other groups ( P>0.05 ) . The incidence of contrast-induced nephropathy was not statistically significant between all the groups ( P=0.944 ) . Although the Cr clearance had no statistically significant difference , it was lower in the NaCl group . Therefore , Na bicarbonate may be the treatment of choice in the prevention of contrast-induced nephropathy , because of less prescribed fluid volume and a lesser time required for infusion of the fluid BACKGROUND Acetylcysteine may provide prophylaxis against contrast nephropathy ( CN ) in some patients . Its benefit may vary according to the characteristics of patients and contrast used . The objective is to evaluate the effectiveness of oral acetylcysteine in preventing CN after coronary procedures in our practice . METHODS We prospect ively studied 397 patients with a creatinine level equal to or above 1.3 mg/dl , diabetes mellitus , or 70 + years of age who underwent a coronary procedure . Patients were r and omly assigned to receive either acetylcysteine or placebo and 0.9 % saline before and after the contrast agent . High- or low-osmolality contrast was used according to the discretion of the interventional cardiologist . Serum creatinine was measured before and 24 to 48 hours after the procedure . RESULTS An increase of greater than or equal to 25 % in the baseline creatinine level 24 to 48 hours after the procedure occurred in 14 ( 7.1 % ) of 196 acetylcysteine patients and in 17 ( 8.4 % ) of 201 placebo patients ( p=0.62 ) . In the acetylcysteine group , the mean baseline serum creatinine concentration was 1.30+/-0.56 mg/dl and increased 0.076+/-0.21 mg/dl 24 to 48 hours after administration of contrast , whereas in the placebo group , it was 1.27+/-0.51 mg/dl and increased 0.101+/-0.28 mg/dl ( p=0.33 ) . In the subgroup with estimated baseline creatinine clearance < 60 ml/minute , no difference was found in the incidence of CN ( 9.1 % in the acetylcysteine group ; 11.7 % in the placebo ; p=0.66 ) . By multivariate analysis , left ventricular ejection fraction less than or equal to 40 % , volume of contrast > 200 ml , and estimated creatinine clearance ( but not acetylcysteine ) were related to CN . CONCLUSIONS Oral acetylcysteine was not effective as a prophylactic treatment against CN for patients with a potential risk and su bmi tted to coronary angiographic procedures with predominantly high-osmolality contrast Objectives — This study was design ed to determine whether acetylcysteine could provide a protective effect on renal function in a population of patients with normal renal function or mild to moderate chronic renal failure , usually referred for a coronary procedure . Background — Contrast-induced nephropathy is a well-recognized complication of coronary angiography . Recent studies suggest that saline hydration and acetylcysteine reduce the incidence of contrast-induced worsening of renal function in patients with pre-existing chronic renal failure who are undergoing computed tomography examinations . Methods — One hundred eight patients were blindly and r and omly assigned to receive either acetylcysteine or placebo before and after administration of contrast agent in association with a moderate hydration protocol . Serum creatinine and urea nitrogen were measured before and 24 hours after coronary procedure . Results — The mean serum creatinine concentration remained unchanged 24 hours after contrast agent administration in both groups : from 1.04 ± 0.26 to 1.03 ± 0.29 mg/dl in the acetylcysteine group and from 1.16 ± 1.1 to 1.06 ± 0.41 mg/dl in the control group ( p = 0.29 , for the comparison between two groups , NS ) . We divided the population into 3 subgroups according to their creatinine clearance : no significant change of serum creatinine concentration was observed in patients with normal renal function nor in patients with pre-existing mild to moderate chronic renal failure in both groups . There was no significant difference for the incidence of contrast-induced nephropathy between both groups ( 2 of the 53 patients in the acetylcysteine group and 3 of the 51 patients in the placebo group , p = 0.98 , NS ) . Conclusions — Our data do not support the systematic use of acetylcysteine before a coronary procedure in patients with normal renal function or mild to moderate chronic renal failure , to prevent contrast-induced nephropathy BACKGROUND The administration of radiographic contrast agents remains an important cause of acute renal failure . The optimal infusion for hydration has not been evaluated . OBJECTIVE To compare the incidence of contrast media-associated nephrotoxicity with isotonic or half-isotonic hydration . DESIGN Prospect i ve , r and omized , controlled , open-label study . METHODS Patients scheduled for elective or emergency coronary angioplasty were r and omly assigned to receive isotonic ( 0.9 % saline ) or half-isotonic ( 0.45 % sodium chloride plus 5 % glucose ) hydration beginning the morning of the procedure for elective interventions and immediately before emergency interventions . An increase in serum creatinine of at least 0.5 mg/dL ( 44 micromol/L ) within 48 hours was defined as contrast media-associated nephrotoxicity . Secondary end points were cardiac and peripheral vascular complications . RESULTS A total of 1620 patients were assigned to receive isotonic ( n = 809 ) or half-isotonic ( n = 811 ) hydration . Primary end point analysis was possible in 1383 patients . Baseline characteristics were well matched . Contrast media-associated nephropathy was significantly reduced with isotonic ( 0.7 % , 95 % confidence interval , 0.1%-1.4 % ) vs half-isotonic ( 2.0 % , 95 % confidence interval , 1.0%-3.1 % ) hydration ( P = .04 ) . Three predefined subgroups benefited in particular from isotonic hydration : women , persons with diabetes , and patients receiving 250 mL or more of contrast . The incidence of cardiac ( isotonic , 5.3 % vs half-isotonic , 6.4 % ; P = .59 ) and peripheral vascular ( isotonic , 1.6 % vs half-isotonic , 1.5 % , P = .93 ) complications was similar between the 2 hydration groups . CONCLUSION Isotonic hydration is superior to half-isotonic hydration in the prevention of contrast media-associated nephropathy BACKGROUND Contrast-associated nephropathy ( CAN ) is associated with increased morbidity and mortality following percutaneous coronary intervention ( PCI ) . N-acetylcysteine ( NAC ) has been shown to reduce the risk of nephropathy ; however , the impact of NAC on long-term clinical outcomes has not been assessed . METHODS This r and omized , double-blind , placebo-controlled trial enrolled 180 patients with moderate renal dysfunction undergoing PCI or coronary angiography with a high likelihood of ad hoc PCI ; 171 patients completed the clinical follow-up . Patients received oral NAC ( 2000 mg/dose , n = 95 ) or placebo ( n = 85 ) twice a day for 3 doses if r and omized the night prior to the procedure , and 2 doses if r and omized the day of the procedure . The primary end point was the incidence of a > or = 25 % increase in serum creatinine level 48 to 72 hours after PCI . Secondary end points were the inhospital incidence of death , nonfatal myocardial infa rct ion , or urgent dialysis , and the 9-month incidence of death , nonfatal myocardial infa rct ion , need for dialysis , or repeat hospitalization for cardiac reasons . RESULTS CAN occurred in 9.6 % of patients assigned to NAC and 22.2 % of patients assigned to placebo ( P = .04 ) ; 1 patient receiving NAC required urgent dialysis . The inhospital composite end point occurred in 7 ( 7.4 % ) NAC-treated and 3 ( 3.5 % ) placebo-treated patients , P = NS . At 9 months , the composite end point occurred in 23 ( 24.2 % ) NAC-treated patients and 18 ( 21.2 % ) placebo-treated , P = NS . CONCLUSION Although high-dose NAC prevented periprocedural CAN , this benefit did not translate into a decrease in adverse outcomes over 9 months . Further studies to determine the clinical utility of this drug are required BACKGROUND The use of N-acetylcysteine or theophylline in specific subgroups of patients has been suggested to reduce the incidence of contrast-induced nephropathy ( CIN ) in patients undergoing angiographic procedures . Our purpose was to compare the use of N-acetylcysteine versus N-acetylcysteine + theophylline for the prevention of CIN . MATERIAL S AND METHODS We r and omized 217 patients with estimated glomerular filtration rate ( eGFR ) ( calculated by Modification of Diet in Renal Disease formula ) between 30 and 60 mL min(-1 ) 1.73 m(-2 ) who were undergoing coronary angiography to three prophylactic treatment groups : Group 1 : Intravenous hydration with isotonic saline ( 1 mL kg(-1 ) h(-1 ) for 12 h before and after contrast , n = 72 ) . Group 2 : Intravenous hydration with isotonic saline ( 1 mL kg(-1 ) h(-1 ) for 12 h before and after contrast)+ N-acetylcysteine ( 600 mg p.o . twice daily the preceding day and the day of angiography , n = 73 ) . Group 3 : Intravenous hydration with isotonic saline ( 1 mL kg(-1 ) h(-1 ) for 12 h before and after contrast)+ N-acetylcysteine + theophylline ( 600 mg N-acetylcysteine p.o . and 200 mg theophylline p.o . twice daily for the preceding day and the day of angiography , n = 72 ) . The incidence of CIN ( 0.5 mg dL(-1 ) increase in serum creatinine from the baseline value 48 h after intravascular injection of contrast ) was compared in three groups . RESULTS Of the 217 patients , 12 patients ( 5.5 % ) experienced CIN . Five patients ( 6.9 % ) in group 1 , seven patients ( 9.6 % ) in group 2 and zero ( 0 % ) patients in group 3 experienced CIN ( P < 0.033 ) . CONCLUSION Among patients with eGFR between 30 and 60 mL min(-1 ) 1.73 m(-2 ) undergoing coronary angiography , oral administration of N-acetylcysteine + theophylline in addition to saline hydration has a beneficial effect in the prevention of CIN |
1,925 | 24,979,199 | Authors ' conclusions In individual patients , PQ added to malaria treatments reduces gametocyte prevalence when given in doses greater than 0.4 mg/kg .
No included trials evaluated whether this policy has an impact on community malaria transmission either in low-endemic setting s approaching elimination , or in highly-endemic setting s where many people are infected but have no symptoms and are unlikely to be treated .
For the currently recommended low dose regimen , there is little direct evidence to be confident that the effect of reduction in gametocyte prevalence is preserved .
Most trials excluded people with G6PD deficiency , and thus there is little reliable evidence from controlled trials of the safety of PQ in single dose or short course .
Overall the safety of PQ given as a single dose was poorly evaluated across all studies , so these data do not demonstrate whether the drug is safe or potentially harmful at this dosing level | Background Mosquitoes become infected with Plasmodium when they ingest gametocyte-stage parasites from an infected person 's blood .
Plasmodium falciparum gametocytes are sensitive to the drug primaquine ( PQ ) and other 8-aminoquinolines ( 8AQ ) ; these drugs could prevent parasite transmission from infected people to mosquitoes , and consequently reduce the incidence of malaria .
However , PQ will not directly benefit the individual , and could be harmful to those with glucose-6-phosphate dehydrogenase ( G6PD ) deficiency .
In 2010 , The World Health Organization ( WHO ) recommended a single dose of PQ at 0.75 mg/kg , alongside treatment for P. falciparum malaria to reduce transmission in areas approaching malaria elimination .
In 2013 the WHO revised this to 0.25 mg/kg due to concerns about safety .
Objectives To assess whether giving PQ or an alternative 8AQ alongside treatment for P. falciparum malaria reduces malaria transmission , and to estimate the frequency of severe or haematological adverse events when PQ is given for this purpose .
We sought evidence of an impact on transmission ( community incidence ) , infectiousness ( mosquitoes infected from humans ) and potential infectiousness ( gametocyte measures ) .
What is primaquine and how might it reduce transmission Primaquine is an antimalarial drug which does not cure malaria illness , but is known to kill the gametocyte stage of the malaria parasite which infects mosquitoes when they bite humans .
Primaquine is also known to have potentially serious side effects in people with an enzyme deficiency common in many malaria endemic setting s ( glucose-6-phosphate dehydrogenase ( G6PD ) deficiency ) .
In these people , high doses of primaquine given over several days sometimes destroys red blood cells , causing anaemia and , in some cases , possibly life-threatening effects .
The World Health Organization ( WHO ) recommends adding a single dose of primaquine to malaria treatment with the intention of reducing malaria transmission and to contribute to malaria elimination .
This review examines the evidence of benefits and harms of using primaquine in this way , and looks for evidence that primaquine will reduce malaria transmission in communities . | Background The WHO recommends that adults with uncomplicated P. falciparum successfully treated with a blood schizonticide receive a single dose of primaquine ( PQ ) 45 mg as a gametocytocidal agent . An earlier pilot study suggested that 75 mg of bulaquine ( BQ ) , of which PQ is a major metabolite , may be a useful alternate to PQ . Methods In a r and omized , partial blind study , 90 hospitalized adults with Plasmodium falciparum malaria that was blood schizonticide-responsive and a gametocytemia of > 55/μl within 3 days of diagnosis were r and omized to receive single doses of either PQ 45 mg or BQ 75 mg on day 4 . We assessed gametocytemia on days 8 , 15 , 22 and 29 and gametocyte viability as determined by exflagellation ( 2 ° end point ) on day 8 . Results On day 8 , 20/31 ( 65 % ) primaquine recipients versus 19/59 ( 32 % ) bulaquine recipients showed persistence of gametocytes ( P = 0.002 ) . At day 15 and beyond , all patients were gametocyte free . On day 8 , 16/31 PQ and 7/59 BQ volunteers showed gametocyte viability ( p = 0.000065 ) . Conclusion BQ is a safe , useful alternate to PQ as a Plasmodium falciparum gametocytocidal agent and may clear gametocytemia faster than PQ Abstract The prophylactic and sporontocidal efficacy of st and ard antimalarials was studied among non-immune adult male volunteers challenged by mosquitoes heavily infected with two strains of chloroquine resistant Plasmodium falciparum from Malaya . The Poo . strain from Trengganu broke through in 12 of 15 men receiving chloroquine 300 mg . ( base ) and primaquine 45 mg . ( base ) at weekly intervals , whereas 8 weeks of this treatment protected all 3 men challenged with the Tay . strain from Kota Tinggi , Johore State . The Poo . strain broke through in 5 men given amodiaquine base 300 mg . and DDS 300 mg . weekly . Proguanil 200 mg . ( 2·1–3·2 mg . per kg . body weight ) given daily for 8 weeks after challenge provided complete suppression of the Poo . strain in 4 men ( and probably a fifth ) , and also of the Tay . strain in 4 men , nor did parasitaemia develop after completion of the prophylactic course . Pyrimethamine 25 mg . given weekly failed to protect 2 of 3 men challenged with Poo . , and the Tay . strain also broke through in both men receiving this regimen . A single dose of 45 mg . ( base ) of primaquine was gametocytocidal for both strains and , in one case of Poo . infection studied , rendered gametocytes non-infective to an efficient vector mosquito fed on the patient 24 hours later ABSTRACT The current interest in malaria elimination has led to a renewed interest in drugs that can be used for mass administration to minimize malaria transmission . Primaquine ( PQ ) is the only generally available drug with a strong activity against mature Plasmodium falciparum gametocytes , the parasite stage responsible for transmission . Despite concerns about PQ-induced hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals , a single dose of PQ may be safe and efficacious in clearing gametocytes that persist after conventional treatment . As part of a mass drug intervention , we determined the hemolytic effect of sulfadoxine-pyrimethamine ( SP ) plus artesunate ( AS ) plus a single dose of primaquine ( PQ ; 0.75 mg/kg of body weight ) in children aged 1 to 12 years . Children were r and omized to receive SP+AS+PQ or placebo ; those with a hemoglobin ( Hb ) level below 8 g/dl were excluded from receiving PQ and received SP+AS . The Hb concentration was significantly reduced 7 days after SP+AS+PQ treatment but not after placebo or SP+AS treatment . This reduction in Hb was most pronounced in G6PD-deficient ( G6PD A− ) individuals ( −2.5 g/dl ; 95 % confidence interval [ 95 % CI ] , −1.2 to −3.8 g/dl ) but was also observed in heterozygotes ( G6PD A ) ( −1.6 g/dl ; 95 % CI , −0.9 to −2.2 g/dl ) and individuals with the wild-type genotype ( G6PD B ) ( −0.5 g/dl ; 95 % CI , −0.4 to −0.6 g/dl ) . Moderate anemia ( Hb level of < 8 g/dl ) was observed in 40 % ( 6/15 individuals ) of the G6PD A− , 11.1 % ( 3/27 individuals ) of the G6PD A , and 4.5 % ( 18/399 individuals ) of the G6PD B individuals ; one case of severe anemia ( Hb level of < 5 g/dl ) was observed . PQ may cause moderate anemia when coadministered with artemisinins , and excluding individuals based on G6PD status alone may not be sufficient to prevent PQ-induced hemolysis ABSTRACT The activities of primaquine in combination with quinine or artesunate against asexual- and sexual-stage parasites were assessed in 176 adult Thai patients with uncomplicated Plasmodium falciparum malaria . Patients were r and omized to one of the six following 7-day oral treatment regimens : ( i ) quinine alone , ( ii ) quinine with tetracycline , ( iii ) quinine with primaquine at 15 mg/day , ( iv ) quinine with primaquine at 30 mg/day , ( v ) artesunate alone , or ( vi ) artesunate with primaquine . Clinical recovery occurred in all patients . There were no significant differences in fever clearance times , rates of P. falciparum reappearance , or recurrent vivax malaria between the six treatment groups . Patients treated with artesunate alone or in combination with primaquine had significantly shorter parasite clearance times ( mean ± st and ard deviation = 65± 18 versus 79 ± 21 h ) and lower gametocyte carriage rates ( 40 versus 62.7 % ) than those treated with quinine ( P ≤ 0.007 ) . Primaquine did not affect the therapeutic response ( P > 0.2 ) . Gametocytemia was detected in 98 patients ( 56 % [ 22 % before treatment and 34 % after treatment ] ) . Artesunate reduced the appearance of gametocytemia ( relative risk [ 95 % confidence interval ] = 0.34 [ 0.17 to 0.70 ] ) , whereas combinations containing primaquine result ed in shorter gametocyte clearance times ( medians of 66 versus 271 h for quinine groups and 73 versus 137 h for artesunate groups ; P≤ 0.038 ) . These results suggest that artesunate predominantly inhibits gametocyte development whereas primaquine accelerates gametocyte clearance in P. falciparum malaria Background Effective mass drug administration ( MDA ) with anti-malarial drugs can clear the human infectious reservoir for malaria and thereby interrupt malaria transmission . The likelihood of success of MDA depends on the intensity and seasonality of malaria transmission , the efficacy of the intervention in rapidly clearing all malaria parasite stages and the degree to which symptomatic and asymptomatic parasite carriers participate in the intervention . The impact of MDA with the gametocytocidal drug combination sulphadoxine-pyrimethamine ( SP ) plus artesunate ( AS ) plus primaquine ( PQ , single dose 0.75 mg/kg ) on malaria transmission was determined in an area of very low and seasonal malaria transmission in northern Tanzania . Methods In a cluster-r and omized trial in four villages in Lower Moshi , Tanzania , eight clusters ( 1,110 individuals ; cluster size 47- 209 ) were r and omized to observed treatment with SP+AS+PQ and eight clusters ( 2,347 individuals , cluster size 55- 737 ) to treatment with placebo over three days . Intervention and control clusters were 1 km apart ; households that were located between clusters were treated as buffer zones where all individuals received SP+AS+PQ but were not selected for the evaluation . Passive case detection was done for the entire cohort and active case detection in 149 children aged 1 - 10 year from the intervention arm and 143 from the control arm . Four cross-sectional surveys assessed parasite carriage by microscopy and molecular methods during a five-month follow-up period . Results The coverage rate in the intervention arm was 93.0 % ( 1,117/1,201 ) . Parasite prevalence by molecular detection methods was 2.2 - 2.7 % prior to the intervention and undetectable during follow-up in both the control and intervention clusters . None of the slides collected during cross-sectional surveys had microscopically detectable parasite densities . Three clinical malaria episodes occurred in the intervention ( n = 1 ) and control clusters ( n = 2 ) . Conclusions This study illustrates the possibility to achieve high coverage with a three-day intervention but also the difficulty in defining suitable outcome measures to evaluate interventions in areas of very low malaria transmission intensity . The decline in transmission intensity prior to the intervention made it impossible to assess the impact of MDA in the chosen study setting .Trial Registration Clinical Trials.gov : Background P. falciparum gametocytes may persist after treatment with sulphadoxine-pyrimethamine ( SP ) plus artesunate ( AS ) and contribute considerably to malaria transmission . We determined the efficacy of SP+AS plus a single dose of primaquine ( PQ , 0.75 mg/kg ) on clearing gametocytaemia measured by molecular methods . Methodology The study was conducted in Mnyuzi , an area of hyperendemic malaria in north-eastern Tanzania . Children aged 3–15 years with uncomplicated P. falciparum malaria with an asexual parasite density between 500–100,000 parasites/µL were r and omized to receive treatment with either SP+AS or SP+AS+PQ . P. falciparum gametocyte prevalence and density during the 42-day follow-up period were determined by real-time nucleic acid sequence-based amplification ( QT-NASBA ) . Haemoglobin levels ( Hb ) were determined to address concerns about haemolysis in G6PD-deficient individuals . Results 108 individuals were r and omized . Pfs25 QT-NASBA gametocyte prevalence was 88–91 % at enrolment and decreased afterwards for both treatment arms . Gametocyte prevalence and density were significantly lower in children treated with SP+AS+PQ . On day 14 after treatment 3.9 % ( 2/51 ) of the SP+AS+PQ treated children harboured gametocytes compared to 62.7 % ( 32/51 ) of those treated with SP+AS ( p<0.001 ) . Hb levels were reduced in the week following treatment with SP+AS+PQ and this reduction was related to G6PD deficiency . The Hb levels of all patients recovered to pre-treatment levels or greater within one month after treatment . Conclusions PQ clears su bmi croscopic gametocytes after treatment with SP+AS and the persisting gametocytes circulated at densities that are unlikely to contribute to malaria transmission . For individuals without severe anaemia , addition of a single dose of PQ to an efficacious antimalarial drug combination is a safe approach to reduce malaria transmission following treatment . Trial Registration Controlled-Trials.com IS RCT Background In areas of seasonal malaria transmission , treatment of asymptomatic carriers of malaria parasites , whose parasitaemia persists at low densities throughout the dry season , could be a useful strategy for malaria control . We carried out a r and omized trial to compare two drug regimens for clearance of parasitaemia in order to identify the optimum regimen for use in mass drug administration in the dry season . Methodology and Principal Findings A two-arm open-label r and omized controlled trial was conducted during the dry season in an area of distinct seasonal malaria in two villages in Gedarif State in eastern Sudan . Participants were asymptomatic adults and children aged over 6 months , with low-density P. falciparum infection detected by PCR . Participants were r and omized to receive artesunate/sulfadoxine-pyrimethamine ( AS+SP ) combination for three days with or without a dose of primaquine ( PQ ) on the fourth day . Parasitaemia detected by PCR on days 3 , 7 and 14 after the start of treatment and gametocytes detected by RT-PCR on days 7 and 14 were then recorded . 104 individuals who had low density parasitaemia at screening were r and omized and treated during the dry season . On day 7 , 8.3 % were positive by PCR in the AS+SP+PQ group and 6.5 % in the AS+SP group ( risk difference 1.8 % , 95%CI −10.3 % to + 13.8 % ) . At enrolment , 12 % ( 12/100 ) were carrying gametocytes . This was reduced to 6.4 % and 4.4 % by day 14 ( Risk difference 1.9 % ( 95%CI −9.3 % to + 13.2 % ) in AS+SP+PQ and AS+SP groups , respectively . Conclusion Addition of primaquine to artemisinin combination treatment did not improve elimination of parasitaemia and prevention of gametocyte carriage in carriers with low-density parasitaemia in the dry season . Trial Registration Clinical Trials.gov Background Glucose-6-phosphate dehydrogenase ( G6PD ) deficiency is common in population s living in malaria endemic areas . G6PD genotype and phenotype were determined for malaria patients enrolled in the chlorproguanil-dapsone-artesunate ( CDA ) phase III clinical trial programme . Methods Study participants , aged > 1 year , with microscopically confirmed uncomplicated Plasmodium falciparum malaria , and haemoglobin ≥ 70 g/L or haematocrit ≥ 25 % , were recruited into two clinical trials conducted in six African countries ( Burkina Faso , Ghana , Kenya , Nigeria , Tanzania , Mali ) . G6PD genotype of the three most common African forms , G6PD*B , G6PD*A ( A376 G ) , and G6PD*A- ( G202A , A542 T , G680 T and T968C ) , were determined and used for frequency estimation . G6PD phenotype was assessed qualitatively using the NADPH fluorescence test . Exploratory analyses investigated the effect of G6PD status on baseline haemoglobin concentration , temperature , asexual parasitaemia and anti-malarial efficacy after treatment with CDA 2/2.5/4 mg/kg or chlorproguanil-dapsone 2/2.5 mg/kg ( both given once daily for three days ) or six-dose artemether-lumefantrine . Results Of 2264 malaria patients enrolled , 2045 had G6PD genotype available and comprised the primary analysis population ( 1018 males , 1027 females ) . G6PD deficiency prevalence was 9.0 % ( 184/2045 ; 7.2 % [ N = 147 ] male hemizygous plus 1.8 % [ N = 37 ] female homozygous ) , 13.3 % ( 273/2045 ) of patients were heterozygous females , 77.7 % ( 1588/2045 ) were G6PD normal . All deficient G6PD*A- genotypes were A376G/G202A . G6PD phenotype was available for 64.5 % ( 1319/2045 ) of patients : 10.2 % ( 134/1319 ) were G6PD deficient , 9.6 % ( 127/1319 ) intermediate , and 80.2 % ( 1058/1319 ) normal . Phenotype test specificity in detecting hemizygous males was 70.7 % ( 70/99 ) and 48.0 % ( 12/25 ) for homozygous females . Logistic regression found no significant effect of G6PD genotype on adjusted mean baseline haemoglobin ( p = 0.154 ) , adjusted mean baseline temperature ( p = 0.9617 ) , or adjusted log mean baseline parasitaemia ( p = 0.365 ) . There was no effect of G6PD genotype ( p = 0.490 ) or phenotype ( p = 0.391 ) on the rate of malaria recrudescence , or reinfection ( p = 0.134 and p = 0.354 , respectively ) . Conclusions G6PD deficiency is common in African patients with malaria and until a reliable and simple G6PD test is available , the use of 8-aminoquinolines will remain problematic . G6PD status did not impact baseline haemoglobin , parasitaemia or temperature or the outcomes of anti-malarial therapy . Trial registration Clinical trials.gov : NCT00344006 and NCT00371735 BACKGROUND Artemisinin-combination therapy ( ACT ) is recommended as first-line treatment of falciparum malaria throughout the world , and fixed-dose combinations are preferred by WHO ; whether a single gametocytocidal dose of primaquine should be added is unknown . We aim ed to compare effectiveness of four fixed-dose ACTs and a loose tablet combination of artesunate and mefloquine , and assess the addition of a single gametocytocidal dose of primaquine . METHODS In an open-label r and omised trial in clinics in Rakhine state , Kachin state , and Shan state in Myanmar ( Burma ) between Dec 30 , 2008 , and March 20 , 2009 , we compared the effectiveness of all four WHO-recommended fixed-dose ACTs ( artesunate-mefloquine , artesunate-amodiaquine , dihydroartemisinin-piperaquine , artemether-lumefantrine ) and loose artesunate-mefloquine in Burmese adults and children . Eligible patients were those who presented to the clinics with acute uncomplicated Plasmodium falciparum malaria or mixed infection , who were older than 6 months , and who weighed more than 5 kg . Treatments were r and omised in equal numbers within blocks of 50 and allocation was in sealed envelopes . All patients were also r and omly assigned to receive either a single dose of primaquine 0·75 mg base/kg or not . Patients were followed up for 63 days . Treatment groups were compared by analysis of variance and multiple logistic regression . The primary outcome was the 63 day recrudescence rate . This study is registered with clinical trials.gov , number NCT00902811 . FINDINGS 155 patients received artesunate-amodiaquine , 162 artemether-lumefantrine , 169 artesunate-mefloquine , 161 loose artesunate-mefloquine , and 161 dihydroartemisinin-piperaquine . By day 63 of follow-up , 14 patients ( 9·4 % ; 95 % CI 5·7 - 15·3 % ) on artesunate-amodiaquine had recrudescent P falciparum infections , a rate significantly higher than for artemether-lumefantrine ( two patients ; 1·4 % ; 0·3 - 5·3 ; p=0·0013 ) , fixed-dose artesunate-mefloquine ( 0 patients ; 0 - 2·3 ; p<0·0001 ) , loose artesunate-mefloquine ( two patients ; 1·3 % ; 0·3 - 5·3 ; p=0·0018 ) , and dihydroartemisinin-piperaquine ( two patients 1·3 % ; 0·3 - 5·2 % ; p=0·0012 ) . Hazard ratios for re-infection ( 95 % CI ) after artesunate-amodiaquine were 3·2 ( 1·3 - 8·0 ) compared with the two artesunate-mefloquine groups ( p=0·01 ) , 2·6 ( 1·0 - 6 - 0 ) compared with artemether-lumefantrine ( p=0·04 ) , and 2·3 ( 0·9 - 6·0 ) compared with dihydroartemisinin-piperaquine ( p=0·08 ) . Mixed falciparum and vivax infections were common : 129 ( 16 % ) had a mixed infection at presentation and 330 ( 41 % ) patients had one or more episodes of Plasmodium vivax infection during follow-up . The addition of a single dose of primaquine ( 0·75 mg/kg ) reduced P falciparum gametocyte carriage substantially : rate ratio 11·9 ( 95 % CI 7·4 - 20·5 ) . All regimens were well tolerated . Adverse events were reported by 599 patients , most commonly vomiting and dizziness . Other side-effects were less common and were not related to a specific treatment . INTERPRETATION Artesunate-amodiaquine should not be used in Myanmar , because the other ACTs are substantially more effective . Artesunate-mefloquine provided the greatest post-treatment suppression of malaria . Adding a single dose of primaquine would substantially reduce transmission potential . Vivax malaria , not recurrent falciparum malaria , is the main complication after treatment of P falciparum infections in this region . FUNDING Médecins sans Frontières ( Holl and ) and the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme Objectives : Treatment of Plasmodium falciparum malaria with sulfadoxine-pyrimethamine ( SP ) is followed by a sharp rise in the prevalence and density of gametocytes . We did a r and omized trial to determine the effect of treatment of asymptomatic infections with SP or SP plus one dose of artesunate ( SP+AS ) on gametocyte carriage . Design : The study was a three-arm open-label r and omized trial . We r and omized asymptomatic carriers of P. falciparum to receive antimalarial treatment or placebo , and recorded the prevalence and density of gametocytes over the next 2 mo . Setting : The trial was conducted during the dry ( low malaria transmission ) season in four rural villages in Gambia . Participants : Participants were adults and children aged over 6 mo with asexual P. falciparum infection and confirmed free of clinical symptoms of malaria over a 2-d screening period . Interventions : Participants were r and omized to receive a single dose of SP or SP+AS or placebo . Outcome Measures : The outcome measures were the presence of gametocytes 7 and 56 d after treatment , and the duration and density of gametocytaemia over 2 mo . Results : In total , 372 asymptomatic carriers were r and omized . Gametocyte prevalence on day 7 was 10.5 % in the placebo group , 11.2 % in the SP group ( risk difference to placebo 0.7 % , 95 % confidence interval −7.4 % to 8.7 % , p = 0.87 ) , and 7.1 % in the SP+AS group ( risk difference to placebo 4.1 % , 95 % confidence interval −3.3 % to 12 % , p = 0.28 ) . By day 56 , gametocyte prevalence was 13 % in the placebo group and 2 % in both drug-treated groups . Gametocyte carriage ( the area under the curve of gametocyte density versus time ) , was reduced by 71 % in the SP group , and by 74 % in the SP+AS group , compared to placebo . Gametocyte carriage varied with age and was greater among children under 15 than among adults . Conclusions : Treatment of asymptomatic carriers of P. falciparum with SP does not increase gametocyte carriage or density . Effective treatment of asexual parasitaemia in the dry season reduces gametocyte carriage to very low levels after 4 wk BACKGROUND Primaquine is the only available drug that clears mature Plasmodium falciparum gametocytes in infected human hosts , thereby preventing transmission of malaria to mosquitoes . However , concerns about dose-dependent haemolysis in people with glucose-6-phosphate dehydrogenase ( G6PD ) deficiencies have limited its use . We assessed the dose-response association of single-dose primaquine for gametocyte clearance and for safety in P falciparum malaria . METHODS We undertook this r and omised , double-blind , placebo-controlled trial with four parallel groups in Jinja district , eastern Ug and a. We r and omly allocated Ug and an children aged 1 - 10 years with uncomplicated falciparum malaria and normal G6PD enzyme function to receive artemether-lumefantrine , combined with either placebo or with 0.1 mg/kg , 0.4 mg/kg , or 0.75 mg/kg ( WHO reference dose ) primaquine base . R and omisation was done with computer-generated four-digit treatment assignment codes allocated to r and om dose groups in block sizes of 16 . Study staff who provided care or assessed outcomes and the participants remained masked to the intervention group after assignment . The primary efficacy endpoint was the non-inferiority of the mean duration of gametocyte carriage in the test doses compared with the reference group of 0.75 mg primaquine per kg , with a non-inferiority margin of 2.5 days . The primary safety endpoint was the superiority of the arithmetic mean maximum decrease in haemoglobin concentration from enrolment to day 28 of follow-up in the primaquine treatment groups compared with placebo , with use of significance testing of pairwise comparisons with a cutoff of p=0.05 . The trial is registered with Clinical Trials.gov , number NCT01365598 . FINDINGS We r and omly allocated 468 participants to receive artemether-lumefantrine combined with placebo ( 119 children ) or with 0.1 mg/kg ( 116 ) , 0.4 mg/kg ( 116 ) , or 0.75 mg/kg ( 117 ) primaquine base . The mean duration of gametocyte carriage was 6.6 days ( 95 % CI 5.3 - 7.8 ) in the 0.75 mg/kg reference group , 6.3 days ( 5.1 - 7.5 ) in the 0.4 mg/kg primaquine group ( p=0.74 ) , 8.0 days ( 6.6 - 9.4 ) in the 0.1 mg/kg primaquine group ( p=0.14 ) , and 12.4 days ( 9.9 - 15.0 ) in the placebo group ( p<0.0001 ) . No children showed evidence of treatment-related haemolysis , and the mean maximum decrease in haemoglobin concentration was not associated with the dose of primaquine received-it did not differ significantly compared with placebo ( 10.7 g/L , SD 11.1 ) in the 0.1 mg/kg ( 11.4 g/L , 9.4 ; p=0.61 ) , 0.4 mg/kg ( 11.3 g/L , 10.0 ; p=0.67 ) , or 0.75 mg/kg ( 12.7 g/L , 8.2 ; p=0.11 ) primaquine groups . INTERPRETATION We conclude that 0.4 mg/kg primaquine has similar gametocytocidal efficacy to the reference 0.75 mg/kg primaquine dose , but a dose of 0.1 mg/kg was inconclusive for non-inferiority . Our findings call for the prioritisation of further trials into the efficacy and safety of doses of primaquine between 0.1 mg/kg and 0.4 mg/kg ( including the dose of 0.25 mg/kg recently recommended by WHO ) , in view of the potential for widespread use of the drug to block malaria transmission . FUNDING Wellcome Trust and the Bill & Melinda Gates Foundation Objectives For the purpose of blocking transmission of Plasmodium falciparum malaria from humans to mosquitoes , a single dose of primaquine is recommended by the WHO as an addition to artemisinin combination therapy . Primaquine clears gametocytes but causes dose-dependent haemolysis in individuals with glucose-6-phosphate dehydrogenase ( G6PD ) deficiency . Evidence is needed to inform the optimal dosing of primaquine for malaria elimination programmes and for the purpose of interrupting the spread of artemisinin-resistant malaria . This study investigates the efficacy and safety of reducing doses of primaquine for clearance of gametocytes in participants with normal G6PD status . Methods and analysis In this prospect i ve , four-armed r and omised placebo-controlled double-blinded trial , children aged 1–10 years , weighing over 10 kg , with haemoglobin ≥8 g/dl and uncomplicated P falciparum malaria are treated with artemether lumefantrine and r and omised to receive a dose of primaquine ( 0.1 , 0.4 or 0.75 mg base/kg ) or placebo on the third day of treatment . Participants are followed up for 28 days . Gametocytaemia is measured by quantitative nucleic acid sequence-based analysis on days 0 , 2 , 3 , 7 , 10 and 14 with a primary endpoint of the number of days to gametocyte clearance in each treatment arm and secondarily the area under the curve of gametocyte density over time . Analysis is for non-inferiority of efficacy compared to the reference dose , 0.75 mg base/kg . Safety is assessed by pair-wise comparisons of the arithmetic mean ( ±SD ) change in haemoglobin concentration per treatment arm and analysed for superiority to placebo and incidence of adverse events . Ethics and dissemination Approval was obtained from the ethical committees of Makerere University School of Medicine , the Ug and an National Council of Science and Technology and the London School of Hygiene and Tropical Medicine . Results These will be disseminated to inform malaria elimination policy , through peer- review ed publication and academic presentations Artemisinin-based combination therapy ( ACT ) is currently promoted as a strategy for treating both uncomplicated and severe falciparum malaria , targeting asexual blood-stage Plasmodium falciparum parasites . However , the effect of ACT on sexual-stage parasites remains controversial . To determine the clearance of sexual-stage P. falciparum parasites from 342 uncomplicated , and 217 severe , adult malaria cases , we review ed and followed peripheral blood sexual-stage parasites for 4 wk after starting ACT . All patients presented with both asexual and sexual stage parasites on admission , and were treated with artesunate-mefloquine as the st and ard regimen . The results showed that all patients were asymptomatic and negative for asexual forms before discharge from hospital . The percentages of uncomplicated malaria patients positive for gametocytes on days 3 , 7 , 14 , 21 , and 28 were 41.5 , 13.1 , 3.8 , 2.0 , and 2.0 % , while the percentages of gametocyte positive severe malaria patients on days 3 , 7 , 14 , 21 , and 28 were 33.6 , 8.2 , 2.7 , 0.9 , and 0.9 % , respectively . Although all patients were negative for asexual parasites by day 7 after completion of the artesunate-mefloquine course , gametocytemia persisted in some patients . Thus , a gametocytocidal drug , e.g. , primaquine , may be useful in combination with an artesunate-mefloquine regimen to clear gametocytes , so blocking transmission more effectively than artesunate alone , in malaria transmission areas BACKGROUND Artemisinin-based combination therapy is very effective in clearing asexual stages of malaria and reduces gametocytemia , but may not affect mature gametocytes . Primaquine is the only commercially available drug that eliminates mature gametocytes . METHODS We conducted a 2-arm , open-label , r and omized , controlled trial to evaluate the efficacy of single-dose primaquine ( 0.75 mg/kg ) following treatment with dihydroartemisinin-piperaquine ( DHP ) on Plasmodium falciparum gametocytemia , in Indonesia . Patients aged ≥5 years with uncomplicated falciparum malaria , normal glucose-6-phosphate dehydrogenase enzyme levels , and hemoglobin levels ≥8 g/dL were assigned by computerized-generating sequence to a st and ard 3-day course of DHP alone ( n = 178 ) or DHP combined with a single dose of primaquine on day 3 ( n = 171 ) . Patients were seen on days 1 , 2 , 3 , and 7 and then weekly for 42 days to assess the presence of gametocytes and asexual parasites by microscopy . Survival analysis was stratified by the presence of gametocytes on day 3 . RESULTS DHP prevented development of gametocytes in 277 patients without gametocytes on day 3 . In the gametocytemic patients ( n = 72 ) , primaquine was associated with faster gametocyte clearance ( hazard ratio = 2.42 [ 95 % confidence interval , 1.39 - 4.19 ] , P = .002 ) and reduced gametocyte densities ( P = .018 ) . The day 42 cure rate of asexual stages in the DHP + primaquine and DHP-only arms were : polymerase chain reaction ( PCR ) unadjusted , 98.7 % vs 99.4 % , respectively ; PCR adjusted , 100 % for both . Primaquine was well tolerated . CONCLUSIONS Addition of single-dose 0.75 mg/kg primaquine shortens the infectivity period of DHP-treated patients and should be considered in low-transmission regions that aim to control and ultimately eliminate falciparum malaria . Clinical Trials Registration . NCT01392014 Introduction Antimalarial resistance has led to a global policy of artemisinin-based combination therapy . Despite growing resistance chloroquine ( CQ ) remained until recently the official first-line treatment for falciparum malaria in Pakistan , with sulfadoxine-pyrimethamine ( SP ) second-line . Co-treatment with the gametocytocidal primaquine ( PQ ) is recommended for transmission control in South Asia . The relative effect of artesunate ( AS ) or primaquine , as partner drugs , on clinical outcomes and gametocyte carriage in this setting were unknown . Methods A single-blinded , r and omized trial among Afghan refugees in Pakistan compared six treatment arms : CQ ; CQ+(single-dose)PQ ; CQ+(3 d)AS ; SP ; SP+(single-dose)PQ , and SP+(3 d)AS . The objectives were to compare treatment failure rates and effect on gametocyte carriage , of CQ or SP monotherapy against the respective combinations ( PQ or AS ) . Outcomes included trophozoite and gametocyte clearance ( read by light microscopy ) , and clinical and parasitological failure . Findings A total of 308 ( 87 % ) patients completed the trial . Failure rates by day 28 were : CQ 55/68 ( 81 % ) ; CQ+AS 19/67 ( 28 % ) , SP 4/41 ( 9.8 % ) , SP+AS 1/41 ( 2.4 % ) . The addition of PQ to CQ or SP did not affect failure rates ( CQ+PQ 49/67 ( 73 % ) failed ; SP+PQ 5/33 ( 16 % ) failed ) . AS was superior to PQ at clearing gametocytes ; gametocytes were seen on d7 in 85 % of CQ , 40 % of CQ+PQ , 21 % of CQ+AS , 91 % of SP , 76 % of SP+PQ and 23 % of SP+AS treated patients . PQ was more effective at clearing older gametocyte infections whereas AS was more effective at preventing emergence of mature gametocytes , except in cases that recrudesced . Conclusions CQ is no longer appropriate by itself or in combination . These findings influenced the replacement of CQ with SP+AS for first-line treatment of uncomplicated falciparum malaria in the WHO Eastern Mediterranean Region . The threat of SP resistance remains as SP monotherapy is still common . Three day AS was superior to single-dose PQ for reducing gametocyte carriage . Trial Registration Clinical Trials.gov bold Abstract The efficacy of a single dose of 45 mg primaquine , as a gametocytocidal agent , was assessed in Mumbai , India , among adults with uncomplicated or severe Plasmodium falciparum malaria . All the patients investigated had been found gametocytaemic , with at least 56 gametocytes/μl blood , within the first 72 h of their illness . Those with uncomplicated malaria , like those with severe malaria , were r and omized to receive or not receive primaquine . All the patients were followed up for 29 days post-admission , for gametocytaemia and gametocyte viability ( as determined by exflagellation ) . Among those with uncomplicated malaria , six ( 27.3 % ) of the 22 who did not receive primaquine but only one ( 4.2 % ) of the 24 who did receive the drug , on day 4 , remained gametocytaemic on day 29 ( P < 0.05 ) . Similarly , seven ( 31.8 % ) of the 22 severe cases who did not receive primaquine but only two ( 9.5 % ) of the 21 severe cases who received the drug , on day 8 , were found gametocytaemic on day 15 ( P < 0.05 ) . While the single , 45-mg dose of primaquine recommended by the World Health Organization was effective in clearing gametocytes from the blood of > 90 % of the present cases of malaria , > 4 % of the patients with uncomplicated malaria and > 9 % of those with the severe disease continued to harbour gametocytes in their peripheral blood 29 and 15 days after taking the primaquine , respectively OBJECTIVE To evaluate the efficacy and side effects of artemether combined with primaquine in the treatment of falciparum malaria . METHODS R and omization and comparison methods were used in 121 falciparum malaria cases in the Republic of Central Africa . Sixty-one cases were treated with artemether combined with primaquine ( Group A used artemether orally , Group B used artemether intramuscularly ) . And 60 cases received single artemether ( Group C used artemether orally , Group D used artemether intramuscularly ) were taken as control . RESULTS In Group A and B the mean fever clearance time were 47.6 + /- 15.7 and 36.9 + /- 10.7 hours , clinical cure rates 84.4 % and 100 % , relapse rates 6.3 % and 3.4 % , respectively . In Group C and D the mean fever clearance time were 48.2 + /- 18.4 and 42.2 + /- 9.5 hours , clinical cure rates 90.1 % and 96.3 % , relapse rates 21.2 % and 18.5 % , respectively . Side effects in cases of all groups were mild . CONCLUSION Artemether combined with primaquine and single artemether(via both routes ) showed good therapeutic effects in falciparum malaria cases , while artemether combined with primaquine was more effective than single artemether in reducing relapes rate of malaria OBJECTIVES To study a new combination , based on dihydroartemisinin and piperaquine ( CV8 ) and atovaquone/proguanil ( Malarone ) for treatment of uncomplicated falciparum malaria in Vietnam . METHODS Vietnamese adults with falciparum malaria were allocated r and omly to treatment with dihydroartemisinin/piperaquine/trimethoprim/primaquine 256/2560/720/40 mg ( CV8 , n = 84 ) or Malarone 3000/1200 mg ( n = 81 ) , both over 3 days . Patients were followed-up for 28 days . RESULTS All patients recovered rapidly . The mean ( 95 % CI ) parasite elimination half-life of CV8 was 6.8 h ( 6.2 - 7.4 ) and of Malarone 6.5 h ( 6.1 - 6.9 ) ( P = 0.4 ) . Complete parasite clearance time was 35 ( 31 - 39 ) and 34 h ( 31 - 38 ) ( P = 0.9 ) . The 28-day cure rate was 94 % and 95 % , respectively ( odds ratio 0.84 , 95 % CI 0.18 - 3.81 ) . No significant side-effects were found . CONCLUSION CV8 and Malarone are effective combinations against multi-drug resistant falciparum malaria . CV8 has the advantage of a low price In the city of Mumbai ( formerly Bombay ) , chloroquine ( CQ ) continues to be recommended as the drug of first choice for the treatment of Plasmodium vivax and P. falciparum infections , even though > 50 % of local isolates of P. falciparum are resistant to it . Primaquine , an 8-aminoquinoline is also given to patients with falciparum malaria , in a single , 45-mg dose , to kill the gametocytes and so reduce transmission . The gametocytocidal activity of supervised primaquine ( 45 mg given on day 8) was investigated in 90 patients who had been treated with CQ . Of these , 15 were found to be CQ-sensitive patients , 61 were resistant ( 49 , eight and four considered RI , RII and RIII , respectively ) and 14 were lost before completion of the follow-up . The mean ( S.D. ) baseline gametocytaemias in the CQ-sensitive and RI-resistant cases were 665.1 ( 411.3 ) and 1537.4 (1045.5)/microliter , respectively . Despite supervised primaquine treatment , four of the 15 CQ-sensitive patients and 32 of the 49 patients found to be RI-resistant had gametocytes on day 29 . There therefore appears to be a need to review the current , gametocytocidal , primaquine-dosage schedule and to re-treat patients who remain gametocytaemic with higher doses of primaquine , as an important , transmission-blocking strategy Chloroquine combined with primaquine was evaluated for therapy of uncomplicated malaria caused by Plasmodium falciparum in nonimmune Javanese migrants to northeastern Papua , Indonesia . Subjects were r and omized to treatment with st and ard chloroquine therapy ( 25 mg/kg in 3 doses over the course of 48 hours ) with 30 mg primaquine administered daily for 28 days ( n = 25 ) or a placebo of primaquine ( n = 28 ) . The 14-day cumulative incidence of therapeutic failure was 56 % with primaquine and 79 % with placebo ( odds ratio [ OR ] , 0.35 ; 95 % confidence interval [ CI ] , 0.1 - 1.3 ; P = 0.08 ) . Primaquine administered daily created a marginally significant improvement in therapeutic efficacy at day 14 , but not at day 7 ( 20 % versus 36 % ; OR , 0.2 ; 95 % CI , 0.1 - 1.8 ; P = 0.2 ) or day 28 ( 82 % versus 93 % ; OR , 0.31 ; 95 % Cl , 0.04 - 2.1 ; P = 0.23 ) . This report corroborates studies suggesting that therapeutic doses of primaquine exert no discernible effect on parasitemia by P. falciparum Summary A triple combination of mefloquine , sulfadoxine and pyrimethamine ( MSP ) was used with primaquine for the radical treatment of falciparum malaria in Thail and . Primaquine was reported to inhibit hepatic microsomal enzymes and drug metabolism in animal and man . 23 children hospitalized in the Hospital for Tropical Diseases , Faculty of Tropical Medicine , Bangkok , Thail and , were r and omly allocated into two groups , group I received MSP equivalent to 20 mg base of mefloquine/kg body weight and group II received MSP plus primaquine ( 0.75 mg/kg ) . No statistical difference was noted for clinical response except the gametocyte clearance time was shorter in children given MSP plus primaquine ( 7±2.7 days ) than the children given MSP alone ( 21.9±4.4 days ) ( P<0.01 ) . No serious side effects were recorded in this study . The plasma sample s were obtained for kinetic calculations by HPLC in 18 children ( 11 in group I , 7 in group II ) . Mean Cmax was 7.4±5.2 h in group I and 6.6±7.0 h in group II . Mean t1/2 , Cl/f and Vd/f were 9.8±1.6 days , 0.43±0.16 ml/min/kg and 8.84±4.21 l/kg in group I , 9.3±1.4 days , 0.43±0.12 ml/min/kg and 8.91±3.00 l/kg group II , respectively . The comparison of kinetic parameters in groups I and II revealed no significant difference ( P>0.05 ) suggesting no drug interaction . These kinetic values in children given MSP suspension were considerably different to those in adult patients with shorter tmax , t1/2 and MRT . The coadministration of MSP and primaquine in children would benefit by reducing the transmission of malaria in endemic areas BACKGROUND On the western border of Thail and the efficacy of mefloquine in the treatment of falciparum malaria has declined while gametocyte carriage rates have increased , which suggests increased transmissibility of these resistant infections . We compared the following antimalarial drugs in relation to subsequent Plasmodium falciparum gametocyte carriage : mefloquine , halofantrine , quinine , and the artemisinin derivatives . METHODS Between 1990 and 1995 we assessed gametocytaemia in a series of prospect i ve studies of antimalarial drug treatment in 5193 adults and children with acute uncomplicated falciparum malaria in an area of malarious hill forest on the western border of Thail and . Weekly parasite counts from thick and thin blood films were done during the 4-week ( 1990 - 93 ) or 9-week ( 1993 - 95 ) follow-up period . Gametocyte positivity rates and person gametocyte week ( PGW ) rates were calculated to measure gametocyte carriage and transmission potential . FINDINGS In primary P falciparum infections the gametocyte carriage rate was significantly higher after treatment with mefloquine than after treatment with the artemisinin derivatives ( PGW 34.1 [ 95 % CI 25.2 - 42.9 ] vs 3.9 [ 1.9 - 5.9 ] per 1000 person weeks ; relative risk 8.0 [ 4.1 - 15.6 ] ; p<0.0001 ) . Recrudescent infections were associated with increased gametocyte carrier rates ( relative risk 2.2 [ 1.6 - 3.0 ] ; p<0.0001 ) , but retreatment with artemisinin derivatives reduced subsequent gametocyte carriage 18.5 fold [ 3.5 - 98 ] compared with mefloquine retreatment and 6.8 fold ( 3.1 - 15.1 ) compared with quinine retreatment ( p<0.001 ) . The introduction of the artemisinin derivatives in routine treatment at this study site in mid 1994 was associated with a reduction in the subsequent incidence of falciparum malaria of 47 (25 - 69)% INTERPRETATION Although environmental changes affect vector numbers , and hence malaria incidence , artemisinin derivatives were found to reduce the transmission potential of falciparum malaria . Widespread introduction of artemisinin derivatives in the treatment of falciparum malaria may prevent the spread of multidrug resistance WR 238605 is an 8-aminoquinoline drug currently under development for prophylaxis and treatment of malaria . Pre clinical studies have demonstrated that it has greater efficacy and less toxicity compared with primaquine . In this first-time-in-human r and omized , double-blind , placebo-controlled study design ed to evaluate the safety , tolerance and pharmacokinetics , WR 238605 was administered to 48 men in single oral doses ranging from four to 600 mg ( base ) . It was well tolerated , with gastrointestinal disturbances as possible side effects . Linear kinetics were demonstrated at these doses . WR 238605 has a long absorption phase and is slowly metabolized , with a tmax of 12 hr and an elimination half-life of 14 days . These safety , efficacy and pharmacokinetic properties make this drug an excellent c and i date for further testing as a prophylactic , radical curative , and terminal eradication drug BACKGROUND DB289 is the orally active prodrug of the diamidine DB75 , which was developed for the treatment of human African trypanosomiasis . METHODS We tested the safety and efficacy of DB289 for the treatment of Plasmodium vivax and acute , uncomplicated P. falciparum infections in an open-label pilot study at the Hospital for Tropical Diseases in Bangkok . Nine patients with P. vivax infections and 23 patients with P. falciparum infections were admitted and treated with 100 mg of DB289 given orally twice a day for 5 days and were followed for 28 days . Patients with P. vivax infections were also treated with primaquine on days 10 - 23 . RESULTS All patients cleared parasites by day 7 , with a mean+/-SD clearance time of 43+/-41 h. One patient with a P. vivax infection had a recurrence of parasitemia on day 9 . Of the 23 patients with P. falciparum infections , 3 had recurrences of parasitemia caused by P. vivax and 2 had recurrences of parasitemia caused by P. falciparum . In only 1 of 2 recurrences of parasitemia caused by P. falciparum were the parasites genotypically distinct from the infecting parasites the patient had at enrollment , which means there was a 96 % cure rate . CONCLUSIONS DB289 is a promising new antimalarial compound that could become an important component of new antimalarial combinations ABSTRACT Artemisinin combination therapies eliminate immature Plasmodium falciparum gametocytes but not mature gametocytes , which may persist for up to 1 month posttreatment . A single dose of primaquine , which is inexpensive and effective against mature gametocytes , could be added to further reduce the potential for posttreatment parasite transmission . Currently , we have few data regarding the effectiveness or safety of doing so . We collected data from 21 therapeutic efficacy trials of the National Antimalarial Drug Resistance Monitoring System of India conducted during 2009 to 2010 , wherein 9 sites used single-dose primaquine ( 0.75 mg/kg of body weight ) administered on day 2 along with artesunate plus sulfadoxine-pyrimethamine ( AS+SP ) while 12 did not . We estimated the effect of primaquine on posttreatment gametocyte clearance and the total number of gametocyte-weeks as determined by microscopy . We compared the median area under the curve for gametocyte density and reported adverse events . One thous and three hundred thirty-five patients completed the antimalarial drug treatment . Adjusting for region , primaquine increased the rate of gametocyte clearance ( hazard ratio , 1.9 ; 95 % confidence interval [ CI ] , 1.1 to 3.3 ) , prevented 45 % ( 95 % CI , 19 to 62 ) of posttreatment gametocyte-weeks , and decreased the area under the gametocyte density curve over the 28-day follow-up compared to AS+SP alone ( P value = 0.01 ) . The results were robust to other adjustment sets , and the estimated effect of primaquine increased during sensitivity analysis on the measurement of exposure time . No serious adverse events were detected . In conclusion , the addition of primaquine to AS+SP was effective in reducing the posttreatment presence of P. falciparum gametocytes . Primaquine was well tolerated and could be administered along with an artemisinin combination therapy as the first-line therapy INTRODUCTION The treatment of Plasmodium falciparum malaria requires a safe and effective therapeutic treatment regimen , which in turn has high impact on the transmission . In 2006 , an artesunate (AS)-mefloquine ( MQ ) treatment program was implemented in Antioquia . In addition , primaquine ( PQ ) was added to eliminate malaria gametocytes in the bloodstream . OBJECTIVE The efficacy and gametocytocidal activity was evaluated for two treatment regimens , AS-MQ-PQ and AS-MQ , in patients with uncomplicated P. falciparum malaria . MATERIAL S AND METHODS Between April 2007 and February 2008 , 50 patients were recruited for the trial in Turbo , Antioquia . A r and omized clinical trial was conducted . Treatment compliance was supervised , with a clinical and parasitological assessment on days 1 , 2 , 3 , 7 , 14 , 21 , 28 , 35 , and 42 to evaluate response rate according to the WHO 2003 protocol . RESULTS Clinical response and parasite elimination efficacy of AS-MQ ( with or without PQ ) was 100 % ( 95 % CI 86.3%-100 % ) , and parasitemia and fever were absent on day 3 of treatment in all patients . Gametocyte elimination was superior when PQ was used--92 % ( 95 % CI : 74%-99 % ) of patients who received PQ had no gametocytes on day 3 , compared to 78.3 % ( 95 % CI : 59%-93 % ) of patients who only received AS-MQ . Furthermore , circulating gametocytes were eliminated on average one week faster when the AS-MQ-PQ treatment scheme was used compared to the scheme without PQ . CONCLUSION These studies recommend the use of AS-MQ to treat P. falciparum malaria given its good therapeutic efficacy . However , further assessment is suggested concerning the benefit of adding PQ to this treatment scheme 109 ( 9.8 % ) of 1103 malaria patients examined in Sabah were deficient in glucose-6-phosphate dehydrogenase ( G6PD ) . 69 of these G6PD-deficient patients were r and omly allocated to 1 of 3 treatment regimes with chloroquine , chloroquine and primaquine , or sulfadoxine-pyrimethamine ( Fansidar ) . No hemolysis was observed in the 1st group ; except for a single mild case , no case of hemolysis was seen in the 3rd group . However , in the 2nd group of 23 patients , hemolysis occurred in 7 of 16 patients who had complete G6PD deficiency . Of these 7 , 5 required blood transfusion and the other 2 developed acute renal failure , 1 even requiring peritoneal dialysis . In the Fansidar group , 4 of 22 patients took more than 15 days to clear the parasitemia . Chloroquine resistance to falciparum infection was common in the patients given this antimalarial drug An open r and omized controlled study of mefloquine-artesunate and mefloquine-primaquine for the treatment of uncomplicated Plasmodium falciparum malaria was carried out in Kanchanaburi in the Saiyok District in western Thail and . Weekly parasite counts from thick and thin blood films were done for six weeks . The gametocyte carriage rate was calculated and compared between the two treatment groups . Gametocytes on presentation , recrudescent infection , and reinfection were the significant factors associated with subsequent development of gametocytemia . It is the increased propensity of recrudescent infections to produce gametocytes that drives drug resistance . The results of this study confirmed that the complete eradication of a sexual forms of P. falciparum by effective antimalarial treatment , but not by combination treatment with primaquine , is the most effective means to prevent subsequent gametocytemia In the treatment of human malaria , the 8-aminoquinolines , such as primaquine ( PQ ) , are unique because they exhibit activity against several stages in the life-cycle of the parasites causing the disease ( WHO , 1990 ) . The World Health Organization ( 1990 ) recommends that PQ is used as a gametocytocide against Plasmodium falciparum ( in a single , 45-mg dose ) and as a tissue schizonticide against P. vivax ( at a dose of 15 mg/day for 14 days ) . The clinical utility of PQ is limited by its haematological toxicity , however , particularly in individuals who have glucose-6-phosphate-dehydrogenase ( G6PDH ) deficiency . There is also some evidence , that , at least in India , the efficacy of a single dose of PQ in the treatment of chloroquine-sensitive P. falciparum malaria is declining ( Gogtay et al. , 1999 ) . During the last decade , attempts have been made to synthesis e newer 8-aminoquinolines or modify the basic structure of PQ to produce derivatives which have the antiparasitic activity of PQ but lower toxicity . Bulaquine ( formerly called CDRI 80/53 ) is one such compound . It differs from PQ only in having a 2,4 dihydrofuran group in the basic side chain that is anchored to the quinoline nucleus in the 8 position . In a pre clinical study using Rhesus monkeys with sporozoite-induced P. cynomolgi B malaria , bulaquine was found to be almost as effective as PQ , 100 % radical cure been achieved using 7 days of treatment with either bulaquine at 1.25 mg base/kg.day or PQ at 1 mg base/kg.day ( Dutta et al. , 1989 ) . In a subsequent 3-day test ( Puri and Dutta , 1990 ) , again using Rhesus moneys with P. cynomolgi B malaria , the doses of bulaquine needed to give causal prophylaxis ( 3.16 mg/ kg.day for 3 days ) were similar to those of PQ ( 1.78 mg/kg.day for 3 days ) . Bulaquine has been licensed for use in India — for use , at 25 mg base/day for 5 days , to prevent relapses of P. vivax malaria — since 2001 . In the present study , as there have been no published studies on the use of this drug as a gametocytocidal agent , the gametocytaemias in adult patients suffering from acute , uncomplicated , P. falciparum malaria were followed after they had been treated with quinine and either bulaquine or PQ . The study protocol was approved both by the Drugs Controller General of India and the ethics committees of the K.E.M. Hospital and Kasturba Hospital for Infectious Diseases — the institutions in Mumbai , India , where the patients were examined and treated . Written informed consent was obtained from all participating subjects . To be enrolled , a patient had to be aged > 18 years , have at least 55 P. falciparum gametocytes/μl blood ( and therefore be infective to mosquitoes ; Fleck et al. , 1996 ) in the first 72 h of admission , and have normal G6PDH status . Patients with symptoms and signs indicative of complicated malaria and those unwilling to comply with the protocol instructions ( including attending for all scheduled follow-up examinations ) were excluded . On the day of admission ( ‘ day 1 ’ ) each patient received the first of seven daily doses of quinine ( 30 mg/kg.day ) in combination with doxycycline ( 100 mg/day ; Na-Bangchang and Karbwang , 1993 ) . On day 4 , each patient was also given a single S This study compared the efficacy against Plasmodium falciparum gametocytes of four regimens : amodiaquine-sulfadoxine/pyrimethamine ( AQ-SP ) and mefloquine-artesunate ( MQ-AS ) , with and without primaquine ( PQ ) administered with the second dose of the schizonticide ( AQ-SP ; AQ-SP-PQ ; MQ-AS ; MQ-AS-PQ ) . Efficacy was determined by thick smear on days 1 , 4 and 8 after the beginning of treatment . A total of 82 patients ( 19 - 23/group ) were recruited . After AQ-SP administration , gametocytemia steadily increased until day 8 . With AQ-SP-PQ , a marked decline in gametocytemia was detected on days 4 and 8 . MQ-AS treatment result ed in reduced gametocytemia on days 4 and 8 , and with MQ-AS-PQ it was reduced even further . None of the treatments cleared gametocytemia by day 8 . Currently , artemisinin-based combination therapies plus PQ are the recommended treatment option against falciparum malaria ; however , further studies are required to optimize the use of PQ . Issues to be addressed include the optimal time of administration , treatment duration , optimal daily and total dose , and day of evaluation of the gametocytocidal effect . In falciparum malaria , the WHO recommends a maximum of 4days of treatment ; consequently , an effective regimen must clear asexual parasites and symptoms within this time frame . The same criteria should be taken into account when evaluating the anti-gametocyte activity Introduction In the era of malaria elimination and eradication , drug-based and vaccine-based approaches to reduce malaria transmission are receiving greater attention . Such interventions require assays that reliably measure the transmission of Plasmodium from humans to Anopheles mosquitoes . Methods We compared two commonly used mosquito feeding assay procedures : direct skin feeding assays and membrane feeding assays . Three conditions under which membrane feeding assays are performed were examined : assays with i ) whole blood , ii ) blood pellets resuspended with autologous plasma of the gametocyte carrier , and iii ) blood pellets resuspended with heterologous control serum . Results 930 transmission experiments from Cameroon , The Gambia , Mali and Senegal were included in the analyses . Direct skin feeding assays result ed in higher mosquito infection rates compared to membrane feeding assays ( odds ratio 2.39 , 95 % confidence interval 1.94–2.95 ) with evident heterogeneity between studies . Mosquito infection rates in membrane feeding assays and direct skin feeding assays were strongly correlated ( p<0.0001 ) . Replacing the plasma of the gametocyte donor with malaria naïve control serum result ed in higher mosquito infection rates compared to own plasma ( OR 1.92 , 95 % CI 1.68–2.19 ) while the infectiousness of gametocytes may be reduced during the replacement procedure ( OR 0.60 , 95 % CI 0.52–0.70 ) . Conclusions Despite a higher efficiency of direct skin feeding assays , membrane feeding assays appear suitable tools to compare the infectiousness between individuals and to evaluate transmission-reducing interventions . Several aspects of membrane feeding procedures currently lack st and ardization ; this variability makes comparisons between laboratories challenging and should be addressed to facilitate future testing of transmission-reducing interventions |
1,926 | 30,235,574 | Limited evidence regarding a correlation between palatability and treatment adherence in pediatric patients was identified | Background : Palatability and swallowability of oral dosage forms are important considerations in the development of medications for pediatric population s. As a result of recent legislation , the number of pharmaceutical products being developed with formulations for children is increasing .
However , there are limited recommendations and published literature regarding appropriate palatability and swallowability assessment scales in pediatric patients .
Objective : This systematic literature review aim ed to identify and evaluate tools currently utilized to assess palatability and swallowability in clinical trials for pediatric oral dosage forms and identify any potential relationships between palatability and treatment adherence .
However , based on results of this review , palatability is often assessed in clinical trials of pediatric dosage forms through the utilization of 2 unvali date d , yet widely accepted , visual scales . | Purpose Sunitinib is an oral tyrosine kinase inhibitor of VEGF , PDGF , c-KIT , and flt-3 receptors . A pediatric phase I study of sunitinib capsules identified the maximum tolerated dose as 15 mg/m2/day . This study was conducted to evaluate sunitinib given as a powder formulation . Methods Sunitinib 15 mg/m2 was administered orally daily for 4 weeks on/2 weeks off to patients < 21 years old with refractory solid tumors . Sunitinib capsules were opened , and the powder sprinkled onto applesauce or yogurt . Plasma levels of sunitinib and an active metabolite , SU12662 , were measured , and pharmacokinetic parameters were estimated . Results 12 patients , median age 13 ( range 4–21 ) years , were treated . The most common first-cycle toxicities were leucopenia ( n = 6 ) , fatigue ( n = 5 ) , neutropenia ( n = 4 ) , and hypertension ( n = 4 ) . Three patients had dose-limiting toxicities ( DLTs ) in cycle 1 ( dizziness/back pain , h and –foot syndrome , and intratumoral hemorrhage/hypoxia ) . A median peak plasma sunitinib concentration of 21 ( range 6–36 ) ng/ml was reached at a median of 4 ( range 4–8 ) h after the first dose . The median exposure ( AUC0–48 ) was 585 ( range 196–1,059 ) h ng/l . The median half-life was 23 ( range 13–36 ) h. The median trough concentration measured before day 14 dosing was 32 ( range 12–58 ) ng/ml . Conclusions The pharmacokinetic profile of sunitinib appears similar between a powder formulation and published data using capsules . The powder formulation allows patients unable to swallow capsules to receive sunitinib ABSTRACT Two multicenter , open-label , single-arm , two-phase studies evaluated single-dose pharmacokinetics and single- and multiple-dose safety of a pediatric oral famciclovir formulation ( prodrug of penciclovir ) in children aged 1 to 12 years with suspicion or evidence of herpes simplex virus ( HSV ) or varicella-zoster virus ( VZV ) infection . Pooled pharmacokinetic data were generated after single doses in 51 participants ( ∼12.5 mg/kg of body weight [ BW ] for children weighing < 40 kg and 500 mg for children weighing ≥40 kg ) . The average systemic exposure to penciclovir was similar ( 6- to 12-year-olds ) or slightly lower ( 1- to < 6-year-olds ) than that in adults receiving a 500-mg dose of famciclovir ( historical data ) . The apparent clearance of penciclovir increased with BW in a nonlinear manner , proportional to BW0.696 . An eight-step weight-based dosing regimen was developed to optimize exposure in smaller children and was used in the 7-day multiple-dose safety phases of both studies , which enrolled 100 patients with confirmed/suspected viral infections . Twenty-six of 47 ( 55.3 % ) HSV-infected patients who received famciclovir twice a day and 24 of 53 ( 45.3 % ) VZV-infected patients who received famciclovir three times a day experienced at least one adverse event . Most adverse events were gastrointestinal in nature . Exploratory analysis following 7-day famciclovir dosing regimen showed resolution of symptoms in most children with active HSV ( 19/21 [ 90.5 % ] ) or VZV disease ( 49/53 [ 92.5 % ] ) . Famciclovir formulation ( sprinkle capsules in OraSweet ) was acceptable to participants /caregivers . In summary , we present a weight-adjusted dosing schedule for children that achieves systemic exposures similar to those for adults given the 500-mg dose Background Efforts to ease administration and enhance acceptability of the oral anti-malarial artemether-lumefantrine ( A-L ) crushed tablet to infants and children triggered the development of a novel dispersible tablet of A-L. During early development of this new formulation , two studies were performed in healthy subjects , one to evaluate the palatability of three flavours of A-L , and a second one to compare the bioavailability of active principles between the dispersible tablet and the tablet ( administered crushed and intact ) . Methods Study 1 was performed in 48 healthy schoolchildren in Tanzania . Within 1 day , all subjects tasted a strawberry- , orange- and cherry-flavoured oral A-L suspension for 10 seconds ( without swallowing ) in a r and omized , single-blind , crossover fashion . The palatability of each formulation was rated using a visual analogue scale ( VAS ) . Study 2 was an open , r and omized crossover trial in 48 healthy adults given single doses of A-L ( 80 mg artemether + 480 mg lumefantrine ) with food . The objectives were to compare the bioavailability of artemether , dihydroartemisinin ( DHA ) and lumefantrine between the dispersible tablet and the tablet administered crushed ( primary objective ) and intact ( secondary objective ) . Results Study 1 showed no statistically significant difference in VAS scores between the three flavours but cherry had the highest score in several ratings ( particularly for overall liking ) . Study 2 demonstrated that the dispersible and crushed tablets delivered bioequivalent artemether , DHA and lumefantrine systemic exposure ( area under the curve [ AUC ] ) ; mean ± SD AUC0-tlast were 208 ± 113 vs 195 ± 93 h.ng/ml for artemether , 206 ± 81 vs 199 ± 84 h.ng/ml for DHA and 262 ± 107 vs 291 ± 106 h.μg/ml for lumefantrine . Bioequivalence was also shown for peak plasma concentrations ( Cmax ) of DHA and lumefantrine . Compared with the intact tablet , the dispersible tablet result ed in bioequivalent lumefantrine exposure , but AUC and Cmax values of artemether and DHA were 20 - 35 % lower . Conclusions Considering that cherry was the preferred flavour , and that the novel A-L dispersible tablet demonstrated similar pharmacokinetic performances to the tablet administered crushed , a cherry-flavoured A-L dispersible tablet formulation was selected for further development and testing in a large efficacy and safety study in African children with malaria The aim of this work was to develop indinavir pediatric anti-HIV/AIDS formulations enabling convenient dose adjustment , ease of oral administration , and improved organoleptic properties by means of the generation of drug-loaded microparticles made of a polymer that is insoluble under intake conditions and dissolves fast in the stomach in order to completely release the active agent . Indinavir-loaded microparticles made of a pH-dependent polymeric excipient soluble at pH < 5 , Eudragit E100 , were prepared using a double emulsion solvent diffusion technique and the in vitro release profiles characterized . Finally , taste masking properties were evaluated in blind r and omized sensory experiments by ten healthy human volunteers . The use of a w/o/o emulsion system result ed in indinavir loads around 90 % . Thermal analysis of the microparticles by differential scanning calorimetry revealed that indinavir appeared mainly dispersed at the molecular level . Concentrations of residual organic solvents as determined by gas chromatography were below the upper limits specified by the European Pharmacopeia for pharmaceutical oral formulations . Then , the behavior of drug-containing microparticles in aqueous media at different pH values was assessed . While they selectively dissolved in gastric-like medium , in tap water ( intake conditions ) , the matrix remained almost unchanged and efficiently prevented drug dissolution . Finally , sensoring taste tests performed by volunteers indicated that systems with indinavir loads ∼15 % displayed acceptable taste . This work explored the production of indinavir-containing microparticles based on a common pharmaceutical excipient as a means for the improvement of medicines of drugs involved in the treatment of HIV/AIDS . For systems containing about 15 % drug , taste studies confirmed the acceptability of the formulation . In pediatric regimes , this composition would require an acceptable amount of formulation ( 0.7–1.5 g ) Verrotti A , Nanni G , Agostinelli S , Tozzi Alleva E , Aloisi P , Franzoni E , Spalice A , Chiarelli F , Coppola G. Effects of the abrupt switch from solution to modified‐release granule formulation of valproate . Acta Neurol Sc and : 2012 : 125 : e14–e18 . © 2011 John Wiley & Sons Abstract Objectives : Traditional Chinese medicine ( TCM ) is popular as an alternative medicine in children with atopic dermatitis ( AD ) . A concoction of five herbs in a capsular preparation has been confirmed to be efficacious in improving the quality of life and sparing topical corticosteroid usage . We evaluated the clinical efficacy and tolerability of the same concoction in syrup form . Methods : This was a prospect i ve self-controlled trial set in the pediatric dermatology clinic of a teaching hospital . Children aged 4–7 years with moderate-to-severe AD received 20 ml of TCM syrup daily . Clinical parameters and laboratory markers were measured before and at 2 weeks , 7 weeks and 12 weeks of treatment , and at 4 weeks after completion . Disease severity was evaluated by the SCORing Atopic Dermatitis ( SCORAD ) index and quality of life by the Children 's Dermatology Life Quality Index ( CDLQI ) . Blood was obtained for a complete blood count , total IgE , eosinophil count , and biochemical studies prior to and after 3 months of TCM usage . Results : Twenty-two patients participated in the study . There were significant improvements in the objective SCORAD , pruritus and CDLQI scores 4 weeks after study completion . There was no change in sleep score or amount of topical steroid consumption . No biochemical evidence of any adverse drug reaction was observed during the study period . The TCM syrup was generally palatable and well tolerated by the children . Adverse effects were generally mild but two patients with rash withdrew during the study . Conclusion : The palatability means that further evaluations and dosage studies of the concoction will be possible in young children BACKGROUND Palatability is an important factor in medication compliance for children where the acceptability of a liquid medication and its ease of administration will be greatly affected by its taste . OBJECTIVES The objective of this study was to determine which , if any of two steroid preparations , oral dexamethasone or oral prednisolone , was more palatable to children requiring steroid treatment for asthma . METHODS A single-blind taste test of 2 different steroid suspensions , liquid prednisolone ( 1mg/ml ) versus liquid dexamethasone ( 1mg/ml ) , was conducted in children aged 5 - 12 years , presenting to the pediatric emergency department with an exacerbation of asthma requiring steroid treatment . Children received 2.5mls of either prednisolone or dexamethasone and were asked to score their impression of taste on a 10 cm visual analog scale . After cleansing of the palate they were given the other steroid and scored its taste . RESULTS Thirty-nine children ( 54 % male ) were enrolled in the study . The mean age was 7.1 years ( SD=2.0 ) . The median visual analog scale measurement for dexamethasone was 8.2 cm ( IQR= 5.2 ) whilst the median measurement for prednisolone was 5.0 cm ( IQR= 7.3 ) , p=0.03 . Male children were more likely to prefer dexamethasone than females with a median score of 9.9 cm ( IQR=3.8 ) for males vs. 5.9 cm ( IQR=9.3 ) for females , p=0.005 . There was no gender preference for prednisolone . CONCLUSIONS There was a statistically significant difference between the taste of dexamethasone and prednisolone , with dexamethasone being the preferred steroid among pediatric patients with asthma . Males were much more likely to prefer dexamethasone than females BACKGROUND Deferasirox is a once-daily , oral iron chelator that was developed out of a need for a long-acting , conveniently-administered chelator for patients with transfusional hemosiderosis . The approved mode of administration requires taking deferasirox on an empty stomach with water , apple juice , or orange juice to limit variation in bioavailability . This required administration schedule might not be palatable for patients . Additionally , approximately one-quarter of patients experience mild to moderate gastrointestinal ( GI ) symptoms , which may pose additional challenges , particularly in the younger and older age ranges . We present a trial to assess the palatability and safety of various administration modes of deferasirox in pediatric and adult patients . PROCEDURES Participants rated palatability in a 4-week run-in phase , where deferasirox was administered per label . Subsequently , patients rated several administration modes during a 3-month assessment phase . RESULTS Palatability was more favorable during the assessment phase , with 47 % of patient ratings for palatability being favorable while only 38 % were favorable during the run-in phase . The most highly rated choice was deferasirox taken with a soft food at breakfast . In addition , there was an indication of improved GI tolerability during the assessment phase ( symptoms were reported in 37 % of patients during run-in and 32 % during the assessment phase ; rates of diarrhea decreased significantly ) . Although trough PK values increased , no major new toxicities were observed . CONCLUSIONS These data indicate that different administration options may improve palatability and GI tolerability , which could have a positive impact on treatment adherence . ( Clinical Trials.gov number , NCT00845871 Background : The pharmacokinetics of rabeprazole after a single oral dose and once-daily administration for 5 consecutive days was characterized in children 1 to 11 years old with gastroesophageal reflux disease ( GERD ) . Patients and Methods : The initial 8 patients received rabeprazole sodium ( hereafter referred to as rabeprazole ) 0.14 mg/kg ( part 1 ) ; the next 20 patients were r and omized to receive 0.5 or 1 mg/kg ( part 2 ) to target concentrations in plasma expected to be safe and effective . Pharmacokinetic parameters of rabeprazole and the thioether metabolite were calculated using noncompartmental methods . Subjective evaluations of GERD severity , rabeprazole short-term effectiveness , palatability , and safety were also characterized . Results : Rabeprazole concentrations increased in a dose-dependent manner . Little or no accumulation was observed after repeated administration . The results suggest that formation of the thioether is an important metabolic pathway in young patients , which is consistent with adults . Plasma area under the concentration-time curve values of rabeprazole and the metabolite were poorly correlated with individual age and body weight . Furthermore , oral rabeprazole clearance values ( not adjusted for weight ) were similar to historical adult data . However , weight-adjusted values were higher for the pediatric patients , and approximately 2 to 3 times the milligram per kilogram dose of rabeprazole in these children was necessary to achieve comparable concentrations in adults . Subjective evaluations demonstrated an improvement of GERD symptoms in most patients after rabeprazole treatment . Conclusions : Palatability of the formulation was reported to be good or excellent . Rabeprazole was well tolerated , with no notable differences in safety among the dose groups Objectives : To develop an oral solid dosage form of levamisole suitable for the paediatric population in terms of dose accuracy , palatability , stability and ease of administration . Methods : Small undividable tablets ( Ø5 – 8 mm ) in four different strengths were manufactured to allow for flexible and accurate dosing . In vitro dissolution testing was used to determine drug release in different media . The bitter taste of levamisole was masked using a film-coat and assessed in healthy volunteers . Suitability and acceptability of the tablets were evaluated in 100 patients with nephrotic syndrome aged 2 – 18 years participating in a double blind , placebo-controlled , r and omised trial . Results : All tablet strengths showed good taste-masking characteristics and similar , pH independent , dissolution profiles . Successful taste masking was achieved without affecting the dissolution rate . In a total of 100 paediatric patients , more than 20,000 levamisole tablets were swallowed without any difficulties , choking or aspiration . Conclusion : The formulated tablets were found to be suitable for children aged 2 – 18 years and to provide good dose accuracy PURPOSE To assess incidence , indicators and outcome of satisfaction with antiepileptic drugs in children . METHODS Multicenter , observational , open , prospect i ve survey of children and adolescents with epilepsy with three-month follow-up . Included were patients aged 3 - 17 years with newly diagnosed ( " new diagnosis " ) or chronic epilepsy ( " old diagnosis " ) requiring treatment start or change . Satisfaction was assessed with the Hedonic Visual Scale or direct questions , depending on patient 's age . Quality of life of adolescents ( QOLIE-48 ) and of caregivers ( SF-36 ) and predictors of (dis)satisfaction were also assessed . RESULTS 293 patients completed the study . Most had generalized idiopathic epilepsy , and a disease lasting < 12 months . Newly diagnosed patients were 60.8 % . Patients declaring satisfaction were 70.6 % at one month and 75.8 % at three months . Compared to old diagnosis , new diagnosis carried a higher satisfaction rate and improved satisfaction at end of follow-up . Independent predictors of dissatisfaction were an old diagnosis , adverse events and SF-36 score . The latter remained the only independent predictor of persisting dissatisfaction when adjusting for the presence of and the interaction with adverse events . CONCLUSIONS About one-fourth of children and adolescents with epilepsy are dissatisfied with treatment . Chronic epilepsy , adverse events , and parents/caregivers with poor quality of life predict dissatisfaction UNLABELLED Children with uncomplicated malaria are generally treated with oral medication , except those unable to take oral drugs . Even though quinine has shown to be effective in treatment of African children with uncomplicated malaria its high bitterness limited the paediatric use . This study aim ed to develop taste-masked quinine tablets suitable for children and offering dosing flexibility to adjust the quinine dose in function of body weight . METHODS Insoluble quinine pamoate was used to formulate fast-disintegrating tablets , using a specific tablet design ( rectangular tablet which can be divided into 8 subunits ) to allow dosing flexibility . The physical properties of tablets were evaluated in vitro , as well as the quinine bioavailability in healthy adults ( n=18 ) and the efficacy for treatment of children with uncomplicated Plasmodium falciparum malaria ( n=56 ) using a 7-day regimen of 8 mg quinine/kg . RESULTS Quinine pamoate tablets complied with the pharmacopoeial requirements for mass uniformity , friability , content uniformity , breakability , disintegration and dissolution . The quinine pharmacokinetic parameters after single administration of a quinine pamoate tablet were similar to a commercially available quinine sulfate tablet . The fast decline in parasitemia ( 28.6%/24h ) , the reduction rate of fever ( all children were apyretic after 72 h ) and the steady state quinine plasma concentration ( 5.7 - 15.8 microg/ml ) proved the efficacy of the quinine pamoate tablets against P. falciparum . CONCLUSION Fast-dispersible and taste-masked quinine pamoate tablets improved dosing accuracy , allowed easy administration and result ed in a high efficacy during the treatment of children with uncomplicated malaria Background : Pancreatic enzyme replacement therapy ( PERT ) improves nutritional status and growth in patients with cystic fibrosis ( CF ) with pancreatic insufficiency ( PI ) . The current recommendation for infants and young children , who are not able to swallow the whole capsule , is to open the capsule and mix the beads in a spoon with some applesauce ; however , the efficacy and safety data of this approach are currently lacking . The aim of this study was to assess the efficacy , palatability ( ease of swallowing ) , and safety of 4 dose levels of pancrelipase microtablets ( Pancrease MT ) in infants and young children with CF-related PI . Patients and Methods : This study was a phase II r and omized , investigator-blinded , parallel-group pilot study in DNA-proven infants with CF and PI . The study design included a run-in period ( days 1–5 ) and an experimental period ( days 6–11 ) . Pancrelipase microtablets ( 2-mm , enteric coated ) were provided orally . Sixteen subjects , 6 to 30 months of age , were provided 500 U lipase/kg/meal for 5 days ( baseline period ) . Subsequently , subjects were r and omly assigned to 1 of 4 treatment groups ( each n = 4 ) , receiving 500 , 1000 , 1500 , or 2000 U ( Ph . EUR ) of lipase/kg/meal , respectively , for 5 days ( experimental period ) . The primary endpoint was medication efficacy assessed by the 72-hour fecal fat excretion , expressed as coefficient of fecal fat absorption ( CFA ) , and 13C mixed triglyceride breath test . Secondary endpoints were safety and palatability . Results : Overall compliance , defined as used study medication , was 89 % to 99 % for the entire study . None of the 4 dose regimens significantly influenced the CFA , relative to the baseline period ( median range 83%–93 % ) . During the run-in period the median cumulative % 13C was 11 ( range −8 to 59 ) . After r and omization the median cumulative % 13C was 18 ( range 14–23 ) in the 500-U , 14 ( range −1 to 17 ) in the 1000-U , 10 ( range 10–27 ) in the 1500-U , and 3 ( range 1–49 ) in the 2000-U groups . Palatability was scored fair to good by the parents in each of the treatment groups . Gastrointestinal symptoms were reported in some patients , including common adverse events reported in clinical trials involving pancreatic enzyme therapy . No serious or other adverse events were reported . Conclusion : Treatment with Pancrease MT at a dosage of 500 U lipase/kg/meal result ed in a CFA of approximately 89 % in pediatric subjects ages 6 to 30 months with PI result ing from CF . Pancrease MT doses were well tolerated and mean palatability was scored as fair to good . Present results do not indicate that a dosage higher than 500 U ( Ph . EUR ) lipase/kg/meal increases the coefficient of fat absorption in a cohort of infants 6 to 30 months of age AIM This study examined children 's opinions on the taste of three analgesic medicines : paracetamol , ibuprofen and codeine . BACKGROUND Many medicines for children are unpleasant and unacceptable . Research has shown that children 's taste preferences differ to adults , in whom palatability is often tested . Little British research exists on children 's opinions on the palatability of medicines . This study aim ed to address this gap in knowledge . DESIGN Prospect i ve observational study . METHODS Between May-September 2008 , hospital in patients aged 5 - 16 years rated the taste of required analgesics on a 100-mm visual analogue scale . This incorporated a 5-point facial hedonic scale . They were also asked their favourite flavour and colour for a medicine . RESULTS A total of 159 children took part . Eighty-five males ( 53·5 % ) and 74 females ( 46·5 % ) . The median age was 8 years ( Inter-quartile range 6 - 11 ) . The taste of ibuprofen was significantly preferred to paracetamol or codeine . Significant differences were observed depending if the medicine rated was taken first or second ( for example pre-medication with paracetamol and ibuprofen ) . Younger children ( 5 - 8 years ) were more likely to choose the extremes of the scale when grading than older children were . Preferred flavours on question ing were strawberry 44 % and banana 17 % . Favourite colours were pink 25·8 % and red 20·8 % , with girls more likely to choose pink and boys blue . CONCLUSION Ibuprofen was the most palatable analgesic medicine tested . Children reported they preferred fruit flavours and colour was sex dependent . Nurses when administering two medicines together should consider giving the least palatable first , for example paracetamol before ibuprofen for pre-medication Objective Unlicensed liquid captopril formulations are commonly used to treat children with heart disease . This study assessed the bioequivalence of two liquid preparations against a licensed tablet form . Design An open label , single dose , three-treatment , three-period , crossover trial . Setting Outpatient . Patients Healthy adult volunteers ( n=18 ) . Interventions Each subject was r and omly assigned to one of six dosing sequences , and dosed with 25 mg captopril on each of three dosing visits separated by a washout of at least 14 days . Blood sample s for pharmacokinetic analysis were taken at regular intervals ( 0 min to 10 h ) post-dose . Main outcome measures Bioequivalence of the formulations would be concluded if the 90 % CI for the estimated ratio of the means of Cmax ( maximum plasma concentrations ) and area under curve(AUC ) ( extent of absorption ) lay entirely within the range 0.8 to 1.25 Results Both liquid formulations failed the bioequivalence assessment with respect to Cmax and AUC . The 90 % CI of the mean ratios of liquid/licensed tablet for both Cmax and AUC , fell outside the 0.8 to 1.25 limits . There was also considerable within-subject variability in Cmax ( 97.5 % ) and AUC ( 78.5 % ) . Conclusions Unlicensed captopril formulations are not bioequivalent to the licensed tablet form , or to each other , and so can not be assumed to behave similarly in therapeutic use . Thus formulation substitution must be done with care and may require a period of increased monitoring of the patient . There is also significant within-subject variability in performance which has clinical implication s with respect to titrating to an optimum therapeutic dose Objective To explore the acceptance of uncoated drug-free mini-tablets 2 mm in diameter in children aged 0.5–6 years and their ability to swallow the mini-tablets . Methods 60 children aged 0.5–6 years ( 10 subjects per year of life ) were enrolled in our prospect i ve , open r and om , two-way cross-over exploratory pilot study . The children were administered either an uncoated drug-free mini-tablet 2 mm in diameter with a beverage of their choice or 3 ml of glucose syrup 15 % followed by the other formulation . Deglutition was visually assessed for the two different dosage forms using a predefined criteria list . Results The study hypothesis was that children would accept the liquid formulation better than the solid mini-tablets . Surprisingly , the authors found that the acceptance of the mini-tablets , defined as immediate swallowing or chewing first with subsequent swallowing , was higher or at least equal to that of the syrup . Very young children ( 6–12 months ) were fully capable of swallowing the mini-tablets and may even accept them better than the sweet liquid formulation . Some children aged between 2 and 4 years chewed the tablets before swallowing , but still accepted them quite well . The acceptance rate of the mini-tablets in the different age groups was much higher than expected . Conclusions Uncoated mini-tablets seem to be a very promising alternative to liquid formulations and could be used at an earlier age in paediatric drug therapy than previously anticipated |
1,927 | 30,794,145 | Based on several large , multicenter studies , there was a trend toward a higher frequency of limitation of LST over time .
However , there is large variability between ICUs in the proportion of patients with limitations and on the proportion of deaths preceded by a limitation .
Increases in the frequency of limitations of LST over time suggests changing attitudes about aggressive end-of-life-care .
Limitations are more common for patients with worse premorbid health and greater ICU illness severity .
While some differences in the frequency of limitations of LST may be explained by personal factors such as race , there is unexplained wide variability between units | When life-sustaining treatments ( LST ) are no longer effective or consistent with patient preferences , limitations may be set so that LSTs are withdrawn or withheld from the patient .
Many studies have examined the frequency of limitations of LST in intensive care unit ( ICU ) setting s in the past 30 years .
This systematic review describes variation and patient characteristics associated with limitations of LST in critically ill patients in all types of ICUs in the United States . | Objectives : Withdrawal of life-sustaining therapy may lead to premature limitations of life-saving treatments among patients with intracranial hemorrhage , representing a self-fulfilling prophecy . We aim ed to determine whether our algorithm for the withdrawal of life-sustaining therapy decision would accurately identify patients with a high probability of poor outcome , despite aggressive treatment . Design : Retrospective analysis of prospect ively collected data . Setting : Tertiary-care Neuro-ICU . Patients : Intraparenchymal , subdural , and subarachnoid hemorrhage patients . Interventions : Baseline demographics , clinical status , and hospital course were assessed to determine the predictors of in-hospital mortality and 12-month death/severe disability among patients receiving maximal therapy . Multivariable logistic regression models developed on maximal therapy patients were applied to patients who underwent withdrawal of life-sustaining therapy to predict their probable outcome had they continued maximal treatment . A validation cohort of propensity score – matched patients was identified from the maximal therapy cohort , and their predicted and actual outcomes compared . Measurements and Main Results : Of 383 patients enrolled , there were 128 subarachnoid hemorrhage ( 33.4 % ) , 134 subdural hematoma ( 35.0 % ) , and 121 intraparenchymal hemorrhage ( 31.6 % ) . Twenty-six patients ( 6.8 % ) underwent withdrawal of life-sustaining therapy and died , 41 ( 10.7 % ) continued maximal therapy and died in hospital , and 316 ( 82.5 % ) continued maximal therapy and survived to discharge . The median predicted probability of in-hospital death among withdrawal of life-sustaining therapy patients was 35 % had they continued maximal therapy , whereas the median predicted probability of 12-month death/severe disability was 98 % . In the propensity-matched validation cohort , 16 of 20 patients had greater than or equal to 80 % predicted probability of death/severe disability at 12 months , matching the observed outcomes and supporting the strength and validity of our prediction models . Conclusions : The withdrawal of life-sustaining therapy decision may contribute to premature in-hospital death in some patients who may otherwise have been expected to survive to discharge . However , based on probability models , nearly all of the patients who underwent withdrawal of life-sustaining therapy would have died or remained severely disabled at 12 months had maximal therapy been continued . Withdrawal of life-sustaining therapy may not represent a self-fulfilling prophecy Objective : To study the impact of neurologic prognostication on the decision to withdraw life-sustaining therapies ( LST ) in comatose patients resuscitated after cardiac arrest . Methods : The authors prospect ively studied a consecutive series of post-resuscitation comatose patients referred for neurologic prognostication at a single center for 4 years . For most patients , neurologic prognostication was not sought due to early death or rapid return to consciousness . Prognostication was based on Glasgow Coma Score ( GCS ) and Brainstem Reflex Score ( BRS ) , with EEG and cortical evoked potentials ( CEP ) , which were grade d as benign , uncertain , and malignant . The outcomes were as follows : survivors ( Group S ) , brain or cardiac death ( Group D ) , and death from withdrawal of life sustaining therapy ( Group W ) . In Group W , the time interval to withdrawal of LST was analyzed by EEG and CEP grade s. Results : Of 58 patients studied , 10 were in Group S , 8 in Group D , and 40 in Group W. Initial median GCS and BRS was similar for all groups with significant improvement noted in Group S , but not in Group D or Group W. In Group W , CEP grade correlated with the median duration of continued therapy before a decision to withdraw LST : 7 days for benign CEP , 2 days for uncertain CEP , and 1 day for malignant CEP , p = 0.0004 . Conclusion : In patients with poor neurologic recovery early after resuscitation from cardiac arrest , physicians appear to use the cortical evoked potential grade to estimate prognosis . Cortical evoked potential grade correlated with the waiting time until life sustaining therapies were withdrawn after no improvement in neurologic examination was seen Background Prognostication of mortality or severe disability often prompts withdrawal of technological life support in patients following aneurysmal subarachnoid hemorrhage ( aSAH ) . We assessed admission factors impacting decisions to withdraw treatment after aSAH . Methods Prospect ively collected data of aSAH patients admitted to our institution between 1991 and 2009 were review ed . Patients given comfort care measures were identified , including early withdrawal of treatment ( < 72 h after admission ) . Independent predictors of treatment withdrawal were assessed with multivariable analysis . Results The study included 1,134 patients , of whom 72 % were female , 58 % white , and 38 % black or African-American . Mean age was 52.5 ± 14.0 years . In-hospital mortality was 18.3 % . Of the 207 patients who died , treatment was withdrawn in 72 ( 35 % ) and comfort measures instituted early in 31 ( 15 % ) . Among patients who died , WOLST was associated with older age ( 63.6 ± 14.2 years , WOLST vs. 55.6 ± 13.7 years , no WOLST , p < 0.001 ) ; GCS score < 8 ( 62 % of WOLST vs. 44 % with no WOLST , p = 0.010 ) ; HH > 3 ( 72 % of WOLST vs. 53 % with no WOLST , p = 0.008 ) ; and hydrocephalus ( 81 % of WOLST vs. 63 % with no WOLST , p = 0.009 ) . Independent predictors of WOLST were poorer Hunt and Hess grade ( AOR 1.520 , 95 % CI 1.160–1.992 , p = 0.002 ) and older age ( AOR 1.045 , 95 % CI 1.022–1.068 , p < 0.001 ) with the latter also impacting early WOLST decisions . Conclusions Older age and poor clinical grade on presentation predicted WOLST , and age predicted decisions to withdraw treatment earlier following aSAH . While based on prognosis , and in some cases patient wishes , this may also constitute a self-fulfilling prophecy in others Objective : Many intensive care unit ( ICU ) physicians have withdrawn life-support from a patient who lacked decision-making capacity and a surrogate decision-maker , yet little is known about the decision-making practice s for these patients . We sought to determine how often such patients are admitted to the ICU of a metropolitan hospital and how end-of-life decisions are made for them . Design : Prospect i ve , observational cohort study . Patients and Setting : Consecutive adult patients admitted to the medical ICU of a metropolitan West Coast hospital during a 7-month period in 2003 to 2004 . Measurements : Attending physicians completed a question naire about the decision-making process for each patient for whom they considered limiting life-support who lacked decisional capacity and a legally recognized surrogate decision-maker . Main Results : Of the 303 patients admitted during the study period , 49 ( 16 % ; 95 % confidence interval [ CI ] , 12–21 % ) lacked decision-making capacity and a surrogate during the entire ICU stay . Compared with all other ICU patients , these patients were more likely to be male ( 88 % vs. 69 % ; p = .002 ) , white ( 42 % vs. 23 % ; p = .028 ) , and ≥65 yrs old ( 29 % vs. 13 % ; p = .007 ) . Physicians considered withholding or withdrawing treatment from 37 % ( 18 ) of the 49 patients who lacked both decision-making capacity and a surrogate decision-maker . For 56 % ( 10 ) of these 18 patients , the opinion of another attending physician was obtained ; for 33 % ( 6 of 18 ) , the ICU team made the decision independently , and for 11 % ( 2 of 18 ) , the input of the courts or the hospital ethics committee was obtained . Overall , 27 % of deaths ( 13 of 49 ) during the study period were in incapacitated patients who lacked a surrogate ( 95 % CI , 15–41 % ) . Conclusions : Sixteen percent of patients admitted to the medical ICU of this hospital lacked both decision-making capacity and a surrogate decision-maker . Decisions to limit life support were generally made by physicians without judicial or institutional review . Further research and debate are needed to develop optimal decision-making strategies for these difficult cases Withdrawal of care has increased in recent years as the population older than 65 years of age has increased . We sought to investigate the impact of this decision on our mortality rate . We retrospectively review ed a prospect ively collected data base to determine the percentage of cases in which care was actively withdrawn . Neurologic injury as the cause for withdrawal , age of the patient , number of days to death , number of cases thought to be treatment failures , and the reason for failure were analyzed . Between January 2008 and December 2012 , there were 536 trauma service deaths ; 158 ( 29.5 % ) had care withdrawn . These patients were 67 ( 6 18.5 ) years old and neurologic injury was responsible in 63 per cent ( 6 5.29 % ) . Fifty-two per cent of the patients died by Day 3 ; 65 per cent by Day 5 ; and 74 per cent Day 7 . A total of 22.7 per cent ( 6 7.9 % ) could be considered a treatment failure . Accounting for cases in which care was withdrawn for futility would decrease the overall mortality rate by approximately 23 per cent . Trauma center mortality calculation does not account for care withdrawn . Treating an active , aging population , with advance directives , requires method ologies that account for such decision-making when determining mortality rates Objectives : To characterize the prevalence of withdrawal of life-sustaining treatment , as well as the time to awakening , short-term neurologic outcomes , and cause of death in comatose survivors of out-of-hospital resuscitated cardiopulmonary arrests treated with therapeutic hypothermia . Design : Single center , prospect i ve observational cohort study of consecutive patients with out-of-hospital cardiopulmonary arrests . Setting : Academic tertiary care hospital and level one trauma center in Minneapolis , MN . Patients : Adults with witnessed , nontraumatic , out-of-hospital cardiopulmonary arrests regardless of initial electrocardiographic rhythm with return of spontaneous circulation who were admitted to an ICU . Interventions : None . Measurements and Main Results : The study cohort included 154 comatose survivors of witnessed out-of-hospital cardiopulmonary arrests who were admitted to an ICU during the 54-month study period . One hundred eighteen patients ( 77 % ) were treated with therapeutic hypothermia . The mean age was 59 years , 104 ( 68 % ) were men , and 83 ( 54 % ) had an initial rhythm of ventricular tachycardia or fibrillation . Only eight of all 78 patients ( 10 % ) who died qualified as brain dead ; and 81 % of all patients ( 63 of 78 ) who died did so after withdrawal of life-sustaining treatment . Twenty of 56 comatose survivors ( 32 % ) treated with hypothermia who awoke ( as defined by Glasgow Motor Score of 6 ) and had good neurologic outcomes ( defined as Cerebral Performance Category 1–2 ) did so after 72 hours . Conclusions : Our study supports delaying prognostication and withdrawal of life-sustaining treatment to beyond 72 hours in cases treated with therapeutic hypothermia . Larger multicenter prospect i ve studies are needed to better define the most appropriate time frame for prognostication in comatose cardiac arrest survivors treated with therapeutic hypothermia . These data are also consistent with the notion that a majority of out-of-hospital cardiopulmonary arrest survivors die after a decision to withdrawal of life-sustaining treatment and that very few of these survivors progress to brain death In some intensive care units ( ICUs ) , fewer patients who die now undergo attempts at cardiopulmonary resuscitation ( CPR ) , and many more have life support actively withdrawn prior to death than did a decade ago . To determine the frequency of withdrawal of life support , we contacted every American postgraduate training program with significant clinical exposure to critical care medicine , asking them prospect ively to classify patients who died into one of five mutually exclusive categories . We received data from 131 ICUs at 110 institutions in 38 states . There were 6,303 deaths , of which 393 patients were brain dead . Of the remaining 5,910 patients who died , 1,544 ( 23 % ) received full ICU care including failed cardiopulmonary resuscitation ( CPR ) ; 1,430 ( 22 % ) received full ICU care without CPR ; 797 ( 10 % ) had life support withheld ; and 2,139 ( 38 % ) had life support withdrawn . There was wide variation in practice among ICUs , with ranges of 4 to 79 % , 0 to 83 % , 0 to 67 % , and 0 to 79 % in these four categories , respectively . Variation was not related to ICU type , hospital type , number of admissions , or ICU mortality . We conclude that limitation of life support prior to death is the predominant practice in American ICUs associated with critical care training programs . There is wide variation in end-of-life care , and efforts are needed to underst and practice patterns and to establish st and ards of care for patients dying in ICUs To determine whether limits to life-sustaining care are becoming more common , we attempted to quantify the incidence of recommendations to withhold or withdraw life support from critically ill patients , to describe how patients respond to these recommendations , and to examine how conflicts over these recommendations are resolved . In 1992 and 1993 we prospect ively enrolled 179 consecutive patients from two intensive care units ( ICUs ) for whom a recommendation was made to withhold or withdraw life support . Where possible , we compared results with data collected in the same units over a similar time period in 1987 and 1988 . Recommendations to withhold or withdraw life support preceded 179 of 200 deaths ( 90 % ) in 1992 and 1993 , compared with 114 of 224 deaths ( 51 % ) in 1987 and 1988 ( chi2 = 73.76 , p < 0.001 ] . Cardiopulmonary resuscitation was initiated in 10 % of deaths in 1992 and 1993 as compared with 49 % in 1987 and 1988 . Ninety percent of patients agreed within less than 5 d , and only eight patients ( 4 % ) refused physicians ' recommendations to limit life support . In cases of conflict , physicians in 1992 and 1993 deferred to patients with one exception : physicians were willing to refuse surrogate requests for resuscitation of patients they considered hopelessly ill . We conclude that 90 % of patients who die in these ICUs now do so following a decision to limit therapy , that this represents a major change in practice in these institutions over a period of 5 yr , that most patients and surrogates accept an appropriate recommendation to withhold or withdraw life support , and that physicians will refuse surrogate requests in certain circumstances Objective The objective of this study was to identify factors associated with the decision to withdraw mechanical ventilation from patients in a neurology/neurosurgery intensive care unit . Specifically , the following factors were considered : the severity of the neurologic illness , the healthcare delivery system , and social factors . Design Retrospective analysis of prospect ively collected clinical data base . Setting Neurology/neurosurgery intensive care unit of a large academic tertiary care hospital . Patients Patients were 2,109 nonelective admissions to the neurology/neurosurgery intensive care unit who received mechanical ventilation over a period of 82 months . Interventions None . Measurements and Main Results The average age was 56 ± 19.7 yrs , 53 % were male , and 81 % were functionally normal before admission . The median Glasgow Coma Scale score was 14 , the average Acute Physiology and Chronic Health Evaluation II severity of illness score was 13.5 ± 8.3 , and probability of death was 18.2 ± 22.0 % . Mechanical ventilation was withdrawn from 284 ( 13.5 % ) . Factors that were independently associated with withdrawal of mechanical ventilation were as follows : more severe neurologic injury [ admission Glasgow Coma Scale score ( odds ratio 0.86/point , confidence interval 0.82–0.90 ) , diagnosis of subarachnoid hemorrhage ( odds ratio 2.44 , confidence interval 1.50–3.99 ) , or ischemic stroke ( odds ratio 1.72 , confidence interval 1.13–2.60 ) ] , older age ( odds ratio 1.04/yr , confidence interval 1.03–1.05 ) , and higher Acute Physiology and Chronic Health Evaluation II probability of death ( odds ratio 1.03/% , confidence interval 1.02–1.04 ) . Mechanical ventilation was less likely to be withdrawn if patients were African-American ( odds ratio 0.50 , confidence interval 0.36–0.68 ) or had undergone surgery ( odds ratio 0.44 , confidence interval 0.2– 0.67 ) . Marital status , premorbid functional status , clinical service ( neurology vs. neurosurgery ) , attending status ( private vs. academic ) , and type of health insurance were not associated with decisions to withdraw mechanical ventilation . Conclusions We conclude that decisions to withdraw mechanical ventilation in the neurology/neurosurgery intensive care unit are based primarily on the severity of the acute neurologic condition and age but not on characteristics of the healthcare delivery system . Care is less likely to be withdrawn from African-American patients or those who had surgery BACKGROUND There is an increased emphasis on benchmarking of trauma mortality outcomes as a measure of quality . Differences in approaches to end-of-life care or perceptions of salvageability might account for some of the variability in outcomes across centers . We postulated that these differences in perceptions or practice might lead to significant variation in the use of do not resuscitate ( DNR ) orders and sought to identify institutional characteristics associated with their use . METHODS Patients surviving > 24 hours and admitted to an intensive care unit ( ICU ) in one of 68 centers across the United States were identified from a large prospect i ve cohort study of severely injured patients . Independent predictors of a DNR order at both the patient and institutional level were identified using multivariate hierarchical modeling stratified by age < 55 or > /=55 . RESULTS Of 6,765 patients , 7 % had a DNR order , of whom 88 % died . The proportion of patients in each center with a DNR order ranged from 0 % to 57 % . Independent patient-level predictors associated with a DNR order were increasing age , preinjury comorbidity burden , severe injury , and organ failure . Institutional predictors of DNR orders differed by age . Care in an open ICU was associated with a DNR order ( odds ratio , 1.7 ; 95 % confidence interval , 1.0 - 3.0 ) in the elderly , whereas care in a combined medical-surgical ICU ( vs. surgical or trauma ICU ) was associated with greater likelihood ( odds ratio , 2.0 ; 95 % confidence interval , 1.1 - 4.1 ) of a DNR order in the young . CONCLUSIONS DNR orders are relatively common in seriously injured trauma patients , and there is significant variability in their use across centers . Given the institutional characteristics independently associated with DNR status , it is likely that both differences in the ethos of end-of-life care and perceptions of salvageability affect decision making Objective : Substantial variability exists in the timing of limitations in life support for critically ill patients . Our objective was to investigate how the timing of limitations in life support varies with changes in organ failure status and time since acute lung injury onset . Design , Setting , and Patients : This evaluation was performed as part of a prospect i ve cohort study evaluating 490 consecutive acute lung injury patients recruited from 11 ICUs at three teaching hospitals in Baltimore , MD . Interventions : None . Measurements : The primary exposure was proportion of days without improvement in Sequential Organ Failure Assessment score , evaluated as a daily time-varying exposure . The outcome of interest was a documented limitation in life support defined as any of the following : 1 ) no cardiopulmonary resuscitation , 2 ) do not reintubate , 3 ) no vasopressors , 4 ) no hemodialysis , 5 ) do not escalate care , or 6 ) other limitations ( e.g. , “ comfort care only ” ) . Main Results : For medical ICU patients without improvement in daily Sequential Organ Failure Assessment score , the rate of limitation in life support tripled in the first 3 days after acute lung injury onset , increased again after day 5 , and peaked at day 19 . Compared with medical ICU patients , surgical ICU patients had a rate of limitations that was significantly lower during the first 5 days after acute lung injury onset . In all patients , more days without improvement in Sequential Organ Failure Assessment scores was associated with limitations in life support , independent of the absolute magnitude of the Sequential Organ Failure Assessment score . Conclusions : Persistent organ failure is associated with an increase in the rate of limitations in life support independent of the absolute magnitude of Sequential Organ Failure Assessment score , and this association strengthens during the first weeks of treatment . During the first 5 days after acute lung injury onset , limitations were significantly more common in medical ICUs than surgical ICUs |
1,928 | 31,387,588 | However , the considerable heterogeneity was found in the impact of community-delivered models in reducing , parasitaemia and hyperparasitaemia prevalence , anaemia incidence , fever prevalence and malaria caseload .
Conclusion Overall , the community-delivered model is effective in improving the coverage of malaria interventions and reducing malaria-associated mortality . | Background Community-delivered models have been widely used to reduce the burden of malaria .
This review aim ed to explore different community-delivered models and their relative effectiveness in terms of coverage and malaria-metric outcomes in order to inform the design and implementation of Community Health Worker ( CHW ) programmes for malaria control and elimination . | Background Malaria continues to be a prominent global public health challenge . This study tested the effectiveness of two service delivery models for reducing the malaria burden , e.g. supportive supervision of community health workers ( CHW ) and community mobilization in promoting appropriate health-seeking behaviour for febrile illnesses in Odisha , India . Methods The study population comprised 120 villages from two purposively chosen malaria-endemic districts , with 40 villages r and omly assigned to each of the two treatment arms , one with both supportive supervision and community mobilization and one with community mobilization alone , as well as an observational control arm . Outcome measures included changes in the utilization of bed nets and timely care-seeking for fever from a trained provider compared to the control group . Analysis was by intention-to-treat . Results Significant improvements were observed in the reported utilization of bed nets in both intervention arms ( 84.5 % in arm A and 82.4 % in arm B versus 78.6 % in the control arm ; p < 0.001 ) . While overall rates of treatment-seeking were equal across study arms , treatment-seeking from a CHW was higher in both intervention arms ( 28 % ; p = 0.005 and 27.6 % ; p = 0.007 ) than in the control arm ( 19.2 % ) . Fever cases were significantly more likely to visit a CHW and receive a timely diagnosis of fever in the combined interventions arm than in the control arm ( 82.1 % vs. 67.1 % ; p = 0.025 ) . Care-seeking from trained providers also increased with a substitution away from untrained providers . Further , fever cases from the combined interventions arm ( 60.6 % ; p = 0.004 ) and the community mobilization arm ( 59.3 % ; p = 0.012 ) were more likely to have received treatment from a skilled provider within 24 hours than fever cases from the control arm ( 50.1 % ) . In particular , women from the combined interventions arm were more likely to have received timely treatment from a skilled provider ( 61.6 % vs. 47.2 % ; p = 0.028 ) . Conclusion A community-based intervention combining the supportive supervision of community health workers with intensive community mobilization and can be effective in improving care-seeking and preventive behaviour and may be used to strengthen the national malaria control programme 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 Intermittent preventive treatment for malaria in children ( IPTc ) is a promising new intervention for the prevention of malaria but its delivery is a challenge . We have evaluated the coverage of IPTc that can be achieved by two different delivery systems in Ghana . Methods IPTc was delivered by volunteers in six villages ( community-based arm ) and by health workers at health centres or at Exp and ed Programme on Immunisation outreach clinics ( facility based ) in another six communities . The villages were selected r and omly and drugs were administered in May , June , September and October 2006 . The first dose of a three-dose regimen of amodiaquine plus sulphadoxine-pyrimethamine was administered under supervision to 3–59 month-old children ( n = 964 ) in the 12 study villages ; doses for days 2 and 3 were given to parents/guardians to administer at home . Results The proportion of children who received at least the first dose of 3 or more courses of IPTc was slightly higher in the community based arm ( 90.5 % vs 86.6 % ; p = 0.059 ) . Completion of the three dose regimen was high and similar with both delivery systems ( 91.6 % and 91.7 % respectively ) . Conclusion Seasonal IPTc delivered through community-based or facility-based systems can achieve a high coverage rate with the support and supervision of the district health management team . However , in order to maximise the impact of IPTc , both delivery systems may be needed in some setting s. Trial Registration Clinical Trials.gov 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 No satisfactory strategy for reducing high child mortality from malaria has yet been established in tropical Africa . We compared the effect on under-5 mortality of teaching mothers to promptly provide antimalarials to their sick children at home , with the present community health worker approach . METHODS Of 37 tabias ( cluster of villages ) in two districts with hyperendemic to holoendemic malaria , tabias reported to have the highest malaria morbidity were selected . A census was done which included a maternity history to determine under-5 mortality . Tabias ( population 70,506 ) were paired according to under-5 mortality rates . One tabia from each pair was allocated by r and om number to an intervention group and the other was allocated to the control group . In the intervention tabias , mother coordinators were trained to teach other local mothers to recognise symptoms of malaria in their children and to promptly give chloroquine . In both intervention and control tabias , all births and deaths of under-5s were recorded monthly . FINDINGS From January to December 1997 , 190 of 6383 ( 29.8 per 1000 ) children under-5 died in the intervention tabias compared with 366 of 7294 ( 50.2 per 1000 ) in the control tabias . Under-5 mortality was reduced by 40 % in the intervention localities ( 95 % CI from 29.2 - 50.6 ; paired t test , p<0.003 ) . For every third child who died , a structured verbal autopsy was undertaken to ascribe cause of mortality as consistent with malaria or possible malaria , or not consistent with malaria . Of the 190 verbal autopsies , 13 ( 19 % ) of 70 in the intervention tabias were consistent with possible malaria compared with 68 ( 57 % ) of 120 in the control tabias . INTERPRETATION A major reduction in under-5 mortality can be achieved in holoendemic malaria areas through training local mother coordinators to teach mothers to give under-5 children antimalarial drugs Background Over thirty years have passed since the Alma-Ata Declaration on primary health care in 1978 . Many governments in the first decade following the declaration responded by developing national programmes of community health workers ( CHWs ) , but evaluations of these often demonstrated poor outcomes . As many CHW programmes have responded to the HIV/AIDS p and emic , international interest in them has returned and their role in the response to other diseases should be examined carefully so that lessons can be applied to their new roles . Over half of the deaths in African children under five years of age are due to malaria , diarrhoea and pneumonia - a situation which could be addressed through the use of cheap and effective interventions delivered by CHWs . However , to date there is very little evidence from r and omised controlled trials of the impacts of CHW programmes on child mortality in Africa . Evidence from non-r and omised controlled studies has not previously been review ed systematic ally . Methods We search ed data bases of published and unpublished studies for RCTs and non-r and omised studies evaluating CHW programmes delivering curative treatments , with or without preventive components , for malaria , diarrhoea or pneumonia , in children in sub-Saharan Africa from 1987 to 2007 . The impact of these programmes on morbidity or mortality in children under six years of age was review ed . A descriptive analysis of interventional and context ual factors associated with these impacts was attempted . Results The review identified seven studies evaluating CHWs , delivering a range of interventions . Limited descriptive data on programmes , context s or process outcomes for these CHW programmes were available . CHWs in national programmes achieved large mortality reductions of 63 % and 36 % respectively , when insecticide-treated nets and anti-malarial chemoprophylaxis were delivered , in addition to curative interventions . Conclusions CHW programmes could potentially achieve large gains in child survival in sub-Saharan Africa if these programmes were implemented at scale . Large-scale rigorous studies , including RCTs , are urgently needed to provide policymakers with more evidence on the effects of CHWs delivering these interventions Background In the rural areas of sub-Saharan Africa , the majority of young children affected by malaria have no access to formal health services . Home treatment through mothers of febrile children supported by mother groups and local health workers has the potential to reduce malaria morbidity and mortality . Methods A cluster-r and omized controlled effectiveness trial was implemented from 2002–2004 in a malaria endemic area of rural Burkina Faso . Six and seven villages were r and omly assigned to the intervention and control arms respectively . Febrile children from intervention villages were treated with chloroquine ( CQ ) by their mothers , supported by local women group leaders . CQ was regularly supplied through a revolving fund from local health centres . The trial was evaluated through two cross-sectional surveys at baseline and after two years of intervention . The primary endpoint of the study was the proportion of moderate to severe anaemia in children aged 6–59 months . For assessment of the development of drug efficacy over time , an in vivo CQ efficacy study was nested into the trial . The study is registered under http://www.controlled-trials.com ( IS RCT N 34104704 ) . Results The intervention was shown to be feasible under program conditions and a total of 1.076 children and 999 children were evaluated at baseline and follow-up time points respectively . Self-reported CQ treatment of fever episodes at home as well as referrals to health centres increased over the study period . At follow-up , CQ was detected in the blood of high proportions of intervention and control children . Compared to baseline findings , the prevalence of anaemia ( 29 % vs 16 % , p < 0.0001 ) and malaria parameters such as prevalence of P. falciparum parasitaemia , fever and palpable spleens was lower at follow-up but there were no differences between the intervention and control group . CQ efficacy decreased over the study period but this was not associated with the intervention . Discussion The decreasing prevalence of malaria morbidity including anaemia over the study period can be explained by an overall increase of malaria prevention and treatment activities in the study area . The lack of effectiveness of the intervention was likely caused by contamination , pre-existing differences in the coverage of malaria treatment in both study groups and an unexpectedly rapid increase of resistance against CQ , the first-line treatment drug at the time of the study Insecticide treatment of bed nets ( " mosquito nets " ) may be a cheap and acceptable method of reducing the morbidity and mortality caused by malaria . In a rural area of The Gambia , bed nets in villages participating in a primary health-care ( PHC ) scheme were treated with permethrin at the beginning of the malaria transmission season . Additionally , children aged 6 months to 5 years were r and omised to receive weekly either chemoprophylaxis with maloprim or a placebo throughout the malaria transmission season . We measured mortality in children in PHC villages before and after the interventions described , and compared this with mortality in villages where no interventions occurred ( non-PHC villages ) . About 92 % of children in PHC villages slept under insecticide-treated bed nets . In the year before intervention , mortality in children aged 1 - 4 years was lower in non-PHC villages . After intervention , the overall mortality and mortality attributable to malaria of children aged 1 - 4 in the intervention villages was 37 % and 30 % , respectively , of that in the non-PHC villages . Among children who slept under treated nets , we found no evidence of an additional benefit of chemoprophylaxis in preventing deaths . Insecticide-treated bed nets are simple to introduce and can reduce mortality from malaria OBJECTIVE To determine the extent to which the community-directed approach used in onchocerciasis control in Africa could effectively and efficiently provide integrated delivery of other health interventions . METHODS A three-year experimental study was undertaken in 35 health districts from 2005 to 2007 in seven research sites in Cameroon , Nigeria and Ug and a. Four trial districts and one comparison district were r and omly selected in each site . All districts had established ivermectin treatment programmes , and in the trial districts four other established interventions - vitamin A supplementation , use of insecticide-treated nets , home management of malaria and short-course , directly-observed treatment for tuberculosis patients - were progressively incorporated into a community-directed intervention ( CDI ) process . At the end of each of the three study years , we performed quantitative evaluations of intervention coverage and provider costs , as well as qualitative assessment s of the CDI process . FINDINGS With the CDI strategy , significantly higher coverage was achieved than with other delivery approaches for all interventions except for short-course , directly-observed treatment . The coverage of malaria interventions more than doubled . The district-level costs of delivering all five interventions were lower in the CDI districts , but no cost difference was found at the first-line health facility level . Process evaluation showed that : ( i ) participatory processes were important ; ( ii ) recurrent problems with the supply of intervention material s were a major constraint to implementation ; ( iii ) the communities and community implementers were deeply committed to the CDI process ; ( iv ) community implementers were more motivated by intangible incentives than by external financial incentives . CONCLUSION The CDI strategy , which builds upon the core principles of primary health care , is an effective and efficient model for integrated delivery of appropriate health interventions at the community level in Africa Non-r and omised studies of the effects of interventions are critical to many areas of healthcare evaluation , but their results may be biased . It is therefore important to underst and and appraise their strengths and weaknesses . We developed ROBINS-I ( “ Risk Of Bias In Non-r and omised Studies - of Interventions ” ) , a new tool for evaluating risk of bias in estimates of the comparative effectiveness ( harm or benefit ) of interventions from studies that did not use r and omisation to allocate units ( individuals or clusters of individuals ) to comparison groups . The tool will be particularly useful to those undertaking systematic review s that include non-r and omised studies Background The use of community volunteers is expected to improve access to accurate diagnosis and timely treatment of malaria , using rapid diagnostic test ( RDT ) and artemisinin-based combination therapy ( ACT ) . However , empirical data from the field are still limited . The aim of this study was to assess whether training village volunteers on the use of Paracheck-Pf ® RDT and ACT ( artemether-lumefantrine ( AL ) ) for Plasmodium falciparum and presumptive treatment with chloroquine for Plasmodium vivax had an effect on the coverage of timely diagnosis and treatment and on mortality in malaria-endemic villages without health staff in Myanmar . Methods The study was design ed as a cluster r and omized controlled trial with a cross-sectional survey at baseline , a monthly visit for six months following the intervention ( village volunteers trained and equipped with Paracheck-Pf ® ) and an endline survey at six months follow-up . Survey data were supplemented by the analysis of logbooks and field-based verbal autopsies . Villages with midwives ( MW ) in post were used as a third comparison group in the endline survey . Intention-to-treat analysis was used . Results Of 38 villages selected , 21 were r and omly assigned to the intervention ( two villages failed to participate ) and 17 to the comparison group . The two groups had comparable baseline statistics . The blood tests provided by volunteers every month declined over time from 279 tests to 41 but not in MW group in 18 villages ( from 326 to 180 ) . In the endline survey , among interviewed subjects ( 268 intervention , 287 in comparison , 313 in MW ) , the coverage of RDT was low in all groups ( 14.9 % , SE 2.4 % in intervention ; 5.7 % , SE 1.7 % in comparison ; 21.4 % , SE 2.6 % in MW ) although the intervention ( OR 3.2 , 95 % CI 1.5 - 6.7 ) and MW ( OR 5.4 , 95 % CI 2.6 - 11.0 ) were more likely to receive a blood test . Mean ( SE ) of blood tests after onset of fever in days was delayed ( intervention 3.6 ( 0.3 ) ; comparison 4.8 ( 1.3 ) ; MW 3.2 ( 0.4 ) ) . Malaria mortality rates per 100,000 population s in a year were not significantly different ( intervention 130 SE 37 ; comparison 119 SE 34 ; MW 50 SE 18 ) . None of the dead cases had consulted volunteers . Conclusions The results show that implementing volunteer programmes to improve the coverage of accurate and timely diagnosis with RDT and early treatment may be beneficial but the timeliness of detection and sustainability must be improved BACKGROUND Malaria infections are a major public health problem in Africa and prompt treatment is one way of controlling the disease and saving lives . METHODS This cluster-r and omised controlled community intervention conducted in 2003 - 2005 aim ed at improving early malaria case management in under five children . Health workers were trained to train community-based women groups in recognizing malaria symptoms , providing first-line treatment for uncomplicated malaria and referring severe cases . Evaluation was through a pre- ( 2004 ) and a post-intervention survey ( 2005 ) . Anaemia prevalence was the primary outcome . RESULTS 1715 children aged 6 - 59 months were included in the pre-intervention survey and 2169 in the post-intervention survey . The prevalence of anaemia decreased significantly from 37 % [ 95 % CI 34.7 - 39.3 ] to 0.5 % [ 95 % CI 0.2 - 0.7 ] after the intervention ( p<0.001 ) ; slightly more in the intervention ( from 43.9 % to 0.8 % ) than in the control ( 30.8 % to 0.17 % ) group ( p=0.038 ) . Fever and reported fever decreased significantly and the mean body weight of the children increased significantly over the study period in both control and intervention groups . CONCLUSION The decrease in anaemia was significantly associated with the intervention , whereas the fever and body weight trends might be explained by other malaria control activities or seasonal/climate effects in the area . The community intervention was shown to be feasible in the study context OBJECTIVES We piloted a community-based proactive malaria case detection model in rural Senegal to evaluate whether this model can increase testing and treatment and reduce prevalence of symptomatic malaria in target communities . METHODS Home care providers conducted weekly sweeps of every household in their village throughout the transmission season to identify patients with symptoms of malaria , perform rapid diagnostic tests ( RDT ) on symptomatic patients and provide treatment for positive cases . The model was implemented in 15 villages from July to November 2013 , the high transmission season . Fifteen comparison villages were chosen from those implementing Senegal 's original , passive model of community case management of malaria . Three sweeps were conducted in the comparison villages to compare prevalence of symptomatic malaria using difference in differences analysis . RESULTS At baseline , prevalence of symptomatic malaria confirmed by RDT for all symptomatic individuals found during sweeps was similar in both sets of villages ( P = 0.79 ) . At end line , prevalence was 16 times higher in the comparison villages than in the intervention villages ( P = 0.003 ) . Adjusting for potential confounders , the intervention was associated with a 30-fold reduction in odds of symptomatic malaria in the intervention villages ( AOR = 0.033 ; 95 % CI : 0.017 , 0.065 ) . Treatment seeking also increased in the intervention villages , with 57 % of consultations by home care providers conducted between sweeps through routine community case management . CONCLUSIONS This pilot study suggests that community-based proactive case detection reduces symptomatic malaria prevalence , likely through more timely case management and improved care seeking behaviour . A r and omised controlled trial is needed to further evaluate the impact of this model OBJECTIVE The main objective of the study was to assess the impact of a community-based delivery system of intermittent preventive treatment ( IPT ) for malaria in pregnancy with sulfadoxine-pyrimethamine ( SP ) on access , parasitemia , anemia and low birth weight as primary outcome measures . METHODS A study was design ed to test the community-based delivery system of IPT through traditional birth attendants ( TBAs ) , drug-shop vendors ( DSVs ) , community reproductive health workers ( CRHWs ) and adolescent peer mobilizers ( APMs ) , and to compare these with IPT at health units in an area of high malaria transmission - Mukono District , Ug and a. RESULTS Two thous and seven hundred and eighty-five pregnant women participated in the study . The majority of the women ( 92.4 % ) at the community-based approaches received their first dose of IPT during their second trimester compared to 76.1 % at health units ( p<0.0001 ) . At both health units and the community-based approaches , IPT increased mean hemoglobin by 6.7 % ( p<0.0001 ) for all parities and by 10.2 % among primigravidae . IPT reduced the prevalence of severe anemia from 5.7 % to 3.1 % ( p<0.04 ) . The prevalence of parasitemia was reduced from 24.5 % to 16.1 % ( p<0.001 ) , and parasite density reduced significantly ( p<0.02 ) after the first dose and remained stable with the second dose . Overall the proportion of low birth weight was 6.3 % ( 8.3 % at health units versus 6.0 % at the community-based approaches , p<0.03 ) highlighting the importance of access and adherence to IPT . This intervention was acceptable to 89.6 % of the women at the community-based approaches intending to use IPT in the future , while 48.1 % of them had recommended it to other women . CONCLUSIONS The community-based approaches increased access and adherence to IPT with an effect on anemia , severe anemia , parasitemia and low birth weight . However the reduced effect of IPT on parasitemia points to drug resistance with SP and this requires further evaluation ; research into the identification of other more efficacious drugs for malaria prevention in pregnancy is also required BACKGROUND Community health workers in Dangme-West district , Ghana , treated children aged 2 - 59 months with fever with either artesunate-amodiaquine ( AAQ ) or AAQ plus amoxicillin ( AAQ + AMX ) within a cluster-r and omized controlled trial ( registration no. TDR/UNDP Trial registration A : 20189 ) . The intervention was introduced in a stepped-wedge manner . The aim of the study was reduction of mortality . This paper reports on the reduction of morbidity , notably anaemia , severe anaemia and severe illness . Clusters of 100 children were r and omized in to AAQ , AAQ + AMX and pre-intervention arms . Six months later the pre-intervention clusters were r and omized in to the AAQ and AAQ + AMX arms . METHODS Data were collected in eight cross-sectional surveys . Using stratified sampling , 10 clusters were r and omly selected per survey . Blood sample s were taken to assess haemoglobin . Caregivers were interviewed about diseases ( signs and symptoms ) among their children in the preceding 14 days . Multivariate logistic regression analysis was used to determine the impact on anaemia , severe anaemia and severe illness . RESULTS Compared with the pre-intervention clusters , anaemia was reduced in the AAQ ( OR = 0.20 , 95 % CI 0.12 - 0.33 ) and AAQ + AMX ( OR = 0.23 , 95 % CI 0.15 - 0.36 ) clusters , severe anaemia was reduced in the AAQ ( OR = 0.20 , 95 % CI 0.09 - 0.45 ) and AAQ + AMX ( OR = 0.12 , 95 % CI 0.04 - 0.31 ) clusters and severe illness was reduced in the AAQ ( OR = 0.46 , 95 % CI 0.26 - 0.80 ) and AAQ + AMX ( OR = 0.38 , 95 % CI 0.22 - 0.63 ) clusters . No significant differences were found in outcome variables between the AAQ and AAQ + AMX clusters . CONCLUSIONS Treating fever with antimalarials significantly reduced the prevalence of anaemia , severe anaemia and severe illness . We found no significant reduction in outcomes when the AAQ and AAQ+AMX clusters were compared Two drug strategies for the control of malaria in children aged 3 - 59 months have been compared in a rural area of The Gambia -- treatment of presumptive episodes of clinical malaria with chloroquine by village health workers , and treatment combined with fortnightly chemoprophylaxis with ' Maloprim ' ( pyrimethamine/dapsone ) which was also given by village health workers . Treatment alone did not have any significant effect on mortality or morbidity from malaria . In contrast , treatment and chemoprophylaxis reduced overall mortality in children aged 1 - 4 years , mortality from probable malaria , and episodes of fever associated with malaria parasitaemia . A high level of compliance with chemoprophylaxis was obtained and no harmful consequences of chemoprophylaxis were observed The Home-Based Management of Fever/Malaria ( HBMF ) strategy in rural Ug and a was evaluated in a quasi-experimental study . The intervention consisted of volunteers educating mothers and providing a 3-day course of pre-packaged chloroquine plus sulfadoxine/pyrimethamine tablets ( HOMAPAK ) , free of charge , for the treatment of under-five fevers . Using a structured question naire , information was obtained on care-seeking and treatment practice s before ( n=498 ) and 18 months after the introduction of HBMF ( n=587 ) . Assessment of the intervention effect indicated 13.5 % improvement in the accumulated proportion of patients ( 1 ) treated , ( 2 ) treated within 24h of illness onset , ( 3 ) treated with the recommended antimalarials , ( 4 ) treated at an adequate dosage and ( 5 ) treated for the correct duration . Combining this with the antimalarial drug efficacy result ed in a 10.4 % improvement in the community effectiveness of malaria treatment . HOMAPAK use was reported in 25 % of 156 febrile children ; 23 % in the most poor compared with 50 % in the least poor . Using HOMAPAK instead of other allopathic antimalarials increased the likelihood of completing all steps ( odds ratio 37 , 95 % CI 4.8 - 286 ) . Similar to other large-scale public health interventions , this study demonstrates modest practice changes at the population level . However , practice s improved markedly among HOMAPAK users , suggesting that intensifying implementation efforts to increase HOMAPAK use , especially among the poorest , would be beneficial |
1,929 | 29,220,311 | TT ( −16.2 ± 4.3 % ; 95 % CI −22.9 % to −9 % ) and TTE ( −44.5 ± 6.9 % ; 95 % CI −51.3 % to −36.7 % ) elicited a negative effect , whilst indicating a quadratic relationship between hypoxic magnitude and both TTE and TT performance .
Furthermore , exercise less than 2 min exhibited no ergolytic effect from acute hypoxia .
Summary / Conclusion : This review highlights the ergolytic effect of acute hypoxic exposure , which is curvilinear for TTE and TT performance with increasing hypoxic levels , but short duration intermittent and sprint exercise seem to be unaffected | Abstract Objective : To quantify the effects of acute hypoxic exposure on exercise capacity and performance , which includes continuous and intermittent forms of exercise . | The effect of hypoxia on the response to interval exercise was determined in eight elite female cyclists during two interval sessions : a sustained 3 x 10-min endurance set ( 5-min recovery ) and a repeat sprint session comprising three sets of 6 x 15-s sprints ( work-to-relief ratios were 1:3 , 1:2 , and 1:1 for the 1st , 2nd , and 3rd sets , respectively , with 3 min between each set ) . During exercise , cyclists selected their maximum power output and breathed either atmospheric air ( normoxia , 20.93 % O(2 ) ) or a hypoxic gas mix ( hypoxia , 17.42 % O(2 ) ) . Power output was lower in hypoxia vs. normoxia throughout the endurance set ( 244+/-18 vs. 226+/-17 , 234+/-18 vs. 221+/-25 , and 235+/-18 vs. 221+/-25 W for 1st , 2nd , and 3rd sets , respectively ; P < 0.05 ) but was lower only in the latter stages of the second and third sets of the sprints ( 452+/-56 vs. 429+/-49 and 403+/-54 vs. 373+/- 43 W , respectively ; P<0.05 ) . Hypoxia lowered blood O(2 ) saturation during the endurance set ( 92.9+/-2.9 vs. 95.4+/-1.5 % ; P<0.05 ) but not during repeat sprints . We conclude that , when elite cyclists select their maximum exercise intensity , both sustained ( 10 min ) and short-term ( 15 s ) power are impaired during hypoxia , which simulated moderate ( approximately 2,100 m ) altitude PURPOSE Lower barometric air pressure at altitude can affect competitive performance of athletes in some sports . Reported here are the effects of various altitudes on elite track- and -field athletes ' performance . METHODS Lifetime track- and -field performances of athletes placed in the top 16 in at least 1 major international competition between 2000 and 2009 were downloaded from the data base at tilastopaja.org . There were 132,104 performances of 1889 athletes at 794 venues . Performances were log-transformed and analyzed using a mixed linear model with fixed effects for 6 levels of altitude and r and om quadratic effects to adjust for athlete age . RESULTS Men 's and women 's sprint events ( 100 - 400 m ) showed marginal improvements of ~0.2 % at altitudes of 500 - 999 m , and above 1500 m all but the 100- and 110-m hurdles showed substantial improvements of 0.3 - 0.7 % . Some middle- and long-distance events ( 800 - 10,000 m ) showed marginal impairments at altitudes above 150 m , but above 1000 m the impairments increased dramatically to ~2 - 4 % for events > 800 m. There was no consistent trend in the effects of altitude on field events up to 1000 m ; above 1000 m , hammer throw showed a marginal improvement of ~1 % and discus was impaired by 1 - 2 % . Above 1500 m , triple jump and long jump showed marginal improvements of ~1 % . CONCLUSIONS In middle- and long-distance runners , altitudes as low as 150 to 299 m can impair performance . Higher altitudes ( ≥1000 m ) are generally required before decreases in discus performance or enhancements in sprinting , triple and long jump , or hammer throw are seen Purpose To investigate the interaction between the development of peripheral locomotor muscle fatigue , muscle recruitment and performance during repeated-sprint exercise ( RSE ) . Method In a single-blind , r and omised and cross-over design , ten male team-sport athletes performed two RSE ( fifteen 5-s cycling sprints interspersed with 25 s of rest ; power self-selected ) in normoxia and in acute moderate hypoxia ( FIO2 0.138 ) . Mechanical work , total electromyographic intensity ( summed quadriceps electromyograms , RMSsum ) and muscle ( vastus lateralis ) and pre-fontal cortex near-infrared spectroscopy ( NIRS ) parameters were calculated for every sprint . Blood lactate concentration ( [ Lac- ] ) was measured throughout the protocol . Peripheral quadriceps fatigue was assessed via changes in potentiated quadriceps twitch force ( ΔQtw , pot ) pre- versus post-exercise in response to supra-maximal magnetic femoral nerve stimulation . The central activation ratio ( QCAR ) was used to quantify completeness of quadriceps activation . Results Compared with normoxia , hypoxia reduced arterial oxygen saturation ( -13.7 % , P=0.001 ) , quadriceps RMSsum ( -13.7 % , P=0.022 ) , QCAR ( -3.3 % , P=0.041 ) and total mechanical work ( -8.3 % , P=0.019 ) . However , the magnitude of quadriceps fatigue induced by RSE was similar in the two conditions ( ΔQtw , pot : -53.5 % and -55.1 % , P=0.71 ) . The lower cycling performance in hypoxia occurred despite similar metabolic ( muscle NIRS parameters and blood [ Lac- ] ) and functional ( twitch and M-wave ) muscle states . Conclusion Results suggest that the central nervous system regulates quadriceps muscle recruitment and , thereby , performance to limit the development of muscle fatigue during intermittent , short sprints . This finding highlights the complex interaction between muscular perturbations and neural adjustments during sprint exercise , and further supports the presence of pacing during intermittent sprint exercise PURPOSE To underst and the role of O2 utilization in the sex differences of fatigue during intermittent activity , we compared the cerebral ( prefrontal lobe ) and muscle ( vastus lateralis ) oxygenation of men and women during repeated-sprint exercise ( RSE ) . METHODS Ten men and 10 women matched for initial-sprint mechanical work performed ten , 10 s cycle sprints ( with 30 s of rest ) under normoxic ( NM : 21 % FIO2 ) and acute hypoxic ( HY : 13 % FIO2 ) conditions in a r and omized single-blind and crossover design . Mechanical work was calculated and arterial O2 saturation ( SpO2 ) was estimated via pulse oximetry during every sprint . Cerebral and muscle oxy- ( O2Hb ) and deoxy-hemoglobin ( HHb ) were monitored continuously by near-infrared spectroscopy . RESULTS Compared with NM , work decrement was accentuated ( P = 0.01 ) in HY for both men ( -16.4 ± 10.3 % ) and women ( -16.8 ± 9.0 % ) . This was associated with lower SpO2 and lower cerebral Δ[O2Hb ] in both sexes ( -13.6 ± 7.5 % , P = .008 , and -134.5 ± 73.8 % , P = .003 , respectively ) . These HY-induced changes were nearly identical in these men and women matched for initial-sprint work . Muscle Δ[HHb ] increased 9-fold ( P = .009 ) and 5-fold ( P = .02 ) in men and women , respectively , and plateaued . This muscle deoxygenation was not exacerbated in HY . CONCLUSIONS Results indicate that men and women matched for initial-sprint work experience similar levels of fatigue and systemic , cerebral , and peripheral adjustments during RSE performed in NM and HY . These data suggest that cerebral deoxygenation imposes a limitation to repeated-sprint performance The study examined the influence of cerebral ( prefrontal cortex ) and muscle ( vastus lateralis ) oxygenation on the ability to perform repeated , cycling sprints . Thirteen team-sport athletes performed ten , 10-s sprints ( with 30 s of rest ) under normoxic ( FIO2 0.21 ) and acute hypoxic ( FIO2 0.13 ) conditions in a r and omised , single-blind fashion and crossover design . Mechanical work was calculated and arterial O2 saturation ( SpO2 ) was estimated via pulse oximetry for every sprint . Cerebral and muscle oxy-(O2Hb ) , deoxy-(HHb ) , and total haemoglobin ( THb ) were monitored continuously by near-infrared spectroscopy . Compared with normoxia , hypoxia induced larger decrements in SpO2 and work ( 11.6 and 7.6 % , respectively ; P < 0.05 ) . In the muscle , we observed a fairly constant level of deoxygenation across sprints , with no effect of the condition . In normoxia , regional cerebral oxygenation increased during the first two sprints and slightly fluctuated thereafter . In contrast , this initial cerebral hyper-oxygenation was attenuated in hypoxia . Changes in [ O2Hb ] and [ HHb ] occurred earlier and were larger in hypoxia compared with normoxia ( P < 0.05 ) , while regional blood volume ( Δ[THb ] ) remained unaffected by the condition . Changes in cerebral [ HHb ] and mechanical work were strongly correlated in normoxia and hypoxia ( R2 = 0.81 and R2 = 0.85 , respectively ; P < 0.05 ) , although the slope of this relationship differed ( normoxia , −351.3 ± 183.3 vs. hypoxia , −442.4 ± 227.2 ; P < 0.05 ) . The results of this NIRS study show that O2 availability influences prefrontal cortex , but not muscle , oxygenation during repeated , short sprints . By using a hypoxia paradigm , the study suggests that cerebral oxygenation contributes to the impairment of repeated-sprint ability Athletes regularly compete at 2,000–3,000 m altitude where peak oxygen consumption $ $ ( \dot{V}\hbox{\rm O}_{2{\rm peak}})$$ declines ∼10–20 % . Factors other than $ $ \dot{V}\hbox{\rm O}_{2{\rm peak}}$$ including gross efficiency ( GE ) , power output , and pacing are all important for cycling performance . It is therefore imperative to underst and how all these factors and not just $ $ \dot{V}\hbox{\rm O}_{2{\rm peak}}$$ are affected by acute hypobaric hypoxia to select athletes who can compete successfully at these altitudes . Ten well-trained , non-altitude-acclimatised male cyclists and triathletes completed cycling tests at four simulated altitudes ( 200 , 1,200 , 2,200 , 3,200 m ) in a r and omised , counter-balanced order . The exercise protocol comprised 5 × 5-min submaximal efforts ( 50 , 100 , 150 , 200 and 250 W ) to determine submaximal $ $ \dot{V}\hbox{\rm O}_{2}$$ and GE and , after 10-min rest , a 5-min maximal time-trial ( 5-minTT ) to determine $ $ \dot{V}\hbox{\rm O}_{2{\rm peak}}$$ and mean power output ( 5-minTTpower ) . $ $ \dot{V}\hbox{\rm O}_{2{\rm peak}}$$ declined 8.2 ± 2.0 , 13.9 ± 2.9 and 22.5 ± 3.8 % at 1,200 , 2,200 and 3,200 m compared with 200 m , respectively , P < 0.05 . The corresponding decreases in 5-minTTpower were 5.8 ± 2.9 , 10.3 ± 4.3 and 19.8 ± 3.5 % ( P < 0.05 ) . GE during the 5-minTT was not different across the four altitudes . There was no change in submaximal $ $ \dot{V}\hbox{\rm O}_{2}$$ at any of the simulated altitudes , however , submaximal efficiency decreased at 3,200 m compared with both 200 and 1,200 m. Despite substantially reduced power at simulated altitude , there was no difference in pacing at the four altitudes for athletes whose first trial was at 200 or 1,200 m ; whereas athletes whose first trial was at 2,200 or 3,200 m tended to mis-pace that effort . In conclusion , during the 5-minTT there was a dose – response effect of hypoxia on both $ $ \dot{V}\hbox{\rm O}_{2{\rm peak}}$$ and 5-minTTpower but no effect on GE The present study examined the effect of oxygen fraction in inspired air ( FIO2 ) on exercise performance and maximum oxygen consumption ( VO2max ) . Six national level male rowers exercised three 2500-m all-out tests on a Concept II rowing ergometer . Each subject performed one test in normoxia ( FIO2 20.9 % ) , one in simulated hyperoxia ( FIO2 62.2 % ) and one in simulated hypoxia ( FIO2 15.8 % ) in a r and omized single-blind fashion . The mean final rowing time was 2.3 + /- 0.9 % ( P < 0.01 ; 95 % CI 1.4 - 3.2 ) shorter in hyperoxia and 5.3 + /- 1.8 % ( P < 0.01 ; 95 % CI 3.1 - 7.5 ) longer in hypoxia when compared with normoxia . The effect of FIO2 on VO2max exceeded its effect on exercise performance as VO2max was 11.1 + /- 5.7 % greater ( P < 0.01 ; 95 % CI 5.1 - 17.1 ) in hyperoxia and 15.5 + /- 3.2 % smaller in hypoxia ( P < 0.01 ; 95 % CI 12.2 - 19.0 ) than in normoxia . Blood lactate concentration and O2 consumption per power unit ( ml O2.W-1 ) failed to indicate statistically significant differences in anaerobic metabolism between normoxia and the other two conditions . These data suggest that there are other parameters besides those of energy metabolism that affect exercise performance as FIO2 is modified . These possible mechanisms are discussed in this paper The present study compared the performance ( peak speed , distance , and acceleration ) of ten amateur team-sport athletes during a clustered ( i.e. , multiple sets ) repeated-sprint protocol , ( 4 sets of 4 , 4-s running sprints ; i.e. , RSR444 ) in normobaric normoxia ( FiO2 = 0.209 ; i.e. , RSN ) with normobaric hypoxia ( FiO2 = 0.140 ; i.e. , RSH ) . Subjects completed two separate trials ( i. RSN , ii . RSH ; r and omised order ) between 48 h and 72 h apart on a non-motorized treadmill . In addition to performance , we examined blood lactate concentration [ La(- ) ] and arterial oxygen saturation ( SpO2 ) before , during , and after the RSR444 . While there were no differences in peak speed or distance during set 1 or set 2 , peak speed ( p = 0.04 and 0.02 , respectively ) and distance ( p = 0.04 and 0.02 , respectively ) were greater during set 3 and set 4 of RSN compared with RSH . There was no difference in the average acceleration achieved in set 1 ( p = 0.45 ) , set 2 ( p = 0.26 ) , or set 3 ( p = 0.23 ) between RSN and RSH ; however , the average acceleration was greater in RSN than RSH in set 4 ( p < 0.01 ) . Measurements of [ La(- ) ] were higher during RSH than RSN immediately after Sprint 16 ( 10.2 ± 2.5 vs 8.6 ± 2.6 mM ; p = 0.02 ) . Estimations of SpO2 were lower during RSH than RSN , respectively , immediately prior to the commencement of the test ( 89.0 ± 2.0 vs 97.2 ± 1.5 % ) , post Sprint 8 ( 78.0 ± 6.3 vs 93.8 ± 3.6 % ) and post Sprint 16 ( 75.3 ± 6.3 vs 94.5 ± 2.5 % ; all p < 0.01 ) . In summary , the RSR444 is a practical protocol for the implementation of a hypoxic repeated-sprint training intervention into the training schedules of team-sport athletes . However , given the inability of amateur team-sport athletes to maintain performance in hypoxic ( FiO2 = 0.140 ) conditions , the potential for specific training outcomes ( i.e. speed ) to be achieved will be compromised , thus suggesting that the RSR444 should be used with caution . Key pointsThe RSR444 is a practical , multiple-set repeated-sprint running protocol design ed for team-sport athletes . During performance of the RSR444 in hypoxia ( FiO2 = 0.140 ) , amateur team-sport athletes were unable to replicate the peak speed , distance covered or acceleration achieved in the final set(s ) during sprints in normoxia . A decrease in SpO2 and an increase in [ La(- ) ] were observed during performance of the RSR444 in hypoxia , compared with normoxia PURPOSE This study investigated the efficacy of an intermittent critical power ( CP ) model , termed the " work-balance " ( W'BAL ) model , during high-intensity exercise in hypoxia ( HYPO ) . METHODS Eleven trained male cyclists ( mean ± SD age , 27 ± 6.6 yr ; V˙O2peak , 4.79 ± 0.56 L·min(-1 ) ) completed a maximal ramp test and a 3-min " all-out " test to determine CP and work performed above CP ( W ' ) . On another day , an intermittent exercise test to task failure was performed . All procedures were performed in normoxia ( NORM ) and HYPO ( FiO2 ≈ 0.155 ) in a single-blind , r and omized , and counter-balanced experimental design . The W'BAL model was used to calculate the minimum W ' ( W'BALmin ) achieved during the intermittent test . The W'BALmin in HYPO was also calculated using CP + W ' derived in NORM ( N + H ) . RESULTS In HYPO , there was an 18 % decrease in V˙O2peak ( 4.79 ± 0.56 vs 3.93 ± 0.47 L·min(-1 ) ; P < 0.001 ) and a 9 % decrease in CP ( 347 ± 45 vs 316 ± 46 W ; P < 0.001 ) . No significant change for W ' occurred ( 13.4 ± 3.9 vs 13.7 ± 4.9 kJ ; P = 0.69 ; NORM vs HYPO ) . The change in V˙O2peak was significantly correlated with the change in CP ( r = 0.72 ; P = 0.01 ) . There was no difference between NORM and HYPO for W'BALmin ( 1.1 ± 0.9 kJ vs 1.2 ± 0.6 kJ ) . The N + H analysis grossly overestimated W'BALmin ( 7.8 ± 3.4 kJ ) compared with HYPO ( P < 0.001 ) . CONCLUSION The W'BAL model produced similar results in HYPO and NORM , but only when model parameters were determined under the same environmental conditions as the performance task . Application of the W'BAL model at altitude requires a modification of the model or that CP and W ' are measured at altitude The effects of heat and /or hypoxia have been well-documented in match-play data . However , large match-to-match variation for key physical performance measures makes environmental inferences difficult to ascertain from soccer match-play . Therefore , the present study aims to investigate the hot ( HOT ) , hypoxic ( HYP ) , and hot-hypoxic ( HH ) mediated-decrements during a non-motorized treadmill based soccer-specific simulation . Twelve male University soccer players completed three familiarization sessions and four r and omized crossover experimental trials of the intermittent Soccer Performance Test ( iSPT ) in normoxic-temperate ( CON : 18 ° C 50 % rH ) , HOT ( 30 ° C ; 50 % rH ) , HYP ( 1000 m ; 18 ° C 50 % rH ) , and HH ( 1000 m ; 30 ° C ; 50 % rH ) . Physical performance and its performance decrements , body temperatures ( rectal , skin , and estimated muscle temperature ) , heart rate ( HR ) , arterial blood oxygen saturation ( SaO2 ) , perceived exertion , thermal sensation ( TS ) , body mass changes , blood lactate , and plasma volume were all measured . Performance decrements were similar in HOT and HYP [ Total Distance ( −4 % ) , High-speed distance ( ~−8 % ) , and variable run distance ( ~−12 % ) covered ] and exacerbated in HH [ total distance ( −9 % ) , high-speed distance ( −15 % ) , and variable run distance ( −15 % ) ] compared to CON . Peak sprint speed , was 4 % greater in HOT compared with CON and HYP and 7 % greater in HH . Sprint distance covered was unchanged ( p > 0.05 ) in HOT and HYP and only decreased in HH ( −8 % ) compared with CON . Body mass ( −2 % ) , temperatures ( + 2–5 % ) , and TS ( + 18 % ) were altered in HOT . Furthermore , SaO2 ( −8 % ) and HR ( + 3 % ) were changed in HYP . Similar changes in body mass and temperatures , HR , TS , and SaO2 were evident in HH to HOT and HYP , however , blood lactate ( p < 0.001 ) and plasma volume ( p < 0.001 ) were only significantly altered in HH . Perceived exertion was elevated ( p < 0.05 ) by 7 % in all conditions compared with CON . Regression analysis identified that absolute TS and absolute rise in skin and estimated muscle temperature ( r = 0.82 , r = 0.84 r = 0.82 , respectively ; p < 0.05 ) predicted the hot-mediated-decrements in HOT . The hot , hypoxic , and hot-hypoxic environments impaired physical performance during iSPT . Future interventions should address the increases in TS and body temperatures , to attenuate these decrements on soccer performance The aim of this study was to analyse the influence of inspiratory muscle training ( IMT ) on ventilatory efficiency , in normoxia and hypoxia , and to investigate the relationship between ventilatory efficiency and cycling performance . Sixteen sport students ( 23.05 ± 4.7 years ; 175.11 ± 7.1 cm ; 67.0 ± 19.4 kg ; 46.4 ± 8.7 ml·kg−1·min−1 ) were r and omly assigned to an inspiratory muscle training group ( IMTG ) and a control group ( CG ) . The IMTG performed two training sessions/day [ 30 inspiratory breaths , 50 % peak inspiratory pressure ( Pimax ) , 5 days/week , 6-weeks ] . Before and after the training period subjects carried out an incremental exercise test to exhaustion with gas analysis , lung function testing , and a cycling time trial test in hypoxia and normoxia . Simulated hypoxia ( FiO2 = 16.45 % ) , significantly altered the ventilatory efficiency response in all subjects ( p < 0.05 ) . Pimax increased significantly in the IMTG whereas no changes occurred in the CG ( time × group , p < 0.05 ) . Within group analyses showed that the IMTG improved ventilatory efficiency ( VE/VCO2 slope ; EqCO2VT2 ) in hypoxia ( p < 0.05 ) and cycling time trial performance [ WTTmax ( W ) ; WTTmean ( W ) ; PTF(W ) ] ( p < 0.05 ) in hypoxia and normoxia . Significant correlations were not found in hypoxia nor normoxia found between ventilatory efficiency parameters ( VE/VCO2 slope ; LEqCO2 ; EqCO2VT2 ) and time trial performance . On the contrary the oxygen uptake efficiency slope ( OUES ) was highly correlated with cycling time trial performance ( r = 0.89 ; r = 0.82 ; p < 0.001 ) under both conditions . Even though no interaction effect was found , the within group analysis may suggest that IMT reduces the negative effects of hypoxia on ventilatory efficiency . In addition , the data suggest that OUES plays an important role in submaximal cycling performance Purpose We sought to determine if expiratory flow limitation influences intensive aerobic exercise performance in mild hypoxia . Methods Fourteen trained male cyclists were separated into flow-limited ( FL , n = 7 ) and non-FL ( n = 7 ) groups based on the extent of expiratory flow limitation exhibited during maximal exercise in normoxia . Participants performed two self-paced 5-km cycling time trials , one in normoxic ( FIO2 = 0.21 ) and one in mild hypoxic ( FIO2 = 0.17 ) conditions in a r and omized , balanced order with the subjects blinded to composition of the inspirate . Percent change from normoxia to hypoxia in average power output ( % ΔPTT ) and time to completion ( % ΔTTT ) were used to assess performance . Results Hypoxia result ed in a significant decline in estimated arterial O2 saturation and decrements in performance in both groups , although FL had a significantly smaller % ΔPTT ( −4.0 ± 0.5 vs. −9.0 ± 1.8 % ) and % ΔTTT ( 1.3 ± 0.3 vs. 3.7 ± 0.9 % ) compared to non-FL . At the 5th km of the time trial , minute ventilation did not change from normoxia to hypoxia in FL ( 3.4 ± 3.1 % ) or non-FL ( 2.3 ± 3.7 % ) , but only the non-FL reported a significantly increased dyspnea rating in hypoxia compared to normoxia ( ~9 % ) . Non-FL athletes did not utilize their ventilatory reserve to defend arterial oxygen saturation in hypoxia , which may have been due to an increased measure of dyspnea in the hypoxic trial . Conclusion FL athletes experience less hypoxia-related aerobic exercise performance impairment as compared to non-FL athletes , despite having less ventilatory reserve The aim of this study was to evaluate the effects of severe acute hypoxia on exercise performance and metabolism during 30-s Wingate tests . Five endurance- ( E ) and five sprint- ( S ) trained track cyclists from the Spanish National Team performed 30-s Wingate tests in normoxia and hypoxia ( inspired O(2 ) fraction = 0.10 ) . Oxygen deficit was estimated from submaximal cycling economy tests by use of a nonlinear model . E cyclists showed higher maximal O(2 ) uptake than S ( 72 + /- 1 and 62 + /- 2 ml x kg(-1 ) x min(-1 ) , P < 0.05 ) . S cyclists achieved higher peak and mean power output , and 33 % larger oxygen deficit than E ( P < 0.05 ) . During the Wingate test in normoxia , S relied more on anaerobic energy sources than E ( P < 0.05 ) ; however , S showed a larger fatigue index in both conditions ( P < 0.05 ) . Compared with normoxia , hypoxia lowered O(2 ) uptake by 16 % in E and S ( P < 0.05 ) . Peak power output , fatigue index , and exercise femoral vein blood lactate concentration were not altered by hypoxia in any group . Endurance cyclists , unlike S , maintained their mean power output in hypoxia by increasing their anaerobic energy production , as shown by 7 % greater oxygen deficit and 11 % higher postexercise lactate concentration . In conclusion , performance during 30-s Wingate tests in severe acute hypoxia is maintained or barely reduced owing to the enhancement of the anaerobic energy release . The effect of severe acute hypoxia on supramaximal exercise performance depends on training background UNLABELLED Sildenafil improves maximal exercise capacity at high altitudes ( ∼4350 - 5800 m ) by reducing pulmonary arterial pressure and enhancing oxygen delivery , but the effects on exercise performance at less severe altitudes are less clear . PURPOSE To determine the effects of sildenafil on cardiovascular hemodynamics ( heart rate , stroke volume , and cardiac output ) , arterial oxygen saturation ( SaO2 ) , and 6-km time-trial performance of endurance-trained men and women at a simulated altitude of ∼3900 m. METHODS Twenty men and 15 women , endurance-trained , completed one experimental exercise trial ( 30 min at 55 % of altitude-specific capacity + 6-km time trial ) at sea level ( SL ) and two trials at simulated high altitude ( HA ) while breathing hypoxic gas ( 12.8 % FIo2 ) after ingestion of either placebo or 50 mg sildenafil in double-blind , r and omized , and counterbalanced fashion . RESULTS Maximal exercise capacity and SaO2 were significantly reduced at HA compared to SL ( 18%-23 % ) , but sildenafil did not significantly improve cardiovascular hemodynamics or time-trial performance in either men or women compared to placebo and only improved SaO2 in women ( 4 % ) . One male subject ( 5 % of male subjects , 2.8 % of all subjects ) exhibited a meaningful 36-s improvement in time-trial performance with sildenafil compared to placebo . CONCLUSIONS In this group of endurance trained men and women , sildenafil had very little influence on cardiovascular hemodynamics , SaO2 , and 6-km time-trial performance at a simulated altitude of ∼3900 m. It appears that a very small percentage of endurance-trained men and women derive meaningful improvements in aerobic performance from sildenafil at a simulated altitude of ∼3900 Sildenafil improves oxygen delivery and maximal exercise capacity at very high altitudes ( ≥4,350 m ) , but it is unknown whether sildenafil improves these variables and longer- duration exercise performance at moderate and high altitudes where competitions are more common . The purpose of this study was to determine the effects of sildenafil on cardiovascular hemodynamics , arterial oxygen saturation ( SaO2 ) , peak exercise capacity ( Wpeak ) , and 15-km time trial performance in endurance-trained subjects at simulated moderate ( MA ; ~2,100 m , 16.2 % FIO2 ) and high ( HA ; ~3,900 m , 12.8 % FIO2 ) altitudes . Eleven men and ten women completed two HA Wpeak trials after ingesting placebo or 50 mg sildenafil . Subjects then completed four exercise trials ( 30 min at 55 % of altitude-specific Wpeak + 15-km time trial ) at MA and HA after ingesting placebo or 50 mg sildenafil . All trials were performed in r and omized , counterbalanced , and double-blind fashion . Sildenafil had little influence on cardiovascular hemodynamics at MA or HA , but did result in higher SaO2 values ( + 3 % , p < 0.05 ) compared to placebo during steady state and time trial exercise at HA . Wpeak at HA was 19 % lower than SL ( p < 0.001 ) and was not significantly affected by sildenafil . Similarly , the significantly slower time trial performance at MA ( 28.1 ± 0.5 min , p = 0.016 ) and HA ( 30.3 ± 0.6 min , p < 0.001 ) compared to SL ( 27.5 ± 0.6 min ) was unaffected by sildenafil . We conclude that sildenafil is unlikely to exert beneficial effects at altitudes < 4,000 m for a majority of the population The purpose of this study was to investigate whether hypoxia can alter anaerobic energy release during supramaximal exercise . Seven male subjects performed 12 submaximal cycling tests to establish the relationship between workload and O2 dem and . The subjects also performed 40 s Wingate tests ( WT ) under normoxia ( room air ) , two levels of moderate hypoxia of 16.4 % O2 and 12.7 % O2 . We measured the power output and oxygen uptake ( VO2 ) during each test and estimated the O2 dem and , O2 deficit and percentage of anaerobic energy release ( % AnAER ) . These data were analyzed for each 20 s interval . At all intervals , there were no differences in Pmean·body mass (BM)−1 , O2 dem and · BM−1 or O2 deficit·BM−1 among the three O2 conditions . However , under hypoxia of 12.7 % , VO2·BM−1 was significantly decreased and % AnAER was significantly increased in the late phase ( 20–40 s ) of the WT , compared to normoxia ( P<0.05 ) . There were no such significant differences between normoxia and hypoxia of 16.4 % . Thus , the present results show that the degree of hypoxia affects the magnitude of the hypoxia-induced increase in anaerobic energy release in the late phase of the WT and suggest that certain degrees of hypoxia induce significant increases in the amount of anaerobic energy released , compared to normoxia It has been hypothesized that one reason for decreased .VO(2max ) in hypoxia could be the lower maximal exercise intensity achieved in incremental , time or distance trial tests . We hypothesized that (1).VO(2max ) would be decreased at altitude even when exercising at the same absolute maximal exercise intensity as at sea level and ; ( 2 ) the decline in .VO(2max ) in endurance-trained athletes ( ETA ) would be linear across the range from sea level through moderate altitudes . Eight ETA performed combined .VO(2max ) and performance tests running to exhaustion at the same speed in a r and omized double blind fashion at simulated altitudes of 300 , 800 , 1,300 , 1,800 , 2,300 and 2,800 m above sea level using a hypobaric chamber . Douglas bag system was used for respiratory measurements and pulse oximetry was used to estimate arterial O(2 ) saturation . .VO(2max ) declined linearly from 66+/-1.6 ml kg(-1 ) min(-1 ) at 300 m to 55+/-1.6 ml kg(-1 ) min(-1 ) at 2,800 m corresponding to a 6.3 % decrease per 1,000 m increasing altitude ( range 4.6 - 7.5 % ) . Time to exhaustion ( performance ) at a constant velocity associated with 107 % of sea level .VO(2max ) decreased with 14.5 % ( P<0.001 ) per 1,000 m altitude between 300 and 2,800 m. Both .VO(2max ) and performance decreased from 300 to 800 m ( P<0.01 ; P<0.05 ) . Arterial haemoglobin oxygen saturation at test cessation ( SpO(2min ) ) declined from 89.0+/-2.9 % at 300 m to 76.5+/-4.0 % at 2,800 m ( P=0.001 ) . This study report that in ETA during acute exposure to altitude both performance and .VO(2max ) decline from 300 to 800 m above sea level and continued to decrease linearly to 2,800 We examined the effects of hypoxia severity on peripheral versus central determinants of exercise performance . Eight cyclists performed constant-load exercise to exhaustion at various fractions of inspired O2 fraction ( FIO2 0.21/0.15/0.10 ) . At task failure ( pedal frequency < 70 % target ) arterial hypoxaemia was surreptitiously reversed via acute O2 supplementation ( FIO2 = 0.30 ) and subjects were encouraged to continue exercising . Peripheral fatigue was assessed via changes in potentiated quadriceps twitch force ( DeltaQ(tw , pot ) ) as measured pre- versus post-exercise in response to supramaximal femoral nerve stimulation . At task failure in normoxia ( haemoglobin saturation ( SpO2 ) approximately 94 % , 656 + /- 82 s ) and moderate hypoxia ( SpO2 ) approximately 82 % , 278 + /- 16 s ) , hyperoxygenation had no significant effect on prolonging endurance time . However , following task failure in severe hypoxia ( SpO2 ) approximately 67 % ; 125 + /- 6 s ) , hyperoxygenation elicited a significant prolongation of time to exhaustion ( 171 + /- 61 % ) . The magnitude of DeltaQ(tw , pot ) at exhaustion was not different among the three trials ( -35 % to -36 % , P = 0.8 ) . Furthermore , quadriceps integrated EMG , blood lactate , heart rate , and effort perceptions all rose significantly throughout exercise , and to a similar extent at exhaustion following hyperoxygenation at all levels of arterial oxygenation . Since hyperoxygenation prolonged exercise time only in severe hypoxia , we repeated this trial and assessed peripheral fatigue following task failure prior to hyperoxygenation ( 125 + /- 6 s ) . Although Q(tw , pot ) was reduced from pre-exercise baseline ( -23 % ; P < 0.01 ) , peripheral fatigue was substantially less ( P < 0.01 ) than that observed at task failure in normoxia and moderate hypoxia . We conclude that across the range of normoxia to severe hypoxia , the major determinants of central motor output and exercise performance switches from a predominantly peripheral origin of fatigue to a hypoxia-sensitive central component of fatigue , probably involving brain hypoxic effects on effort perception The purpose of this study was to examine the influence of hypoxia on the O2 uptake response , on the arterial and muscular desaturation and on the test duration and test duration at VO2max during exhaustive exercise performed in normoxia and hypoxia at the same relative workload . Nine well-trained males cyclists performed an incremental test and an exhaustive constant power test at 90 % of maximal aerobic power on a cycling ergometer , both in normoxia and hypoxia ( inspired O2 fraction = 16 % ) . Hypoxic normobar conditions were obtained using an Alti Trainer200 and muscular desaturation was monitored by near-infrared spectroscopy instrument ( Niro-300 ) . The mean response time ( 66 + /- 4 s vs. 44 + /- 7 s ) was significantly lower in hypoxia caused by the shorter time constant of the VO2 slow component . This result was due to the lower absolute work rate in hypoxia which decreased the amplitude of the VO2 slow component . The arterial ( 94.6 + /- 0.3 % vs. 84.2 + /- 0.7 % ) and muscular desaturation ( in the vastus lateralis and the lateral gastrocnemius ) were reduced by hypoxia . The test duration ( 440 + /- 31 s vs. 362 + /- 36 s ) and the test duration at VO2max ( 286 + /- 53 s vs. 89 + /- 33 s ) were significantly shorter in hypoxia . Only in normoxia , the test duration was correlated with arterial and muscular saturation ( r = 0.823 and r = 0.828 ; p < 0.05 ) . At the same relative workload , hypoxia modified performance , arterial and muscular oxygen desaturation but not the oxygen uptake response . In normoxia , correlation showed that desaturation seems to be a limiting factor of performance ABSTRACT We determined if performance and mechanical running alterations during repeated treadmill sprinting differ between severely hot and hypoxic environments . Six male recreational sportsmen ( team- and racket-sport background ) performed five 5-s sprints with 25-s recovery on an instrumented treadmill , allowing the continuous ( step-by-step ) measurement of running kinetics/kinematics and spring-mass characteristics . These were r and omly conducted in control ( CON ; 25 ° C/45 % RH , inspired fraction of oxygen = 20.9 % ) , hot ( HOT ; 38 ° C/21 % RH , inspired fraction of oxygen = 20.9 % ; end-exercise core temperature : ~38.6 ° C ) and normobaric hypoxic ( HYP , 25 ° C/45 % RH , inspired fraction of oxygen = 13.3%/simulated altitude of ~3600 m ; end-exercise pulse oxygen saturation : ~84 % ) environments . Running distance was lower ( P < 0.05 ) in HOT compared to CON and HYP for the first sprint but larger ( P < 0.05 ) sprint decrement score occurred in HYP versus HOT and CON . Compared to CON , the cumulated distance covered over the five sprints was lower ( P < 0.01 ) in HYP but not in HOT . Irrespective of the environmental condition , significant changes occurred from the first to the fifth sprint repetitions ( all three conditions compounded ) in selected running kinetics ( mean horizontal forces , P < 0.01 ) or kinematics ( contact and swing times , both P < 0.001 ; step frequency , P < 0.001 ) and spring-mass characteristics ( vertical stiffness , P < 0.001 ; leg stiffness , P < 0.01 ) . No significant interaction between sprint number and condition was found for any mechanical data . Preliminary evidence indicates that repeated-sprint ability is more impaired in hypoxia than in a hot environment , when compared to a control condition . However , as sprints are repeated , mechanical alterations appear not to be exacerbated in severe ( heat , hypoxia ) environmental conditions We investigated the effects of dietary nitrate ( NO3 ( - ) ) supplementation on the concentration of plasma nitrite ( [ NO2 ( - ) ] ) , oxygen uptake ( V̇o2 ) kinetics , and exercise tolerance in normoxia ( N ) and hypoxia ( H ) . In a double-blind , crossover study , 12 healthy subjects completed cycle exercise tests , twice in N ( 20.9 % O2 ) and twice in H ( 13.1 % O2 ) . Subjects ingested either 140 ml/day of NO3 (-)-rich beetroot juice ( 8.4 mmol NO3 ; BR ) or NO3 (-)-depleted beetroot juice ( PL ) for 3 days prior to moderate-intensity and severe-intensity exercise tests in H and N. Preexercise plasma [ NO2 ( - ) ] was significantly elevated in H-BR and N-BR compared with H-PL ( P < 0.01 ) and N-PL ( P < 0.01 ) . The rate of decline in plasma [ NO2 ( - ) ] was greater during severe-intensity exercise in H-BR [ -30 ± 22 nM/min , 95 % confidence interval ( CI ) ; -44 , -16 ] compared with H-PL ( -7 ± 10 nM/min , 95 % CI ; -13 , -1 ; P < 0.01 ) and in N-BR ( -26 ± 19 nM/min , 95 % CI ; -38 , -14 ) compared with N-PL ( -1 ± 6 nM/min , 95 % CI ; -5 , 2 ; P < 0.01 ) . During moderate-intensity exercise , steady-state pulmonary V̇o2 was lower in H-BR ( 1.91 ± 0.28 l/min , 95 % CI ; 1.77 , 2.13 ) compared with H-PL ( 2.05 ± 0.25 l/min , 95 % CI ; 1.93 , 2.26 ; P = 0.02 ) , and V̇o2 kinetics was faster in H-BR ( τ : 24 ± 13 s , 95 % CI ; 15 , 32 ) compared with H-PL ( 31 ± 11 s , 95 % CI ; 23 , 38 ; P = 0.04 ) . NO3 ( - ) supplementation had no significant effect on V̇o2 kinetics during severe-intensity exercise in hypoxia , or during moderate-intensity or severe-intensity exercise in normoxia . Tolerance to severe-intensity exercise was improved by NO3 ( - ) in hypoxia ( H-PL : 197 ± 28 ; 95 % CI ; 173 , 220 vs. H-BR : 214 ± 43 s , 95 % CI ; 177 , 249 ; P = 0.04 ) but not normoxia . The metabolism of NO2 ( - ) during exercise is altered by NO3 ( - ) supplementation , exercise , and to a lesser extent , hypoxia . In hypoxia , NO3 ( - ) supplementation enhances V̇o2 kinetics during moderate-intensity exercise and improves severe-intensity exercise tolerance . These findings may have important implication s for individuals exercising at altitude This study examined the influence of muscle deoxygenation and reoxygenation on repeated-sprint performance via manipulation of O2 delivery . Fourteen team-sport players performed 10 10-s sprints ( 30-s recovery ) under normoxic ( NM : FI O2 0.21 ) and acute hypoxic ( HY : FI O2 0.13 ) conditions in a r and omized , single-blind fashion and crossover design . Mechanical work was calculated and arterial O2 saturation ( Sp O2 ) was estimated via pulse oximetry for every sprint . Muscle deoxyhemoglobin concentration ( [ HHb ] ) was monitored continuously by near-infrared spectroscopy . Differences between NM and HY data were analyzed for practical significance using magnitude-based inferences . HY reduced Sp O2 ( -10.7 ± 1.9 % , with chances to observe a higher/similar/lower value in HY of 0/0/100 % ) and mechanical work ( -8.2 ± 2.1 % ; 0/0/100 % ) . Muscle deoxygenation increased during sprints in both environments , but was almost certainly higher in HY ( 12.5 ± 3.1 % , 100/0/0 % ) . Between-sprint muscle reoxygenation was likely more attenuated in HY ( -11.1 ± 11.9 % ; 2/7/91 % ) . The impairment in mechanical work in HY was very largely correlated with HY-induced attenuation in muscle reoxygenation ( r = 0.78 , 90 % confidence limits : 0.49 ; 0.91 ) . Repeated-sprint performance is related , in part , to muscle reoxygenation capacity during recovery periods . These results extend previous findings that muscle O2 availability is important for prolonged repeated-sprint performance , in particular when the exercise is taken in hypoxia Summary The purpose of this study was to evaluate the effect of hypoxia ( 10.8±0.6 % oxygen ) on performance of 30 s and 45 s of supramaximal dynamic exercise . Twelve males were r and omly allocated to perform either a 30 s or 45 s Wingate test ( WT ) on two occasions ( hypoxia and room air ) with a minimum of 1 week between tests . After a 5-min warm-up at 120 W subjects breathed the appropriate gas mixture from a wet spirometer during a 5-min rest period . Resting blood oxygen saturation was monitored with an ear oximeter and averaged 97.8 ± 1.5 % and 83.2 ± 1.9 % for the air ( normoxic ) and hypoxic conditions , respectively , immediately prior to the WT . Following all WT trials , subjects breathed room air for a 10-min passive recovery period . Muscle biopsies from the vastus lateralis were taken prior to and immediately following WT . Arterialized blood sample s , for lactate and blood gases , were taken before and after both the warm-up and the performance of WT , and throughout the recovery period . Opencircuit spirometry was used to calculate the total oxygen consumption ( Vo2 ) , carbon dioxide production and expired ventilation during WT . Hypoxia did not impair the performance of the 30-s or 45-s WT.Vo3 was reduced during the 45-s hypoxic WT ( 1.71±0.21 I ) compared with the normoxic trial ( 2.16±0.261 ) , but there was no change during the 30-s test ( 1.22±0.11 vs 1.04±0.171 for the normoxic and hypoxic conditions , respectively ) . Muscle lactate ( LA ) increased more during hypoxia following both the 30-s and 45-s WT ( 67.1±25.0 mmol · kg−1 dry weight ) compared with normoxia ( 30.8 ± 18.0 mmol · kg−1 dry weight ) . Hypoxia did not influence the change in intramuscular adenosine triphosphate , creatine phosphate and glucose-6-phosphate . The performance of WT during hypoxia was associated with a greater decrease in muscle glycogen ( P<0.06 ) . Throughout the recovery period , blood LA was lower following the hypoxia ( 8.43±2.88 mmol · l−1 ) comparedwith normoxia ( 9.15±3.06 mmol · 1−1 ) . Breathing the hypoxic gas mixture prior to the performance of WT increased blood pH to 7.44±0.03 , compared with 7.39±0.03 for normoxia . Blood pH remained higher during the 10-min recovery period following the hypoxic WT trials ( 7.24±0.08 ) compared with the normoxic WT ( 7.22±0.06 ) . BloodPCO2 was reduced prior to and immediately following WT during hypoxia , but there were no differences between the normoxic and hypoxic trials during the 10 min recovery period . These data indicate that more energy was transduced from the catabolism of glycogen to lactate during the hypoxic WT trials , which offset the reduced O2 availability and maintained performance comparable with normoxic conditions . It is suggested that the induced respiratory alkalosis associated with breathing the hypoxic gas could account for the increased rate of muscle LA accumulation Eight unacclimatized long-distance runners performed , on a level treadmill , an incremental test to determine the maximal oxygen uptake ( VO2max ) and the minimal velocity eliciting VO2max ( vVO2max ) in normoxia ( N ) and acute moderate hypoxia ( H ) corresponding to an altitude of 2,400 m ( PIO 2 of 109 mmHg ) . Afterwards , on separate days , they performed two all-out constant velocity runs at vO2 max in a r and om order ( one in N and the other in H ) . The decrease in VO2max between N and H showed a great degree of variability amongst subjects as VO2max decreased by 8.9 + /- 4 ml x min(-1 ) x kg)(-1 ) in H vs. N conditions ( -15.3 + /- 6.3 % with a range from -7.9 % to -23.8 % ) . This decrease in VO2max was proportional to the value of VO2max ( VO2max vs. delta VO2max N-H , r = 0.75 , p = 0.03 ) . The time run at vVO2max was not affected by hypoxia ( 483 + /- 122 vs. 506 + /- 148 s , in N and H , respectively , p = 0.37 ) . However , the greater the decrease in vVO2max during hypoxia , the greater the runners increased their time to exhaustion at vVO2max ( vVO2max N-H vs. tlim @vVO2max N-H , r = -0.75 , p = 0.03 ) . In conclusion , this study showed that there was a positive association between the extent of decrease in vVO2max , and the increase in run time at vVO2max in hypoxia PURPOSE This study aim ed to assess the impact of 3 heights of simulated altitude exposure on repeat-sprint performance in team-sport athletes . METHODS Ten trained male team-sport athletes completed 3 sets of repeated sprints ( 9 × 4 s ) on a nonmotorized treadmill at sea level and at simulated altitudes of 2000 , 3000 , and 4000 m. Participants completed 4 trials in a r and om order over 4 wk , with mean power output ( MPO ) , peak power output ( PPO ) , blood lactate concentration ( Bla ) , and oxygen saturation ( SaO2 ) recorded after each set . RESULTS Each increase in simulated altitude corresponded with a significant decrease in SaO2 . Total work across all sets was highest at sea level and correspondingly lower at each successive altitude ( P < .05 ; sea level < 2000 m < 3000 m < 4000 m ) . In the first set , MPO was reduced only at 4000 m , but for subsequent sets , decreases in MPO were observed at all altitudes ( P < .05 ; 2000 m < 3000 m < 4000 m ) . PPO was maintained in all sets except for set 3 at 4000 m ( P < .05 ; vs sea level and 2000 m ) . BLa levels were highest at 4000 m and significantly greater ( P < .05 ) than at sea level after all sets . CONCLUSIONS These results suggest that " higher may not be better , " as a simulated altitude of 4000 m may potentially blunt absolute training quality . Therefore , it is recommended that a moderate simulated altitude ( 2000 - 3000 m ) be employed when implementing intermittent hypoxic repeat-sprint training for team-sport athletes Beetroot juice ( BR ) has been shown to lower the oxygen cost of exercise in normoxia and may have similar effects in hypoxia . We investigated the effect of BR on steady-state exercise economy and 10-km time trial ( TT ) performance in normoxia and moderate hypoxia ( simulated altitude : ~2500 m ) . Eleven trained male cyclists ( VO 2peak ≥ 60 ml · kg(-1 ) · min(-1 ) ) completed four exercise trials . Two hours before exercise , subjects consumed 70 mL BR ( ~6 mmol nitrate ) or placebo ( nitrate-depleted BR ) in a r and omized , double-blind manner . Subjects then completed a 15-min self-selected cycling warm-up , a 15-min steady-state exercise bout at 50 % maximum power output , and a 10-km time trial ( TT ) in either normoxia or hypoxia . Environmental conditions were r and omized and single-blind . BR supplementation increased plasma nitrate concentration and fraction of exhaled nitric oxide relative to PL ( p < .05 for both comparisons ) . Economy at 50 % power output was similar in hypoxic and normoxic conditions ( p > .05 ) , but mean power output was greater in the normoxic TT relative to the hypoxic TT ( p < .05 ) . BR did not affect economy , steady-state SpO2 , mean power output , or 10-km TT completion time relative to placebo in either normoxia or hypoxia ( p > .05 in all comparisons ) . In conclusion , BR did not lower the oxygen cost of steady-state exercise or improve exercise performance in normoxia or hypoxia in a small sample of well-trained male cyclists |
1,930 | 25,525,066 | Whole body vibration was not associated with a significant reduction in Western Ontario and McMaster Universities index pain and stiffness score .
Conclusion : Eight-week and 12-week whole body vibration is beneficial for improving physical functions in patients with knee osteoarthritis and could be included in rehabilitation programs | Objective : To assess the effects of whole body vibration for pain , stiffness and physical functions in patients with knee osteoarthritis . | Abstract Salmon , JR , Roper , JA , and Tillman , MD . Does acute whole-body vibration training improve the physical performance of people with knee osteoarthritis ? J Strength Cond Res 26(11 ) : 2983–2989 , 2012—The purpose of this study was to determine the effects of a single session of whole-body vibration training ( WBVT ) on the physical performance of individuals with knee osteoarthritis ( OA ) in 3 tests design ed to simulate activities of daily living ( ADLs ) . Fifteen individuals with symptomatic knee OA completed the Timed-Up- and -Go Test , step test , 20-m walk test , and visual analog scale ( VAS ) recordings of knee pain intensity . A main effect was detected for time to complete the step test ( F[2,28 ] = 6.243 , p = 0.006 , ) . Post hoc analyses revealed that the time to complete the step test at 5 minutes after WBVT improved significantly ( p = 0.042 ) from that of the pretest . A moderate correlation ( r = 0.465 , p = 0.001 ) was found between the VAS scores and the time to complete the step test across all trials . A main effect was found for time to complete the walk test ( F[2,28 ] = 4.370 , p = 0.022 , ) . Post hoc analyses did not indicate significant improvements from pretest seen at 5 minutes after WBVT ( p = 0.110 ) and 1 hour after WBVT ( p = 0.224 ) . The WBVT was well tolerated in nearly all the participants , and we observed that an acute bout of WBVT was effective in improving the ability of individuals with knee OA to perform a step test and 20-m walk test . Our findings suggest that WBVT may be an effective nonpharmacologic modality to treat some knee OA symptoms and improve ADLs Objective To investigate the effect on pain reduction and strengthening of the whole body vibration ( WBV ) in chronic knee osteoarthritis ( OA ) . Methods Patients were r and omly divided into two groups : the study group ( WBV with home based exercise ) and control group ( home based exercise only ) . They performed exercise and training for 8 weeks . Eleven patients in each group completed the study . Pain intensity was measured with the Numeric Rating Scale ( NRS ) , functional scales were measured with Korean Western Ontario McMaster score ( KWOMAC ) and Lysholm Scoring Scale ( LSS ) , quadriceps strength was measured with isokinetic torque and isometric torque and dynamic balance was measured with the Biodex Stability System . These measurements were performed before training , at 1 month after training and at 2 months after training . Results NRS was significantly decreased in each group , and change of pain intensity was significantly larger in the study group than in the control group after treatment . Functional improvements in KWOMAC and LSS were found in both groups , but no significant differences between the groups after treatment . Dynamic balance , isokinetic strength of right quadriceps and isometric strengths of both quadriceps muscles improved in both groups , but no significant differences between the groups after treatment . Isokinetic strength of left quadriceps did not improve in both groups after treatment . Conclusion In chronic knee OA patients , WBV reduced pain intensity and increased strength of the right quadriceps and dynamic balance performance . In comparison with the home based exercise program , WBV was superior only in pain reduction and similarly effective in strengthening of the quadriceps muscle and balance improvement The aim of this study was to investigate the effect of adding whole-body vibration ( WBV ; frequency = 35 to 40 Hz ; amplitude = 4 mm ) to squat training on the T-cell proliferative response of elderly patients with osteoarthritis ( OA ) of the knee . This study was a r and omized controlled trial in which the selected variables were assessed before and after 12 weeks of training . Twenty-six subjects ( 72 ± 5 years of age ) were divided into three groups : 1 ) squat training with WBV ( WBV , N = 8) ; 2 ) squat training without WBV ( N = 10 ) , and 3 ) a control group ( N = 8) . Women who were ≥60 years of age and had been diagnosed with OA in at least one knee were eligible . The intervention consisted of 12 uninterrupted weeks of squatting exercise training performed 3 times/week . Peripheral blood mononuclear cells were obtained from peripheral blood collected before and after training . The proliferation of TCD4 + and TCD8 + cells was evaluated by flow cytometry measuring the carboxyfluorescein succinimidyl ester fluorescence decay before and after the intervention ( Δ ) . The proliferative response of TCD4 + cells ( P = 0.02 , effect size = 1.0 ) showed a significant decrease ( 23 % ) in the WBV group compared to the control group , while there was no difference between groups regarding the proliferative response of TCD8 + cells ( P = 0.12 , effect size = 2.23 ) . The data suggest that the addition of WBV to squat exercise training might modulate T-cell-mediated immunity , minimizing or slowing disease progression in elderly patients with OA of the knee Background Osteoarthritis ( OA ) is the most common degenerative arthropathy . Load-bearing joints such as knee and hip are more often affected than spine or h and s. The prevalence of gonarthrosis is generally higher than that of coxarthrosis . Because no cure for OA exists , the main emphasis of therapy is analgesic treatment through either mobility or medication . Non-pharmacologic treatment is the first step , followed by the addition of analgesic medication , and ultimately by surgery . The goal of non-pharmacologic and non-invasive therapy is to improve neuromuscular function , which in turn both prevents formation of and delays progression of OA . A modification of conventional physiotherapy , whole body vibration has been successfully employed for several years . Since its introduction , this therapy is in wide use at our facility not only for gonarthrosis , but also coxarthrosis and other diseases leading to muscular imbalance . Methods / Design This study is a r and omized , therapy-controlled trial in a primary care setting at a university hospital . Patients presenting to our outpatient clinic with initial symptoms of gonarthrosis will be assessed against inclusion and exclusion criteria . After patient consent , 6 weeks of treatment will ensue . During the six weeks of treatment , patients will receive one of two treatments , conventional physiotherapy or whole-body-vibration exercises of one hour three times a week . Follow-up examinations will be performed immediately after treatment and after another 6 and 20 weeks , for a total study duration of 6 months . 20 patients will be included in each therapy group . Outcome measurements will include objective analysis of motion and ambulation as well as examinations of balance and isokinetic force . The Western Ontario and McMaster Universities Arthritis Index and SF-12 scores , the patients ' overall status , and clinical examinations of the affected joint will be carried out . Discussion As new physiotherapy techniques develop for the treatment of OA , it is important to investigate the effectiveness of competing strategies . With this study , not only patient-based scores , but also objective assessment s will be used to quantify patient-derived benefits of therapy . Trial registration Deutsches Register Klinischer Studien ( DRKS ) DRKS00000415 Clinical trials.gov NCT01037972EudraCT 2009 - 017617 - In this study , we investigated a new method of training for maximal strength and flexibility , which included exertion with superimposed vibration ( vibratory stimulation , VS ) on target muscles . Twenty-eight male athletes were divided into three groups , and trained three times a week for 3 weeks in one of the following conditions : ( A ) conventional exercises for strength of the arms and VS stretching exercises for the legs ; ( B ) VS strength exercises for the arms and conventional stretching exercises for the legs ; ( C ) irrelevant training ( control group ) . The vibration was applied at 44 Hz while its amplitude was 3 mm . The effect of training was evaluated by means of isotonic maximal force , heel-to-heel length in the two-leg split across , and flex- and -reach test for body flexion . The VS strength training yielded an average increase in isotonic maximal strength of 49.8 % , compared with an average gain of 16 % with conventional training , while no gain was observed for the control group . The VS flexibility training result ed in an average gain in the legs split of 14.5 cm compared with 4.1 cm for the conventional training and 2 cm for the control groups , respectively . The ANOVA revealed significant pre-post training effects and an interaction between pre-post training and ' treatment ' effects ( P < 0.001 ) for the isotonic maximal force and both flexibility tests . It was concluded that superimposed vibrations applied for short periods allow for increased gains in maximal strength and flexibility BACKGROUND AND PURPOSE Assessment of the quality of r and omized controlled trials ( RCTs ) is common practice in systematic review s. However , the reliability of data obtained with most quality assessment scales has not been established . This report describes 2 studies design ed to investigate the reliability of data obtained with the Physiotherapy Evidence Data base ( PEDro ) scale developed to rate the quality of RCTs evaluating physical therapist interventions . METHOD In the first study , 11 raters independently rated 25 RCTs r and omly selected from the PEDro data base . In the second study , 2 raters rated 120 RCTs r and omly selected from the PEDro data base , and disagreements were resolved by a third rater ; this generated a set of individual rater and consensus ratings . The process was repeated by independent raters to create a second set of individual and consensus ratings . Reliability of ratings of PEDro scale items was calculated using multirater kappas , and reliability of the total ( summed ) score was calculated using intraclass correlation coefficients ( ICC [ 1,1 ] ) . RESULTS The kappa value for each of the 11 items ranged from.36 to.80 for individual assessors and from.50 to.79 for consensus ratings generated by groups of 2 or 3 raters . The ICC for the total score was.56 ( 95 % confidence interval=.47-.65 ) for ratings by individuals , and the ICC for consensus ratings was.68 ( 95 % confidence interval=.57-.76 ) . DISCUSSION AND CONCLUSION The reliability of ratings of PEDro scale items varied from " fair " to " substantial , " and the reliability of the total PEDro score was " fair " to " good . OBJECTIVES The study objectives were to evaluate the effects of adding whole-body vibration to squat training on functional performance and self-report of disease in elderly individuals with knee osteoarthritis ( OA ) . DESIGN This was a prospect i ve , r and omized trial in which selected variables were evaluated at three periods : 3 weeks prior to the training , immediately prior , and after the end of the training . SUBJECTS Twenty-three ( 23 ) elderly subjects were evaluated using four functional performance tests : Berg Balance Scale ( BBS ) , Timed Get Up and Go Test ( TGUG ) , Chair St and Test ( CST ) , and 6-Minute Walk Test ( 6MWT ) , and a self-report of the status of disease ( WOMAC ) . INTERVENTIONS The intervention lasted for 12 weeks , 3 times per week . The participants were r and omized into two groups : ( 1 ) squat training with whole-body vibration , and ( 2 ) squat training without vibration . RESULTS Although there was no statistical difference in functional performance and self-report of disease status between the groups , performance in all the functional tests and in all the domains of WOMAC improved in the vibration group compared to their initial status . In the exercise group , performance improved only two tests ( BBS and 6MWT ) , and there was a reduction in self-reported pain ( WOMAC ) compared to their initial status . CONCLUSIONS Although the addition of whole-body vibration to squat training failed to result in a significant improvement in functional performance and self-reported status of knee osteoarthritis in the elderly , the intragroup results suggest that whole-body vibration may represent a feasible and effective way of improving the functionality and self-perception of disease status in older adults with knee OA The purpose of this study was to assess the effect of whole body vibration ( WBV ) exercise on muscle strength and proprioception in female patients with osteoarthritis in the knee ( knee-OA ) . A single blinded , r and omised , controlled trial was performed in an outpatient clinic on 52 female patients diagnosed with knee-OA ( mean age 60.4 years+/-9.6 ) . They were r and omly assigned to one of 3 groups : 1 . WBV-exercise on a stable platform ( VibM ; n=17 ( mean age , 61.5+/-9.2 ) ) , WBV-exercise on a balance board ( VibF ; n=18 ( mean age , 58.7+/-11.0 ) ) , or control group ( Con ; n=18 ( mean age , 61.1+/-8.5 ) ) . The WBV groups trained twice a week for 8 weeks , with a progressively increasing intensity . The WBV groups performed unloaded static WBV exercise . The following were measured : knee muscle strength ( extension/flexion ) and proprioception ( threshold for detection of passive movement ( TDPM ) ) . Self-reported disease status was measured using WOMAC . It was found that muscle strength increased significantly ( p<0.001 ) in VibM compared to Con . Isometric knee-extension significantly increased ( p=0.021 ) in VibM compared to Con . TDPM was significantly improved ( p=0.033 ) in VibF compared to Con , while there was a tendency ( p=0.051 ) for VibM to perform better compared to Con . There were no effects in the self-reported disease status measures . This study showed that the WBV-exercise regime on a stable platform ( VibM ) yielded increased muscle strength , while the WBV-exercise on a balance board ( VibF ) showed improved TDPM . The WBV-exercise is a time-saving and safe method for rehabilitation of women with knee-OA OBJECTIVE To determine whether a platform exercise program with vibration is more effective than platform exercise alone for improving lower limb muscle strength and power in women ages 45 to 60 with risk factors for knee osteoarthritis ( OA ) . DESIGN R and omized , controlled study . SETTING Academic center . PARTICIPANTS A total of 48 women ages 45 - 60 years with risk factors for knee OA ( a history of knee injury or surgery or body mass index ≥25 kg/m(2 ) ) . INTERVENTIONS Subjects were r and omly assigned to a twice-weekly lower limb exercise program ( quarter squat , posterolateral leg lifts , calf raises , step-ups , and lunges ) on either a vertically vibrating platform ( 35 Hz , 2 mm ) or a nonvibrating platform . MAIN OUTCOME MEASUREMENTS Change in isokinetic quadriceps strength , leg press power , and stair climb power by 12 weeks . RESULTS A total of 39 of 48 enrolled participants completed the study ( 26 vibration and 13 control exercise ) . Nine participants discontinued the study after r and omization mainly because of a lack of time . No intergroup differences in age , body mass index , or activity level existed . Isokinetic knee extensor strength did not significantly improve in either group . Leg press power improved by 92.0 ± 69.7 W in the vibration group ( P < .0001 ) and 58.2 ± 96.2 W in the control group ( P = .0499 ) but did not differ between groups ( P = .2262 ) . Stair climb power improved by 53.4 ± 64.7 W in the vibration group ( P = .0004 ) and 55.7 ± 83.3 W in the control group ( P = .0329 ) but did not differ between groups ( P = .9272 ) . CONCLUSIONS Whole body vibration platforms have been marketed for increasing strength and power . In this group of asymptomatic middle-aged women with risk factors for knee OA , the addition of vibration to a 12-week exercise program did not result in significantly greater improvement in lower limb strength or power than did participation in the exercise program without vibration OBJECTIVE To investigate the effects of squat exercises combined with whole-body vibration on the plasma concentration of inflammatory markers and the functional performance of elderly individuals with knee osteoarthritis ( OA ) . DESIGN Clinical , prospect i ve , r and omized , single-blinded study . SETTING Exercise physiology laboratory . PARTICIPANTS Elderly subjects with knee OA ( N=32 ) were divided into 3 groups : ( 1 ) squat exercises on a vibratory platform ( platform group , n=11 ) ; ( 2 ) squat exercises without vibration ( squat group , n=10 ) ; and ( 3 ) the control group ( n=11 ) . INTERVENTIONS The structured program of squat exercises in the platform and squat groups was conducted 3 times per week , on alternate days , for 12 weeks . MAIN OUTCOME MEASURES Plasma soluble tumor necrosis factor-α receptors 1 ( sTNFR1 ) and 2 ( sTNFR2 ) were measured using immunoassays ( the enzyme-linked immunosorbent assay method ) . The Western Ontario and McMaster Universities Osteoarthritis Index question naire was used to evaluate self-reported physical function , pain , and stiffness . The 6-minute walk test , the Berg Balance Scale , and gait speed were used to evaluate physical function . RESULTS In the platform group , there were significant reductions in the plasma concentrations of the inflammatory markers sTNFR1 and sTNFR2 ( P<.001 and P<.05 , respectively ) and self-reported pain ( P<.05 ) compared with the control group , and there was an increase in balance ( P<.05 ) and speed and distance walked ( P<.05 and P<.001 , respectively ) . In addition , the platform group walked faster than the squat group ( P<.01 ) . CONCLUSIONS The results suggest that whole-body vibration training improves self-perception of pain , balance , gait quality , and inflammatory markers in elderly subjects with knee OA |
1,931 | 26,919,194 | There were no significant differences for discontinuation rates . | OBJECTIVES Narrative , un systematic review s revealed no differences in efficacy between the various first-generation antipsychotics ( FGAs ) result ing in the psychopharmacological assumption of comparable efficacy between the different FGAs .
We sought to determine if the assumption of comparable efficacy of all FGAs can be regarded as evidence -based using meta-analytic statistics . | Zuclopenthixol acetate — a new injectable formulation with a duration of action of 2–3 days — was compared with conventional intramuscular and oral formulations of haloperidol and zuclopenthixol in the initial treatment of acutely disturbed , psychotic patients . The patients were stratified into 3 diagnostic categories : acute psychoses ( 48 patients ) , mania ( 22 patients ) , and exacerbation of chronic psychoses ( 73 patients ) . The patients were rated on the Brief Psychiatric Rating Scale ( BPRS ) , the Bech‐Rafaelsen Mania Rating Scale ( brmas ) ( only manic patients ) and globally on the Clinical Global Impression ( CGI ) . The study was an open , r and omized multicentre trial with a 6‐day treatment period . The zuclopenthixol acetate patients received 1–4 doses , the haloperidol patients 1–26 and the zuclopenthixol patients 1–22 doses . The assessment s on the CGI showed that all 3 treatments caused a clear reduction of the severity of illness scores in all 3 diagnostic categories , with no differences between treatments . The ratings of the acute and chronic psychotic patients on the BPRS also showed significant reductions in scores with no differences between treatments . All 3 treatments caused a rapid remission of symptoms on the BRMAS . Haloperidol induced hypokinesia in significantly more patients than zuclopenthixol acetate after 24 h. Later there were no significant differences between treatments . Zuclopenthixol acetate fulfils many desires for an amended neuroleptic formulation for the initial treatment of acutely disturbed psychotic patients OBJECTIVE Despite the frequent use of the Positive and Negative Syndrome Scale ( PANSS ) for rating the symptoms of schizophrenia , the clinical meaning of its total score and of the cut-offs that are used to define treatment response ( e.g. at least 20 % or 50 % reduction of the baseline score ) are as yet unclear . We therefore compared the PANSS with simultaneous ratings of Clinical Global Impressions ( CGI ) . METHOD PANSS and CGI ratings at baseline ( n = 4091 ) , and after one , two , four and six weeks of treatment taken from a pooled data base of seven pivotal , multi-center antipsychotic drug trials on olanzapine or amisulpride in patients with exacerbations of schizophrenia were compared using equipercentile linking . RESULTS Being considered " mildly ill " according to the CGI approximately corresponded to a PANSS total score of 58 , " moderately ill " to a PANSS of 75 , " markedly ill " to a PANSS of 95 and severely ill to a PANSS of 116 . To be " minimally improved " according to the CGI score was associated with a mean percentage PANSS reduction of 19 % , 23 % , 26 % and 28 % at weeks 1 , 2 , 4 and 6 , respectively . The corresponding figures for a CGI rating " much improved " were 40 % , 45 % , 51 % and 53 % . CONCLUSIONS The results provide a better framework for underst and ing the clinical meaning of the PANSS total score in drug trials of schizophrenia patients with acute exacerbations . Such studies may ideally use at least a 50 % reduction from baseline cut-off to define response rather than lower thresholds . In treatment resistant population s , however , even a small improvement can be important , so that a 25 % cut-off might be appropriate Poor neuroleptic response is a major unresolved clinical problem . Precise data concerning the frequency of poor neuroleptic response are not available . The implementation of treatment modalities that are specifically recommended for non‐responders ( such as clozapine ) increases the desirability of such data . This study evaluated the proportion of acutely exacerbated schizophrenics who remained unimproved by consecutive administration of haloperidol , chlorpromazine and perphenazine , in r and omly determined order . The overall improvement rate was 95 % . The frequency of good responses to the first , second and third drug were 67 % , 55 % , and 67 % respectively . Differences in receptor affinity profile might explain the added beneficial effect of a second or third drug Forty acutely psychotic patients were treated either with flupenthixol drops or haloperidol drops in an open , 28-day controlled study . The flupenthixol group comprised 11 schizophrenic , 8 manic , and 1 paranoid patient and there were 10 schizophrenic , 5 manic , and 5 paranoid patients in the haloperidol group . Mean daily dosage was approximately 112 mg flupenthixol and 18 mg haloperidol . Clinical ly , both drugs showed an antipsychotic effect . In the schizophrenic patients there was a definite trend towards a more rapid relief of the psychotic symptoms after flupenthixol treatment . In contrast to haloperidol , flupenthixol showed a mood elevating effect and an effect on the negative symptoms , e.g. emotional withdrawal , motor retardation , blunted affect , and disorientation . With both drugs , the most troublesome side-effects were extrapyramidal in nature . Initially , they were more common in the flupenthixol group : later the incidence was similar The relative efficacy of 4 tranquilizers was investigated in 66 chronic schizophrenics who had been hospitalized for 10.01 years ( mean ) . The role of adding an anti-depressant was also studied . Following a 4 week placebo period , high dosage tranquilizers were given for 16 weeks and amitriptyline was added for the following 16 weeks . Statistical analyses of the various change measures revealed that patients worsened significantly on placebo , all 4 tranquilizers were significantly better than placebo for symptom reduction and maximum improvement was attained within 16 weeks of tranquilizer administration . No significant differences in efficacy were observed among the 4 tranquilizers and addition of amitriptyline did not confer any additional therapeutic advantage Subjects Thirty-four newly admitted acute schizophrenic patients were studied : they included first admissions and others undergoing acute exacerbations with a history of previous acute schizophrenic episodes . None of these patients had received tranquillizing medication for at least one month prior to admission to hospital , or electroconvulsive therapy for at least two months . They ranged in age from seventeen to fifty-four years with a mean age of thirty-four . Some preliminary . findings with the first twenty subjects in this series have already been published ( 4 ) . coefficient of variation ( CV ) than the other fifty-five patients who were receiving a variety of drugs . The procedure described here permitted a more detailed analysis of the effects of two antipsychotic agents ( quite different in chemical structure ) upon the integrated EEG measures in a more systematic comparative design of shortterm drug effects . It also permitted a comparison of effects , both clinical and EEG , over a time period ( seven days ) similar to that in which the clinician might ordinarily decide whether his patient was showing satisfactory response , leading him to continue a particular antipsychotic compound or switch to another An experimental method was utilized to compare the masking effects of two neuroleptic agents -- molindone and haloperidol -- on 18 neuroleptic-treated schizophrenic patients exhibiting operationally defined withdrawal-exacerbated tardive dyskinesia . After a week on one of these two medications at preestablished doses equivalent to that of the pre- study neuroleptic , molindone-masked total AIMS scores by significantly less ( 12 % ) than haloperidol ( 27 % ) . Similarly , during a second week when the dose of these neuroleptics was equivalent to 200 % that of the pre- study dose , molindone masked the total AIMS score significantly less ( 23 % ) as compared to haloperidol ( 53 % ) . Several interpretations of this finding are considered . This study demonstrates the feasibility of a method that may offer a model for underst and ing pharmacological differences among neuroleptic medications Remitted schizophrenic out patients were treated in order to prevent relapse with three doses of haloperidol or propericiazine for 1 year in a double-blind controlled study employing a r and omized design . The drug 's ability to prevent relapse was evaluated by counting the number of symptom-free days for each patient before any sign of relapse or over-dose appeared . Patients were r and omly assinged to the following drugs orally administered once per day at night : placebo ; haloperidol 1 mg , 3 mg , and 6 mg ; propericiazine 10 mg , 30 mg , and 60 mg . Serum prolactin levels in each patient were estimated by radioimmunoassay . All patients treated with placebo relapsed within 1 year and the relapse rate with placebo was significantly higher than with any dose of the two neuroleptics . Haloperidol increased the number of symptom-free days in a dose-dependent manner . Propericiazine at 10 mg and 30 mg also increased the number of symptom-free days dose-dependently but at 60 mg , the number decreased . It appears that propericiazine shows an inverted U-shaped dose-response curve . Prolactin levels were elevated dose-dependently by both drugs but failed to show a significant correlation with the number of symptom-free days . The present results indicate that haloperidol is superior to propericiazine from the viewpoint of the wider “ therapeutic window ” in maintenance treatment and antidopaminergic properties of neuroleptics , wherein it is important to prevent relapse even in remitted schizophrenics BACKGROUND Second-generation antipsychotic drugs were introduced over a decade ago for the treatment of schizophrenia ; however , their purported clinical effectiveness compared with first-generation antipsychotic drugs is still debated . We aim ed to compare the effectiveness of second-generation antipsychotic drugs with that of a low dose of haloperidol , in first-episode schizophrenia . METHODS We did an open r and omised controlled trial of haloperidol versus second-generation antipsychotic drugs in 50 sites , in 14 countries . Eligible patients were aged 18 - 40 years , and met diagnostic criteria for schizophrenia , schizophreniform disorder , or schizoaffective disorder . 498 patients were r and omly assigned by a web-based online system to haloperidol ( 1 - 4 mg per day ; n=103 ) , amisulpride ( 200 - 800 mg per day ; n=104 ) , olanzapine ( 5 - 20 mg per day ; n=105 ) , quetiapine ( 200 - 750 mg per day ; n=104 ) , or ziprasidone ( 40 - 160 mg per day ; n=82 ) ; follow-up was at 1 year . The primary outcome measure was all-cause treatment discontinuation . Patients and their treating physicians were not blinded to the assigned treatment . Analysis was by intention to treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N68736636 . FINDINGS The number of patients who discontinued treatment for any cause within 12 months was 63 ( Kaplan-Meier estimate 72 % ) for haloperidol , 32 ( 40 % ) for amisulpride , 30 ( 33 % ) for olanzapine , 51 ( 53 % ) for quetiapine , and 31 ( 45 % ) for ziprasidone . Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride ( hazard ratio [ HR ] 0.37 , [ 95 % CI 0.24 - 0.57 ] ) , olanzapine ( HR 0.28 [ 0.18 - 0.43 ] ) , quetiapine ( HR 0.52 [ 0.35 - 0.76 ] ) , and ziprasidone ( HR 0.51 [ 0.32 - 0.81 ] ) . However , symptom reductions were virtually the same in all the groups , at around 60 % . INTERPRETATION This pragmatic trial suggests that clinical ly meaningful antipsychotic treatment of first-episode of schizophrenia is achievable , for at least 1 year . However , we can not conclude that second-generation drugs are more efficacious than is haloperidol , since discontinuation rates are not necessarily consistent with symptomatic improvement The schizophrenic patient 's early psychological response to neuroleptic treatment has been demonstrated to be a significant predictor of treatment response . The validity of the construct of subjective response is evaluated by comparison of two measures . Fifty-five recently admitted and unmedicated schizophrenic patients were r and omly allocated to chlorpromazine or haloperidol . Subjective responses at 24 and 48 hours as assessed by two different scales , the Van Putten & May scale and the self-administered Drug Attitude Inventory , were strongly correlated with outcome at three weeks . Early emergence of extrapyramidal symptoms was not related to subjective response , but dysphoric patients had a greater incidence of EPS by the end of treatment than did non-dysphoric patients . The two measures showed high concordance in identification of early drug dysphoria Neurochemical distinctions have been made between neuroleptic drugs that affect D-1 receptors as well as D-2 receptors , compared with those neuroleptic drugs that affect only D-2 receptors . However , a controlled double-blind study of haloperidol vs. chlorprothixene in schizophrenic patients found no significant differences BACKGROUND The relative effectiveness of second-generation ( atypical ) antipsychotic drugs as compared with that of older agents has been incompletely addressed , though newer agents are currently used far more commonly . We compared a first-generation antipsychotic , perphenazine , with several newer drugs in a double-blind study . METHODS A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and r and omly assigned to receive olanzapine ( 7.5 to 30 mg per day ) , perphenazine ( 8 to 32 mg per day ) , quetiapine ( 200 to 800 mg per day ) , or risperidone ( 1.5 to 6.0 mg per day ) for up to 18 months . Ziprasidone ( 40 to 160 mg per day ) was included after its approval by the Food and Drug Administration . The primary aim was to delineate differences in the overall effectiveness of these five treatments . RESULTS Overall , 74 percent of patients discontinued the study medication before 18 months ( 1061 of the 1432 patients who received at least one dose ) : 64 percent of those assigned to olanzapine , 75 percent of those assigned to perphenazine , 82 percent of those assigned to quetiapine , 74 percent of those assigned to risperidone , and 79 percent of those assigned to ziprasidone . The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine ( P<0.001 ) or risperidone ( P=0.002 ) group , but not in the perphenazine ( P=0.021 ) or ziprasidone ( P=0.028 ) group . The times to discontinuation because of intolerable side effects were similar among the groups , but the rates differed ( P=0.04 ) ; olanzapine was associated with more discontinuation for weight gain or metabolic effects , and perphenazine was associated with more discontinuation for extrapyramidal effects . CONCLUSIONS The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons . Olanzapine was the most effective in terms of the rates of discontinuation , and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine , risperidone , and ziprasidone . Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism In a double-blind cross-over trial , 20 chronic schizophrenic patients were treated with sulpiride and haloperidol in two 12-week periods . The final median dose of sulpiride was 2000 mg/day ( range 800 - 3200 ) and of haloperidol 12 mg/day ( range 6 - 24 ) . Sulpiride had an antipsychotic effect and therapeutic profile not significantly different from that of haloperidol . In spite of the high doses of sulpiride , extrapyramidal side-effects were seen less frequently during the first four weeks of the sulpiride period than during the corresponding haloperidol period ( P less than 0.05 ) , whereas autonomic side-effects were equally rare for both drugs . A positive correlation was found between daily dose and plasma concentration of both sulpiride ( P less than 0.001 ) and haloperidol ( P less than 0.05 ) , but no correlation could be established between clinical effects and plasma levels of either neuroleptic Improvement of acute psychotic exacerbations under neuroleptic therapy can depend on the time course of the disease itself , on the individual patient or on the specific neuroleptic applied . Previous studies demonstrated that neither the characteristics of the patients nor the disease qualities could predict the outcome of neuroleptic therapy ( review by May and Goldberg 1978 ) . In this study the initial improvement after the onset of neuroleptic treatment was tested for its predictive value . In 33 patients treated with constant doses of butyrophenones the decrease of psychotic symptomatology during the first 5 days of treatment not only accounted for the major part of the overall improvement , but was also a relatively reliable predictor for the further course of the therapy In a double blind chlorpromazine-controlled trial , high dosage haloperidol ( 100 mg daily ) given for three months , appreciably improved the mental state of male chronic ' drug resistant ' schizophrenic in patients in the rehabilitation/long-stay unit of one psychiatric hospital . The results of a three-month follow-up suggested that the improvement could be maintained in some patients on lower doses of the drug . Serious extrapyramidal side effects were not seen at high doses . However , the majority of patients on haloperidol showed a deterioration in ward behaviour , possibly related to drowsiness , and developed raised serum alkaline phosphatase levels . These side effects disappeared in the follow-up period when either the drug was discontinued or the dose of haloperidol reduced In a parallel groups , double-blind study , 54 acutely psychotic schizophrenics were given loxapine or haloperidol parenterally for 24 to 72 hours , then orally for a total study period of up to 10 days . Dosage ratios of loxapine to haloperidol ranged from a minimum of 2.7:1 to a maximum of 4.4:1 . Both groups showed significant and rapid improvement from baseline . Forty-eight percent of the loxapine patients and 33 % of the haloperidol patients achieved and maintained a global severity of illness rating of mild or better . By the end of the study , 84 % of the loxapine patients and 63 % of the haloperidol patients had achieved an improvement rating of moderate or marked . This difference approached significance ( p less than .10 ) . The most frequently reported adverse experiences were dystonic reactions and akathisia . The number and severity of adverse experiences did not differ significantly between drug groups . Intramuscular loxapine was at least as effective as haloperidol in the initial management of hostile and aggressive schizophrenic patients . The maintenance of therapeutic response after conversion to oral concentrate was comparable with the two drugs Preliminary findings are reported for a study of the relative efficacy of conventional treatment alternatives routinely used to treat acutely relapsed schizophrenic patients who fail an initial course of st and ard neuroleptic therapy . A sample of 156 acutely ill schizophrenic , schizoaffective , and schizophreniform patients who had been hospitalized recently in an acute-care inpatient facility were treated openly with fluphenazine ( FPZ ) 20 mg/day and with prophylactic benztropine for 4 weeks . Those subjects who failed to meet a priori criteria for substantial therapeutic response at the end of Week 4 were r and omized to receive double-blind treatment for an additional 4 weeks with one of the following : ( 1 ) the same dose of neuroleptic ( FPZ 20 mg/day ) ; ( 2 ) an increased dose of neuroleptic ( FPZ 80 mg/day ) ; or ( 3 ) a different class of neuroleptic ( haloperidol 20 mg/day ) . Of the 115 subjects who completed the open phase of study , 32 percent were identified as responders . Higher negative symptom scores and increased acute extrapyramidal side effect ratings appeared to distinguish the nonresponder from the responder group . Of the nonresponders who went on to r and omized treatment , only 4 of 47 subjects ( 9 % ) subsequently responded . No superior efficacy was associated with any of the specific alternative treatments studied |
1,932 | 12,535,391 | REVIEW ER 'S CONCLUSIONS Drugs given routinely for malaria during pregnancy reduce severe antenatal anaemia in the mother , and are associated with higher birthweight and probably reduced perinatal mortality .
This effect appears to be limited to low parity women | BACKGROUND Malaria contributes to maternal illness and anaemia in pregnancy , especially in first-time mothers , and could harm the mother and the baby .
Interventions to prevent or mitigate the effects of malaria during pregnancy are often recommended .
OBJECTIVES To assess drugs given to prevent malaria infection and its consequences in pregnant women living in malarial areas . | Two hundred Hausa primigravidae at Zaria were divided into five groups in a r and omized double-blind trial of antenatal oral antimalarial prophylaxis , and haematinic supplements . Group 1 received no active treatment . Groups 2 to 5 were given chloroquine 600 mg base once , followed by proguanil 100 mg per day . In addition , group 3 received iron 60 mg daily , group 4 folic acid 1 mg daily , and group 5 iron plus folic acid . Forty-five percent were anaemic ( haemoglobin ( Hb ) less than 11.0 g dl-1 ) at first attendance before 24 weeks of gestation , and malaria parasitaemia ( predominantly Plasmodium falciparum ) was seen in 27 % , of whom 60 % were anaemic . The mean Hb fell during pregnancy in group 1 , and seven patients in this group had to be removed from the trial and treated for severe anaemia ( packed cell volume ( PCV ) less than 0.26 ) . Only five patients in the other groups developed severe anaemia ( P = 0.006 ) , two of whom had malaria following failure to take treatment . Patients in group 1 had the lowest mean Hb at 28 and 36 weeks of gestation , and patients receiving antimalarials and iron ( groups 3 and 5 ) had the highest Hb at 28 weeks , but differences were not significant , possibly due to removal from the trial of patients with severe anaemia . Anaemia ( Hb less than 12.0 g dl-1 ) at six weeks after delivery was observed in 61 % of those not receiving active treatment ( group 1 ) , in 39 % of those protected against malaria but not receiving iron supplements ( groups 2 and 4 ) and in only 18 % of patients receiving both antimalarials and iron ( groups 3 and 5 ) . Folic acid had no significant effect on mean Hb . Proguanil was confirmed to be a highly effective causal prophylaxis . Prevention of malaria , without folic acid supplements , reduced the frequency of megaloblastic erythropoiesis from 56 % to 25 % . Folic acid supplements abolished megaloblastosis , except in three patients who were apparently not taking the treatment prescribed . Red cell folate ( RCF ) concentrations were higher in subjects with malaria , probably due to intracellular synthesis by plasmodia . Infants of mothers not receiving antimalarials appeared to have an erythroid hyperplasia . Maternal folate supplements raised infants ' serum folate and RCF . Fourteen per cent had low birth weight ( less than 2500 g ) , and the perinatal death rate was 11 % ; the greatest number were in group 1 , but not significantly . A regime is proposed for the prevention of malaria , iron deficiency , folate deficiency and anaemia in pregnancy in the guinea savanna of Nigeria To determine the effect of chloroquine chemoprophylaxis during pregnancy on birth weights , a r and omized trial was carried out in 1987 and 1988 in Banfora , Burkina Faso ( West Africa ) . Seven hundred forty-five r and omly selected women treated with chloroquine sulfate were compared to with 719 controls who received no treatment . In spite of an un question able effect of chloroquine in preventing placental infection ( 4.1 % infected placentas in the treated group versus 19.0 % in the controls ) , the mean difference in birth weights between the two groups ( 6 g ) was not significant . The difference in the proportion of low birth weight ( LBW ) newborn babies in two groups ( 16.3 % versus 16.4 % ) was also not significant . However , there was a strong relationship between placental infection and birth weight ( the mean birth weight difference between infected and uninfected placentas was 113 g , and the proportion of LBW babies was 26.0 % in infected placentas versus 14.8 % in uninfected placentas ) . The small difference in birth weights observed between the two groups may be due to the fact that the prevalence rate of placental infection is low and that prophylaxis is effective only on a portion of the subjects in the treated group . It may also indicate that malaria is only one of several risk factors responsible for LBW . The relatively small increase in birth weight , the expected poor acceptance of mass prophylaxis , and the spreading of chloroquine-resistant Plasmodium strains should be considered before extending malaria chemoprophylaxis to all pregnant women . It might be worth considering to limit prophylaxis to primigravidae BACKGROUND In areas of endemic transmission , malaria in pregnancy is associated with severe maternal anaemia and low-birthweight babies . We studied the efficacy of intermittent treatment doses of sulphadoxine-pyrimethamine in preventing malaria and severe anaemia in pregnancy in a double-blind placebo-controlled trial among primigravid women living in Kilifi District , Kenya . METHODS Between January , 1996 , and April , 1997 , 1264 primigravid women were recruited when they attended for antenatal care , and r and omly assigned sulphadoxine-pyrimethamine ( 640 ) or placebo ( 624 ) . Women received one , two , or three doses of study medication depending on the duration of gestation at enrolment . Primary outcome measures were severe anaemia ( haemoglobin < 8 g/dL ) and malaria parasitaemia , assessed at 34 weeks of gestation . Analyses were based on intention to treat among women who had study blood tests at 34 weeks . FINDINGS 30 ( 5.3 % ) of 567 women in the sulphadoxine-pyrimethamine group and 199 ( 35.3 % ) of 564 in the placebo group had peripheral parasitaemia ( protective efficacy 85 % [ 95 % CI 78 - 90 ] , p<0.0001 ) . 82 ( 14.5 % ) and 134 ( 23.7 % ) had severe anaemia ( protective efficacy 39 % [ 22 - 52 ] , p<0.0001 ) . Even women who booked late and received only one dose of sulphadoxine-pyrimethamine benefited significantly from the intervention . The effects were seen both in women who owned insecticide-treated bednets and in women who did not . INTERPRETATION Intermittent presumptive treatment with sulphadoxine-pyrimethamine is an effective , practicable strategy to decrease the risk of severe anaemia in primigravidae living in malarious areas The effectiveness of insecticide-treated bednets ( ITBN ) in preventing malaria and anaemia among primigravidae living in Kilifi District , Kenya , was assessed by a r and omized controlled trial between September 1994 and November 1995 . All residents within 28 community clusters received ITBN in July 1993 , whilst residents of another 28 clusters served as contemporaneous controls . All resident primigravid women with singleton pregnancies attending antenatal care at Kilifi District Hospital were eligible for recruitment . 503 primigravidae were recruited . 91.4 % were anaemic antenatally ( Hb < 11 g/dl ) : 91.0 % from the intervention arm and 92.0 % from the control arm . Severe anaemia ( Hb < 7 g/dl ) was found among 15.1 % of intervention women and 20.1 % of control women ( P = 0.28 ) . No significant differences were observed in reports of febrile illness or the presence of chloroquine in the serum or peripheral parasitaemia during the third trimester between the two groups . In the women delivering in hospital ( n = 130 ) , there was no association between placental malaria infection and the intervention : 77.4 % of placentas from control women had evidence of past or active infection , compared with 72.0 % of placentas from intervention women ( P = 0.76 ) . Similarly , in the women delivering in hospital , ITBN did not improve birth weight , and there were no differences in perinatal mortality between the two study groups . Despite ITBN having a great impact on paediatric severe malaria and mortality in this transmission setting , there was very little impact of ITBN on the morbidity associated with malaria infection in primigravidae . Alternative strategies are required to tackle this continued public health problem for pregnant women living in endemic areas similar to the Kenyan Coast A r and omized trial was carried out from 1991 to 1993 among women attending an antenatal clinic in Ebolowa , Cameroon where malaria is hyperendemic and transmission occurs at a high level all year round . All pregnant women attending the clinic for their first prenatal visit between October 1991 and November 1992 were alternately assigned to chloroquine ( CQ ) or control ( CT ) groups . Chloroquine was given under observation at a weekly oral dose of 300 mg . At delivery , smears from maternal , cord , and placental blood were made and stained with Giemsa for parasites . An in vivo chloroquine sensitivity investigation was carried out on women attending the postnatal consultation to evaluate the level of chloroquine resistance in the target population . The efficacy of chloroquine was moderate in placental infection ( 39.2 % infected in the CQ group versus 57.8 % in the CT group : P = 0.05 ) , probably because of a resistance to chloroquine estimated to be 10.9 % . In the CQ group , the mean birth weight was significantly higher ( P = 0.02 ) and the proportion of low birth weight newborns was lower ( 10.5 % versus 27.7 % ; P = 0.02 ) . A strong correlation between placental infection and birth weight was observed : the mean birth weight difference between infected and noninfected placentae was 359 g ( P < 0.0001 ) and the proportion of low birth weight new born babies was 35.6 % versus 5.9 % ( P = 0.0001 ) . In Cameroon , in spite of a moderate resistance to chloroquine , this drug proved to be highly effective in increasing birth weight when administered to primigravidae . We therefore think such a prophylaxis should be recommended only to primigravidae in high transmission areas To define an effective and deliverable antimalarial regimen for use during pregnancy , pregnant women at highest risk of malaria ( those in their first or second pregnancy ) in an area of Malawi with high transmission of chloroquine (CQ)-resistant Plasmodium falciparum were placed on CQ and /or sulfadoxine-pyrimethamine ( SP ) . Of 38 pregnant women who received CQ treatment followed by weekly CQ prophylaxis ( CQ/CQ ) for at least 45 days prior to delivery , 32 % had placental malaria infection , compared with 26 % of 50 pregnant women who received a treatment dose of SP followed by weekly CQ prophylaxis ( SP/CQ ) , and only 9 % of 71 pregnant women who received a two-dose SP regimen ( SP/SP ; given once during the second trimester and repeated at the beginning of the third trimester ) ( P = 0.006 , by chi-square test ) . During the peak transmission season from April to July , 47 % of the women who received CQ/CQ had placental malaria infection at delivery , as compared with 37 % of the women who received SP/CQ , and 10 % of women who received SP/SP ( P = 0.004 , by chi-square test ) . Among women in their first or second pregnancy , two treatment doses of SP were highly effective in decreasing the proportion of women with placental malaria infection at delivery A r and omized , double blind , placebo-controlled community based trial of Maloprim ( pyrimethamine 12.5 mg+dapsone 100 mg ) administered to primigravid pregnant women by Traditional Birth Attendants was carried out in a rural area of The Gambia , West Africa . Placental histology showed less malaria infection in women who received chemoprophylaxis than in those who received placebo . The birth weight of children born to women who received chemoprophylaxis was increased by an average of 153 g. Within the treatment groups , there were no significant differences in the birthweights of babies born to women who had histological evidence of malaria infection of the placenta compared to those who had no malaria infection . This study confirms the beneficial effect of malaria prophylaxis for primigravid pregnant women but questions the mechanism by which malaria affects foetal development The safety of daily application of N , N-diethyl-m-toluamide ( DEET ) ( 1.7 g of DEET/day ) in the second and third trimesters of pregnancy was assessed as part of a double-blind , r and omized , therapeutic trial of insect repellents for the prevention of malaria in pregnancy ( n = 897 ) . No adverse neurologic , gastrointestinal , or dermatologic effects were observed for women who applied a median total dose of 214.2 g of DEET per pregnancy ( range = 0 - 345.1 g ) . DEET crossed the placenta and was detected in 8 % ( 95 % confidence interval = 2.6 - 18.2 ) of cord blood sample s from a r and omly selected subgroup of DEET users ( n = 50 ) . No adverse effects on survival , growth , or development at birth , or at one year , were found . This is the first study to document the safety of DEET applied regularly in the second and third trimesters of pregnancy . The results suggest that the risk of DEET accumulating in the fetus is low and that DEET is safe to use in later pregnancy A prospect i ve comparison of the antimalarial efficacy of bed nets was conducted with 341 pregnant women living in a mesoendemic malarious area of the Thai-Burmese border . Women in 3 adjacent study sites were allocated at r and om to receive either a single size permethrin-impregnated bed net ( PIB ) , a non-impregnated bed net ( NIB ) , or to a control group who used either their own family size non-impregnated bed net ( FNIB ) or no net . In one study site , but not the other 2 , PIB significantly reduced parasite densities and , together with FNIB , reduced the incidence of malaria in pregnancy from 56 % to 33 % ( relative risk = 1.67 , confidence interval = 1.07 - 2.61 , P = 0.03 , allowing for parity ) . Anaemia proved a more sensitive marker of bed net antimalarial efficacy than parasite rates . The incidence of anaemia ( haematocrit < 30 % ) at all study sites was significantly lower at delivery in the PIB ( 27 % ) and FNIB groups ( 21 % ) than in the NIB group ( 41 % ) or those using no net ( 56 % ) . This suggests that a significant proportion of the malaria in pregnancy in this mesoendemic area was sub-patent . Both patent Plasmodium falciparum parasitaemia and anaemia were associated with a reduction in birth weight . Infant mortality was high ( 16 % ) and strongly associated with prematurity , low birth weight and maternal anaemia . PIB were well tolerated and had no apparent adverse effect on the pregnancy or infant development . Although the overall effect of bed nets on patent parasitaemia was marginal , they were associated with a significant reduction in maternal malaria-associated anaemia . ( ABSTRACT TRUNCATED AT 250 WORDS A trial of malaria chemoprophylaxis given by traditional birth attendants was undertaken in a rural area of The Gambia where access to antenatal clinics is difficult . Women received one or more doses of Maloprim or placebo from a traditional birth attendant during 1049 of 1208 pregnancies ( 87 % ) recorded in 16 villages over a 3-year period . Primigravidae who received Maloprim had a lower parasite rate and a significantly higher mean packed cell volume than primigravidae who received placebo , and their babies were significantly heavier ( 6 % low birth weight vs 22 % ) . In multigravidae chemoprophylaxis reduced malaria parasitaemia but it had no beneficial effect on haemoglobin level and much less effect on birth weight than was observed in primigravidae . However , the mean birth weight of babies born to gr and emultigravidae who received chemoprophylaxis was significantly higher than that of babies born to gr and emultigravidae who did not Despite international recommendations to use malaria treatment and prevention in pregnant women in malaria-endemic areas , few studies have evaluated the efficacy of available antimalarial regimens . This issue is of particular concern in the face of spreading chloroquine (CQ)-resistance of Plasmodium falciparum in malarious areas of sub-Saharan Africa . In a prospect i ve trial in rural Malawian pregnant women , we examined three regimens using CQ ( including the existing national policy regimen ) and one regimen using mefloquine ( MQ ) . The efficacy of the regimens was determined by comparing rates of clearance of initial parasitemia ; prevention of breakthrough infection ; and parasitemia at delivery in maternal peripheral blood , placental blood , and in infant umbilical cord blood . Among 1,528 parasitemic women at enrollment , 281 ( 18.4 % ) had persistent infections ; and among 1,852 initially aparasitemic women , 320 ( 17.3 % ) had breakthrough parasitemia on one or more follow-up visits . Compared with women on MQ , women on a CQ regimen were at significantly greater risk of persistent and breakthrough infection ( odds ratios [ OR ] = 30.9 and 11.1 , respectively , P < 10(-6 ) ) . Other significant risk factors for persistent and breakthrough infections in a multivariate model included first pregnancy ; enrollment in the rainy or postrainy season ; maternal age < or = 25 years ; seropositivity to the human immunodeficiency virus ( HIV ) ( persistent infections only ) ; and no use of antimalarial prophylaxis before enrollment ( breakthrough infections only ) . At delivery , compared with women on MQ , women on a CQ regimen were at significantly greater risk of peripheral , placental , or umbilical cord blood parasitemia ( OR = 8.7 , 7.4 , and 4.1 , respectively , P < 10(-6 ) ) . Additional risk factors for parasitemia at delivery in multivariate models included first pregnancy ; delivery in the rainy or postrainy season ; HIV-seropositivity ; and maternal age < or = 25 years ( risk for peripheral and placental blood parasitemia only ) . Maternal anemia ( hematocrit < 30 % ) at enrollment or at delivery was not associated with persistent or breakthrough parasitemia or parasitemia at deliver in these multivariate models . While factors leading to increased malaria parasite exposure ( high transmission seasons ) and lowered or altered host immune response ( low pregnancy number , young age , and HIV infection ) are important risk factors for malaria in pregnant women , the use of an ineffective intervention ( CQ in a setting with CQ-resistant parasites ) was the most important determinant of P. falciparum parasitemia in these pregnant women . Strategies to reduce the impact of malaria in pregnant women must use efficacious interventions and may need to consider targeting the intervention to the most susceptible women during the seasons of high malaria exposure 73 pregnant women in Malawi were given weekly antimalarial chemoprophylaxis under observation and were monitored for Plasmodium falciparum parasitaemia and placental infection . 3 of 19 women ( 16 % ) who were parasitaemic at the time they began chemoprophylaxis were infected with chloroquine-resistant P. falciparum . After clearance of initial infections , 25 % of the 73 women became parasitaemic while taking prophylaxis and 56 % had evidence of active or past placental infection at the time of delivery . None of the women who were parasitaemic at the time of enrollment , and only 11 % of those who had breakthrough parasitaemias while taking prophylaxis , had a history of fever and signs or symptoms that they recognized as malaria . Although the density of P. falciparum infection and rates of placental infection appeared to be lower among women taking regular chloroquine prophylaxis , this drug did not prevent P. falciparum infection among pregnant women A double-blind , placebo-controlled study of mefloquine antimalarial prophylaxis in pregnancy ( > 20 weeks of gestation ) was conducted in 339 Karen women living in an area of multidrug-resistant malaria transmission on the Thai-Burmese border . Mefloquine gave > or = 86 % ( 95 % confidence interval [ CI ] , 59%-94 % ) protection against Plasmodium falciparum and complete protection against Plasmodium vivax infections . Mefloquine prophylaxis was well tolerated ; use of an initial loading dose ( 10 mg/kg ) was associated with transient dizziness , but there were no other significant adverse effects on the mother , the pregnancy , or infant survival or development ( followed for 2 years ) . Falciparum malaria was associated with maternal anemia and a mean reduction in birth weight in gravidae I , II , and III of 225 g ( 95 % CI , 26 - 423 ) . Maternal anemia at delivery ( hematocrit < 30 % ) was associated with increased infant mortality : 26 % versus 15 % ( relative risk , 1.9 ; 95 % CI , 1.1 - 3.2 ) . Mefloquine is safe and effective for antimalarial prophylaxis in the second half of pregnancy The control of malaria in pregnant African women , one of several child survival strategies applied through antenatal care , has been particularly challenging . Prevention and control recommendations for typical areas of high Plasmodium falciparum transmission have promoted the use of antimalarial chemoprophylaxis to prevent placental infection . Persistently low program coverage coupled with diminishing intervention effectiveness have forced a re-evaluation of the relative importance of malaria in pregnancy . The Mangochi Malaria Research Project ( MMRP ) , a prospect i ve evaluation of malaria prevention in pregnant women in rural Malawi conducted during 1987 - 1990 , contributed to establishing new criteria for policy and program development for malaria prevention in pregnancy . The principle findings of the MMRP include : 1 ) population s at risk of the adverse consequences of malaria in pregnancy include women with low parity , women infected with human immunodeficiency virus , pregnancy during the high malaria transmission season , and the use of a malaria drug that is suboptimally efficacious ; 2 ) the estimated maximum benefits of an antimalarial intervention that clears placental and umbilical cord parasitemia are a 5 - 12 % reduction of low birth weight ( LBW ) , an approximately 35 % reduction in the risk of LBW for risks that are actually preventable once a woman has become pregnant ( e.g. , risks such as infectious disease or poor nutrition during gestation ) , and a 3 - 5 % reduction in the rate of infant mortality ; 3 ) the intervention must be capable of rendering the woman malaria parasite free , including clearance of parasites from the placental vascular space and umbilical cord blood ; 4 ) other diseases adversely affect pregnancy outcome and , while the control of malaria in pregnancy may not warrant independent programming , if coupled with prevention programs to provide a range of antenatal services , the incremental costs of malaria control may prove to be highly cost-effective ; and 5 ) the choice of a regimen must balance intervention efficacy with safety , availability , affordability , and simplicity of delivery , and several antimalarials may meet these criteria . The Malawi Ministry of Health has modified its malaria prevention in pregnancy recommendations and now faces the challenge of effective programming to improve child survival A r and omized , double-blind , placebo-controlled trial , which compared the effects of three interventions ( weekly chloroquine prophylaxis , daily iron and weekly folic-acid supplementation , and case management of malaria ) on congenital malaria , maternal haemoglobin ( Hb ) and foetal outcome , was conducted among primigravidae resident in Hoima district , Ug and a. Among 473 babies examined at birth or within 7 days of birth , 198 ( 42 % ) were parasitaemic , the level of parasitaemia in an infant being strongly correlated with those of placental ( P < 0.01 ) and maternal , peripheral parasitaemia ( P < 0.01 ) . However , 33 ( 17 % ) of the parasitaemic babies were born to mothers who had placental but not peripheral parasitaemia , 22 ( 11 % ) to mothers who had peripheral but not placental parasitaemia , and 12 ( 6 % ) to mothers with neither peripheral nor placental parasitaemia . Overall , 163 babies were each examined for malarial parasites at birth and 1 month later . Of the 76 ( 47 % ) found to have parasitaemia at birth , 37 ( 23 % ) appeared aparasitaemic at the 1-month follow-up but 28 ( 17 % ) were still parasitaemic at that time . Among the babies born to the mothers who only received case management of malaria during pregnancy , parasitaemia at birth was associated with infant anaemia at birth ( i.e. < 140 g Hb/litre ; P = 0.03 ) . Infants found to be parasitaemic at the 1-month follow-up had lower mean concentrations of Hb at that time than their aparasitaemic counterparts ( P= 0.03 ) . Parasitaemia at birth was not significantly associated with low birthweight , in any of three intervention groups . The intervention given to the mother had no significant effect on the parasitaemia of her baby , either at birth or at the age of 1 month . Congenital malaria per se may have little influence on birthweight but may have an impact on infant anaemia . In conclusion , congenital parasitaemia was not associated with birthweight , but was related to anaemia at birth in infants born to women who had only received active case management during their pregnancies Maternal mortality has recently received attention as a neglected public health problem in many developing countries where mortality rates are estimated to be 8 - 200 times those in developed countries . Most maternal mortality estimates in sub-Saharan Africa have used retrospective methods because of the lack of large population -based studies . The Mangochi Malaria Research Project , a trial of antimalarial chemoprophylaxis in pregnant women , provided an opportunity to examine prospect ively mortality among the study women . Among 4,053 monitored pregnant women , 27 women were known to have died during pregnancy , labor , delivery and the one-year follow-up period . Three women died during the antenatal period and 12 died within six weeks of delivery for an estimated maternal mortality rate of 370 per 100,000 pregnant women ; this rate was consistent with rates reported from retrospective surveys in Malawi . Twelve women died between three and 10 months after delivery , and the mortality rate in this nonmaternal period was estimated to be 341 per 100,000 . Mortality rates in the maternal and nonmaternal periods were surprisingly similar . Human immunodeficiency virus type-1 ( HIV-1 ) infection and anemia were strongly associated with death in the nonmaternal period . Mortality among infants of mothers who died was 3.7 times higher than the rate of death among infants born to mothers who survived . This study highlights that for rural Malawian women , pregnancy and delivery are risky periods , that the death of the mother adversely affects the survival of her children , and that HIV and anemia are important contributors to nonmaternal mortality in reproductive-age women . Strategies to reduce mortality among women of child-bearing age in sub-Saharan Africa must focus on decreasing the complications of pregnancy and delivery , and address important preventable causes of death , such as anemia and HIV infection To evaluate the efficacy of pyrimethamine on the blood stage ( suppressive prophylaxis ) and liver stage ( causal prophylaxis ) of Plasmodium falciparum in pregnant women , in vivo and in vitro field studies were conducted in Ilorin , Nigeria , from Jan 1 to June 30 , 1988 . For pregnant women with P falciparum infections who received 25 mg of pyrimethamine weekly for suppressive prophylaxis , 67 % ( 59/88 ) of in vivo and 60 % ( 6/10 ) of in vitro tests showed pyrimethamine resistance . A second group of parasitaemic and parasite-free pregnant women was enrolled to evaluate the efficacy of pyrimethamine as a primary tissue schizonticide ; after receiving a curative dose of chloroquine ( 25 mg/kg ) , half the women were given 25 mg of pyrimethamine weekly and half received no prophylaxis . Parasitologic failure rates did not differ between the pyrimethamine-treated ( 8/34 ) and the control ( 11/37 ) groups during the 16-week follow-up . Thus , pyrimethamine is not effective for suppressive or causal prophylaxis in pregnant women in Ilorin Malaria infection due to Plasmodium falciparum has been widely recognized as associated with important adverse consequences in pregnant women , particularly in areas of high transmission . Although strategies using antimalarial drugs for prevention had been recommended , even by the late 1980s , few studies had been carried out to examine the efficacy of these prevention efforts . The objectives of the Mangochi Malaria Research Project investigation were to determine the comparative efficacy of regimens containing chloroquine ( CQ ) or mefloquine ( MQ ) antimalarial treatment and chemoprophylaxis in an area of CQ-resistant P. falciparum on the following outcomes : 1 ) the frequency of placental malaria infection ; 2 ) the frequency of low birth weight ; 3 ) the frequency of prematurity or intrauterine growth retardation ; 4 ) the frequency of maternal fever illness and severe anemia ; and 5 ) the likelihood of infant acquisition of malaria infection . Although the investigation was not design ed to evaluate the role of antimalarial chemoprophylaxis and treatment on infant mortality reduction , because babies born to study women were scheduled to be followed for up to two years of life , the study allowed for an examination of mortality and morbidity in this population . The sample size was insufficient to provide more than descriptive analysis of mortality and morbidity in the fetal , perinatal , neonatal , postneonatal , and infant time intervals . The study design allowed for the evaluation of two additional aspects of maternal and infant health : other determinants of the above-listed outcomes in addition to malaria prevention ( e.g. , maternal age , gravidity , socioeconomic status , infection with human immunodeficiency virus or syphilis ) and reported cause-specific mortality in the fetal-to-infant intervals . The study design included 22 months of enrollment of pregnant women at their first antenatal clinic visit from four clinic sites in Mangochi District , Malawi , with assignment to one of four antimalarial regimens and prospect i ve follow-up through pregnancy , at delivery , and during infancy . All drug dosing was performed under supervision by the study team , making this an evaluation of intervention efficacy ( excluding the role of patient compliance ) The distribution of birth weights among the infants of 172 Gambian primigravidae who had received chemoprophylaxis with Maloprim ( pyrimethamine+dapsone ) during pregnancy was compared with that of the infants of 149 primigravidae who had received placebo . Administration of chemoprophylaxis led to a reduction in the prevalence of low birth weight babies and to an increase in the median birth weight . However , these changes were not accompanied by a comparable increase in the prevalence of high birth weight babies . The perinatal mortality rate was lower , although not significantly so , among the babies of women who had received chemoprophylaxis . Thus , no evidence was found to support the view that administration of chemoprophylaxis might increase the risks of delivery by causing cephalo/pelvic disproportion The widespread problem of low and non-compliance to antimalarial chemoprophylaxis during pregnancy dem and s that attention be focused on alternative approaches to programming , product acceptability and dem and for preventive services . This study describes the testing of three interventions to determine their effect on use of chloroquine ( currently the most widely used drug for chemoprophylaxis ) during pregnancy . The strategies evolved from community-based formative research undertaken to learn about the local concept of malaria and issues surrounding malaria prevention and treatment during pregnancy . The result ing interventions were tested in four clinics , and included a change in the health education message given during antenatal sessions , distribution of a sugar-coated chloroquine tablet , and an intervention combining the two strategies . The results showed a 45 % increase in chloroquine use when the health education message was changed , and a 64 % increase when the product was changed . High use levels were maintained with the combined intervention ; an additive effect was seen . The study shows that improving the product was the most important factor in increasing the use of the program , and that changing the health education message can also make an impact on use The effects of weekly chloroquine prophylaxis , daily iron-weekly folic acid supplementation or passive case management on maternal haemoglobin and parasitaemia and on birthweight were examined in primigravidae in a r and omized , double-blind placebo-controlled intervention trial in 1996 - 98 in Hoima District , western Ug and a. Iron-folic acid supplementation significantly increased mean birthweight as compared to case management ( P = 0.03 ) . Low birthweight ( < 2.5 kg ) occurred in 2 % of babies of women receiving chloroquine prophylaxis for > or = 8 weeks and in 9 % in the case management group ( RR = 0.36 , 95 % CI 0.13 - 1.00 , P = 0.009 ) . Parasitaemia at enrolment significantly correlated with low birthweight in the case management group as compared to the intervention groups ( P = 0.02 ) . Women in the case management group who were parasitaemia and had haemoglobin levels < 100 g/L at delivery had babies with lower mean birthweight as compared to babies in the other groups ( P = 0.04 ) . Low haemoglobin level at enrolment , irrespective of parasitaemia status , was a predictor of low birthweight in the case management group only ( P = 0.04 ) . Chloroquine prophylaxis and iron-folic acid supplementation significantly increased maternal haemoglobin levels during pregnancy as compared to case management ( P = 0.01 and 0.007 , respectively ) and the increase correlated to the duration of the intervention OBJECTIVE To determine baseline data among pregnant women consenting to participate in a r and omised trial of alternative strategies of malaria chemoprophylaxis in Kigoma urban district , western Tanzania . DESIGN Cross-sectional study . SETTING The study was conducted in an urban MCH clinic in Kigoma town in western Tanzania . SUBJECTS All consenting pregnant women who fulfilled entry criteria were recruited into the study . BASELINE STUDIES : Baseline data were collected prior to r and omisation of women to antimalarial prophylactic regimens . Baseline measurements included examination for blood depleting parasitic infections ( stool and urine examinations ) , haemoglobin levels , haematocrit , sickling test , and blood slide for malaria parasites . RESULTS A total of 728 pregnant women consented to participate in the interview and of these 705 participated in baseline studies constituting a participation rate of 96.8 % . The age of participating women ranged from 14 to 45 years with a mean age of 23.7 years ( st and ard deviation [ SD ] = 5.4 ) while the mean number of pregnancies ranged from 1 to 13 with a mean of 3.2 ( SD = 2.2 ) . The prevalence of malaria parasitaemia among the pregnant women examined was 9.4 % ( N = 705 ) while the prevalence of anaemia ( defined as Hb < 8.5 gdl-1 ) was 12.4 % ( N = 579 ) . No significant difference was observed in prevalence proportions of malaria parasitaemia in relation to age , parity , marital status and use of mosquito bednets . However the prevalence of anaemia among women in the age group 31 - 45 years was significantly lower than that observed among women in the age group 14 - 20 years ( 2.9 % versus 18.9 % ; crude odds ratio [ OR ] = 0.13 ; 95 % confidence interval [ CI ] , 0.02 - 0.55 ) . Sickle cell disease ( HbAS ) was found in 2.3 % ( N = 564 ) of the pregnant women examined . CONCLUSION It is concluded that the prevalence of malaria parasitaemia and anaemia was very high in this population suggesting the need for interventions directed at controlling these major causes of maternal morbidity and mortality in Tanzania The problems of Plasmodium falciparum infection in pregnant women have been described in numerous sub-Saharan African countries , but the frequency of parasitemia at the first antenatal visit and risk factors for infection have not been fully investigated . During a prospect i ve antimalarial treatment and prophylaxis trial in pregnant women in Malawi ( three groups receiving a chloroquine regimen and one group receiving a mefloquine regimen ) , we examined women at their first antenatal clinic visit to evaluate these issues and to verify that subjects in the study treatment/prevention arms were similar . Among 4,127 women with enrollment blood smear results , 1,836 ( 44.5 % ) were parasitemic . The highest infection rates and densities were observed in primigravidas ( 66 % infected , geometric mean parasite density [ GMPD ] = 1,588 parasites/mm3 of whole blood ) , followed by second pregnancies ( 46 % infected , GMPD = 615 parasites/mm3 ) and subsequent pregnancies ( 29 % infected , GMPD = 238 parasites/mm3 ) , ( P < 10(-6 ) for both infection prevalence and density , by chi-square test for trend ) . Significant risk factors for parasitemia at first antenatal clinic visit in a multivariate model included low gravidity , high transmission season , no use of prophylaxis before first antenatal clinic visit , young age ( < 20 years ) , human immunodeficiency virus ( HIV ) infection , low hematocrit , short stature , and second trimester ( compared with third trimester ) . Women in the different treatment arms of the study were generally similar in many characteristics ; statistically significant differences , where present , were small . Targeting malaria control efforts to women in their first or second pregnancy and during the high transmission season will be an important strategy to reach most parasitemic women and minimize re source expenditure . Women infected with HIV had a 55 % increased risk of parasitemia at their first antenatal clinic visit and may represent an additional important risk group whose numbers may be increasing and who may benefit from identification and management for malaria |
1,933 | 26,355,573 | Younger cohort age was associated with greater growth reconstitution .
Protease inhibitor and nonnucleoside reverse-transcriptase inhibitor regimens yielded comparable growth .
Supplement benefits were attenuated after adjusting for baseline cohort growth .
RLS children had substantial growth deficits compared with developed setting s counterparts at ART ; growth shortfalls in RLS persisted despite reconstitution .
Earlier age and nutritional supplementation at ART may improve growth outcomes . | OBJECTIVE As antiretroviral therapy ( ART ) exp and s for HIV-infected children , it is important to determine its impact on growth . | OBJECTIVE . Few studies have investigated the efficacy of antiretroviral therapy among HIV-infected children in re source -poor setting s. This observational , retrospective analysis describes the clinical , immunologic , and virologic effects of highly active antiretroviral therapy in treatment-naive , HIV-infected children in Mombasa , Kenya . In keeping with a public health approach , all children were treated by using a simplified , nationally approved , triple-drug regimen . METHODS . Clinical data and stored plasma sample s from 29 children who were followed prospect ively between April 2003 and October 2004 were analyzed . All children received generic formulations of nevirapine , zidovudine , and lamivudine and were evaluated at baseline and at 3 , 6 , 9 , 12 , and 15 months . At each visit , weight and CD4 lymphocyte counts were measured and plasma sample s were stored for analysis . HIV RNA load was determined retrospectively at baseline and 9 months after initiation of therapy . RESULTS . The mean age of the children was 8.5 years ( range : 2–16 years ) . At baseline , the mean CD4 count ( ±SD ) was 182.3 × 106 cells per μL ( ±145.6 ) . On treatment , CD4 counts increased step-wise by a mean of 187 × 106 cells per μL at 3 months , 293 cells per μL at 6 months , 308 cells per μL at 9 months , 334 cells per μL at 12 months , and 363 cells per μL at 15 months . The mean plasma viral load decreased from a baseline level of 622 712 to 35369 copies per mL , and at 9 months was undetectable in 55 % of the patients . Mean z scores for weight for age increased from a baseline of −1.61 to −1.12 at 12 months into therapy . CONCLUSIONS . A public health approach using 1 treatment regimen in generic form showed excellent efficacy among treatment-naive , HIV-infected children in a re source -limited country . Clinical and immunologic improvement occurred in all patients , but 9 months after the start of therapy , only 55 % of the children had an undetectable viral load BACKGROUND Data are limited about the effectiveness of pediatric antiretroviral therapy ( ART ) in low-income countries . METHODS We report the outcomes of consecutively treating 236 human immunodeficiency virus type 1 (HIV-1)-infected treatment-naive children with triple ART in Port-au-Prince , Haiti , between 1 May 2003 and 30 April 2006 . RESULTS Kaplan-Meier survival analysis at follow-up demonstrated that 191 children ( 81 % ) remained in care , 21 ( 9 % ) were dead , and 24 ( 10 % ) were lost to follow-up . Independent baseline predictors of mortality were age < 18 months , CD4(+ ) T cell percentage < or = 5 % , and weight-for-age Z score ( WAZ ) less than -3 . Twelve months into ART , 56 % of tested subjects had undetectable HIV-1 RNA loads . Median CD4(+ ) T cell percentages at 12 months increased by 15 % , 11 % , and 5 % in children with baseline percentages of < or = 5 % , 6%-24 % , and > or = 25 % , respectively ( P<.01 ) . The median WAZ at 12 months increased by 1.0 , 0.6 , and 0.2 in children with baseline WAZ less than -2 , -2 to -1.1 , and -1 or more , respectively ( P<.01 ) . CONCLUSION With continuous donor support , trained providers , and the availability of pediatric antiretroviral drug formulations , it proved feasible to deliver pediatric ART in Haiti . The effectiveness of this program should encourage efforts to make ART available for HIV-infected children in poor countries Background There are limited data of immunologic and virologic failure in Asian HIV-infected children using non-nucleoside reverse transcriptase inhibitor (NNRTI)-based highly active antiretroviral therapy ( HAART ) . We examined the incidence rate of immunologic failure ( IF ) and virologic failure ( VF ) and the accuracy of using IF to predict VF in Thai HIV-infected children using first-line NNRTI-based HAART . Methods Antiretroviral (ART)-naïve HIV-infected children from 2 prospect i ve cohorts treated with NNRTI-based HAART during 2001 - 2008 were included . CD4 counts were performed every 12 weeks and plasma HIV-RNA measured every 24 weeks . Immune recovery was defined as CD4%≥25 % . IF was defined as persistent decline of ≥5 % in CD4 % in children with CD4%<15 % at baseline or decrease in CD4 count ≥30 % from baseline . VF was defined as HIV-RNA>1,000 copies/ml after at least 24 weeks of HAART . Clinical and laboratory parameter changes were assessed using a paired t-test , and a time to event approach was used to assess predictors of VF . Sensitivity and specificity of IF were calculated against VF . Results 107 ART-naive HIV-infected children were included , 52 % female , % CDC clinical classification N : A : B : C 4:44:30:22 % . Baseline data were median ( IQR ) age 6.2 ( 4.2 - 8.9 ) years , CD4 % 7 ( 3 - 15 ) , HIV-RNA 5.0 ( 4.9 - 5.5 ) log10copies/ml . Nevirapine ( NVP ) and efavirenz (EFV)-based HAART were started in 70 % and 30 % , respectively . At 96 weeks , none had progressed to a CDC clinical classification of AIDS and one had died from pneumonia . Overall , significant improvement of weight for age z-score ( p = 0.014 ) , height for age z-score , hemoglobin , and CD4 were seen ( all p < 0.001 ) . The median ( IQR ) CD4 % at 96 weeks was 25 (18 - 30)% . Eighty-nine percent of children had immune recovery ( CD4%≥25 % ) and 75 % of children had HIV-RNA < 1.7log10copies/ml . Thirty five ( 32.7 % ) children experienced VF within 96 weeks . Of these , 24 ( 68.6 % ) and 31 ( 88.6 % ) children had VF in the first 24 and 48 weeks respectively . Only 1 ( 0.9 % ) child experienced IF within 96 weeks and the sensitivity ( 95%CI ) of IF to VF was 4 (0.1 - 20.4)% and specificity was 100 (93.9 - 100)% . Conclusion Immunologic failure , as defined here , had low sensitivity compared to VF and should not be recommended to detect treatment failure . Plasma HIV-RNA should be performed twice , at weeks 24 and 48 , to detect early treatment failure . Trial Registration Clinical trials.gov identification BACKGROUND Nevirapine-based antiretroviral therapy is the predominant ( and often the only ) regimen available for children in re source -limited setting s. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus ( HIV ) transmission is common , a problem that has led to the recommendation of ritonavir-boosted lopinavir in such setting s. Regardless of whether there has been prior exposure to nevirapine , the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established . METHODS In a r and omized trial conducted in six African countries and India , we compared the initiation of HIV treatment with zidovudine , lamivudine , and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine . The primary end point was virologic failure or discontinuation of treatment by study week 24 . RESULTS A total of 288 children were enrolled ; the median percentage of CD4 + T cells was 15 % , and the median plasma HIV type 1 ( HIV-1 ) RNA level was 5.7 log(10 ) copies per milliliter . The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group ( 40.8 % vs. 19.3 % ; P<0.001 ) . Among the nevirapine-treated children with virologic failure for whom data on resistance were available , more than half ( 19 of 32 ) had resistance at the time of virologic failure . In addition , the time to a protocol -defined toxicity end point was shorter in the nevirapine group ( P=0.04 ) , as was the time to death ( P=0.06 ) . CONCLUSIONS Outcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine . Factors that may have contributed to the suboptimal results with nevirapine include elevated viral load at baseline , selection for nevirapine resistance , background regimen of nucleoside reverse-transcriptase inhibitors , and the st and ard ramp-up dosing strategy . The results of this trial present policymakers with difficult choices . ( Funded by the National Institute of Allergy and Infectious Diseases and others ; P1060 Clinical Trials.gov number , NCT00307151 . ) Growth failure is a common problem in HIV-infected children . The extent to which this growth failure could be reversed after the children receive antiretroviral therapy ( ART ) is not known . This study assessed the incidence of growth failure in HIV-infected Thai children , impact of ART on growth , and the predictors of growth reversal after initiating ART . Growth parameters and other characteristics were extracted from the data base of a prospect i ve cohort of HIV-infected children ( age < or=15 years ) who were enrolled to initiate non-nucleoside reverse transcriptase inhibitor-based ART between August 2002 and May 2007 . Body weight and height measurements , CD4 cell counts , plasma HIV RNA levels were collected at baseline and 24-week intervals . A total of 225 HIV-infected children were included , 116 ( 51 % ) were males . The median age at baseline was 7.4 years ( interquartile range [ IQR ] 5.2 - 9.8 ) . Fifty-three percent were in Centers for Disease Control and Prevention ( CDC ) category C and 54 % had CD4 percentage 5 or less . The mean ( st and ard deviation [ SD ] ) of baseline weight-for-age ( WAZ ) and height-for-age ( HAZ ) z-scores were -2.02 ( 1.17 ) and -2.22 ( 1.51 ) . The median follow-up time was 216 weeks ( IQR 120 - 240 ) . The cumulative probability of growth reversal among the 179 subjects with growth failure at entry was 58 % ( 95 % confidence interval [ CI ] 49 - 67 ) at week 240 . In a multivariate Cox regression model , higher entry WAZ ( p < 0.001 ) and HAZ ( p < 0.001 ) , use of a nevirapine-based regimen ( compared to efavirenz , p = 0.027 ) and larger CD4 % gains to week 48 ( p < 0.001 ) were significant predictors of growth reversal after initiating ART . NNRTI-based ART leads to a substantial improvement in growth of HIV-infected children . Initiation of ART before the children developed growth failure should be encouraged OBJECTIVE To describe the outcomes of antiretroviral therapy ( ART ) in a large cohort of HIV-infected children in Thail and . METHODS The data were obtained from four collaborative referral sites around the country . Data from 2008 to March 2011 were collected prospect ively , and data before 2008 were collected retrospectively . RESULTS Of the 1139 children , 599 ( 52.6 % ) were female , and the duration of ART was a median 2.9 years ( interquartile range ( IQR ) 3.3 - 5.5 years ) . At ART initiation , the median age was 7.1 years ( IQR 3.4 - 10.0 years ) , CD4 percentage was 9.0 % ( IQR 3.0 - 17.0 % ) , and 61.3 % were in World Health Organization ( WHO ) stage 3 or 4 . Seventy-four percent were initiated on an NNRTI-based regimen . The death and lost to follow-up rates were 1.3 ( 95 % confidence interval ( CI ) 1.1 - 1.6 ) and 2.2 ( 95 % CI 1.6 - 2.6)/100 patient-years of follow-up , respectively . At the last clinic visit of 919 children , the median CD4 percentage was 27.0 % ( IQR 23.0 - 32.0 % ) and 80.2 % had HIV-RNA < 40 copies/ml . WHO stage 1 or 2 at ART initiation was associated with having a viral load < 40 copies/ml ( p < 0.002 ) , and baseline CD4 ≥15 % and starting with a three-drug regimen were associated with achieving CD4 ≥25 % ( p<0.001 ) . CONCLUSIONS Although most children initiated ART at low CD4 levels , the majority achieved immune reconstitution and long-term virological control . Earlier treatment may improve these outcomes BACKGROUND Previous observational studies found highly active antiretroviral therapy ( HAART ) to be associated with improved survival among human immunodeficiency virus (HIV)-infected children and adolescents . However , these studies had limited follow-up of HIV-infected children undergoing HAART . Given that HIV infection is chronic and that exposure to HAART is likely to be life-long , there is a need to evaluate the long-term effect of HAART on survival in this population . METHODS The study included 1236 children and adolescents who were perinatally infected with HIV , who were on study or enrolled after January 1996 in a United States-based multicenter prospect i ve cohort study ( Pediatric AIDS Clinical Trials Group 219/219C ) , and who were not receiving HAART at baseline ; subjects were observed for a maximum of 10 years through June 2006 . A weighted Cox regression model was used to estimate the effect of HAART on survival , appropriately adjusted for time-varying confounding by severity . RESULTS At the end of the 10-year follow-up period ( median duration of follow-up , 6.3 years ; interquartile range , 4.3 - 9.8 years ) , 70 % of participants had initiated HAART . Lower CD4 cell percentages , total lymphocyte counts , and albumin levels were associated with an increased probability of initiating HAART . Eighty-five deaths were observed , and the mortality hazard ratio associated with HAART , compared with non-HAART regimens , was 0.24 after adjusting for measured confounding by severity ( 95 % confidence interval , 0.11 - 0.51 ) . CONCLUSIONS The use of HAART was highly effective in reducing mortality during the period 1996 - 2006 among children and adolescents infected with HIV . With improved long-term survival , continued follow-up is necessary to evaluate the effects of prolonged use of HAART on potential adverse events , immune function , growth , sexual maturation , and quality of life in this population INTRODUCTION Growth failure is a common feature of children with human immunodeficiency virus type 1 ( HIV-1 ) infection . Children who are treated with mono or dual nucleoside analogue reverse transcriptase inhibitor ( NRTI ) therapy show a temporary increase in weight gain and linear growth rate . In adults , protease-inhibitor-containing antiretroviral therapy is associated with a sustained weight gain and increased body mass index ( BMI ) . Experience with protease inhibitors and growth in children is still limited . The data mainly deal with short-term effects on growth . OBJECTIVE To evaluate the effect of highly active antiretroviral therapy ( HAART ) on growth in children with HIV-1 infection . DESIGN AND METHODS We analyzed selected growth parameters , clinical data , and laboratory results as part of a prospect i ve , open , uncontrolled , multicenter study to evaluate the clinical , immunologic , and virologic response to HAART consisting of indinavir , zidovudine , and lamivudine in children with HIV-1 infection . Height and weight were measured at 0 , 12 , 24 , 36 , 48 , 60 , 72 , 84 , and 96 weeks after initiation of HAART . Information about the children 's growth before enrollment in the study was retrieved from the hospital medical records and /or the school doctor or health center . BMI was calculated . z Scores were used to express the st and ard deviation ( SD ) in SD units from the Dutch reference curves for age and gender . Viral loads and CD4 + T-cell counts were examined prospect ively and related to these growth parameters . z Scores were also calculated for CD4 + T-cell counts to correct for age-related differences . A z score of 0 represents the P50 , which is exactly the age/sex-appropriate median . A height z score of -1 indicates that a child 's height is 1 SD below the age- and gender-specific median height for the normal population . Virologic responders were defined as those who either reached an undetectable viral load ( < 500 copies/mL ) or had a > 1.5 log reduction in viral load compared with baseline at week 12 after the initiation of HAART , which was maintained during the follow-up period . RESULTS . PATIENTS Twenty-four patients were included ( age : 0.4 - 16.3 years at baseline ) , with a median HIV-1 RNA load of 105 925 copies/mL ( 5.03 log ) , a median CD4 + T-cell count of 0.586 x 10(9)/L ( median z score : -2.28 SD ) , a median height z score of -1.22 , a median weight z score of -0.74 , and a median baseline BMI z score of -0.32 . Eleven patients were naive to antiretroviral therapy , and 13 patients had received previous treatment with NRTI monotherapy . Twenty children used indinavir and 4 children used nelfinavir as part of HAART . VIROLOGIC AND IMMUNOLOGIC RESPONSES TO HAART : Seventeen children were virologic responders , and 7 children were virologic nonresponders . In patients naive to NRTIs , median baseline viral loads were significantly higher than in pretreated patients . However , at weeks 48 and 96 , there was no significant difference between the viral loads of both groups . At baseline , there was no significant difference in CD4+a T-cell z scores between virologic responders and nonresponders or between naive and pretreated patients . During 96 weeks of HAART , the increase of CD4 + T-cell z score was significantly higher in responders than in nonresponders . The increase in CD4 + T-cell z score was not significantly different for naive and pretreated patients . HEIGHT , WEIGHT , AND BMI z SCORE CHANGES : We found that there was a trend toward a significantly increased z score change during 96 weeks of HAART compared with the z score change before HAART initiation for height and weight , but not for BMI . GROWTH AND VIROLOGIC RESPONSE TO HAART : When the data were analyzed separately for virologic responders and nonresponders , virologic responders showed significant increases in height and weight . The height and weight of virologic nonresponders did not change significantly . The BMI did not change significantly in responders or in nonresponders . GROWTH AND IMMUNOLOGIC RESPONSE TO HAART : The increase of weight and BMI z scores from baseline correlated positively with the CD4 + T-cell z score increase from baseline . It did not correlate with absolute CD4 + T-cell count increase . Height z score increase did not correlate with CD4 + T-cell z score or with absolute CD4 + T-cell counts . GROWTH AND PREVIOUS NRTI TREATMENT : The height z score decrease from week -48 to baseline was significantly larger in naive than in pretreated patients . The weight and BMI z score change from week -48 to baseline was not significantly different for pretreated and naive patients . From baseline to week 96 , the height and weight z score change increased significantly in naive patients but not in pretreated patients compared with the change from week -48 to baseline . The BMI z score did not change significantly over 96 weeks of HAART for naive or pretreated patients . GROWTH AND CLINICAL STAGE OF INFECTION : The clinical stage of infection according to the Centers for Disease Control and Prevention classification correlated negatively with the BMI z score and the weight z score at baseline but not with the height z score . Thus , children with the most severe clinical disease had the lowest BMI and weight z scores at baseline . The BMI z score increased more in children with more advanced clinical infection at baseline , who had lower BMI at baseline . The clinical stage of infection did not correlate with the change in weight z score from baseline to week 96 . CONCLUSIONS HAART has a positive influence effect on the growth of HIV-1-infected children . This effect is sustained for at least 96 weeks . Height and weight are favorably influenced in children in whom HAART leads to a reduction of the viral load of at least 1.5 log or to < 500 copies/mL and to an increase in the CD4 + T-cell z score . In contrast to the increase of the BMI in adults on HAART , BMI did not increase in all children effectively treated with HAART . BMI increased more in children with an advanced stage of infection and a poor nutritional status at baseline . Data from pretreated and naive patients were difficult to interpret , because the baseline characteristics of these 2 groups differed too much OBJECTIVE To examine beneficial or detrimental effects of protease inhibitor (PI)-containing antiretroviral regimens on height and weight growth in children with human immunodeficiency virus ( HIV ) infection . METHODS A prospect i ve cohort study was conducted of 906 HIV-infected children , from pediatric research clinics in the United States , who were between 3 months and 18 years of age and who had height and weight assessed in 1995 ( before introduction of PIs in this population ) and at least once more through 1999 . Changes in age- and gender-adjusted height and weight growth associated with PI use were assessed . RESULTS Compared with a healthy reference population , children were more affected in height ( mean z score : -0.90 [ 18th percentile ] ) than in weight ( mean z score : -0.42 [ 34th percentile ] ) at baseline ( 1995 ) . Two thirds of children received at least 1 PI during 1996 to 1999 . In the multivariate mixed effects regression models adjusted for baseline log(10 ) CD4 cell count , baseline age , gender , and race/ethnicity , the use of PIs was associated with per-year gains of 0.13 z scores in height and 0.05 z scores in weight relative to the expected growth with non-PI-containing regimens ( eg , after 1 year of PI use , a representative 6-year-old boy in our study would be approximately 0.7 cm taller and 0.1 kg heavier than if he had not received PIs ) . No significant differential effects of PIs on height or weight growth according to specific agents or children 's sociodemographic or clinical characteristics were found . CONCLUSIONS Although the use of PI-containing regimens was not associated with growth retardation , it was associated with only small annual increments in height and weight growth in HIV-infected children Objective : To investigate the longitudinal pharmacokinetics , safety and efficacy of lopinavir/ritonavir ( LPV/r ) in HIV-infected infants initiating combination antiretroviral therapy ( cART ) between 2 weeks and 6 months of age . Method : A prospect i ve , open-label , multicenter Phase I/II study of LPV/r-based cART at a dose of 300/75 mg/m2/dose LPV/r twice daily . Intensive pharmacokinetic sampling at 12 months of age and quarterly predose LPV concentrations were collected and safety , virologic and immunologic responses were monitored every 4–12 weeks up to 252 weeks . Results : Thirty-one HIV-infected infants enrolled into two age cohorts , 14 days to < 6 weeks and 6 weeks to < 6 months ; 29 completed ≥48 weeks of follow-up ( median = 123 weeks , range 4–252 ) . At 12 months of age , median LPV area under the curve was comparable for both age cohorts and similar to older children and adults . At week 48 , 22 of 31 patients ( 71 % ) had HIV-1 RNA < 400 copies/ml and 11 of 15 ( 73 % ) had < 50 copies/ml ; 29 of 31 achieved HIV-1 RNA < 400 copies/ml on study treatment and 19 ( 66 % ) remained durably suppressed until the end of study ; viral suppression correlated with a higher percentage of predose time points exceeding the LPV target of 1 μg/ml ( 92 vs. 71 % , P = 0.002 ) . Conclusion : LPV/r at 300/75 mg/m2/dose as part of a cART regimen result ed in viral suppression through 96 weeks of treatment in > 65 % of young infants . Due to initially low LPV exposure in infants < 6 weeks of age , frequent dose adjustment for weight gain is advisable and consideration should be given to study ing a higher dose for very young infants Objectives : To describe the early response to World Health Organization (WHO)-recommended nonnucleoside reverse transcriptase inhibitor (NNRTI)-based first-line highly active antiretroviral therapy ( HAART ) in HIV-1-infected Kenyan children unexposed to nevirapine . Design : Observational prospect i ve cohort . Methods : HIV-1 RNA level , CD4 lymphocyte count , weight for age z score , and height for age z score were measured before the initiation of HAART and every 3 to 6 months thereafter . Children received no nutritional supplements . Results : Sixty-seven HIV-1-infected children were followed for a median of 9 months between August 2004 and November 2005 . Forty-seven ( 70 % ) used zidovudine , lamivudine ( 3TC ) , and an NNRTI ( nevirapine or efavirenz ) , whereas 25 % used stavudine ( d4 T ) , 3TC , and an NNRTI . Nevirapine was used as the NNRTI by 46 ( 69 % ) children , and individual antiretroviral drug formulations were used by 63 ( 94 % ) , with only 4 ( 6 % ) using a fixed-dose combination of d4 T , 3TC , and nevirapine ( Triomune ; Cipla , Mumbai , India ) . In 52 children , the median height for age z score and weight for age z score rose from −2.54 to −2.17 ( P < 0.001 ) and from −2.30 to −1.67 ( P = 0.001 ) , respectively , after 6 months of HAART . Hospitalization rates were significantly reduced after 6 months of HAART ( 17 % vs. 58 % ; P < 0.001 ) . The median absolute CD4 count increased from 326 to 536 cells/μL ( P < 0.001 ) , the median CD4 lymphocyte percentage rose from 5.8 % before treatment to 15.4 % ( P < 0.001 ) , and the median viral load fell from 5.9 to 2.2 log10 copies/mL after 6 months of HAART ( P < 0.001 ) . Among 43 infants , 47 % and 67 % achieved viral suppression to less than 100 copies/mL and 400 copies/mL , respectively , after 6 months of HAART . Conclusion : Good early clinical and virologic response to NNRTI-based HAART was observed in HIV-1-infected Kenyan children with advanced HIV-1 disease OBJECTIVE To assess 12-month survival , pharmacokinetics , immunologic and virologic efficacy , tolerance , compliance and drug resistance in HIV-infected children in Bobo-Dioulasso , Burkina Faso , receiving once-daily highly-active antiretroviral therapy as a combination of didanosine ( DDI ) , lamivudine ( 3TC ) and efavirenz ( EFV ) . METHODS In the ANRS 12103 open phase II trial , HIV-infected children were examined at inclusion and monthly thereafter . CD4 + T-lymphocyte ( CD4 ) count , plasma concentration of ribonucleic acid ( RNA ) of human immunodeficiency virus type 1 ( HIV-1 ) and haematologic and biochemical parameters were measured at baseline and every trimester . HIV-1 resistance testing was performed in case of viral escape . Drug plasma concentrations were determined with high-performance liquid chromatography . FINDINGS From February 2006 to November 2007 , 51 children ( 39 % girls ) with a mean age of 6.8 years were enrolled and treated for 12 months . At baseline , Z scores for mean weight-for-age and mean height-for-age were -2.01 and -2.12 , respectively . Mean CD4 % was 9.0 . Median plasma HIV-1 RNA viral load was 5.51 log(10 ) copies per millilitre ( cp/ml ) . Two children ( 3.9 % ) died and another 11 ( 22 % ) suffered 13 severe clinical events . At month 12 , mean WAZ had improved by 0.63 ( P < 0.001 ) and mean HAZ by 0.57 ( P < 0.001 ) . Mean CD4 % had risen to 24 ( P < 0.001 ) . Viral load was below 300 RNA cp/ml in 81 % of the children ; HIV resistance mutations were detected in 11 ( 21.6 % ) . CONCLUSION The once-a-day combination of DDI + 3TC + EFV is an alternative first-line treatment for HIV-1-infected children . Dose adjustment should further improve efficacy OBJECTIVE To determine the effect of protease inhibitors ( PIs ) on growth and body composition in children with human immunodeficiency virus type 1 ( HIV-1 ) infection . BACKGROUND HIV-1-infected children have chronic problems with both linear growth and weight gain . Viral load may directly influence growth and nutritional status of HIV-1-infected children with reduction of viral load improving the nutritional condition . DESIGN / METHODS Data from 67 patients who initiated PI therapy between 1996 and 1999 and who were enrolled in a prospect i ve , longitudinal study of growth and nutrition in HIV-1-infected children were analyzed . Outcomes included pre-PI versus post-PI measures of height , weight , weight-for-height , triceps skinfold thickness , and arm muscle circumference . Predictor covariates included age , race , gender , Tanner stage , CD4 z score , Centers for Disease Control and Prevention stage , route of infection , plasma HIV-1 RNA , other antiretroviral therapy , recommended daily allowances for calories , treatment with megestrol acetate , and PI therapy . RESULTS Sixty-seven children were followed for a median of 2.4 years with a total of 362 visits ( median : 5 visits ; range : 1 - 12 ) . During follow-up , they received PIs for a median of 5 months . Fifty-one percent were girls , 54 % black , 15 % Hispanic , and 25 % white . The mean age at first visit was 6.8 years . In a univariate analysis , weight z score ( -0.67 to -0.35 ) and weight/height z score ( 0.25 - 0.76 ) improved on PI therapy . Using repeated- measures regression analysis , controlling for the above named covariates , PI treatment showed a significant effect on weight z score ( increase in z score by 0.46 ) , weight/height z score ( increase in z score by 0.49 ) , and arm muscle circumference ( increase in percentile by 11.5 ) . A borderline effect was found for height z score ( increase in z score by 0.17 ) and no effect was found for triceps skinfold thickness . In a separate analysis , PI therapy increased CD4 counts twofold and reduced plasma HIV-1 RNA copies by 79 % . CONCLUSION In addition to a significant reduction in viral load , PI therapy in children has a positive effect on several growth parameters , including weight , weight/height , and muscle mass Background Scale up of paediatric antiretroviral therapy in re source limited setting s continues despite limited access to routine laboratory monitoring . We documented the weight and height responses in HIV infected Ug and an children on highly active antiretroviral therapy and determined clinical factors associated with successful treatment outcomes . Methods A prospect i ve cohort of HIV infected children were initiated on HAART and followed for 48 weeks . Body mass index for age z scores(BAZ ) , weight and height-for-age z scores ( WAZ & HAZ ) were calculated : CD4 cell % and HIV-1 RNA were measured at baseline and every 12 weeks . Treatment outcomes were classified according to ; both virological and immunological success ( VS/IS ) , virological failure and immunological success ( VF/IS ) . virological success and immunological failure ( VS/IF ) and both virological and immunological failure ( VF/IF ) . Results From March 2004 until May 2006 , 124 HIV infected children were initiated on HAART . The median age ( IQR ) was 5.0 years ( 2.1 - 7.0 ) and 49 % ( 61/124 ) were female . The median [ 95 % confidence interval ( CI ) ] BAZ , WAZ and HAZ at baseline were 0.29 ( -2.9 , -1.2 ) , -1.2 ( -2.1 , -0.5 ) and -2.06 ( -2.9 , -1.2 ) respectively . Baseline median CD4 cell % and log10 HIV-1 RNA were ; 11.8 % ( 7.5 - 18.0 ) and 5.6 ( 5.2 - 5.8 ) copies/ml . By 48 weeks , mean WAZ and HAZ in the VF/IS group , which was younger , increased from - 0.98 ( SD 1.7 ) to + 1.22 ( SD 1.2 ) and from -1.99 ( 1.7 ) to + 0.76 ( 2.4 ) respectively . Mean increase in WAZ and HAZ in the VS/IF group , an older group was modest , from -1.84 ( 1.3 ) to - 0.41 ( 1.2 ) and -2.25 ( 1.2 ) to -1.16 ( 1.3 ) respectively . Baseline CD4 cell % [ OR 6.97 95 % CI ( 2.6 -18.6 ) ] , age [ OR 4.6 95 % CI ( 1.14 -19.1 ) ] and WHO clinical stage [ OR 3.5 95%CI ( 1.05 -12.7 ) ] were associated with successful treatment outcome . Conclusions HIV infected Ug and an children demonstrated a robust increase in height and weight z scores during the first 48 weeks of HAART , including those who failed to completely suppress virus . Older children initiating HAART with severe immune suppression were less likely to achieve a successful treatment outcome . These data emphasize the importance of initiating HAART early to ensure adequate immune and growth responses BACKGROUND South African guidelines recommend protease-inhibitor-based antiretroviral therapy ( ART ) with lopinavir-ritonavir for human immunodeficiency virus (HIV)-infected children < 36 months of age . We investigated factors associated with viral suppression and mortality among young children initiating ART . METHODS Treatment-naive , ART-eligible , HIV-infected children ( aged 6 - 104 weeks ) were enrolled in an ART strategies trial in South Africa and initiated protease-inhibitor-based ART . Mortality and the probability of viral suppression ( defined as HIV RNA load of < 400 copies/mL ) by 39 weeks after ART initiation were investigated . RESULTS Of 254 children who initiated ART , 99 ( 39 % ) were cotreated for tuberculosis during follow-up . The mortality rate was 14 % . Factors predicting mortality were lower pre-ART weight-for-age z score and higher HIV RNA load . By 39 weeks , 84 % of surviving children achieved viral suppression . Children who were not cotreated for tuberculosis were more likely to achieve viral suppression ( 94.8 % ) than were children who were receiving cotreatment at ART initiation ( 74.2 % ) or who started tuberculosis cotreatment after ART initiation ( 51.6 % ; P < .001 ) . Other factors predicting lower probability of viral suppression were lower pre-ART weight- and length-for-age z score , higher HIV RNA load , and World Health Organization disease stage . CONCLUSION High rates of viral suppression can be achieved among infants and young children who initiate protease-inhibitor-based ART . Cotreatment for tuberculosis reduced viral suppression . How best to treat HIV-infected children who require tuberculosis treatment warrants urgent investigation Background : Weight and height growth of HIV-infected children tends to lag behind that of uninfected children of similar age . Previous reports of the effect of highly active antiretroviral therapy ( HAART ) on the growth of HIV-infected children have been contradictory . Methods : Age- and gender-adjusted height and weight z scores were studied for 192 HIV-infected children , 4 months to 17 years of age , who had been treated with antiretroviral therapy for at least 16 weeks . These children , in clinical ly and immunologically stable condition , were enrolled into one of 4 HAART regimens and evaluated for 96 weeks . Results : At baseline , these HIV-infected children were significantly shorter than uninfected children ( mean z score , −0.57 ; 95 % confidence interval , −0.73 to −0.41 ; P < 0.001 ) . Children with greater viral loads at baseline were significantly shorter and lighter than children with smaller viral loads ( both P < 0.001 ) . Administration of HAART led to an increase in mean weight z scores to normal values ( mean z score increase , from −0.16 to > 0 ) by week 48 and an increase in mean height z scores of 72 % toward normal values ( mean z score increase , from −0.57 to −0.16 ) by week 96 . Younger children gained height more rapidly ( P < 0.001 ) , and children with greater baseline viral loads gained weight more rapidly ( P < 0.001 ) . There was no evidence of differential height or weight changes in 48 weeks between children with different degrees of virologic control . Conclusions : HAART improved the average weight gain of HIV-infected children from subnormal to normal after 1 year and improved average height growth to nearly normal after 2 years Anemia is a common complication of pediatric HIV infection and is associated with suboptimal cognitive performance and growth failure . Routine iron supplementation is not provided to South African HIV-infected children . We hypothesized that dietary iron intake without supplementation is sufficient to protect against iron deficiency ( ID ) in HIV-infected children receiving highly active antiretroviral therapy . In this prospect i ve study , the difference between dietary intakes of iron-deficient children ( soluble transferrin receptor > 9.4 mg/L ) and iron-sufficient children after 18 months on highly active antiretroviral therapy was examined . The association between iron intake and hemoglobin ( Hb ) concentration was also assessed . Longitudinal data collected for 18 months from 58 HIV-infected African children were assessed by generalized estimation equations , with adjustment for demographic information , dietary intakes , growth parameters , and CD4 % . After adjustment for covariates , the longitudinal association between dietary iron intake and Hb concentration remained significant . This association shows that for every 1-mg increase in iron intake per day , Hb increases by 1.1 g/L ( P < .001 ) . Mean Hb increased significantly after 18 months of follow-up ( 106 ± 14 to 129 ± 14 g/L , P < .01 ) , but soluble transferrin receptor also increased ( 7.7 ± 2.7 to 8.9 ± 3.0 mg/L , P < .01 ) . The incidence of ID increased from 15.2 % at baseline to 37.2 % after 18 months . Children with animal protein intakes greater than > 20 g/d had significantly lower odds for ID at 18 months than did children with lower intakes ( odds ratio , 0.40 ; 95 % confidence interval , 0.21 - 0.77 ) . Dietary iron intake was insufficient to protect against ID , pointing to a need for low-dose iron supplementation for iron-deficient HIV-infected children and interventions to increase the consumption of animal protein Background : Few data are available on the outcomes of pediatric antiretroviral therapy ( ART ) in the developing world . Methods : Eighty-three children were followed prospect ively in China from July 2005 to August 2006 and received ( zidovudine or stavudine ) plus lamivudine plus ( nevirapine or efavirenz ) . Results : Fifty-one children were ART naive at enrollment , and 32 were ART experienced . After 12 months , median weight increased by 0.3 weight for age z-score , median CD4 count increased from 116 to 340 cells/mm3 ( P < 0.0001 ) , and median viral load decreased from 5.53 to < 2.60 log10 copies/mL ( P < 0.0001 ) in the previously ART-naive children . In the ART-experienced children , median CD4 count increased from 193 to 318 cells/mm3 ( P = 0.13 ) , despite little change in median viral load ( 4.85 to 4.58 log10 copies/mL ; P = 0.83 ) . The viral load was < 400 copies/mL in 55 % of the previously ART-naive children and in 16 % of the ART-experienced children . Conclusions : Weight and CD4 cell counts improved , and more than half of previously ART-naive patients had undetectable viral loads at 1 year . Future efforts should focus on improved virologic suppression through improved adherence and access to second-line regimens Introduction . Growthfailure is a common presenting sign in children with HIV disease and is a sensitive indicator of disease progression in children with AIDS . Highly active antiretroviral therapy ( HAART ) is associated with a significant decrease in viral load and a subsequent rise in CD4 + T cell counts in HIV-1-infected children and also with increased height and weight . The underlying mechanisms of catch-up growth during HAART are yet unknown . Methods . Height and weight measurements , blood sample analyses for HIV-1 RNA and peripheral blood CD4 + T cell counts were obtained twice within 1 month before the start of HAART and after 12 , 24 , 36 and 48 weeks of treatment . Serum concentrations of insulin-like growth factor I ( IGF-1 ) , IGFs complexed to specific , structurally homologous binding proteins ( IGFBP-3 ) , cortisol , free thyroxine and tumor necrosis factor alpha ( TNF-alpha ) were measured before the start of therapy and after 24 weeks . In addition serum IGF-1 and IGFBP-3 values were determined after 48 weeks . Results . Twenty-seven HIV-1-infected children with a median age of 5.5 years ( range , 0.3 to 14.9 years ) were included . Overall no significant changes in height and body mass index ( BMI ) z scores were observed . The median baseline plasma viral load of 68 800 copies/ml decreased to less than the detection limit of 500 copies/ml in 80 % of the children after 48 weeks . TNF-alpha values were elevated ( 44 pg/ml ) at baseline and decreased significantly to 37 pg/ml after 24 weeks . At baseline elevated TNF-alpha was observed in 78 % , which decreased to 55 % after 24 weeks . Baseline free thyroxine and cortisol values were normal and did not change during therapy . Baseline serum of IGF-1 and IGFBP-3 concentrations were normal , but IGF-1 tended to be lower than IGFBP-3 . Both values increased significantly after the initiation of therapy . IGFBP-3 decreased after 48 weeks whereas IGF-1 stabilized . The increase in IGF-1 was significantly higher in children in whom the BMI and length ( after correction for age and sex ) increased the most . Conclusion . Hypothyroidism and adrenal axis abnormalities are not associated with restoration of growth after the initiation of antiretroviral therapy in HIV-1-infected children . The combination of relatively high serum IGFBP-3 concentration and relatively lower serum IGF-1 suggests the presence of a growth hormone-resistant state . During treatment with a protease inhibitor-containing regimen , decreased serum IGFBP-3 and stabilization of IGF-1 after a significant initial increase suggest restoration of normal sensitivity to growth hormone and recovery to an anabolic condition BACKGROUND AND PURPOSE Paediatric HIV/AIDS remains a significant challenge in developing countries . We describe the effectiveness of interventions in HIV-infected children attending Paediatric Infectious Diseases Clinics in Jamaica . METHODS One hundred and ninety-seven HIV-infected children were followed prospect ively in multicentre ambulatory clinics between September 1 , 2002 and August 31 , 2005 , in the Kingston Paediatric and Perinatal HIV/AIDS Programme , Jamaica , and their outcomes described . RESULTS Median follow-up was 23 child-months ( interquartile range [ IQR ] 12 - 31 ) with 12 children ( 6.0 % ) lost to follow-up and deaths ( n=13 ) occurred at 4.64 per 100 child-years of follow-up . Median age was 5.0 years ( IQR 2.2 - 8.1 ) and 32.1 % had Centers for Disease Control and Prevention ( CDC ) category C disease at enrollment ; 62 % were ever on antiretroviral therapy ( ART ) with median duration of 15.4 months ( IQR 5.5 - 25.5 ) ; 85 % initiated ART with zidovudine/lamivudine/nevirapine . Mean weight-for-height 0.13 + /- 1.02 ( mean difference -1.71 [ 95 % Confidence interval ( CI ) -2.73 , -0.69 ] ; p = 0.001 ) and body mass index-for-age 0.05 + /- 1.11 ( mean difference -1.11 , [ CI -1.79 , -0.43 ] ; p = 0.002 ) ; z scores increased after 24 months on ART ; however , children remained stunted . Reductions in the incidence of hospitalizations ( mean diff 30.95 , [ CI 3.12 , 58.78 ] ; p = 0.03 ) and in episodes of pneumonia , culture-positive sepsis and tuberculosis occurred in those on ART . CONCLUSIONS A successfully implemented ambulatory model for paediatric HIV care in Jamaica has improved the quality of life and survival of HIV-infected children BACKGROUND Single-dose nevirapine is the cornerstone of the regimen for prevention of mother-to-child transmission of human immunodeficiency virus ( HIV ) in re source -limited setting s , but nevirapine frequently selects for resistant virus in mothers and children who become infected despite prophylaxis . The optimal antiretroviral treatment strategy for children who have had prior exposure to single-dose nevirapine is unknown . METHODS We conducted a r and omized trial of initial therapy with zidovudine and lamivudine plus either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 6 to 36 months of age , in six African countries , who qualified for treatment according to World Health Organization ( WHO ) criteria . Results are reported for the cohort that included children exposed to single-dose nevirapine prophylaxis . The primary end point was virologic failure or discontinuation of treatment by study week 24 . Enrollment in this cohort was terminated early on the recommendation of the data and safety monitoring board . RESULTS A total of 164 children were enrolled . The median percentage of CD4 + lymphocytes was 19 % ; a total of 56 % of the children had WHO stage 3 or 4 disease . More children in the nevirapine group than in the ritonavir-boosted lopinavir group reached a primary end point ( 39.6 % vs. 21.7 % ; weighted difference , 18.6 percentage-points ; 95 % confidence interval , 3.7 to 33.6 ; nominal P=0.02 ) . Baseline resistance to nevirapine was detected in 18 of 148 children ( 12 % ) and was predictive of treatment failure . No significant between-group differences were seen in the rate of adverse events . CONCLUSIONS Among children with prior exposure to single-dose nevirapine for perinatal prevention of HIV transmission , antiretroviral treatment consisting of zidovudine and lamivudine plus ritonavir-boosted lopinavir result ed in better outcomes than did treatment with zidovudine and lamivudine plus nevirapine . Since nevirapine is used for both treatment and perinatal prevention of HIV infection in re source -limited setting s , alternative strategies for the prevention of HIV transmission from mother to child , as well as for the treatment of HIV infection , are urgently required . ( Funded by the National Institutes of Health ; Clinical Trials.gov number , NCT00307151 . ) OBJECTIVES To describe baseline nutritional anthropometry and its determinants in a cohort of children commencing HAART , and subsequent longitudinal anthropometric trajectories over 2 years . METHODS Prospect i ve observational study in a prepubertal cohort of children commencing HAART in Durban , South Africa . RESULTS Among 151 children with a median baseline age of 61.3 months ( IQR 29.6 , 90.1 ) , prevalence of stunting was 54 % ( 95 % CI 46 , 62 ) and of underweight , 37 % ( 95 % CI 29 , 45 ) . There was high prevalence of preceding respiratory and diarrhoeal comorbidities , which were associated with poorer anthropometry . There were significant improvements in height , weight and mid-upper-arm circumference z-scores after initiation of HAART regardless of preceding comorbidities . Stunted children remained shorter on average after 24 months , but younger children had better catch-up . Children who eventually died had persistently worse anthropometry . Children who were exposed to improved programs for prevention of mother-to-child transmission ( PMTCT ) were younger and had more severe growth impairments at baseline . CONCLUSION Anthropometric status of children on HAART is influenced by age , preceding comorbidities , and by programmatic factors . With improved PMTCT programs , infants who would previously have died in infancy are now surviving to commence HAART . Poor outcomes are preceded by persistent anthropometric failure on HAART reaffirming the need for growth velocity monitoring Background . To assess tolerance and efficacy of early multitherapy including a protease inhibitor for infants perinatally infected with HIV . Methods . Observational study of tolerance and clinical and immunovirologic evolution in HIV-infected infants treated before the age of 1 year in the French Perinatal Study . Results . Thirty-one infants were included . The median age was 3.7 months at initiation of multitherapy . Clinical stage was C ( n = 8) , B ( n = 5 ) or A/N ( n = 18 ) . The median HIV RNA viral load was 5.8 log copies/ml , and the median CD4 cell percentage was 29 % . Median follow-up of treatment was 27 months . Of 31 infants 15 experienced mild to moderate adverse events . No infant had clinical or immunologic progression . The median change in viral load was −2.7 log copies/ml after 3 months , −2.0 log after 12 months and −1.7 log after 24 months of treatment . The proportion of infants with a viral load below 500 copies/ml decreased from 53 % at 6 months to 18 % at 24 months of treatment . The virologic response was not correlated with viral load at baseline . However , the slope of the viral load decrease during the first month of treatment was predictive of the virologic response at 3 and 6 months . Fourteen infants with a viral load of > 500 copies/ml after 6 months of treatment displayed viruses with antiretroviral resistance mutations in reverse transcriptase and /or protease genes . Conclusions . Despite the absence of clinical or immunologic progression , the high frequency of virologic failure associated with genotypic resistance reveals the difficulties associated with implementing antiretroviral multitherapy in infants . Suboptimal doses of protease inhibitor could be a factor contributing to treatment failure Background : Few studies have directly compared response to antiretroviral therapy ( ART ) between children living in well-re source d and re source -limited setting s. In re source -limited setting s non-HIV contributors could reduce the beneficial effects of ART . We compare predictors of short-term immunological , virological , and growth response to ART in HIV-infected children in the United Kingdom/Irel and and Kampala . Methods : We analyzed prospect i ve cohort data from 54 UK/Irish hospitals ( the Collaborative HIV Paediatric Study ) and Mulago Hospital , Kampala , Ug and a. Six- and 12-month responses are described among children initiating combination ART ( ≥3 drugs , ≥2 classes ) . Six months post-ART , predictors of viral load ( VL ) suppression < 400 copies/mL , CD4 % increases > 10 % , and height- and weight-for-age z-score increases ≥+0.5 were investigated using logistic regression . Results : In all , 582 UK/Irish children ( 76 % black African ) were younger than 876 Kampala children at ART initiation ( median 5.0 vs 7.6 years ) , with higher CD4 % ( 14 % , 8 % ) , lower VL ( 172,491 and 346,809 copies/mL ) , and less stunting ( −0.8 , −2.8 ) and wasting ( −0.6 , −2.8 ) . Post-ART , median 12-month changes in the United Kingdom/Irel and and Kampala in CD4 % ( + 12 % , + 13 % ) and weight ( + 0.4 , + 0.5 ) were similar , but growth was less in Kampala ( + 0.20 , + 0.06 , P < 0.001 ) . Younger children in both cohorts had better immunological , weight , and growth responses ( all P < 0.001 ) . However , lower pre-ART CD4 % predicted better immunological response in the United Kingdom/Irel and but poorer response in Kampala ( heterogeneity P = 0.004 ) . Although 70 % children in both cohorts had suppressed < 400 copies/mL at 6 months , adolescents starting ART in the United Kingdom/Irel and had somewhat poorer VL responses than those in Kampala ( P = 0.15 ) . Conclusions : Overall immunological and virologic ART responses were similar in children in both cohorts . Poorer CD4 recovery in more immunosuppressed Kampala children and blunted growth responses likely reflect higher background malnutrition and infection rates in Ug and a , suggesting the need for earlier HIV diagnosis , nutritional support , cotrimoxazole prophylaxis , and ART Abstract Background : Typical treatment of moderate acute malnutrition , simple wasting , in sub-Saharan Africa consists of dietary counselling and /or general or targeted distribution of corn/soy-blended flour ( CSB ) . A r and omised clinical effectiveness trial in 2007 showed CSB to be less effective than ready-to-use supplementary food ( RUSF ) . Aim : To determine the operational effectiveness of treating moderate acute malnutrition with RUSF . Methods : Children aged 6–59 months were recruited in rural southern Malawi . Each child received 65 kcal/kg/d of locally produced soy/peanut RUSF , a product that provided about 1 RDA of each micronutrient . Anthropometric measurements were taken every 2 weeks and additional rations of RUSF were distributed at this time if the child remained wasted . Study participation lasted up to 8 weeks . Results : Of the 2417 children enrolled , 80 % recovered , 4 % defaulted , 0.4 % died , 12 % remained moderately wasted and 3 % developed severe acute malnutrition . Weight , length and MUAC gain were 2.6 g/kg/d , 0.2 mm/d and 0.1 mm/d respectively . Cost per child treated was $ 5.39 . Conclusions : This intervention proved to be robust , maintaining high recovery rates and low default rates when instituted without the additional supervision and beneficiary incentives of a research setting CONTEXT Protease inhibitor (PI)-based therapy is recommended for infants infected with human immunodeficiency virus ( HIV ) who were exposed to nevirapine for prevention of mother-to-child HIV transmission . However , there are limitations of continuing PI-based therapy indefinitely and reuse of nevirapine has many advantages . OBJECTIVE To test whether nevirapine-exposed infants who initially achieve viral suppression with PI-based therapy can maintain viral suppression when switched to nevirapine-based therapy . DESIGN , SETTING , AND PATIENTS R and omized trial conducted between April 2005 and May 2009 at a hospital in Johannesburg , South Africa , among 195 children who achieved viral suppression less than 400 copies/mL for 3 or more months from a cohort of 323 nevirapine-exposed children who initiated PI-based therapy before 24 months of age . INTERVENTIONS Control group children continued to receive ritonavir-boosted lopinavir , stavudine , and lamivudine ( n = 99 ) . Switch group children substituted nevirapine for ritonavir-boosted lopinavir ( n = 96 ) . MAIN OUTCOME MEASURES Children were followed up for 52 weeks after r and omization . Plasma HIV-1 RNA of greater than 50 copies/mL was the primary end point . Confirmed viremia greater than 1000 copies/mL was used as a criterion to consider regimen changes for children in either group ( safety end point ) . RESULTS Plasma viremia greater than 50 copies/mL occurred less frequently in the switch group ( Kaplan-Meier probability , 0.438 ; 95 % CI , 0.334 - 0.537 ) than in the control group ( 0.576 ; 95 % CI , 0.470 - 0.668 ) ( P = .02 ) . Confirmed viremia greater than 1000 copies/mL occurred more frequently in the switch group ( 0.201 ; 95 % CI , 0.125 - 0.289 ) than in the control group ( 0.022 ; 95 % CI , 0.004 - 0.069 ) ( P < .001 ) . CD4 cell response was better in the switch group ( median CD4 percentage at 52 weeks , 34.7 ) vs the control group ( CD4 percentage , 31.3 ) ( P = .004 ) . Older age ( relative hazard [ RH ] , 1.71 ; 95 % CI , 1.08 - 2.72 ) was associated with viremia greater than 50 copies/mL in the control group . Inadequate adherence ( RH , 4.14 ; 95 % CI , 1.18 - 14.57 ) and drug resistance ( RH , 4.04 ; 95 % CI , 1.40 - 11.65 ) before treatment were associated with confirmed viremia greater than 1000 copies/mL in the switch group . CONCLUSION Among HIV-infected children previously exposed to nevirapine , switching to nevirapine-based therapy after achieving viral suppression with a ritonavir-boosted lopinavir regimen result ed in lower rates of viremia greater than 50 copies/mL than maintaining the primary ritonavir-boosted lopinavir regimen . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00117728 A recent r and omized trial showed dramatic improvement in survival of HIV-infected infants receiving early combination antiretroviral therapy ( cART ) . However , few data are available for re source -limited setting s. Therefore we conducted a chart review of HIV-infected infants initiated on cART between 2005 and 2008 . Of 129 treated infants , 94 completed 6 months , 62 completed 12 months , and 39 completed 18 months of cART . Median age at initiation of cART was 8.6 months ( range 2.1 - 11.9 ) and 77.2 % had advanced disease . Undetectable VL was found in 78.8 % of children who reached 18 months of treatment . CD4 % increased from a median of 15.4 % at baseline to 33.1 % at 18 months . Weight for age Z-score increased from a mean ± SD of -2.7 ± 1.97 to 0.02 ± 1.10 at 18 months . Findings show favourable response to cART in HIV-infected infants outside a research environment , despite initial advanced disease . Efforts should be made to initiate cART as early as possible BACKGROUND Interim results from the children with HIV early antiretroviral ( CHER ) trial showed that early antiretroviral therapy ( ART ) was life-saving for infants infected with HIV . In view of the few treatment options and the potential toxicity associated with lifelong ART , in the CHER trial we compared early time-limited ART with deferred ART . METHODS CHER was an open-label r and omised controlled trial of HIV-infected asymptomatic infants younger than 12 weeks in two South African trial sites with a percentage of CD4-positive T lymphocytes ( CD4 % ) of 25 % or higher . 377 infants were r and omly allocated to one of three groups : deferred ART ( ART-Def ) , immediate ART for 40 weeks ( ART-40W ) , or immediate ART for 96 weeks ( ART-96W ) , with subsequent treatment interruption . The r and omisation schedule was stratified by clinical site with permuted blocks of r and om sizes to balance the numbers of infants allocated to each group . Criteria for ART initiation in the ART-Def group and re-initiation after interruption in the other groups were CD4 % less than 25 % in infancy ; otherwise , the criteria were CD4 % less than 20 % or Centers for Disease Control and Prevention severe stage B or stage C disease . Combination therapy of lopinavir-ritonavir , zidovudine , and lamivudine was the first-line treatment regimen at ART initiation and re-initiation . The primary endpoint was time to failure of first-line ART ( immunological , clinical , or virological ) or death . Comparisons were done by intention-to-treat analysis , with use of time-to-event methods . This trial is registered with Clinical Trials.gov , number NCT00102960 . FINDINGS 377 infants were enrolled , with a median age of 7·4 weeks , CD4 % of 35 % , and HIV RNA log 5·7 copies per mL. Median follow-up was 4·8 years ; 34 infants ( 9 % ) were lost to follow-up . Median time to ART initiation in the ART-Def group was 20 weeks ( IQR 16 - 25 ) . Time to restarting of ART after interruption was 33 weeks ( 26 - 45 ) in ART-40W and 70 weeks ( 35 - 109 ) in ART-96W ; at the end of the trial , 19 % of patients in ART-40W and 32 % of patients in ART-96W remained off ART . Proportions of follow-up time spent on ART were 81 % in the ART-Def group , 70 % in the ART-40W group , and 69 % in the ART-96W group . 48 ( 38 % ) of 125 children in the ART-Def group , 32 ( 25 % ) of 126 in the ART-40W group , and 26 ( 21 % ) of 126 in the ART-96W group reached the primary endpoint . The hazard ratio , relative to ART-Def , was 0·59 ( 95 % CI 0·38 - 0·93 , p=0·02 ) for ART-40W and 0·47 ( 0·27 - 0·76 , p=0·002 ) for ART-96W . Three children in ART-Def , three in ART-40W , and one in ART-96W switched to second-line ART . INTERPRETATION Early time-limited ART had better clinical and immunological outcomes than deferred ART , with no evidence of excess disease progression during subsequent treatment interruption and less overall ART exposure than deferred ART . Longer time on primary ART permits longer subsequent interruption , with marginally better outcomes . FUNDING US National Institutes of Health BACKGROUND The optimum time to start antiretroviral therapy for children diagnosed with HIV infection after 1 year of age is unknown . We assessed whether antiretroviral therapy could be deferred until CD4 percentages declined to less than 15 % without affecting AIDS-free survival . METHODS In our multicentre , r and omised , open-label trial at nine research sites in Thail and and Cambodia , we enrolled children aged 1 - 12 years who were infected with HIV and had CD4 percentages of 15 - 24 % . Participants were r and omly assigned ( 1:1 ) by a minimisation scheme to start antiretroviral therapy at study entry ( early treatment group ) or antiretroviral therapy to start when CD4 percentages declined to less than 15 % ( deferred treatment group ) . The primary endpoint was AIDS-free survival ( based on US Centers for Disease Control and Prevention category C events ) at week 144 , assessed with the Kaplan-Meier analysis and the log-rank approach . This study is registered with Clinical Trials.gov , number NCT00234091 . FINDINGS Between March 28 , 2006 , and Sept 10 , 2008 , we enrolled 300 Thai and Cambodian children infected with HIV , with a median age of 6·4 years ( IQR 3·9 - 8·4 ) . 150 children were r and omly allocated early antiretroviral therapy ( one participant was excluded from analyses after withdrawing before week 0 ) and 150 children were r and omly allocated deferred antiretroviral therapy . Median baseline CD4 percentage was 19 % ( 16 - 22 % ) . 69 children ( 46 % ) in the deferred treatment group started antiretroviral therapy during the study . AIDS-free survival at week 144 in the deferred treatment group was 98·7 % ( 95 % CI 94·7 - 99·7 ; 148 of 150 patients ) compared with 97·9 % ( 93·7 - 99·3 ; 146 of 149 patients ) in the early treatment group ( p=0·6 ) . INTERPRETATION AIDS-free survival in both treatment groups was high . This low event rate meant that our study was underpowered to detect differences between treatment start times and thus additional follow-up of study participants or future studies are needed to answer this clinical question Objective : To analyze the determinants of CD4 change in children during 3 periods : before highly active antiretroviral therapy ( HAART ) , during the first year after HAART initiation , and past 1 year after HAART initiation . Methods : One hundred seventy-seven children enrolled in a prospect i ve cohort in Abidjan received HAART during a mean follow-up of 30 months . A linear mixed-effects model was used for the first period , a mixed-effects piecewise model for the second period , and an asymptotic mixed-effects model for long-term CD4 dynamics . Results : Before HAART initiation , CD4 percentage decreased along time [ β = −0.59 ( −0.92 to −0.26 ) ] was positively associated with body mass index for age [ β = 0.47 ( 0.22 to 0.72 ) ] and negatively associated with viral load [ β = −1.01 ( −1.90 to −0.13 ) ] . During the first year of treatment , the CD4 decrease reverted to a steep increase that was negatively associated with age at HAART initiation [ β = −0.24 ( −0.4 to −0.07 ) ] and with the mean viral load under HAART [ β = −1.51 ( −2.21 to −0.81 ) ] . The long-term CD4 percentage was also negatively associated with the mean viral load under HAART [ β = −4.97 ( −6.22 to −3.72 ) ] and age at HAART initiation [ β = −0.82 ( −1.12 to −0.51 ) ] . Conclusions : Before HAART initiation , the CD4 cell percentage was associated with growth indicators whereas , after HAART , an early increase and a long-term plateau were negatively associated with the viral load and age at HAART initiation Twenty-six Thai HIV-infected children , aged 2 years or less were prospect ively enrolled to receive non-nucleoside reverse transcription inhibitor-based highly active antiretroviral therapy ( HAART ) . Twenty-two children ( 85 % ) had World Health Organization clinical stage 3 or 4 . The median baseline CD4 cell percentage and plasma HIV RNA were 17 % and 5.9 log 10 copies/mL , respectively . The median age at HAART initiation was 9.8 months ( range , 1.5–24.0 ) . One child died . The mean CD4 cell percentages at 24 , 48 , and 96 weeks of treatment were 26 % , 31 % , and 37 % , respectively . The proportions of children with virologic suppression ( < 400 copies/mL ) at week 24 and 48 were 14/26 ( 54 % ) and 19/26 ( 73 % ) , respectively . Non-nucleoside reverse transcription inhibitor-based HAART is safe and effective in HIV-infected young children in a re source -limited setting We assembled a prospect i ve cohort of 3144 human immunodeficiency virus ( HIV ) infected children aged < 15 years initiating antiretroviral therapy ( ART ) in Dar es Salaam , Tanzania . The prospect i ve relationships of baseline covariates with growth were examined using linear regression models . ART led to improvement in mean weight-for-age ( WAZ ) , height/length-for-age ( HAZ ) and weight-for-length or body mass index ( WLZ/ BMI Z ) scores . However , normal HAZ values were not attained over an average follow-up of 17.2 months . After 6 months of ART , underweight ( P < 0.001 ) , low CD4 count or percent ( P < 0.001 ) , stavudine containing regimens ( P = 0.05 ) and advanced WHO disease stage ( P < 0.001 ) at ART initiation were associated with better WAZ scores . Age > 5 years on the other h and was associated with less increase in WAZ score after 6 months of ART ( P < 0.001 ) . These findings suggest that although ART improved the growth of the HIV-infected children in Tanzania , adjunct nutritional interventions may be needed to ensure that the growth of these children is optimized to the greatest extent possible Objective : To assess the feasibility and impact of highly active antiretroviral therapy ( HAART ) started in vertically HIV-1-infected infants less than 3 months of age . Design : A multicentre , phase I/II , non-r and omized , open-label study ( PENTA 7 ) . Methods : Adverse events , plasma HIV-1 RNA , CD4 cell counts , CD4 cell percentage ( CD4 % ) and clinical progression were recorded at baseline and prospect ively to 72 weeks in order to assess the toxicity , tolerability and efficacy of a combination of stavudine , didanosine and nelfinavir . Selection of genotypic resistance was also investigated . Results : Twenty infants , of whom only three had Centers for Disease Control and Prevention stage B , initiated HAART at median age 2.5 months ( range , 0.9–4.7 ) with median HIV-1 RNA concentration 5.5 log10 copies/ml ( range , 3.2–6.8 ) and CD4 % 33 % ( range , 11–66 ) . Median follow-up was 96 weeks ( range , 60–144 ) . At week 72 , 11 infants were still taking the original treatment . Few adverse events were reported related to treatment , all minor and causing treatment interruption in only three infants . No AIDS-defining events occurred ; one child died of non-HIV-related causes ( prematurity ) . All but two had CD4 % > 25 % at 72 weeks ; however , 14 infants had virological failure and six acquired resistance mutations . Conclusions : Early treatment with stavudine , didanosine and nelfinavir was well tolerated and associated with good clinical and immunological outcomes at week 72 . However , a high rate of virological failure with emergence of genotypic resistance is of great concern . More palatable drug combinations for infants and closer drug monitoring are required BACKGROUND Children with HIV will be on antiretroviral therapy ( ART ) longer than adults , and therefore the durability of first-line ART and timing of switch to second-line are key questions . We assess the long-term outcome of protease inhibitor and non-nucleoside reverse transcriptase inhibitor ( NNRTI ) first-line ART and viral load switch criteria in children . METHODS In a r and omised open-label factorial trial , we compared effectiveness of two nucleoside reverse transcriptase inhibitors ( NRTIs ) plus a protease inhibitor versus two NRTIs plus an NNRTI and of switch to second-line ART at a viral load of 1000 copies per mL versus 30,000 copies per mL in previously untreated children infected with HIV from Europe and North and South America . R and om assignment was by computer-generated sequentially numbered lists stratified by age , region , and by exposure to perinatal ART . Primary outcome was change in viral load between baseline and 4 years . Analysis was by intention to treat , which we defined as all patients that started treatment . This study is registered with IS RCT N , number IS RCT N73318385 . FINDINGS Between Sept 25 , 2002 , and Sept 7 , 2005 , 266 children ( median age 6.5 years ; IQR 2.8 - 12.9 ) were r and omly assigned treatment regimens : 66 to receive protease inhibitor and switch to second-line at 1000 copies per mL ( PI-low ) , 65 protease inhibitor and switch at 30,000 copies per mL ( PI-higher ) , 68 NNRTI and switch at 1000 copies per mL ( NNRTI-low ) , and 67 NNRTI and switch at 30,000 copies per mL ( NNRTI-higher ) . Median follow-up was 5.0 years ( IQR 4.2 - 6.0 ) and 188 ( 71 % ) children were on first-line ART at trial end . At 4 years , mean reductions in viral load were -3.16 log(10 ) copies per mL for protease inhibitors versus -3.31 log(10 ) copies per mL for NNRTIs ( difference -0.15 log(10 ) copies per mL , 95 % CI -0.41 to 0.11 ; p=0.26 ) , and -3.26 log(10 ) copies per mL for switching at the low versus -3.20 log(10 ) copies per mL for switching at the higher threshold ( difference 0.06 log(10 ) copies per mL , 95 % CI -0.20 to 0.32 ; p=0.56 ) . Protease inhibitor resistance was uncommon and there was no increase in NRTI resistance in the PI-higher compared with the PI-low group . NNRTI resistance was selected early , and about 10 % more children accumulated NRTI mutations in the NNRTI-higher than the NNRTI-low group . Nine children had new CDC stage-C events and 60 had grade 3/4 adverse events ; both were balanced across r and omised groups . INTERPRETATION Good long-term outcomes were achieved with all treatments strategies . Delayed switching of protease-inhibitor-based ART might be reasonable where future drug options are limited , because the risk of selecting for NRTI and protease-inhibitor resistance is low . FUNDING Paediatric European Network for Treatment of AIDS ( PENTA ) and Pediatric AIDS Clinical Trials Group ( PACTG/IMPAACT ) OBJECTIVE . To improve adherence and virologic suppression , we assessed the feasibility and effectiveness of a once-daily regimen of efavirenz with 3 nucleoside reverse transcriptase inhibitors as first-line or second-line highly active antiretroviral therapy in a cohort of HIV-1–infected children . METHODS . HIV-1–infected children naive to efavirenz were treated with a combination of efavirenz , abacavir , didanosine , and lamivudine in an observational , prospect i ve , single-center study . Virologic failure-free survival was assessed with Kaplan-Meier analysis . The CD4 + T-cell increase was estimated by using a generalized linear model incorporating repeated measurements . RESULTS . Thirty-six children received the study medication for a median of 69 weeks . Virologic failure-free survival rates were 76 % and 67 % after 48 weeks and 96 weeks , respectively . No significant difference was found in efficacy between first-line and second-line highly active antiretroviral therapy . All children receiving highly active antiretroviral therapy showed a sustained CD4 + T-cell increase , irrespective of virologic suppression . Growth rates improved with highly active antiretroviral therapy . Study medication administration was stopped for 14 children , mostly because of nonadherence ( 4 cases ) or virologic rebound ( 5 cases ) and because of adverse events ( unrelated death and grade 2 liver toxicity ) in 2 cases . Lipid abnormalities and abacavir-related hypersensitivity were not observed . CONCLUSIONS . For the first time , once-daily highly active antiretroviral therapy is demonstrated to be a safe , convenient , and potent antiretroviral regimen for HIV-1–infected children |
1,934 | 27,468,933 | Results : There is greater consistency in the content being delivered as part of end-of-life care education within medical schools .
The most frequently taught topics include attitudes to death and dying , communication skills , and pain management .
Pediatric care and religious/cultural issues are less frequently addressed .
Teaching institutions are also utilising a broader range of teaching modalities .
Conclusion : There is significant progress in palliative care education within medical schools .
Ongoing challenges relate to correlating our current practice in medical education to professional recommendations and the expressed needs of junior doctors to practice competent end-of-life care | Purpose : There is an increasing dem and for quality palliative care teaching within undergraduate medical education .
Studies suggest that many junior doctors feel underprepared to perform end-of-life care .
Previous systematic review s on palliative care teaching within medical schools have identified significant variability and lack of consistency in teaching .
This review aims to up date the literature on the current status of palliative care teaching to undergraduates within medical schools . | OBJECTIVE To assess the impact , retention , and magnitude of effect of a required didactic and experiential palliative care curriculum on third-year medical students ' knowledge , confidence , and concerns about end-of-life care , over time and in comparison to benchmark data from a national study of internal medicine residents and faculty . DESIGN Prospect i ve study of third-year medical students prior to and immediately after course completion , with a follow-up assessment in the fourth year , and in comparison to benchmark data from a large national study . SETTING Internal Medicine Clerkship in a public accredited medical school . PARTICIPANTS Five hundred ninety-three third-year medical students , from July 2002 to December 2007 . MAIN OUTCOME MEASURES Pre- and postinstruction performance on : knowledge , confidence ( self-assessed competence ) , and concerns ( attitudes ) about end-of-life care measures , vali date d in a national study of internal medicine residents and faculty . Medical student 's reflective written comments were qualitatively assessed . INTERVENTION Required 32-hour didactic and experiential curriculum , including home hospice visits and inpatient hospice care , with content drawn from the AMA-sponsored Education for Physicians on End-of-life Care ( EPEC ) Project . RESULTS Analysis of 487 paired t tests shows significant improvements , with 23 % improvement in knowledge ( F(1,486)=881 , p<0.001 ) , 56 % improvement in self-reported competence ( F(1,486)=2,804 , p<0.001 ) , and 29 % decrease in self-reported concern ( F(1,486)=208 , p<0.001 ) . Retesting medical students in the fourth year showed a further 5 % increase in confidence ( p<0.0002 ) , 13 % increase in allaying concerns ( p<0.0001 ) , but a 6 % drop in knowledge . The curriculum 's effect size on M3 students ' knowledge ( 0.56 ) exceeded that of a national cross-sectional study comparing residents at progressive training levels ( 0.18 ) Themes identified in students ' reflective comments included perceived relevance , humanism , and effectiveness of methods used to teach and assess palliative care education . CONCLUSIONS We conclude that required structured didactic and experiential palliative care during the clinical clerkship year of medical student education shows significant and largely sustained effects indicating students are better prepared than a national sample of residents and attending physicians Background By 2013 Palliative Care will become a m and atory examination subject in the medical curriculum in Germany . There is a pressing need for effective and well- design ed curricula and assessment methods . Debates are on going as how Undergraduate Palliative Care Education ( UPCE ) should be taught and how knowledge and skills should be assessed . It is evident by this time that the development process of early curricula in the US and UK has led to a plethora of diverse curricula which seem to be partly ineffective in improving the care for the seriously ill and dying offered by newly qualified doctors , as is demonstrated in controlled evaluations . The goals of this study were to demonstrate an evidence -based approach towards developing UPCE curricula and investigate the change in medical students ’ self-perceived readiness to deal with palliative care patients and their families . Methods To evaluate the effects of the UPCE curriculum we chose a prospect i ve , controlled , quasi-experimental , pre , retrospective-pre , post study design . A total of n = 37 3rd and 4th –year medical students were assigned to the intervention group ( n = 15 ; 4th -year ) and to the control group ( n = 22 ; 3rd-year ) . Resting on the self-efficacy concept of B and ura the measurement was conducted by a refined test-battery based on two independent measurements ( the revised Collet-Lester-Fear-of-Death-Scale and the instrument of the “ Program in Palliative Care Education and Practice ” at Harvard Medical School ) including 68 items altogether in a five-point Likert-scale . These items were design ed to test elementary skills in caring for the dying and their relatives as perceived by medical undergraduates . Data sets from both groups were analysed by paired and independent two- sample t-test . The TREND statement for reporting non-r and omized evaluations was applied for reporting on this quasi-experimental study . Results Three constructs showed statistically significant differences comparing the intervention group before and after . Willingness to accompany a dying patient increased from 21.40 to 37.30 ( p < .001 ) . Self-estimation of competence in communication with dying patients and their relatives increased from 12.00 to 23.60 ( p = .001 ) . Finally , self-estimation of knowledge and skills in Palliative Care increased from 8.30 to 13.20 ( p = .001 ) . Conclusions This study is a small but systematic step towards rigorous curricular development in palliative care . Our manualised curriculum is available for scrutiny and scientific feedback to support an open and constructive process of best- practice comparison in palliative care OBJECTIVE : To assess the status of medical education in end-of-life care and identify opportunities for improvement . DESIGN : Telephone survey . SETTING : U.S. academic medical centers . PARTICIPANTS : National probability sample of 1,455 students , 296 residents , and 287 faculty ( response rates 62 % , 56 % , and 41 % , respectively ) affiliated with a r and om sample of 62 accredited U.S. medical schools . MEASUREMENTS AND MAIN RESULTS : Measurements assessed attitudes , quantity and quality of education , preparation to provide or teach care , and perceived value of care for dying patients . Ninety percent or more of respondents held positive views about physicians ’ responsibility and ability to help dying patients . However , fewer than 18 % of students and residents received formal end-of-life care education , 39 % of students reported being unprepared to address patients ’ fears , and nearly half felt unprepared to manage their feelings about patients ’ deaths or help bereaved families . More than 40 % of residents felt unprepared to teach end-of-life care . More than 40 % of respondents reported that dying patients were not considered good teaching cases , and that meeting psychosocial needs of dying patients was not considered a core competency . Forty-nine percent of students had told patients about the existence of a life-threatening illness , but only half received feedback from residents or attendings ; nearly all residents had talked with patients about wishes for end-of-life care , and 33 % received no feedback . CONCLUSIONS : Students and residents in the United States feel unprepared to provide , and faculty and residents unprepared to teach , many key components of good care for the dying . Current educational practice s and institutional culture in U.S. medical schools do not support adequate end-of-life care , and attention to both curricular and cultural change are needed to improve end-of-life care education Prompted by directives from the GMC , ‘ care of the dying ’ is identified as ‘ core curricula ’ for undergraduate medical education . However , there are many technical and interpersonal challenges faced in learning the practice of palliative medicine . Accordingly , the design and delivery of education programmes need to be both carefully considered and evaluated . Using B and ura ’s Social Cognitive Theory as a driver , appropriate methodology for evaluating a novel education programme in palliative medicine was drafted . A pre- and post-survey of an education programme and palliative care placement for fourth year medical undergraduate students from Liverpool University ( n = 216 ) was completed using a composite question naire containing ; i ) Self-efficacy in Palliative Care Scale ( SEPC ) and ii ) Thanatophobia Scale . Both scales have shown reliability and validity within the sample population . Additionally , a r and omly selected Focus Group was conducted to provide qualitative information on the students ’ experience . A total of 139 pre- and post- question naires ( 64 % ) were completed . Analysis identified significant improvements in perceived efficacy ( SEPC Communication t = −16.41 , P < 0.001 ; SEPC Patient Management t = −22.31 , P < 0.001 ; SEPC Multidisciplinary Teamwork t = −15.56 , P < 0.001 ) . Significant improvements in thanatophobia were also recorded ( z = −7.51 , P < 0.001 ) although some interesting anomalies were noted . This study demonstrates that considered and appropriately structured clinical education has been shown to significantly improve students ’ belief in their ability to practice palliative medicine and to improve their attitude towards care . In accordance with the study ’s theoretical driver , it is reasonable to propose that the engaged active learning will have a positive effect on the future care of dying patients Purpose Few studies have compared the effect of Web-based eLearning versus small-group learning on medical student outcomes . Palliative and end-of-life ( PEOL ) education is ideal for this comparison , given uneven access to PEOL experts and content nationally . Method In 2010 , the authors enrolled all third-year medical students at the University of California , Davis School of Medicine into a quasi-r and omized controlled trial of Web-based interactive education ( eDoctoring ) compared with small-group education ( Doctoring ) on PEOL clinical content over two months . Students participated in three 3-hour PEOL sessions with similar content . Outcomes included a 24-item PEOL-specific self-efficacy scale with three domains ( diagnosis/treatment [ Cronbach alpha = 0.92 ; CI : 0.91–0.93 ] , communication/prognosis [ alpha = 0.95 ; CI : 0.93–0.96 ] , and social impact/self-care [ alpha = 0.91 ; CI : 0.88–0.92 ] ) ; 8 knowledge items ; 10 curricular advantage/disadvantages ; and curricular satisfaction ( both students and faculty ) . Results Students were r and omly assigned to Web-based eDoctoring ( n = 48 ) or small-group Doctoring ( n = 71 ) curricula . Self-efficacy and knowledge improved equivalently between groups ( e.g. , prognosis self-efficacy , 19 % ; knowledge , 10%–42 % ) . Student and faculty ratings of the Web-based eDoctoring curriculum and the small-group Doctoring curriculum were equivalent for most goals , and overall satisfaction was equivalent for each , with a trend toward decreased eDoctoring student satisfaction . Conclusions Findings showed equivalent gains in self-efficacy and knowledge between students participating in a Web-based PEOL curriculum in comparison with students learning similar content in a small-group format . Web-based curricula can st and ardize content presentation when local teaching expertise is limited , but it may lead to decreased user satisfaction Purpose . To describe attitudes and practice s of end-of-life care teaching in the undergraduate medical curriculum in the United States as reported by administrative leadership and identify opportunities for improvement . Method . A telephone survey of associate deans for medical education or curricular affairs at a r and om sample of 62 accredited U.S. medical schools was conducted in 2002 . Results . Fifty-one deans participated ( 82 % response rate ) . Most ( 84 % ) described end-of-life care education as “ very important ” and supported incorporating more end-of-life care teaching into the undergraduate curriculum . Sixty-seven percent reported that insufficient time is currently given to palliative care in their curriculum . Although a majority opposed required courses ( 59 % ) or clerkships ( 70 % ) that focused on end-of-life care , they did unanimously endorse integrating teaching end-of-life care into existing courses or clerkships . Key barriers to incorporating more end-of-life care into the curriculum included lack of time in the curriculum , lack of faculty expertise , and absence of a faculty leader . Conclusion . Associate deans for medical education or curricular affairs in the United States support integrating end-of-life care content into existing courses and clerkships throughout the undergraduate medical curriculum . Successful integration will require institutional investment in faculty development , including both the development of faculty leaders to drive change efforts , and the education of all faculty who teach students and exert influence as role models and mentors . The strong support for end-of-life care education expressed by academic leaders in this study , combined with the high level of interest expressed in the authors ’ 2001 national survey of students , provide evidence of the potential for meaningful change in the undergraduate medical curriculum Aim This study evaluates the impact of an interprofessional home hospice visit ( HHV ) on third-year medical students ’ attitudes toward , and underst and ing of , end-of-life care and the visit 's effect on students ’ views of their emerging professional roles and identities . Methods All third-year medical students at Stony Brook School of Medicine in Stony Brook , New York , USA , participated in an HHV . A didactic session preceded the HHV . Subsequently , students were required to su bmi t a piece of reflective writing detailing the impact of the visit . We conducted a qualitative analysis of a r and om sample drawn from the 467 su bmi tted reflections . Results Six themes emerged from the student reflections : three were related to the students ’ direct observations during the HHV , and three were related to the reflective learning of the students based on their HHV experience . Conclusion The qualitative analysis of the reflective writings showed that the students gained a deep appreciation of the human identity of hospice patients and a humanistic underst and ing of their own role as future physicians The purpose of this study was to assess the impact of an elective geriatric palliative care course on medical students ' attitudes , knowledge , and behaviors regarding communication with terminally ill patients . Surveys were administered at the beginning and end of the elective . Despite a significant increase in knowledge about geriatric and palliative medicine ( F = 24.80 ; P < .001 ) , there were no significant changes in students ' self-reported behaviors when applying curriculum-based communication strategies . However , the qualitative analysis of open-ended questions showed that the curriculum intervention did result in an improvement in empowering message strategies for breaking bad news . The evaluation of the end-of-life curriculum needs to exceed the measurement of attitudes and knowledge and include behavioral assessment of end-of-life communication skills |
1,935 | 28,655,977 | H. pylori eradication is associated with a significantly lower risk of GC ; this finding has significant implication s for the prevention of this cancer .
The benefit is maximized when H. pylori eradication is applied at early stages of the infection | BACKGROUND Increasing evidence has suggested that Helicobacter pylori ( H. pylori ) eradication might prevent the development of gastric cancer ( GC ) .
This systematic review and meta- analysis aim ed to better explore the role of H. pylori eradication in preventing GC , with particular reference to patients with precancerous lesions at baseline histology . | In the Sh and ong Intervention Trial , 2 weeks of antibiotic treatment for Helicobacter pylori reduced the prevalence of precancerous gastric lesions , whereas 7.3 years of oral supplementation with garlic extract and oil ( garlic treatment ) or vitamin C , vitamin E , and selenium ( vitamin treatment ) did not . Here we report 14.7-year follow-up for gastric cancer incidence and cause-specific mortality among 3365 r and omly assigned subjects in this masked factorial placebo-controlled trial . Conditional logistic regression was used to estimate the odds of gastric cancer incidence , and the Cox proportional hazards model was used to estimate the relative hazard of cause-specific mortality . All statistical tests were two-sided . Gastric cancer was diagnosed in 3.0 % of subjects who received H pylori treatment and in 4.6 % of those who received placebo ( odds ratio = 0.61 , 95 % confidence interval = 0.38 to 0.96 , P = .032 ) . Gastric cancer deaths occurred among 1.5 % of subjects assigned H pylori treatment and among 2.1 % of those assigned placebo ( hazard ratio [ HR ] of death = 0.67 , 95 % CI = 0.36 to 1.28 ) . Garlic and vitamin treatments were associated with non-statistically significant reductions in gastric cancer incidence and mortality . Vitamin treatment was associated with statistically significantly fewer deaths from gastric or esophageal cancer , a secondary endpoint ( HR = 0.51 , 95 % CI = 0.30 to 0.87 ; P = .014 ) AIM To investigate the effects of Helicobacter pylori ( H pylori ) eradication therapy for treatment of peptic ulcer on the incidence of gastric cancer . METHODS A multicenter prospect i ve cohort study was conducted between November 2000 and December 2007 in Yamagata Prefecture , Japan . The study included patients with H pylori-positive peptic ulcer who decided themselves whether to receive H pylori eradication ( eradication group ) or conventional antacid therapy ( non-eradication group ) . Incidence of gastric cancer in the two groups was determined based on the results of annual endoscopy and question naire surveys , as well as Yamagata Prefectural Cancer Registry data , and was compared between the two groups and by results of H pylori therapy . RESULTS A total of 4133 patients aged between 13 and 91 years ( mean 52.9 years ) were registered , and 56 cases of gastric cancer were identified over a mean follow-up of 5.6 years . The sex- and age-adjusted incidence ratio of gastric cancer in the eradication group , as compared with the non-eradication group , was 0.58 ( 95 % CI : 0.28 - 1.19 ) and ratios by follow-up period ( < 1 year , 1 - 3 years , > 3 years ) were 1.16 ( 0.27 - 5.00 ) , 0.50 ( 0.17 - 1.49 ) , and 0.34 ( 0.09 - 1.28 ) , respectively . Longer follow-up tended to be associated with better prevention of gastric cancer , although not to a significant extent . No significant difference in incidence of gastric cancer was observed between patients with successful eradication therapy ( 32/2451 patients , 1.31 % ) and those with treatment failure ( 11/639 patients , 1.72 % ) . Among patients with duodenal ulcer , which is known to be more prevalent in younger individuals , the incidence of gastric cancer was significantly less in those with successful eradication therapy ( 2/845 patients , 0.24 % ) than in those with treatment failure ( 3/216 patients , 1.39 % ) . CONCLUSION H pylori eradication therapy for peptic ulcer patients with a mean age of 52.9 years at registration did not significantly decrease the incidence of gastric cancer OBJECTIVE --To investigate the association between gastric cancer and prior infection with Helicobacter pylori . DESIGN --Case-control comparison of prevalence of IgG antibodies to H pylori in blood sample s collected prospect ively , before diagnosis of gastric cancer in the cases . Presence of H pylori antibody ( greater than 10 micrograms IgG/ml ) determined by enzyme linked immunosorbent assay ( ELISA ) . SUBJECTS--29 men with a subsequent diagnosis of gastric cancer and 116 aged matched controls selected from over 22,000 middle aged men participating in two ongoing cohort studies ( the British United Provident Association study and the Caerphilly collaborative heart disease study ) , who had provided blood sample s during 1975 - 1982 . RESULTS --20 of the 29 cases ( 69 % ) and 54 of the 116 controls ( 47 % ) were positive for H pylori specific antibody . The median specific IgG concentration was significantly higher in the cases than controls ( 90 micrograms/ml v 3.6 micrograms/ml , p less than 0.01 ) . The estimated odds ratio for the risk of gastric cancer in those with a history of infection with H pylori was 2.77 ( 95 % confidence interval 1.04 to 7.97 , 2p = 0.039 ) . CONCLUSIONS --H pylori infection may be an important cause of gastric cancer ; between 35 % and 55 % of all cases may be associated with such an infection Objective Helicobacter pylori infection and overexpression of cyclo-oxygenase-2 ( COX-2 ) are associated with gastric cancer and its precursors . To evaluate the effect of a selective COX-2 inhibitor alone and combined with H pylori eradication on the evolution of precancerous gastric lesions , a r and omised , placebo-controlled trial was conducted in Linqu County , Sh and ong Province , China . Methods A total of 1024 participants aged 35–64 years with H pylori infection and advanced gastric lesions were r and omly assigned in a factorial design to two interventions or placebo : anti-H pylori treatment for 7 days , and a COX-2 inhibitor ( celecoxib ) for 24 months . The effects of the interventions were evaluated by the regression or progression of advanced gastric lesions . Results Of the 1024 participants who received anti-H pylori treatment or placebo , 919 completed a subsequent 24-month treatment with celecoxib or placebo . The H pylori eradication rate by per- protocol analysis was 78.2 % . Compared with placebo , the proportions of regression of gastric lesions significantly increased in the celecoxib treatment ( 52.8 % vs 41.2 % ) and anti-H pylori treatment ( 59.3 % vs 41.2 % ) group , and OR by per- protocol analysis was 1.72 ( 95 % CI 1.07 to 2.76 ) for celecoxib and 2.19 ( 95 % CI 1.32 to 3.64 ) for H pylori eradication . No statistically significant effect was found for H pylori eradication followed by celecoxib on the regression of advanced gastric lesions ( OR 1.48 , 95 % CI 0.91 to 2.40 ) . Conclusion This population -based intervention trial revealed that celecoxib treatment or H pylori eradication alone had beneficial effects on the regression of advanced gastric lesions . No favourable effects were seen for H pylori eradication followed by celecoxib treatment . Trial registration HARECCTR0500053 in accordance with WHO ICTRP requirements CONTEXT Although chronic Helicobacter pylori infection is associated with gastric cancer , the effect of H pylori treatment on prevention of gastric cancer development in chronic carriers is unknown . OBJECTIVE To determine whether treatment of H pylori infection reduces the incidence of gastric cancer . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve , r and omized , placebo-controlled , population -based primary prevention study of 1630 healthy carriers of H pylori infection from Fujian Province , China , recruited in July 1994 and followed up until January 2002 . A total of 988 participants did not have precancerous lesions ( gastric atrophy , intestinal metaplasia , or gastric dysplasia ) on study entry . INTERVENTION Patients were r and omly assigned to receive H pylori eradication treatment : a 2-week course of omeprazole , 20 mg , a combination product of amoxicillin and clavulanate potassium , 750 mg , and metronidazole , 400 mg , all twice daily ( n = 817 ) ; or placebo ( n = 813 ) . MAIN OUTCOME MEASURES The primary outcome measure was incidence of gastric cancer during follow-up , compared between H pylori eradication and placebo groups . The secondary outcome measure was incidence of gastric cancer in patients with or without precancerous lesions , compared between the 2 groups . RESULTS Among the 18 new cases of gastric cancers that developed , no overall reduction was observed in participants who received H pylori eradication treatment ( n = 7 ) compared with those who did not ( n = 11 ) ( P = .33 ) . In a subgroup of patients with no precancerous lesions on presentation , no patient developed gastric cancer during a follow-up of 7.5 years after H pylori eradication treatment compared with those who received placebo ( 0 vs 6 ; P = .02 ) . Smoking ( hazard ratio [ HR ] , 6.2 ; 95 % confidence interval [ CI ] , 2.3 - 16.5 ; P<.001 ) and older age ( HR , 1.10 ; 95 % CI , 1.05 - 1.15 ; P<.001 ) were independent risk factors for the development of gastric cancer in this cohort . CONCLUSIONS We found that the incidence of gastric cancer development at the population level was similar between participants receiving H pylori eradication treatment and those receiving placebo during a period of 7.5 years in a high-risk region of China . In the subgroup of H pylori carriers without precancerous lesions , eradication of H pylori significantly decreased the development of gastric cancer . Further studies to investigate the role of H pylori eradication in participants with precancerous lesions are warranted Background We previously reported that eradication of Helicobacter pylori could reduce the risk of developing gastric cancer in patients with peptic ulcer diseases . In the present study , we further followed up our patient groups to identify factors associated with the development of gastric cancer . Methods Prospect i ve posteradication evaluations were conducted in 1342 consecutive patients ( 1191 men and 151 women ; mean age , 50 years ) with peptic ulcer disease who had received H. pylori eradication therapy . The patients had undergone endoscopic examination before eradication therapy to evaluate peptic ulcers , background gastric mucosa , and H. pylori infection . After confirmation of eradication , follow-up endoscopy was performed yearly . Results A total of 1131 patients were followed for up to 9.5 years ( mean , 3.9 years ) . Gastric cancer developed in 9 of 953 patients cured of infection and in 4 of 178 who had persistent infection ( P = 0.04 ) . The risk of developing gastric cancer after receiving H. pylori eradication therapy was increased according to the grade of baseline gastric mucosal atrophy ( P = 0.01 ) . In patients with peptic ulcer diseases , persistent infection of H. pylori ( hazard ratio , 3.9 ; P = 0.03 ) , the grade of baseline gastric mucosal atrophy ( 3.3 , P = 0.01 ) and age ( 2.0 , P = 0.04 ) were identified as significant risk factors for developing gastric cancer . Conclusions The grade of gastric atrophy was closely related to the development of gastric cancer after receiving H. pylori eradication therapy . Thus , eradication of H. pylori before the significant expansion of atrophy is most beneficial to prevent gastric cancer Among 2258 Helicobacter pylori-seropositive subjects r and omly assigned to receive one-time H. pylori treatment with amoxicillin-omeprazole or its placebo , we evaluated the 15-year effect of treatment on gastric cancer incidence and mortality in subgroups defined by age , baseline gastric histopathology , and post-treatment infection status . We used conditional logistic and Cox regressions for covariable adjustments in incidence and mortality analyses , respectively . Treatment was associated with a statistically significant decrease in gastric cancer incidence ( odds ratio = 0.36 ; 95 % confidence interval [ CI ] = 0.17 to 0.79 ) and mortality ( hazard ratio = 0.26 ; 95 % CI = 0.09 to 0.79 ) at ages 55 years and older and a statistically significant decrease in incidence among those with intestinal metaplasia or dysplasia at baseline ( odds ratio = 0.56 ; 95 % CI = 0.34 to 0.91 ) . Treatment benefits for incidence and mortality among those with and without post-treatment infection were similar . Thus H. pylori treatment can benefit older members and those with advanced baseline histopathology , and benefits are present even with post-treatment infection , suggesting treatment can benefit an entire population , not just the young or those with mild histopathology BACKGROUND R and omized trials have yielded mixed results on the effects of treatment for Helicobacter pylori and little information on the effects of vitamins or garlic supplements on precancerous gastric lesions . We conducted a r and omized trial to test the effects of one-time H. pylori treatment and long-term vitamin or garlic supplements in reducing the prevalence of advanced precancerous gastric lesions . METHODS Most of the adults aged 35 - 64 years in 13 r and omly selected villages in Linqu County , Sh and ong Province , China , were identified and given baseline endoscopies in 1994 . In 1995 , 3365 eligible subjects were r and omly assigned in a factorial design to three interventions or placebos : amoxicillin and omeprazole for 2 weeks in 1995 ( H. pylori treatment ) ; vitamin C , vitamin E , and selenium for 7.3 years ( vitamin supplement ) ; and aged garlic extract and steam-distilled garlic oil for 7.3 years ( garlic supplement ) . Subjects underwent endoscopies with biopsies in 1999 and 2003 , and the prevalence of precancerous gastric lesions was determined by histopathologic examination of seven st and ard biopsy sites . The 3365 eligible r and omized subjects represented 93.5 % of those with baseline endoscopy and included all baseline histologic categories except gastric cancer . Only 0.18 % had normal gastric mucosa . Logistic regression was used to estimate the intervention effects on the odds of advanced precancerous gastric lesions , and t-tests were used to assess effects on histologic severity . All statistical tests were two-sided . RESULTS H. pylori treatment result ed in statistically significant decreases in the combined prevalence of severe chronic atrophic gastritis , intestinal metaplasia , dysplasia , or gastric cancer in 1999 ( odds ratio [ OR ] = 0.77 ; 95 % confidence interval [ CI ] = 0.62 to 0.95 ) and in 2003 ( OR = 0.60 ; 95 % CI = 0.47 to 0.75 ) , and had favorable effects on the average histopathologic severity and on progression and regression of precancerous gastric lesions in 2003 . H. pylori treatment did not reduce the combined prevalence of dysplasia or gastric cancer . However , fewer subjects receiving H. pylori treatment ( 19/1130 ; 1.7 % ) than receiving placebo ( 27/1128 ; 2.4 % ) developed gastric cancer ( adjusted P = .14 ) . No statistically significant favorable effects were seen for garlic or vitamin supplements . CONCLUSION H. pylori treatment reduces the prevalence of precancerous gastric lesions and may reduce gastric cancer incidence , but further data are needed to prove the latter point . Long-term vitamin or garlic supplementation had no beneficial effects on the prevalence of precancerous gastric lesions or on gastric cancer incidence BACKGROUND Previous research has identified a high risk of gastric carcinoma as well as a high prevalence of cancer precursor lesions in rural population s living in the province of Nariño , Colombia , in the And es Mountains . METHODS A r and omized , controlled chemoprevention trial was conducted in subjects with confirmed histologic diagnoses of multifocal nonmetaplastic atrophy and /or intestinal metaplasia , two precancerous lesions . Individuals were assigned to receive anti-Helicobacter pylori triple therapy and /or dietary supplementation with ascorbic acid , beta-carotene , or their corresponding placebos . Gastric biopsy specimens taken at baseline were compared with those taken at 72 months . Relative risks of progression , no change , and regression from multifocal nonmetaplastic atrophy and intestinal metaplasia were analyzed with multivariate polytomous logistic regression models to estimate treatment effects . All statistical tests were two-sided . RESULTS All three basic interventions result ed in statistically significant increases in the rates of regression : Relative risks were 4.8 ( 95 % confidence interval [ CI ] = 1.6 - 14.2 ) for anti-H. pylori treatment , 5 . 1 ( 95 % CI = 1.7 - 15.0 ) for beta-carotene treatment , and 5.0 ( 95 % CI = 1.7 - 14.4 ) for ascorbic acid treatment in subjects with atrophy . Corresponding relative risks of regression in subjects with intestinal metaplasia were 3.1 ( 95 % CI = 1.0 - 9.3 ) , 3.4 ( 95 % CI = 1.1 - 9.8 ) , and 3.3 ( 95 % CI = 1.1 - 9.5 ) . Combinations of treatments did not statistically significantly increase the regression rates . Curing the H. pylori infection ( which occurred in 74 % of the treated subjects ) produced a marked and statistically significant increase in the rate of regression of the precursor lesions ( relative risks = 8.7 [ 95 % CI = 2.7 - 28.2 ] for subjects with atrophy and 5.4 [ 95 % CI = 1.7 - 17.6 ] for subjects with intestinal metaplasia ) . CONCLUSIONS In the very high-risk population studied , effective anti-H. pylori treatment and dietary supplementation with antioxidant micronutrients may interfere with the precancerous process , mostly by increasing the rate of regression of cancer precursor lesions , and may be an effective strategy to prevent gastric carcinoma Although epidemiological studies strongly suggest an association between gastric cancer and Helicobacter pylori infection , there has been no clinical report indicating that cure of the infection prevents cancer . We conducted a nonr and omized H. pylori eradication trial in patients whose gastric cancer was removed by endoscopic resection ( ER ) . We investigated the effect of treatment on the histopathology of the gastric mucosa , as well as on the incidence of metachronous gastric cancer during the long-term clinical and endoscopic follow-up . One hundred and thirty-two patients with early gastric cancer underwent ER and had H. pylori infection . Sixty-five ( group A ) were treated with omeprazole and antibiotics to eradicate the infection , and 67 ( group B ) were not . All patients were followed for 2 years post ER . After eradication treatment in group A , the disappearance of neutrophil infiltration in the antrum and body of the stomach was observed as was a decrease of the severity of intestinal metaplasia . Endoscopy after ER detected no new gastric cancers in these patients . After 3 years of follow-up , 6 ( 9 % ) of the 67 patients in group B had a new early-stage , intestinal-type gastric cancer endoscopically diagnosed . The above results suggest that H. pylori eradication may improve neutrophil infiltration and intestinal metaplasia in the gastric mucosa and inhibit the development of new carcinomas . This finding should be confirmed in a r and omized , controlled trial BACKGROUND A nonr and omized trial of Helicobacter pylori eradication was conducted in patients with endoscopically diagnosed gastric adenoma to determine the long-term effect of antimicrobial treatment on progression of the adenoma . METHODS Of 64 patients with an endoscopically diagnosed gastric adenoma and H pylori infection , 32 were treated with omeprazole and antibiotics to eradicate the infection , and 32 were not . RESULTS During 2 years of follow-up , 4 ( 12.5 % ) of the 32 patients in the untreated group developed an early stage , intestinal-type gastric cancer , whereas no gastric cancer was found in the 32 patients in the treated group . CONCLUSION H Pylori eradication may inhibit progression of gastric adenoma to carcinoma |
1,936 | 31,412,986 | Evidence is insufficient to assess the effects on health outcomes because of the limited number and power of studies and important flaws in their design or conduct in classifying PEG-asparaginase as a superior drug or not , in the pharmacotherapy of ALL in children and adolescents .
PEG-asparaginase can be used as a substitute for native E. coli L-asparaginase , demonstrating similar efficacy and safety . | INTRODUCTION Acute lymphoblastic leukemia ( ALL ) is the cancer with the highest incidence in childhood and adolescence , and pharmacotherapy is the primary form of treatment . | The Dana-Farber Cancer Institute ( DFCI ) acute lymphoblastic leukemia ( ALL ) Consortium Protocol 91 - 01 was design ed to improve the outcome of children with newly diagnosed ALL while minimizing toxicity . Compared with prior protocol s , post-remission therapy was intensified by substituting dexamethasone for prednisone and prolonging the asparaginase intensification from 20 to 30 weeks . Between 1991 and 1995 , 377 patients ( age , 0 - 18 years ) were enrolled ; 137 patients were considered st and ard risk ( SR ) , and 240 patients were high risk ( HR ) . Following a 5.0-year median follow-up , the estimated 5-year event-free survival ( EFS ) + /- SE for all patients was 83 % + /- 2 % , which is superior to prior DFCI ALL Consortium protocol s conducted between 1981 and 1991 ( P = .03 ) . There was no significant difference in 5-year EFS based upon risk group ( 87 % + /- 3 % for SR and 81 % + /- 3 % for HR , P = .24 ) . Age at diagnosis was a statistically significant prognostic factor ( P = .03 ) , with inferior outcomes observed in infants and children 9 years or older . Patients who tolerated 25 or fewer weeks of asparaginase had a significantly worse outcome than those who received at least 26 weeks of asparaginase ( P < .01 , both univariate and multivariate ) . Older children ( at least 9 years of age ) were significantly more likely to have tolerated 25 or fewer weeks of asparaginase ( P < .01 ) . Treatment on Protocol 91 - 01 significantly improved the outcome of children with ALL , perhaps due to the prolonged asparaginase intensification and /or the use of dexamethasone . The inferior outcome of older children may be due , in part , to increased intolerance of intensive therapy BACKGROUND l-asparaginase is a universal component of treatment for childhood acute lymphoblastic leukaemia , and is usually administered intramuscularly . Pegylated Escherichia coli asparaginase ( PEG-asparaginase ) has a longer half-life and is potentially less immunogenic than the native Escherichia coli ( E coli ) preparation , and can be more feasibly administered intravenously . The aim of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05 - 001 ( DFCI 05 - 001 ) was to compare the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E colil-asparaginase in children with newly diagnosed acute lymphoblastic leukaemia . METHODS DFCI 05 - 001 enrolled patients aged 1 - 18 years with newly diagnosed acute lymphoblastic leukaemia from 11 consortium sites in the USA and Canada . Patients were assigned to an initial risk group on the basis of their baseline characteristics and then underwent 32 days of induction therapy . Those who achieved complete remission after induction therapy were assigned to a final risk group and were eligible to participate in a r and omised comparison of intravenous PEG-asparaginase ( 15 doses of 2500 IU/m(2 ) every 2 weeks ) or intramuscular native E colil-asparaginase ( 30 doses of 25 000 IU/m(2 ) weekly ) , beginning at week 7 after study entry . R and omisation ( 1:1 ) was unmasked , and was done by a statistician-generated allocation sequence using a permuted blocks algorithm ( block size of 4 ) , stratified by final risk group . The primary endpoint of the r and omised comparison was the overall frequency of asparaginase-related toxicities ( defined as allergy , pancreatitis , and thrombotic or bleeding complications ) . Predefined secondary endpoints were disease-free survival , serum asparaginase activity , and quality of life during therapy as assessed by PedsQL surveys . All analyses were done by intention to treat . This study is registered with Clinical Trials.gov , number NCT00400946 . FINDINGS Between April 22 , 2005 , and Feb 12 , 2010 , 551 eligible patients were enrolled . 526 patients achieved complete remission after induction , of whom 463 were r and omly assigned to receive intramuscular native E colil-asparaginase ( n=231 ) or intravenous PEG-asparaginase ( n=232 ) . The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities ( 65 [ 28 % ] of 232 patients in the intravenous PEG-asparaginase group vs 59 [ 26 % ] of 231 patients in the intramuscular native E colil-asparaginase group , p=0·60 ) , or in the individual frequency of allergy ( p=0·36 ) , pancreatitis ( p=0·55 ) , or thrombotic or bleeding complications ( p=0·26 ) . Median follow-up was 6·0 years ( IQR 5·0 - 7·1 ) . 5-year disease-free survival was 90 % ( 95 % CI 86 - 94 ) for patients assigned to intravenous PEG-asparaginase and 89 % ( 85 - 93 ) for those assigned to intramuscular native E colil-asparaginase ( p=0·58 ) . The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E colil-asparaginase . Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E colil-asparaginase group than in the intravenous PEG-asparaginase group . Scores for other domains were similar between the groups . The most common grade 3 or worse adverse events were bacterial or fungal infections ( 47 [ 20 % ] of 232 in the intravenous PEG-asparaginase group vs 51 [ 22 % ] of 231 patients in the intramuscular E colil-asparaginase group ) and asparaginase-related allergic reactions ( 14 [ 6 % ] vs 6 [ 3 % ] ) . INTERPRETATION Intravenous PEG-asparaginase was not more toxic than , was similarly efficacious to , and was associated with decreased anxiety compared with intramuscular native E colil-asparaginase , supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia . FUNDING National Cancer Institute and Enzon Pharmaceuticals For this study , 118 children with st and ard-risk acute lymphoblastic leukemia ( ALL ) were given r and omized assignments to receive native or pegylated Escherichia coli asparaginase as part of induction and 2 delayed intensification phases . Patients treated with pegaspargase had more rapid clearance of lymphoblasts from day 7 and day 14 bone marrow aspirates and more prolonged asparaginase activity than those treated with native asparaginase . In the first delayed intensification phase , 26 % of native asparaginase patients had high-titer antibodies , whereas 2 % of pegaspargase patients had those levels . High-titer antibodies were associated with low asparaginase activity in the native arm , but not in the pegaspargase arm . Adverse events , infections , and hospitalization were similar between arms . Event-free survival at 3 years was 82 % . A population pharmacodynamic model using the nonlinear mixed effects model ( NONMEM ) program was developed that closely fit the measured enzyme activity and asparagine concentrations . Half-lives of asparaginase were 5.5 days and 26 hours for pegaspargase and native asparaginase , respectively . There was correlation between asparaginase enzymatic activity and depletion of asparagine or glutamine in serum . In cerebrospinal fluid asparagine , depletion was similar with both enzyme preparations . Intensive pegaspargase for newly diagnosed ALL should be tested further in a larger population PURPOSE To improve efficacy and reduce toxicity of treatment for children with acute lymphoblastic leukemia . PATIENTS AND METHODS Patients from all risk groups , including infants and those with T-cell disease , were treated between 1987 and 1991 . St and ard-risk ( SR ) patients did not receive cranial irradiation , whereas high-risk ( HR ) and very high-risk ( VHR ) patients participated in a r and omized comparison of 18 Gy of cranial irradiation conventionally fractionated versus two fractions per day ( hyperfractionated ) . RESULTS At a median follow-up of 9.2 years , the 9-year event-free survival ( EFS + /- SE ) was 75 % + /- 2 % for all 369 patients , 77 % + /- 4 % for the 142 SR patients , and 73 % + /- 3 % for the 227 HR/VHR patients ( P = .37 comparing SR and HR/VHR ) . The CNS , with or without concomitant bone marrow involvement , was the first site of relapse in 19 ( 13 % ) of the 142 SR patients : 16 ( 20 % ) of 79 SR boys and three ( 5 % ) of 63 SR girls . This high incidence of relapses necessitated a recall of SR boys for additional therapy . CNS relapse occurred in only two ( 1 % ) of 227 HR and VHR patients . There were no outcome differences found among r and omized treatment groups . Nine-year overall survival was 84 % + /- 2 % for the entire population , 93 % + /- 2 % for SR children , and 79 % + /- 3 % for HR and VHR children ( P < .01 comparing SR and HR/VHR ) . CONCLUSION A high overall survival outcome was obtained for SR patients despite the high risk of CNS relapse for SR boys , which was presumed to be associated with eliminating cranial radiation without intensifying systemic or intrathecal chemotherapy . For HR/VHR patients , inability to salvage after relapse ( nearly all of which were in the bone marrow ) remains a significant clinical problem Background . L‐asparaginase has been a mainstay of therapy along with vincristine and prednisone in the treatment of acute lymphoblastic leukemia ( ALL ) in children for almost 30 years . Because L‐asparaginase is a foreign protein , the potential exists for severe , dose‐limiting hypersensitivity reactions . To reduce this toxicity , L‐asparaginase has been linked with polyethylene glycol ( PEG ) Background : Administration of L-asparaginase is limited by hypersensitivity reactions mediated by anti-asparaginase antibodies . To overcome this problem , native Escherichia coli L-asparaginase was conjugated to polyethylene glycol ( PEG ) to formulate PEG-L-asparaginase , a preparation with decreased immunogenicity and increased circulating half-life . In early trials , PEG-L-asparaginase was tolerated by patients known to be hypersensitive to the native E. coli product . Methods : The Pediatric Oncology Group conducted a phase II , r and omized trial to compare the efficacy and toxicity of PEG-L-asparaginase compared with native E. coli asparaginase in children with acute lymphoblastic leukemia in second bone marrow relapse . All patients ( n=76 ) received st and ard doses of vincristine and prednisone . Nonhypersensitive patients ( n=34 ) were r and omized to receive either PEG-L-asparaginase of 2500 IU/m2/dose intramuscularly on days 1 and 15 ( treatment I ) or native E. coli asparaginase of 10,000 IU/m2/dose intramuscularly on days 1 , 3 , 5 , 8 , 10 , 12 , 15 , 17 , 19 , 22 , 24 , and 26 ( treatment II ) . Patients with a clinical history of an allergic reaction to unmodified asparaginase were directly assigned to treatment with PEG-L-asparaginase ( n=42 ) . Asparaginase levels and anti-asparaginase antibody titers were monitored in all patients . Response and toxicity were scored using conventional criteria . Results : The complete response rate for the total study population was 41 % . There was no difference in complete response between patients r and omized to PEG ( 47 % ) and native asparaginase ( 41 % ) . PEG was well tolerated even in patients with prior allergic reactions to native asparaginase . PEG half-life was shorter in patients with prior allergy . Conclusions : PEG asparaginase is a useful agent in patients with allergic reactions to native asparaginase The Dana-Farber Cancer Institute ( DFCI ) Childhood ALL Consortium Protocol 95 - 01 was design ed to minimize therapy-related morbidity for children with newly diagnosed ALL without compromising efficacy . Patients participated in r and omized comparisons of ( 1 ) doxorubicin given with or without dexrazoxane , a cardioprotectant ( high-risk patients ) , ( 2 ) intensive intrathecal chemotherapy and cranial radiation ( st and ard-risk patients ) , and ( 3 ) Erwinia and Escherichia coli asparaginase ( all patients ) . Between 1996 and 2000 , 491 patients ( aged 0 - 18 years ) were enrolled ( 272 st and ard risk and 219 high risk ) . With a median of 5.7 years of follow-up , the estimated 5-year event-free survival ( EFS ) for all patients was 82%+/-2 % . Dexrazoxane did not have a significant impact on the 5-year EFS of high-risk patients ( P=.99 ) , and there was no significant difference in outcome of st and ard-risk patients based on type of central nervous system ( CNS ) treatment ( P=.26 ) . Compared with E coli asparaginase , Erwinia asparaginase was associated with a lower incidence of toxicity ( 10 % versus 24 % ) , but also an inferior 5-year EFS ( 78%+/-4 % versus 89%+/-3 % , P=.01 ) . We conclude that ( 1 ) dexrazoxane does not interfere with the antileukemic effect of doxorubicin , ( 2 ) intensive intrathecal chemotherapy is as effective as cranial radiation in preventing CNS relapse in st and ard-risk patients , and ( 3 ) once-weekly Erwinia is less toxic than E coli asparaginase , but also less efficacious |
1,937 | 27,243,372 | Homocysteine-lowering therapy had little or no effect on all-cause mortality or any other of this review 's secondary outcomes .
Homocysteine-lowering therapies were not found to reduce mortality ( cardiovascular and all-cause ) or cardiovascular events among people with ESKD | BACKGROUND People with end-stage kidney disease ( ESKD ) have high rates of cardiovascular events .
R and omised controlled trials ( RCTs ) of homocysteine-lowering therapies have not shown reductions in cardiovascular event rates in the general population .
However , people with kidney disease have higher levels of homocysteine and may have different mechanisms of cardiovascular disease .
We performed a systematic review of the effect of homocysteine-lowering therapies in people with ESKD .
OBJECTIVES To evaluate the benefits and harms of established homocysteine lowering therapy ( folic acid , vitamin B6 , vitamin B12 ) on all-cause mortality and cardiovascular event rates in patients with ESKD . | BACKGROUND Haemodialysis ( HD ) is associated with the acute loss through the dialysis membrane of biochemical factors either enhancing [ folic acid ( F ) ] or impairing [ asymmetric dimethylarginine ( ADMA ) ] arterial function . Changes in these opposing factors might explain the absence of significant modifications in arterial function during HD . We speculated that intra-HD , instead of pre-HD , F administration would provide beneficial effects on arterial wave reflections and endothelial function by preventing HD-induced F loss . METHODS Arterial wave reflections [ augmentation index ( AIx ) , pulse-wave analysis ] , endothelium-dependent vasodilation ( salbutamol-mediated changes in AIx ) and plasma concentrations of F and ADMA were measured pre-HD and end-HD in 10 patients ( age 67.7 + /- 10.3 years ) . Each subject received F 5 mg either pre-HD or intra-HD in two separate studies 2 - 4 weeks apart , in an open-label r and omized cross-over trial . RESULTS Pre-HD F administration did not prevent significant reductions in F during HD ( end-HD vs. pre-HD , -865 + /- 465 nmol l(-1 ) , P < 0.001 ) , but no significant changes in AIx ( + 1.4 + /- 5.7 % ) or salbutamol-mediated AIx modifications ( + 0.4 + /- 5.5 % ) were observed . By contrast , intra-HD F administration was associated with significant increases in F ( + 298 + /- 283 nmol l(-1 ) , P = 0.010 ) and a significant reduction of AIx ( -4.7 + /- 7.2 % , P = 0.013 ) , but no effects on salbutamol-mediated AIx changes ( + 1.5 + /- 4.4 % ) . There was a trend towards greater HD-induced reductions in plasma ADMA concentrations with intra-HD F administration ( P = 0.066 ) . CONCLUSIONS Intra-HD F administration reduces arterial wave reflections but not endothelial function during HD . Given the prognostic significance of arterial wave reflections in HD patients , the timing of F administration is important in the design of interventional trials in this cohort Background —Increased oxidative stress , elevated plasma homocysteine concentration , increased pulse pressure , and impaired endothelial function constitute risk factors for increased mortality in patients with end-stage renal failure . Methods and Results —We investigated the metabolic and hemodynamic effects of intravenous administration of acetylcysteine , a thiol-containing antioxidant , during a hemodialysis session in a prospect i ve , r and omized , placebo-controlled crossover study in 20 patients with end-stage renal failure . Under control conditions , a hemodialysis session reduced plasma homocysteine concentration to 58±22 % predialysis ( mean±SD ) , whereas in the presence of acetylcysteine , the plasma homocysteine concentration was significantly more reduced to 12±7 % predialysis ( P < 0.01 ) . The reduction of plasma homocysteine concentration was significantly correlated with a reduction of pulse pressure . A 10 % decrease in plasma homocysteine concentration was associated with a decrease of pulse pressure by 2.5 mm Hg . Analysis of the second derivative of photoplethysmogram waveform showed changes of arterial wave reflectance during hemodialysis in the presence of acetylcysteine , indicating improved endothelial function . Conclusions —Acetylcysteine-dependent increase of homocysteine removal during a hemodialysis session improves plasma homocysteine concentration , pulse pressure , and endothelial function in patients with end-stage renal failure BACKGROUND Hyperhomocysteinaemia is a putative risk factor for atherothrombotic cardiovascular disease in the haemodialysis population . High-dose vitamin B therapy does not entirely normalize elevated plasma total homocysteine ( tHcy ) levels in haemodialysis patients . Alternative therapies to reduce tHcy further are therefore required . Modifications of the dialysis regimen may result in a better removal of Hcy . We examined the effect of dialyser membrane pore size on tHcy levels in vitamin-replete chronic haemodialysis patients . METHODS Forty-five haemodialysis patients were dialysed during 4 weeks with a low-flux , a high-flux and a super-flux membrane , in r and om order . Pre-dialysis tHcy was determined at baseline and every 4 weeks . In 18 patients , plasma tHcy before and after dialysis and dialysate tHcy concentrations were measured . RESULTS Pre-dialysis tHcy decreased significantly during 4 weeks super-flux dialysis ( -14.6 + /- 2.8 % ) , whereas it remained stable during high-flux ( + 0.5 + /- 2.4 % ) and low-flux dialysis ( + 1.7 + /- 3.2 % ) . The homocysteine reduction ratio was not different for the three membranes : 0.39 + /- 0.03 for the super-flux , 0.47 + /- 0.02 for the high-flux and 0.39 + /- 0.02 for the low-flux dialyser . The amount of Hcy recovered in the dialysate during a single dialysis session was also similar : 117.5 + /- 3.6 micro mol during super-flux , 95.3 + /- 11.5 micro mol during high-flux and 116.5 + /- 11.6 micro mol during low-flux dialysis . CONCLUSION Super-flux dialysis significantly lowers tHcy in chronic haemodialysis patients . Improved removal of middle-molecule uraemic toxins with inhibitory effects on Hcy-metabolizing enzymes , rather than better dialytic clearance of Hcy itself , may explain the beneficial effect of the super-flux membrane BACKGROUND Patients with chronic kidney disease ( CKD ) have an increased risk of cardiovascular disease ( CVD ) . Preliminary evidence suggests a role for global DNA hypomethylation in the pathogenesis of atherosclerotic complications in CKD . The aims of this study in patients with stage 2 - 4 CKD were ( 1 ) to assess the association between renal function and DNA methylation , ( 2 ) to assess the association between DNA methylation and two markers of atherosclerosis [ common carotid intima-media thickness ( CCA-IMT ) ] and brachial artery endothelium-dependent , flow-mediated dilatation ( BA-FMD ) and ( 3 ) to examine the effect of a multi-step treatment strategy on DNA methylation . METHODS In the Anti-Oxidant Therapy In Chronic Renal Insufficiency study ( ATIC- study ) , 93 patients with stage 2 - 4 CKD were included . In a r and omized , double-blind , placebo-controlled design , the treatment group received pravastatin to which vitamin E was added after 6 months and homocysteine-lowering B-vitamin therapy after another 6 months . DNA methylation was assessed using t and em mass spectrometry . CCA-IMT and BA-FMD were assessed using B-mode ultrasonography . RESULTS At baseline , global DNA methylation was not associated with the estimated glomerular filtration rate ( P = 0.32 ) or with CCA-IMT ( P = 0.62 ) or BA-FMD ( P = 0.51 ) . No effect of the treatment strategy including B-vitamin on global DNA methylation was found either in the total study group or within separate strata of homocysteine concentration and renal function . CONCLUSION In patients with stage 2 - 4 CKD , global DNA methylation is not associated with renal function or with CCA-IMT or BA-FMD . A treatment strategy that includes B-vitamins did not alter global DNA methylation in these patients . These data do not support the role of DNA hypomethylation in CKD-associated vascular disease in patients with stage 2 - 4 CKD The Homocysteine Study ( HOST ) Veterans Affairs Cooperative Studies Program No. 453 , is a prospect i ve , r and omized , two arm , double blind study of patients with end stage renal disease ( ESRD ) or advanced chronic kidney disease ( ACKD , defined as an estimated creatinine clearance of 30 ml/min or less ) . Its primary objective is to determine whether administration of high doses of three vitamins , folic acid , vitamin B6 and vitamin B12 , to lower the high plasma homocysteine levels , will reduce all cause mortality . The secondary objectives are to examine whether the treatment lowers the incidence of myocardial infa rct ion , stroke , amputation of a lower extremity , a composite of death and the foregoing three events , the plasma homocysteine level , and , in ESRD patients undergoing hemodialysis , thrombosis of the vascular access . A unique feature of this trial is that after initial evaluation at enrollment and one return visit the follow up is exclusively by phone ( or , if necessary , by mail ) . The subject is contacted every three months throughout the duration of the study from a central location . The study drug is shipped to the patient from a central location rather supplied locally . In a two year enrollment period , 2006 patients are to be enrolled . The duration of the observation period is four to six years . Data will be stored and analyzed at a coordinating center . The study design has the power to detect a reduction in all cause mortality rate of 17 % . Issues related to the unique features of the design of this study are discussed BACKGROUND Considerable evidence suggests that hyperhomocysteinemia is an independent vascular risk factor that promotes atherosclerosis by inducing endothelial dysfunction . Although folic acid reduces hyperhomocysteinemia , the effect on adverse vascular events is unknown . We hypothesized that in patients with chronic renal failure , a condition associated with both hyperhomocysteinemia and atherosclerosis , treatment with folic acid would improve endothelial function . METHODS AND RESULTS In a prospect i ve , double-blind protocol , 100 patients ( mean age 62 years , 67 men ) with predialysis chronic renal failure were r and omized to 5 mg folic acid or placebo daily for 12 weeks . Endothelial function was assessed by measuring ( 1 ) endothelium-dependent dilation of the brachial artery , ( 2 ) combined serum nitrite/nitrate concentrations , and ( 3 ) plasma von Willebr and factor concentration . Baseline characteristics of the 2 groups were similar . At the end of the study , both serum and red cell folate concentrations were greater in the folic acid group than the placebo group [ mean ( 95 % CI ) 39.0 ( 29.8 to 51.0 ) versus 7.7 ( 6.6 to 8.9 ) microg/L and 739 ( 613 to 891 ) versus 220 ( 184 to 262 ) microg/L , respectively ; both P<0.001 ] . Despite a reduction in hyperhomocysteinemia in the folic acid group compared with the placebo group [ 15.1 ( 14.1 to 16.2 ) versus 20.1 ( 18.2 to 22.2 ) micromol/L ; P<0.001 ] , there were no significant differences in endothelium-dependent dilation , combined serum nitrite/nitrate concentrations , or plasma von Willebr and factor concentration between the 2 groups . CONCLUSIONS High-dose folic acid lowers but fails to normalize hyperhomocysteinemia in patients with predialysis chronic renal failure . This was not accompanied by an improvement of endothelial function and suggests that treatment with folic acid may not reduce the burden of vascular disease in uremia BACKGROUND The hyperhomocysteinemia found in most hemodialysis patients is refractory to combined oral B-vitamin supplementation featuring supraphysiological doses of folic acid ( FA ) . We evaluated whether a high-dose L-folinic acid-based regimen provided improved total homocysteine (tHcy)-lowering efficacy in chronic hemodialysis patients , as suggested by a recent uncontrolled report . METHODS We block-r and omized 48 chronic , stable hemodialysis patients based on their screening predialysis tHcy levels , sex , and dialysis center into two groups of 24 subjects treated for 12 weeks with oral FA at 15 mg/day or an equimolar amount ( 20 mg/day ) of oral L-folinic acid ( FNA ) [ L-5-formyltetrahydrofolate ] . All 48 subjects also received 50 mg/day of oral vitamin B6 and 1.0 mg/day of oral vitamin B12 . RESULTS The mean percentage ( % ) reductions ( with 95 % CIs ) in predialysis tHcy were not significantly different [ FNA = 22.1 % ( 11.8 to 31.4 % ) , FA = 20.7 % ( 11.7 to 30.5 % ) , P = 0.950 by paired t test ] . Final on-treatment values ( mean with 95 % CI ) were as follows : FNA , 15.9 micromol/L ( 14.0 to 18.0 ) ; FA , 16.9 micromol/L ( 14.8 to 18.8 ) . Moreover , in those subjects with baseline tHcy levels > /=14 micromol/L , neither treatment result ed in " normalization " of tHcy levels ( that is , final on-treatment values < 12 micromol/L ) among a significantly different or clinical ly meaningful number of patients [ FNA = 2 out of 22 ( 9.1 % ) ; FA = 2 out of 24 ( 8.3 % ) ; Fisher 's exact test of between groups difference , P = 1.000 ] . CONCLUSIONS Relative to high-dose FA , high-dose oral L-folinic acid-based supplementation does not afford improved tHcy-lowering efficacy in hemodialysis patients . The preponderance of hemodialysis patients ( that is , > 90 % ) exhibits mild hyperhomocysteinemia refractory to treatment with either regimen BACKGROUND The hyperhomocysteinemia regularly found in hemodialysis patients is largely refractory to combined oral B-vitamin supplementation featuring supraphysiological doses of folic acid . We evaluated whether a high-dose L-5-methyltetrahydrofolate-based regimen provided improved total homocysteine (tHcy)-lowering efficacy in chronic hemodialysis patients . METHODS AND RESULTS We block-r and omized 50 chronic , stable hemodialysis patients on the basis of their screening predialysis tHcy levels , sex , and dialysis center into 2 groups of 25 subjects treated for 12 weeks with oral folic acid at 15 mg/d ( FA group ) or an equimolar amount ( 17 mg/d ) of oral L-5-methyltetrahydrofolate ( MTHF group ) . All 50 subjects also received 50 mg/d of oral vitamin B(6 ) and 1.0 mg/d of oral vitamin B(12 ) . The mean percent reductions ( + /-95 % CIs ) in predialysis tHcy were not significantly different : MTHF , 17.0 % ( 12.0 % to 22.0 % ) ; FA , 14.8 % ( 9.6 % to 20.1 % ) ; P=0.444 by matched ANCOVA adjusted for pretreatment tHcy . Final on-treatment values ( mean with 95 % CI ) were MTHF , 20.0 micromol/L ( 18.8 to 21.2 micromol/L ) ; FA , 19.5 micromol/L ( 18.3 to 20.7 micromol/L ) . Moreover , neither treatment result ed in " normalization " of tHcy levels ( ie , final on-treatment values < 12 micromol/L ) among a significantly different or clinical ly meaningful number of patients : MTHF , 2 of 25 ( 8 % ) ; FA , 0 of 25 ( 0 % ) ; Fisher 's exact test of between-groups difference , P=0.490 . CONCLUSIONS Relative to high-dose folic acid , high-dose oral L-5-methyltetrahydrofolate-based supplementation does not afford improved tHcy-lowering efficacy in hemodialysis patients . The preponderance of hemodialysis patients ( ie , > 90 % ) exhibit mild hyperhomocysteinemia refractory to treatment with either regimen . This treatment refractoriness is not related to defects in folate absorption or circulating plasma and tissue distribution Patients treated with haemodialysis are at high risk of sudden cardiac death ( SCD ) often caused by arrhythmias . Atrial fibrillation ( AF ) is frequent among haemodialysis patients and is associated with increased mortality . Prolonged QTc is a risk marker of ventricular arrhythmia and is thereby associated with SCD . Studies have suggested that n-3 PUFA may have an antiarrhythmic effect , but the exact mechanism is not clear . The aim of this study was to examine whether AF was associated with n-3 PUFA in plasma phospholipids and whether supplementation with n-3 PUFA would shorten the QTc interval in haemodialysis patients compared to placebo . In a double-blinded r and omised , placebo-controlled intervention trial 206 haemodialysis patients with CVD were treated with 1·7 g n-3 PUFA or placebo ( olive oil ) daily for 3 months . Blood sample s and electrocardiogram evaluations were carried out at baseline and after 3 months . The QT interval , PQ interval and heart rate were measured in all patients with sinus rhythm ( SR ) . At baseline 13 % of patients had AF . The content of the n-3 PUFA , DHA , was significantly lower ( P < 0·05 ) in serum of patients with AF compared with patients with SR . Thus , the DHA content was independently negatively associated with AF . Supplementation with n-3 PUFA did not shorten the QT interval significantly compared to the placebo group ( P = 0·42 ) , although subgroup analysis within the n-3 PUFA group revealed a shortening effects on QTc ( P = 0·01 ) . In conclusion , an inverse association was found between the presence of AF and the plasma DHA in haemodialysis patients . Intervention with n-3 PUFA did not shorten the QTc interval compared to placebo BACKGROUND Oral ingestion of proteins or amino acids is associated with endothelial dysfunction . The effect of commercial amino acid peritoneal dialysis solutions on vascular function is unknown . OBJECTIVE We compared the acute effect of intraperitoneal amino acid administration with that of intraperitoneal glucose administration on vascular function in peritoneal dialysis patients . DESIGN In an open-label r and omized , controlled , crossover and observer-blinded trial , we examined the acute effect of an intraperitoneal application of 2 L commercial 1.1 % amino acid solution compared with that of a 2.27 % glucose solution in 13 peritoneal dialysis patients . The primary endpoint was the change in forearm reactive hyperemia 6 h after instillation of either dialysis solution . RESULTS After 6 h of dwell time , reactive hyperemia was substantially impaired after administration of the amino acid solution compared with the glucose solution ( median difference : 202 % ; 95 % CI : 57 % , 368 % ; P = 0.007 ) . In a comparison of differences between values at 6 h and those before treatment , reactive hyperemia significantly decreased during the dwell with the amino acid dialysis solution compared with that with the glucose dialysis solution ( median difference : 242 % ; 95 % CI : 53 % , -457 % ; P = 0.013 ) . In an analysis of smoking and nonsmoking patients separately , the difference in forearm blood flow between the 2 treatments was still statistically significant . CONCLUSIONS One 6-h dwell with a commercial amino acid dialysis solution acutely impairs forearm reactive hyperemia in smoking and nonsmoking peritoneal dialysis patients . Because endothelial dysfunction is associated with increased morbidity and mortality , the long-term use of these solutions may increase the risk of cardiovascular disease BACKGROUND In a recent uncontrolled retrospective report we suggested that the long-term supplementation of high-dose , i.v . folinic acid combined with high-dose i.v . pyridoxine was highly effective in correcting plasma total homocysteine ( tHcy ) concentrations in haemodialysis patients . To confirm these findings , we conducted a r and omized , controlled trial aim ed at evaluating whether i.v . or oral folinic acid provided improved tHcy-lowering efficacy in haemodialysis patients compared with oral folic acid . METHODS In a 6-month prospect i ve , r and omized , controlled trial , 60 chronic haemodialysis patients , matched for age , gender , dialysis duration , and average screening pre-treatment-fasting tHcy levels , were given either 50 mg/week of i.v . calcium folinate ( group 1 ) , 50 mg/week of oral calcium folinate ( group 2 ) , or 45 mg/week oral folic acid ( group 3 ) . All 60 patients also received 750 mg/week of i.v . vitamin B6 and 3 mg/week of oral vitamin B12 . RESULTS Fasting tHcy decreased significantly and to a similar extent in the three groups after 2 months of treatment and remained stable at 4 and 6 months ( 16.6+/-3.5 , 18.3+/-4 , and 19.1+/-3.1 , in groups 1 , 2 , and 3 , respectively , P = NS ) . Mean percentage reduction at 6 months was also similar in the three treatment groups ( 46 , 43 , and 42 % in groups 1 , 2 , and 3 , respectively , P = NS ) . CONCLUSIONS These findings show that the tHcy-lowering effects of high-dose i.v . folinic acid , oral folinic acid , or oral folic acid were comparable , suggesting that the hyperhomocysteinaemia observed in haemodialysis patients is not due to abnormal folate metabolism . Furthermore , they are compatible with the view that other abnormalities are also involved in the impaired clearance of homocysteine in uraemic patients Background — The relationship between total homocysteine ( tHcy ) and outcomes has not been investigated in patients with chronic kidney disease stages 3 to 4 . Methods and Results — The Modification of Diet in Renal Disease Study was a r and omized , controlled trial of 840 patients . Serum tHcy was measured in frozen sample s collected at baseline ( n=804 ) . Survival status and cause of death were obtained from the National Death Index . To evaluate its association with all-cause and cardiovascular disease ( CVD ) mortality , tHcy was evaluated both as tertiles ( < 14.7 , 14.7 to 19.5 , ≥19.6 & mgr;mol/L ) and as a continuous variable ( per 10/&mgr;mol/L ) . Participants had a mean age of 52±12 years and glomerular filtration rate ( GFR ) of 33±12 mL/min per 1.73 m2 ; 60 % were male , and 85 % were white . During a median follow-up of 10 years , 195 ( 24 % ) died from any cause , and 118 ( 15 % ) from CVD . The level of GFR was lower and proteinuria higher in the highest tHcy tertile . There was no association between the highest tertile of tHcy and all-cause ( hazard ratio [ HR ] ; 95 % confidence interval [ CI [ , 1.32 , 0.94 to 1.85 ) or CVD ( HR ; 95 % CI , 1.50 , 0.96 to 2.34 ) mortality in univariate analyses ; this association was further attenuated by adjustment for GFR ( HR ; 95 % CI all-cause , 1.04 , 0.72 to 1.51 ; CVD , 1.20 , 0.73 to 1.95 ) . There was no association between tHcy as a continuous variable and all-cause ( 0.98 , 0.83 to 1.16 ) or CVD ( 1.04 , 0.85 to 1.27 ) mortality . Conclusions — Hyperhomocystinemia does not appear to be a risk factor for all-cause or CVD mortality in the Modification of Diet in Renal Disease Study . Prior studies demonstrating an association between tHcy and CVD risk may have inadequately adjusted for the confounding effects of kidney function OBJECTIVE Hyperhomocysteinemia is an independent risk factor for atherosclerotic vascular disease in chronic hemodialysis patients . This stratified r and omized controlled trial was design ed to measure the effect of high dose oral vitamin B6 , vitamin B12 , and folic acid on homocysteine levels , and to evaluate the effect on atherosclerosis as measured by Intima-Media Thickness ( IMT ) of carotid arteries . MATERIAL AND METHOD Fifty-four chronic hemodialysis patients with hyperhomocysteinemia were r and omized to receive oral 15 mg folic acid , 50 mg vitamin B6 , and 1 mg vitamin B12 daily ( treatment group ) or oral 5 mg folic acid alone ( control group ) for 6 months . Homocysteine level and IMT were measured in both groups . RESULTS At 6 months , homocysteine levels in the treatment group were significantly reduced from 27.94 + /- 8.54 to 22.71 + /- 3.68 mmol/l ( p = 0.009 ) and were not significantly increased from 26.81 + /- 7.10 to 30.82 + /- 8.76 mmol/l in control group ( p = 0.08 ) . Mean difference between both groups was statistically significant ( p = 0.002 ) . There was no significant difference of IMT of carotid arteries , however , a tendency that the treatment group would have less thickness was observed ( 0.69 + /- 0.29 mm and 0.62 + /- 0.16 mm , p = 0.99 ) . CONCLUSION Treatment of hyperhomocysteinemia in chronic hemodialysis patients with daily oral 15 mg folic acid , 50 mg vitamin B6 , and 1 mg vitamin B12 for 6 months decreases homocysteine levels and tends to reduce IMT of carotid arteries . A long term study for the prevention of atherosclerosis is warranted Background — Patients with end-stage renal failure have increased oxidative stress and show elevated cardiovascular mortality . Whether increased cardiovascular events can be prevented by the administration of antioxidants is unknown . Methods and Results —We evaluated the effects of acetylcysteine , a thiol-containing antioxidant , on cardiovascular events in patients undergoing hemodialysis . A prospect i ve , r and omized , placebo-controlled trial was conducted between October 1 , 1999 , and September 30 , 2001 , in 134 patients ( 76 male and 58 female ) with a mean age of 62±16 years ( mean±SD ) who had been undergoing maintenance hemodialysis for a minimum of 3 months 3 times weekly in an ambulatory center . Median ( range ) follow-up was 14.5 ( 1 to 24 ) months . Patients were r and omly assigned either to receive acetylcysteine ( 600 mg BID ) or placebo . The primary end point was a composite variable consisting of cardiac events including fatal and nonfatal myocardial infa rct ion , cardiovascular disease death , need for coronary angioplasty or coronary bypass surgery , ischemic stroke , peripheral vascular disease with amputation , or need for angioplasty . Secondary end points included each of the component outcomes , total mortality , and cardiovascular mortality . A total of 18 ( 28 % ) of the 64 hemodialysis patients assigned to acetylcysteine group and 33 ( 47 % ) of the 70 hemodialysis patients assigned to control group had a primary end point ( relative risk , 0.60 [ 95 % CI , 0.38 to 0.95 ] , P = 0.03 ) . No significant differences in secondary end points or total mortality were detected . Conclusions —In hemodialysis patients , treatment with acetylcysteine ( 600 mg BID ) reduces composite cardiovascular end points BACKGROUND Hyperhomocysteinemia is seen in most hemodialysis ( HD ) patients and is an independent risk factor for cardiovascular disease . Homocysteine metabolism via remethylation requires activated folate and vitamin B12 and metabolism via transsulfuration requires serine and vitamin B6 . Prior studies have shown highly variable effects of supplemental B vitamin and folate therapy for hyperhomocysteinemia . We undertook a fully controlled trial with abnormally high doses of folic acid alone or with supplemental vitamin B6 and B12 compared with active folate alone or with serine . METHODS Two prospect i ve studies were undertaken in hemodialysis patients . In the first study ( protocol A ) , hyperhomocysteinemia was treated in 77 patients with 30 or 60 mg folic acid with or without vitamins B6 and B12 for eight weeks and compared with matching placebos . In the second study ( protocol B ) , hyperhomocysteinemia was treated in 37 patients with intravenous folinic acid given alone or with serine and compared with matching placebos . All patients received the st and ard of care treatment with a multivitamin tablet before and throughout the protocol to test the hypothesis that additional therapy is required over and above the routine therapy for maximum reduction in total homocysteine ( tHcy ) . RESULTS Normal volunteers ; The mean ( SD ) tHcy of 128 normal subjects was 6.5 ( 4 ) micromol/L. Protocol A ; Plasma folate increased significantly in the groups given folic acid at both four and eight weeks ( P = 0.0001 at both time points ) . Plasma vitamin B12 was significantly increased at four weeks ( P = 0.0018 ) but not at eight weeks ( P = 0.064 ) in those given Vitamin B12 . However , tHcy did not differ between treatment groups at baseline ( P = 0.63 ) , four weeks ( P = 0.79 ) or eight weeks ( P = 0.74 ) . Protocol B : Plasma folate increased significantly at four weeks in those receiving folinic acid ( P = 0.0001 ) but tHcy was not significantly different between groups ( P = 0.92 ) . In neither study was there any significant change in tHcy comparing before and during any treatment intervention . CONCLUSIONS In our studies high dose oral folic acid , intravenous folinic acid , vitamins B6 and B12 and oral serine were ineffective at lowering tHcy in patients on hemodialysis when given folic acid , folinic acid serine or B vitamins in addition to routine folic acid and B vitamin supplements OBJECTIVE This study sought to examine the effect of n-3 supplementation on lipoprotein(a ) ( Lp(a ) ) levels in end-stage renal disease ( ESRD ) patients undergoing chronic hemodialysis . DESIGN The present study was conducted using a double-blind , permuted-r and omized , controlled experimental protocol . SETTING This study took place at the Central Texas Nephrology Associates Dialysis Clinic ( Waco , TX ) . PATIENTS Patients with ESRD and associated with the Central Texas Nephrology Associates who were undergoing chronic hemodialysis participated in this study . INTERVENTION Patients with ESRD were followed prospect ively while receiving supplements of fish oil ( treatment , eicosapentaenoic acid , 0.96g/day , and docosahexaenoic acid , 0.6g/day ) or corn oil ( control subjects ) for 6 months . After a 12-hour fast , participants donated 12mL of blood for analysis of Lp(a ) at baseline and at 6 months . MAIN OUTCOME MEASURE The comparison of Lp(a ) concentration by group at 6 months was the primary outcome measure of the study . RESULTS Our study suggests that fish-oil supplementation did not decrease levels of Lp(a ) ( P=.66 ) , compared with control subjects . CONCLUSION We failed to show a significant effect of 6 months of over-the-counter fish-oil supplementation on Lp(a ) status in an ESRD population , although results from this study support findings from other studies suggesting that African Americans have higher Lp(a ) concentrations than persons of Caucasian decent CONTEXT Hyperhomocysteinemia is frequently observed in patients with diabetic nephropathy . B-vitamin therapy ( folic acid , vitamin B(6 ) , and vitamin B(12 ) ) has been shown to lower the plasma concentration of homocysteine . OBJECTIVE To determine whether B-vitamin therapy can slow progression of diabetic nephropathy and prevent vascular complications . DESIGN , SETTING , AND PARTICIPANTS A multicenter , r and omized , double-blind , placebo-controlled trial ( Diabetic Intervention with Vitamins to Improve Nephropathy [ DIVINe ] ) at 5 university medical centers in Canada conducted between May 2001 and July 2007 of 238 participants who had type 1 or 2 diabetes and a clinical diagnosis of diabetic nephropathy . INTERVENTION Single tablet of B vitamins containing folic acid ( 2.5 mg/d ) , vitamin B(6 ) ( 25 mg/d ) , and vitamin B(12 ) ( 1 mg/d ) , or matching placebo . MAIN OUTCOME MEASURES Change in radionuclide glomerular filtration rate ( GFR ) between baseline and 36 months . Secondary outcomes were dialysis and a composite of myocardial infa rct ion , stroke , revascularization , and all-cause mortality . Plasma total homocysteine was also measured . RESULTS The mean ( SD ) follow-up during the trial was 31.9 ( 14.4 ) months . At 36 months , radionuclide GFR decreased by a mean ( SE ) of 16.5 ( 1.7 ) mL/min/1.73 m(2 ) in the B-vitamin group compared with 10.7 ( 1.7 ) mL/min/1.73 m(2 ) in the placebo group ( mean difference , -5.8 ; 95 % confidence interval [ CI ] , -10.6 to -1.1 ; P = .02 ) . There was no difference in requirement of dialysis ( hazard ratio [ HR ] , 1.1 ; 95 % CI , 0.4 - 2.6 ; P = .88 ) . The composite outcome occurred more often in the B-vitamin group ( HR , 2.0 ; 95 % CI , 1.0 - 4.0 ; P = .04 ) . Plasma total homocysteine decreased by a mean ( SE ) of 2.2 ( 0.4 ) micromol/L at 36 months in the B-vitamin group compared with a mean ( SE ) increase of 2.6 ( 0.4 ) micromol/L in the placebo group ( mean difference , -4.8 ; 95 % CI , -6.1 to -3.7 ; P < .001 , in favor of B vitamins ) . CONCLUSION Among patients with diabetic nephropathy , high doses of B vitamins compared with placebo result ed in a greater decrease in GFR and an increase in vascular events . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N41332305 An increased level of total plasma homocysteine ( tHcy ) is a risk factor for poor cardiovascular outcome in the general population . However , a decreased , rather than an increased , tHcy concentration may predict poor outcome in maintenance hemodialysis ( MHD ) patients , a phenomenon referred to as reverse epidemiology . Associations were examined between tHcy level and markers of malnutrition-inflammation complex syndrome and 12-mo prospect i ve hospitalization and mortality in 367 MHD patients , aged 54.5 + /- 14.7 ( mean + /- SD ) years , who included 199 men and 55 % individuals with diabetes . tHcy was 24.4 + /- 11.8 micro mol/L , and 94 % of the patients had hyperhomocysteinemia ( tHcy > 13.5 micro mol/L ) . tHcy had weak to moderate but statistically significant bivariate and multivariate correlations with some laboratory markers of nutrition ( serum albumin , prealbumin , creatinine , and urea nitrogen ) but no significant correlation with serum C-reactive protein or two proinflammatory cytokines ( IL-6 and TNF-alpha ) . During 12 mo of follow-up , 191 MHD patients were hospitalized , 37 died , nine underwent renal transplantation , and 38 transferred out . Hospitalization rates were significantly higher in patients with lower tHcy levels . Mortality rate in the lowest tHcy quartile ( 17.4 % ) was significantly higher compared with other three quartiles ( 6.5 to 9.8 % ; Kaplan-Meier P = 0.04 ) . Relative risk of death for the lowest tHcy quartile , even after adjustment for case-mix and serum albumin , was 2.27 ( 95 % confidence interval , 1.14 to 4.53 ; P = 0.02 ) . Hence , tHcy may be a more exclusive nutritional marker in MHD patients with no association with inflammatory measures . Despite a very high prevalence of hyperhomocysteinemia in MHD patients , lower values of tHcy are paradoxically associated with increased hospitalization and mortality . The lowest tHcy quartile confers a twofold increase in risk of death independent of hypoalbuminemia . The nutritional feature of tHcy in MHD patients may explain its reverse association with outcome Abstract Background : Lipid abnormalities , especially high serum lipoprotein ( a ) [ Lp ( a ) ] concentration , and anemia are two major causes of cardiovascular diseases ( CVDs ) in hemodialysis patients . Therefore , this study was design ed to investigate the effects of marine omega-3 fatty acids on serum lipids , Lp ( a ) , and hematologic factors in hemodialysis patients . Methods : Thirty-four hemodialysis patients were r and omly assigned to either omega-3 fatty acid supplement or placebo group . Patients in the omega-3 fatty acids group received 2080 mg marine omega-3 fatty acids , daily for 10 weeks , whereas the placebo group received a corresponding placebo . At baseline and the end of week 10 , 7 mL blood was collected after a 12- to 14-h fast and serum triglyceride , total cholesterol , low-density lipoprotein cholesterol ( LDL-C ) , high-density lipoprotein cholesterol ( HDL-C ) , Lp ( a ) , blood hemoglobin , hematocrit , red blood cells ( RBCs ) , mean corpuscular volume ( MCV ) , mean corpuscular hemoglobin ( MCH ) , and mean corpuscular hemoglobin concentration ( MCHC ) were measured . Results : Serum triglyceride decreased significantly in the omega-3 fatty acids group at the end of week 10 compared with baseline ( p < 0.05 ) and this reduction was significant in comparison with the placebo group ( p < 0.01 ) . No significant differences were observed between the two groups in mean changes of serum total cholesterol , LDL-C , HDL-C , Lp ( a ) , blood hemoglobin , hematocrit , RBC , MCV , MCH , and MCHC . Conclusion : The results of our study indicate that marine omega-3 fatty acids can reduce serum triglyceride , as a risk factor for CVD , but it does not affect other serum lipids , Lp ( a ) , and hematologic factors in hemodialysis patients AIM Results from several studies indicate that the total homocysteine ( tHcy ) concentration in plasma is an independent risk factor for cardiovascular disease in hemodialysis patients . Folic acid is the established mainstay of homocysteine-lowering treatment , but since such treatment does not normalize plasma tHcy concentration in hemodialysis patients , it is of importance to search for additional therapy . METHODS Twenty-eight folate-replete hemodialysis patients were r and omized to 2 equally sized groups , a treatment group and a control group . The treatment group received vitamin B12 tablets at a dose of 2 mg 3 times a week for 6 weeks ( after each dialysis session ) while the control group received no such treatment . Blood sample s were collected before and at the end of the treatment period for analysis of tHcy in plasma and vitamin B12 , methylmalonic acid as well as folate in serum . RESULTS At the end of the study period , serum vitamin B12 concentrations were significantly higher in the treatment group than in the control group . Plasma tHcy concentrations decreased significantly in both groups during the study period . However , there was no difference between the responses of the 2 groups . CONCLUSION The results of this open , r and omized controlled study did not support the hypothesis that treatment with oral vitamin B12 has considerable homocysteine-lowering effect in folate-replete hemodialysis patients BACKGROUND Medications affect many measures of hemodialysis patients ' well-being . METHODS The Dialysis Outcomes and Practice Patterns Study ( DOPPS ) has evaluated the use of hydroxymethyl glutaryl coenzyme A reductase inhibitors ( statins ) , analgesics , antidepressants , and multivitamins . Additionally , DOPPS has reported on the associations between vascular access outcomes and related medications . RESULTS Prescription of statins varied widely across countries , with the highest use in the United States . Patients prescribed statins had lower risk of cardiac and noncardiac causes of mortality than those who were not prescribed statins . DOPPS data also show that statins are underprescribed relative to recent Kidney Disease Outcomes Quality Initiative guidelines . No guidelines have been established for analgesic use , but high pain levels self-reported by hemodialysis patients suggest opportunities for improved pain management strategies . Guidelines for analgesic use in dialysis patients may help balance improved quality of life against potential side effects of analgesics . Medical and patient question naires show that depression in hemodialysis patients is common , frequently underdiagnosed , usually untreated , and associated with increased rates of mortality and hospitalization . Calcium channel blockers were associated with improved primary graft patency , aspirin with improved secondary graft patency , and angiotensin-converting enzyme inhibitors with improved secondary fistula patency . All 3 medications were associated with significantly decreased relative risk for access failure . There is large country variation in multivitamin use , with significantly higher use in the United States compared with Europe and Japan . Patients taking multivitamins had lower mortality risk than patients not taking multivitamins . CONCLUSION DOPPS findings on medications indicate that prospect i ve trials are needed before guidelines can be developed for appropriate medication use in these different therapeutic categories BACKGROUND Hyperhomocysteinemia is a well-recognized independent risk factor for cardiovascular disease in end-stage renal disease ( ESRD ) patients . Since homocysteine ( Hcy ) largely binds to serum proteins ( 80 to 90 % ) , in this study we investigated the possibility that polymethylmethacrylate (PMMA)-based protein-leaking dialyzers could reduce total plasma Hcy ( tHcy ) levels in ESRD patients . METHODS Two matched groups of patients ( N = 13 ) showing mild to intermediate hyperhomocysteinemia on st and ard hemodialysis ( HD ) with conventional non-protein-leaking dialyzers were included . In the control group membranes were maintained the same , while the study group was switched to protein-leaking dialyzers ( BK-F series ; Toray , Japan ) and studied for 6 months . tHcy was measured by high performance liquid chromatography ( HPLC ) at baseline and after 1 , 3 , and 6 months . Proteins and Hcy were also measured in the spent dialysate . RESULTS The pre-HD levels of tHcy in the control group remained close to baseline values ( 26.6 + /- 5.0 micromol/L ) , while in the study group at 1 , 3 , and 6 months they decreased from a baseline value ( in micrormol/L ) of 25.3 + /- 5.9 to 21.5 + /- 4.5 , 16.9 + /- 4.0 , and 17.2 + /- 4.2 , respectively ( P < 0.01 for values at 3 and 6 months vs. baseline ) . The intra-HD drop of tHcy ( Delta HDHcy ) slightly but progressively decreased during the 3 steps on protein-leaking dialyzers and a positive correlation was found between Delta HDHcy and pre-HD levels of tHcy . In spent dialysate sample s from protein-leaking dialyzer-treated patients , the amount of protein-bound Hcy ( bHcy ) was approximately 10 times higher than in non-protein-leaking dialyzers , but the Delta HDHcy observed in non-protein-leaking dialyzers and protein-leaking dialyzers was comparable . Serum proteins and albumin were only slightly affected by protein-leaking dialyzers . CONCLUSION This study demonstrates that protein-leaking dialyzers used with a pure diffusive technique significantly lower pre-HD tHcy ( approximately 33 % of starting levels after 3 months of treatment ) in ESRD patients . A possible underlying mechanism for this effect could be the removal of large molecular weight solutes responsible for a defective metabolism of the Hcy , as the removal of bHcy with protein-leaking dialyzers seems not sufficient , per se , to explain this steady reduction of tHcy levels in pre-HD BACKGROUND Patients with end-stage renal disease ( ESRD ) have a very high mortality mainly caused by cardiovascular disease ( CVD ) . It has been suggested that plasma concentrations of asymmetric dimethyl arginine ( ADMA ) , an endogenous nitric oxide synthase inhibitor , are markedly elevated in patients with ESRD . Elevation of ADMA is linked to CVD and an adverse prognosis . Supplementation with n-3 fatty acids has previously been shown to prevent CVD , but there is very little data regarding the effect of n-3 fatty acids on levels of ADMA . METHODS Patients with ESRD and documented CVD were r and omized to treatment with 1.7 g of n-3 fatty acids ( n=103 , 34 % women ) or olive oil ( n=103 , 38 % women ) for three months . ADMA , symmetric dimethyl arginine ( SDMA ) , L-arginine , and the relative content of eicosapentaenoic acid ( EPA ) and docosahexaenoic acid ( DHA ) in serum phospholipids were measured before and after treatment . RESULTS ADMA was normally distributed with a mean value of 0.56+/-0.13 micromol/L ( range 0.21 - 1.01 ) and only 14/206 ( 6.8 % ) had elevated levels of ADMA . SDMA was generally elevated with a mean value of 1.88+/-0.64 micromol/L ( range 0.67 - 4.56 ) . Supplementation with n-3 fatty acids for three months did not change plasma levels of ADMA , SDMA or L-arginine . CONCLUSIONS The present data do not support a beneficial effect of n-3 fatty acids on methylarginines in patients with ESRD OBJECTIVE Hyperhomocysteinemia occurs in nearly 100 % of patients with end-stage renal disease ( ESRD ) and is associated with increased morbidity and mortality . Means to reduce elevated homocysteine concentrations is supplementation with folic acid , vitamin B6 , and vitamin B12 . However , doses of vitamins required for optimized treatment are subject of debate . Therefore , the effect of 2 different multivitamin preparations on the homocysteine concentrations in patients with ESRD were compared . DESIGN Patients received 3 times per week either 2 tablets of preparation A ( 800 microg folic acid , 6 microg vitamin B12 , 10 mg vitamin B6 ) , 2 tablets of preparation B ( 160 microg folic acid , no vitamin B12 , 10 mg vitamin B6 ) , or placebo for a period of 12 weeks with control of total homocysteine ( tHcy ) levels at baseline , and at 4 , 8 , and 12 weeks . SETTING The study was performed at the University Hospital of Magdeburg , Germany in patients with ESRD treated with chronic intermittent maintenance hemodialysis . RESULTS Preparation A reduced the tHcy concentration significantly by nearly 50 % , whereas preparation B did not change the tHcy concentration in comparison with placebo . However , tHcy was not normalized in the majority of patients receiving preparation A. CONCLUSION The reduction of tHcy achieved by a multivitamin containing 800 microg folic acid was substantial and even higher than the reduction reported in supplementation studies using higher doses of folic acid alone . Nevertheless , hyperhomocysteinemia in ESRD patients appears relatively refractory to vitamin supplementation , in contrast with results obtained in healthy volunteers Background —Accelerated vascular disease is common in chronic renal failure ( CRF ) and accounts for significant mortality and morbidity . Elevated homocysteine levels may contribute by an effect on endothelial function . Methods and Results —We performed a double-blind placebo-controlled r and omized crossover trial of folic acid at 5 mg/m2 in 25 normotensive children 12±3 ( 7 to 17 ) years of age with CRF ( glomerular filtration rate 26.8±13.2 mL/min per 1.73 m2 ) of noninflammatory etiology . Each subject underwent two 8-week periods of folic acid and placebo separated by an 8-week washout period . The effect of folic acid on homocysteine levels , LDL oxidation , and both endothelial-dependent and -independent vascular function were measured . After oral folic acid , serum folate levels rose from 11.7±4.25 to 635±519 & mgr;g/L ( P = 0.001 ) , red cell folate levels rose from 364±195 to 2891±2623 & mgr;g/L ( P < 0.001 ) , and total homocysteine levels fell from 10.28±4.16 to 8.62±2.32 & mgr;mol/L ( P = 0.03 ) . In addition , there was a significant improvement in flow-mediated dilatation ( FMD ) ( endothelial-dependent dilatation ) from 7.21±2.8 % to 8.47±3.01 % ( P = 0.036 ) with no change in response to glyceryl trinitrate ( endothelial-independent dilatation ) . There was no significant change in FMD or glyceryl trinitrate during the placebo phase . There was , however , no significant difference in final FMD after placebo or folic acid . Lag times for LDL oxidation were prolonged during the treatment phase ( 58.4±18.7 to 68.1±25.9 minutes , P = 0.01 ) . Conclusion —Folic acid supplementation in children with CRF may improve endothelial function with an increased resistance of LDL to oxidation Patients who are treated with chronic hemodialysis ( HD ) experience premature cardiovascular disease and an increased mortality . N-3 polyunsaturated fatty acids ( PUFA ) may be effective in the secondary prevention of cardiovascular disease , but the effects of n-3 PUFA has not previously been examined in HD patients . It was hypothesized that secondary prevention with n-3 PUFA would reduce the number of cardiovascular events and death in patients who are treated with chronic HD . A r and omized , double-blind , placebo-controlled intervention trial compared the effect of n-3 PUFA and a control treatment as secondary prevention of cardiovascular events in HD patients . The primary outcome was a composite of total cardiovascular events and death . A total of 206 patients were r and omly assigned to treatment with n-3 PUFA or control treatment and followed for 2 yr or until reaching a predefined end point . During the trial , 121 ( 59 % ) of 206 patients reached a primary end point . N-3 PUFA had no significant effect on the primary composite end point of cardiovascular events and death ( 62 versus 59 ; NS ) . In the n-3 PUFA group , a significant reduction was seen in the number of myocardial infa rct ions ( four versus 13 ; P = 0.036 ) . This trial was limited by a relatively small number of patients and a large number of withdrawals . However , it is concluded that treatment with n-3 PUFA did not reduce the total number of cardiovascular events and death in this high-risk population . N-3 PUFA significantly reduced the number of myocardial infa rct ions as a secondary outcome , a finding that might be of clinical interest Patients with end-stage renal disease ( ESRD ) have a high morbidity and mortality from cardiovascular disease . An elevated homocysteine level is an independent predictor of cardiovascular events in patients with ESRD . Interestingly , some studies have found an inverse relationship between the content of marine n-3 polyunsaturated fatty acids ( PUFAs ) and homocysteine levels , but data are ambiguous . In patients with ESRD , we hypothesized that serum phospholipid n-3 PUFA content would inversely correlate with homocysteine levels in plasma and that supplementation with n-3 PUFA would reduce plasma homocysteine levels . In a double-blind , r and omized , controlled design , 206 patients with documented cardiovascular disease and treated with hemodialysis for a minimum of 6 months were r and omized to treatment with daily supplement of 1.7 g n-3 PUFA or placebo ( olive oil ) for 3 months . The content of n-3 PUFA in serum phospholipids and homocysteine levels in plasma were measured at baseline and after 3 months of intervention . A dietary question naire was filled out at baseline , and study participants were divided into groups of low , intermediate , and high fish intake . Docosahexaenoic acid was inversely correlated with homocysteine at baseline ( coefficient = -0.161 ; P = .03 ) . Homocysteine was not related to self-reported fish intake . Supplementation with n-3 PUFA did not reduce homocysteine levels compared with placebo ( mean ± SD difference , -0.3 ± 7.8 versus 0.3 ± 7.1 ; P = .58 ) . The content of docosahexaenoic acid in serum phospholipids is inversely correlated with plasma homocysteine levels , and supplementation with n-3 PUFA does not reduce homocysteine levels in patients with ESRD BACKGROUND Mild hyperhomocysteinemia is common among maintenance hemodialysis ( HD ) patients and renal transplant recipients ( RTR ) and may contribute to the excess incidence of arteriosclerotic outcomes experienced by both patient groups . Relative to their RTR counterparts , the hyperhomocysteinemia of HD patients seems to be considerably more refractory to treatment with high-dose folic acid (FA)-based B-vitamin supplementation regimens , although controlled comparison data are lacking . METHODS We compared the relative responsiveness of ( n=10 ) RTR and ( n=39 ) HD patients with equivalent baseline total homocysteine ( tHcy ) levels ( i.e. , RTR range=14.2 - 23.6 micromol/L ; HD range=14.4 - 24.9 micromol/L ) to 12 weeks of tHcy-lowering treatment . The RTR received 2.4 mg/day of FA , 50.0 mg/day of vitamin B6 , and 0.4 mg/day of vitamin B12 , while the HD patients received 15 mg/day of FA or an equimolar amount ( 17 mg/day ) of the reduced folate , L-5-methyltetrahydrofolate , in addition to 50.0 mg/day of vitamin B6 , and 1.0 mg/day of vitamin B12 . RESULTS The mean percent ( % ) reductions ( + /-95 % confidence interval ) in tHcy were : RTR=28.1 % ( 16.2 - 40.0 % ) ; HD=12.1 % ( 6.6 - 17.7 % ) , P=0.027 for comparison of between-groups differences by analysis of covariance adjusted for baseline tHcy levels . Moreover , ( 50.0 % ) of 10 of the RTR versus only ( 5.1 % ) of 39 of the HD patients had final on-treatment tHcy levels < 12 micromol/L ; P=0.002 for comparison of between-groups differences by Fisher 's exact test . CONCLUSION Relative to RTR with comparable baseline tHcy levels , the mild hyperhomocysteinemia of maintenance HD patients is much more refractory to tHcy-lowering B-vitamin treatment regimens featuring supraphysiological amounts of FA or the reduced folate , L-5-methyltetrahydrofolate . Accordingly , RTR are a preferable target population for controlled clinical trials testing the hypothesis that tHcy-lowering B-vitamin intervention may reduce arteriosclerotic cardiovascular disease event rates in patients with chronic renal disease Increased homocysteine ( hCys ) level is an independent risk factor for cardiovascular complications in end-stage renal disease ( ESRD ) patients . The aim of this study was to evaluate effect of zinc ( Zn ) supplement on serum hCys level in ESRD patients . One hundred ESRD patients with Zn deficiency were enrolled in this double-blind r and omized clinical trial . They were r and omly subdivided into two groups and supplemented with Zn ( Zn group ) or placebo ( control group ) for 6 weeks . Fasting plasma hCys and Zn levels were measured before and at 43rd days after the start of the study . Serum Zn levels increased significantly ( p < 0.0001 ) , in Zn-treated group in comparison to placebo-treated group . In the Zn-treated group , serum hCys levels reduced significantly ( p < 0.0001 ) , compared to placebo group ( p > 0.05 ) . There was a significant ( p < 0.0001 ) reduction of mean percentage of hCys in Zn-treated group compared to the placebo group . Our study showed that Zn supplementation decreases serum hCys levels in ESRD patients with Zn deficiency Background and Purpose — Elevated total homocysteine is associated with a higher risk of cerebrovascular disease . It is not known whether lowering homocysteine impacts on stroke risk , both in terms of severity and ischemic vs hemorrhagic stroke subtypes . Our aim was to determine whether vitamin therapy reduces the risk of ischemic and hemorrhagic stroke , as well as stroke-related disability . Methods — We analyzed stroke outcomes among participants of the Heart Outcomes Prevention Evaluation 2 ( HOPE 2 ) trial that r and omized 5522 adults with known cardiovascular disease to a daily combination of 2.5 mg of folic acid , 50 mg of vitamin B6 , and 1 mg of vitamin B12 , or matching placebo , for 5 years . Results — Among 5522 participants , stroke occurred in 258 ( 4.7 % ) individuals during a mean of 5 years of follow-up . The geometric mean homocysteine concentration decreased by 2.2 & mgr;mol/L in the vitamin therapy group and increased by 0.80 & mgr;mol/L in the placebo group . The incidence rate of stroke was 0.88 per 100 person-years in the vitamin therapy group and 1.15 per 100 person-years in the placebo group ( hazard ratio [ HR ] , 0.75 ; 95 % CI , 0.59–0.97 ) . Vitamin therapy also reduced the risk of nonfatal stroke ( HR , 0.72 ; 95 % CI , 0.54–0.95 ) but did not impact on neurological deficit at 24 hours ( P=0.45 ) or functional dependence at discharge or at 7 days ( OR , 0.95 ; 95 % CI , 0.57–1.56 ) . In subgroup analysis , patients aged younger than 69 years , from regions without folic acid food fortification , with higher baseline cholesterol and homocysteine levels , and those not receiving antiplatelet or lipid-lowering drugs at enrollment had a larger treatment benefit . Conclusions — Lowering of homocysteine with folic acid and vitamins B6 and B12 did reduce the risk of overall stroke , but not stroke severity or disability Background Treatment with folic acid and vitamin B12 appears capable of reducing total plasma homocysteine levels ( tHcy ) , but it is unknown whether vitamin B12 alone reduces tHcy values . In this study we investigate the effects of alternate vitamins supplementation on homocysteine levels in patients treated by diffusive and convective dialysis techniques . Methods 74 patients were r and omized blindly into two groups of 37 subjects each . The first group was treated initially with vitamin B12 for 2 months and with folic acid for the following 2 months . The second group was treated initially with folic acid . A wash out period of 2 months followed the treatment in both groups . Results Total homocysteine levels decreased in both groups following the alternate vitamins therapy and dialysis , without significant difference between diffusive and convective techniques . Surprisingly , after the wash-out period , tHcy increased remarkably , regardless of the dialysis procedure used . At the end of the study , folate levels showed a higher reduction with haemodialysis compared to haemodiafiltration . In contrast , vitamin B12 levels showed a significant increase using diffusive haemodialysis , confirming a decisive role of membrane performance . Conclusions In conclusion we show for the first time that , even if total homocysteine levels decreased in both dialysis procedures , the convective techniques demonstrate a superior capacity on the reduction of tHcy levels compared to the diffusive method . Moreover , the lower depletion of vitamin B12 by diffusive techniques could determine a higher reduction of folate levels , demonstrating the decisive role of the membrane performance in the treatment of this patients Plasma total homocysteine ( tHcy ) concentrations are markedly increased in end-stage renal disease and only partially corrected by folic acid supplementation . We and others have reported that cobalamin , administered parenterally , reduces plasma tHcy substantially below the lowest concentrations attainable with folic acid . We have now carried out a r and omized controlled clinical trial to compare the plasma Hcy-lowering effect of 3 intravenous cyanocobalamin dose regimens in maintenance hemodialysis patients : 1 mg postdialysis every 28 , 14 , and 7 days in addition to routine oral vitamin B supplementation . All patients in the hemodialysis unit where the study was carried out routinely received 1 mg intravenous cyanocobalamin every month , so participants who were r and omized to receive the vitamin every 28 days simply continued with their existing treatment program . Serum cobalamin and plasma tHcy concentrations in the control group did not change over the course of the study . As measured after 8 weeks of therapy , intravenous cyanocobalamin every 14 days increased serum cobalamin approximately 2.5-fold and reduced plasma tHcy by 11.5 % ( P = .035 ) below the concentration previously attained with monthly administration , whereas treatment every 7 days increased serum cobalamin concentrations approximately 5-fold and reduced plasma tHcy by 11.0 % ( P = .013 ) . These results show that intravenous cyanocobalamin at 7- or 14-day intervals reduces plasma tHcy concentrations of hemodialysis patients below the levels brought about by prior long-term administration every 4 weeks and confirms that plasma tHcy lowering with parenteral cobalamin is a true pharmacological effect and not merely correction of a latent deficiency state BACKGROUND Individuals with advanced chronic kidney disease ( CKD ) and end-stage renal disease ( ESRD ) have high plasma total homocysteine ( tHcy ) levels , which may be a risk factor for cognitive impairment . Whether treatment with high-dose B vitamins to decrease high tHcy levels improves cognition in persons with kidney disease is unknown . STUDY DESIGN R and omized controlled trial . SETTING & PARTICIPANTS A sub study of 659 patients ( mean age , 67.3 + /- 11.7 years ) who participated in a r and omized double-blind clinical trial 5 years in duration conducted in 36 US Department of Veterans Affairs medical centers of the effect on all-cause mortality of vitamin-induced lowering of plasma tHcy level . 236 ( 35.8 % ) were treated by using dialysis ( ESRD ) and 423 ( 64.2 % ) had a Cockcroft-Gault estimated creatinine clearance of 30 mL/min or less ( advanced CKD ) . All had high tHcy levels ( > or = 15 micromol/L ) at baseline . Cognitive assessment s began during the follow-up period of the main trial 3 years after treatment began ; participants subsequently were retested 1 year later to assess cognitive change . INTERVENTION Daily high-dose B vitamin capsule ( 40 mg of folic acid , 100 mg of vitamin B(6 ) , and 2 mg of vitamin B(12 ) ) or placebo . OUTCOMES Cognitive function at initial assessment and 1 year later . MEASUREMENTS Telephone Interview of Cognitive Status-modified , supplemented with attention , working memory , and executive function tests . RESULTS Initial cognitive function was impaired in approximately 19 % of patients regardless of treatment assignment ( vitamin or placebo ) or kidney disease status ( advanced CKD or ESRD ) . Treatment decreased tHcy levels by 26.7 % . Unadjusted and adjusted analyses showed that treatment did not improve initial cognitive outcomes or affect subsequent cognitive status 1 year later . LIMITATIONS Cognitive assessment s began after treatment was initiated ; cognitive assessment was limited . CONCLUSION Treatment with high daily doses of B vitamins , which decreased tHcy levels , did not affect cognitive outcomes in patients with advanced CKD and ESRD The effectiveness of intravenous folinic acid or intravenous folic acid for the treatment of hyperhomocysteinemia of hemodialysis patients is unknown . In a r and omized , controlled , double-blind trial , 66 hemodialysis patients were administered either 15 mg of folic acid or an equimolar amount ( 16.1 mg ) of folinic acid intravenously three times weekly . Normalization of total homocysteine ( tHcy ) plasma levels after 4 weeks of treatment was achieved in 10 patients ( 30.3 % ) in the folic-acid group and 6 patients ( 18.2 % ; P : = 0.389 ) in the folinic-acid group ( normalization at any time during the study period in 39.4 % and 33.3 % of the patients ; P : = 0.798 ) . The relative reduction in tHcy plasma levels at week 4 was 32.2 % in the folic-acid group and 34.1 % in the folinic-acid group . A high baseline tHcy plasma concentration ( P : = 0.00001 ) , methylenetetrahydrofolate reductase ( MTHFR ) 677TT/1298AA genotype ( P : = 0.03540 ) , and low red blood cell folate concentrations ( P : = 0.02285 ) were associated with a better relative response to treatment . Normalization of tHcy plasma levels was dependent on a lower baseline tHcy level ( P : = 0.01976 ) , younger age ( P : = 0.00896 ) , and MTHFR 677TT/1298AA or 677CT/1298AC genotypes ( P : = 0.00208 and P : = 0.02320 , respectively ) . A 4-week course of intravenous folinic acid is not superior to intravenous folic acid in reducing elevated tHcy plasma levels in hemodialysis patients . The response to treatment is predicted by tHcy plasma level , red blood cell folate content , and MTHFR genotype INTRODUCTION Hyperhomocysteinemia is common in patients with end-stage renal disease . It is one of the risk factors for cardiovascular disease . We evaluated the effect of different doses of folic acid on serum homocysteine level in patients on hemodialysis . MATERIAL S AND METHODS Patients on maintenance hemodialysis were r and omized into 4 groups to receive oral folic acid at doses of 2 , 5 , 10 , and 15 mg/d , each for a period of 4 weeks . Serum homocysteine level was measured in all of the patients before and at the end of each week of therapy . Folic acid supplementation was discontinued during a washout period of 1 week between each of the four phases of the trial . RESULTS Thirty-one hemodialysis patients completed the four phases of treatment with each dose of folic acid ( 17 women and 14 men ) . The mean age of patients was 57.6 ± 14.6 years . Serum homocysteine level was reduced significantly compared to its basal level after treatment with folic acid at different doses ( P < .001 ) . Different doses of folic acid were not significantly different in lowering serum homocysteine levels . CONCLUSIONS Our study failed to show any difference between high-dose and low-dose folic acid therapy regarding their effect on serum homocysteine level . It seems folic acid , 2 mg/d , is an adequate dose , and there is no need to administer a higher dose of it BACKGROUND Patients with renal insufficiency have an increased risk of cardiovascular disease that is not fully explained by the presence of known cardiovascular risk factors . In patients with end-stage renal disease , increased serum concentration of asymmetric dimethylarginine ( ADMA ) , an endogenous inhibitor of nitric oxide synthase ( NOS ) , has been linked to excess cardiovascular morbidity . We investigated , in patients with mild-to-moderate renal failure , the relationship between plasma ADMA and three surrogate markers of atherosclerosis that have been shown to have prognostic value , namely carotid intima-media thickness ( IMT ) , plasma soluble vascular cell adhesion molecule-1 ( sVCAM-1 ) , and plasma C-reactive protein ( CRP ) . METHODS We used baseline data of an ongoing r and omized trial in which the effects of oxidative stress-lowering treatment on vascular function and structure are studied in patients with chronic nondiabetic renal failure without clinical evidence of atherosclerosis ( GFR 15 to 70 mL/min/per 1.73 m(2 ) according to the Cockcroft-Gault equation ; ATIC study ) . RESULTS Data from 93 patients were used . Creatinine clearance was inversely related to plasma ADMA concentration ( st and ardized beta after adjustment = -0.342 , P = 0.023 ) . Plasma ADMA was strongly related to carotid IMT in univariate ( beta = 0.459 , P < 0.0001 ) and multivariate analysis ( beta= 0.444 , P < 0.0001 ) . Plasma ADMA was also significantly related with plasma soluble vascular cell adhesion molecule-1 ( sVCAM-1 ) in univariate ( beta = 0.260 , P = 0.010 ) and multivariate ( beta = 0.242 , P = 0.022 ) analysis . Plasma ADMA was not significantly related to C-reactive protein ( beta = -0.134 , P = 0.204 ) . CONCLUSION In patients with mild-to-moderate renal failure , renal function is inversely associated with plasma ADMA , which , in turn , is positively associated with carotid IMT and plasma sVCAM-1 concentration . Increased plasma ADMA may be a link between renal function and cardiovascular disease in patients with mild-to-moderate renal failure BACKGROUND Abnormalities of endothelial function are likely to contribute to the accelerated atherosclerotic risk in subjects with end-stage renal disease ( ESRD ) . While folates can improve endothelial function , their role in ESRD has not been fully studied . The objective was to determine the acute and 12 week-effect of folinic acid on endothelium-dependent vasodilation in subjects with ESRD . METHODS Forearm blood flow ( FBF ) was assessed by strain gauge plethysmography at baseline and after 12 weeks in 34 ESRD patients ( 57 + /- 14 years ) . Vascular function was assessed with acetylcholine ( ACh ) , and sodium nitroprusside ( SNP ) . Patients were r and omized to receive folinic acid ( 50 mg i.v . once weekly ) or a matching placebo . A subset of 25 subjects also received folinic acid ( 500 microg/min intra-arterially ) or placebo to determine the acute effect on ACh and SNP mediated dilation at the time of the baseline vascular study . RESULTS Folinic acid acutely improved the maximum change in ACh mediated FBF ( 10.0 + /- 2.4 to 12.8 + /- 2.2 ml/min/100 ml , P = 0.017 ) , but did not change SNP responses . Chronic active therapy did not change ACh or SNP-mediated increases in FBF . Folinic acid result ed in a non-significant decrease in homocysteine ( 21 + /- 6 vs 28 + /- 18 micromol/l , P = 0.16 ) and diastolic blood pressure was significantly reduced ( P = 0.05 ) . CONCLUSIONS The present study demonstrated that folinic acid acutely improved endothelium-dependent vasodilatation in patients with ESRD suggesting a direct vascular effect . Chronic treatment with folinic acid did not show benefit in endothelial function , but did lower diastolic blood pressure . Further work is required to determine the optimal regime to protect vascular health in subjects with ESRD BACKGROUND Retrospective and case-control studies show that hyperhomocysteinemia is an independent risk factor for atherosclerosis in patients with end-stage renal disease . We studied prospect ively the association between total homocysteine and cardiovascular outcomes . METHODS AND RESULTS In all , 167 patients ( 93 men , 74 women ; mean age , 56.3+/-14.7 years ) were followed for a mean duration of 17.4+/-6.4 months . Cardiovascular events and causes of mortality were related to total homocysteine values and other cardiovascular risk factors . Cox regression analysis was used to identify the independent predictors for cardiovascular events and mortality . Fifty-five patients ( 33 % ) developed cardiovascular events and 31 ( 19 % ) died , 12 ( 8 % ) of cardiovascular causes . Total plasma homocysteine values ranged between 7.9 and 315.0 micromol/L. Levels were higher in patients who had cardiovascular events or died of cardiovascular causes ( 43.0+/-48.6 versus 26.9+/-14.9 micromol/L , P=.02 ) . The relative risk ( RR ) for cardiovascular events , including death , increased 1 % per micromol/L increase in total homocysteine concentration ( RR , 1.01 ; CI , 1.00 to 1.01 ; P=.01 ) . CONCLUSIONS These prospect i ve observations confirm that hyperhomocysteinemia is an independent risk factor for cardiovascular morbidity and mortality in end-stage renal disease , with an increased RR of 1 % per micromol/L increase in total homocysteine concentration . Interventional studies are needed to evaluate the possible effects of modifying this risk factor in these patients BACKGROUND Hemodialysis ( HD ) patients have a greatly increased risk of cardiovascular morbidity and mortality . For this reason , attempts are often made to normalize hyperhomocysteinemia . This r and omized prospect i ve study sought to determine which risk factors are predictors of mortality and whether high doses of folates or 5-methyltetrahydrofolate ( 5-MTHF ) could improve hyperhomocysteinemia and survival in HD patients . METHODS 341 patients were divided into two groups : group A was treated with 50 mg i.v . 5-MTHF , and group B was treated with 5 mg/day oral folic acid . Both groups received i.v . vitamin B(6 ) and B(12 ) . By dividing patients into C-reactive protein ( CRP ) quartiles , group A had the highest survival for CRP < 12 mg/l , whereas no survival difference was found for group B. CRP was the only predictive risk factor for death ( RR 1.17 , range 1.04 - 1.30 , p = 0.02 ) . Dialysis age , hyperhomocysteinemia , methylenetetrahydrofolate reductase polymorphism , albumin , lipoprotein ( a ) and folate did not influence mortality risk . Survival in group A was higher than that in group B , namely 36.2 + /- 20.9 vs. 26.1 + /- 22.2 months ( p = 0.003 ) . RESULTS Our results suggest that CRP , but not hyperhomocysteinemia , is the main risk factor for mortality in HD patients receiving vitamin supplements . Intravenous 5-MTHF seems to improve survival in HD patients independent from homocysteine lowering BACKGROUND Epidemiological studies suggest that raised plasma concentrations of total homocysteine might be a risk factor for major vascular events . Whether lowering total homocysteine with B vitamins prevents major vascular events in patients with previous stroke or transient ischaemic attack is unknown . We aim ed to assess whether the addition of once-daily supplements of B vitamins to usual medical care would lower total homocysteine and reduce the combined incidence of non-fatal stroke , non-fatal myocardial infa rct ion , and death attributable to vascular causes in patients with recent stroke or transient ischaemic attack of the brain or eye . METHODS In this r and omised , double-blind , parallel , placebo-controlled trial , we assigned patients with recent stroke or transient ischaemic attack ( within the past 7 months ) from 123 medical centres in 20 countries to receive one tablet daily of placebo or B vitamins ( 2 mg folic acid , 25 mg vitamin B6 , and 0.5 mg vitamin B12 ) . Patients were r and omly allocated by means of a central 24-h telephone service or an interactive website , and allocation was by use of r and om permuted blocks stratified by hospital . Participants , clinicians , carers , and investigators who assessed outcomes were masked to the assigned intervention . The primary endpoint was the composite of stroke , myocardial infa rct ion , or vascular death . All patients r and omly allocated to a group were included in the analysis of the primary endpoint . This trial is registered with Clinical Trials.gov , NCT00097669 , and Current Controlled Trials , IS RCT N74743444 . FINDINGS Between Nov 19 , 1998 , and Dec 31 , 2008 , 8164 patients were r and omly assigned to receive B vitamins ( n=4089 ) or placebo ( n=4075 ) . Patients were followed up for a median duration of 3.4 years ( IQR 2.0 - 5.5 ) . 616 ( 15 % ) patients assigned to B vitamins and 678 ( 17 % ) assigned to placebo reached the primary endpoint ( risk ratio [ RR ] 0.91 , 95 % CI 0.82 to 1.00 , p=0.05 ; absolute risk reduction 1.56 % , -0.01 to 3.16 ) . There were no unexpected serious adverse reactions and no significant differences in common adverse effects between the treatment groups . INTERPRETATION Daily administration of folic acid , vitamin B6 , and vitamin B12 to patients with recent stroke or transient ischaemic attack was safe but did not seem to be more effective than placebo in reducing the incidence of major vascular events . These results do not support the use of B vitamins to prevent recurrent stroke . The results of ongoing trials and an individual patient data meta- analysis will add statistical power and precision to present estimates of the effect of B vitamins . FUNDING Australia National Health and Medical Research Council , UK Medical Research Council , Singapore Biomedical Research Council , Singapore National Medical Research Council , Australia National Heart Foundation , Royal Perth Hospital Medical Research Foundation , and Health Department of Western Australia Renal failure causes hyperhomocysteinemia , an important risk factor for cardiovascular disease and venous access thrombosis in end-stage renal disease ( ESRD ) . Folic acid is necessary for homocysteine ( Hcy ) metabolism , and therapy with 1 mg/d or more of folic acid reduces plasma total Hcy ( tHcy ) concentrations in ESRD , although seldom to normal . In contrast to folic acid , the Hcy-lowering effect of vitamin B(12 ) has not been well studied in ESRD . We performed a prospect i ve r and omized controlled clinical trial involving 24 maintenance hemodialysis patients with normal or supranormal serum folate and vitamin B(12 ) concentrations who received either st and ard therapy , which included 5 to 6 mg folic acid , 5 to 10 mg pyridoxine , and 6 to 10 microg oral vitamin B(12 ) per day , or st and ard therapy plus 1 mg hydroxocobalamin administered subcutaneously once per week after dialysis . Plasma tHcy and serum methylmalonic acid ( MMA ) concentrations were measured before and after 8 and 16 weeks of continuous treatment . Hydroxocobalamin reduced plasma tHcy by an average of 32 % ( P < .005 ) and serum MMA by an average of 19 % ( P < .001 ) . The Hcy-lowering effect of hydroxocobalamin was independent of baseline serum vitamin B(12 ) , folic acid , and MMA concentrations . Patients with higher baseline plasma tHcy concentrations had the greatest response ( r = 0.80 ; P < .002 ) . These results show that parenteral hydroxocobalamin reduces plasma tHcy dramatically in vitamin B(12)-replete hemodialysis patients . Persons with considerable persisting hyperhomocysteinemia despite high-dose folic acid therapy are likely to respond to the addition of hydroxocobalamin , irrespective of their serum vitamin B(12 ) concentrations Various regimens of folic acid-based and vitamin B12 ( Vit B12 ) supplementations have been tried for lowering plasma homocysteine ( Hcy ) levels in uremic patients . However , the therapeutic potency of low-dose folic acid and Vit B12 alone is not properly understood . In this study , seventy-five patients on chronic hemodialysis ( HD ) therapy were r and omized into three groups . The FNA group received intravenous ( IV ) supplementation with folinic acid 3 mg weekly ; the Vit B12 group received IV supplementation with vitamin B12 1 mg weekly ; and the combination group received IV supplementation with both agents weekly . Blood levels of Hcy , folic acid , and Vit B12 were measured monthly for three months . After three months of treatment , plasma levels of Hcy decreased significantly in all three groups when compared with their baselines ( all p < 0.05 ) . The final Hcy level was significantly lower in the combination group ( 11.5 ± 2.3 μmol/L ) when compared with that of the FNA group ( 15.9 ± 5.6 μmol/L , p < 0.05 ) but not with the Vit B12 group ( 15.9 ± 11.6 μmol/L ) , although their baseline levels were similar . The percentage decreases of tHcy at the end of the treatment in the FNA group , Vit B12 group , and combination group were 16.4 % , 29.3 % , and 38.9 % respectively . Our study showed that IV pharmacologic dose of Vit B12 alone is as effective as low-dose folic acid in correcting hyperhomocysteinemia in chronic HD patients , and combining both drugs in low doses may have added effects Abstract Background : Hyperhomocysteinaemia is an independent cardiovascular risk factor in patients with renal disease . The current study aim ed to determine the effect of intravenous N-acetylcysteine on plasma homocysteine levels when administered during haemodialysis in patients with end-stage renal failure . Patients and methods : Sixty patients with end-stage renal failure were r and omised to receive a 4-hour intravenous infusion of N-acetylcysteine or placebo during a 4-hour haemodialysis session . Plasma homocysteine levels were measured before and after haemodialysis . Haemodynamic parameters , including pulse pressure , were also measured . Results : After haemodialysis in the placebo treatment group , plasma homocysteine was reduced by 23.7 % from the pre-dialysis level , whereas patients treated with N-acetylcysteine exhibited an 88.3 % decrease ( p < 0.001 ) . Reduction of plasma homocysteine concentration was significantly correlated with a reduction of pulse pressure ( p = 0.001 ) . A 10 % decrease in plasma homocysteine concentration was associated with a 1.45 mm Hg decrease in pulse pressure . Conclusions : Intravenous administration of N-acetylcysteine during haemodialysis normalises plasma homocysteine concentration , and this is associated with improved pulse pressure in patients with end-stage renal failure . Intravenous administration of N-acetylcysteine during haemodialysis may be a promising approach to help reduce cardiovascular risk in this vulnerable group of patients BACKGROUND The chronic hemodialysis population has an accelerated rate of cardiovascular morbidity and death . Furthermore , elevated levels of the putative atherothrombotic risk factor homocysteine are almost ubiquitous in this population . Attempts to normalize elevated plasma total homocysteine ( tHcy ) levels in dialysis patients using pharmacological-dose vitamin therapy or other strategies generally have been unsuccessful . Preliminary uncontrolled evidence suggests that N-acetylcysteine ( NAC ) may be an effective tHcy-lowering agent . We design ed a r and omized placebo-controlled study to determine the effect of prolonged oral NAC therapy on lowering tHcy levels in vitamin-replete chronic hemodialysis patients . METHODS Thirty-eight subjects were treated before intervention with a st and ard dialysis vitamin supplement to ensure a uniform vitamin-replete state . They were then block r and omized to treatment with NAC , 1.2 g twice a day , for 4 weeks or matched placebo . RESULTS There were no significant baseline differences between the two groups , although differences in pyridoxal 5'-phosphate ( active form of vitamin B(6 ) ) levels approached significance ( P = 0.06 ) . In a paired analysis , there was no statistically significant difference between the NAC and placebo groups . NAC was very well tolerated in hemodialysis patients . CONCLUSION This r and omized placebo-controlled trial found that chronic oral NAC therapy did not significantly reduce tHcy levels in hemodialysis patients . Although a larger sample size theoretically could have increased the statistical significance between groups , implication s of the potentially very modest reduction in tHcy levels are not yet known . Finally , based on this limited study , NAC appears to be a safe and well-tolerated therapy in the hemodialysis population BACKGROUND Arterial stiffness is increased in chronic kidney disease ( CKD ) . Intervention studies aim ed at reduction of arterial stiffness in dialysis patients have been disappointing . We therefore investigated the effect of pravastatin , vitamin E , and homocysteine lowering on arterial compliance and distensibility coefficients in mild-to-moderate CKD . METHODS This is a sub- study of the ATIC study , a r and omized , double-blind trial in 93 CKD patients . The treatment group received pravastatin to which vitamin E supplementation was added after 6 months and homocysteine lowering therapy after another 6 months . Measurement of the distensibility coefficient ( DC ) and the compliance coefficient ( CC ) of the common carotid ( CCA ) , femoral ( FA ) and brachial artery ( BA ) was performed at 0 , 6 , 12 , 18 months . Young 's elastic modulus ( YEM ) was measured in the common carotid artery . RESULTS After 18 months , CCA-DC increased from mean ( SD ) 15.15 ( 6.67 ) to 16.52 ( 6.37 ) × 10 - 3kPa-1 in the treatment and decreased from 18.44 ( 8.19 ) to 16.26 ( 7.35 ) in the placebo group ( p = 0.057 ) . CCA-CC increased from 0.64 ( 0.24 ) to 0.71 ( 0.26 ) mm2kPa-1 in the treatment and decreased from 0.77 ( 0.28 ) to 0.69 ( 0.25 ) in the placebo group ( p < 0.0001 ) . FA-DC had increased from 6.64 ( 3.45 ) to 11.46 ( 6.83 ) in the treatment group , and from 6.46 ( 2.85 ) to 7.08 ( 2.73 ) in the placebo group ( p = 0.0001 ) . FA-CC had increased from 0.46 ( 0.24 ) to 0.74 ( 0.44 ) in the treatment group , and from 0.48 ( 0.27 ) to 0.53 ( 0.21 ) in the placebo group ( p = 0.008 ) . BA-DC and CC , and CCA YEM were not significantly different between the groups . CONCLUSION In patients with mild-to-moderate CKD , 18 months of treatment consisting of pravastatin , vitamin E and homocysteine lowering result ed in significant improvement of compliance and distensibility in CCA and FA . Since pravastatin was used throughout the observation period , it remains unclear whether the beneficial effects are attributable solely to the ongoing effect of pravastatin treatment , or if the additional interventions further slowed the progression of vascular stiffness . Therefore , larger studies with a longer period of follow-up observing the separate effects are needed BACKGROUND Patients with end-stage renal disease ( ESRD ) have an increased mortality , mainly due to cardiovascular disease ( CVD ) . ESRD is accompanied by several lipid abnormalities , which may be responsible for part of the increased risk of CVD in this population . n-3 polyunsaturated fatty acids ( PUFA ) lower plasma triglycerides in patients with normal renal function . The aim of the present study was to examine the effect of n-3 PUFA on serum lipid and lipoproteins in patients treated with chronic haemodialysis ( HD ) . METHODS In a double-blind r and omized placebo-controlled design , patients with documented CVD , treated with HD for a minimum of 6 months , were r and omized to treatment with n-3 PUFA or a control treatment ( olive oil ) . A dietary intake of n-3 PUFA was assessed with a dietary question naire . Plasma lipids and lipoproteins and the content of n-3 PUFA in serum phospholipids were measured at baseline and after 3 months . RESULTS Two hundred and six patients were included . Serum phospholipid levels of n-3 PUFA were significantly higher in patients reporting a high fish intake compared to patients reporting a low fish intake . After 3 months , a significant decrease was seen in serum triglycerides in the n-3 PUFA group compared to the control group ( P = 0.01 ) . No significant effect was seen on total cholesterol , high-density lipoprotein ( HDL ) cholesterol , low-density lipoprotein ( LDL ) cholesterol , Lp(a ) or apoB. CONCLUSION In patients treated with HD , consumption of fish increases levels of n-3 PUFA . Additional supplementation with n-3 PUFA for 3 months further increases levels of n-3 PUFA and lowers serum triglycerides , but does not significantly affect other plasma lipids or lipoproteins BACKGROUND Treatment with folic acid and vitamin B 12 appears to be effective in lowering total plasma Homocysteine ( tHcy ) concentration , but whether vitamin B 12 alone decreases tHcy in patients with normal vitamin B 12 status is still unknown . The aims of the present study were to explore the effect of alternate vitamin supplementation with folic acid or vitamin B 12 on tHcy concentrations in haemodialysis ( HD ) patients , and to compare changes in tHcy concentrations with MTHFR genotype . METHODS 74 patients , 44 men and 30 women , were recruited and r and omized blindly into two groups of 37 subjects each . The first group was initially treated with vitamin B 12 for two months , and with folic acid for the following two months ; the second group was supplemented in the reverse order . In both groups the treatment was followed by a 2-month washout period . tHcy levels were measured at the beginning of treatment ( T0 ) , after two months ( T1 ) , four months ( T2 ) , and at the end of the washout period ( T3 ) . Vitamin B 12 and folate were taken at T0 and T3 . RESULTS The genotype frequency was : C/C 37 % , C/T 34 % , T/T 29 % . tHcy decreased in both groups following the alternate vitamins therapy . This decrease was greater for the T/T genotype ( p<0.05 ) and was more significant when the treatment start-ed with folic acid ( p<0.01 ) . Moreover , after the washout period , tHcy increased remarkably without significant differences between diffusive and convective techniques . Folate levels at the end of study appeared to be reduced in haemodialysis patients . Vitamin B 12 concentration significantly increased in patients on diffusive haemodialysis , confirming the fundamental role of membrane performance . CONCLUSION The alternate vitamin treatment demonstrated the importance of folate therapy and the secondary contribution of vitamin B 12 in lowering tHcy in HD patients Context In observational studies , elevated plasma homocysteine levels were associated with venous thromboembolism . A multicenter trial of folic acid and B vitamins to reduce cardiovascular events investigated the effect of homocysteine lowering on venous thromboembolism . Contribution In this trial , 5522 adults were r and omly assigned to receive placebo , or folic acid and vitamins B6 and B12 daily for 5 years . Vitamin therapy decreased homocysteine levels , but the incidence of venous thromboembolism was the same in both groups , even in participants with the highest levels of homocysteine . Caution Venous thromboembolism events were not central ly adjudicated . Implication Decreasing homocysteine levels with supplements containing folic acid and vitamins B6 and B12 does not reduce the incidence of venous thromboembolism . The Editors Observational studies have found an association between elevated total plasma homocysteine levels and venous thromboembolism ( 14 ) . Homocysteine is thought to promote thrombosis through enhanced platelet activation , increased thrombin generation , and impaired fibrinolysis and by causing endothelial dysfunction ( 5 ) . Although homocysteine levels can be decreased by 25 % by using a supplement of folic acid and vitamins B6 and B12 ( 6 ) , whether the risk for venous thromboembolism is reduced as a result is not known . The Heart Outcomes Prevention Evaluation 2 ( HOPE-2 ) evaluated the effect of homocysteine-lowering therapy on the risk for major vascular arterial disease ( 7 ) . In conjunction with the trial , we collected data prospect ively to determine whether decreasing homocysteine levels would reduce the occurrence of symptomatic venous thromboembolism . Methods Design The design of HOPE-2 , a large r and omized , placebo-controlled clinical trial , is described elsewhere ( 7 , 8) . Soon after HOPE-2 began , a decision was made to include venous thromboembolism as a study outcome . A diagnosis of venous thromboembolism was based on prespecified , accepted criteria ( 7 ) . An independent data and safety monitoring board evaluated the safety of the participants and the overall quality and scientific integrity of HOPE-2 . The research ethics review board of each participating center approved the trial , and all participants provided written informed consent . Participants The HOPE-2 included 5522 participants 55 years of age or older who had a history of coronary , cerebrovascular , or peripheral vascular disease ; diabetes mellitus ; and at least 1 additional risk factor for cardiovascular disease , regardless of baseline homocysteine level ( 7 , 8) . Persons taking daily vitamin supplementation that contained more than 0.2 mg of folic acid were excluded . A history of venous thromboembolism or the presence or absence of risk factors for venous thromboembolism did not affect eligibility . A complete list of inclusion and exclusion criteria appears elsewhere ( 7 , 8) . Data on all persons who were enrolled in HOPE-2 are included in the current report . Centers Individuals were recruited from 145 centers in 13 countries , including Canada ( n= 3568 ) , the United States ( n= 414 ) , Brazil ( n= 265 ) , western European countries ( n= 426 ) , and Slovakia ( n= 849 ) . Intervention and R and omization Between January 2000 and December 2000 , participants were r and omly assigned to receive a once-daily supplement containing 2.5 mg of folic acid , 50 mg of vitamin B6 , and 1 mg of vitamin B12 , or matching placebo . R and omization was computer generated , with a block size of 4 ; was stratified by clinical center ; and was performed by having clinical centers call an automated central ized system . Information about block size and whether it was r and om or fixed was kept confidential for all study investigators . The r and omization sequence was concealed , and all study personnel and study participants were masked to treatment allocation . The vitamin and placebo pill formulations were indistinguishable by size , color , weight , taste , or dissolution in water . Changes in blood levels of folate , vitamins B6 and B12 , and homocysteine , which are affected by the study intervention , are not commonly measured in clinical practice , and the results of any such measurements that were performed as part of the study were kept confidential . No request was made to unmask treatment allocation for a participant . Baseline Measurements and Follow-up Baseline demographic data ; medical history ; and medication use , including current anticoagulant therapy , were recorded for all participants at study entry . History of venous thromboembolism was not documented . Baseline homocysteine levels were obtained in 3306 r and omly selected participants ( 60 % of total ) who had fasted overnight . Stratified r and om sampling was used to achieve proportional representation of a subset of participants in countries with folic acid food fortification ( Canada and the United States ) and countries without this st and ard ( all other countries with participating centers ) . Homocysteine was measured by using a fluorescence polarization immunoassay ( Abbott IMx , Abbott Laboratories , Abbott Park , Illinois ) . The distribution of homocysteine was statistically significantly skewed ; thus , these measures were log-transformed and inverse transformations were used to generate geometric mean values . The first evaluation for venous thromboembolism occurred 18 months after r and omization ; at this visit , all participants were assessed for any venous thromboembolism event arising between trial entry and the 18-month visit . Thereafter , venous thromboembolism was assessed routinely every 6 months , to an average follow-up of 5 years . The trial used simple case report forms , which were faxed toll-free to the study coordinating office and were entered into a data base by using optical character recognition ( Data Fax , Clinical Data Fax Systems , Hamilton , Ontario , Canada ) . The data base was fit for quality control assessment s and statistical analyses . At each 6-month interval , participants were assessed in the study clinics . These assessment s were directed primarily to ascertain study end points . Side effects were also evaluated , and adherence to treatment was assessed by interview and pill count . When in-person visits were not possible , participants were contacted by telephone . Outcomes The primary outcome in our study was symptomatic venous thromboembolism , which included deep venous thrombosis or pulmonary embolism ( or both ) . In the original HOPE-2 report ( 8) , venous thromboembolism was included under other outcomes . Diagnosis of deep venous thrombosis required confirmation with duplex leg ultrasonography or venography . Diagnosis of pulmonary embolism required confirmation with ventilationperfusion lung scanning , computed tomographic pulmonary angiography , or conventional pulmonary angiography . When diagnostic testing had indeterminate results or was not done , which rarely occurred , we required oral anticoagulant therapy to be initiated at the same time that new-onset venous thromboembolism was recorded on the case report form . A maximum of 1 episode of venous thromboembolism per participant was counted during follow-up . We subcategorized episodes as unprovoked venous thromboembolism if they occurred in participants who did not have cancer at baseline and occurred 90 days or more after a lower limb fracture or 30 days or more after a hospitalization . We ascertained all events with concealment to r and omization for study participants and assessors . Statistical Analysis Our primary analysis was a comparison of the incidence of venous thromboembolism in the 2 study groups . We prespecified secondary analyses and included comparisons between the groups of rates of venous thromboembolism ( including unprovoked events ) according to subgroups and strata ( Figure 1 ) . Figure 1 . Risk for venous thromboembolism ( VTE ) in prespecified subgroups . We used an intention-to-treat analysis to compare the effect of homocysteine-lowering therapy with that of placebo on the subsequent development of venous thromboembolism . We conducted the time-to-event analysis by using a Cox proportional hazards regression model and expressed unadjusted risk as hazard ratios and 95 % CIs . We examined the proportional hazards assumption by fitting the models with the interaction terms between time and treatment . We estimated a survival curve according to the KaplanMeier procedure and compared treatment groups by using a log-rank test . At each interval clinic visit , follow-up was greater than 99 % . In the rare circumstance that an individual could not be assessed at a clinic visit and could not be contacted by telephone , we considered the individual to be free of venous thromboembolism at that point . Individuals who were lost to follow-up were censored at the time of last contact . The original HOPE-2 was design ed to recruit 5000 participants , with a mean of 5 years of follow-up , to detect a relative risk reduction of 17 % to 20 % and a statistical power of 80 % and 90 % in the primary composite outcome of cardiovascular death , myocardial infa rct ion , and stroke , given an annual event rate of 4 % in the placebo group and a 2-sided P value of 0.05 . We did not estimate a formal sample size . A 2-sided P value less than 0.05 was considered significant for all analyses , which we performed by using SAS , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) . Role of the Funding Sources The study was funded by the Canadian Institutes of Health Research and Jamieson Laboratories . The funding sources had no role in the design , conduct , or reporting of the study or in the decision to su bmi t the manuscript for publication . Results Study Participants and Homocysteine Levels Of the 5522 study participants , 2758 were r and omly assigned to receive homocysteine-lowering therapy and 2764 were assigned to receive placebo ( Table 1 ) . A total of 3982 participants ( 72 % ) were from Canada and the United States , where universal food fortification with folic acid was in place before the start of the trial . Adherence to BACKGROUND In observational studies , lower homocysteine levels are associated with lower rates of coronary heart disease and stroke . Folic acid and vitamins B6 and B12 lower homocysteine levels . We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease . METHODS We r and omly assigned 5522 patients 55 years of age or older who had vascular disease or diabetes to daily treatment either with the combination of 2.5 mg of folic acid , 50 mg of vitamin B6 , and 1 mg of vitamin B12 or with placebo for an average of five years . The primary outcome was a composite of death from cardiovascular causes , myocardial infa rct ion , and stroke . RESULTS Mean plasma homocysteine levels decreased by 2.4 micromol per liter ( 0.3 mg per liter ) in the active-treatment group and increased by 0.8 micromol per liter ( 0.1 mg per liter ) in the placebo group . Primary outcome events occurred in 519 patients ( 18.8 percent ) assigned to active therapy and 547 ( 19.8 percent ) assigned to placebo ( relative risk , 0.95 ; 95 percent confidence interval , 0.84 to 1.07 ; P=0.41 ) . As compared with placebo , active treatment did not significantly decrease the risk of death from cardiovascular causes ( relative risk , 0.96 ; 95 percent confidence interval , 0.81 to 1.13 ) , myocardial infa rct ion ( relative risk , 0.98 ; 95 percent confidence interval , 0.85 to 1.14 ) , or any of the secondary outcomes . Fewer patients assigned to active treatment than to placebo had a stroke ( relative risk , 0.75 ; 95 percent confidence interval , 0.59 to 0.97 ) . More patients in the active-treatment group were hospitalized for unstable angina ( relative risk , 1.24 ; 95 percent confidence interval , 1.04 to 1.49 ) . CONCLUSIONS Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease . ( Clinical Trials.gov number , NCT00106886 ; Current Controlled Trials number , IS RCT N14017017 . ) BACKGROUND AND OBJECTIVES Increased plasma total homocysteine is a grade d , independent risk factor for the development of atherosclerosis and thrombosis . More than 90 % of patients with end-stage renal disease have hyperhomocysteinemia despite vitamin supplementation . It was shown in previous studies that a single intravenous dose of mesna 5 mg/kg caused a drop in plasma total homocysteine that was significantly lower than predialysis levels 2 d after dosing . It was hypothesized 5 mg/kg intravenous mesna administered thrice weekly , before dialysis , for 8 wk would cause a significant decrease in plasma total homocysteine compared with placebo . DESIGN , SETTING , PARTICIPANTS , & MEASUREMENTS Patients with end-stage renal disease were r and omly assigned to receive either intravenous mesna 5 mg/kg or placebo thrice weekly before dialysis . Predialysis plasma total homocysteine concentrations at weeks 4 and 8 were compared between groups by paired t test . RESULTS Mean total homocysteine at 8 wk in the placebo group was 24.9 micromol/L compared with 24.3 micromol/L in the mesna group ( n = 22 [ 11 pairs ] ; mean difference 0.63 ) . Interim analysis at 4 wk also showed no significant difference between mesna and placebo ( n = 32 [ 16 pairs ] ; placebo 26.3 micromol/L , mesna 24.5 micromol/L ; mean difference 1.88 ) . Multivariable adjustments for baseline characteristics did not alter the analysis . Plasma mesna seemed to reach steady-state concentrations by 4 wk . CONCLUSIONS It is concluded that 5 mg/kg mesna does not lower plasma total homocysteine in hemodialysis patients and that larger dosages may be required ABSTRACT Objective : Folic acid and vitamin B complex administration in uremic patients has been reported to lower plasma total homocysteine ( tHcy ) levels , but whether or not this has a beneficial effect on the inflammatory state is not clear . Methods : We conducted a r and omized open labeled study to determine the effects of folic acid ( 5 mg daily ) and vitamin B complex administration on plasma tHcy levels as well as inflammatory ( serum high-sensitivity C reactive protein , hs‑CRP ) and nutritional ( serum albumin ) markers in patients on maintenance hemodialysis . Treatment was given for 3 consecutive months to 61 patients on maintenance hemodialysis . Another 60 patients , all age- , sex- , hemodialysis duration -matched served as control group . Main outcome measures : Plasma tHcy , serum hs‑CRP , albumin , creatinine ( Cr ) , post-dialysis body weight ( BW ) , and normalized protein catabolism rate ( nPCR ) . Results : After 3 months , levels of plasma tHcy and serum hs‑CRP , Cr , and nPCR were significantly decreased while levels of serum albumin , vitamin B12 , folate , and BW were significantly increased . The dialytic dose ( KT/V ) and dietary intake remained unchanged . However , correlations between the magnitude of reduction of tHcy & hs‑CRP , tHcy & Cr , and Cr & nPCR were statistically significant . Conclusions : Folic acid and vitamin B complex co-administration effectively lowers tHcy and hs‑CRP levels and increases albumin levels in stable hemodialysis subjects , underscoring their potential benefit to attenuate the state of inflammation and possibly improve the nutritional status in patients on hemodialysis To evaluate the efficacy of supplementation with high dose folic acid with and without vitamin B 12 in lowering plasma total homocysteine ( tHcy ) concentrations in hemodialysis ( HD ) patients , we studied 36 HD patients r and omized into four groups according to the received therapeutic regimen : group I ( only folic acid ( FA ) , 5 mg/day ) , group II ( FA , 5 mg/day + vitamin B 12 , 1 mg/day ) group III ( only FA , 15 mg/day ) , group IV ( FA , 15 mg/day , vitamin B 12 , 1 mg/day ) for a period of 8 weeks . Plasma tHcy and serum FA and vitamin B 12 levels were measured at baseline and after the supplementation period . Dietary intakes were assessed during the study period . At baseline , 27.8 % of the patients had normal levels of tHcy and 72.2 % had hyperhomocysteinemia . After supplementation , plasma tHcy increased by 1.35 % in group I and decreased by 6.99 % , 14.54 % and 30.09 % in groups II , III and IV respectively , which was only significant in group IV ( P= 0.014 ) . The patients did not show any significant changes in serum folic acid , but a significant change in serum vitamin B 12 in group IV ( P= 0.006 ) . Percentage of patients reaching normal levels of plasma tHcy was 5.6 fold higher in group IV than in the reference group ( group I ) . No correlations were found between changes of plasma tHcy levels and dietary intakes . We conclude that oral supplementation with 15 mg/day folic acid together with 1 mg/day of vitamin B 12 is effective in reducing tHcy levels in HD patients . These supplements also have a desirable effect on serum folic acid and vitamin B12 Background / Aims : Recent data have addressed the issue of higher levels of homocysteine ( Hcy ) and endothelin-1 ( ET-1 ) in end-stage renal disease ( ESRD ) that may be considered an independent predictor for cardiovascular disease . The prevalence of peripheral arterial disease ( PAD ) in patients with ESRD has been reported to be relevant , highlighting its clinical importance . We aim ed to explore the therapeutic role of propionyl-L-carnitine ( PLC ) in hemodialysis patients with PAD by measuring ankle/brachial index ( ABI ) , ET-1 and Hcy . Design : R and omized , double-blind , placebo-controlled trial . Methods : Sixty-four patients on hemodialysis with chronic renal insufficiency and PAD were assigned to receive either intravenous PLC ( 600 mg ) or placebo 3 times weekly for 12 months . The ABI and plasma levels of ET-1 and Hcy were measured at baseline , 6 and 12 months . Results : In the PLC-treated group , progressive increases in ABI were observed , while in the placebo group the reverse trend was seen . Highly significant and progressive reductions in plasma levels of ET-1 and Hcy , compared to baseline , were also seen in the PLC-treated group . Conclusions : Hemodynamic flow , endothelial profile and Hcy levels were ameliorated by the administration of PLC in hemodialysis patients with ESRD and PAD BACKGROUND Abnormalities in the gene regulating methylenetetrahydrofolate reductase ( MTHFR ) are associated with increased homocysteine levels and increased mortality in normal and chronic kidney disease ( CKD ) population s. STUDY DESIGN Gene association study . SETTING & PARTICIPANTS This was a sub study of 677 patients from 21 Veterans Affairs medical centers participating in a r and omized clinical trial ( Homocysteinemia in Kidney and End-Stage Renal Disease [ HOST ] ) of the effect on all-cause mortality of vitamin-induced lowering of plasma homocysteine levels . Of 677 patients , 213 ( 31 % ) were treated by using dialysis ( end-stage renal disease [ ESRD ] ) and 464 ( 69 % ) had a Cockcroft-Gault estimated creatinine clearance less than 30 mL/min ( advanced CKD ) . PREDICTOR Polymorphisms C677 T ( rs1801133 ) and A1298C ( rs1801131 ) of the MTHFR gene . OUTCOMES Unadjusted and adjusted all-cause mortality . MEASUREMENTS DNA was extracted from blood sample s and amplified by means of polymerase chain reaction . RESULTS The adjusted hazard ratio in a recessive model of the relationship between the C677 T polymorphism and all-cause mortality in all patients was 1.47 ( 95 % confidence interval , 1.00 to 2.16 ; P = 0.05 ) . In patients with ESRD with the mutant TT genotype , the adjusted hazard ratio for mortality in all patients was 2.27 ( 95 % confidence interval , 1.07 to 4.84 ; P = 0.03 ) ; patients with advanced CKD showed a similar , although not significant , trend . The risk of myocardial infa rct ion ( P = 0.05 ) and composite risk of myocardial infa rct ion , stroke , lower-extremity amputation , and mortality ( P = 0.02 ) were greater in patients with ESRD with the mutant T allele at nucleotide 677 . The overall relationship between the A1298C polymorphism and mortality was not significant ( P = 0.6 ) . LIMITATIONS Participants were 98 % men ; DNA sample s were not obtained at enrollment in HOST ; linkage disequilibrium with another causal polymorphism is a potential confounding factor ; and power was reduced by the limited number of participants . CONCLUSIONS These findings provide additional support for the hypothesis that the mutant TT genotype at nucleotide 677 of the gene regulating MTHFR activity may increase the mortality risk in patients with ESRD Hyperhomocysteinemia is a risk factor for cardiovascular disease in patients on hemodialysis . Causes include genetic enzyme deficiencies , chronic renal failure , and vitamin deficiencies . Homocysteine correlates negatively with folate status . In patients on hemodialysis , supraphysiologic doses of B vitamins and folate reduce homocysteine by 26 - 33 % . No study has examined the effect of a st and ard multivitamin ( Nephro-Vite Rx ) , containing B vitamins and 1 mg of folate , on erythrocyte-folate ( RBC-folate ) and homocysteine in patients on dialysis . We examined RBC-folate and homocysteine levels in 11 stable chronic patients on hemodialysis , mean duration of dialysis 9.8+/-4.1 months , who were not on vitamin or folate supplements , and repeated these levels after 3 weeks of once daily Nephro-Vite Rx dosage . Plasma homocysteine levels fell by 23.7 % from 27.8+/-5.9 to 21.2+/-6.6 micromol/L ( p = 0.007 ) , whereas RBC-folate levels rose 60 % from 631.2+/-208.3 to 1007.5+/-423.7 nmol/L ( p = 0.001 ) . The optimum dose of B vitamins and folate remains to be established , and a clinical benefit from lowering homocysteine has not yet been demonstrated . In summary , a st and ard multivitamin such as Nephro-Vite Rx reduces plasma homocysteine levels and increases RBC-folate levels in patients on hemodialysis . Our results may have implication s for the modification of cardiovascular risk in these patients BACKGROUND The excess of cardiovascular disease in end-stage renal disease ( ESRD ) patients is unexplained , but could relate to altered intrinsic vascular wall properties , such as increased arterial stiffness , which could be mediated by hyperhomocysteinemia . We investigated potential determinants of carotid artery stiffness in ESRD patients and the effect of long-term homocysteine-lowering treatment . PATIENTS AND METHODS Fifty-four patients on maintenance dialysis treatment were studied at baseline . Fourty-one patients completed the treatment protocol , which consisted of a 12-week treatment with folic acid 5 mg daily with or without betaine 4 g per day , and of 1 or 5 mg of folic acid thereafter for 40 weeks . Both phases were r and omized . Compliance and distensibility coefficients ( CC and DC ) and the stiffness index ( beta ) of the common carotid artery were determined at baseline and after 52 weeks of treatment using a non-invasive vessel wall movement detector system . RESULTS At baseline , plasma total homocysteine was elevated ( 44.1+/-33.7 micromol/l ) , but showed no relationship with CC , DC or beta . Age and mean arterial pressure ( MAP ) were the only independent determinants of CC and DC , whereas beta was associated with age only . Plasma homocysteine showed a sustained decrease after therapy ( 20.7+/-9.0 micromol/l at week 52 ) . No significant changes occurred in CC ( from 0.59+/-0.21 to 0.60+/-0.22 mm2/kPa ; p = 0.47 ) , in DC ( from 14.9+/-6.1 to 15.3+/-6.2 10(-3)/kPa ; p = 0.55 ) , or in beta ( from 10.9+/-4.7 to 11.2+/-4.4 ; p = 0.64 ) . No independent determinants were detected for the change in CC , whereas the change in DC was inversely related to the change in MAP ( st and . r = -0.58 ; p<0.0002 ) . The decrease in MAP after therapy was significant ( p = 0.003 ) and was related to the dialysis mode ( p = 0.003 ) and smoking status ( p = 0.02 ) . CONCLUSION Folic acid treatment of hyperhomocysteinemia has no major effect on carotid artery stiffness in chronic dialysis patients . The results do , however , emphasize the importance of tight blood pressure control in these patients Homocysteine is associated with atherosclerosis and enhanced cardiovascular risk . In previous studies , treatment with folic acid up to 15 mg/d failed to correct hyperhomocysteinemia in the majority of end-stage renal disease patients . A dose of 30 or 60 mg of folic acid per day was compared with 15 mg/d in an attempt to normalize hyperhomocysteinemia in 150 hemodialysis patients . In a r and omized , double-blind , multicenter study , 144 patients completed the 4-wk treatment period and 121 patients completed the 6-mo follow-up . Total homocysteine plasma levels were reduced by 32.1 % ( 15 mg/d ) , 29 . 9 % ( 30 mg/d ) , or 37.8 % ( 60 mg/d ) with no significant differences found between the three treatment groups . Baseline total homocysteine plasma concentration was an independent predictor of the response to folic acid therapy ( P = 0.0001 ) , whereas the 5 , 10-methylenetetrahydrofolate reductase polymorphisms ( MTHFR 677C -- > T and 1298A -- > C ) had no influence . Nevertheless , patients with the MTHFR 677TT genotype more frequently attained normal total homocysteine plasma levels than patients with the CC or CT genotype ( P = 0.025 ) . In response to 60 mg of folic acid per day , TT genotype patients had lower folate plasma levels compared to CC or CT genotype patients ( P = 0.016 ) . After completion of the 4-wk treatment period with 30 or 60 mg of folic acid per day , there was a marked rebound of total homocysteine plasma levels at the end of the follow-up in patients with the MTHFR 677TT genotype , which even exceeded baseline values in several patients ( P = 0.0001 ) . This study clearly demonstrates that doses of 30 or 60 mg of folic acid per day are not more effective than 15 mg/d in reducing hyperhomocysteinemia in regular hemodialysis patients . Patients with the MTHFR 677TT genotype are more likely to realize normal total homocysteine plasma levels . Folic acid at 30 or 60 mg/d but not 15 mg/d results in a rebound of total homocysteine plasma concentrations when treatment is stopped OBJECTIVES To study fasting and postmethionine-loading ( increment and decrement ) plasma homocysteine levels in end-stage renal disease ( ESRD ) patients in relation to B-vitamin status and after folic acid treatment without or with betaine . DESIGN Plasma total homocysteine ( tHcy ) and methionine levels were measured in chronic haemodialysis patients after an overnight fast , and 6 and 24 h after an oral methionine load ( 0.1 g kg-1 ) . The patients were subsequently r and omized to treatment with folic acid 5 mg daily with or without betaine 4 g daily , and the loading test was repeated after 12 weeks . The patients were then re-r and omized to treatment with 1 or 5 mg folic acid daily for 40 weeks , after which a third loading test was performed . SETTING Haemodialysis unit of university hospital and centre for haemodialysis . SUBJECTS Twenty-nine consecutive maintenance ( > 3 months ) haemodialysis patients , not on folic acid supplementation , 26 of whom completed the study . RESULTS At baseline , the mean fasting , the 6 h postload and the 6 h postload increment plasma tHcy levels were increased as compared with those in healthy controls ( 46.8 + /- 6.9 ( SEM ) , 92.8 + /- 9.1 and 46.0 + /- 4.2 mumol L-1 , respectively ) and correlated with serum folate ( r = -0.42 , P = 0.02 ; r = -0.61 , P = 0.001 and r = -0.54 , P = 0.003 , respectively ) , but not with vitamin B6 or vitamin B12 . At week 12 , these variables had all decreased significantly . Betaine did not have additional homocysteine-lowering effects . At week 52 , fasting and postload tHcy levels did not differ significantly between patients on 1 or 5 mg folic acid daily . Plasma tHcy half-life and plasma methionine levels after methionine loading were not altered by folic acid treatment . CONCLUSIONS In chronic haemodialysis patients , fasting as well as postmethionine-loading plasma tHcy levels depend on folate status and decrease after folic acid therapy . Increased postload homocysteine levels in these patients therefore do not necessarily indicate an impaired transsulphuration capacity only ; alternatively , folate may indirectly influence transsulphuration . The elucidation of the complex pathogenesis of hyperhomocysteinaemia in chronic renal failure requires further investigation INTRODUCTION . Hyperhomocysteinemia is common in patients with chronic kidney disease . There is a direct relationship between cardiovascular mortality and increase of blood homocysteine . Folic acid is used as common treatment in such patients . Folinic acid , a shortened form of folic acid , is not affected by inhibitors of dihydrofolate reductase enzyme such as methoterxate . This study was performed to evaluate the effect of oral folinic acid on the blood homocysteine level of hemodialysis patients , in comparison with folic acid . MATERIAL S AND METHODS . This clinical trial was performed on 60 hemodialysis patients . The participants were divided into 2 groups to receive either 15 mg of oral folic acid or 15 mg of oral folinic acid , daily . Blood homocysteine levels were measured before dialysis and after the study period . RESULTS . Folic acid and folinic acid decreased the blood homocysteine levels by 33.0 % and 28.7 % , respectively ( P < .001 ) . However , only 3 patients ( 6.5 % ) enjoyed a normalized homocysteine level . CONCLUSIONS . Our study showed that both folic and folinic acid decreased the blood homocysteine level and no meaningful difference was observed between them ; therefore , we suggest they can be used interchangeably BACKGROUND Hyperhomocysteinemia is a well-recognized risk factor for accelerated atherosclerosis in hemodialysis patients . OBJECTIVES To examine the effects of two doses of vitamins B6 and B12 and folic acid on homocysteine levels in hemodialysis patients and assess the functional impact of the methylenetetrahydrofolate reductase genotype on the response to treatment . METHODS In a r and omized prospect i ve study , we assessed the effects of folic acid and two doses of B-vitamins in 50 hemodialysis patients with hyperhomocysteinemia . Patients were divided into two groups : 26 patients ( group A ) who received 25 mg of vitamin B6 daily and one monthly injection of 200 microg vitamin B12 , and 24 patients ( group B ) who received 100 mg of vitamin B6 daily and one monthly injection of 1,000 microg vitamin B12 . In addition , both groups received 15 mg folic acid daily . Patients were evaluated for homocysteine levels as well as for coagulation and a thorough lipid profile . Baseline Hcy levels were determined after at least 4 weeks washout from all folic acid and B-vitamins that were given . MFTHR alleles were analyzed , as were activated protein C resistance , von Willebr and factor and lupus anticoagulant . RESULTS Basal plasma Hcy levels were significantly elevated in hemodialysis patients compared with normal subjects ( 33.8 + /- 4.3 vs. 4.5 to 14.0 micromol/L ) . Following treatment , Hcy levels were significantly reduced to 21.2 + /- 1.6 in group A and 18.6 + /- 1.4 micromol/L in group B ( P < 0.01 ) . There was no difference in Hcy reduction following the administration of either high or low dosage of vitamins B6 and B12 utilized in the present study . There was no correlation between Hcy levels or thrombophilia and high incidence of thrombotic episodes in hemodialysis patients . Genotypic evaluation of MTHFR revealed that the presence of homozygous thermolabile MTHFR ( n = 5 ) was associated with higher Hcy levels and better response to treatment ( Hcy levels decreased by 58 % , from 46.2 + /- 14.6 to 19.48 + 4.1 micromol/ L following treatment ) . In patients with heterozygous thermolabile MTHFR ( n = 25 ) , Hcy levels decreased by 34 % , from 31.2 + /- 3.7 to 18.1 + /- 1.1 micromol/L following treatment . The efficacy of high and low doses of B-vitamins on the reduction of homocysteine levels was comparable . CONCLUSIONS Treatment with B-vitamins in combination with folic acid significantly decreased homocysteine levels in hemodialysis patients , independently of the tested doses . In addition , mutations in MTHFR were associated with elevated plasma levels of Hcy . Neither vascular access nor the presence of diabetes was associated with higher pre- or post-treatment homocysteine level ♦ Background : Lipid abnormalities , particularly high serum concentration of lipoprotein(a ) [ Lp(a ) ] , are one of the major risk factors for cardiovascular disease ( CVD ) in peritoneal dialysis ( PD ) patients . The present study was design ed to investigate the effects of soy consumption on serum lipids and apoproteins , especially Lp(a ) , in PD patients . ♦ Methods : This study was a r and omized clinical trial in which 40 PD patients ( 20 males , 20 females ) were r and omly assigned to either the soy or the control group . Patients in the soy group received 28 g/day textured soy flour ( containing 14 g of soy protein ) for 8 weeks , whereas patients in the control group received their usual diet , without any soy . At baseline and the end of week 8 of the study , 5 mL of blood was collected from each patient after a 12- to 14-hour fast and serum triglyceride , total cholesterol , low density lipoprotein-cholesterol ( LDL-C ) , high density lipoprotein-cholesterol ( HDL-C ) , apoprotein B100 ( apo B100 ) , apoprotein AI ( apo AI ) , and Lp(a ) were measured . ♦ Results : In the present study , serum Lp(a ) concentrations were above the normal range in 86 % of the PD patients . Mean serum Lp(a ) concentration was reduced significantly , by 41 % , in the soy group at the end of week 8 compared to baseline ( p < 0.01 ) ; the reduction was also significant compared to the control group ( p < 0.05 ) . During the study , mean serum Lp(a ) concentration did not change significantly in the control group . There were no significant differences between the two groups in mean changes in serum triglyceride , total cholesterol , HDL-C , LDL-C , apo B100 , or apoAI . ♦ Conclusion : The results of our study indicate that soy consumption reduces serum Lp(a ) concentration , which is a risk factor for cardiovascular disease in peritoneal dialysis patients BACKGROUND Uncontrolled studies have found that high-flux haemodialysis favourably modifies homocysteine and lipid profiles . We sought to confirm these findings by carrying out a r and omized prospect i ve comparison of high-flux and low-flux polysulphone in chronic , stable dialysis patients . METHODS Forty-eight patients were r and omly assigned to either high or low-flux dialysis for 3 months . Serum levels of homocysteine , lipoprotein ( a ) , and lipids were compared between the treatment groups at monthly intervals . RESULTS All patient characteristics and laboratory variables were equally distributed between the groups at baseline . Over the study duration , we observed no differences between high- and low-flux treatment groups for the following outcomes : pre-dialysis homocysteine , lipoprotein ( a ) , total cholesterol , HDL cholesterol , LDL cholesterol , triglycerides ( all P>0.05 ) . Geometric mean ( interquartile range ) homocysteine at baseline was 20.0 ( 16.8 - 24.5 ) and 19.5 ( 15.3 - 22.0 ) micromol/l for the high- and low-flux groups respectively ( P=0.80 ) , and levels did not change significantly during the study . We did demonstrate a more pronounced intradialytic effect of high-flux dialysis on homocysteine levels , which fell during dialysis by 42 % , compared to 32 % with low-flux dialysis ( P<0 . 001 ) . CONCLUSIONS In this r and omized controlled trial , the effects of high-flux and low-flux haemodialysis on homocysteine and lipid profiles were comparable . The greater intradialytic effect of high-flux dialysis on homocysteine did not translate into a significant difference in pre-dialysis levels after 3 months of study INTRODUCTION We compared the effect of higher and lower doses of folic acid compared to our routine daily dose on plasma homocysteine levels , in our hemodialysis patients . MATERIAL S AND METHODS Eighty patients on hemodialysis receiving oral folic acid , 10 mg/d , were r and omized to receive folic acid at either doses of 5 mg/d ( group 1 ) or 15 mg/d ( group 2 ) for 2 months . Plasma levels of total homocysteine were measured before and after the study period . RESULTS Hyperhomocysteinemia was seen in 75 patients ( 93.8 % ) before , and in 37 patients of group 1 ( 92.5 % ) and 39 of group 2 ( 97.5 % ) after the study period . In group 1 , a nonsignificant decrease occurred in plasma homocysteine level ( 29.67 + /- 12.26 micromol/L to 27.78 + /- 9.94 micromol/L , P = .30 ) , while in group 2 , there was a significant decrease in homocysteine level ( 32.40 + /- 9.76 micromol/L to 29.58 + /- 9.62 micromol/L , P = .01 ) . Changes in homocysteine level correlated with its baseline level ( r = -0.42 , P < .001 ) . In both groups , significant reductions in homocysteine level were seen mostly in those patients with high baseline homocysteines . CONCLUSIONS Routine folic acid supplementation of 10 mg/d could not normalize plasma homocysteine levels in most of our patients . Increasing folic acid dose made a statistically significant but clinical ly trivial decrease in homocysteine levels , and could not normalize homocysteine level in most patients . Patients with a higher baseline homocysteine level achieved a greater reduction , which may be explained by primary noncompliance of some patient . Further investigation of folic acid dosage is suggested AIMS A greater decrease in total homocystein ( tHcy ) has been reported in patients on hemodialysis ( HD ) following the administration of reduced forms of folic acid ( FA ) , however , the effect of the administration of moderated doses of oral levofolinic acid has not been compared with that of FA . We decided to perform a study to evaluate the therapeutic effectiveness of oral levofolinic acid , the pharmacologically active form of folinic acid in our population of HD patients already on treatment with oral FA and vitamin B6 . MATERIAL AND METHODS We undertook a prospect i ve study in HD patients who had been receiving oral supplements of both FA 5 mg every 48 hours and vitamin B6 40 mg every 7 days during at least 6 months , with a 17 % initial decrease of tHcy levels . Patients matched for age , sex and time on HD were assigned to 1 of 2 groups : Those in group A continued to receive their previous supplements while in group B , FA was substituted by calcium levofolinate 5 mg given orally every 48 hours . The following parameters were measured at baseline and at month 6 : urea kinetic model and concentrations of plasma albumin , C-reactive protein , folate , vitamin B12 , pyridoxal phosphate and tHcy . RESULTS Group A : 30 patients aged 63.4 ( 57.9 , 68.9 ) years , with a time on HD of 23.4 ( 15.8 , 30.8 ) months , group B : 32 age-matched patients 66.2 ( 62.1 , 70.3 ) years old , with a time on HD of 23.8 ( 16.7 , 30.9 ) months . No differences were found either in folate levels ( 72.7 ( 47.9 , 97.5 ) vs. 71.9 ( 44.0 . 99.9 ) ng/ml ) , tHcy ( 23.5 ( 21.1 , 25.9 ) vs. 23.3 ( 20.8 , 25.8 ) micromol/l ) , or any other study variables . In the 2 groups a significant reduction in both residual renal function ( RRF ) and vitamin B12 levels was observed after supplementation , but no changes in tHcy values , folate levels or any of the other parameters were found . The prevalence of hyperhomocysteinemia in group A was 93.3 % at study start and 100 % at month 6 , in group B the corresponding values were 93.8 % and 96.9 % . After 6 months , multiple regression analysis showed that tHcy levels were not influenced by the type of treatment ( p = 0.543 ) . CONCLUSIONS After 6 months of calcium-levofolinate supplementation tHcy levels did not decrease and were similar to those in patients given the same dose of FA Objective We explored the efficacy of intravenous therapy with propionyl L-carnitine in patients with both peripheral arterial disease ( PAD ) and chronic renal insufficiency requiring haemodialysis . Methods The trial was a r and omised , double-blind , placebo-controlled trial . Sixty-four patients on haemodialysis ( 32 per treatment arm ) with chronic renal insufficiency and PAD were assigned to receive either intravenous propionyl L-carnitine 600 mg or placebo 3 times weekly for 12 months . The main outcome measures were the ankle/brachial index ( ABI ) , plasma malondialdehyde ( MDA ) and 4-hydroxynonenal ( 4-HNE ) concentrations , and the plasma nitrite/nitrate ratio ( NO2/NO3 ) ; these were measured at baseline and at 6 and 12 months . Results Significant increases in ABI were observed in the propionyl L-carnitine group , whereas in the placebo group the reverse trend was seen . In patients treated with propionyl L-carnitine , significant progressive decreases were seen in plasma MDA , 4-HNE and the NO2/NO3 ratio from baseline . In the placebo-treated group , only weakly significant or no differences were seen . Conclusion Intravenous administration of propionyl L-carnitine to haemodialysis patients with PAD improves both haemodynamic flow and the oxidative profile BACKGROUND Treatment with folic acid and vitamin B12 appears to be effective in lowering total plasma homocysteine ( tHcy ) concentrations , but whether vitamin B12 alone lowers tHcy in patients with normal vitamin B12 status is unknown . The aims of the present study were to explore the effect of individual supplementation with folic acid or vitamin B12 on tHcy concentrations in hemodialysis ( HD ) patients and to compare changes in tHcy concentrations with MTHFR genotype . METHODS We recruited 200 HD patients ( 119 men ) from the " Umberto I " Hospital ( Frosinone , Italy ) and the Dialysis Unit of University Hospital " Tor Vergata " . These patients were r and omized blindly into 2 groups of 100 each . Unfortunately , during the study , 36 patients in the first group and 16 in the second group died . The first group was treated initially with vitamin B12 for 2 months and with folic acid for a following 2 months . The second group was treated initially with folic acid and then with vitamin B12 . Sample s were drawn before administration of either , after the first and second periods , and again 2 months after treatment . RESULTS The concentrations of tHcy decreased in both groups after the consecutive vitamin therapies , and the decrease was genotype-dependent . The decrease was greater for the T/T genotype ( P < 0.05 ) and was more significant when the treatment was started with folic acid ( P < 0.01 ) . CONCLUSION The alternating vitamin treatment demonstrated for the first time the importance of folate therapy and the secondary contribution of vitamin B12 in lowering tHcy in HD patients BACKGROUND Although multiple risk factor intervention ( MRFI ) is recommended to reduce the increased morbidity and mortality of cardiovascular disease ( CVD ) in chronic kidney disease ( CKD ) , its efficacy is unknown . We studied the efficacy of a MRFI program in CKD . METHODS This r and omized controlled study of 200 patients with stage 4 or 5 CKD compared a physician-supervised , nurse-driven MRFI clinic ( focused on dyslipidemia , hyperhomocysteinemia , blood pressure [ BP ] , anemia , and hyperphosphatemia ) with conventional care in CKD . One hundred eleven subjects completed 2 years of follow-up ( median follow-up 674 days [ interquartile range { IQR } 348 - 719 days ] ) . Outcome measures were atheroma burden ( carotid intimamedia thickness [ IMT ] ) and endothelial function ( brachial artery reactivity [ BAR ] ) . RESULTS The MRFI group showed significant improvements , compared with usual care , in serum low-density lipoprotein cholesterol ( -30.9 mg/dL vs -12.7 mg/dL , P = .001 ) , homocysteine ( -6.95 vs -0.67 micromol/L , P < .001 ) , systolic BP ( -6.9 vs -0.2 mm Hg , P = .049 ) , and diastolic BP ( -4.8 vs -1.0 mm of Hg , P = .043 ) . No significant changes were seen in serum phosphate or hemoglobin level . Despite observed improvements in risk factors , no differences from baseline were demonstrated for IMT ( -0.00 vs -0.01 mm , P = .533 ) or BAR ( 0.09 % vs 0.22 % , P = .834 ) . Forty-two patients reached a composite end point of CVD death , acute coronary syndrome , revascularization , nonfatal stroke , and amputation and this was similar between groups ( 23 vs 19 events , P = .475 ) . CONCLUSIONS A MRFI program was not associated with improvement in vascular structure or function in stage 4 or 5 patients with CKD Hyperhomocysteinemia has been shown to constitute an independent risk factor for premature occlusive arterial disease ( N Engl J Med 324:1149 ) , a frequent complication in chronic uremic patients in whom homocysteine ( Hcy ) accumulation has been reported to occur . We prospect ively determined fasting plasma level of total , protein-bound Hcy in 118 adult chronic uremic patients , either dialyzed or not . In 79 non-dialyzed patients ( 47 male ) with various degrees of chronic renal failure ( RF ) assessed by creatinine clearance ( CCr ) , none receiving folate , B6 or B12 vitamin supplementation , mean ( + /- 1 SD ) plasma Hcy level was 16.2 + /- 8.1 mumol/liter in 28 patients with mild RF ( CCr 30 to 75 ml/min ) , 23.3 + /- 14.7 in 29 patients with moderate RF ( CCr 10 to 29.9 ) , and 29.5 + /- 14.4 in 22 patients with advanced RF ( CCr < 10 ) , a significant difference ( P < 0.01 for all groups ) compared to 45 healthy controls ( 8.2 + /- 2.2 mumol/liter ) . Linear regression analysis showed a significant correlation between plasma creatinine and Hcy concentrations ( r = 0.49 , P < 0.0001 ) . Hcy was significantly higher in 20 patients ( 16 males ) who had past histories of occlusive arterial disease than in the 59 ( 31 males ) who did not ( 30.9 + /- 19.1 vs. 19.6 + /- 9.7 mumol/liter , P < 0.001 ) and all of the former had Hcy level > 14.1 mumol/liter ( the upper limit in healthy controls ) versus 35 of 59 in the latter . ( ABSTRACT TRUNCATED AT 250 WORDS Background : There are no data available on the effects of intravenous ( i.v . ) methylcobalamin ( Me-Cbl ) , the coenzymatically active form of vitamin B12 that acts as a cofactor for methionine synthase in the conversion of total homocysteine ( tHcy ) to methionine , with or without oral folic acid ( FA ) supplementation , on fasting tHcy levels in hemodialysis ( HD ) patients . Methods : We performed a prospect i ve r and omized trial in which 62 chronic HD patients without previous vitamin supplementation were divided into four groups . Group A received Me-Cbl 500 µg twice/week plus FA 10 mg/day ; group B received FA 10 mg/day alone ; group C received no vitamin supplementation , and group D was on Me-Cbl 500 µg twice/week alone . Fasting tHcy , vitamin B12 , serum ( s ) FA and erythrocytic ( e ) FA were measured predialysis before and after 4 months of therapy . Results : Final tHcy levels were significantly lower in group A ( 10.2 ± 3.1 µmol/l ) compared to groups C ( 27.3 ± 9.7 µmol/l , p < 0.001 ) and group D ( 24.3 ± 11.8 µmol/l , p < 0.001 ) and similar to group B ( 11.2 ± 1.9 µmol/l , p = n.s . ) . Mean tHcy levels showed a significant decrease in group A from 22.5 ± 15.6 to 10.2 ± 3.1 µmol/l ( p = 0.003 ) and in group B from 19.9 ± 4.0 to 11.2 ± 1.9 µmol/l ( p = 0.012 ) , while no significant changes were observed in groups C ( 25.9 ± 9.3 vs. 27.3 ± 9.7 µmol/l , p = n.s . ) and D ( 26.6 ± 14.3 vs. 24.3 ± 11.8 µmol/l , p = n.s . ) . Conclusion : Oral FA ( 10 mg/day ) supplementation appears to be an effective approach to normalize plasma tHcy in chronic HD patients ; the addition of i.v . Me-Cbl ( 500 µg twice/week ) to this regimen showed no benefit . Separately , FA corrected hyperhomocysteinemia ( HtHcy ) , while Me-Cbl showed no change BACKGROUND Indices of arterial structure and stiffness are proposed as surrogate markers of cardiovascular disease in patients with chronic kidney disease ( CKD ) , but no study examined multiple markers in the same population . STUDY DESIGN Prospect i ve observational study . SETTING & PARTICIPANTS 315 subjects with stages 4 to 5 CKD , aged 24 to 79 years ( mean age , 56.6 + /- 13.6 [ SD ] years ) , enrolled in the Atherosclerosis and Folic Acid Supplementation Trial . PREDICTORS Carotid arterial intima-medial thickness ( IMT ; n = 315 ) and indices of arterial stiffness ( n = 207 ) , including aortofemoral pulse wave velocity ( PWV[a-f ] ) , systemic arterial compliance ( SAC ) , and carotid-derived augmentation index . OUTCOMES The primary outcome was a composite of all fatal and nonfatal cardiovascular events . RESULTS During follow-up ( median , 3.6 years ) , 95 cardiovascular events occurred . On Cox proportional-hazard modeling , mean maximum IMT , PWV(a-f ) , and SAC were predictive of the composite clinical end point of all cardiovascular events , but carotid-derived augmentation index was not ( hazard ratio [ HR ] for every 0.01-mm increase in IMT , 1.09 ; P = 0.001 ; 95 % confidence interval [ CI ] , 1.03 to 1.14 ; HR for every 1-m/s increase in PWV(a-f ) , 1.18 ; P < 0.001 ; 95 % CI , 1.12 to 1.25 ; HR for every 0.01-U/mm Hg decrease in SAC , 0.98 ; P = 0.01 ; 95 % CI , 0.97 to 0.99 ) . After adjustment for age , sex , blood pressure , diabetes , past cardiovascular disease , cholesterol level , and smoking , PWV(a-f ) remained a significant independent predictor of cardiovascular events ( adjusted HR , 1.12 ; P = 0.001 ; 95 % CI , 1.05 to 1.20 ) , but IMT and SAC did not . LIMITATIONS Study power to analyze differences between predialysis and dialysis stages of CKD . CONCLUSIONS PWV(a-f ) is the only arterial index independently associated with cardiovascular outcome in patients with CKD BACKGROUND Low vitamin D concentrations are prevalent in patients with chronic kidney disease ( CKD ) . We investigated the relationship between plasma 25-hydroxyvitamin D ( 25[OH]D ) or 1,25-dihydroxyvitamin D ( 1,25[OH](2)D ) concentrations with death , cardiovascular events , and dialysis therapy initiation in patients with advanced CKD . STUDY DESIGN The HOST ( Homocysteinemia in Kidney and End Stage Renal Disease ) Study was a r and omized double-blind trial evaluating the effects of high doses of folic acid on death and long-term dialysis therapy initiation in patients with advanced CKD ( stages 4 and 5 not yet on dialysis therapy ) . 25(OH)D and 1,25(OH)(2)D were measured in stored plasma sample s obtained 3 months after trial initiation and evaluated at clinical ly defined cutoffs ( < 10 , 10 - 30 , and > 30 ng/mL ) and tertiles ( < 15 , 15 - 22 , and > 22 pg/mL ) , respectively . Cox proportional hazard models were used to examine the association between vitamin D concentrations and clinical outcomes . SETTING & PARTICIPANTS 1,099 patients with advanced CKD from 36 Veteran Affairs Medical Centers . PREDICTORS 25(OH)D and 1,25(OH)(2)D concentrations . OUTCOMES Death , cardiovascular events , and time to initiation of long-term dialysis therapy . RESULTS After a median follow-up of 2.9 years , 41 % ( n = 453 ) died , whereas 56 % ( n = 615 ) initiated dialysis therapy . Mean 25(OH)D and 1,25(OH)(2)D concentrations were 21 ± 10 ng/mL and 20 ± 11 pg/mL , respectively . After adjustment for potential confounders , the lowest tertile of 1,25(OH)(2)D was associated with death ( HR , 1.33 ; 95 % CI , 1.01 - 1.74 ) and initiation of long-term dialysis therapy ( HR , 1.78 ; 95 % CI , 1.40 - 2.26 ) compared with the highest tertile . The association with death and initiation of dialysis therapy was moderately attenuated after adjustment for plasma fibroblast growth factor 23 ( FGF-23 ) concentrations ( HRs of lower tertiles of 1.20 [ 95 % CI , 0.91 - 1.58 ] and 1.56 [ 95 % CI , 1.23 - 1.99 ] , respectively , compared with highest tertile ) . There was no association between 25(OH)D concentrations and outcomes . LIMITATIONS Participants were mostly men . CONCLUSIONS Low plasma 1,25(OH)(2)D concentrations are associated with death and initiation of long-term dialysis therapy in patients with advanced CKD . FGF-23 level may attentuate this relationship BACKGROUND It is unclear whether total serum homocysteine ( tHcy ) and the C677 T mutation of methylenetetrahydrofolate reductase ( MTHFR ) are associated with cardiovascular disease ( CVD ) in patients with end-stage renal disease ( ESRD ) . METHODS A cross-sectional sample of 459 patients with ESRD on chronic dialysis was assessed to determine whether tHcy and the C677 T mutation are associated with CVD prevalence in multiple logistic regression . As CVD mortality is high , we examined the relationship between homozygosity and duration of dialysis . RESULTS Mean tHcy was higher in patients without a history of CVD ( 35.2 micromol/L vs. 30.4 micromol/L , P = 0.02 ) . In multivariate models , CVD was negatively associated with tHcy and positively associated with TT genotype , male gender , and body mass index . Mean tHcy levels were higher among those with the TT genotype compared with those with the CC genotype when adjusted for age , folate , creatinine , and albumin ( 37.9 micromol/L vs. 31.9 micromol/L , P = 0.005 ) . Among whites , the prevalence of the TT genotype was higher in those having undergone less than one year of dialysis ( P = 0.002 ) . CONCLUSIONS The C677 T genotype of MTHFR is associated with CVD in ESRD and may be a more meaningful marker than tHcy for abnormal homocysteine metabolism in ESRD . Prospect i ve data from ongoing clinical trials are needed to improve our underst and ing of these findings . Screening for this polymorphism may help guide prevention measures Homocysteine is a risk factor for atherosclerosis in the general population , and serum homocysteine levels are almost universally elevated in chronic renal failure patients . When such patients are treated with dialysis , cardiovascular disease accounts for more than 50 % of their mortality , which , in some proportion , may be pathophysiologically related to the elevated serum homocysteine levels . From April 2003 to March 2005 , we conducted a 2-year , double-blind , r and omized , placebo-controlled trial of 186 patients with end-stage kidney disease due to any cause , who were older than 18 years and stable on hemodialysis . Patients were assigned to receive either oral folic acid 10 mg 3 times a week immediately after every dialysis session under nurse supervision or an identical-appearing placebo for the entire study . On admission , plasma total homocysteine ( tHcy ) levels were above 13.9 micromol/L in 96.7 % of patients ( median 25.0 micromol/L , range 9.3 - 104.0 micromol/L ) . In the placebo group , tHcy levels remained elevated at 6 , 12 , and 24 months , while oral folate significantly decreased tHcy to a median value of 10.5 ( 2.8 - 20.3 ) micromol/L , ( p<0.01 ) . During the study , 38 patients ( folic acid group 17 vs. placebo group 21 ; p=0.47 ) died from cardiovascular disease . Kaplan-Meier life table analysis dealing with the incidence of cardiovascular events , both fatal and nonfatal ( myocardial infa rct ion , arrhythmias , angina , heart failure , cerebrovascular accident ) , showed that 2 years of folic acid treatment and the lowering of the homocysteine blood levels had no effect on cardiovascular events ( p=0.41 ; hazard ratio 1.24 , 95 % CI 0.74 - 2.10 ) . However , the carotid artery intima-media wall thickness measured in a blinded fashion decreased from 1.94 + /- 0.59 mm to 1.67 + /- 0.38 mm ( p<0.01 ) after 2 years of folate therapy . In this short-term study of uremic patients , 2 years of folic acid supplementation normalized the tHcy blood levels in 92.3 % of patients but did not change the incidence of cardiovascular events compared with the control group . However , ultrasonography of the common carotid arteries performed at entry and 24 months later showed a significant decrease in intima-media thickness with folate supplementation . This suggests that early folate supplementation may benefit patients with chronic renal failure by preventing cardiovascular deterioration The possible role of folate supplementation in reducing hyperhomocysteinemia in dialysis patients has been reported in several recent papers . However , scant data are available for peritoneal dialysis patients ; besides , none of these studies investigated either the role of intraerythrocyte folate concentration or the presence of side effects caused by folate administration . Sixty-six peritoneal dialysis patients with hyperhomocysteinemia ( > 15 µmol/l ) and normal folate status ( as assessed by erythrocyte folate level > 600 nmol/l ) were r and omly allocated to receive either oral folate ( 5 mg/day ) or no vitamin supplementation . After 2 months of therapy , patients were requested to answer a question naire investigating the occurrence of symptoms possibly related to folate supplementation . Twenty-nine treated patients and 30 untreated controls completed the study . In the treated patients , serum and erythrocyte folate increased significantly ( p < 0.0001 ) ( respectively from 10.6 ± 4.9 to 237 ± 231 nmol/l and from 1,201 ± 297 to 2,881 ± 294 nmol/l ) to levels at the uppermost limit of detection by laboratory methods . Serum vitamin B12 levels did not change . Plasma homocysteine levels decreased from 54 ± 32 to 23 ± 14 µmol/l after folate supplementation and remained unchanged in the control group . After 4 months of folate therapy , homocysteine concentration was within the normal range in 5 patients ( 17 % ) and below 30 µmol/l in the other 21 ( 72 % ) . Folate therapy result ed in a decrease in homocysteine of more than 50 % in 45 % of the patients and decrease of more than 20 % in a further 38 % . No significant symptoms were reported . Thus , serum and erythrocyte folate increase confirms that normal folate levels are inadequate in dialysis patients , even if serum and erythrocyte levels before folate supplementation can not predict the effect on homocysteine plasma levels BACKGROUND Elevated plasma homocysteine levels are reported to be associated with higher rates of vascular diseases . Plasma homocysteine increases in chronic kidney disease ( CKD ) and could contribute to the increased cardiovascular risk in CKD . METHODS Participants aged 55 years or older with CKD , defined as estimated GFR<60 ml/min and at high cardiovascular risk , were r and omly assigned to the combination of folic acid , 2.5 mg , vitamin B6 , 50 mg and vitamin B12 , 1 mg ( n = 307 ) or placebo ( n = 312 ) daily for 5 years . The primary outcome was a composite of death from cardiovascular causes , myocardial infa rct ion and stroke . RESULTS Mean baseline plasma homocysteine was 15.9 + /- 7.3 micromol/l in the active treatment group and 15.7 + /- 5.7 micromol/l in placebo group and decreased to 11.9 + /- 3.3 micromol/l ( P < 0.001 ) on active treatment ( 15.5 + /- 4.5 on placebo ) . Primary outcome events occurred in 90 participants ( 29.3 % ) on active therapy and in 80 ( 25.6 % ) on placebo ( relative risk , 1.19 ; 95 % confidence interval , 0.88 - 1.61 ; P = 0.25 ) . There were no significant treatment benefits on death from cardiovascular causes ( 1.24 ; 0.84 - 1.83 ) , myocardial infa rct ion ( 1.10 ; 0.76 - 1.61 ) and stroke ( 1.00 ; 0.54 - 1.85 ) . More participants in the active treatment group were hospitalized for heart failure ( 1.98 ; 1.21 - 3.26 ; P = 0.007 ) and for unstable angina ( 1.70 ; 1.02 - 2.83 ; P = 0.04 ) . Incidence of primary outcome increased with decreasing GFR . CONCLUSIONS Active treatment with B vitamins lowered homocysteine levels in participants with CKD but did not reduce cardiovascular risk BACKGROUND Epidemiological studies suggest that mild to moderate elevation in plasma homocysteine concentration is associated with increased risk of atherothrombotic cardiovascular ( CV ) disease . Simple , inexpensive and nontoxic therapy with folic acid and vitamins B6 and B12 reduces plasma homocysteine levels by approximately 25 % to 30 % and may reduce CV events . Therefore , a large , r and omized clinical trial -- the Heart Outcomes Prevention Evaluation (HOPE)-2 study --is being conducted to evaluate this therapy in patients at high risk for CV events . OBJECTIVES To evaluate whether long-term therapy with folic acid and vitamins B6 and B12 reduces the risk of major CV events in a high-risk population . The primary study outcome is the composite of death from CV causes , myocardial infa rct ion and stroke . METHODS A total of 5522 patients aged 55 years or older with pre-existing CV disease or with diabetes and additional risk factor(s ) at 145 centres in 13 countries were r and omly assigned to daily therapy with combined folic acid 2.5 mg , vitamin B6 50 mg and vitamin B12 1 mg , or to placebo . Follow-up will average five years , to be completed by the end of 2005 . RESULTS The patients ' baseline characteristics confirmed their high-risk status . Baseline homocysteine levels varied between countries and regions . HOPE-2 is one of the largest trials of folate and vitamins B6 and B12 and is expected to significantly contribute to the evaluation of the role of homocysteine lowering in CV prevention BACKGROUND Atherosclerosis and Folic Acid Supplementation Trial ( ASFAST ) is a r and omized placebo controlled trial assessing whether high-dose folic acid can reduce cardiovascular events and atherosclerosis progression in patients with chronic renal failure ( CRF ) . Here we report the baseline results and compare indices of arterial structure ( carotid intima-medial thickness ( IMT ) ) and function ( systemic arterial compliance ( SAC ) ) , pressure augmentation index ( AI(x ) ) and pulse wave velocity ( PWV a-f and PWV f-d ) ) to age- and sex-matched controls . METHODS Three hundred and fifteen subjects with CRF ( serum creatinine > or = 0.40 mmol/L ) aged 24 - 79 years ( mean + /- SD : 56.6 + /- 13.6 years ) and 213 healthy controls ( 58.2 + /- 10.2 years ) were studied . Fasting blood sample s were assayed for lipids ( both groups ) , total homocysteine ( tHcy ) , red cell folate , cobalamin and fibrinogen ( CRF group ) . Ultrasound B mode measurements were used to determine mean carotid IMT and applanation tonometry techniques to determine SAC , AI(x ) , PWV ( a-f ) , PWV ( f-d ) and central pressures . RESULTS Ninety-six per cent of the CRF group had at least one of : hypertension , hypercholesterolaemia , diabetes or smoking ; 35 % had established cardiovascular disease . The mean IMT was greater in CRF patients than in controls ( 0.86 + /- 0.19 vs 0.68 + /- 0.11 mm , P < 0.001 ) . The SAC was significantly lower , and PWV ( a-f ) and AI(x ) significantly higher . The tHcy was increased in 97 % of the CRF group ( 27.3 + /- 2.9 micromol/L ( normal < 13 ) ) . Total homocysteine did not correlate with IMT or any other measure of arterial function . However , those in the upper quantile of tHcy ( > or = 25 micromol/L ) did have higher PWV ( a-f ) and lower SAC than those in the lower quantile . CONCLUSIONS Compared to normals , patients with CRF exhibited a 10 - 15-year shift to the right in age-related increases in carotid IMT and PWV ( a-f ) , and significantly increased central pressure augmentation . This 5-year study is examining the impact of high-dose folic acid therapy on cardiovascular end-points , IMT progression and arterial function in CRF AIM Elevated total homocysteine ( tHcy ) levels are commonplace among end-stage renal disease ( ESRD ) patients increasing risk for poor cardiovascular outcomes . Specifically , when plasma levels become significantly elevated , tHcy levels appear to contribute to vascular damage and premature atherosclerosis . The purpose of this study was to examine the effect of an over-the-counter omega-3 ( n-3 ) fatty acid supplementation on tHcy levels in ESRD patients undergoing chronic haemodialysis . METHODS The present study was conducted using a double-blind , permuted-r and omized and placebo-controlled experimental protocol . ESRD patients were followed prospect ively while supplementing n-3 or corn oil ( n-6 ) prospect ively for 6 months . PATIENTS Sixty-nine patients were recruited that had previously demonstrated compliance with dialysis and medication . Following a 12 h fast , participants donated 12 mL of blood for analysis of tHcy at baseline and at 6 months . RESULTS The results of this study using regression models revealed no differences in age and gender regarding homocysteine levels at the post-test with P-values of 0.6818 , 0.6709 and 0.3331 for each regression model . The study findings also revealed that daily administration of 6 g of n-3 fatty acids containing 160 mg of eicosapentaenic acid ( 0.96 g/day ) and 100 mg of docosahexaenoic acid ( 0.6 g/day ) had no effect on tHcy levels when compared with control . CONCLUSION Potential reasons for this non-significant result may be found in a dose-response relationship , advancement of disease progression in our sample population , or potentially the lack of a significant relationship between fish oil and tHcy . Future studies should address whether a dose-response relationship between n-3 fatty acid supplementation and tHcy levels exists , and how stage of disease progression affects intervention success or failure High serum total homocysteine ( tHcy ) is gaining scrutiny as a risk factor for cardiovascular disease in the general population . The relationship between tHcy and mortality and cardiovascular events in patients with end-stage renal disease ( ESRD ) is unsettled . This r and omized trial evaluates the efficacy of high-dose folic acid in preventing events in ESRD . A total of 510 patients on chronic dialysis were r and omized to 1 , 5 , or 15 mg of folic acid contained in a renal multivitamin with a median follow-up of 24 mo . Mortality , cardiovascular events , and homocysteine levels were assessed . There were 189 deaths , and 121 patients experienced at least one cardiovascular event . Composite rates of mortality and cardiovascular events among the folic acid groups did not differ ( at 24 mo : 43.7 % in 1 mg group , 38.6 % in 5 mg group , 47.1 % in 15 mg group ; log-rank P = 0.47 ) . Unexpectedly , high baseline tHcy was associated with lower event rates . From lowest to highest quartile , event rates at 24 mo were 54.5 % for Q1 , 41.8 % for Q2 , 41.2 % for Q3 , and 34.7 % for Q4 ( log-rank P = 0.033 ) . In contrast to some studies describing tHcy as a risk factor for mortality and cardiovascular events , this study found a reverse relationship between tHcy and events in ESRD patients . Administration of high-dose folic acid did not affect event rates BACKGROUND High-efficiency hemodialysis may induce a deficiency in hydrosoluble vitamins . Supplementation with B-complex vitamins has been shown to lower serum homocysteine concentrations in several groups , but relatively few studies have concerned hemodialysis patients . Our objectives were to determine the status in B-complex vitamins in a large cohort of unsupplemented hemodialysis patients and to assess the effects of supplementation with hydrosoluble vitamins on serum homocysteine over one year . METHODS Serum total homocysteine ( tHcy ) , vitamin B12 , folate , pyridoxal-5'-phosphate ( P-5'-P ; the active moiety of vitamin B6 ) , as well as red blood cell folate concentrations , were measured in 168 chronic dialysis patients on three times weekly high-efficiency hemodialysis and not supplemented with hydrosoluble vitamins . Their methylenetetrahydrofolate reductase C677 T ( MTHFR ) genotypes were also determined ( homozygotes TT , heterozygotes CT , without mutation CC ) . All involved patients were then supplemented with hydrosoluble vitamins ( once daily by mouth , DiaVite ; R&D Laboratories , Minneapolis , MN , USA ) , and half of them were r and omized to receive in addition 10 mg intravenously of folic acid posthemodialysis ( 30 mg intravenously per week ) . Serum tHcy was monitored after 6 and 12 months of supplementation in the 140 and 128 patients available for follow-up . RESULTS At baseline , serum and red blood cell folate concentrations were within normal limits in all patients except for two with borderline serum folate ( mean values of 21 + /- 8 and 1195 + /- 454 nmol/L ) , whereas serum vitamin B12 and P-5'-P were below normal in 11 and 65 patients , respectively ( mean values of 327 + /- 215 pmol/L and 19 + /- 16 nmol/L for the 168 patients ) . Initial tHcy levels were increased in all patients ( mean 33.3 + /- 16.6 for a normal below 11.8 + /- 1.5 micromol/L ) ; tHcy significantly decreased to 23.5 + /- 7.6 micromol/L after six months ( P < 0.0001 vs. baseline ) and to 21.7 + /- 6.1 micromol/L after 12 months ( P < 0.0001 vs. baseline ) for the entire group , but was normalized in only four patients at 12 months . After six months , the mean reduction in tHcy was slightly but significantly greater for patients receiving intravenous folic acid ( 12.2 + /- 18.5 micromol/L ) compared with patients not receiving it ( 8.3 + /- 9.8 micromol/L , P < 0.05 ) . However , at 12 months , no difference between both subgroups persisted . When considering the different genotypes , tHcy at baseline tended to be higher for TT than CT and CC ( 39.8 + /- 30.9 vs. 31.4 + /- 10.5 vs. 31.6 + /- 11.8 micromol/L ) and decreased to respective values of 21.1 + /- 6.9 versus 21.4 + /- 6.1 versus 22.2 + /- 5.9 micromol/L at 12 months . The impact of the addition of folic acid to DiaVite appeared particularly significant in TT patients at six months . CONCLUSIONS ( 1 ) Hyperhomocysteinemia was present in 100 % of our hemodialysis patients . ( 2 ) Nearly 40 % of our unsupplemented hemodialysis patients were deficient in vitamin B6 . ( 3 ) Supplementation with DiaVite(R ) has result ed in significant tHcy reductions for all three genotypes . ( 4 ) The impact of the proposed supplementation protocol was found after six months and was maintained , but did not increase further after 12 months of the same regimen . ( 5 ) The addition of intravenous folic acid has been associated with a more pronounced decrease in tHcy in TT patients BACKGROUND Hyperhomocysteinaemia , which is considered to be induced by impairment of the remethylation pathway in patients with chronic renal failure ( CRF ) , can not be cured solely by folic acid therapy . In the present study , we investigated the additional benefit of administration of methylcobalamin , which is a co-enzyme in the remethylation pathway , on lowering total homocysteine ( tHcy ) plasma concentrations in haemodialysis ( HD ) patients receiving high-dose folic acid supplementation . METHODS In order to assess the efficacy on lowering plasma tHcy levels ( fasting concentration ) , 21 HD patients , were r and omly assigned and provided folic acid supplementation : 15 mg/day orally ( group I , n=7 ) ; methylcobalamin 500 mg intravenously after each HD , in addition to folic acid ( group II , n=7 ) ; or vitamin B(6 ) ( B(6 ) ) , 60 mg/day orally , in addition to folic acid and methylcobalamin ( group III , n=7 ) . All patients were treated for 3 weeks . A methionine-loading test was conducted before and after supplementation . The following measurements were also made before and after supplementation for each group : serum folic acid , B(6 ) , and vitamin B(12 ) ( B(12 ) ) concentrations ( including measurement of proportion of methylcobalamin fraction ) . Twelve HD patients receiving methylcobalamin alone served as the HD control group and seven healthy volunteers served as the normal control group for this study . RESULTS In our r and omized HD patients the proportions of methylcobalamin fraction ( 48.3+/-7.5 % ) and plasma vitamin B(6 ) concentration ( 2.9+/-1.1 ng/ml ) were significantly lower than in the normal controls ( methylcobalamin 58.7+/-2.2 % , P<0.01 ; B(6 ) 20.1+/-10.8 ng/ml , P<0.01 ) , while folic acid and vitamin B(12 ) were not significantly different from the normal controls . Mean percentage reduction in fasting tHcy was 17.3+/-8.4 % in group I , 57.4+/-13.3 % in group II , 59.9+/-5.6 % in group III , and 18.7+/-7.5 % in HD controls . The power of the test to detect a reduction of tHcy level was 99.6 % in group II and 99.9 % in group III when type I error level was set at 0.05 . Groups II and III had normal results for the methionine-loading test after treatment . Treatment result ed in normalization of fasting tHcy levels ( < 12 ng/ml ) in all 14 patients treated by the combined administration of methylcobalamin and supplementation of folic acid regardless of whether there was supplementation of vitamin B(6 ) . CONCLUSION The benefit of methylcobalamin administration on lowering plasma tHcy levels in HD patients was remarkable . Our study suggested that both supplementations of high-dose folic acid and methylcobalamin are required for the remethylation pathway to regain its normal activity . This method could be a therapeutic strategy to combat the risk associated with atherosclerosis and cardiovascular disease in patients with chronic renal failure The aim of this study was to study the effect of adding polyunsaturated fatty acid ( PUFA ) n-3 or placebo ( containing oleic acid ) to a combined statin-fibrate treatment on plasma lipoproteins , lipoperoxidation , glucose homeostasis , total homocysteine ( tHcy ) and microalbuminuria ( MA ) in patients with diabetic dyslipidemia ( DDL ) . Twenty-four patients , who did not fulfill the recommended target lipid values with combined hypolipidemic therapy ( pravastatin 20 mg+micronized fenofibrate 200 mg daily ) , were supplemented with 3.6 g PUFA n-3 daily for 3 months or placebo ( olive oil ) for the next 3 months . The concentrations of plasma lipids , fatty acid ( FA ) profiles of phosphatidylcholine ( PC ) , cholesteryl esters ( CE ) and triglycerides ( TG ) , tHcy levels , concentrations of conjugated dienes ( CD ) in low-density lipoprotein ( LDL ) , and MA were determined in baseline state , after the PUFA n-3 and placebo treatment period . Supplementation with PUFA n-3 led to a significant decrease in plasma tHcy ( -29 % , P < .01 ) and TG ( -28 % , P < .05 ) levels , as well as to a significant decrease in MA ( -24 % , P < .05 ) . The decrease in MA correlated significantly with the increase in total PUFA n-3 ( r = -.509 , P < or = .05 ) and docosahexaenoic acid ( r = -.52 , P < .01 ) in TG . The concentrations of CD in LDL increased significantly ( + 15 % , P < .05 ) . The supplementation with PUFA n-3 to the combined statin-fibrate treatment in patients with DDL decreased the TG and tHcy levels as well as MA . It could lead to decreased risk of atherothrombosis and delay of diabetic nephropathy onset and progression OBJECTIVE We evaluated the effects of folic acid on homocysteine levels and oxidative stress in 46 stable patients on hemodialysis . METHODS This double-blind , placebo-controlled , r and omized trial assessed the effects of 6 mo of 10 mg of folic acid ( 26 patients ) or placebo ( 20 patients ) given three times weekly after each dialysis under nurse supervision on homocysteine levels , total plasma antioxidant capacity , and hydroperoxide plasma levels . RESULTS Folic acid treatment normalized plasma homocysteine levels in most patients , significantly increased total plasma antioxidant capacity levels , but had no significant effect on hydroperoxide levels . Placebo treatment had no statistically significant effect on the three parameters . CONCLUSION The folic acid therapy protocol effectively lowered plasma homocysteine levels and improved the total plasma antioxidant capacity in hemodialysis patients . Further studies are required to assess the usefulness of folic acid for decreasing cardiovascular mortality in patients with chronic kidney disease OBJECTIVE We studied the effects of soy consumption on oxidative stress , blood homocysteine , coagulation factors , and phosphorus in peritoneal dialysis patients . DESIGN This was an unblinded , r and omized clinical trial . SETTING This study involved peritoneal dialysis centers in Tehran , Iran . PATIENTS We included 40 peritoneal dialysis patients ( 20 males and 20 females ) . INTERVENTION Peritoneal dialysis patients were r and omly assigned to either a soy or control group . Patients in the soy group received 28 g/day textured soy flour ( containing 14 g of soy protein ) for 8 weeks , whereas patients in the control group received their usual diet , without any soy . MAIN OUTCOME MEASURES Blood oxidized low-density lipoprotein ( ox-LDL ) , homocysteine , phosphorus , fibrinogen concentrations , and the activities of coagulation factors VII , IX , and X were measured at baseline and at the end of week 8 of the study . RESULTS The percentage of plasma coagulation factor IX activity decreased significantly by 17 % in the soy group at the end of week 8 compared with baseline ( P < .01 ) , and the reduction was significant compared with the control group ( P < .05 ) . There were no significant differences between the two groups in mean changes of blood ox-LDL , homocysteine , phosphorus , fibrinogen concentrations , and the activities of coagulation factors VII and X. CONCLUSION Soy consumption reduces plasma coagulation factor IX activity , which is a risk factor for thrombosis in peritoneal dialysis patients BACKGROUND AND AIM In subjects without kidney disease , adiponectin appears to have anti-inflammatory , anti-diabetic , and anti-atherogenic effects . n-3 polyunsaturated fatty acids ( PUFA ) from seafood have several beneficial effects in patients with endstage renal disease ( ESRD ) and the aim of the present study was to assess the effect of n-3 PUFA supplementation on plasma adiponectin levels in ESRD patients . METHODS In a double blinded intervention trial , 162 ESRD patients ( mean age 67 years  ± 13 , 56 women and 106 men ) undergoing chronic hemodialysis were r and omized to 1.7 g n-3 PUFA daily or placebo for 3 months . Adiponectin , plasma lipids and lipoproteins were measured at baseline and after the intervention period . RESULTS At baseline , adiponectin was positively correlated to HDL-cholesterol ( r = 0.55 , p < 0.001 ) and inversely correlated to plasma triglycerides , body mass index ( BMI ) and high sensitive C-reactive protein ( Hs-CRP ) ( r = -0.32 , p < 0.01 , r = -0.43 , p < 0.01 , and r = -0.21 , p < 0.01 , respectively ) . Furthermore , adiponectin was inversely correlated to the plasma levels of the two major n-3 PUFA docosahexaenoic acid ( DHA ) and eicosapentaenoic acid ( EPA ) ( r = -0.19 , p < 0.001 , and r = -0.30 , p < 0.001 , respectively ) . Baseline plasma adiponectin levels were high in both groups but after 3 months of supplementation no significant change was observed in the groups . Thus , n-3 PUFA supplementation did not change adiponectin levels . CONCLUSION We found an elevated plasma adiponectin level , which was inversely associated with plasma levels of DHA and EPA at baseline . Supplementation with n-3 PUFAs for 3 months did not change adiponectin levels . The negative result in this study may be related to a relatively low dose and future studies with higher dose and longer duration are needed to explore this mechanism BACKGROUND Cardiovascular disease is the major cause of death in the end-stage renal disease population . Novel risk factors such as homocysteine ( Hcy ) are of considerable interest in this group as hyperhomocysteinaemia is highly prevalent in the setting of renal impairment . Folic acid-vitamin B group therapies are only partially effective treatments . Hcy is highly protein-bound and thus poorly dialysed . Dialyzers with albumin-leaking properties have been shown to result in lowering of plasma Hcy . As the FX-class ( Advanced Fresenius Polysulfone dialyzer ) has greater clearance of larger molecular weight substances but is non-albumin-leaking , we explored the capacity of this new technology membrane to reduce plasma Hcy levels . METHODS A prospect i ve r and omized cross-over trial in 35 prevalent haemodialysis patients , one group receiving 12 weeks dialysis using FX dialyzer then 12 weeks with st and ard high flux dialysis ( SHF ) and the other group SHF followed by FX dialyzer . All patients received vitamin B(6 ) 25 mg and folic acid 5 mg daily throughout the study . RESULTS The primary outcome was plasma Hcy pre-dialysis at week 12 . FX vs SHF showed no significant difference , 25+/-6.6 vs 25.9+/-5.8 microg/l , Delta95 % CI = -2.77 to 4.59 , P = 0.31 . There was a non-significant trend toward a decrease in Hcy in both groups ( 27.43+/-7.68 to 25.91+/-5.78 micromol/l for SHF , P = 0.23 and 26.0+/-4.58 to 25.0+/-6.61 micromol/l for FX , P = 0.28 ) . Analysis by repeated measures method demonstrated a statistically significantly lower Hcy with FX vs SHF dialyzer ( adjusted beta = -1.30 , 95 % CI = -2.41 to -0.19 , P = 0.022 ) . K(t)/V(urea ) was higher in FX vs SHF ( 1.35+/-0.18 vs 1.22+/-0.2 ; P = 0.013 ) . Folate and B(6 ) levels did not change . CONCLUSIONS The primary outcome analysis did not show any significant difference in pre-Hcy comparing FX and SHF membranes . Although our secondary analysis demonstrated a statistically significant difference between membranes , the magnitude of the difference ( 1.3 mumol/l ) is not clinical ly significant . Thus the use of the FX dialyzer did not result in a clinical ly significant benefit in relation to improving pre-dialysis Hcy compared with st and ard high-flux dialysis CONTEXT High plasma homocysteine levels are a risk factor for mortality and vascular disease in observational studies of patients with chronic kidney disease . Folic acid and B vitamins decrease homocysteine levels in this population but whether they lower mortality is unknown . OBJECTIVE To determine whether high doses of folic acid and B vitamins administered daily reduce mortality in patients with chronic kidney disease . DESIGN , SETTING , AND PARTICIPANTS Double-blind r and omized controlled trial ( 2001 - 2006 ) in 36 US Department of Veterans Affairs medical centers . Median follow-up was 3.2 years for 2056 participants aged 21 years or older with advanced chronic kidney disease ( estimated creatinine clearance < or = 30 mL/min ) ( n = 1305 ) or end-stage renal disease ( n = 751 ) and high homocysteine levels ( > or = 15 micromol/L ) . INTERVENTION Participants received a daily capsule containing 40 mg of folic acid , 100 mg of pyridoxine hydrochloride ( vitamin B6 ) , and 2 mg of cyanocobalamin ( vitamin B12 ) or a placebo . MAIN OUTCOME MEASURES The primary outcome was all-cause mortality . Secondary outcomes included myocardial infa rct ion ( MI ) , stroke , amputation of all or part of a lower extremity , a composite of these 3 plus all-cause mortality , time to initiation of dialysis , and time to thrombosis of arteriovenous access in hemodialysis patients . RESULTS Mean baseline homocysteine level was 24.0 micromol/L in the vitamin group and 24.2 micromol/L in the placebo group . It was lowered 6.3 micromol/L ( 25.8 % ; P < .001 ) in the vitamin group and 0.4 micromol/L ( 1.7 % ; P = .14 ) in the placebo group at 3 months , but there was no significant effect on mortality ( 448 vitamin group deaths vs 436 placebo group deaths ) ( hazard ratio [ HR ] , 1.04 ; 95 % CI , 0.91 - 1.18 ) . No significant effects were demonstrated for secondary outcomes or adverse events : there were 129 MIs in the vitamin group vs 150 for placebo ( HR , 0.86 ; 95 % CI , 0.67 - 1.08 ) , 37 strokes in the vitamin group vs 41 for placebo ( HR , 0.90 ; 95 % CI , 0.58 - 1.40 ) , and 60 amputations in the vitamin group vs 53 for placebo ( HR , 1.14 ; 95 % CI , 0.79 - 1.64 ) . In addition , the composite of MI , stroke , and amputations plus mortality ( P = .85 ) , time to dialysis ( P = .38 ) , and time to thrombosis in hemodialysis patients ( P = .97 ) did not differ between the vitamin and placebo groups . CONCLUSION Treatment with high doses of folic acid and B vitamins did not improve survival or reduce the incidence of vascular disease in patients with advanced chronic kidney disease or end-stage renal disease . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00032435 Elevated plasma homocysteine ( Hcy ) , dyslipidemia and hemorheological abnormalities all occur commonly in end-stage renal disease ( ESRD ) and are recognized risk factors for arteriosclerosis . To study the effect of folate supplementation on these factors we conducted a r and omized controlled trial . Thirteen hemodialysis ( HD ) and 8 continuous ambulatory peritoneal dialysis ( CAPD ) patients received either 5 mg folic acid daily or placebo for 3 months . After 1 and 3 months , fasting blood sample s were taken for Hcy , lipid profile , blood and plasma viscosity , red blood cell ( RBC ) osmotic fragility , plasma fibrinogen concentration and in vivo platelet aggregability . At baseline , the CAPD patients had a higher mean plasma fibrinogen concentration than the HD patients and they also tended to have higher mean plasma viscosity . Folate-treated patients showed marked increases in RBC folate and an average decrease in plasma Hcy concentration of 33 % . Mean total cholesterol , LDL cholesterol and triglyceride concentrations decreased significantly in the CAPD patients who took folate . Folate had no significant effect on hemorheology . In conclusion , folate supplements in ESRD reduce plasma Hcy concentrations and may improve lipid profiles . In our patients , hemorheological abnormalities were more marked in patients on CAPD than in those on HD and were not improved by folate supplementation The doses of folic acid , neeessary to avoid folic acid deficiency in patients being maintained on hemodialysis , have been estimated to be between l and 5 mg daily . To more precisely define an adequate dose of folic acid , 6 anephric patients were studied . The patients were maintained on hemodialysis and received , in a crossover fashion , 1 mg and 5 mg of folic acid for 3 wk . In a second crossover study , 3 anephric patients were first maintained on 0 and then on 1 mg of folic acid after each dialysis for 3‐wk periods . Pre‐ and postdialysis folic acid blood levels were measured and dialyzer clearances of folic acid were determined . The results of this study support the conclusion of the Food and Drug Administration report suggesting that daily doses of 1 mg of folic acid are adequate to sustain therapeutic folate levels . The data further indicate that the administration of 1 mg of folic acid after each dialysis , rather than 1 mg of folic acid daily , can provide adequate folate BACKGROUND Hyperhomocysteinemia is an independent risk factor for cardiovascular disease in chronic hemodialysis ( CHD ) patients . Treatment with folic acid normalizes total homocysteine ( tHcy ) in only a minority of the patients . The present investigation has been conducted to study the influence of various dialyzers with different flux characteristics on the reduction of tHcy in the long term . METHODS Total Hcy , folate , vitamin B6 , vitamin B12 , and albumin levels were assessed prospect ively in 10 patients undergoing HD with high-flux polysulfon ( PS ; F 60 ) and 20 patients with super-flux dialyzers ( N = 10 PS , F 500S ; N = 10 CTA , Tricea 150 G ) . Blood sample s were collected before hemodialysis both at the beginning of the study and after 12 weeks . RESULTS At baseline , all the groups showed similar tHcy levels . During high-flux dialysis , tHcy remained stable . In contrast , during dialysis with both super-flux modalities , tHcy decreased significantly ( F 500S week 1 , 29.6 + /- 9.9 micromol/L , and week 12 , 21.5 + /- 8.5 micromol/L , P = 0.007 ; Tricea 150 G week 1 , 24.4 + /- 8.7 micromol/L , and week 12 , 15.3 + /- 3.7 micromol/L , P = 0.008 ) . The difference between high-flux and super-flux dialyzers was highly significant ( mean : high-flux increase 15.6 % , super-flux decrease 33 . 3 % , P = 0.001 ) . Multivariate analysis showed a significant effect of super-flux dialysis on tHcy ( P = 0.001 ) , independently of the previously mentioned variables . CONCLUSIONS Our findings clearly show that both types of super-flux dialyzers reduced tHcy significantly . As the molecular weight of free homocysteine is less than 268 D , the most likely explanation seems to be the removal of uremic toxins with inhibitory activities against enzymes involved in the extrarenal homocysteine metabolism BACKGROUND We have previously reported that a daily oral high dose of l-folinic acid for the treatment of hyperhomocysteinemia in hemodialysis patients does not provide significantly greater reduction in fasting total homocysteine ( tHcy ) levels than an equimolar dose of folic acid . The present study uses the affinity/HPLC method to analyze the distribution of plasma folate forms in patients who received l-folinic acid versus those who received folic acid . This was done to investigate cl aims that renal insufficiency is associated with impaired folate interconversion , a stance that is supportive of the premise that tHcy lowering in these patients is more efficacious with folinic acid and other reduced folates , than folic acid . METHODS Forty-eight chronic and stable hemodialysis patients were block-r and omized , based on their screening predialysis tHcy levels , sex , and dialysis center , into two groups treated for 12 weeks with oral folic acid at 15 mg/day or an equimolar amount ( 20 mg/day ) of oral l-folinic acid . All 48 subjects also received 50 mg/day of oral vitamin B6 and 1 mg/day of oral vitamin B12 . Folate distribution was determined in plasma of 46 participants ( Folinic acid group , N = 22 ; Folic acid group , N = 24 ) by using the affinity/HPLC method , with electrochemical ( coulometric ) detection . RESULTS Both groups had similar baseline geometric means of plasma total folate and similar folate forms distribution . Following treatment , both groups demonstrated similar marked elevation in plasma total folate ( geometric mean of the increase : Folinic acid group , + 337 ng/mL ; Folic acid group , + 312 ng/mL ; P = 0.796 ) . In the folinic acid-treated group , practically all of the increase in total folate was due to 5-methyltetrahydrofolate . In the folic acid-treated group 5-methyltetrahydrofolate accounted for 35 % of the increase in total folate and the remainder was unmethylated folic acid . CONCLUSIONS Data from the present findings suggest that defects in folate absorption or impairment in folate interconversion are not the cause of the persistent hyperhomocysteinemia in hemodialysis patients Background Hyperhomocysteinemia occurs in renal failure and may increase the risk for cardiovascular disease , possibly by damaging the endothelium . Folic acid and betaine are required in two separate homocysteine conversion pathways and may therefore lower plasma homocysteine . Objective To study the therapeutic role of betaine and the effect on endothelial function of long-term homocysteine-Iowering therapy with folic acid , in peritoneal dialysis ( PO ) patients . Patients and Design Thirty PO patients were r and omized to a 12-week treatment with 5 mg folic acid and 4 g betaine daily , or to 5 mg folic acid alone daily . They were then rer and omized to treatment with 1 or 5 mg folic acid daily for 40 weeks . Measurements At baseline and after 52 weeks , endothelial function was assessed by determination of endothelium-dependent vasodilatation and biochemical markers . Results Plasma total homocysteine ( tHcy ) was elevated at baseline : 42.6 ( 5.8 ) μmol/L. Only 1 patient ( 3 % ) had a normal plasma homocysteine ( i.e. , ≤ 15 μmol/L ) before therapy . Normalization of plasma homocysteine occurred in 39 % of the patients at 12 weeks . Betaine had no additional homocysteine-Iowering effect . Plasma tHcy levels were similar during treatment with 1 or 5 mg folic acid daily . Endothelial function was impaired at baseline and had not improved after 52 weeks of treatment . Conclusions Peritoneal dialysis patients have hyperhomocysteinemia , which can be normalized with folic acid alone in about 40 % of patients . Betaine does not further lower plasma homocysteine . A maintenance dose of 1 or 5 mg folic acid daily results in equivalent plasma homocysteine levels . Long-term reduction in plasma homocysteine did not result in improvement of endothelial function as assessed by our methods OBJECTIVES The Atherosclerosis and Folic Acid Supplementation Trial ( ASFAST ) aim ed to establish whether high-dose folic acid would slow the progression of atherosclerosis and reduce cardiovascular events in patients with chronic renal failure ( CRF ) . BACKGROUND Hyperhomocysteinemia is a potential contributor to the high rates of cardiovascular morbidity and mortality in patients with CRF . METHODS A total of 315 subjects with CRF , mean age 57 years ( range 24 to 79 years ) were r and omized to 15 mg folic acid daily or placebo and followed for a median of 3.6 years . The primary intima-media thickness ( IMT ) and clinical end points were : rate of progression of mean maximum carotid IMT and a composite of myocardial infa rct ion ( MI ) , stroke , and cardiovascular death . Secondary end points included all cardiovascular events and change in pulse wave velocity , systemic arterial compliance and augmentation index . Data were analyzed by intention-to-treat . RESULTS Plasma total homocysteine was reduced by 19 % in the folic acid group . There was no significant difference between the treatment groups in rate of change of IMT or any measure of artery function . Seventy-seven events occurred in the folic acid group ( 14.9 per 100 patient-years ) as compared with 86 in the placebo group ( 16.3 per 100 patient-years ) . The rates of the primary and secondary clinical end points at five years were not significantly different after adjustment for baseline differences between the groups ( adjusted hazard ratio for MI , stroke , and cardiovascular death : 0.98 [ 95 % confidence interval : 0.66 to 1.47 ] ; p = 0.94 ; for all cardiovascular events : 0.95 [ 95 % confidence interval : 0.69 to 1.30 ] ; p = 0.75 ) . CONCLUSIONS High-dose folic acid does not slow atheroma progression or improve cardiovascular morbidity or mortality in patients with CRF BACKGROUND Cardiovascular disease is the most important cause of morbidity and mortality in hemodialysis patients . These patients frequently have hyperhomocysteinemia , a putative risk factor for cardiovascular disease . Treatment with folate , B6 and B12 partially reduces hyperhomocysteinemia . We conducted a long-term study to evaluate whether 15 mg is more effective than 5 mg oral folic acid as a daily dosage to decrease hyperhomocysteinemia , and to assess whether homocysteine-lowering treatment reduces the risk of cardiovascular disease in hemodialysis patients . MATERIAL / METHODS In a 1-year prospect i ve r and omised trial , 81 chronic hemodialysis patients , matched for age , gender and dialytic age , were divided into three groups : 30 untreated patients , 26 patients receiving 5 mg per day , and 25 patients receiving 15 mg per day . RESULTS There was a significant reduction in hyperhomocysteinemia over time in treated patients as compared to untreated , but there were no significant differences between the two treated groups . Only 12 % of the treated patients reached normal total homocysteine plasma levels . We observed a trend towards a significant difference in survival rate in cardiovascular morbidity between treated and untreated patients . Furthermore , hemodialysis patients with new vascular events showed higher homocysteine levels than patients without events . CONCLUSIONS High-dose folic acid treatment did not improve outcome in hyperhomocysteinemia , and 88 % of treated patients maintained higher than normal homocysteine levels . There was a trend towards a decreased rate of cardiovascular events in treated participants as compared to untreated ones BACKGROUND Patients treated with hemodialysis ( HD ) have been reported to have decreased levels of ω-3 polyunsaturated fatty acids ( PUFAs ) in plasma and cells . The aim of this study was to investigate the effect of ω-3 PUFAs administered intravenously during HD , as well as the effect of HD treatment , on the fatty acid composition of plasma free fatty acids ( FFAs ) , plasma phospholipids , and platelet phospholipids . METHODS Forty-four HD patients were r and omized to groups receiving either a single dose of a lipid emulsion containing 4.1 g of ω-3 PUFAs or placebo ( saline ) administered intravenously during HD . Blood was drawn immediately before ( baseline ) and after ( 4 hours ) HD and before the next HD session ( 48 hours ) . Fatty acid composition was measured using gas chromatography . RESULTS The increase in ω-3 FFAs was greater in the ω-3 PUFA group compared with the placebo group , whereas the increase in total FFAs was similar between the 2 groups . In the ω-3 PUFA group , ω-3 PUFAs in plasma phospholipids were higher after 48 hours than at baseline , and in platelet phospholipids , ω-3 PUFAs increased after 4 hours . In the placebo group , no changes were observed in ω-3 PUFAs in plasma and platelet phospholipids . CONCLUSIONS Intravenous ω-3 PUFAs administered during HD caused a transient selective increase in ω-3 FFA concentration . Furthermore , ω-3 PUFAs were rapidly incorporated into platelets , and the content of ω-3 PUFAs in plasma phospholipids increased after 48 hours BACKGROUND & AIMS Hyperhomocysteinaemia ( HHCY ) , a common finding in patients with chronic kidney disease ( CKD ) , has been shown to contribute to adverse cardiac remodelling and failure . We hypothesised that in human subjects with CKD , HHCY would be associated with myocardial dysfunction , and that homocysteine (HCY)-lowering therapy would improve myocardial remodelling and heart-failure ( HF ) outcomes . METHODS AND RESULTS Post hoc analysis of the Homocysteinemia in Kidney and End Stage Renal Disease ( HOST ) trial ( n=2056 ) was performed to determine if HCY-lowering therapy with high dose B vitamins affects HF outcomes in patients with CKD . In addition , effects on myocardial remodelling were assessed in a subgroup of 220 trial subjects who had transthoracic echocardiograms done before study r and omisation and during the course of the study as part of their routine clinical care . HF outcomes were not significantly affected by treatment compared to the placebo . HCY levels were inversely correlated with diastolic function ( R=-0.21 ; p=0.038 ) . Vitamin therapy result ed in a significant increase in left atrial size ( + 0.15±0.8 cm vs. -0.13±0.07 cm ; p=0.0095 ) . No other echocardiographic parameters were significantly associated with baseline HCY levels or changes with vitamin therapy . CONCLUSION HHCY is associated with diastolic dysfunction in patients with CKD . However , B-vitamin therapy did not improve HF outcomes despite lowering of plasma HCY levels , and was associated with an increase in left atrial size , which is a surrogate for worsening left ventricular diastolic dysfunction . These findings suggest that high-dose B vitamin therapy may be harmful in patients with CKD BACKGROUND Serum asymmetric dimethylarginine ( ADMA ) levels are increased in maintenance hemodialysis patients , and this abnormality may increase cardiovascular risk . We investigated whether combined administration of oral folate and intravenous methylcobalamin in such patients is more beneficial than oral folate alone at decreasing circulating ADMA levels . STUDY DESIGN R and omized controlled trial . SETTING & PARTICIPANTS Patients undergoing hemodialysis . INTERVENTION 40 patients were r and omly assigned to 1 of 2 groups . For 3 weeks , they received supplementation with either folate alone ( 15 mg/d ; n = 20 ; folate group ) or coadministered folate ( 15 mg/d ) and methylcobalamin ( 500 mug after each hemodialysis treatment 3 times weekly ; n = 20 ; methylcobalamin group ) . OUTCOMES PRIMARY OUTCOMES normalization of plasma homocysteine levels ( < 15 mumol/L ) , decrease in serum ADMA levels . SECONDARY OUTCOMES change in augmentation index in the carotid artery and ratios of S-adenosylmethionine to S-adenosylhomocysteine ( as a transmethylation indicator ) and dimethylamine to ADMA ( as an indicator of ADMA hydrolysis ) . MEASUREMENTS Blood sample s were collected under fasting conditions during the prehemodialysis procedure . RESULTS The proportion showing normalization of plasma homocysteine levels was much greater in the methylcobalamin group ( 18 of 20 patients ; 90 % ) than in the folate group ( 6 of 20 ; 30 % ; P < 0.001 ) . The percentage of decrease in ADMA levels was greater in the methylcobalamin than folate group ( 25.4 % + /- 10.2 % vs 13.2 % + /- 11.2 % ; P < 0.001 ) . The increase in ratio of S-adenosylmethionine to S-adenosylhomocysteine was not different between the 2 groups ; however , the ratio of dimethylamine to ADMA was increased in only the methylcobalamin group ( P = 0.04 ) . Augmentation index was decreased in only the methylcobalamin group ( P = 0.03 ) . LIMITATIONS This study had an open-label nature and did not examine long-term effects of homocysteine-normalizing therapy ( no clinical end points ) . CONCLUSION Coadministration of intravenous methylcobalamin and oral folate in hemodialysis patients normalized hyperhomocysteinemia and decreased ADMA levels and arterial stiffness . We suggest that this regimen may have greater potential than folate alone to decrease cardiovascular risk in such patients BACKGROUND Elevated total homocysteine ( tHcy ) levels may represent a potentially modifiable risk factor for cardiovascular disease in hemodialysis patients . Current therapies , including multivitamins , have been ineffective at normalizing homocysteine levels in this population ; hence , new therapies are needed . There is increasing interest in the use of thiol pharmaceutical agents to displace homocysteine from albumin and improve its dialyzability . We design ed a r and omized , double-blind , placebo-controlled trial to determine the effect of prolonged administration of oral dimercaptosuccinic acid ( DMSA ) on plasma tHcy levels in vitamin-replete hemodialysis patients . METHODS Forty-four long-term stable dialysis patients were treated for a minimum of 4 weeks with a st and ard multivitamin , ensuring a vitamin-replete state , then matched on the basis of tHcy levels and r and omly assigned as pairs to the administration of DMSA , 2.5 mg/kg/d , or identical placebo for 8 weeks . Multivitamins were continued for the duration of the trial . RESULTS Thirty-eight subjects ( including 16 pairs ) completed the trial . All important determinants of homocysteine level were balanced , and the only significant baseline difference was weight ( P = 0.02 ) . At 8 weeks , by paired analysis , there was no statistically significant difference in tHcy levels between the placebo and DMSA groups , at 21.2 micromol/L ( 2.87 mg/L ) and 22.6 micromol/L ( 3.06 mg/L ) , respectively ( mean difference , -1.4 ; 95 % confidence interval , -5.3 to 2.5 ; P = 0.45 ) . The same was true for unpaired and multivariable analyses . CONCLUSION This r and omized placebo-controlled trial found that prolonged oral administration of the thiol DMSA had no impact on tHcy levels in hemodialysis patients . Additional strategies to test the homocysteine hypothesis in this population require investigation Whether high total serum homocysteine levels ( tHcy ) contribute to increase mortality or offer a survival advantage in chronic hemodialysis patients remains controversial . We conducted a prospect i ve study to determine the impact of tHcy on survival in this population with special respect to chronic inflammation-malnutrition state ( CIMS ) . In this prospect i ve study , 459 hemodialysis patients from 10 dialysis centers located in two regions of France were included . A number of baseline parameters were measured including tHcy and markers of CIMS . Over a mean follow-up period of 54 months , 219 deaths ( 47.7 % ) occurred , of which 114 ( 52 % ) were of cardiovascular ( CV ) origin . tHcy of equal to or greater than 30 micromol/l was associated with a higher risk of all-cause mortality in patients without CIMS ( hazard ratio ( HR ) : 1.55 ( confidence interval ( CI ) : 1.12 - 4.72 ) ) , but not in overall dialysis population or those with CIMS . When only CV mortality was considered , tHcy of equal to or greater than 30 micromol/l was associated with a higher risk in patients without ( CIMS HR : 1.91 ( CI : 1.23 - 3.23 ) ) , but not in those with CIMS . Hyperhomocysteinemia is a strong risk factor for all-cause and CV mortality in hemodialysis patients who do not present CIMS . This association might be masked in patients with CIMS Objective : To examine whether aggressive risk factor modification in chronic kidney disease ( CKD ) can limit the development of new ischaemia or reduce cardiac events . Methods : Patients with CKD were r and omly assigned to either an aggressive risk factor modification strategy ( targeted treatment of hypertension , dyslipidaemia , homocysteine , haemoglobin and phosphate ) or st and ard care . An intention to treat analysis was performed on 152 patients who had baseline dobutamine stress echocardiography ( DSE ) , including 107 who had follow-up DSE . Biochemical parameters , cardiac risk factors and investigations ( ECG , two-dimensional echocardiography ) were recorded at baseline . New ischaemia was classed as new or worsening stress wall motion abnormality between follow-up and baseline DSE . Patients were followed up for the development of new ischaemia or cardiac death , acute coronary syndrome and non-fatal myocardial infa rct ion over 1.8 years . Results : The development of new ischaemia was common but not different between the st and ard and aggressively treated groups ( 15 ( 21 % ) v 18 ( 23 % ) , p = 0.8 ) . Independent predictors of new ischaemia were older age , abnormal ECG , higher systolic blood pressure and lower serum high density lipoprotein cholesterol , but not treatment arm . The st and ard and aggressively treated groups did not differ in cardiac event rate ( 10 % v 13 % , p = 0.6 ) or all-cause mortality ( 10 % v 19 % , p = 0.2 ) . In patients with an abnormal baseline DSE ( non-diagnostic , scar or ischaemia ) , the event rate was similar ( 22 % v 20 % , p = 0.9 ) . Conclusion : Aggressive risk factor modification in CKD does not limit the development of new ischaemia or reduce cardiac events in patients with an abnormal DSE BACKGROUND Chronic kidney disease ( CKD ) is associated with an increased incidence of cardiovascular disease ( CVD ) . The Anti-oxidant Therapy In Chronic Renal Insufficiency ( ATIC ) Study showed that a multistep treatment strategy improved carotid intima-media thickness , endothelial function , and microalbuminuria in patients with stages 2 to 4 CKD . Increased plasma concentrations of asymmetric dimethylarginine ( ADMA ) , an endogenous inhibitor of nitric oxide synthase , have been linked to greater CVD risk in patients with CKD . The aim of this study is to assess effects of the multistep intervention on plasma ADMA concentrations in the ATIC Study . STUDY DESIGN Secondary analysis of a r and omized double-blind placebo-controlled trial . SETTING & PARTICIPANTS 93 patients with creatinine clearance of 15 to 70 mL/min/1.73 m(2 ) ( according to the Cockcroft-Gault equation ) from 7 outpatient clinics in Amsterdam , The Netherl and s. INTERVENTION The treatment group received sequential treatment consisting of pravastatin , 40 mg/d . After 6 months , vitamin E , 300 mg/d , was added , and after another 6 months , homocysteine-lowering therapy ( folic acid , 5 mg/d ; pyridoxine , 100 mg/d ; and vitamin B(12 ) , 1 mg/d , all in 1 tablet ) were added and continued for another year . The control group received matching placebos . OUTCOME & MEASURES Plasma ADMA levels . RESULTS 36 participants ( 77 % ) in the treatment group and 38 ( 83 % ) in the placebo group completed the study . Mean ADMA and symmetric dimethylarginine concentrations in the total study population were 0.53 + /- 0.07 ( SD ) and 1.14 + /- 0.46 mumol/L , respectively . After 24 months , there was no overall effect of the treatment strategy on ADMA concentrations ( beta = -0.006 ; P = 0.27 ) . Analysis of separate treatment effects suggested that vitamin E significantly decreased ADMA levels by 4 % in the treatment group compared with the placebo group ( multiple adjusted P = 0.02 ) . LIMITATIONS The study was a secondary analysis , power calculation was based on the primary end point of carotid intima-media thickness , mean plasma ADMA levels were relatively low . CONCLUSION Overall , a multistep treatment strategy consisting of pravastatin , vitamin E , and B vitamins had no effect on plasma ADMA levels in a stage 2 to 4 CKD population . This suggests that the beneficial effects of the intervention were not mediated by changes in ADMA levels . Possible ADMA-lowering effects of vitamin E deserve further attention Hyperhomocysteinemia , an arteriosclerotic risk factor , persists in 75 % of dialysis patients despite routine low dose supplementation with the B-vitamin co-factors/substrates for homocysteine ( Hcy ) metabolism , and normal or supernormal plasma status of these vitamins ( Atherosclerosis 114:93 , 1995 ) . We conducted a placebo-controlled eight-week trial of the effect on plasma homocysteine of adding supraphysiologic dose folic acid ( 15 mg/day ) , B-6 ( 100 mg/day ) , and B-12 ( 1 mg/day ) to the usual daily dosing of 1 mg folic acid , 10 mg B-6 , and 12 micrograms B-12 , in 27 hyperhomocysteinemic dialysis patients . Total plasma homocysteine was measured at baseline , and after four and eight weeks . Blinded analyses revealed no evidence of toxicity in the group r and omized to supraphysiologic dose B-vitamin supplementation . Plasma homocysteine was significantly reduced after both four weeks ( -29.8 % vs. -2.0 % ; P = 0.0024 ) and eight weeks ( -25.8 % vs. + 0.6 % ; P = 0.0009 ) of active versus placebo treatment . Also , 5 of 15 treated versus 0 of 12 placebo group patients had their plasma Hcy reduced to within the normative range ( < 15 mumol/liter ) . Supraphysiologic doses of B-vitamins may be required to correct hyperhomocysteinemia in dialysis patients OBJECTIVE The aim of this study was to test the hypothesis that omega-3 fatty acids have an effect on serum lipids and inflammation markers in chronic hemodialysis ( HD ) patients . DESIGN The study followed a single-blind , r and omized , crossover design . SETTING The study was conducted at the Hemodialysis Unit of the Laikon General Hospital in Athens , Greece . PATIENTS A total of 25 chronic HD patients were included in the study ( 16 men , 9 women , age : 51 ± 15 years ) . INTERVENTION Patients were r and omly assigned to one of the following 2 intervention groups : omega-3 fatty acids plus α-tocopherol ( 920 mg eicosapentaenoic Acid ( EPA ) , 760 mg docosahexaenoic acid ( DHA ) , 8 mg α-tocopherol in total per day ) or α-tocopherol supplement ( 100 mg/week result ing in 14.2 mg/day ) alone for 4 weeks . After a washout period of 4 weeks , the 2 groups were crossed . MAIN OUTCOME MEASURES Medical history data were collected and anthropometric and nutritional intake evaluation was performed at the beginning and at the end of both interventions . Hematological and biochemical parameters as well as C-reactive protein levels were measured . RESULTS No statistically significant results were recorded in the lipidemic profiles of the participants between baseline and the 2 interventions . C-reactive protein levels also did not change significantly between the 2 interventions ( 5.54 ± 3.33 to 6.70 ± 5.01 mg/L [ P = .19 ] with vitamin E vs. 7.13 ± 5.04 to 6.87 ± 5.24 [ P = .78 ] with omega-3 , P overall = .53 ) . CONCLUSION The results of this study do not provide support for the positive effects of omega-3 fatty acid supplementation in HD patients End-stage renal disease ( ESRD ) is associated with marked hyperhomocysteinemia which is only partially corrected by folic acid and pyridoxine supplementation . We and others have reported that various forms of parenteral cobalamin reduce plasma total homocysteine ( tHcy ) concentrations of patients with ESRD substantially below the lowest levels attainable with folic acid . We here report a 16-week r and omized controlled crossover trial which directly compared the Hcy-lowering effect of intravenous hydroxocobalamin ( HC ) with that of cyanocobalamin ( CC ) . Folic acid- and vitamin B12-replete maintenance hemodialysis patients were r and omly assigned to receive either 1 mg intravenous HC weekly for 8 weeks followed by CC for a further 8 weeks , or CC for 8 weeks followed by HC for 8 weeks . Hydroxocobalamin increased serum cobalamin concentrations 40-fold , whereas CC increased them only 10-fold , but both treatments reduced plasma tHcy concentrations similarly by 33 % ( P < .001 ) . Crossover to the alternate form of the vitamin greatly affected the serum cobalamin concentration but was without further effect on the plasma tHcy concentration . These results confirm that weekly cobalamin injections lower plasma tHcy concentrations of hemodialysis patients well below the level attainable with folic acid . Hydroxocobalamin and CC are equipotent despite producing very different serum cobalamin concentrations AIM Cardiovascular disease is the main cause of mortality in chronic kidney disease patients . Moreover , uremic patients are in a pro-oxidant state and show an increase in asymmetric dimethylarginine ( ADMA ) levels due to inhibition of the enzyme dimethylarginine dimethylaminohydrolase ( DDAH ) . Asymmetric dimethylarginine per se seems responsible for a 52 % increase in the risk of death and for a 34 % increase in the risk of cardiovascular events in dialysis patients . N-acetylcysteine ( NAC ) is a thiol molecule that has direct and indirect antioxidant effects which decrease reactive oxidant species and increase the bioavailability of the DDAH enzyme . The aim of the current study was to determine the effect of intravenous NAC on plasma ADMA level when administered during hemodialysis in end-stage renal disease ( ESRD ) patients . MATERIAL S AND METHODS 40 patients with ESRD were r and omized to receive a 4-hour intravenous infusion of NAC or placebo during a 4-hour hemodialysis session . There were 3 diabetic patients ( 15 % ) in the treatment group and 6 patients in the control group . Plasma ADMA levels were measured before and immediately after hemodialysis . Hemodynamic parameters , including pulse pressure , were also measured . The paired t-test was used to compare the difference of ADMA levels before and after hemodialysis in each group , while the independent t-test was used to compare the difference of ADMA levels between the groups . RESULTS Compared with the pre-dialysis condition , there was a decrease of ADMA level in the control group ( 1.1253 + /- 0.1797 microM to 0.8676 + /- 0.1449 microM ) ( p < 0.001 ) , and in the NAC group ( 1.1522 + /- 0.1737 microM to 0.7844 + /- 0.1586 microM ) ( p < 0.001 ) . Compared with hemodialysis alone , NAC had a greater lowering effect on the ADMA level ( 21.3 vs. 31.9 % , p < 0.05 ) . CONCLUSION N-acetylcysteine ( NAC ) administered intravenously during hemodialysis reduced asymmetric dimethylarginine ( ADMA ) levels more significantly than hemodialysis alone BACKGROUND Hyperhomocysteinaemia is frequent in chronic haemodialysis patients . Because of its potential role in athero- and thrombogenesis , the effects of long-term homocysteine-lowering treatment on endothelial function are of interest . METHODS We conducted a r and omized , controlled trial in 35 haemodialysis patients . In phase 1 , patients were treated with 5 mg folic acid or 5 mg folic acid and 4 g betaine per day for 12 weeks , and in phase 2 with 1 or 5 mg folic acid daily for 40 weeks . In phase 3 , all patients received 15 mg folic acid daily for four weeks . Endothelial function was assessed before and after 52 weeks of treatment by determination of flow-mediated vasodilatation of the brachial artery , and by measuring plasma levels of endothelium-derived proteins . RESULTS Non-fasting predialysis plasma total homocysteine was markedly elevated at baseline ( 46.9 + /- 6.3 mumol/l ) and decreased rapidly after initiation of therapy . Significant differences in plasma homocysteine between the groups were found neither during phase 1 nor phase 2 . Plasma total homocysteine had normalized in only two out of 30 patients at the end of phase 2 . Increasing the daily folic acid dose to 15 mg did not further reduce plasma total homocysteine . Endothelial function parameters did not improve . CONCLUSIONS We concluded that betaine is not effective in conjunction with folic acid in the treatment of hyperhomocysteinaemia in haemodialysis patients . Normalization of plasma total homocysteine is seldom achieved with 1 , 5 or 15 mg folic acid daily , which may explain why long-term homocysteine-lowering treatment with 1 or 5 mg folic acid does not ameliorate endothelial function Background and Aims : High concentrations of serum inflammation markers , especially vascular inflammation markers , are an important risk factor for cardiovascular diseases in hemodialysis patients . The present study was design ed to investigate the effects of marine omega-3 fatty acids on serum systemic and vascular inflammation markers and oxidative stress in hemodialysis patients . Methods : Thirty-four hemodialysis patients were r and omly assigned to either the marine omega-3 fatty acid or the placebo group . Patients in the omega-3 fatty acid group received 2,080 mg marine omega-3 fatty acids daily for 10 weeks , whereas the placebo group received a corresponding placebo . At baseline and the end of week 10 , 5 ml blood was collected after a 12- to 14-hour fast . Results : Mean serum soluble intercellular adhesion molecule type 1 ( sICAM-1 ) decreased significantly in the omega-3 fatty acid group at the end of week 10 compared to baseline ( p < 0.05 ) and this reduction was significant in comparison with the placebo group ( p < 0.05 ) . No significant differences were observed between the two groups in mean changes in serum soluble vascular cell adhesion molecule type 1 , sE-selectin , sP-selectin , C-reactive protein , interleukin-6 , tumor necrosis factor-α , malondialdehyde and total antioxidant capacity . Conclusion : The results of the present study indicate that marine omega-3 fatty acids can reduce serum sICAM-1 , a risk factor for cardiovascular diseases , but it has no effect on serum systemic inflammation markers and oxidative stress in hemodialysis patients BACKGROUND Plasma homocysteine is elevated in patients with end-stage renal disease ( ESRD ) and is a risk factor for cardiovascular disease . Folic acid has been shown to partially reduce homocysteine levels in dialysis patients . It is not known whether vitamin B12 reduces homocysteine independent of folic acid in patients who are not vitamin B12 deficient . AIM To determine whether 1 mg vitamin B12 lowers homocysteine in stable , chronic , haemodialysis patients independent of folic acid . METHODS Twenty-eight haemodialysis patients were r and omized to receive three doses of 1 mg vitamin B12 or 1 mL saline placebo in a double-blind fashion at 1-month intervals . Fasting plasma total homocysteine , folic acid , red-cell folate , vitamin B12 and haemoglobin levels were determined prior to each dose and 4 weeks after the final injection . The study was powered to detect a 30 % reduction in homocysteine over the 3 months . RESULTS Both the two groups were well matched with respect to total homocysteine levels , folic acid , red-cell folate and vitamin B12 levels . Serum vitamin B12 levels were significantly higher in the treatment group compared to placebo ( 217.7 pmol/L ; 95 % confidence interval ( CI ) 103.0 - 332.5 ; P < 0.001 ) at the end of the trial but homocysteine levels were not significantly different ( 3.08 micromol/L ; 95 % CI -4.44 - 10.61 ; P= 0.406 ) . CONCLUSIONS The administration of intramuscular vitamin B12 over a 3-month period does not result in any reduction of plasma homocysteine levels in haemo-dialysis patients independent of folate status , however reductions of < 30 % can not be excluded by the present study . High-dose folic acid remains the treatment of choice in reducing homocysteine , but whether this results in a reduction in cardiovascular events remains to be determined BACKGROUND Hyperhomocysteinemia , a putative atherothrombotic risk factor , is observed in at least 85 % of patients undergoing maintenance hemodialysis ( HD ) , as well as 65 to 70 % of renal transplant recipients ( RTRs ) . The hyperhomocysteinemia regularly found in HD patients is largely refractory to combined oral vitamin B supplementation featuring supraphysiological doses of folic acid ( FA ) . Relative to their HD counterparts , the hyperhomocysteinemia of RTRs appears to be considerably less refractory to treatment with high-dose FA-based vitamin B supplementation regimens , although controlled comparison data are lacking . We evaluated whether improved total homocysteine (tHcy)-lowering efficacy could be achieved in chronic HD patients with a high-dose L-5-methyltetrahydrofolate (MTHF)-based regimen , as suggested by recent uncontrolled findings , and compared the relative responsiveness of RTRs and HD patients with equivalent baseline tHcy levels , to 12 weeks of tHcy lowering with combined folate-based vitamin B treatment . METHODS First , we blocked r and omized 50 chronic , stable HD patients based on their screening predialysis tHcy levels , sex , and dialysis center into two groups of 25 subjects treated for 12 weeks with oral FA at 15 mg/day , or an equimolar amount ( 17 mg/day ) of oral MTHF . All 50 subjects also received 50 mg/day of oral vitamin B6 and 1.0 mg/day of oral vitamin B12 . RESULTS The mean percentage ( % ) reductions ( + /- 95 % confidence intervals ) in predialysis tHcy were not significantly different [ MTHF 17.0 % ( 12.0 to 22.0 % ) , FA 14.8 % ( 9.6 to 20.1 % ) , P = 0.444 by matched analysis of covariance adjusted for pretreatment tHcy ] . Final on-treatment values ( mean with 95 % confidence interval ) were : MTHF , 20.0 micromol/L ( 18.8 to 21.2 ) ; and FA , 19.5 micromol/L ( 18.3 to 20.7 ) . Moreover , neither treatment result ed in " normalization " of tHcy levels ( that is , final on-treatment values < 12 micromol/L ) among a significantly different or clinical ly meaningful number of patients [ MTHF , 2 out of 25 ( 8 % ) ; FA , 0 out of 25 ( 0 % ) ; Fisher 's exact test of between groups difference , P = 0.490 ] . Second , we compared the relative responsiveness of ( N = 10 ) RTRs and ( N = 39 ) HD patients with equivalent baseline tHcy levels ( RTR range of 14.2 to 23.6 micromol/L , and HD range of 14.4 to 24.9 micromol/L ) to 12 weeks of tHcy-lowering treatment . The RTRs received 2.4 mg/day of FA , 50.0 mg/day of vitamin B6 , and 0.4 mg/day of vitamin B12 , while the HD patients received 15 mg/day of FA or an equimolar amount ( 17 mg/day ) of the reduced folate , MTHF , in addition to 50.0 mg/day of vitamin B6 and 1.0 mg/day of vitamin B12 . The mean percentage ( % ) reductions ( + /- 95 % confidence interval ) in tHcy were as follows : RTR 28.1 % ( 16.2 to 40.0 % ) ; HD 12.1 % ( 6.6 to 17.7 % , P = 0.027 for comparison of between groups differences by analysis of covariance adjusted for baseline tHcy levels ) . Moreover , 5 out of 10 ( 50.0 % ) of the RTR versus only 2 out of 39 ( 5.1 % ) of the HD patients had final on-treatment tHcy levels < 12 micromol/L ( P = 0.002 for comparison of between groups differences by Fisher 's exact test ) . CONCLUSIONS First , in comparison to high-dose FA , high-dose oral MTHF-based supplementation does not afford improved tHcy-lowering efficacy among HD patients . The preponderance of HD patients ( that is , > 90 % ) exhibits mild hyperhomocysteinemia refractory to treatment with either regimen . This treatment refractoriness is not related to defects in folate absorption or circulating plasma and tissue distribution . Second , relative to RTR with comparable baseline tHcy levels , the mild hyperhomocysteinemia of maintenance HD patients is much more refractory to tHcy-lowering vitamin B treatment regimens featuring supraphysiological amounts of FA or the reduced folate MTHF . Accordingly , RTRs are a preferable target population for controlled clinical trials testing the hypothesis that tHcy-lowering vitamin B intervention may reduce arteriosclerotic cardiovascular disease event rates in patients with chronic renal disease BACKGROUND Hyper-homocyst(e)inemia is an independent risk factor for atherosclerotic vascular disease in patients with end-stage renal disease ( ESRD ) , although optimal treatment remains unknown . This r and omized , double-blind , placebo-controlled study was design ed to measure the effect of high-dose oral vitamin B(12 ) and folic acid on predialysis total homocyst(e)ine levels in patients with ESRD . METHODS We studied 81 hemodialysis patients who had hyper-homocyst(e)inemia ( > 16 micromol/L ) on varied doses of a multivitamin containing 1 mg of folic acid/day . After screening blood work , all patients were switched to daily multivitamin therapy , including 1 mg of folic acid for four weeks . For all patients , vitamin B(12 ) , 1 mg/day , was added for an additional four weeks . Patients were then r and omized to receive four weeks of 0 , 5 , or 20 mg of folic acid in addition to the multivitamin and vitamin B(12 ) ( all given daily ) . RESULTS Screening homocyst(e)ine levels ( mean 27.7 micromol/L ) decreased by 19.2 % after four weeks of treatment with a daily multivitamin containing 1 mg of folic acid ( P < 0.001 ) . Homocyst(e)ine levels were reduced further from 22.3 to 18.6 micromol/L ( mean reduction 16.7 % , 95 % CI 11.8 to 21.6 % , P < 0.001 ) after four weeks of therapy with vitamin B(12 ) ( 1 mg/day ) . There was no significant difference in mean reduction of homocyst(e)ine levels after therapy with high-dose folic acid compared with placebo ( P = 0.35 ) . CONCLUSIONS The optimal oral treatment of hyper-homocyst(e)inemia in hemodialysis patients consists of 1 mg of folic acid and 1 mg of oral vitamin B(12 ) daily . Whether this treatment will lower the risk of future atherosclerotic vascular events remains to be investigated Background — In observational studies , hyperhomocysteinemia has been found to be a risk factor for total mortality and cardiovascular events in patients with end-stage renal disease . These patients have grossly elevated homocysteine levels that can be lowered by supplementation with folic acid and vitamin B12 . We conducted a r and omized clinical trial with B vitamins to reduce homocysteine levels and therefore cardiovascular events and total mortality . Methods and Results — This r and omized , double-blind multicenter study was conducted in 33 dialysis centers in north and east Germany between July 2002 and July 2008 . We r and omly assigned 650 patients with end-stage renal disease who were undergoing hemodialysis to 2 postdialysis treatments : 5 mg folic acid , 50 & mgr;g vitamin B12 , and 20 mg vitamin B6 ( active treatment ) or 0.2 mg folic acid , 4 & mgr;g vitamin B12 , and 1.0 mg vitamin B6 ( placebo ) given 3 times per week for an average of 2 years . The primary outcome was total mortality ; the secondary outcome was fatal and nonfatal cardiovascular events . The primary outcome occurred in 102 patients ( 31 % ) receiving the active treatment and in 92 ( 28 % ) receiving placebo ( hazard ratio , 1.13 ; 95 % confidence interval , 0.85 to 1.50 ; P=0.51 ) . The secondary outcome occurred in 83 patients ( 25 % ) receiving the active treatment and in 98 ( 30 % ) receiving placebo ( hazard ratio , 0.80 ; 95 % confidence interval , 0.60 to 1.07 ; P=0.13 ) . Conclusions — Increased intake of folic acid , vitamin B12 , and vitamin B6 did not reduce total mortality and had no significant effect on the risk of cardiovascular events in patients with end-stage renal disease . Clinical Trial Registration — URL : www.anzctr.org.au . Unique identifier : ACTRN12609000911291 . URL : www.cochrane-renal.org . Unique identifier : CRG010600027 |
1,938 | 31,813,103 | The subgroup analyses and sensitivity analyses further illustrated these results of renal outcome and its robustness .
Circulating TNFR-1 and TNFR-2 are independently associated with higher risk of renal disease progression , CVD events , and mortality in patients with diabetes and might contribute to the clinical risk assessment in the future | Inflammation plays an important role in the pathogenesis of diabetes complications .
This study aims to assess the association between circulating inflammatory biomarkers TNF receptors ( TNFRs ) and the risk of renal disease progression , cardiovascular disease ( CVD ) events , and mortality in patients with diabetes . | Abstract Background Inflammation signaled by Janus kinases ( JAKs ) promotes progression of diabetic kidney disease ( DKD ) . Baricitinib is an oral , reversible , selective inhibitor of JAK1 and JAK2 . This study tested the efficacy of baricitinib versus placebo on albuminuria in adults with Type 2 diabetes at high risk for progressive DKD . Methods In this Phase 2 , double-blind , dose-ranging study , participants were r and omized 1:1:1:1:1 to receive placebo or baricitinib ( 0.75 mg daily ; 0.75 mg twice daily ; 1.5 mg daily ; or 4 mg daily ) , for 24 weeks followed by 4–8 weeks of washout . Results Participants ( N = 129 ) were 63±9.1 ( mean±st and ard deviation ) years of age , 27.1 % ( 35/129 ) women and 11.6 % ( 15/129 ) African-American race . Baseline hemoglobin A1c ( HbA1c ) was 7.3±1 % and estimated glomerular filtration rate was 45.0±12.1 mL/min/1.73 m2 with first morning urine albumin – creatinine ratio ( UACR ) of 820 ( 407–1632 ) ( median ; interquartile range ) mg/g . Baricitinib , 4 mg daily , decreased morning UACR by 41 % at Week 24 compared with placebo ( ratio to baseline 0.59 , 95 % confidence interval 0.38–0.93 , P = 0.022 ) . UACR was decreased at Weeks 12 and 24 and after 4–8 weeks of washout . Baricitinib 4 mg decreased inflammatory biomarkers over 24 weeks ( urine C – X – C motif chemokine 10 and urine C – C motif lig and 2 , plasma soluble tumor necrosis factor receptors 1 and 2 , intercellular adhesion molecule 1 and serum amyloid A ) . The only adverse event rate that differed between groups was anemia at 32.0 % ( 8/25 ) for baricitinib 4 mg daily versus 3.7 % ( 1/27 ) for placebo . Conclusions Baricitinib decreased albuminuria in participants with Type 2 diabetes and DKD . Further research is required to determine if baricitinib reduces DKD progression OBJECTIVE Renal dysfunction is a key risk factor for all-cause mortality in patients with type 2 diabetes ( T2D ) . Circulating tumor necrosis factor receptor 1 ( TNFR1 ) was recently suggested as a strong biomarker for end-stage renal failure in T2D . However , its relevance regarding all-cause death has yet to be conclusively established . We aim ed to assess the prognostic value of serum TNFR1 concentration for all-cause death in T2D and diabetic kidney disease ( DKD ) from the SURDIAGENE ( Survie , Diabete de type 2 et Genetique ) study . RESEARCH DESIGN AND METHODS A total of 522 T2D patients with DKD ( estimated glomerular filtration rate [ eGFR ] < 60 and /or urinary albumin-to-creatinine ratio [ uACR ] > 30 mg/mmol ) were followed for a median duration of 48 months , and 196 deaths occurred . RESULTS Incidence rate ( 95 % CI ) for death increased as quartiles of TNFR1 concentration increased ( first quartile : 4.7 % patient-years [ 3.0–6.3 % ] ; second quartile : 7.7 % [ 5.4–10.0 % ] ; third quartile : 9.3 % [ 6.7–11.9 % ] ; fourth quartile : 15.9 % [ 12.2–19.5 % ] ) . In multivariate analysis taking age , diabetes duration , HbA1c , uACR , and eGFR into account , compared with the first quartile , patients from the fourth quartile had an adjusted hazard ratio for death of 2.98 ( 95 % CI 1.70–5.23 ) . The integrated discrimination improvement index was statistically significant when adding TNFR1 concentration to the UK Prospect i ve Diabetes Study outcome equation ( P = 0.031 ) . CONCLUSIONS TNFR1 is a strong prognostic factor for all-cause mortality in T2D with renal dysfunction , and its clinical utility is suggested in addition to established risk factors for all-cause mortality Background We aim ed to assess the associations and predictive powers between the soluble receptors for tumor necrosis factor (TNF)‐α ( TNFR1 and TNFR2 ) and cardiovascular outcomes in patients with stable coronary heart disease . Methods and Results CLARICOR ( Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease ) is a r and omized clinical trial comparing clarithromycin with placebo in patients with stable coronary heart disease . The primary outcome was a composite of nonfatal acute myocardial infa rct ion , unstable angina pectoris , cerebrovascular disease , and all‐cause mortality . Patients were followed up for 10 years ; discovery sample , those assigned placebo ( 1204 events in n=1998 ) ; and replication sample , those assigned clarithromycin ( 1220 events in n=1979 ) . We used Cox regression adjusted for C‐reactive protein level , established cardiovascular risk factors , kidney function , and cardiovascular drugs . After adjustments , higher serum levels of TNFR1 and TNFR2 were associated with the composite outcome in the discovery sample ( hazard ratio per SD increase , 1.13 ; 95 % confidence interval , 1.05–1.22 ; P=0.001 for TNFR1 ; hazard ratio , 1.16 ; 95 % confidence interval , 1.08–1.24 ; P<0.001 for TNFR2 ) . The associations were similar in the replication sample . The associations with the composite outcome were mainly driven by acute myocardial infa rct ion , cardiovascular mortality , and noncardiovascular mortality . The addition of TNFR1 and TNFR2 to established cardiovascular risk factors improved prediction only modestly ( < 1 % ) . Conclusions Increased concentrations of circulating TNFR1 and TNFR2 were associated with increased risks of cardiovascular events and mortality in patients with stable coronary heart disease . Yet , the utility of measuring TNFR1 and TNFR2 to improve risk prediction in these patients appears limited . Clinical Trial Registration URL : https://www . clinical trials.gov . Unique identifier : NCT00121550 Abstract Cardiovascular disease ( CVD ) is the main public health problem in patients with chronic kidney disease ( CKD ) ; however , there is no established biomarker for predicting CVD morbidity and mortality in CKD . The aim of this study was to evaluate the role of circulating tumor necrosis factor receptors ( cTNFRs ) in predicting CVD risk in CKD patients . We prospect ively recruited 984 patients with CKD from 11 centers between 2006 and 2012 . The levels of cTNFR1 and cTNFR2 were determined by performing an enzyme-linked immunosorbent assay . During the mean follow-up period of 4 years , 36 patients experienced a CVD event . The median serum concentrations of cTNFR1 and cTNFR2 were 2703.4 ( 225.6–13,057.7 ) and 5661.0 ( 634.9–30,599.6 ) pg/mL , respectively , and the cTNFR1 level was closely correlated with the cTNFR2 level ( r = 0.86 , P < .0001 ) . The urinary protein-to-creatinine ratio ( UPCR ) and estimated glomerular filtration rate ( eGFR ) were significantly correlated with the cTNFR2 level ( r = 0.21 for UPCR , r = −0.67 for eGFR ; P < .001 for all ) . Similar correlations were observed for serum cTNFR1 ( r = 0.21 for UPCR , r = −0.75 for eGFR ; P < .001 for all ) . In the Cox proportional hazard analyses , cTNFR1 ( hazard ratio [ HR ] 2.506 , 95 % confidence interval [ CI ] 1.186–5.295 , P = .016 ) and cTNFR2 ( HR 4.156 , 95 % CI 1.913–9.030 , P < .001 ) predicted CVD risk even after adjustment for clinical covariates , such as UPCR , eGFR , and high-sensitivity C-reactive protein . cTNFR1 and 2 are associated with CVD and other risk factors in CKD , independently of eGFR and UPCR . Furthermore , cTNFRs could be relevant predictors of CVD in CKD patients BACKGROUND Several studies have demonstrated that levels of circulating inflammatory markers such as tumour necrosis factorα ( TNFα ) , are associated with early progression of diabetic nephropathy ( DN ) . The aim of this study was to investigate whether there is an association between circulating TNFα receptor and disease progression in patients with advanced type 2 DN and severe proteinuria . METHODS Between 2006 and 2011 , we measured levels of circulating soluble TNFα receptor 1 ( TNFR1 ) and soluble TNFα receptor 2 ( TNFR2 ) at baseline and 4 and 12 months in 101 patients included in a multicenter r and omized controlled trial to compare the effect of optimal doses of renin-angiotensin system blockers in monotherapy or in combination ( dual blockade ) to slow progression of established type 2 DN . The primary composite endpoint was a > 50 % increase in baseline serum creatinine , end-stage renal disease , or death . RESULTS The median follow-up was 32 months ( IQR , 18 - 48 ) , during which time 28 patients ( 22.7 % ) achieved the primary endpoint . The TNFR1 level , but not the TNFR2 level , was correlated with other inflammatory markers . Cox regression analysis showed that the highest TNFR1 levels ( HR , 2.60 ; 95%CI , 1.11 - 86.34 ) and baseline proteinuria ( HR 1.32 ; 95%CI 1.15 - 1.52 ) were associated with the primary endpoint . The mixed model analysis revealed that TNFR1 and the TNFR2 levels did not change after starting treatment with renin-angiotensin system blockers . CONCLUSIONS Our results show that the highest levels of TNFR1 are independently associated with progression of renal disease and death in type 2 DN . The renin angiotensin blockers have no effect on these inflammatory markers Aims /hypothesisMultiplex proteomics could improve underst and ing and risk prediction of major adverse cardiovascular events ( MACE ) in type 2 diabetes . This study assessed 80 cardiovascular and inflammatory proteins for biomarker discovery and prediction of MACE in type 2 diabetes . Methods We combined data from six prospect i ve epidemiological studies of 30–77-year-old individuals with type 2 diabetes in whom 80 circulating proteins were measured by proximity extension assay . Multivariable-adjusted Cox regression was used in a discovery/replication design to identify biomarkers for incident MACE . We used gradient-boosted machine learning and lasso regularised Cox regression in a r and om 75 % training sub sample to assess whether adding proteins to risk factors included in the Swedish National Diabetes Register risk model would improve the prediction of MACE in the separate 25 % test sub sample . Results Of 1211 adults with type 2 diabetes ( 32 % women ) , 211 experienced a MACE over a mean ( ±SD ) of 6.4 ± 2.3 years . We replicated associations ( < 5 % false discovery rate ) between risk of MACE and eight proteins : matrix metalloproteinase (MMP)-12 , IL-27 subunit α ( IL-27a ) , kidney injury molecule (KIM)-1 , fibroblast growth factor (FGF)-23 , protein S100-A12 , TNF receptor (TNFR)-1 , TNFR-2 and TNF-related apoptosis-inducing lig and receptor (TRAIL-R)2 . Addition of the 80-protein assay to established risk factors improved discrimination in the separate test sample from 0.686 ( 95 % CI 0.682 , 0.689 ) to 0.748 ( 95 % CI 0.746 , 0.751 ) . A sparse model of 20 added proteins achieved a C statistic of 0.747 ( 95 % CI 0.653 , 0.842 ) in the test sample . Conclusions /interpretationWe identified eight protein biomarkers , four of which are novel , for risk of MACE in community residents with type 2 diabetes , and found improved risk prediction by combining multiplex proteomics with an established risk model . Multiprotein arrays could be useful in identifying individuals with type 2 diabetes who are at highest risk of a cardiovascular event BACKGROUND TNF receptor-1 ( TNFR-1 ) , which plays a causative role in endothelial cell dysfunction and inflammation , is expressed on the cell surface in glomerular and peritubular capillary endothelium of the kidneys . Higher soluble TNF receptor-1 ( sTNFR-1 ) concentrations are associated with kidney disease progression among persons with established diabetic kidney disease . However , no studies have assessed sTNFR-1 's role in long-term kidney function changes in a multiethnic population without cardiovascular disease at baseline . METHODS We tested associations between baseline sTNFR-1 concentrations and 10-year decline in eGFR ( incident ≥40 % decline and annual proportional decline ) among 2548 participants in the Multi-Ethnic Study of Atherosclerosis ( MESA ) , a prospect i ve cohort study . Serum creatinine concentrations were determined at enrollment and study years 3 , 5 , and 10 . RESULTS Mean age of participants was 61 years old , 53 % were women , and mean baseline eGFR was 79 ml/min per 1.73 m2 . Serum sTNFR-1 was inversely associated with baseline eGFR . Over median follow-up of 9.3 years , 110 participants developed ≥40 % decline in eGFR ; each SD higher concentration of sTNFR1 was associated with higher risk of 40 % eGFR decline ( adjusted hazard ratio , 1.43 ; 95 % confidence interval [ 95 % CI ] , 1.16 to 1.77 ; P<0.001 ) . The highest sTNFR-1 tertile was associated with adjusted annualized decline in eGFR of 1.94 % ( 95 % CI , 1.79 to 2.09 ) . Associations persisted across subgroups defined by demographics , hypertension , diabetes , and baseline CKD status . CONCLUSIONS Elevated serum sTNFR-1 concentrations are associated with faster declines in eGFR over the course of a decade in a multiethnic population , independent of previously known risk factors for kidney disease progression Chronic inflammation is postulated to be involved in the development of end-stage renal disease in diabetes , but which specific circulating inflammatory proteins contribute to this risk remain unknown . To study this , we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with type 1 and type 2 diabetes . In each cohort , we identified an extremely robust kidney risk inflammatory signature ( KRIS ) , consisting of 17 proteins enriched in tumor necrosis factor-receptor superfamily members , that was associated with a 10-year risk of end-stage renal disease . All these proteins had a systemic , non-kidney source . Our prospect i ve study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying end-stage renal disease development in both types of diabetes . These proteins point to new therapeutic targets and new prognostic tests to identify subjects at risk of end-stage renal disease , as well as biomarkers to measure responses to treatment of diabetic kidney disease . A robust signature of circulating inflammatory proteins is causally associated with 10-year risk of progression to end-stage renal disease in diabetic Biomarkers of diverse pathophysiologic mechanisms may improve risk stratification for incident or progressive diabetic kidney disease ( DKD ) in persons with type 2 diabetes . To evaluate such biomarkers , we performed a nested case-control study ( n=190 cases of incident DKD and 190 matched controls ) and a prospect i ve cohort study ( n=1156 ) using banked baseline plasma sample s from participants of r and omized , controlled trials of early ( ACCORD ) and advanced ( VA NEPHRON-D ) DKD . We assessed the association and discrimination obtained with baseline levels of plasma TNF receptor-1 ( TNFR-1 ) , TNFR-2 , and kidney injury molecule-1 ( KIM-1 ) for the outcomes of incident DKD ( ACCORD ) and progressive DKD ( VA-NEPHRON-D ) . At baseline , median concentrations of TNFR-1 , TNFR-2 , and KIM-1 were roughly two-fold higher in the advanced DKD population ( NEPHRON-D ) than in the early DKD population ( ACCORD ) . In both cohorts , patients who reached the renal outcome had higher baseline levels than those who did not reach the outcome . Associations between doubling in TNFR-1 , TNFR-2 , and KIM-1 levels and risk of the renal outcomes were significant for both cohorts . Inclusion of these biomarkers in clinical models increased the area under the curve ( SEM ) for predicting the renal outcome from 0.68 ( 0.02 ) to 0.75 ( 0.02 ) in NEPHRON-D. Systematic review of the literature illustrated high consistency in the association between these biomarkers of inflammation and renal outcomes in DKD . In conclusion , TNFR-1 , TNFR-2 , and KIM-1 independently associated with higher risk of eGFR decline in persons with early or advanced DKD . Moreover , addition of these biomarkers to clinical prognostic models significantly improved discrimination for the renal outcome OBJECTIVE To determine whether biomarkers of inflammation and endothelial dysfunction are associated with the development of kidney dysfunction and the time frame of their association . RESEARCH DESIGN AND METHODS Biomarkers were measured at four time points during 28 years of treatment and follow-up in patients with type 1 diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications ( DCCT/EDIC ) cohort . In addition to traditional biomarkers of inflammation ( C-reactive protein and fibrinogen ) , we measured interleukin-6 ( IL-6 ) and soluble tumor necrosis factor receptors 1 and 2 ( sTNFR-1/2 ) , markers of endothelial dysfunction ( soluble intracellular adhesion molecule-1 , vascular cell adhesion molecule-1 , and E-selectin [ sE-selectin ] ) , and fibrinolysis ( total and active plasminogen activator inhibitor-1 [ PAI-1 ] ) . Renal outcomes were defined as progression to incident chronic kidney disease ( stage 3 or more severe ) or macroalbuminuria ( albumin excretion rate ≥300 mg/24 h ) . Prospect i ve multivariate event-time analyses were used to determine the association of each biomarker with each subsequent event within prespecified intervals ( 3-year and 10-year windows ) . RESULTS Multivariate event-time models indicated that several markers of inflammation ( sTNFR-1/2 ) , endothelial dysfunction ( sE-selectin ) , and clotting/fibrinolysis ( fibrinogen and PAI-1 ) are significantly associated with subsequent development of kidney dysfunction . Although some markers showed variations in the associations between the follow-up windows examined , the results indicate that biomarkers ( sTNFR-1/2 , sE-selectin , PAI-1 , and fibrinogen ) are associated with progression to chronic kidney disease in both the 3-year and the 10-year windows . CONCLUSIONS Plasma markers of inflammation , endothelial dysfunction , and clotting/fibrinolysis are associated with progression to kidney dysfunction in type 1 diabetes during both short-term and long-term follow-up |
1,939 | 32,341,258 | Improvements were observed in perceptions of health , quality of life , knowledge , self-efficacy , self-management , and caregiver support .
Nurses and CHWs play a pivotal role in community-based care .
Evidence suggests community-based interventions facilitate the necessary support for stroke survivors , caregivers , families , and communities to optimize stroke recovery . | ABSTRACT BACKGROUND Community-based interventions are vital for facilitating poststroke recovery , increasing community participation , and raising awareness about stroke survivors .
To optimize recovery and community reintegration , there is a need to underst and research findings on community-based interventions that focus on stroke survivors and their caregivers .
Although nurses and community health workers ( CHWs ) are commonly involved in community-based interventions , less is known about their roles relative to other poststroke rehabilitation professionals ( physical therapists , occupational therapists , and speech- language pathologists ) .
Thus , the purpose of this review is to explore research focused on improving community-based stroke recovery for adult stroke survivors , caregivers , or both when delivered by nurses or CHWs . | In a cluster r and omized trial , Kojo Yeboah-Antwi and colleagues find that integrated management of malaria and pneumonia in children under five by community health workers is both feasible and effective Background Human re source limitations are a challenge to the delivery of antiretroviral therapy ( ART ) in low-re source setting s. We conducted a cluster r and omized trial to assess the effect of community-based peer health workers ( PHW ) on AIDS care of adults in Rakai , Ug and a. Methodology /Principal Findings 15 AIDS clinics were r and omized 2∶1 to receive the PHW intervention ( n = 10 ) or control ( n = 5 ) . PHW tasks included clinic and home-based provision of counseling , clinical , adherence to ART , and social support . Primary outcomes were adherence and cumulative risk of virologic failure ( > 400 copies/mL ) . Secondary outcomes were virologic failure at each 24 week time point up to 192 weeks of ART . Analysis was by intention to treat . From May 2006 to July 2008 , 1336 patients were followed . 444 ( 33 % ) of these patients were already on ART at the start of the study . No significant differences were found in lack of adherence ( < 95 % pill count adherence risk ratio [ RR ] 0.55 , 95 % confidence interval [ CI ] 0.23–1.35 ; < 100 % adherence RR 1.10 , 95 % CI 0.94–1.30 ) , cumulative risk of virologic failure ( RR 0.81 , 95 % CI 0.61–1.08 ) or in shorter-term virologic outcomes ( 24 week virologic failure RR 0.93 , 95 % CI 0.65–1.32 ; 48 week , RR 0.83 , 95 % CI 0.47–1.48 ; 72 week , RR 0.81 , 95 % CI 0.44–1.49 ) . However , virologic failure rates ≥96 weeks into ART were significantly decreased in the intervention arm compared to the control arm ( 96 week failure RR 0.50 , 95 % CI 0.31–0.81 ; 120 week , RR 0.59 , 95 % CI 0.22–1.60 ; 144 week , RR 0.39 , 95 % CI 0.16–0.95 ; 168 week , RR 0.30 , 95 % CI 0.097–0.92 ; 192 week , RR 0.067 , 95 % CI 0.0065–0.71 ) . Conclusions / Significance A PHW intervention was associated with decreased virologic failure rates occurring 96 weeks and longer into ART , but did not affect cumulative risk of virologic failure , adherence measures , or shorter-term virologic outcomes . PHWs may be an effective intervention to sustain long-term ART in low-re source setting s. Trial Registration Clinical Trials.gov BACKGROUND African American ( AA ) women with Type 2 diabetes mellitus ( T2DM ) in the rural south experience less weight loss and poorer glycemic control in traditional diabetes management programs compared to Caucasians . This paper describes the design , rationale , and baseline characteristics from an innovative community health worker ( CHW ) delivered intervention program in this population . METHODS / DESIGN This prospect i ve trial r and omized rural AA women with uncontrolled T2DM ( HbA1c ≥ 7.0 ) to receive a behaviorally-centered , culturally-tailored lifestyle intervention during 16 contacts from a trained AA CHW or 16 approved diabetes educational mailings . Changes from baseline in glycosylated hemoglobin levels ( HbA1c ) , blood pressure ( BP ) , weight , body mass index ( BMI ) , self-reported dietary and physical activity patterns , and psychosocial measures including diabetes distress , empowerment , depression , self-care , medication adherence , and life satisfaction will be assessed at 6- and 12-months . BASELINE RESULTS Two hundred AA women ( mean age = 53.09 ± 10.89 years ) with T2DM from impoverished rural communities were enrolled . Baseline data demonstrated profoundly uncontrolled diabetes of long term duration ( mean HbA1c = 9.11 ± 1.82 ; mean BMI = 37.68 ± 8.20 ; mean BP = 134.51 ± 20.39/84.19 ± 11.68 ; 10.5 ± 0.7 years ) . Self-care behavior assessment revealed poor dietary and medication adherence and sedentary lifestyle . Most psychosocial measures ranged within normal limits . CONCLUSION The present sample of AA women from impoverished rural communities exhibited significantly uncontrolled T2DM of long duration with associated obesity and poor lifestyle behaviors . An innovative CHW led lifestyle intervention may lead to more effective strategies for T2DM management in this population OBJECTIVE Latinos with type 2 diabetes ( T2D ) face major healthcare access and disease management disparities . We examined the impact of the Diabetes Among Latinos Best Practice s Trial ( DIALBEST ) , a community health worker (CHW)–led structured intervention for improving glycemic control among Latinos with T2D . RESEARCH DESIGN AND METHODS A total of 211 adult Latinos with poorly controlled T2D were r and omly assigned to a st and ard of healthcare ( n = 106 ) or CHW ( n = 105 ) group . The CHW intervention comprised 17 individual sessions delivered at home by CHWs over a 12-month period . Sessions addressed T2D complications , healthy lifestyles , nutrition , healthy food choices and diet for diabetes , blood glucose self-monitoring , and medication adherence . Demographic , socioeconomic , lifestyle , anthropometric , and biomarker ( HbA1c , fasting blood glucose , and lipid profile ) data were collected at baseline and 3 , 6 , 12 , and 18 months ( 6 months postintervention ) . Groups were equivalent at baseline . RESULTS Participants had high HbA1c at baseline ( mean 9.58 % [ 81.2 mmol/mol ] ) . Relative to participants in the control group , CHWs had a positive impact on net HbA1c improvements at 3 months ( −0.42 % [ −4.62 mmol/mol ] ) , 6 months ( −0.47 % [ −5.10 mmol/mol ] ) , 12 months ( −0.57 % [ −6.18 mmol/mol ] ) , and 18 months ( −0.55 % [ −6.01 mmol/mol ] ) . The overall repeated- measures group effect was statistically significant ( mean difference −0.51 % [ −5.57 mmol/mol ] , 95 % CI −0.83 , −0.19 % [ −9.11 , −2.03 mmol/mol ] , P = 0.002 ) . CHWs had an overall significant effect on fasting glucose concentration that was more pronounced at the 12- and 18-month visits . There was no significant effect on blood lipid levels , hypertension , and weight . CONCLUSIONS DIALBEST is an effective intervention for improving blood glucose control among Latinos with T2D Background Early diagnosis and prompt , effective treatment of uncomplicated malaria is critical to prevent severe disease , death and malaria transmission . We assessed the impact of rapid malaria diagnostic tests ( RDTs ) by community health workers ( CHWs ) on provision of artemisinin-based combination therapy ( ACT ) and health outcome in fever patients . Methodology /Principal Findings Twenty-two CHWs from five villages in Kibaha District , a high-malaria transmission area in Coast Region , Tanzania , were trained to manage uncomplicated malaria using RDT aided diagnosis or clinical diagnosis ( CD ) only . Each CHW was r and omly assigned to use either RDT or CD the first week and thereafter alternating weekly . Primary outcome was provision of ACT and main secondary outcomes were referral rates and health status by days 3 and 7 . The CHWs enrolled 2930 fever patients during five months of whom 1988 ( 67.8 % ) presented within 24 hours of fever onset . ACT was provided to 775 of 1457 ( 53.2 % ) patients during RDT weeks and to 1422 of 1473 ( 96.5 % ) patients during CD weeks ( Odds Ratio ( OR ) 0.039 , 95 % CI 0.029–0.053 ) . The CHWs adhered to the RDT results in 1411 of 1457 ( 96.8 % , 95 % CI 95.8–97.6 ) patients . More patients were referred on inclusion day during RDT weeks ( 10.0 % ) compared to CD weeks ( 1.6 % ) . Referral during days 1–7 and perceived non-recovery on days 3 and 7 were also more common after RDT aided diagnosis . However , no fatal or severe malaria occurred among 682 patients in the RDT group who were not treated with ACT , supporting the safety of withholding ACT to RDT negative patients . Conclusions / Significance RDTs in the h and s of CHWs may safely improve early and well-targeted ACT treatment in malaria patients at community level in Africa . Trial registration Clinical Trials.gov 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 OBJECTIVE The Northern Manhattan Diabetes Community Outreach Project evaluated whether a community health worker ( CHW ) intervention improved clinical ly relevant markers of diabetes care in adult Hispanics . RESEARCH DESIGN AND METHODS Participants were adult Hispanics , ages 35–70 years , with recent hemoglobin A1c ( A1C ) ≥8 % ( ≥64 mmol/mol ) , from a university-affiliated network of primary care practice s in northern Manhattan ( New York City , NY ) . They were r and omized to a 12-month CHW intervention ( n = 181 ) , or enhanced usual care ( educational material s mailed at 4-month intervals , preceded by phone calls , n = 179 ) . The primary outcome was A1C at 12 months ; the secondary outcomes were systolic blood pressure ( SBP ) , diastolic blood pressure , and LDL-cholesterol levels . RESULTS There was a nonsignificant trend toward improvement in A1C levels in the intervention group ( from unadjusted mean A1C of 8.77 to 8.40 % ) , as compared with usual care ( from 8.58 to 8.53 % ) ( P = 0.131 ) . There was also a nonsignificant trend toward an increase in SBP and LDL cholesterol in the intervention arm . Intervention fidelity , measured as the number of contacts in the intervention arm ( visits , phone contacts , group support , and nutritional education ) , showed a borderline association with greater A1C reduction ( P = 0.054 ) . When assessed separately , phone contacts were associated with greater A1C reduction ( P = 0.04 ) . CONCLUSIONS The trend toward A1C reduction with the CHW intervention failed to achieve statistical significance . Greater intervention fidelity may achieve better glycemic control , and more accessible treatment models , such as phone-based interventions , may be more efficacious in socioeconomically disadvantaged population Abstract Objectives : To assess the quality and safety of having community health workers ( CHWs ) in rural Zambia use rapid diagnostic tests ( RDTs ) and provide integrated management of malaria and pneumonia . Design / methods : In the context of a cluster-r and omized controlled trial of two models for community-based management of malaria and /or non-severe pneumonia in children under 5 years old , CHWs in the intervention arm were trained to use RDTs , follow a simple algorithm for classification and treat malaria with artemether – lumefantrine ( AL ) and pneumonia with amoxicillin . CHW records were review ed to assess the ability of the CHWs to appropriately classify and treat malaria and pneumonia , and account for supplies . Patients were also followed up to assess treatment safety . Results : During the 12-month study , the CHWs evaluated 1017 children with fever and /or fast/difficult breathing and performed 975 RDTs . Malaria and /or pneumonia were appropriately classified 94–100 % of the time . Treatment based on disease classification was correct in 94–100 % of episodes . Supply management was excellent with over 98 % of RDTs , amoxicillin , and AL properly accounted for . The use of RDTs , amoxicillin , and AL was associated with few minor adverse events . Most febrile children ( 90 % ) with negative RDT results recovered after being treated with an antipyretic alone . Conclusions : Volunteer CHWs in rural Zambia are capable of providing integrated management of malaria and pneumonia to children safely and at high quality IMPORTANCE Socioeconomic and behavioral factors can negatively influence posthospital outcomes among patients of low socioeconomic status ( SES ) . Traditional hospital personnel often lack the time , skills , and community linkages required to address these factors . OBJECTIVE To determine whether a tailored community health worker ( CHW ) intervention would improve posthospital outcomes among low-SES patients . DESIGN , SETTING , AND PARTICIPANTS A 2-armed , single-blind , r and omized clinical trial was conducted between April 10 , 2011 , and October 30 , 2012 , at 2 urban , academically affiliated hospitals . Of 683 eligible general medical in patients ( ie , low-income , uninsured , or Medicaid ) that we screened , 237 individuals ( 34.7 % ) declined to participate . The remaining 446 patients ( 65.3 % ) were enrolled and r and omly assigned to study arms . Nearly equal percentages of control and intervention group patients completed the follow-up interview ( 86.6 % vs 86.9 % ) . INTERVENTIONS During hospital admission , CHWs worked with patients to create individualized action plans for achieving patients ' stated goals for recovery . The CHWs provided support tailored to patient goals for a minimum of 2 weeks . MAIN OUTCOMES AND MEASURES The prespecified primary outcome was completion of primary care follow-up within 14 days of discharge . Prespecified secondary outcomes were quality of discharge communication , self-rated health , satisfaction , patient activation , medication adherence , and 30-day readmission rates . RESULTS Using intention-to-treat analysis , we found that intervention patients were more likely to obtain timely posthospital primary care ( 60.0 % vs 47.9 % ; P = .02 ; adjusted odds ratio [ OR ] , 1.52 ; 95 % CI , 1.03 - 2.23 ) , to report high- quality discharge communication ( 91.3 % vs 78.7 % ; P = .002 ; adjusted OR , 2.94 ; 95 % CI , 1.5 - 5.8 ) , and to show greater improvements in mental health ( 6.7 vs 4.5 ; P = .02 ) and patient activation ( 3.4 vs 1.6 ; P = .05 ) . There were no significant differences between groups in physical health , satisfaction with medical care , or medication adherence . Similar proportions of patients in both arms experienced at least one 30-day readmission ; however , intervention patients were less likely to have multiple 30-day readmissions ( 2.3 % vs 5.5 % ; P = .08 ; adjusted OR , 0.40 ; 95 % CI , 0.14 - 1.06 ) . Among the subgroup of 63 readmitted patients , recurrent readmission was reduced from 40.0 % vs 15.2 % ( P = .03 ; adjusted OR , 0.27 ; 95 % CI , 0.08 - 0.89 ) . CONCLUSIONS AND RELEVANCE Patient-centered CHW intervention improves access to primary care and quality of discharge while controlling recurrent readmissions in a high-risk population . Health systems may leverage the CHW workforce to improve posthospital outcomes by addressing behavioral and socioeconomic drivers of disease . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01346462 Background Health outcomes for Indigenous Australians with diabetes in remote areas remain poor , including high rates of avoidable complications which could be reduced with better primary level care . We aim ed to evaluate the effectiveness of a community-based health-worker led case management approach to the care of Indigenous adults with poorly controlled type 2 diabetes in primary care services in remote northern Australia . Methods Two hundred and thirteen adults with poorly controlled diabetes ( HbA1c > 8.5 % ) and significant comorbidities in 12 remote communities were r and omly assigned by service cluster to receive chronic care co-ordination from a community-based health worker supported by a clinical outreach team , or to a waitlist control group which received usual care . Results At baseline , mean age of participants was 47.9 years , 62.4 % were female , half were Aboriginal and half identified as Torres Strait Isl and er , 67 % had less than 12 years of education , 39 % were smokers , median income was $ 18,200 and 47 % were unemployed . Mean HbA1c was 10.7 % ( 93 mmol/mol ) and BMI 32.5 . At follow-up after 18 months , HbA1c reduction was significantly greater in the intervention group ( −1.0 % vs −0.2 % , SE ( diff ) = 0.2 , p = 0.02 ) . There were no significant differences between the groups for blood pressure , lipid profile , BMI or renal function . Intervention group participants were more likely to receive nutrition and dental services according to scheduled care plans . Smoking rates were unchanged . Conclusions A culturally safe , community level health-worker led model of diabetes care for high risk patients can be effective in improving diabetes control in remote Indigenous Australian communities where there is poor access to mainstream services . This approach can be effective in other remote setting s , but requires longer term evaluation to capture accrued benefits .Trial registration ANZCTR 12610000812099 , Registered 29 September 2010 Objective Hispanics in the USA are affected by the diabetes epidemic disproportionately , and they consistently have lower access to care , poorer control of the disease and higher risk of complications . This study evaluates whether a community health worker ( CHW ) intervention may improve clinical ly relevant markers of diabetes care in adult underserved Hispanics . Methods and analysis The Northern Manhattan Diabetes Community Outreach Project ( NOCHOP ) is a two-armed r and omised controlled trial to be performed as a community-based participatory research study performed in a Primary Care Setting in Northern Manhattan ( New York City ) . 360 Hispanic adults with poorly controlled type 2 diabetes mellitus ( haemoglobin A1c > 8 % ) , aged 35–70 years , will be r and omised at a 1:1 ratio , within Primary Care Provider clusters . The two study arms are ( 1 ) a 12-month CHW intervention and ( 2 ) enhanced usual care ( educational material s mailed at 4-month intervals , preceded by phone calls ) . The end points , assessed after 12 months , are primary = haemoglobin A1c and secondary = blood pressure and low-density lipoprotein-cholesterol levels . In addition , the study will describe the CHW intervention in terms of components and intensity and will assess its effects on ( 1 ) medication adherence , ( 2 ) medication intensification , ( 3 ) diet and ( 4 ) physical activity . Ethics and dissemination All participants will provide informed consent ; the study protocol has been approved by the Institutional Review Board of Columbia University Medical Center . CHW interventions hold great promise in improving the well-being of minority population s who suffer from diabetes mellitus . The NOCHOP study will provide valuable information about the efficacy of those interventions vis-à-vis clinical ly relevant end points and will inform policy makers through a detailed characterisation of the programme and its effects . Clinical trial registration number NCT00787475 at clinical trials.gov OBJECTIVES We assessed whether community health workers ( CHWs ) could improve glycemic control among Mexican Americans with diabetes . METHODS We recruited 144 Mexican Americans with type 2 diabetes between January 2006 and September 2008 into the single-blinded , r and omized controlled Mexican American Trial of Community Health Workers ( MATCH ) and followed them for 2 years . Participants were assigned to either a CHW intervention , delivering self-management training through 36 home visits over 2 years , or a bilingual control newsletter delivering the same information on the same schedule . RESULTS Intervention participants showed significantly lower hemoglobin A1c levels than control participants at both year 1 Δ = -0.55 ; P = .021 ) and year 2 ( Δ = -0.69 ; P = .005 ) . We observed no effect on blood pressure control , glucose self-monitoring , or adherence to medications or diet . Intervention participants increased physical activity from a mean of 1.63 days per week at baseline to 2.64 days per week after 2 years . CONCLUSIONS A self-management intervention delivered by CHWs result ed in sustained improvements in glycemic control over 2 years among Mexican Americans with diabetes . MATCH adds to the growing body of evidence supporting the use of CHWs to reduce diabetes-related health disparities Background —Despite well-publicized guidelines on the appropriate management of cardiovascular disease and type 2 diabetes , the implementation of risk-reducing practice s remains poor . This report describes the results of a r and omized , controlled clinical trial evaluating the effectiveness of a comprehensive program of cardiovascular disease risk reduction delivered by nurse practitioner /community health worker ( NP/CHW ) teams versus enhanced usual care ( EUC ) to improve lipids , blood pressure , glycated hemoglobin ( HbA1c ) , and patient perceptions of the quality of their chronic illness care in patients in urban community health centers . Methods and Results —A total of 525 patients with documented cardiovascular disease , type 2 diabetes , hypercholesterolemia , or hypertension and levels of LDL cholesterol , blood pressure , or HbA1c that exceeded goals established by national guidelines were r and omly assigned to NP/CHW ( n=261 ) or EUC ( n=264 ) groups . The NP/CHW intervention included aggressive pharmacological management and tailored educational and behavioral counseling for lifestyle modification and problem solving to address barriers to adherence and control . Compared with EUC , patients in the NP/CHW group had significantly greater 12-month improvement in total cholesterol ( difference , 19.7 mg/dL ) , LDL cholesterol ( difference,15.9 mg/dL ) , triglycerides ( difference , 16.3 mg/dL ) , systolic blood pressure ( difference , 6.2 mm Hg ) , diastolic blood pressure ( difference , 3.1 mm Hg ) , HbA1c ( difference , 0.5 % ) , and perceptions of the quality of their chronic illness care ( difference , 1.2 points ) . Conclusions —An intervention delivered by an NP/CHW team using individualized treatment regimens based on treat-to-target algorithms can be an effective approach to improve risk factor status and perceptions of chronic illness care in high-risk patients . Clinical Trial Registration —URL : http://www . clinical trials.gov . Unique identifier : NCT00241904 BACKGROUND The Arizona Well-Integrated Screening and Evaluation for Women Across the Nation ( WISEWOMAN ) project used provider counseling , health education , and community health workers ( CHWs ) to target chronic disease risk factors in uninsured , primarily Hispanic women over age 50 . METHODS Participants were recruited from two Tucson clinics participating in the National Breast and Cervical Cancer Early Detection Program ( NBCCEDP ) . Women were r and omly assigned into one of three intervention groups : ( 1 ) provider counseling , ( 2 ) provider counseling and health education , or ( 3 ) provider counseling , health education , and CHW support . At baseline and 12 months ( 1998 - 2000 ) , participants were measured for height , weight , waist and hip circumference , and blood pressure . Blood tests were conducted to check blood glucose , cholesterol , and triglyceride levels . At each time point , participants also completed 24-hour dietary recalls and question naires focusing on their physical activity levels . RESULTS A total of 217 women participated in baseline and 12-month follow-up . Three fourths were Hispanic . All three intervention groups showed an increase in self-reported weekly minutes of moderate-to-vigorous physical activity , with no significant differences between the groups . Significantly more women who received the comprehensive intervention of provider counseling , health education , and CHW support progressed to eating five fruits and vegetables per day , compared with participants who received only provider counseling or provider counseling plus health education . CONCLUSIONS All three interventions increased moderate-to-vigorous physical activity but not fruit and vegetable consumption . The intervention group with provider counseling , health education , and CHW support significantly increased the number of women meeting national recommendations for fruit and vegetable consumption Objective . The study ’s objectives were to calculate the costs and evaluate the cost-effectiveness of implementing a health literacy-focused intervention to promote breast and cervical cancer screenings among Korean American women overdue for these tests . Methods . Research ers estimated the costs of a cluster-r and omized controlled trial that evaluated this intervention . Effectiveness was measured as the number of breast or cervical cancer screenings received by women in either the intervention and control arms of the study . Cost-effectiveness was calculated as the incremental cost of each additional screening received by the intervention group . Results . Comparing the intervention and control group , the incremental cost-effectiveness ratio was estimated to be US$ 236 per screening , without program development costs . Conclusion . These findings suggest this program , when compared with others , offered a more cost-effective approach for promoting cancer screening . Local health officials could use this information to guide decisions about reducing cancer disparities among recent immigrant women BACKGROUND Stimulation and nutrition delivered through health programmes at a large scale could potentially benefit more than 200 million young children worldwide who are not meeting their developmental potential . We investigated the feasibility and effectiveness of the integration of interventions to enhance child development and growth outcomes in the Lady Health Worker ( LHW ) programme in Sindh , Pakistan . METHODS We implemented a community-based cluster-r and omised effectiveness trial through the LHW programme in rural Sindh , Pakistan , with a 2 × 2 factorial design . We r and omly allocated 80 clusters ( LHW catchments ) of children to receive routine health and nutrition services ( controls ; n=368 ) , nutrition education and multiple micronutrient powders ( enhanced nutrition ; n=364 ) , responsive stimulation ( responsive stimulation ; n=383 ) , or a combination of both enriched interventions ( n=374 ) . The allocation ratio was 1:20 ( ie , 20 clusters per intervention group ) . The data collection team were masked to the allocated intervention . All children born in the study area between April , 2009 , and March , 2010 , were eligible for enrolment if they were up to 2·5 months old without signs of severe impairments . Interventions were delivered by LHWs to families with children up to 24 months of age in routine monthly group sessions and home visits . The primary endpoints were child development at 12 and 24 months of age ( assessed with the Bayley Scales of Infant and Toddler Development , Third Edition ) and growth at 24 months of age . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT007159636 . FINDINGS 1489 mother-infant dyads were enrolled into the study , of whom 1411 ( 93 % ) were followed up until the children were 24 months old . Children who received responsive stimulation had significantly higher development scores on the cognitive , language , and motor scales at 12 and 24 months of age , and on the social-emotional scale at 12 months of age , than did those who did not receive the intervention . Children who received enhanced nutrition had significantly higher development scores on the cognitive , language , and social-emotional scales at 12 months of age than those who did not receive this intervention , but at 24 months of age only the language scores remained significantly higher . We did not record any additive benefits when responsive stimulation was combined with nutrition interventions . Responsive stimulation effect sizes ( Cohen 's d ) were 0·6 for cognition , 0·7 for language , and 0·5 for motor development at 24 months of age ; these effect sizes were slightly smaller for the combined intervention group and were low to moderate for the enhanced nutrition intervention alone . Children exposed to enhanced nutrition had significantly better height-for-age Z scores at 6 months ( p<0·0001 ) and 18 months ( p=0·02 ) than did children not exposed to enhanced nutrition . Longitudinal analysis showed a small benefit to linear growth from enrolment to 24 months ( p=0·026 ) in the children who received the enhanced nutrition intervention . INTERPRETATION The responsive stimulation intervention can be delivered effectively by LHWs and positively affects development outcomes . The absence of a major effect of the enhanced nutrition intervention on growth shows the need for further analysis of mediating variables ( eg , household food security status ) that will help to optimise future nutrition implementation design . FUNDING UNICEF BACKGROUND Control of cervical cancer in developing countries has been hampered by a failure to achieve high screening uptake . HPV DNA self- collection could increase screening coverage , but implementation of this technology is difficult in countries of middle and low income . We investigated whether offering HPV DNA self- collection during routine home visits by community health workers could increase cervical screening . METHODS We did a population -based cluster-r and omised trial in the province of Jujuy , Argentina , between July 1 , 2012 , and Dec 31 , 2012 . Community health workers were eligible for the study if they scored highly on a performance score , and women aged 30 years or older were eligible for enrolment by the community health worker . 200 community health workers were r and omly allocated in a 1:1 ratio to either the intervention group ( offered women the chance to self-collect a sample for cervical screening during a home visit ) or the control group ( advised women to attend a health clinic for cervical screening ) . The primary outcome was screening uptake , measured as the proportion of women having any HPV screening test within 6 months of the community health worker visit . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT02095561 . FINDINGS 100 community health workers were r and omly allocated to the intervention group and 100 were assigned to the control group ; nine did not take part . 191 participating community health workers ( 94 in the intervention group and 97 in the control group ) initially contacted 7650 women ; of 3632 women contacted by community health workers in the intervention group , 3049 agreed to participate ; of 4018 women contacted by community health workers in the control group , 2964 agreed to participate . 2618 ( 86 % ) of 3049 women in the intervention group had any HPV test within 6 months of the community health worker visit , compared with 599 ( 20 % ) of 2964 in the control group ( risk ratio 4·02 , 95 % CI 3·44 - 4·71 ) . INTERPRETATION Offering self- collection of sample s for HPV testing by community health workers during home visits result ed in a four-fold increase in screening uptake , showing that this strategy is effective to improve cervical screening coverage . This intervention reduces women 's barriers to screening and results in a substantial and rapid increase in coverage . Our findings suggest that HPV testing could be extended throughout Argentina and in other countries to increase cervical screening coverage . FUNDING Instituto Nacional del Cáncer ( Argentina ) |
1,940 | 23,734,625 | In effective long-term treatment studies , medium and high intensity parental involvement were identified most frequently ; whereas in prevention studies low intensity parental involvement was identified most frequently .
Parenting skills , generic and specific to lifestyle behaviour , scored frequently in effective weight control interventions .
We conclude that intensity of parental involvement and behaviour change techniques are important issues in the effectiveness of long-term childhood weight control interventions | In Europe , about 20 % of children are overweight .
Focus on parental responsibility is an effective method in weight control interventions in children .
In this systematic review we describe the intensity of parental involvement and behaviour change aim ed at parents in long-term European childhood weight control interventions . | OBJECTIVE . The objective of this study was to determine whether a generalizable best- practice individualized behavioral intervention reduced BMI z score relative to st and ard dietetic care among overweight children . METHODS . The design consisted of an assessor-blinded , r and omized , controlled trial involving 134 overweight children ( 59 boys , 75 girls ; BMI ≥ 98th centile relative to United Kingdom 1990 reference data for children aged 5–11 years ) who were r and omly assigned to a best- practice behavioral program ( intervention ) or st and ard care ( control ) . The intervention used family-centered counseling and behavioral strategies to modify diet , physical activity , and sedentary behavior . BMI z score , weight , objective ly measured physical activity and sedentary behavior , fat distribution , quality of life , and height z score were recorded at baseline and at 6 and 12 months . RESULTS . The intervention had no significant effect relative to st and ard care on BMI z score from baseline to 6 months and 12 months . BMI z score decreased significantly in both groups from baseline to 6 and 12 months . For those who complied with treatment , there was a significantly smaller weight increase in those in the intervention group compared with control subjects from baseline to 6 months . There were significant between-group differences in favor of the intervention for changes in total physical activity , percentage of time spent in sedentary behavior , and light-intensity physical activity . CONCLUSIONS . A generalizable , best- practice individualized behavioral intervention had modest benefits on objective ly measured physical activity and sedentary behavior but no significant effect on BMI z score compared with st and ard care among overweight children . The modest magnitude of the benefits observed perhaps argues for a longer-term and more intense intervention , although such treatments may not be realistic for many health care systems OBJECTIVE : To evaluate the effectiveness of active parental involvement in a lifestyle intervention for the management of childhood obesity . DESIGN : Forty-two overweight children ( 32 girls and 10 boys ) , aged 9.2±0.2 years and with percent overweight 39.8±2.7 % , were r and omly allocated either to a child- and -parent group ( N = 23 ) or a child-alone group ( N = 19 ) . Both groups attended a 3-month multidisciplinary program extended by booster sessions during follow-up , which involved many cognitive behavioral therapy principles and assigned high self-regulation to the children , but differed in parental involvement . Percent overweight was evaluated at baseline , and at 3 , 6 , and 18 months thereafter . RESULTS : There was no significant interaction between time and group or a significant difference between groups . Percent overweight decreased by 4.9±1.4 at 18 months ( p < 0.001 ) ; the reduction occurred during the active phase of the treatment ( 0 - 3 months ) and was maintained thereafter . CONCLUSION : In the setting of the present study , the active parental involvement did not significantly modify the results of lifestyle interventions for children ’s overweight management Background Developing effective prevention and intervention programs for the formative preschool years is seen as an essential step in combating the obesity epidemic across the lifespan . The overall goal of the current project is to measure the effectiveness of a healthy eating and childhood obesity prevention intervention , the MEND ( Mind Exercise Nutrition Do It ! ) program that is delivered to parents of children aged 2 - 4 years . Methods / Design This r and omised controlled trial will be conducted with 200 parents and their 2 - 4 year old children who attend the MEND 2 - 4 program in metropolitan and regional Victoria . Parent-child dyads will attend ten 90-minute group workshops . These workshops focus on general nutrition , as well as physical activity and behaviours . They are typically held at community or maternal and child health centres and run by a MEND 2 - 4 trained program leader . Child eating habits , physical activity levels and parental behaviours and cognitions pertaining to nutrition and physical activity will be assessed at baseline , the end of the intervention , and at 6 and 12 months post the intervention . Informed consent will be obtained from all parents , who will then be r and omly allocated to the intervention or wait-list control group . Discussion Our study is the first RCT of a healthy eating and childhood obesity prevention intervention targeted specifically to Australian parents and their preschool children aged 2 - 4 years . It responds to the call by experts in the area of childhood obesity and child health that prevention of overweight in the formative preschool years should focus on parents , given that parental beliefs , attitudes , perceptions and behaviours appear to impact significantly on the development of early overweight . This is ' solution-oriented ' rather than ' problem-oriented ' research , with its focus being on prevention rather than intervention . If this is a positive trial , the MEND2 - 4 program can be implemented as a national program . Trial Registration Australian New Zeal and Clinical Trials Registry To decrease BMI in overweight and obese children , improved dietary intake and increased physical activity are key elements . Our objective was to evaluate the impact of a 1-y food and physical activity intervention on energy and macronutrient intake in overweight and obese children . A r and omized open trial was conducted with 92 overweight or obese 10.4 ± 1.08-y-old children . The intervention included 14 group sessions with different themes regarding food and physical activity . Dietary intake was assessed with diet history interviews covering 14 d at baseline and 4-d food records after 1 y and was evaluated according to national dietary recommendations . The control group participated in the same measurements as the intervention group but did not take part in group sessions . After 1 y , both groups had decreased their energy intake ( EI ) relative to total energy expenditure , but the effect was more pronounced for the intervention group than for the control group . At 1 y follow-up , a larger proportion of children in the intervention group compared with the control group met the recommended intake of refined sugar ( P = 0.019 ) . However , the groups did not differ in the proportion children who met the recommended intake of dietary fiber . Further , SFA intake relative to total EI did not differ between the groups at 1 y follow-up . In conclusion , despite a rather comprehensive intervention , only modest effects were achieved with respect to reduced EI and improved macronutrient intake 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 . Abstract Objective To identify risk factors in early life ( up to 3 years of age ) for obesity in children in the United Kingdom . Design Prospect i ve cohort study . Setting Avon longitudinal study of parents and children , United Kingdom . Participants 8234 children in cohort aged 7 years and a sub sample of 909 children ( children in focus ) with data on additional early growth related risk factors for obesity . Main outcome measures Obesity at age 7 years , defined as a body mass index 3 95th centile relative to reference data for the UK population in 1990 . Results Eight of 25 putative risk factors were associated with a risk of obesity in the final models : parental obesity ( both parents : adjusted odds ratio , 10.44 , 95 % confidence interval 5.11 to 21.32 ) , very early ( by 43 months ) body mass index or adiposity rebound ( 15.00 , 5.32 to 42.30 ) , more than eight hours spent watching television per week at age 3 years ( 1.55 , 1.13 to 2.12 ) , catch-up growth ( 2.60 , 1.09 to 6.16 ) , st and ard deviation score for weight at age 8 months ( 3.13 , 1.43 to 6.85 ) and 18 months ( 2.65 , 1.25 to 5.59 ) ; weight gain in first year ( 1.06 , 1.02 to 1.10 per 100 g increase ) ; birth weight , per 100 g ( 1.05 , 1.03 to 1.07 ) ; and short ( < 10.5 hours ) sleep duration at age 3 years ( 1.45 , 1.10 to 1.89 ) . Conclusion Eight factors in early life are associated with an increased risk of obesity in childhood Objective : The aim of the study was to compare the efficacy of group treatment stressing a health-promoting lifestyle with routine counseling in the treatment of childhood obesity . Design and subjects : Seventy obese children ( weight for height 115–182 % ) aged 7–9 years were r and omized either to routine counseling ( two appointments for children ) or to family-based group treatment ( 15 separate sessions for parents and children ) . These sessions included nutrition education , physical activity education and behavioral therapy . Outcome measures : Children 's weights and heights were measured at baseline , after the 6-month intervention and after the 6-month follow-up . The change of weight for height based on Finnish growth charts was used as the primary , and changes in body mass index ( BMI ) and BMI st and ard deviation scores ( BMI -SDS ) as secondary outcome measures . Results : Children attending the group treatment lost more weight for height ( 6.8 % ) than children receiving routine counseling ( 1.8 % ) ( P=0.001 ) . The difference was significant when the data were analyzed in four groups by the cut-off limits of 0 , −5 and −10 % for the change in weight for height . The respective decreases in BMI were 0.8 vs 0.0 ( P=0.003 ) and in BMI -SDS 0.3 vs 0.2 ( P=0.022 ) . The results remained similar in adjusted analyses . Both group and routine programs were feasible with a high , 87–99 % , participation rate in sessions and appointments and very low , 3 % or less , attrition rate from the programs . Six months after the intervention , beneficial effects were partly lost , but for changes in weight for height and BMI , the differences between the two treatment programs still were significant , and for BMI -SDS , there was a trend . Conclusions : Family-based group treatment that stresses a health-promoting lifestyle and is given separately for parents and children , offers an effective mode of therapy to treat obese school-aged children The effectiveness of a health and nutrition education programme , in changing certain chronic disease risk factors , was assessed after the 6 years intervention period was completed . The school-based intervention programme was applied to all children registered in the first grade ( age 5.5 - 6.5 years ) in 1992 in two counties of Crete , while the children from a third county served as a control group . In order to assess the effectiveness of the intervention , a variety of biological and behavioural parameters were measured before and following completion of the intervention in a r and omly selected school-based sample of 602 intervention group ( IG ) and 444 control group ( CG ) pupils . At the end of the 6-year period , it was found that biochemical indices generally improved significantly more in the IG compared with the CG ( mean change for IG v. CG was -0.27 v. -0.12 mmol/l for total cholesterol ( TC ) ; -0.07 v. + 0.24 for TC : HDL and -0.13 v. + 0.14 for LDL : HDL ) . Similarly , the changes observed in the anthropometric variables in the two groups were in favour of the IG ( + 3.68 v. + 4.28 kg/m2 for BMI ; + 2.97 v. + 4.47 mm for biceps skinfold ) . Total energy intake and consumption of total fat and saturated fat increased significantly less in the IG compared with the CG ( + 747.7 v. 1534.7 kJ ( + 178.7 v. + 366.8 kcal ) ; + 5.9 v. + 18.8 g and + 0.8 v. + 5.1 g respectively ) , while time devoted to leisure time physical activity and cardiovascular run test performance increased significantly more in the IG ( + 281 v. + 174 min/week and + 2.5 v. + 1.2 stages respectively ) . The findings of the present study underline the importance of such programmes in health promotion and disease prevention . Although the long-term effects of these programmes can only be assessed by tracking this population through to adolescence and adulthood , these programmes seem to have the potential to lead to a healthier lifestyle and thus a reduction in risk factor levels BACKGROUND & AIMS To assess the effects of a low cost behavioral prevention program in a preschool setting . METHODS 64 Kindergartens in 4 Bavarian regions were r and omly assigned as intervention or controls in a 2:1 ratio . Sample s of 1318 and 1340 children examined in the school entrance health examination at 5.7+/-2.6 and 17.6+/-2.3 months ( mean+/-st and ard deviation for first and second sample ) after the start of the program were analysed . MEASUREMENTS Main outcome measures were the prevalence of high fruit and vegetable consumption , low consumption of high caloric drinks assessed in parental question naires , overweight and obesity , and secondary , further dietary habits and results of motoric testing . RESULTS The program led to an increased proportion of children with high fruit and vegetable consumption already after 6 months , which was sustainable with adjusted odds ratios of 1.59 ( 1.26 : 2.01 ) and 1.48 ( 1.08 : 2.03 ) after 18 months . Subgroup analyses by gender , overweight and parental education , performed in order to assess consistency of effects , showed similar results . Prevalence of overweight and obesity as well as motoric testing results were not statistically different between intervention and control groups . CONCLUSION This low cost setting based behavioral intervention achieved sustainable effects on fruit and vegetable consumption in young children 18 months after the start of the intervention and showed effects also in the high risk groups of children from families with lower education levels , and children already overweight BACKGROUND The high prevalence of obesity in children in the UK warrants continuing public health attention . ' Families for Health ' is a family-based group programme for the treatment of childhood obesity . Significant improvements in body mass index ( BMI ) z-score ( -0.21 , 95 % CI : -0.35 to -0.07 , P = 0.007 ) and other health outcomes were seen in children at a 9-month follow-up . AIM To undertake a 2-year follow-up of families who attended ' Families for Health ' in Coventry , to assess long-term outcomes and costs . METHODS ' Families for Health ' is a 12-week programme with parallel groups for parents and children , addressing parenting skills , healthy lifestyles and emotional well-being . The intervention was delivered at a leisure centre in Coventry , Engl and , with 27 overweight or obese children aged 7 - 13 years ( 18 girls , 9 boys ) and their parents , from 21 families . A ' before- and -after ' evaluation was completed with 19 ( 70 % ) children followed up at 2 years . The primary outcome was change in BMI z-score from baseline ; secondary outcomes were children 's quality of life , parent-child relationships , eating/activity habits and parents ' mental health . Costs to deliver the intervention and to families were recorded . RESULTS Mean change in BMI z-score from baseline was -0.23 ( 95 % CI : -0.42 to -0.03 , P = 0.027 ) at the 2-year follow-up and eight ( 42 % ) children had a clinical ly significant reduction in BMI z-score . Significant improvements were seen in children 's quality of life and eating habits in the home , while there were sustained reductions in unhealthy foods and sedentary behaviour . Fruit and vegetable consumption and parent 's mental health were not significantly different at 2 years . Costs of the programme were £ 517 per family ( £ 402 per child ) , equivalent to £ 2543 per unit reduction in BMI z-score . CONCLUSIONS Improvements in BMI z-score and certain other outcomes associated with the ' Families for Health ' programme were sustained at the 2-year follow-up . ' Families for Health ' is a promising new childhood obesity intervention , and a r and omized controlled trial is now indicated BACKGROUND : The Freiburg Intervention Trial for Obese Children ( FITOC ) is an interdisciplinary , outpatient program for obese children consisting of regular physical exercise and comprehensive dietary and behavioral education . Parental involvement is required . The study is design ed as a longitudinal , nonr and omized clinical observation study . An 8-month intensive phase preceded a follow-up phase of 1 y or longer . METHODS : Data were collected from 31 groups comprising 496 children ( 267 girls , 229 boys ) , with an average age of 10.5 y. Body height and weight , fasting total-cholesterol ( CH ) , low-density lipoprotein-cholesterol ( LDL-C ) , high-density lipoprotein-cholesterol ( HDL-C ) and physical performance were measured initially and after 8.5 months . A group of n=35 obese children ( 16 girls , 19 boys ) who did not take part in this intervention program served as controls . RESULTS : After the intensive intervention phase , body mass index ( BMI , kg/m2 ) as well as BMI deviation scores ( BMI -SDS ) decreased in both sexes ( P<0.001 ) . In the controls , BMI increased ( P<0.001 ) and BMI -SDS remained constant . Whereas CH was only significantly lower ( P<0.01 ) in boys after 8.5 months , LDL-C decreased significantly in both sexes . HDL-C tended to increase in both sexes ( not significant ) . The controls showed no significant changes in CH , LDL-C and HDL-C. The fitness levels ( W/kg body weight ) improved in the intervention group ( P<0.001 ) , but not in the control group . CONCLUSIONS : The results indicate that obese children can be successfully treated in such an intervention program . BMI -SDS and risk factors decreased and physical performance improved . To maintain therapeutical success , we highly recommended that these children enroll in community-based exercise programs in order to help them maintain a more active lifestyle after the follow-up phase Freiburg Intervention Trial for Obese Children ( FITOC ) is an interdisciplinary treatment program for obese children , which is established in Freiburg since 1987 . Obese children at the age of 8 - 11 are treated in an eight months intensive period and a follow-up period of 4 months or more . Since 1990 data from 283 children coming out of 15 treatment groups ( about 2 groups per year ) were collected and analyzed . The program consists of regular physical training ( 3 times a week ) , comprehensive nutrition and behaviour training ( overall 7 parents evenings each 4 to 6 weeks and 7 cookery courses for the kids in the same time scale ) . The parents evenings are filled with theoretical and practical information about nutrition as well as background information about the psychological and physiological problems in obese children . In the first examination and the regular control examinations anthropometric , biochemical and exercise physiology data are investigated . In addition , question naires for nutrition and behaviour are analysed on a regular basis . At each examination , depending on the progress in therapy , a new orientation with adapted goals will be discussed with the child and the parents . For the growing children a moderate reduction or long term stabilisation of weight will lead to success . Teaching goal for the children in the intensive period is to control themselves and , depending on their specific situation , to establish individual recommendations on a long term basis . The sports program should lead to an increase in self-esteem and a raise in daily energy expenditure . The team includes a physician , a nutritionist , a psychologist and a sports teacher . From 1997 the program was spread to institutions in the surroundings of Freiburg . Training for the external teams is provided for in continuous seminars . Teaching material includes a manual , forms and transparencies . The major goal is to secure quality by continuous training and close interaction between the institutions . Till now the program is performed by a couple of multiplication groups in different regions of Germany . First data analysis has shown that the out-patient program is transferable and comparable results are reachable after a st and ardized training course for the included therapists . The plan for 2000 and 2001 is to increase the number of centers involved to a total of 20 all over Germany Objective : In general , treatment of childhood obesity focuses on treating the obese children . The results of child-directed treatments are disappointing in the long run . In the current study , it is tested whether a treatment aim ed solely at obese children 's parents results in positive effects on the children 's weight status . In addition , potential predictors of treatment success are identified . Methods : The parents of 98 overweight or obese children ( aged 7–13 years ) were r and omly assigned to either the cognitive-behavioural group treatment ( eight sessions ) or the waiting-list control group . Results : With respect to child body mass index ( BMI ) percentile , the parents ’ treatment was successful in reducing overweight from pretreatment to posttreatment : BMI percentile decreased significantly by 2.4 % in the treatment group , whereas there was no change in the waiting-list control group . There was no significant relapse at follow-up ( 3 months ) . Child BMI percentile did not decrease in the waiting-list control group . In addition , significant main effects of time were found for both groups with respect to eating psychopathology ( decrease ) , self-esteem ( increase ) and negative thoughts ( decrease ) . Finally , parental BMI decreased significantly only in the treatment group . Four predictors were identified with respect to treatment success , namely , lower socioeconomic status , younger age of the child , higher parental attendance and lower BMI percentile of the child before treatment . Conclusions : The parents ’ treatment had significant effects on child and parent BMI . Long-term endurance of these positive effects needs to be studied . Striking are the positive effects of time in the waiting-list control group for some psychological outcome measures . Obviously , waiting for treatment already affects psychological processes ( but not behaviour ) in the children The aim of this study was to evaluate the effectiveness of the Mind , Exercise , Nutrition , Do it ( MEND ) Program , a multicomponent community-based childhood obesity intervention ( www.mend central .org ) . One hundred and sixteen obese children ( BMI > or= 98 th percentile , UK 1990 reference data ) were r and omly assigned to intervention or waiting list control ( 6-month delayed intervention ) . Parents and children attended eighteen 2-h group educational and physical activity sessions held twice weekly in sports centers and schools , followed by a 12-week free family swimming pass . Waist circumference , BMI , body composition , physical activity level , sedentary activities , cardiovascular fitness , and self-esteem were assessed at baseline and at 6 months . Children were followed up 12 months from baseline ( 0 and 6 months postintervention for the control and intervention group , respectively ) . Participants in the intervention group had a reduced waist circumference z-score ( -0.37 ; P < 0.0001 ) and BMI z-score ( -0.24 ; P < 0.0001 ) at 6 months when compared to the controls . Significant between-group differences were also observed in cardiovascular fitness , physical activity , sedentary behaviors , and self-esteem . Mean attendance for the MEND Program was 86 % . At 12 months , children in the intervention group had reduced their waist and BMI z-scores by 0.47 ( P < 0.0001 ) and 0.23 ( P < 0.0001 ) , respectively , and benefits in cardiovascular fitness , physical activity levels , and self-esteem were sustained . High-attendance rates suggest that families found this intensive community-based intervention acceptable . Further larger controlled trials are currently underway to confirm the promising findings of this initial trial OBJECTIVES The purpose of this study was to evaluate the effect of a school-based intervention program to reduce overweight and improve fitness in primary school children . METHODS A cluster r and omized controlled design was used over one school year with schools as unit of r and omization . In total 20 schools and 2,622 children aged 6 - 12 years ( grade s 3 - 8 ) from multi-ethnic , low income inner-city neighbourhoods in Rotterdam , Netherl and s , participated . The intervention , named Lekker Fit ! ( Enjoy being fit ! ) was a multi-component intervention based on behavioural and ecological models . Main components of the intervention are the implementation of three physical education ( PE ) sessions a week by a professional PE teacher , additional sport and play activities outside school hours and an educational program . Main primary outcome measures were weight status , body mass index ( BMI ) , waist circumference and fitness ( 20 m shuttle run ) . RESULTS Significant positive intervention effects were found for percentage overweight children ( OR 0.53 ; 95 % CI 0.36 - 0.78 ) , waist circumference ( -1.29 cm ; 95 % CI -2.16 to -0.42 cm ) and 20 m shuttle run ( 0.57 laps ; 95 % CI 0.13 - 1.01 laps ) among pupils of grade s 3 - 5 ( 6 - 9-year olds ) . The prevalence of overweight in grade s 3 - 5 increased by 4.3 % in the control group and by 1.3 % in the intervention group . No significant effects were found for BMI or for grade s 6 - 8 ( 9 - 12-year olds ) . CONCLUSIONS Our results provide evidence for the effectiveness of the multi-component intervention Lekker Fit ! among pupils of grade s 3 - 5 and adds to the growing body of evidence that school-based programs with a focus on PA are most effective in reducing childhood obesity . [ IS RCT N84383524 ] OBJECTIVE To assess the 1-year results of a multidisciplinary , cognitive behavioral therapy treatment program for overweight and obese children . STUDY DESIGN Children ( n = 73 ; 8 to 15 years old ) participated in a prospect i ve study aim ed at reduction of the body mass index-st and ard deviation score ( BMI -SDS ) , adapting a healthy lifestyle and creating a positive self-image and higher self-esteem , by use of a group approach and parental involvement . Reduction in BMI -SDS and percent overweight were measured and analyzed by use of MIXED modeling . RESULTS The participants achieved a 0.6 BMI -SDS reduction , comparable to a weight loss of 18.7 % after 1 year ( P < .0001 ) . The proportion of dropouts was 33 % . Compared with the follow-up group , dropouts were older , increased in BMI -SDS before start of treatment , and were less successful in BMI -SDS reduction during treatment . CONCLUSIONS This treatment program had a positive effect on BMI -SDS in overweight and obese children at 1-year follow-up . Differences between the characteristics of the dropout and follow-up group may reflect predictor variables for treatment outcome BACKGROUND No national policy for health education in schools exists to date in Greece . The first attempt to apply a school-based health education intervention program was launched in 1992 on all 4,171 pupils registered in the first grade in two counties of Crete . The 1,510 pupils registered in a third county served as controls . METHODS The school-based intervention and the seminars organized for parents were primarily aim ed at improving children 's diet , fitness , and physical activity . Pupils in the first grade in a representative sample of 40 schools were examined prior to the intervention program on a variety of health knowledge , dietary , physical activity , fitness , anthropometric , and biochemical indices . The same measurements were taken after 3 years of the program on 288 intervention group and 183 control group pupils . RESULTS Positive serum lipid level changes occurred to a greater extent in the intervention group than the control group . BMI increased less in the intervention group than for controls . The increase in health knowledge and physical activity and fitness levels occurred to a higher extent in the intervention group compared to controls . CONCLUSIONS The short-term changes observed in the present study are markedly encouraging and indicate great potential for progressive improvement . Continuation and expansion of such a program may prove to be beneficial in initiating long-term changes Background : Parent-child treatments have been shown to be superior to child-focused treatments of childhood obesity . Yet until now , the comparative effectiveness of parent-only and parent-child approaches has been little studied . Method : Fifty-six obese children and their families were r and omly assigned to a 16-session cognitive behavioral therapy ( CBT ) for the parents only or for a combined treatment of parents and children . Children ’s percent overweight , the body mass index of their mothers , and behavioral and psychological problems of children and mothers were assessed . Results : Both treatments reduced children ’s percent overweight significantly and equally by 6-month follow-up . Also both treatments provided similar results in reducing general behavior problems ( externalizing and internalizing behavior problems ) , global and social anxiety , and depression . Conclusions : Our results point to a comparable efficacy of the two treatments . Further , psychological well-being of both mothers and children can be improved in a CBT for obese children and their parents . Future studies should focus on finding ways to improve the adherence of families to long-term treatment of obesity in childhood OBJECTIVE To evaluate the 4-year outcome of a school-based health promotion on weight status as part of the Kiel Obesity Prevention Study ( KOPS ) . RESEARCH METHODS AND PROCEDURES Within a cluster- sample d quasi-r and omized controlled trial , 1764 children at 6 and 10 years of age were assessed between 1996 and 2005 in 32 primary schools in Kiel , North Germany . Six nutrition units followed by 20-minute running games were performed within the first year at school . Prevalence , incidence , and remission of overweight were main outcome measures . RESULTS The 4-year change in BMI was + 11.6 % , with increases in prevalence of overweight and obesity from 5.2 % to 11.1 % and 3.9 % to 5.1 % , respectively . Cumulative 4-year incidence of overweight and obesity was 9.2 % and 3.1 % , respectively . Intervention had no effect on mean BMI . The effect on prevalence was significant in children from families with high socioeconomic status [ odds ratio ( OR ) , 0.35 ; 95 % confidence interval ( CI ) , 0.14 to 0.91 ] and marginally significant in children of normal-weight mothers ( OR , 0.57 ; 95 % CI , 0.33 to 1.00 ) . Cumulative 4-year incidence of overweight was lower only in intervention children from families with high socioeconomic status ( OR , 0.26 ; 95 % CI , 0.07 to 0.87 ) . Remission of overweight was most pronounced in children of normal-weight mothers ( OR , 5.43 ; 95 % CI , 1.28 to 23.01 ) . Prevalence of underweight was unchanged . The intervention had minor but favorable effects on lifestyle . DISCUSSION A school-based health promotion has sustainable effects on remission and incidence of overweight ; it was most pronounced in children of normal-weight mothers and children from families with high socioeconomic status . There was no effect on obesity . The data argue in favor of additional measures of prevention Background : Since obesity affects children 's health and social integration , treatment concepts with long-term efficiency are necessary . Methods : We analyzed changes of st and ard deviation score of body mass index ( SDS- BMI ) quarterly in the first year and once a year during the next 3 years in all obese children participating in the 1-year outpatient intervention program ‘ Obeldicks ’ , which was based on physical exercise , nutrition education and behavior therapy . All analyses were performed on the intention-to-treat approach . Results : One hundred and thirty-one children ( 77 % ) of the 170 children ( mean age 10.5 years , 51 % female , mean BMI 26.9 kg/m2 , mean SDS- BMI 2.54 ) attending the ‘ Obeldicks ’ intervention program reduced their overweight at the end of intervention ( mean SDS- BMI reduction 0.41 ) and 122 ( 66 % ) 3 years after end of intervention ( mean SDS- BMI reduction 0.48 ) . The reduction of overweight was independent of the child 's gender , age and parental age and BMI . Reduction of 0.33 SDS- BMI in the first 3 months was the best predictor for long-term success ( 95 % predictive value ) . Conclusions : Participating in the 1-year outpatient obesity intervention program ‘ Obeldicks ’ was associated with a decrease of overweight , which was sustained 3 years after the end of intervention . Reduction of overweight in the first 3 months of the intervention was highly predictive for long-term success Objective : To develop and evaluate “ Families for Health ” , a new community based family intervention for childhood obesity . Design : Programme development , pilot study and evaluation using intention-to-treat analysis . Setting : Coventry , Engl and . Participants : 27 overweight or obese children aged 7–13 years ( 18 girls , 9 boys ) and their parents , from 21 families . Intervention : Families for Health is a 12-week programme with parallel groups for parents and children , addressing parenting , lifestyle change and social and emotional development . Main outcome measures : Change in baseline BMI z score at the end of the programme ( 3 months ) and 9-month follow-up . Attendance , drop-out , parents ’ perception of the programme , child ’s quality of life and self-esteem , parental mental health , parent – child relationships and lifestyle changes were also measured . Results : Attendance rate was 62 % , with 18 of the 27 ( 67 % ) children completing the programme . For the 22 children with follow-up data ( including four who dropped out ) , BMI z score was reduced by −0.18 ( 95 % CI −0.30 to −0.05 ) at 3 months and −0.21 ( −0.35 to −0.07 ) at 9 months . Statistically significant improvements were observed in children ’s quality of life and lifestyle ( reduced sedentary behaviour , increased steps and reduced exposure to unhealthy foods ) , child – parent relationships and parents ’ mental health . Fruit and vegetable consumption , participation in moderate/vigorous exercise and children ’s self-esteem did not change significantly . Topics on parenting skills , activity and food were rated as helpful and used with confidence by most parents . Conclusions : Families for Health is a promising new childhood obesity intervention . Definitive evaluation of its clinical effectiveness by r and omised controlled trial is now required Objective : We investigated the long-term efficacy of two childhood obesity treatment programs , routine counselling ( two appointments for children ) and group treatment ( 15 sessions separately for children and parents ) in a r and omised controlled trial . As published earlier , group treatment was more effective than routine counselling in the treatment of 7–9 year-old obese children in the short term . Design : The children 's heights and weights were measured 2 and 3 years after the beginning of the intervention and changes in weight for height , body mass index ( BMI ) and BMI st and ard deviation scores were used as outcome measures . Results : There were no significant differences between the treatment arms in the changes of outcome measures from baseline to 2- or 3-years follow-up visits . Conclusion : In conclusion , novel efforts are needed for the improvement of the long-term results of childhood obesity treatment programs |
1,941 | 26,340,966 | For the prevention of recurrent plantar foot ulcers , multiple RCTs with low risk of bias show the benefit for the use of daily foot skin temperature measurements and consequent preventative actions , as well as for therapeutic footwear that demonstrates to relieve plantar pressure and that is worn by the patient .
To prevent recurrence , some evidence exists for integrated foot care when it includes a combination of professional foot treatment , therapeutic footwear and patient education ; for just a single session of patient education , no evidence exists .
Surgical interventions can be effective in selected patients , but the evidence base is small .
The evidence base to support the use of specific self-management and footwear interventions for the prevention of recurrent plantar foot ulcers is quite strong , but is small for the use of other , sometimes widely applied , interventions and is practically nonexistent for the prevention of a first foot ulcer and non-plantar foot ulcer | BACKGROUND Prevention of foot ulcers in patients with diabetes is extremely important to help reduce the enormous burden of foot ulceration on both patient and health re sources .
A comprehensive analysis of reported interventions is not currently available , but is needed to better inform caregivers about effective prevention .
The aim of this systematic review is to investigate the effectiveness of interventions to prevent first and recurrent foot ulcers in persons with diabetes who are at risk for ulceration . | Background Foot musculoskeletal deficits are seldom addressed by preventive medicine despite their high prevalence in patients with diabetic polyneuropathy . AIM : To investigate the effects of strengthening , stretching , and functional training on foot rollover process during gait . Methods A two-arm parallel-group r and omized controlled trial with a blinded assessor was design ed . Fifty-five patients diagnosed with diabetic polyneuropathy , 45 to 65 years-old were recruited . Exercises for foot-ankle and gait training were administered twice a week , for 12 weeks , to 26 patients assigned to the intervention group , while 29 patients assigned to control group received recommended st and ard medical care : pharmacological treatment for diabetes and foot care instructions . Both groups were assessed after 12 weeks , and the intervention group at follow-up ( 24 weeks ) . Primary outcomes involved foot rollover changes during gait , including peak pressure ( PP ) . Secondary outcomes involved time-to-peak pressure ( TPP ) and pressure – time integral ( PTI ) in six foot- areas , mean center of pressure ( COP ) velocity , ankle kinematics and kinetics in the sagittal plane , intrinsic and extrinsic muscle function , and functional tests of foot and ankle . Results Even though the intervention group primary outcome ( PP ) showed a not statistically significant change under the six foot areas , intention-to-treat comparisons yielded softening of heel strike ( delayed heel TPP , p=.03 ) , better eccentric control of forefoot contact ( decrease in ankle extensor moment , p<.01 ; increase in function of ankle dorsiflexion , p<.05 ) , earlier lateral forefoot contact with respect to medial forefoot ( TPP anticipation , p<.01 ) , and increased participation of hallux ( increased PP and PTI , p=.03 ) and toes ( increase in PTI , medium effect size ) . A slower COP mean velocity ( p=.05 ) , and an increase in overall foot and ankle function ( p<.05 ) were also observed . In most cases , the values returned to baseline after the follow-up ( p<.05 ) . Conclusions Intervention discreetly changed foot rollover towards a more physiological process , supported by improved plantar pressure distribution and better functional condition of the foot ankle complex . Continuous monitoring of the foot status and patient education are necessary , and can contribute to preserving the integrity of foot muscles and joints impaired by polyneuropathy . Trial registration Clinical Trials.gov Identifier : NCT01207284 , registered in 20th September 2010 PURPOSE To evaluate the effectiveness of home temperature monitoring to reduce the incidence of foot ulcers in high-risk patients with diabetes . METHODS In this physician-blinded , 18-month r and omized controlled trial , 225 subjects with diabetes at high risk for ulceration were assigned to st and ard therapy ( St and ard Therapy Group ) or dermal thermometry ( Dermal Thermometry Group ) groups . Both groups received therapeutic footwear , diabetic foot education , regular foot care , and performed a structured foot inspection daily . Dermal Thermometry Group subjects used an infrared skin thermometer to measure temperatures on 6 foot sites twice daily . Temperature differences > 4 degrees F between left and right corresponding sites triggered patients to contact the study nurse and reduce activity until temperatures normalized . RESULTS A total of 8.4 % ( n=19 ) subjects ulcerated over the study period . Subjects were one third as likely to ulcerate in the Dermal Thermometry Group compared with the St and ard Therapy Group ( 12.2 % vs 4.7 % , odds ratio 3.0 , 95 % confidence interval , 1.0 to 8.5 , P=.038 ) . Proportional hazards regression analysis suggested that thermometry intervention was associated with a significantly longer time to ulceration ( P=.04 ) , adjusted for elevated foot ulcer classification ( International Working Group Risk Factor 3 ) , age , and minority status . Patients that ulcerated had a temperature difference that was 4.8 times greater at the site of ulceration in the week before ulceration than did a r and om 7 consecutive-day sample of 50 other subjects that did not ulcerate ( 3.50+/-1.0 vs 0.74+/-0.05 , P=.001 ) . CONCLUSIONS High temperature gradients between feet may predict the onset of neuropathic ulceration and self-monitoring may reduce the risk of ulceration BACKGROUND Neuropathic foot ulcers are among the major health problems faced by patients with diabetes mellitus . OBJECTIVE To evaluate the preventive efficacy of a therapeutic education and protective footwear program in the incidence and recurrence of neuropathic ulcers due to diabetes . METHODS Fifty-three patients with diabetes and neuropathy from a public healthcare unit in Porto Alegre , Rio Gr and e do Sul , took part in a clinical trial for two years . The participants were r and omly allocated to an intervention group ( n=30 ) or a control group ( n=23 ) . Therapeutic education was provided in group sessions , and protective footwear was supplied in accordance with individual prescriptions . The nonparametric Mann-Whitney test was used to determine differences in incidence and recurrence of ulceration between the groups . Life-table analysis and the Kaplan-Meier method were used to measure the duration of ulcer-free survival . RESULTS In the intervention group , the ulcer incidence rate was 38.1 % compared to 51.1 % in the control group . Among the participants who presented ulcers , 83 % were in the control group and 16.7 % in the intervention group . After one year , the participants in the intervention group had a 75 % chance of being ulcer-free , compared with 61 % in the control group , and these percentages reduced to 60 % and 52 % respectively after two years . There was a tendency toward shorter survival among the control group participants . CONCLUSION Although the proposed program lowered recurrence rates and increased the duration of ulcer-free survival , it was unable to prevent occurrence and recurrence of neuropathic ulcers due to diabetes Abstract Aims /hypothesisThis observer-blind , r and omised controlled trial was design ed to determine the effect of a foot care education programme in the secondary prevention of foot ulcers . Methods People with newly healed foot ulcers attending one of three specialist clinics were allocated to receive either targeted , one-to-one education or usual care , using a computer-generated r and om allocation sequence that had been prepared in advance but which was concealed from the clinical research er . The primary outcome was ulcer incidence at 12 months . Secondary outcomes were ulcer incidence at 6 months and incidence of amputation , mood ( Hospital Anxiety and Depression Scale ) and quality of life ( Diabetic Foot Ulcer Scale ) at 6 and 12 months . Protective foot care behaviours ( Nottingham Assessment of Functional Footcare ) were assessed at 12 months . Results There were 87 ( mean [ SD ] age 63.5 [ 12.1 ] years ) patients in the intervention group and 85 control patients ( mean [ SD ] age 64.9 [ 10.9 ] years ) . The groups were comparable at baseline . No significant differences ( p > 0.05 ) were observed between groups in ulcer incidence at either 6 months ( intervention 30 % , control 21 % ) or 12 months ( intervention 41 % , control 41 % ) . Recommended foot care behaviours at 12 months were better in the intervention than in the control group ( p = 0.03 ) , but education had no significant ( p > 0.05 ) effect on mood , quality of life or amputations . Conclusions /interpretationEven though the intervention was associated with improved foot care behaviour , there was no evidence that this programme of targeted education was associated with clinical benefit in this population when compared with usual care . The usefulness and optimal delivery of education to such a high-risk group requires further evaluation . Trial registration : Clinical Trials.gov NCT00729456 Funding : Diabetes UK project grant BACKGROUND We aim ed to investigate whether a home exercise for self-care program that consists of range of motion ( ROM ) , stretching , and strengthening exercises could improve ROM for foot joints and plantar pressure distribution during walking in diabetic patients to prevent diabetic foot complications . METHODS Seventy-six diabetic patients were recruited ( 38 with neuropathy and 38 without neuropathy ) . Neuropathy and nonneuropathy groups were r and omly divided into a home exercise group ( n = 19 ) and a control group ( n = 19 ) . Exercise groups performed their own respective training programs for 4 weeks , whereas no training was done in the control group . Total contact area and plantar pressure under six foot areas before and after the exercise program were measured . Ankle and first metatarsophalangeal joint ROM were measured before and after the exercise program . RESULTS In the exercise group , there were significant improvements in ROM for the ankle and first metatarsophalangeal joints ( P < .001 ) ; static pedobarographic values showed significant reduction in right forefoot-medial pressure ( P = .010 ) ; and significant decreases were seen in dynamic pedobarographic values of peak plantar pressure at the left forefoot medial ( P = .007 ) , right forefoot lateral ( P = .018 ) , left midfoot ( P < .001 ) , and right hindfoot ( P = .021 ) after exercise . No significant positive or negative correlation was found between the neuropathy and nonneuropathy groups ( P > .05 ) . CONCLUSIONS A home exercise program could be an effective preventive method for improving ROM for foot joints and plantar pressure distribution in diabetic patients independent of the presence of neuropathy Diabetic foot ulceration poses a heavy burden on the patient and the healthcare system , but prevention thereof receives little attention . For every euro spent on ulcer prevention , ten are spent on ulcer healing , and for every r and omized controlled trial conducted on prevention , ten are conducted on healing . In this article , we argue that a shift in priorities is needed . For the prevention of a first foot ulcer , we need more insight into the effect of interventions and practice s already applied globally in many setting s. This requires systematic recording of interventions and outcomes , and well- design ed r and omized controlled trials that include analysis of cost-effectiveness . After healing of a foot ulcer , the risk of recurrence is high . For the prevention of a recurrent foot ulcer , home monitoring of foot temperature , pressure-relieving therapeutic footwear , and certain surgical interventions prove to be effective . The median effect size found in a total of 23 studies on these interventions is large , over 60 % , and further increases when patients are adherent to treatment . These interventions should be investigated for efficacy as a state-of-the-art integrated foot care approach , where attempts are made to assure treatment adherence . Effect sizes of 75 - 80 % may be expected . If such state-of-the-art integrated foot care is implemented , the majority of problems with foot ulcer recurrence in diabetes can be resolved . It is therefore time to act and to set a new target in diabetic foot care . This target is to reduce foot ulcer incidence with at least 75 % Background Diabetic foot ulcers are frequently related to elevated pressure under a bony prominence . Conservative treatment includes offloading with orthopaedic shoes and custom made orthotics or plaster casts . While casting in plaster is usually effective in achieving primary closure of foot ulcers , recurrence rates are high . Minimally invasive surgical offloading that includes correction of foot deformities has good short and long term results . The surgery alleviates the pressure under the bony prominence , thus enabling prompt ulcer healing , negating the patient ’s dependence on expensive shoes and orthotics , with a lower chance of recurrence . The purpose of this protocol is to compare offloading surgery ( percutaneous flexor tenotomy , mini-invasive floating metatarsal osteotomy or Keller arthroplasty ) to non-surgical treatment for patients with diabetic foot ulcers in a semi-crossover design ed RCT . Methods One hundred patients with diabetic neuropathy related foot ulcers ( tip of toe ulcers , ulcers under metatarsal heads and ulcers under the hallux interphalangeal joint ) will be r and omized ( 2:3 ) to a surgical offloading procedure or best available non-surgical treatment . Group 1 ( surgery ) will have surgery within 1 week . Group 2 ( controls ) will be prescribed an offloading cast applied for up to 12 weeks ( based on clinical considerations ) . Following successful offloading treatment ( ulcer closure with complete epithelization ) patients will be prescribed orthopaedic shoes and custom made orthotics . If offloading by cast for at least 6 weeks fails , or the ulcer recurs , patients will be offered surgical offloading . Follow-up will take place till 2 years following r and omization . Outcome criteria will be time to healing of the primary ulcer ( complete epithelization ) , time to healing of surgical wound , recurrence of ulcer , time to recurrence and complications . Discussion The high recurrence rate of foot ulcers and their dire consequences justify attempts to find better solutions than the non-surgical options available at present . To promote surgery , RCT level evidence of efficacy is necessary . Trial registration Israel MOH_2017–08 - 10_000719 . NIH : NCT03414216 Background Synthesis of multiple r and omized controlled trials ( RCTs ) in a systematic review can summarize the effects of individual outcomes and provide numerical answers about the effectiveness of interventions . Filtering of search es is time consuming , and no single method fulfills the principal requirements of speed with accuracy . Automation of systematic review s is driven by a necessity to expedite the availability of current best evidence for policy and clinical decision-making . We developed Rayyan ( http://rayyan.qcri.org ) , a free web and mobile app , that helps expedite the initial screening of abstract s and titles using a process of semi-automation while incorporating a high level of usability . For the beta testing phase , we used two published Cochrane review s in which included studies had been selected manually . Their search es , with 1030 records and 273 records , were uploaded to Rayyan . Different features of Rayyan were tested using these two review s. We also conducted a survey of Rayyan ’s users and collected feedback through a built-in feature . Results Pilot testing of Rayyan focused on usability , accuracy against manual methods , and the added value of the prediction feature . The “ taster ” review ( 273 records ) allowed a quick overview of Rayyan for early comments on usability . The second review ( 1030 records ) required several iterations to identify the previously identified 11 trials . The “ suggestions ” and “ hints , ” based on the “ prediction model , ” appeared as testing progressed beyond five included studies . Post rollout user experiences and a reflexive response by the developers enabled real-time modifications and improvements . The survey respondents reported 40 % average time savings when using Rayyan compared to others tools , with 34 % of the respondents reporting more than 50 % time savings . In addition , around 75 % of the respondents mentioned that screening and labeling studies as well as collaborating on review s to be the two most important features of Rayyan . As of November 2016 , Rayyan users exceed 2000 from over 60 countries conducting hundreds of review s totaling more than 1.6 M citations . Feedback from users , obtained mostly through the app web site and a recent survey , has highlighted the ease in exploration of search es , the time saved , and simplicity in sharing and comparing include-exclude decisions . The strongest features of the app , identified and reported in user feedback , were its ability to help in screening and collaboration as well as the time savings it affords to users . Conclusions Rayyan is responsive and intuitive in use with significant potential to lighten the load of review ers BACKGROUND In this explorative study , we assessed the effect and feasibility of using motivational interviewing to improve footwear adherence in persons with diabetes who are at high risk for foot ulceration and show low adherence to wearing prescribed custom-made footwear . METHODS Thirteen individuals with diabetes , ulcer history , and low footwear adherence ( ie , < 80 % of steps taken in prescription footwear ) were r and omly assigned to st and ard education ( ie , verbal and written instructions ) or to st and ard education plus two 45-min sessions of motivational interviewing . Adherence was objective ly measured over 7 days using ankle- and shoe-worn sensors and was calculated as the percentage of total steps that prescribed footwear was worn . Adherence was assessed at home and away from home at baseline and 1 week and 3 months after the intervention . Feasibility was assessed for interviewer proficiency to apply motivational interviewing and for protocol executability . RESULTS Median ( range ) baseline , 1-week , and 3-month adherence at home was 49 % ( 6%-63 % ) , 84 % ( 5%-98 % ) , and 40 % ( 4%-80 % ) , respectively , in the motivational interviewing group and 35 % ( 13%-64 % ) , 33 % ( 15%-55 % ) , and 31 % ( 3%-66 % ) , respectively , in the st and ard education group . Baseline , 1-week , and 3-month adherence away from home was 91 % ( 79%-100 % ) , 97 % ( 62%-99 % ) and 92 % ( 86%-98 % ) , respectively , in the motivational interviewing group and 78 % ( 32%-97 % ) , 91 % ( 28%-98 % ) , and 93 % ( 57%-100 % ) , respectively , in the st and ard education group . None of the differences were statistically significant . Interviewer proficiency was good , and the protocol could be successfully executed in the given time frame . CONCLUSIONS Footwear adherence at home increases 1 week after motivational interviewing to clinical ly relevant but not statistically significant levels ( ie , 80 % ) but then returns over time to baseline levels . Away from home , adherence is already sufficient at baseline and remains so over time . The use of motivational interviewing seems feasible for the given purpose and patient group . These findings provide input to larger trials and provisionally suggest that additional or adjunctive therapy may be needed to better preserve adherence OBJECTIVE —The purpose of this study was to evaluate the effectiveness of a temperature monitoring instrument to reduce the incidence of foot ulcers in individuals with diabetes who have a high risk for lower extremity complications . RESEARCH DESIGN AND METHODS —In this physician-blinded , r and omized , 15-month , multicenter trial , 173 subjects with a previous history of diabetic foot ulceration were assigned to st and ard therapy , structured foot examination , or enhanced therapy groups . Each group received therapeutic footwear , diabetic foot education , and regular foot care . Subjects in the structured foot examination group performed a structured foot inspection daily and recorded their findings in a logbook . If st and ard therapy or structured foot examinations identified any foot abnormalities , subjects were instructed to contact the study nurse immediately . Subjects in the enhanced therapy group used an infrared skin thermometer to measure temperatures on six foot sites each day . Temperature differences > 4 ° F ( > 2.2 ° C ) between left and right corresponding sites triggered patients to contact the study nurse and reduce activity until temperatures normalized . RESULTS —The enhanced therapy group had fewer foot ulcers than the st and ard therapy and structured foot examination groups ( enhanced therapy 8.5 vs. st and ard therapy 29.3 % , P = 0.0046 and enhanced therapy vs. structured foot examination 30.4 % , P = 0.0029 ) . Patients in the st and ard therapy and structured foot examination groups were 4.37 and 4.71 times more likely to develop ulcers than patients in the enhanced therapy group . CONCLUSIONS —Infrared temperature home monitoring , in serving as an “ early warning sign , ” appears to be a simple and useful adjunct in the prevention of diabetic foot ulcerations This is the first multicenter prospect i ve study of outcomes of tibial neurolysis in diabetics with neuropathy and chronic compression of the tibial nerve in the tarsal tunnels . A total of 38 surgeons enrolled 628 patients using the same technique for diagnosis of compression , neurolysis of four medial ankle tunnels , and objective outcomes : ulceration , amputation , and hospitalization for foot infection . Contralateral limb tibial neurolysis occurred in 211 patients for a total of 839 operated limbs . Kaplan-Meier proportional hazards were used for analysis . New ulcerations occurred in 2 ( 0.2 % ) of 782 patients with no previous ulceration history , recurrent ulcerations in 2 ( 3.8 % ) of 57 patients with a previous ulcer history , and amputations in 1 ( 0.2 % ) of 839 at risk limbs . Admission to the hospital for foot infections was 0.6 % . In patients with diabetic neuropathy and chronic tibial nerve compression , neurolysis can result in prevention of ulceration and amputation , and decrease in hospitalization for foot infection OBJECTIVES To prevent worsening of foot deformities in diabetic patients . DESIGN A population -based and prospect i ve study . SUBJECTS All patients in the county of Umeå with Type 1 diabetes mellitus ( DM ) ( n = 308 ) aged 15 - 50 years . MAIN OUTCOME MEASURES Examination and individual education was performed . Patients with the most pronounced foot deformities ( n = 67 ) were fitted with custom-made insoles and had repeated foot examinations . An identical examination was used at a 3-year follow-up . RESULTS Patients who were fitted with insoles had higher sensory thresholds for vibration compared to those with no insoles . They were older and had longer duration of DM . Improvement of foot deformities was significantly more common in patients after treatment with insoles than in patients without . Plantar ulcers did not occur in patients with moulded insoles . CONCLUSION Information , follow-up examinations and moulded insoles improve neuropathic foot deformities in many patients , even in those with pronounced deformities OBJECTIVE To evaluate the efficacy of manufactured shoes specially design ed for diabetic patients ( Podiabetes by Buratto Italy ) to prevent relapses of foot ulcerations . RESEARCH DESIGN AND METHODS A prospect i ve multicenter r and omized follow-up study of patients with previous foot ulcerations was conducted . Patients were alternatively assigned to wear either their own shoes ( control group , C ; n = 36 ) or therapeutic shoes ( Podiabetes group , P ; n = 33 ) . The number of ulcer relapses was recorded during 1-year follow-up . RESULTS Both C and P groups had similar risk factors for foot ulceration ( i.e. , previous foot ulceration , mean vibratory perception threshold > 25 mV ) . After 1 year , the foot ulcer relapses were significantly lower in P than in C ( 27.7 vs. 58.3 % ; P = 0.009 ; odds ratio 0.26 [ 0.2–1.54 ] ) . In a multiple regression analysis , the use of therapeutic shoes was negatively associated with foot ulcer relapses ( coefficient of variation = −0.315 ; 95 % confidence interval = −0.54 to −0.08 ; P = 0.009 ) . CONCLUSIONS The use of specially design ed shoes is effective in preventing relapses in diabetic patients with previous ulceration Background Flexor tenotomy is a minimally invasive surgical alternative for the treatment of neuropathic diabetic foot ulcers on the distal end of the toe . The influence of infection on healing and time to heal after flexor tenotomy is unknown . Flexor tenotomy can also be used as a prophylactic treatment . The effectiveness as a prophylactic treatment has not been described before . Methods A retrospective study was performed with the inclusion of all consecutive flexor tenotomies from one hospital between January 2005 and December 2011 . Results From 38 ulcers , 35 healed ( 92 % ) , with a mean time to heal of 22 ± 26 days . The longest duration for healing was found for infected ulcers that were penetrating to bone ( 35 days ; p = .042 ) . Cases of prophylactic flexor tenotomies ( n=9 ) did not result in any ulcer or other complications during follow-up . Conclusions The results of this study suggest that flexor tenotomy may be beneficial for neuropathic diabetic foot ulcers on the distal end of the toe , with a high healing percentage and a short mean time to heal . Infected ulcers that penetrated to bone took a significantly longer time to heal . Prospect i ve research , to confirm the results of this retrospective study , should be performed Background . Patient education is capable of reducing the risk for diabetic foot ulcers . However , specific education on foot ulcer prevention was either included in broader programs addressing different parts of diabetes care or provided with time- and re source -consuming curricula . The aim of the study is to assess the feasibility and efficacy of a brief educational program for the prevention of diabetic foot ulcers in high-risk patients . Methods . The study was performed on type 2 diabetic patients , r and omized in a 1 : 1 ratio either to intervention or to control group . The principal endpoint was the incidence of foot ulcers . The intervention was a two-hour program provided to groups of 5–7 patients , including a 30-minute face-to-face lesson on risk factors for foot ulcers , and a 90-minute interactive session with practical exercises on behaviors for reducing risk . Results . The study was prematurely terminated due to a highly significant difference in outcome between the two treatment groups . The final sample was therefore composed of 121 patients . Six patients , all in the control group , developed ulcers during the 6-month follow-up ( 10 % versus 0 % , p = 0.012 ) . Conclusions . A brief , 2-hour , focused educational program is effective in preventing diabetic foot ulcers in high-risk patients OBJECTIVE To evaluate the influence of podiatrist activities on the outpatient care of diabetic patients in terms of knowledge of diabetic foot care , self-care , and minor foot problems . RESEARCH DESIGN AND METHODS There were 733 patients , aged 10–79 years , identified from the national diabetes register . Patients without recent visits to a podiatrist and without an obvious need for foot care were r and omized into a podiatric care group ( education and primary prevention measures , n = 267 ) and a control group ( written instructions only , n = 263 ) . The patients were examined by an independent study podiatrist at baseline and after 1 year . RESULTS Patients in the podiatrist group had greater improvement in knowledge of diabetic foot care ( P = 0.004 ) and self-care ( P < 0.001 ) scores compared with control subjects . The prevalence of callosities in regions other than the calcaneal region decreased more ( P = 0.009 ) in the podiatrist group ( from 54.5 to 39.5 % ) than in the control group ( from 51.3 to 48.2 % ) , and the size of the callosities decreased more ( P < 0.001 ) in the podiatrist group than in the control group . Reduction in the prevalence of callosities was associated with younger age ( < 50 years ) . CONCLUSIONS Education and primary preventive measures provided individually by a podiatrist result in significant improvements in knowledge and foot self-care scores and in improvements in the prevalence of some minor foot problems . Long-term studies are needed to evaluate whether the intervention of podiatrists starting at an early phase would lead to a reduction in major foot problems Objective . The objective of this study was to assess the impact of a structured follow-up program on the incidence of diabetic foot ulceration ( DFU ) in high-risk diabetic patients . Research Design and Methods . A total of 1874 diabetic patients referred to the Diabetic Foot Unit of the University of Pisa were ranked based on the ulcerative risk score proposed by the International Consensus on Diabetic Foot . Out of 334 patients ( 17.8 % ) with a score ≥2 , 298 accepted to participate in this prospect i ve trial and were r and omized into 2 groups : group A , which received st and ard treatment , and group B , in which the patients received , as a part of a structured prevention program , custom-made orthesis and shoes . Incidence of new DFUs was observed for no less than 1 year and in a subset of patients after 3 and 5 years , respectively . Incidence of new DFUs and recurrences were considered as primary endpoints to establish the effectiveness of the program ; costs were also compared . Results . Among the patients enrolled in this follow-up analysis , 46 % had neuropathy and deformities , 20 % had previous ulceration , 25 % had previous minor amputation , and 9 % had neuro-osteoarthropathy . During the first 12-month follow-up , 11.5 % of patients in group B developed a DFU compared with 38.6 % in group A ( P < .0001 ) . In the extended follow-up , the cumulative incidence of ulcer in group B compared with group A was 17.6 % versus 61 % ( P < .0001 ) after 3 years and 23.5 % versus 72 % ( P < .0001 ) after 5 years , respectively . The net balance at the end of the follow-up was highly in favor of the prevention program , with a saving of more than € 100 000 per year . Conclusions . The implementation of a structured follow-up with the use of orthesis and shoes can reduce the incidence of DFU in diabetic patients who are at high ulcerative risk and its related costs Abstract Aims /hypothesisWe investigated skin microcirculation and its association with HbA1c and the incidence of ischaemic foot ulcer in patients with type 1 diabetes formerly r and omised ( 1982–1984 ) to intensified conventional treatment ( ICT ) or st and ard treatment ( ST ) with insulin for a mean of 7.5 years . Methods We re-determined the skin microcirculation of 72 patients ( ICT 35 vs ST 37 ) from the original Stockholm Diabetes Intervention Study with iontophoresis topically applied with the following vasoactive stimuli : acetylcholine ( ACh ) ( endothelial-dependent vasodilatation ) , sodium nitroprusside ( SNP ) ( endothelial-independent vasodilatation ) , and capsaicin ( C-nociceptive-dependent vasodilatation ) . HbA1c levels ( mean of 14 values/patient ) were prospect ively collected between 1990 and 1995 and tested for association with skin microcirculation . The patients were followed until first hospitalisation for an ischaemic foot ulcer or until 2011 . Results During the median 28 years of follow-up , three patients developed ischaemic foot ulcers in the ICT group compared with ten in the ST group ( logrank , p = 0.035 ) . At the time of iontophoresis , HbA1c was lower in the ICT group ( median 57 mmol/mol [ minimum – maximum 40–79 mmol/mol ] ) compared with the ST group ( 68 mmol/mol [ 41–96 mmol/mol ] , p < 0.01 ) ( DCCT : ICT 7.4 % [ 5.8–9.4 % ] vs ST 8.4 % [ 5.9–10.9 % ] ) . Stimulated blood flow was higher in the ICT vs ST group with significantly increased perfusion units ( PU ) for : ACh ( 8.1 PU [ 4.6–24.7 PU ] vs 5.3 PU [ 1.7–21.4 PU ] , p < 0.01 ) ; SNP ( 8.1 PU [ 2.2–20.1 PU ] vs 5.6 PU [ 2.3–19.2 PU ] , p = 0.03 ) ; and capsaicin ( 5.0 PU [ 1.7–22.9 PU ] vs 3.4 PU [ 1.5–8.4 PU ] , p < 0.01 ) . HbA1c was associated with vasodilatation induced by ACh ( b = −0.02 , p < 0.01 ) and capsaicin ( b = −0.02 , p = 0.03 ) . HbA1c was independently associated with ACh ( b = −1.48 , p < 0.01 ) and capsaicin-induced vasodilatation ( b = −1.45 , p < 0.01 ) . Conclusions /interpretationImproved glycaemic control in patients with type 1 diabetes is associated with an improvement in skin microcirculation and with a lower incidence of ischaemic foot ulcers . Trial registration : Clinical Trials.gov This prospect i ve r and omized study evaluated the influence of a simple education program on the incidence of lower extremity amputation in diabetic patients . Two hundred three patients were r and omized into two groups : Group 1 , education ( 103 patients , 203 limbs ) and Group 2 , no education ( 100 patients , 193 limbs ) . There were no significant differences in medical management or clinical risk factors between the two groups . The amputation rate was three times higher in Group 2 ( 21 of 177 limbs versus 7 of 177 limbs ; p less than or equal to 0.025 ) , the ulceration rate was three times higher in Group 2 ( 26 of 177 limbs versus 8 of 177 limbs ; p less than or equal to 0.005 ) , and there was no difference in the overall incidence of infection ( 2 of 177 limbs ) . Overall success in Group 1 was highly significantly different from Group 2 ( 160 of 177 limbs versus 128 of 177 limbs ; p less than or equal to 0.0005 ) . This study demonstrated that a simple education program significantly reduced the incidence of ulcer or foot and limb amputation in diabetic patients OBJECTIVE To evaluate the effectiveness of at-home infrared temperature monitoring as a preventative tool in individuals at high risk for diabetes-related lower-extremity ulceration and amputation . RESEARCH DESIGN AND METHODS Eighty-five patients who fit diabetic foot risk category 2 or 3 ( neuropathy and foot deformity or previous history of ulceration or partial foot amputation ) were r and omized into a st and ard therapy group ( n = 41 ) or an enhanced therapy group ( n = 44 ) . St and ard therapy consisted of therapeutic footwear , diabetic foot education , and regular foot evaluation by a podiatrist . Enhanced therapy included the addition of a h and held infrared skin thermometer to measure temperatures on the sole of the foot in the morning and evening . Elevated temperatures ( > 4 degrees F compared with the opposite foot ) were considered to be " at risk " of ulceration due to inflammation at the site of measurement . When foot temperatures were elevated , subjects were instructed to reduce their activity and contact the study nurse . Study subjects were followed for 6 months . RESULTS The enhanced therapy group had significantly fewer diabetic foot complications ( enhanced therapy group 2 % vs. st and ard therapy group 20 % , P = 0.01 , odds ratio 10.3 , 95 % CI 1.2 - 85.3 ) . There were seven ulcers and two Charcot fractures among st and ard therapy patients and one ulcer in the enhanced therapy group . CONCLUSIONS These results suggest that at-home patient self-monitoring with daily foot temperatures may be an effective adjunctive tool to prevent foot complications in individuals at high risk for lower-extremity ulceration and amputation BACKGROUND Limited ankle dorsiflexion has been implicated as a contributing factor to plantar ulceration of the forefoot in diabetes mellitus . The purpose of this study was to compare outcomes for patients with diabetes mellitus and a neuropathic plantar ulcer treated with a total-contact cast with and without an Achilles tendon lengthening . Our primary hypothesis was that the Achilles tendon lengthening would lead to a lower rate of ulcer recurrence . METHODS Sixty-four subjects were r and omized into two treatment groups , immobilization in a total-contact cast alone or combined with percutaneous Achilles tendon lengthening , with measurements made before and after treatment , at the seven-month follow-up examination , and at the final follow-up evaluation ( a mean [ and st and ard deviation ] of 2.1 + /- 0.7 years after initial healing ) . There were thirty-three subjects in the total-contact cast group and thirty-one subjects in the Achilles tendon lengthening group . There were no significant differences in age , body-mass index , or duration of diabetes between the groups . Outcome measures were time to healing of the ulcer , ulcer recurrence rate , range of dorsiflexion of the ankle , peak torque ( strength ) of the plantar flexor muscles , and peak plantar pressures on the forefoot . RESULTS Twenty-nine ( 88 % ) of thirty-three ulcers in the total-contact cast group and all thirty ulcers ( 100 % ) in the Achilles tendon lengthening group healed after a mean duration ( and st and ard deviation ) of 41 + /- 28 days and 58 + /- 47 days , respectively ( p > 0.05 ) . ( One patient in the Achilles tendon lengthening group died before treatment was completed . ) In the first seven months of follow-up , sixteen ( 59 % ) of the twenty-seven patients in the total-contact cast group who were available for follow-up and four ( 15 % ) of the twenty-seven patients in the Achilles tendon lengthening group who were available for follow-up had an ulcer recurrence ( p = 0.001 ) . At the time of the two-year follow-up , twenty-one ( 81 % ) of the twenty-six patients in the total-contact cast group and ten ( 38 % ) of the twenty-six patients in the Achilles tendon lengthening group had ulcer recurrence ( p = 0.002 ) . Compared with the group treated with the total-contact cast , the group treated with Achilles tendon lengthening had increased dorsiflexion and it remained increased at seven months ( p < 0.001 ) . Plantar flexor peak torque also decreased after Achilles tendon lengthening ( p < 0.004 ) , but it returned to baseline after seven months . Peak plantar pressures on the forefoot during barefoot walking were reduced ( p < 0.0002 ) following Achilles tendon lengthening yet returned to baseline values within seven months after treatment . CONCLUSIONS All ulcers healed in the Achilles tendon lengthening group , and the risk for ulcer recurrence was 75 % less at seven months and 52 % less at two years than that in the total-contact cast group . Achilles tendon lengthening should be considered an effective strategy to reduce recurrence of neuropathic ulceration of the plantar aspect of the forefoot in patients with diabetes mellitus and limited ankle dorsiflexion ( < /=5 degrees ) OBJECTIVE —The ability of readily available clinical information to predict the occurrence of diabetic foot ulcer has not been extensively studied . We conducted a prospect i ve study of the individual and combined effects of commonly available clinical information in the prediction of diabetic foot ulcer occurrence . RESEARCH DESIGN AND METHODS —We followed 1,285 diabetic veterans without foot ulcer for this outcome with annual clinical evaluations and quarterly mailed question naires to identify foot problems . At baseline we assessed age ; race ; weight ; current smoking ; diabetes duration and treatment ; HbA1c ( A1C ) ; visual acuity ; history of laser photocoagulation treatment , foot ulcer , and amputation ; foot shape ; claudication ; foot insensitivity to the 10-g monofilament ; foot callus ; pedal edema ; hallux limitus ; tinea pedis ; and onychomycosis . Cox proportional hazards modeling was used with backwards stepwise elimination to develop a prediction model for the first foot ulcer occurrence after the baseline examination . RESULTS —At baseline , subjects were 62.4 years of age on average and 98 % male . Mean follow-up duration was 3.38 years , during which time 216 foot ulcers occurred , for an incidence of 5.0/100 person-years . Significant predictors ( P ≤ 0.05 ) of foot ulcer in the final model ( hazard ratio , 95 % CI ) included A1C ( 1.10 , 1.06–1.15 ) , impaired vision ( 1.48 , 1.00–2.18 ) , prior foot ulcer ( 2.18 , 1.61–2.95 ) , prior amputation ( 2.57 , 1.60–4.12 ) , monofilament insensitivity ( 2.03 , 1.50–2.76 ) , tinea pedis ( 0.73 , 0.54–0.98 ) , and onychomycosis ( 1.58 , 1.16–2.16 ) . Area under the receiver operating characteristic curve was 0.81 at 1 year and 0.76 at 5 years . CONCLUSIONS —Readily available clinical information has substantial predictive power for the development of diabetic foot ulcer and may help in accurately targeting persons at high risk of this outcome for preventive interventions Background Although monitoring foot skin temperatures has been associated with diabetic foot ulcer recurrence , no studies have been carried out to test the feasibility among European Caucasians . Moreover , the educational and /or motivational models that promote cognitive or psychosocial processes in these studies are lacking . Thus , we conducted a pilot r and omized controlled trial to test the feasibility of monitoring foot skin temperatures in combination with theory-based counselling to st and ard foot care to reduce diabetic foot ulcer recurrence . Methods In a single-blinded nurse-led 1-year controlled trial , conducted at a hospital setting in Norway , 41 patients with diabetic neuropathy and previous foot ulcer were r and omized to the intervention ( n = 21 ) or control groups ( n = 20 ) . All participants were instructed in foot care and recording observations daily . Additionally , the intervention group was taught how to monitor and record skin temperature at baseline , and received counselling every third month supporting them to use the new treatment . Subjects observing temperature differences > 2.0 ° C between corresponding sites on the left and right foot on two consecutive days were asked to contact the study nurse and reduce physical activity . Fisher exact test was used to evaluate the effect of the intervention on the proportion of subjects with a foot ulcer . Kaplan-Meier survival analysis was performed to compare the two groups in regard to the time to development of a foot ulcer . Results In the intervention group , 67 % ( n = 14/21 ) monitored and recorded skin temperatures ≥80 % of the time while 70 % ( n = 14/20 ) of the controls recorded foot inspections . Foot ulcer incidence was 39 % ( 7/21 ) vs. 50 % ( 10/20 ) in the intervention and control groups , respectively ( ns ) . Conclusions This feasibility study showed that the addition of counselling to promote self-monitoring of skin temperature to st and ard care to prevent recurrence of foot ulcer is feasible in patients with diabetes in Norway . Home skin temperature monitoring was performed as frequently by the intervention group as usual foot observations in the controls despite the extra effort required . We did not detect a difference in foot ulcer recurrence between groups , but our study may inform future full scale studies .Trial registration Clinical trials.gov OBJECTIVE Custom-made footwear is the treatment of choice to prevent foot ulcer recurrence in diabetes . This footwear primarily aims to offload plantar regions at high ulcer risk . However , ulcer recurrence rates are high . We assessed the effect of offloading-improved custom-made footwear and the role of footwear adherence on plantar foot ulcer recurrence . RESEARCH DESIGN AND METHODS We r and omly assigned 171 neuropathic diabetic patients with a recently healed plantar foot ulcer to custom-made footwear with improved and subsequently preserved offloading ( ∼20 % peak pressure relief by modifying the footwear ) or to usual care ( i.e. , nonimproved custom-made footwear ) . Primary outcome was plantar foot ulcer recurrence in 18 months . Secondary outcome was ulcer recurrence in patients with an objective ly measured adherence of ≥80 % of steps taken . RESULTS On the basis of intention-to-treat , 33 of 85 patients ( 38.8 % ) with improved footwear and 38 of 86 patients ( 44.2 % ) with usual care had a recurrent ulcer ( relative risk −11 % , odds ratio 0.80 [ 95 % CI 0.44–1.47 ] , P = 0.48 ) . Ulcer-free survival curves were not significantly different between groups ( P = 0.40 ) . In the 79 patients ( 46 % of total group ) with high adherence , 9 of 35 ( 25.7 % ) with improved footwear and 21 of 44 ( 47.8 % ) with usual care had a recurrent ulcer ( relative risk −46 % , odds ratio 0.38 [ 0.15–0.99 ] , P = 0.045 ) . CONCLUSIONS Offloading-improved custom-made footwear does not significantly reduce the incidence of plantar foot ulcer recurrence in diabetes compared with custom-made footwear that does not undergo such improvement , unless it is worn as recommended Background Higher plantar pressures play an important role in the development of plantar foot ulceration in diabetic polyneuropathy and earlier studies suggest that higher pressures under the forefoot may be related to a decrease in lower leg muscle strength . Therefore , in this r and omised controlled trial we evaluated whether lower-extremity strength training can reduce plantar pressures in diabetic polyneuropathy . Methods This study was embedded in an unblinded r and omised controlled trial . Participants had diabetes and polyneuropathy and were r and omly assigned to the intervention group ( n = 48 ) receiving strength training during 24 weeks , or the control group ( n = 46 ) receiving no intervention . Plantar pressures were measured in both groups at 0 , 12 , 24 and 52 weeks . A r and om intercept model was applied to evaluate the effects of the intervention on peak pressures and pressure – time-integrals , displacement of center-of-pressure and the forefoot to rearfoot pressure – time-integral-ratio . Results Plantar pressure patterns were not affected by the strength training . In both the intervention and control groups the peak pressure and the pressure – time-integral under the forefoot increased by 55.7 kPa ( 95 % CI : 14.7 , 96.8 ) and 2.0 kPa.s ( 95 % CI : 0.9 , 3.2 ) over 52 weeks , respectively . Both groups experienced a high number of drop-outs , mainly due to deterioration of health status and lower-extremity disabilities . Conclusions Plantar pressures under the forefoot increase progressively over time in people with diabetic polyneuropathy , but in this study were not affected by strength training . Future intervention studies should take this increase of plantar pressure into account and alternative interventions should be developed to reduce the progressive lower extremity problems in these patients .Trial registration This study was embedded in a clinical trial with trial number NCT00759265 OBJECTIVE To assess the efficacy of in-shoe orthoses that were design ed based on shape and barefoot plantar pressure in reducing the incidence of submetatarsal head plantar ulcers in people with diabetes , peripheral neuropathy , and a history of similar prior ulceration . RESEARCH DESIGN AND METHODS Single-blinded multicenter r and omized controlled trial with subjects r and omized to wear shape- and pressure-based orthoses ( experimental , n = 66 ) or st and ard-of-care A5513 orthoses ( control , n = 64 ) . Patients were followed for 15 months , until a study end point ( forefoot plantar ulcer or nonulcerative plantar forefoot lesion ) or to study termination . Proportional hazards regression was used for analysis . RESULTS There was a trend in the composite primary end point ( both ulcers and nonulcerative lesions ) across the full follow-up period ( P = 0.13 ) in favor of the experimental orthoses . This trend was due to a marked difference in ulcer occurrence ( P = 0.007 ) but no difference in the rate of nonulcerative lesions ( P = 0.76 ) . At 180 days , the ulcer prevention effect of the experimental orthoses was already significant ( P = 0.003 ) when compared with control , and the benefit of the experimental orthoses with respect to the composite end point was also significant ( P = 0.042 ) . The hazard ratio was 3.4 ( 95 % CI 1.3–8.7 ) for the occurrence of a submetatarsal head plantar ulcer in the control compared with experimental arm over the duration of the study . CONCLUSIONS We conclude that shape- and barefoot plantar pressure – based orthoses were more effective in reducing submetatarsal head plantar ulcer recurrence than current st and ard-of-care orthoses , but they did not significantly reduce nonulcerative lesions OBJECTIVE To assess the perceived usability and use of custom- made footwear in diabetic patients who are at high-risk for foot ulceration , and to eluci date the determinants of usability and use . DESIGN Survey . SUBJECTS A total of 153 patients with diabetes , peripheral neuropathy , prior plantar foot ulceration and newly prescribed custom-made footwear , recruited from 10 Dutch multidisciplinary foot clinics . METHODS The Question naire of Usability Evaluation was used to assess the patients ' perception of weight , appearance , comfort , durability , donning/doffing , stability , benefit and overall appreciation of their prescription footwear ( all expressed as visual analogue scores ) . Data on priorities for usability and footwear use ( in h/day ) were obtained from patient reports . Multivariate logistic regression analysis was used to assess determinants of usability and use . RESULTS Median ( interquartile range ) score for overall appreciation was 8.3 ( 7.1 - 9.1 ) . Scores ranged from 6.5 ( 4.5 - 8.6 ) for weight to 9.6 ( 6.3 - 9.9 ) for donning/doffing . Footwear comfort was listed most often ( 33.3 % ) as the highest priority . Footwear use was < 60 % of daytime ( where daytime was defined as 16 h out of bed ) in 58 % of patients . The only significant determinant of footwear use was the perceived benefit of the footwear ( p = 0.045 ) . CONCLUSION Perceived usability of footwear was mostly positive , although individual scores and priorities varied considerably . Footwear use was low to moderate and dependent only on the perceived benefit of the footwear . Therefore , practitioners should focus on enhancing the patient 's ap-preciation of the therapeutic benefit of custom-made footwear The purpose of this study was to determine whether the routine use of a topical antifungal nail lacquer ( AFL ) could reduce the risk for ulceration by theoretically increasing the frequency of patient self-inspection . In this r and omised controlled trial , 70 persons at high risk for diabetic foot ulceration were enrolled into a preventative care program involving daily self-inspection with the possible use of an AFL ( ciclopirox 8 % ) versus self-inspection instructions alone ( NAFL ) . Patients were followed for 12 months or until ulceration . Using an intent to treat analysis , there was no significant difference in proportion of persons ulcerating in the AFL versus the NAFL groups ( 5.9 % versus 5.6 % P = 0.9 ) . There was also no difference in the number of unexpected visits ( P = 0.2 ) or missed appointments ( P = 0.7 ) between treatment arms . Interestingly , while there was no difference in proportion of patients with clinical ly diagnosed hyperkeratosis or tinea pedis on entry into the study ( P = 0.2 ) , a significantly lower proportion of AFL patients had a clinical diagnosis on study termination ( 52.9 % versus 77.8 % P = 0.03 , OR = 1.7 , 95 % confidence interval = 1.1 - 2.7 ) . The results of this study suggest that there may be no immediate prophylactic benefit through the use of AFL to prevent wounds . The incidental finding of a potential reduction in hyperkeratosis and tinea pedis is a compelling one and may deserve further investigation AIM The aim of this study was to assess the effectiveness of a preventative foot care nursing programme for diabetic patients . BACKGROUND Foot complications are common in diabetic patients and prevention of such complications requires foot care . However , there is little information on the effectiveness of foot care nursing on the incidence and recurrence of diabetic foot . METHODS We developed a diabetic foot care programme based on the International Working Group on the Diabetic Foot . We studied 88 patients who attended our foot care programme for 2 years , and collected data from April 2005 to March 2009 . Patients were divided into four groups according to the risk classification , and received foot care . We evaluated the incidence of foot ulceration or recurrence and non-ulcerated foot condition . Characteristics of the patients were analysed using the paired t-test and McNemar 's test , and changes in severity of tinea pedis and grade of callus were analysed using Wilcoxon 's signed rank sum test . RESULTS The programme reduced the severity score of tinea pedis ( P < 0·001 ) and improved callus grade ( P < 0·001 ) . All these were evaluated by Wilcoxon 's signed rank sum test . None of the patients of risk-group-3 ( history of foot ulceration ) showed recurrence of callus-related foot ulcers . Six high-risk patients developed foot ulceration during the programme because of minor injury , but the ulcers healed without development of gangrene . CONCLUSION A nurse-based foot care programme is effective in preventing diabetic foot in diabetic patients CONTEXT Many people with diabetes experience lower-limb ulcers . Footwear has been implicated as a primary cause of foot ulcers , yet research is limited on the efficacy of shoe and insert combinations to prevent reulceration . OBJECTIVE To determine whether extra-depth and -width therapeutic shoes used with 2 types of inserts reduce reulceration in diabetic individuals with a history of foot ulcer . DESIGN , SETTING , AND PARTICIPANTS R and omized clinical trial of 400 diabetes patients with history of foot ulcer in 2 Washington State health care organizations who did not require custom shoes for foot deformity and were enrolled between August 1997 and December 1998 and followed up for 2 years . Data collected at regular intervals documented physical , foot , and diabetes characteristics ; footwear use ; foot lesions ; and ulcers . INTERVENTIONS Participants were r and omly assigned to receive 3 pairs of therapeutic shoes and 3 pairs of customized medium-density cork inserts with a neoprene closed-cell cover ( n = 121 ) ; to receive 3 pairs of therapeutic shoes and 3 pairs of prefabricated , tapered polyurethane inserts with a brushed nylon cover ( n = 119 ) ; or to wear their usual footwear ( controls ; n = 160 ) . MAIN OUTCOME MEASURE Foot reulceration , compared among the 3 groups . RESULTS Two-year cumulative reulceration incidence across the 3 groups was low : 15 % in the cork-insert group , 14 % in the prefabricated-insert group , and 17 % in controls . In the intent-to-treat analysis , patients assigned to therapeutic shoes did not have a significantly lower risk of reulceration compared with controls ( risk ratio [ RR ] for the cork-insert group , 0.88 ; 95 % confidence interval [ CI ] , 0.51 - 1.52 and RR the for prefabricated-insert group , 0.85 ; 95 % CI , 0.48 - 1.48 ) . All ulcer episodes in patients assigned to therapeutic shoes and 88 % wearing non study shoes occurred in patients with foot insensitivity . CONCLUSIONS This study of persons without severe foot deformity does not provide evidence to support widespread dispensing of therapeutic shoes and inserts to diabetic patients with a history of foot ulcer . Study shoes and custom cork or preformed polyurethane inserts conferred no significant ulcer reduction compared with control footwear . This study suggests that careful attention to foot care by health care professionals may be more important than therapeutic footwear but does not negate the possibility that special footwear is beneficial in persons with diabetes who do not receive such close attention to foot care by their health care providers or in individuals with severe foot deformities OBJECTIVE To evaluate the influence of regular chiropodist care on the recurrence rate of diabetic foot ulcers within 1 year . RESEARCH DESIGN AND METHODS Ninety-one diabetic out patients with healed foot ulcers ( age 65 + /- 11 years , 40 women and 51 men , diabetes type 1 ( n = 6 ) or 2 ( n = 85 ) , BMI 28.5 + /- 4.4 , diabetes duration 16 + /- 11 years , HbA(1c ) 8.4 + /- 1.6 % ) were r and omized to a group that received monthly remunerated routine chiropodist care ( n = 47 ) or a control group ( n = 44 ) . RESULTS Within a median follow-up of 386 days , ulceration recurred in 18 patients in the chiropodist group and 25 patients in the control group ( hazard ratio [ HR ] 0.60 ; 95 % CI , 0.32 , 1.08 ; P = 0.09 ) . Analysis of ulceration per foot demonstrated a significant reduction ( 20 vs. 32 ulcerations ; Cox relative risk [ Cox RR ] 0.52 ; 95 % CI , 0.30 , 0.93 ; P = 0.03 ) in favor of chiropodist care . Per protocol , analysis of patients who actually underwent chiropodist foot care on a regular basis also indicates the beneficial influence of chiropodist care with ulceration in 13 vs. 30 patients ( HR , 0.53 ; 95 % CI , 0.30 - 1.01 ; P = 0.05 ) and in 15 vs. 37 feet ( Cox RR , 0.46 ; 95 % CI , 0.24 - 0.90 ; P = 0.02 ) for the intervention and control groups , respectively . Minor amputation was required in two patients in the intervention group and one patient in the control group . Four patients in the control group and two patients in the intervention group died during the trial . CONCLUSIONS These data suggest that secondary preventive measures by a chiropodist may reduce recurrence of foot ulcers in diabetic patients Background Adults on dialysis are at increased risk of foot ulceration , which commonly precedes more serious lower limb complications , including amputation . Limited data exist regarding the prevalence and factors associated with foot disease in this population . Hence , this study set out to investigate factors associated with foot ulceration and amputation in a dialysis cohort . Methods This study presents a cross-sectional analysis of baseline data from a multi-center prospect i ve cohort study . We recruited 450 adults with end-stage renal disease on dialysis from multiple satellite and home-therapy dialysis units in Melbourne , Australia from January to December 2014 . Data collection consisted of a participant interview , medical record review , health-status question naire and non-invasive foot examination . Logistic regression analyses were conducted to evaluate associations between screened variables and study outcomes . Results Mean age was 67.5 ( SD , 13.2 ) years , 64.7 % were male , 94 % were on hemodialysis , median dialysis duration was 36.9 ( IQR , 16.6 to 70.1 ) months , and 50.2 % had diabetes . There was a high prevalence of previous ulceration ( 21.6 % ) and amputation ( 10.2 % ) , 10 % had current foot ulceration , and 50 % had neuropathy and /or peripheral arterial disease . Factors associated with foot ulceration were previous amputation ( OR , 10.19 ) , peripheral arterial disease ( OR , 6.16 ) and serum albumin ( OR , 0.87 ) ; whereas previous and /or current ulceration ( OR , 167.24 and 7.49 , respectively ) and foot deformity ( OR , 15.28 ) were associated with amputation . Conclusions Dialysis patients have a high burden of lower limb complications . There are markedly higher risks of foot ulceration and /or amputation in those with previous and /or current ulceration , previous amputation , peripheral arterial disease , lower serum albumin , and foot deformity . Although not a major risk factor , diabetes in men was an important effect modifier for risk of ulceration BACKGROUND Nerve entrapment , common in diabetes , is considered an associated phenomenon without large consequence in the development of diabetes complications such as ulceration , infection , amputation , and early mortality . This prospect i ve analysis , with controls , of the ulcer recurrence rate after operative nerve decompression ( ND ) offers an objective perspective on the possibility of frequent occult nerve entrapment in the diabetic foot complication cascade . METHODS A multicenter cohort of 42 patients with diabetic sensorimotor polyneuropathy , failed pharmacologic pain control , palpable pulses , and at least one positive Tinel 's nerve percussion sign was treated with unilateral multiple lower-leg external neurolyses for the indication of pain . All of the patients had healed at least one previous ipsilateral plantar diabetic foot ulceration ( DFU ) . This group was retrospectively evaluated a minimum of 12 months after operative ND and again 3 years later . The recurrence risk of ipsilateral DFU in that period was prospect ively analyzed and compared with new ulcer occurrence in the contralateral intact , nonoperated control legs . RESULTS Operated legs developed two ulcer recurrences ( 4.8 % ) , and nine contralateral control legs developed ulcers ( 21.4 % ) , requiring three amputations . Ulcer risk is 1.6 % per patient per year in ND legs and 7 % in nonoperated control legs ( P = .048 ) . CONCLUSIONS Adding operative ND at lower-leg fibro-osseous tunnels to st and ard postulcer treatment result ed in a significantly diminished rate of subsequent DFU in neuropathic high-risk feet . This is prospect i ve , objective evidence that ND can provide valuable ongoing protection from DFU recurrence , even years after primary ulcer healing BACKGROUND In diabetic patients with complications from peripheral neuropathy , the hyperpressure areas can rapidly lead to ulcerative lesions in the absence of protective sensation . Partial digital silicone orthoses could provide an innovative and functional therapeutic solution in the management of preulcerative areas of the forefoot in neuropathic diabetic patients . We clinical ly tested this hypothesis . METHODS Digital off-loading silicone padding was prepared for 89 neuropathic patients with deformities and localized hyperkeratosis in the forefoot . After 3 months and in basal conditions , the number of areas of hyperkeratosis was evaluated together with the hardness of the skin , the number of active lesions , and any adverse events associated with use of the orthosis . The patients were compared to a control group of 78 r and omized patients undergoing st and ard therapy . In a subgroup of 10 patients , a static and dynamic biomechanical evaluation was also conducted with a computerized podobarometric platform . RESULTS Both the number of lesions and the prevalence of hyperkeratosis and skin hardness were significantly lower ( P < .01 ) in the group treated with the silicone orthoses than in the control group . No adverse events were reported during the 3 months of observation . The podobarometric analysis highlighted a significant ( P < .001 ) reduction of peak pressure in the areas undergoing orthotic correction . CONCLUSIONS Silicone padding is effective and safe in the prevention of lesions in neuropathic patients at high risk of ulceration and significantly reduces the incidence of new lesions in the 3-month follow-up period compared to st and ard treatment To test the efficacy of surgical treatment of non-infected neuropathic foot ulcers compared to conventional non-surgical management , a group of diabetic out patients attending our diabetic foot clinic were studied . All patients who came to the clinic for the first time from January to December 1995 inclusive with an uncomplicated neuropathic ulcer were r and omized into two groups . Group A received conservative treatment , consisting of relief of weight-bearing , regular dressings ; group B underwent surgical excision , eventual debridement or removal of bone segments underlying the lesion and surgical closure . Healing rate , healing time , prevalence of infection , relapse during a 6-month period following intervention and subjective discomfort were assessed . Twenty-four ulcers in 21 patients were treated in group A ( 17 Type 2 DM/3 Type 1 DM , age 63.24 + /- 13.46 yr , duration of diabetes 18.2 + /- 8.41 yr , HbA1c 9.5 + /- 3.8 % ) and 22 ulcers in 21 patients in group B ( 19 Type 2 DM/2 Type 1 DM , age 65.53 + /- 9.87yr , duration of diabetes 16.84 + /- 10.61 yr ; HbA1c 8.9 + /- 2.2 % ) . Healing rate was lower ( 79.2 % = 19/24 ulcers ) in group A than in group B ( 95.5 % = 21/22 ulcers ; p < 0.05 ) , and healing time was longer ( 128.9 + /- 86.60 days vs 46.73 + /- 38.94 days ; p < 0.001 ) . Infective complications occurred significantly more often in group A patients ( 3/24 , 12.5 % vs 1/22 , 4.5 % ; p < 0.05 ) , as did relapses of ulcerations ( 8 vs 3 ; p < 0.01 ) . There were only two minor perioperative complications in group B patients . Patients reported a higher degree of satisfaction in group B ( p < 0.01 ) as well as lower discomfort ( p < 0.05 ) and restrictions ( p < 0.05 ) . Thus surgical treatment of neuropathic foot ulcers in diabetic patients proved to be an effective approach compared to conventional treatment in terms of healing time , complications , and relapses , and can be safely performed in an outpatient setting Despite the established role of foot care education in diabetes management , reports evaluating such interventions are rare . The effectiveness of an intensive foot care intervention programme and a conventional one were therefore compared in Type 2 diabetes . The intensive group showed significantly greater improvements than the conventional group in foot care knowledge ( p less than 0.001 ) , compliance with the recommended foot care routine ( p = 0.012 ) , and compliance with the initial advice to consult a podiatrist ( other than the project podiatrist ) for further treatment ( p = 0.008 ) . At the first follow-up visit the intensive group also showed a significantly greater reduction in the number of foot problems requiring treatment than the conventional group Custom‐made footwear is used to offload the diabetic foot to prevent plantar foot ulcers . This prospect i ve study evaluates the offloading effects of modifying custom‐made footwear and aims to provide data ‐driven directions for the provision of effectively offloading footwear in clinical practice PURPOSE the purpose of this study was to test the effectiveness of an educational intervention to improve patients ' foot care knowledge , self-efficacy , and self-care practice s. METHODS A prospect i ve , r and omized , single center , 2-group design was used with a convenience sample of 40 home care patients from a Medicare-certified home health agency . Baseline measures of foot care knowledge , self-efficacy , and reported self-care practice s were obtained at study entry and 6 weeks later to control for foot care interventions provided during routine home care services . After obtaining the 6-week baseline measures , patients who were r and omized to the intervention group received individualized education about proper foot care . All patients were interviewed a third time 3 months after study entry to determine the effectiveness of the intervention . RESULTS The educational intervention improved patients ' knowledge , confidence , and reported foot care behaviors . CONCLUSIONS A brief , individualized educational intervention about st and ard foot care topics improved patients ' foot care knowledge and self-efficacy as well as reported self-care practice s. Incorporating such interventions into routine home care services may enhance the quality of care and decrease the incidence of lower-extremity complications We set out to evaluate a clinical foot-screening programme in terms of primary outcomes ( reductions in the incidence of ulcers and lower limb amputation ) and process outcomes ( compliance with screening , the number of patients not completing the programme and the use of chiropody services and prescribed footwear and cost ) . All but 4 of 2001 patients attending a general diabetic out-patient clinic were allocated r and omly to index and control groups . The exceptions were patients who presented with active ulcers and were placed in the index group . Primary and secondary screening programmes identified 128 high risk patients in the index group and these were admitted to the foot protection programme . At 2-year follow-up , 11 fewer ulcers were reported from the index group . There were 7 amputations ( 1 major , 6 minor ) in the index group and 23 ( 12 major and 13 minor ) in the control group . The differences were not statistically significant for ulceration or minor amputations but significant for major amputations ( p < 0.01 ) . The total cost of the 2-year programme was pounds sterling 100,372 ( 1991 - 92 costs ) , with a mean cost per patient of approximately pounds sterling 100 . Taking pounds sterling 12,000 as a conservative estimate of the cost of a major amputation , the foot clinic was cost-effective in terms of amputations averted . The process outcomes were much less satisfactory . Cost-effectiveness could have been improved if it had been possible to improve patient compliance Between 1993 and 1995 , 93 neuropathic diabetes mellitus patients with foot ulcers underwent a total contact cast ( TCC ) protocol . A r and omly chosen group of 21 patients ( Group I ) demonstrated ulcer healing in a mean time of 43.5 days . Despite 9 weeks of TCC , 15 patients ( Group II ) with forefoot ulcers failed to heal . Physical examination of Group I revealed plantarflexion/dorsiflexion range of motion of the ankle of 33.8 degrees / 1.9 degrees compared to 32.3 degrees / -10.5 degrees of Group II , demonstrating an ankle equinus deformity and limited joint motion . Group II patients underwent a correction of the equinus deformity with percutaneous tendo-Achilles lengthening ( TAL ) , followed by a TCC . All but one ulcer ( 93.3 % ) healed within 39.4 days . Four ( 19.0 % ) ulcers recurred ( at the same site ) in Group I , compared to none in Group II at the latest follow up of 17.3 months . Surgical correction with percutaneous TAL and TCC results in healing of forefoot ulcer and helps prevent ulcer recurrence Background : Weight-bearing exercise has been contraindicated among people with diabetic peripheral neuropathy ( DM+PN ) . However , recent cohort studies have suggested that daily weight-bearing activity is associated with lower risk for foot ulceration . Objective : The objective of this study was to determine the effect of a lower-extremity exercise and walking intervention program on weight-bearing activity and foot ulcer incidence in people with DM+PN . Design : This was an observer-blinded , 12-month r and omized controlled trial . Setting : The setting s were physical therapy offices in part 1 of the intervention and the community in part 2 of the intervention . Participants : The participants were 79 individuals with DM+PN who were r and omly assigned either to a control group ( n=38 ) or an intervention group ( n=41 ) group . Intervention : Intervention components included leg strengthening and balance exercises ; a graduated , self-monitored walking program ( part 1 ) ; and motivational telephone calls every 2 weeks ( part 2 ) . Both groups received diabetic foot care education , regular foot care , and 8 sessions with a physical therapist . Measurements : Total and exercise bout – related daily steps at baseline and at 3 , 6 , and 12 months were measured by accelerometers . Foot lesions/ulcers were photographed and classified by an independent panel of dermatologists . Use of adequate footwear was monitored . Results : At 6 months , bout-related daily steps increased 14 % from baseline in the intervention group and decreased 6 % from baseline in the control group . Although the groups did not differ statistically in the change in total daily steps , at 12 months steps had decreased by 13 % in the control group . Foot ulcer rates did not differ significantly between groups . Conclusion : Promoting weight-bearing activity did not lead to significant increases in foot ulcers . Weight-bearing activity can be considered following adequate assessment and counseling of patients with DM+PN PURPOSE : To enhance the learner ’s competence with knowledge of the effectiveness of shear-reducing insoles for prevention of foot ulceration in patients with high-risk diabetes . TARGET AUDIENCE : This continuing education activity is intended for physicians and nurses with an interest in skin and wound care . OBJECTIVES : After participating in this educational activity , the participant should be better able to : 1 . Demonstrate knowledge of foot ulceration risk , risk factors , incidence , and prevention . 2 . Apply knowledge gained from review ing this study and a literature review about the use of shear-reducing insoles to patient scenarios . ABSTRACT & NA ; OBJECTIVE : The objective of this study was to evaluate the effectiveness of a shear-reducing insole compared with a st and ard insole design to prevent foot ulceration in high-risk patients with diabetes . RESEARCH DESIGN AND METHODS : A total of 299 patients with diabetic neuropathy and loss of protective sensation , foot deformity , or history of foot ulceration were r and omized into a st and ard therapy group ( n = 150 ) or a shear-reducing insole group ( n = 149 ) . Patients were evaluated for 18 months . St and ard therapy group consisted of therapeutic footwear , diabetic foot education , and regular foot evaluation by a podiatrist . The shear-reducing insole group included a novel insole design ed to reduce both pressure and shear on the sole of the foot . Insoles were replaced every 4 months in both groups . The primary clinical outcome was foot ulceration . The authors used Cox proportional hazards regression to evaluate time to ulceration . RESULTS : There were 2 significant factors from the Cox regression model : insole treatment and history of a foot complication . The st and ard therapy group was about 3.5 times more likely to develop an ulcer compared with shear-reducing insole group ( hazard ratio , 3.47 ; 95 % confidence interval , 0.96–12.67 ) . CONCLUSIONS : These results suggest that a shear-reducing insole is more effective than traditional insoles to prevent foot ulcers in high-risk persons with diabetes AIMS Diabetic patients with podopathy ( diabetic foot syndrome ) may need protective footwear , be it customized or industrially produced stock ' diabetic ' shoes ( SDS ) . The effectiveness of each type of ' diabetic ' shoe needs to be proven clinical ly , e.g. in terms of prevention of foot ulceration . The following study assesses a new German SDS , the LucRo shoe , which consists of rocker-shaped walking sole , a st and ardized shock absorption insole , and soft uppers without stiff toe-caps . The LucRo SDS has been registered as a Medicinal Product according to the European Community Guideline 93/42/EC . PATIENTS AND METHODS A total of 92 high-risk diabetic patients ( mean age 63 years , duration of diabetes 13 years ) with healed foot ulcer were recruited prospect ively over 31 months ; 87 patients suffered from polyneuropathy , 24 patients had peripheral ischaemic vessel disease . One group of patients ( n = 60 ) received the LucRo SDS and wore them , while the remaining patients ( n = 32 ) did not receive the SDS and were forced to use their normal footwear . This allocation reflects the haphazard reimbursement policies of the individual patients ' health insurance , and is in accordance with the current German legislation . The patients were followed up for up to 42 months until the first foot ulcer relapse , or the end of the study . RESULTS There were no differences between the groups concerning age , sex , type and duration of diabetes , prevalence of polyneuropathy and peripheral ischaemic vessel disease , frequency of foot care and mortality rate . The first year annual rate of foot ulcer relapse was significantly different between the groups : 60 % without SDS vs. 15 % with SDS . The overall cumulative ulcer-free survival was significantly greater with SDS ( P < 0.0001 , log rank test ) . CONCLUSION The LucRo stock ' diabetic ' shoe appears effective in the prevention of foot re-ulceration in high-risk patients with diabetic podopathy Home health nurses provided individualized instruction in diabetes self-care within the home environment of 393 diabetic individuals . Each subject was r and omly assigned to either the intervention ( those receiving home teaching ) or control ( those not receiving home teaching ) group . At 6 mo postenrollment , intervention subjects showed significantly greater self-care knowledge and skills than control subjects , although the actual differences between the two groups in terms of self-care skills were probably too small to have any practical meaning . The primary objective of the study , which was the reduction of the number of preventable diabetes-related hospitalizations ( ketoacidosis , ketotic coma , nonketotic coma , insulin reaction , and diabetes out of control ) , was not achieved ; no differences between the groups were noted after 12 mo of follow-up . Similarly , length of hospital stay , foot problems , emergency room and physician visits , and sick days were roughly equivalent in both groups during the follow-up year . These results suggest that , in the absence of concurrent changes in the health-care delivery system and strategies for influencing attitudes toward self-care , education alone is ineffective BACKGROUND The efficacy of custom-made shoes to prevent diabetic foot ulcerations is still unsatisfactory and specific conception is lacking . METHOD AND PATIENTS We conducted a prospect i ve study on 32 consecutive patients with diabetic mellitus , sensitive neuropathy and healed minor amputation of the foot . They were following a prevention program ( education , medical consultation every month ) . They were treated by custom-made shoes in order to obtain a tested and effective load-off area ( after trying and modifying a temporary footwear according to a simple qualitative test of the plantar pressure ) . RESULTS At 1 year , 9 % of patients presented a new foot ulceration and 3 % new minor amputations of the foot . The custom-made shoes had very thick multiple layer total-contact soles ( mean thickness 25 mm for a forefoot deformity and 40 mm for a mid-foot deformity ) . CONCLUSION This new concept of custom-made shoes might be effective in enhancing the prevention of neuropathic ulcerations for high-risk patients . A r and omized controlled trial would be needed to establish sound evidence supporting this new approach for therapeutic footwear A r and omized controlled study of 19 patients with diabetes mellitus ( 10 men , 9 women ) was undertaken to determine the effects of home exercise therapy on joint mobility and plantar pressures . Of the 19 subjects , 9 subjects performed unsupervised active and passive range-of-motion exercises of the joints in their feet . Each subject was evaluated for joint stiffness and peak plantar pressures at the beginning and conclusion of the study . After only 1 month of therapy , a statistically significant average decrease of 4.2 % in peak plantar pressures was noted in the subjects performing the range-of-motion exercises . In the control group , an average increase of 4.4 % in peak plantar pressures was noted . Although the joint mobility data revealed no statistically significant differences between the groups , there was a trend for a decrease in joint stiffness in the treatment group . The results of this study demonstrate that an unsupervised range-of-motion exercise program can reduce peak plantar pressures in the diabetic foot . Given that high plantar pressures have been linked to diabetic neuropathic ulceration , it may be possible to reduce the risk of such ulceration with this therapy The Scottish Intercollegiate Guidelines Network ( SIGN ) develops evidence based clinical guidelines for the NHS in Scotl and . The key elements of the methodology are ( a ) that guidelines are developed by multidisciplinary groups ; ( b ) they are based on a systematic review of the scientific evidence ; and ( c ) recommendations are explicitly linked to the supporting evidence and grade d according to the strength of that evidence . Until recently , the system for grading guideline recommendations was based on the work of the US Agency for Healthcare Research and Quality ( formerly the Agency for Health Care Policy and Research ) . 1 2 However , experience over more than five years of guideline development led to a growing awareness of this system 's weaknesses . Firstly , the grading system was design ed largely for application to questions of effectiveness , where r and omised controlled trials are accepted as the most robust study design with the least risk of bias in the results . However , in many areas of medical practice r and omised trials may not be practical or ethical to undertake ; and for many questions other types of study design may provide the best evidence . Secondly , guideline development groups often fail to take adequate account of the method ological quality of individual studies and the overall picture presented by a body of evidence rather than individual studies or they fail to apply sufficient judgment to the overall strength of the evidence base and its applicability to the target population of the guideline . Thirdly , guideline users are often not clear about the implication s of the grading system . They misinterpret the grade of recommendation as relating to its importance , rather than to the strength of the supporting evidence , and may therefore fail to give due weight to low grade recommendations . # # # # Summary points A revised system of determining levels of evidence and grade s This trial assessed whether a simple clinical tool can be used to stratify patients with diabetes , according to risk of developing foot ulceration . This was a prospect i ve , observational follow-up study of 3526 patients with diabetes ( 91 % type 2 diabetes ) attending for routine diabetes care . Mean age was 64.7 ( range 15 - 101 ) years and duration of diabetes was 8.8 ( + /-1.5 SD ) years . Patients were categorised into ' low ' ( 64 % ) , ' moderate ' ( 23 % ) or ' high ' ( 13 % ) risk of developing foot ulcers by trained staff using five clinical criteria during routine patient care . During follow-up ( 1.7 years ) , 166 ( 4.7 % ) patients developed an ulcer . Foot ulceration was 83 times more common in high risk and six times more in moderate risk , compared with low-risk patients . The negative predictive value of a ' low-risk score ' was 99.6 % ( 99.5 - 99.7 % ; 95 % confidence interval ) . This clinical tool accurately predicted foot ulceration in routine practice and could be used direct scarce podiatry re sources towards those at greatest need OBJECTIVE To assess the ability of a multidisciplinary approach to diabetic foot care to reduce the incidence of recurrent ulceration and amputations compared with st and ard care in a 2-year prospect i ve study . RESEARCH DESIGN AND METHODS A total of 145 patients with a past history of neuropathic foot ulcers but no evidence of peripheral vascular disease entered the study . Subjects were screened for their neuropathic and vascular status at baseline , and all received identical foot care education . The intervention group ( n = 56 ) was followed by the multidisciplinary team of physicians , nurses , and podiatrists with regular podiatry and reeducation every 3 months and the provision of specialty footwear as required . The st and ard treatment group was followed in local clinics on a trimonthly basis and received identical screening and education at baseline . RESULTS There were no significant differences at baseline in age ( intervention 59.2+/-13.4 , st and ard treatment 58.5+/-11.5 years ) , duration of diabetes ( 14.0+/-7.1 vs. 15.6+/-7.8 years ) , or neuropathic status ( vibration perception threshold [ VPT ] : 31.1+/-12.1 vs. 33.9+/-11.3 V , neuropathy disability score [ NDS ] : 8.1+/-1.4 vs. 7.9+/-1.7 ) . All patients had an ankle brachial pressure index ( ABPI ) of > 0.9 and at least one palpable foot pulse . Significantly fewer recurrent ulcers were seen in the intervention group than in the st and ard treatment group during the 2-year period ( 30.4 vs. 58.4 % , P < 0.001 ) . CONCLUSIONS This prospect i ve study has demonstrated the effectiveness of a multidisciplinary approach to diabetic foot care together with the provision of specialty footwear in the long-term management of high-risk patients with a history of neuropathic foot ulcers BACKGROUND Use of nerve decompression in diabetic sensorimotor polyneuropathy is a controversial treatment characterized as being of unknown scientific effectiveness owing to lack of level I scientific studies . METHODS Herein , long-term follow-up data have been assembled on 65 diabetic patients with 75 legs having previous neuropathic foot ulcer and subsequent operative decompression of the common peroneal and tibial nerve branches in the anatomical fibro-osseous tunnels . RESULTS The cohort 's previously reported low recurrence risk of less than 5 % annually at a mean of 2.49 years of follow-up has persisted for an additional 3 years , and cumulative risk is now 2.6 % per patient-year . Nine of 75 operated legs ( 12 % ) have developed an ulcer in 4,218 months ( 351 patient-years ) of follow-up . Of the 53 contralateral legs without decompression , 16 ( 30 % ) have ulcerated , of which three have undergone an amputation . Fifty-nine percent of patients are known to be alive with intact feet a mean of 60 months after decompression . CONCLUSIONS The prospect i ve , objective , statistically significant finding of a large , long-term diminution of diabetic foot ulcer recurrence risk after operative nerve decompression compares very favorably with the historical literature and the contralateral legs of this cohort , which had no decompression . This finding invites prospect i ve r and omized controlled studies for validation testing and reconsideration of the frequency and contribution of unrecognized nerve entrapments in diabetic sensorimotor polyneuropathy and diabetic foot complications BACKGROUND AND PURPOSE The effect of a tendo-Achilles lengthening ( TAL ) procedure on ankle muscle performance has not been clearly established . The purpose of this study was to compare the effects of TAL and total-contact casting ( TCC ) with TCC alone on ankle muscle performance in subjects with diabetes mellitus ( DM ) and a neuropathic plantar ulcer . SUBJECTS Subjects were r and omly assigned to either a TAL group ( 3 female and 12 male subjects ) or a TCC group ( 4 female and 10 male subjects ) . METHODS Muscle performance measurements were obtained using an isokinetic dynamometer . RESULTS Concentric plantar-flexor peak torque decreased 31 % after TAL but returned to the baseline level after 8 months . Dorsiflexor peak torque did not change in either group . Plantar-flexor passive torque at 0 degrees of dorsiflexion decreased after TAL but increased to 60 % of the baseline level after 8 months . Maximal dorsiflexion angle increased 11 degrees after TAL and remained increased at 8 months . DISCUSSION AND CONCLUSION The TAL result ed in an increase in ankle dorsiflexion range of motion and a temporary reduction in concentric plantar-flexor peak torque and passive torque at 0 degrees of dorsiflexion . If TAL is being considered for people with DM and a neuropathic forefoot ulcer , the initial compromise in plantar-flexor muscle performance should be addressed Background Home monitoring of foot temperatures in high-risk diabetes patients proves to be a promising approach for early recognition and treatment of pre-signs of ulceration , and thereby ulcer prevention . Despite previous studies demonstrating its efficacy , it is currently not widely applied in ( Dutch ) health care . Methods In a multicenter , outcome -assessor-blinded , r and omized controlled trial , 304 patients with diabetes mellitus types I or II , loss of protective sensation based on peripheral neuropathy , and a history of foot ulceration in the preceding 4 years or a diagnosis of Charcot neuro-osteoarthropathy will be included . Enhanced therapy will consist of usual care and additional at-home daily measurement of foot temperatures at six to eight predefined locations on the foot . If a contralateral foot temperature difference of > 2.2 ° C is found on two consecutive days , the participant is instructed to contact their podiatrist for further foot diagnosis or treatment , and to reduce ambulatory activity by 50 % until temperatures are normalized . Enhanced therapy will be compared to usual care . The primary outcomes are the cost ( savings ) per patient without a foot ulcer ( i.e. , cost-effectiveness ) and per quality -adjusted life year gained ( i.e. , cost-utility ) . The primary clinical outcome in the study is the proportion of patients with foot ulcer recurrence on the plantar foot , apical surfaces of the toes , the interdigital spaces or medial and lateral forefoot surfaces during 18-month follow-up . Discussion Confirmation of the efficacy of at-home foot temperature monitoring in ulcer prevention , together with assessing its usability , cost-effectiveness and cost-utility , could lead to implementation in Dutch health care , and in many setting s across the world . Trial registration Netherl and s Trial Registration : NTR5403 . Registered on 8 September 2015 Background Diabetic polyneuropathy ( DPN ) negatively affects foot and ankle function ( strength and flexibility ) , which itself affects the daily physical activity and quality of life of patients . A physical therapy protocol aim ing to strengthen the intrinsic and extrinsic foot muscles and increase flexibility may be a promising approach to improve lower-extremity function , prevent further complications , and improve autonomy for daily living activities in these patients . Thus , the inclusion of a specific foot-related exercises focused on the main musculoskeletal impairments may have additional effects to the conventional interventions in the diabetic foot . Methods / Design A prospect i ve , parallel-group , outcome -assessor blinded , r and omized controlled trial ( RCT ) will be conducted in 77 patients with DPN who will be r and omly allocated to usual care ( control arm ) or usual care with supervised foot-ankle exercises aim ing to increase strengh and flexibility twice a week for 12 weeks and remotely supervised foot-ankle exercises for a year through a web software . Patients will be evaluated 5 times in a 1 year period regarding daily physical activity level , self-selected and fast gait speeds ( primary outcomes ) , foot ulcer incidence , ulcer risk classification , neuropathy testing , passive ankle range of motion , quality of life , foot health and functionality , foot muscle strength , plantar pressure , and foot-ankle kinematics and kinetics during gait . Discussion This study aims to assess the effect of a foot-ankle strength and flexibility program on a wide range of musculoskeletal , activity-related , biomechanical , and clinical outcomes in DPN patients . We intend to demonstrate evidence that the year-long training program is effective in increasing gait speed and daily physical activity level and in improving quality of life ; foot strength , functionality , and mobility ; and biomechanics while walking . The results will be published as soon as they are available . Trial registration This study has been registered at Clinical Trials.gov as NCT02790931 ( June 6 , 2016 ) under the name “ Effects of foot muscle strengthening in daily activity in diabetic neuropathic patients ” For patients with diabetes mellitus and diabetic foot syndrome customized orthopedic shoes represent the most effective treatment to avoid foot ulceration and amputation . A total of 53 patients suffering from diabetes and treated with customized orthopedic shoes for more than 5 years were included in the study . Of the patients 91 % had peripheral artery occlusion disease , polyneuropathy and diabetic neuropathic osteoarthropathy ( DNOAP ) and in nearly 25 % amputation of one limb had already been carried out . The incidence of ulcers over a time period of 5 years was assessed from the patient records and question ing the patients . Questions on the duration of wearing orthopedic shoes , the durability of the shoes and result ing pain were also included . All patients except for one had problems walking on uneven surfaces . Of the patients 89 % cl aim ed to have used their shoes always or nearly always and 25 % of the shoes had to be replaced after 1 year . The incidence of ulcers was 38 % after 5 years . Treatment with customized orthopedic shoes is an effective method to prevent ulcers and amputation . To be successful it is necessary to control that the shoes are made correctly . Not all shoes last as long as 2 years OBJECTIVE To determine the effects of weight-bearing ( WB ) versus nonweight-bearing ( NWB ) exercise for persons with diabetes mellitus ( DM ) and peripheral neuropathy ( PN ) . DESIGN R and omized controlled trial with evaluations at baseline and after intervention . SETTING University-based physical therapy research clinic . PARTICIPANTS Participants with DM and PN ( N=29 ) ( mean age ± SD , 64.5±12.5y ; mean body mass index [ kg/m(2 ) ] ± SD , 35.5±7.3 ) were r and omly assigned to WB ( n=15 ) and NWB ( n=14 ) exercise groups . All participants ( 100 % ) completed the intervention and follow-up evaluations . INTERVENTIONS Group-specific progressive balance , flexibility , strengthening , and aerobic exercise conducted sitting or lying ( NWB ) or st and ing and walking ( WB ) occurred 3 times a week for 12 weeks . MAIN OUTCOME MEASURES Measures included the 6-minute walk distance ( 6MWD ) and daily step counts . Secondary outcome measures represented domains across the International Classification of Functioning , Disability and Health . RESULTS The WB group showed greater gains than the NWB group over time on the 6MWD and average daily step count ( P<.05 ) . The mean and 95 % confidence intervals ( CIs ) between-group difference over time was 29 m ( 95 % CI , 6 - 51 ) for the 6MWD and 1178 ( 95 % CI , 150 - 2205 ) steps for the average daily step count . The NWB group showed greater improvements than the WB group over time in hemoglobin A1c values ( P<.05 ) . CONCLUSIONS The results of this study indicate the ability of this population with chronic disease to increase 6MWD and daily step count with a WB exercise program compared with an NWB exercise program |
1,942 | 23,460,093 | The evidence from 19 studies that met the inclusion criteria suggests that most multicomponent interventions are effective in preventing onset of delirium in at-risk patients in a hospital setting . | Delirium , an acute decline in attention and cognition , occurs among hospitalized patients at rates estimated to range from 14 % to 56 % and increases the risk for morbidity and mortality .
The purpose of this systematic review was to evaluate the effectiveness and safety of in-facility multicomponent delirium prevention programs . | Introduction .Delirium , or acute confusional state , is a common and serious occurrence among hospitalized older persons . Current estimates suggest that delirium complicates hospital stays for more than 2.3 million older persons each year , involving more than 17.5 million hospital days and accounting for more than $ 4 billion ( 1994 dollars ) of Medicare expenditures . A 40 % reduction was recently reported in the risk for delirium among hospitalized older persons receiving a multicomponent targeted risk factor intervention ( MTI ) strategy to prevent delirium , compared with subjects receiving usual hospital care . 1 Before recommending that this preventive strategy be implemented in clinical practice , however , the cost implication s must be thoroughly examined as well . Methods .The present analysis performs net cost evaluations of the MTI for the prevention of delirium among hospitalized patients . Hospital charge and cost-to-charge ratio data are linked to a data base of 852 subjects , who were treated with MTI or usual care . Multivariable regression methods were used to help isolate the impact of MTI on hospital costs . These results were then combined with our earlier work on the impact of the MTI on delirium prevention to assess the cost effectiveness of this intervention . Results .The MTI significantly reduced nonintervention costs among subjects at intermediate risk for developing delirium , but not among subjects at high risk . When MTI intervention costs were included , MTI had no significant effect on overall health care costs in the intermediate risk cohort , but raised overall costs in the high risk group . Conclusions .Because the MTI prevented delirium in the intermediate risk group without raising costs , the conclusion reached is that it is a cost effective treatment option for patients at intermediate risk for developing delirium . In contrast , the results suggest that the MTI is not cost effective for subjects at high risk OBJECTIVE Delirium is a highly prevalent and deleterious disorder in terminally ill cancer patients . We assessed whether a multicomponent preventive intervention was effective in decreasing delirium incidence and severity among cancer patients receiving end-of-life care . METHODS A cohort of 1516 patients was followed from admission to death at seven Canadian palliative care centers . In two of these centers , routine care included a delirium preventive intervention targeting physicians ( written notice on selective delirium risk factors and inquest on intended medication changes ) , patients , and their family ( orientation to time and place , information about early delirium symptoms ) . Delirium frequency and severity were compared between patients at the intervention ( N = 674 ) and usual-care ( N = 842 ) centers based on thrice-daily symptom assessment s with the Confusion Rating Scale . RESULTS The overall rate of adherence to the intervention was 89.7 % . The incidence of delirium was 49.1 % in the intervention group , compared with 43.9 % in the usual-care group ( odds ratio [ OR ] 1.23 , P = 0.045 ) . When confounding variables were controlled for , no difference was observed between the intervention and the usual-care groups in delirium incidence ( OR 0.94 , P = 0.66 ) , delirium severity ( 1.83 vs. 1.92 ; P = 0.07 ) , total days in delirium ( 4.57 vs. 3.57 days ; P = 0.63 ) , or duration of first delirium episode ( 2.9 vs. 2.1 days ; P = 0.96 ) . Delirium-free survival was similar in the two groups . CONCLUSION A simple multicomponent preventive intervention was ineffective in reducing delirium incidence or severity among cancer patients receiving end-of-life care . Delirium prevention remains a difficult challenge in terminally ill cancer patients OBJECTIVES Delirium ( or acute confusional state ) affects 35 % to 65 % of patients after hip-fracture repair , and has been independently associated with poor functional recovery . We performed a r and omized trial in an orthopedic surgery service at an academic hospital to determine whether proactive geriatrics consultation can reduce delirium after hip fracture . DESIGN Prospect i ve , r and omized , blinded . SETTING Inpatient academic tertiary medical center . PARTICIPANTS 126 consenting patients 65 and older ( mean age 79 + /- 8 years , 79 % women ) admitted emergently for surgical repair of hip fracture . MEASUREMENTS Detailed assessment through interviews with patients and design ated proxies and review of medical records was performed at enrollment to ascertain prefracture status . Subjects were then r and omized to proactive geriatrics consultation , which began preoperatively or within 24 hours of surgery , or " usual care . " A geriatrician made daily visits for the duration of the hospitalization and made targeted recommendations based on a structured protocol . To ascertain study outcomes , all subjects underwent daily , blinded interviews for the duration of their hospitalization , including the Mini-Mental State Examination ( MMSE ) , the Delirium Symptom Interview ( DSI ) , and the Memorial Delirium Assessment Scale ( MDAS ) . Delirium was diagnosed using the Confusion Assessment Method ( CAM ) algorithm . RESULTS The 62 patients r and omized to geriatrics consultation were not significantly different ( P>.1 ) from the 64 usual-care patients in terms of age , gender , prefracture dementia , comorbidity , type of hip fracture , or type of surgical repair . Sixty-one percent of geriatrics consultation patients were seen preoperatively and all were seen within 24 hours postoperatively . A mean of 10 recommendations were made throughout the duration of the hospitalization , with 77 % adherence by the orthopedics team . Delirium occurred in 20 /62 ( 32 % ) intervention patients , versus 32 / 64 ( 50 % ) usual-care patients ( P = .04 ) , representing a relative risk of 0.64 ( 95 % confidence interval ( CI ) = 0.37 - 0.98 ) for the consultation group . One case of delirium was prevented for every 5.6 patients in the geriatrics consultation group . There was an even greater reduction in cases of severe delirium , occurring in 7/ 60 ( 12 % ) of intervention patients and 18 / 62 ( 29 % ) of usual-care patients , with a relative risk of 0.40 ( 95 % CI = 0.18 - 0.89 ) . Despite this reduction in delirium , length of stay did not significantly differ between intervention and usual-care groups ( median + /- interquartile range = 5 + /- 2 days in both groups ) , likely because protocol s and pathways predetermined length of stay . In subgroup analyses , geriatrics consultation was most effective in reducing delirium in patients without prefracture dementia or activities of daily living ( ADL ) functional impairment . CONCLUSIONS Proactive geriatrics consultation was successfully implemented with good adherence after hip-fracture repair . Geriatrics consultation reduced delirium by over one-third , and reduced severe delirium by over one-half . Our trial provides strong preliminary evidence that proactive geriatrics consultation may play an important role in the acute hospital management of hip-fracture patients BACKGROUND delirium is a clinical syndrome associated with multiple short and long-term complications and therefore prevention is an essential part of its management . This study was design ed to assess the efficacy of multicomponent intervention in delirium prevention . METHODS a total of 287 hospitalised patients at intermediate or high risk of developing delirium were r and omised to receive a non-pharmacological intervention delivered by family members ( 144 patients ) or st and ard management ( 143 patients ) . The primary efficacy outcome was the occurrence of delirium at any time during the course of hospitalisation . Three vali date d observers performed the event adjudication by using the confusion assessment method screening instrument . RESULTS there were no significant differences in the baseline characteristics between the two groups . The primary outcome occurred in 5.6 % of the patients in the intervention group and in 13.3 % of the patients in the control group ( relative risk : 0.41 ; confidence interval : 0.19 - 0.92 ; P = 0.027 ) . CONCLUSION the results of this study show that there is a benefit in the non-pharmacological prevention of delirium using family members , when compared with st and ard management of patients at risk of developing this condition BACKGROUND older people undergoing elective surgery have significant post-operative problems prolonging hospitalisation . OBJECTIVE to design , embed , and evaluate an evidence -based comprehensive geriatric assessment ( CGA ) service for at-risk older patients undergoing elective surgery . SETTING urban teaching hospital . SUBJECTS elective surgical patients aged 65 + . INTERVENTION multidisciplinary preoperative CGA service with post-operative follow-through ( proactive care of older people undergoing surgery [ ' POPS ' ] ) . METHODS observational cohort study and multilevel surveys ( development and modelling phase ) . Prospect i ve ' before and after ' comparison ( exploratory evaluation ) . RESULTS findings from the development phase showed high levels of preoperative co-morbidity , no multidisciplinary preoperative input , and multiple potentially preventable post-operative problems delaying discharge in older elective surgery patients . Comparison of 2 cohorts of elective orthopaedic patients ( pre-POPS vs POPS , N = 54 ) showed the POPS group had fewer post-operative medical complications including pneumonia ( 20 % vs 4 % [ p = 0.008 ] ) and delirium ( 19 % vs 6 % [ p = 0.036 ] ) , and significant improvements in areas reflecting multidisciplinary practice including pressure sores ( 19 % vs 4 % [ p = 0.028 ] ) , poor pain control ( 30 % vs 2 % [ p<0.001 ] ) , delayed mobilisation ( 28 % vs 9 % [ p = 0.012 ] ) and inappropriate catheter use ( 20 % vs 7 % [ p = 0.046 ] ) . Length of stay was reduced by 4.5 days . There were fewer delayed discharges relating to medical complications ( 37 % vs 13 % ) or waits for OT assessment or equipment ( 20 % vs 4 % ) . CONCLUSION a proactive evidence -based CGA service for at-risk older elective surgical patients was developed according to MRC framework for complex interventions . Pre/post comparison in elective orthopaedic patients showed improved ( within method ological limitations ) post-operative outcomes indicative of better clinical effectiveness and efficiency , and contributed to the service obtaining mainstream funding . Informed by the present study , a r and omised controlled trial is ongoing Background and aims : Delirium is a common postoperative complication in elderly patients which has a serious impact on outcome in terms of morbidity and costs . We examined whether a postoperative multi-factorial intervention program can reduce delirium and improve outcome in patients with femoral neck fractures . Methods : One hundred and ninety-nine patients , aged 70 years and over ( mean age±SD , 82±6 , 74 % women ) , were r and omly assigned to postoperative care in a specialized geriatric ward or a conventional orthopedic ward . The intervention consisted of staff education focusing on the assessment , prevention and treatment of delirium and associated complications . The staff worked as a team , applying comprehensive geriatric assessment , management and rehabilitation . Patients were assessed using the Mini Mental State Examination and the Organic Brain Syndrome Scale , and delirium was diagnosed according to DSM-IV criteria . Results : The number of days of postoperative delirium among intervention patients was fewer ( 5.0±7.1 days vs 10.2±13.3 days , p=0.009 ) compared with controls . A lower proportion of intervention patients were delirious postoperatively than controls ( 56/102 , 54.9 % vs 73/97 , 75.3 % , p=0.003 ) . Eighteen percent in the intervention ward and 52 % of controls were delirious after the seventh postoperative day ( p<0.001 ) . Intervention patients suffered from fewer complications , such as decubitus ulcers , urinary tract infections , nutritional complications , sleeping problems and falls , than controls . Total postoperative hospitalization was shorter in the intervention ward ( 28.0±17.9 days vs 38.0±40.6 days , p=0.028 ) . Conclusions : Patients with postoperative delirium can be successfully treated , result ing in fewer days of delirium , fewer other complications , and shorter length of hospitalization OBJECTIVES To investigate whether an education program and a reorganization of nursing and medical care improved the outcome for older delirious patients . DESIGN Prospect i ve intervention study . SETTING Department of General Internal Medicine , Sundsvall Hospital , Sweden . PARTICIPANTS Four hundred patients , aged 70 and older , consecutively admitted to an intervention or a control ward . INTERVENTION The intervention consisted of staff education focusing on the assessment , prevention , and treatment of delirium and on caregiver-patient interaction . Reorganization from a task-allocation care system to a patient-allocation system with individualized care . MEASUREMENTS The patients were assessed using the Organic Brain Syndrome Scale and the Mini-Mental State Examination on Days 1 , 3 , and 7 after admission . Delirium was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , criteria . RESULTS Delirium was equally common on the day of admission at the two wards , but fewer patients remained delirious on Day 7 on the intervention ward ( n=19/63 , 30.2 % vs 37/62 , 59.7 % , P=.001 ) . The mean length of hospital stay+/-st and ard deviation was significantly lower on the intervention ward then on the control ward ( 9.4+/-8.2 vs 13.4+/-12.3 days , P<.001 ) especially for the delirious patients ( 10.8+/-8.3 vs 20.5+/-17.2 days , P<.001 ) . Two delirious patients in the intervention ward and nine in the control ward died during hospitalization ( P=.03 ) . CONCLUSION This study shows that a multifactorial intervention program reduces the duration of delirium , length of hospital stay , and mortality in delirious patients OBJECTIVES To ( 1 ) reduce deep sedation and delirium to permit mobilization , ( 2 ) increase the frequency of rehabilitation consultations and treatments to improve patients ' functional mobility , and ( 3 ) evaluate effects on length of stay . DESIGN Seven-month prospect i ve before/after quality improvement project . SETTING Sixteen-bed medical intensive care unit ( MICU ) in academic hospital . PARTICIPANTS 57 patients mechanically ventilated 4 days or longer . INTERVENTION A multidisciplinary team focused on reducing heavy sedation and increasing MICU staffing to include full-time physical and occupational therapists with new consultation guidelines . MAIN OUTCOME MEASURES Sedation and delirium status , rehabilitation treatments , functional mobility . RESULTS Compared with before the quality improvement project , benzodiazepine use decreased markedly ( proportion of MICU days that patients received benzodiazepines [ 50 % vs 25 % , P=.002 ] ) , with lower median daily sedative doses ( 47 vs 15 mg midazolam equivalents [ P=.09 ] and 71 vs 24 mg morphine equivalents [ P=.01 ] ) . Patients had improved sedation and delirium status ( MICU days alert [ 30 % vs 67 % , P<.001 ] and not delirious [ 21 % vs 53 % , P=.003 ] ) . There were a greater median number of rehabilitation treatments per patient ( 1 vs 7 , P<.001 ) with a higher level of functional mobility ( treatments involving sitting or greater mobility , 56 % vs 78 % , P=.03 ) . Hospital administrative data demonstrated that across all MICU patients , there was a decrease in intensive care unit and hospital length of stay by 2.1 ( 95 % confidence interval : 0.4 - 3.8 ) and 3.1 ( 0.3 - 5.9 ) days , respectively , and a 20 % increase in MICU admissions compared with the same period in the prior year . CONCLUSIONS Using a quality improvement process , intensive care unit delirium , physical rehabilitation , and functional mobility were markedly improved and associated with decreased length of stay BACKGROUND A wide variability in the approach towards delirium prevention and treatment in the critically ill results from the dearth of prospect i ve r and omised studies . METHODS We launched a two-stage prospect i ve observational study to assess delirium epidemiology , risk factors and impact on patient outcome , by enrolling all patients admitted to our Intensive Care Unit ( ICU ) over a year . The first step - from January to June 2008 was the observational phase , whereas the second one from July to December 2008 was interventional . All the patients admitted to our ICU were recruited but those with pre-existing cognitive disorders , dementia , psychosis and disability after stroke were excluded from the data analysis . Delirium assessment was performed according with Confusion Assessment Method for the ICU twice per day after sedation interruption . During phase 2 , patients underwent both a re-orientation strategy and environmental , acoustic and visual stimulation . RESULTS We admitted a total of respectively 170 ( I-ph ) and 144 patients ( II-ph ) . The delirium occurrence was significantly lower in ( II-ph ) 22 % vs. 35 % in ( I-ph ) ( P=0.020 ) . A Cox 's Proportional Hazard model found the applied reorientation strategy as the strongest protective predictors of delirium : ( HR 0.504 , 95 % C.I. 0.313 - 0.890 , P=0.034 ) , whereas age ( HR 1.034 , 95 % CI : 1.013 - 1.056 , P=0.001 ) and sedation with midazolam plus opiate ( HR 2.145 , 95 % CI : 2.247 - 4.032 , P=0.018 ) were negative predictors . CONCLUSION A timely reorientation strategy seems to be correlated with significantly lower occurrence of delirium 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 OBJECTIVES To analyze the effectiveness of a multicomponent intervention integrated into daily practice for the prevention of in-hospital delirium in elderly patients . DESIGN Controlled study comparing an intervention in a geriatric unit ( GI ) with usual care in two internal medicine services ( UC ) . SETTING University hospital in Madrid , Spain . PARTICIPANTS Five hundred forty-two consecutive patients ( 170 GI , 372 UC ) , aged 70 and older , with any of the risk criteria for delirium ( cognitive impairment , visual impairment , acute disease severity , dehydration ) . INTERVENTION Educational measures and specific actions in seven risk areas ( orientation , sensory impairment , sleep , mobilization , hydration , nutrition , drug use ) . Daily monitoring of adherence . MEASUREMENTS Baseline characteristics , risk factors for delirium , and quality care indicators were analyzed . The primary endpoint was incidence of delirium assessed daily . The secondary endpoint was functional decline , defined as loss of independence in any of the activities of daily living . The intervention effect was evaluated using logistic regression analysis . RESULTS Delirium affected 11.7 % of the GI group and 18.5 % of the UC group ( P=.04 ) . After adjustment for confounders , the intervention was associated with lower incidence of delirium ( odds ratio=0.4 , 95 % confidence interval=0.24 - 0.77 ; P=.005 ) . In the patients who experienced delirium , severity , length , and recurrence of episodes were similar in both groups . Adherence to the intervention protocol s was 75.7 % . The intervention reduced the rate of functional decline ( 45.5 % in GI vs 56.3 % in UC , P=.03 ) and improved other quality indicators ( e.g. , mobilization and physical restraints reduction ) . CONCLUSION A multicomponent , nonpharmacological intervention integrated into routine practice reduces delirium during hospitalization in older patients , improves quality of care , and can be implemented without additional re sources in a public healthcare system |
1,943 | 14,702,908 | CONCLUSION The consistent reduction in antibiotic usage in the five controlled trials included in this review suggests that delayed prescription is an effective means of reducing antibiotic usage for acute respiratory infections . | BACKGROUND There is concern about the increasing resistance of antibiotics to common bacteria .
Delayed prescribing for respiratory tract infections is a strategy that may reduce the use of antibiotics .
AIM To systematic ally review controlled trials of delayed prescriptions to establish their capacity to reduce antibiotic intake . | Abstract Objective : To determine the effect of antibiotic treatment for acute otitis media in children between 6 months and 2 years of age . Design : Practice based , double blind , r and omised , placebo controlled trial . Setting : 53 general practice s in the Netherl and s. Subjects : 240 children aged 6 months to 2 years with the diagnosis of acute otitis media . Intervention : Amoxicillin 40 mg/kg/day in three doses . Main outcome measures : Persistent symptoms at day four and duration of fever and pain or crying , or both . Otoscopy at days four and 11 , tympanometry at six weeks , and use of analgesic . Results : Persistent symptoms at day four were less common in the amoxicillin group ( risk difference 13 % ; 95 % confidence interval 1 % to 25 % ) . The median duration of fever was two days in the amoxicillin group versus three in the placebo group ( P=0.004 ) . No significant difference was observed in duration of pain or crying , but analgesic consumption was higher in the placebo group during the first 10 days ( 4.1 v 2.3 doses , P=0.004 ) . In addition , no otoscopic differences were observed at days four and 11 , and tympanometric findings at six weeks were similar in both groups . Conclusions : Seven to eight children aged 6 to 24 months with acute otitis media needed to be treated with antibiotics to improve symptomatic outcome at day four in one child . This modest effect does not justify prescription of antibiotics at the first visit , provided close surveillance can be guaranteed CONTEXT The emergence and spread of antibiotic-resistant Streptococcus pneumoniae in US communities is due , in part , to the excessive use of antibiotics for acute respiratory tract infections . OBJECTIVE To decrease total antibiotic use for uncomplicated acute bronchitis in adults . DESIGN Prospect i ve , nonr and omized controlled trial , including baseline ( November 1996-February 1997 ) and study ( November 1997-February 1998 ) periods . SETTING Four selected primary care practice s belonging to a group-model health maintenance organization in the Denver , Colo , metropolitan area . PARTICIPANTS Consecutive adults diagnosed as having uncomplicated acute bronchitis . A total of 2462 adults were included at baseline and 2027 adults were included in the study . Clinicians included 56 physicians , 28 physician assistants or nurse practitioners , and 9 registered nurses . INTERVENTION The full intervention site received household and office-based patient educational material s , as well as a clinician intervention consisting of education , practice -profiling , and academic detailing . A limited intervention site received only office-based educational material s , and control sites provided usual care . MAIN OUTCOME MEASURE Antibiotic prescriptions for uncomplicated acute bronchitis during baseline and study periods . RESULTS Antibiotic prescription rates for uncomplicated acute bronchitis were similar at all 4 sites during the baseline period . During the study period , there was a substantial decline in antibiotic prescription rates at the full intervention site ( from 74 % to 48 % [ P = .003 ] ) , but not at the control and limited intervention sites ( 78 % to 76 % [ P = .81 ] and 82 % to 77 % [ P = .68 ] , respectively ) . Compared with control sites , changes in nonantibiotic prescriptions ( inhaled bronchodilators , cough suppressants , and analgesics ) were not significantly different for intervention sites . Return office visits ( within 30 days of the incident visit ) for bronchitis or pneumonia did not change significantly for any of the sites . CONCLUSIONS Antibiotic treatment of adults diagnosed as having uncomplicated acute bronchitis can be safely reduced using a combination of patient and clinician interventions BACKGROUND Overuse of antibiotics for children 's upper respiratory infections is widespread and contributes to the emergence of antibiotic-resistant bacteria . OBJECTIVE To assess changes in knowledge and awareness regarding antibiotic resistance and appropriate antibiotic use after community-wide educational interventions to reduce inappropriate antibiotic use . DESIGN Baseline survey conducted during June through July 1997 and postintervention survey of baseline participants during June through August 1998 . SETTING Communities in northern Wisconsin . PARTICIPANTS Parents of 729 r and omly selected children < 4 years of age were called until 215 in each of the intervention and control areas were reached . Of the 430 baseline participants , 365 ( 85 % ) participated in the postintervention survey . INTERVENTION Parent-oriented activities included distribution of material s and presentations . Physician-oriented activities included formal presentations and small group meetings . OUTCOME MEASURE Change in awareness about antibiotic resistance and knowledge about antibiotic indications . RESULTS A higher proportion of parents in the intervention area ( 53 % ) were exposed to 2 or more local educational messages , compared with the control area ( 23 % ) . From the baseline to the postintervention survey , the percentage of parents with a high degree of antibiotic resistance awareness increased more in the intervention area ( 58 % to 73 % ) than in the control area ( 60 % to 65 % ) . In the intervention area , there was also a larger increase in knowledge regarding appropriate indications for antibiotic use , compared with the control area . The proportion of parents who expected an antibiotic for their child and did not receive one declined in the intervention area ( 14 % to 9 % ) , while it increased in the control area ( 7 % to 10 % ) . In addition , the percentage of parents in the intervention area who brought their child to another physician because they did not receive an antibiotic decreased ( 5 % to 2 % ) , while it increased in the control area ( 2 % to 4 % ) . CONCLUSION Parental knowledge and awareness about antibiotic indications and antibiotic resistance can be changed with educational interventions directed at parents and clinicians Abstract Objective : To assess three prescribing strategies for sore throat . Design : R and omised follow up study . Setting : 11 general practice s in the South and West region . Subjects : 716 patients aged 4 years and over with sore throat and an abnormal physical sign in the throat ; 84 % had tonsillitis or pharyngitis . Patients were r and omised to three groups : prescription for antibiotics for 10 days ( group 1 , 246 patients ) ; no prescription ( group 2 , 230 patients ) ; or prescription for antibiotics if symptoms were not starting to settle after three days ( group 3 ; 238 patients ) . Main outcome measures : Duration of symptoms ; satisfaction and compliance with and perceived efficacy of antibiotics ; time off school or work . Outcomes were documented in 582 subjects ( 81 % ) . Results : Median duration of antibiotic use differed significantly in the three groups ( 10 v 0 v 0 days , P<0.001 ) ; 69 % of patients in group 3 did not use their prescription . The proportion of patients better by day 3 did not differ significantly ( 37 % v 35 % v 30 % , P=0.28 ) , nor did the duration of illness ( median 4 v 5 v 5 days , P=0.39 ) , days off work or school ( median 2 v 2 v 1 , P=0.13 ) , or proportion of patients satisfied ( 96 % v 90 % v 93 % , P=0.09 ) , although group 1 had fewer days of fever ( median 1 v 2 v 2 days , P=0.04 ) . More patients in group 1 thought the antibiotics were effective ( 87 % v 55 % v 60 % , P<0.001 ) and intended coming to the doctor in future attacks ( 79 % v 54 % v 57 % , P<0.001 ) . “ Legitimation ” of illness — to explain to work or school ( 60 % ) or family or friends (37%)–was an important reason for consultation . Patients who were more satisfied got better more quickly , and satisfaction related strongly to how well the doctor dealt with patient 's concerns . Conclusion : Prescribing antibiotics for sore throat only marginally affects the resolution of symptoms but enhances belief in antibiotics and intention to consult in future when compared with the acceptable strategies of no prescription or delayed prescription . Psychosocial factors are important in the decision to see a general practitioner and in predicting the duration of illness . Key messages Sore throat is one of the commonest presentations of upper respiratory illness to general practitioners , and attendance is increasing Prescribing antibiotics for sore throat does not reduce the extent and duration of symptoms Prescribing antibiotics enhances belief in antibiotics and intention to consult Legitimation of illness is an important reason for attending the doctor Satisfaction predicts duration of illness and closely relates to how well concerns are dealt with — unless patients are very ill , general practitioners should consider exploring concerns and should avoid or delay prescribing OBJECTIVES To identify which children with acute otitis media are at risk of poor outcome and to assess benefit from antibiotics in these children . DESIGN Secondary analysis of r and omised controlled trial cohort . SETTING Primary care . PARTICIPANTS 315 children aged 6 months to 10 years . INTERVENTION Immediate or delayed ( taken after 72 hours if necessary ) antibiotics . MAIN OUTCOME MEASURE Predictors of short term outcome : an episode of distress or night disturbance three days after child saw doctor . RESULTS Distress by day three was more likely in children with high temperature ( adjusted odds ratio 4.5 , 95 % confidence interval 2.3 to 9.0 ) , vomiting ( 2.6,1.3 to 5.0 ) , and cough ( 2.0 , 1.1 to 3.8 ) on day one . Night disturbance by day three was more likely with high temperature 2.4 ( 1.2 to 4.8 ) , vomiting ( 2.1,1.1 to 4.0 ) , cough ( 2.3,1.3 to 4.2 ) , and ear discharge ( 2.1 , 1.2 to 3.9 ) . Among the children with high temperature or vomiting , distress by day three was less likely with immediate antibiotics ( 32 % for immediate v 53 % for delayed , chi2=4.0 ; P=0.045 , number needed to treat 5 ) as was night disturbance ( 26 % v 59 % , chi2=9.3 ; P=0.002 ; number needed to treat 3 ) . In children without higher temperature or vomiting , immediate antibiotics made little difference to distress by day three ( 15 % v 19 % , chi2=0.74 ; P=0.39 ) or night disturbance ( 20 % v 27 % , chi2=1.6 ; P=0.20 ) . Addition of cough did not significantly improve prediction of benefit . CONCLUSION In children with otitis media but without fever and vomiting antibiotic treatment has little benefit and a poor outcome is unlikely Abstract Objective : To assess the medicalising effect of prescribing antibiotics for sore throat . Setting : 11 general practice s in Engl and . Design : R and omised trial of three approaches to sore throat : a 10 day prescription of antibiotics , no antibiotics , or a delayed prescription if the sore throat had not started to settle after three days . Patients : 716 patients aged 4 and over with sore throat and an abnormal physical sign : 84 % had tonsillitis or pharyngitis . Outcome measures : Number and rate of patients making a first return with sore throat , pharyngitis , or tonsillitis . Early returns ( within two weeks ) and complications ( otitis media , sinusitis , quinsy ) . Outcomes were documented in 675 subjects ( 94 % ) . Results : Mean follow up time was similar ( antibiotic group 1.07 years , other two groups 1.03 years ) . More of those initially prescribed antibiotics initially returned to the surgery with sore throat ( 38 % v 27 % , adjusted hazard ratio for return 1.39 , 95 % confidence interval 1.03 to 1.89 ) . Antibiotics prescribed for sore throat during the previous year had an additional effect ( hazard ratio 1.69 , 1.20 to 2.37 ) . Longer duration of illness ( > 5 days ) was associated with increased return within six weeks ( hazard ratio 2.90 , 1.70 to 4.92 ) . Prior attendance with upper respiratory conditions was also associated with increased reattendance . There was no difference between groups in early return ( 13/238 ( 5.5 % ) v 27/437 ( 6 % ) ) , or complications ( 2/236 ( 0.8 % ) v3/434 ( 0.7 % ) ) . Conclusions : Complications and early return result ing from no or delayed prescribing of antibiotics for sore throat are rare . Both current and previous prescribing for sore throat increase reattendance . To avoid medicalising a self limiting illness doctors should avoid antibiotics or offer a delayed prescription for most patients with sore throat . Key messages Sore throat is one of the commonest presentations of upper respiratory illness in primary care and attendence is increasing Complications are rare with no , or delayed , antibiotic prescription Prescribing antibiotics increases reattendance for future episodes Unless patients are very ill general practitioners should consider exploring concerns , explain the natural history , and avoid or delay prescribing Abstract Objective : To assess whether sharing the uncertainty of the value of antibiotics for acute bronchitis in the form of written and verbal advice affects the likelihood of patients taking antibiotics . Design : Nested , single blind , r and omised controlled trial . Setting : Three suburban general practice s in Nottingham . Participants : 259 previously well adults presenting with acute bronchitis . Intervention : In group A , 212 patients were judged by their general practitioner not to need antibiotics that day but were given a prescription to use if they got worse and st and ard verbal reassurance . Half of them ( 106 ) were also given an information leaflet . All patients in group B ( 47 ) were judged to need antibiotics and were given a prescription and encouraged to use it . Main outcome measures : Antibiotic use in the next two weeks . Reconsultation for the same symptoms in the next month . Results : In group A fewer patients who received the information leaflet took antibiotics compared with those who did not receive the leaflet ( 49 v 63 , risk ratio 0.76 , 95 % confidence interval 0.59 to 0.97 , P=0.04 ) . Numbers reconsulting were similar ( 11 v 14 ) . In group B , 44 patients took the antibiotics . Conclusion : Most previously well adults with acute bronchitis were judged not to need antibiotics . Reassuring these patients and sharing the uncertainty about prescribing in a information leaflet supported by verbal advice is a safe strategy and reduces antibiotic use . What is already known on this topic Most adults with acute bronchitis who consult their general practitioner will receive antibiotics For most patients antibiotics do not modify the natural course of the symptoms The widespread belief among patients that infection is the problem and antibiotics the solution has considerable influence on prescribing by general practitioners , even when they judge that antibiotics are not definitely indicated What this study adds General practitioners judged that about four in five adults with acute bronchitis did not definitely need antibiotics on the day they consulted Antibiotic use was reduced by a quarter in such patients , who received verbal and written information and reassurance in addition to a prescription for antibiotics Sharing with the patient the uncertainty about the decision to prescribe seems safe and OBJECTIVE To test the use of a delayed prescription compared with instructions to take antibiotics immediately in patients presenting to family physicians with upper respiratory tract infections ( common colds ) . STUDY DESIGN R and omized controlled single-blind study . POPULATION Subjects were 129 patients presenting with the common cold who requested antibiotics or whose physicians thought they wanted them . All patients were in a family practice in Auckl and , New Zeal and , consisting of 15 physicians ( 9 male , 6 female ) who had completed medical school between 1973 and 1992 . OUTCOMES MEASURED Outcomes were antibiotic use ( taking at least 1 dose of the antibiotic ) , symptom scores , and responses to the satisfaction questions asked at the end of the study . RESULTS Patients in the delayed-prescription group were less likely to use antibiotics ( 48 % , 95 % CI , 35%-60 % ) than were those instructed to take antibiotics immediately ( 89 % , 95 % CI , 76%-94 % ) . Daily body temperature was higher in the immediate-prescription group . The lack of difference in the symptom score between the 2 groups suggests that there is no danger in delaying antibiotic prescriptions for the common cold . CONCLUSIONS Delayed prescriptions are a safe and effective means of reducing antibiotic consumption in patients with the common cold . Clarification of patient expectations for antibiotics may result in a lower prescription rate . When the patient dem and s a prescription , delaying its delivery has the potential to provide gentle education BACKGROUND Despite evidence that uncomplicated lower respiratory tract infection ( cough ) does not respond appreciably to antibiotics and that bacterial resistance is increasing , general practitioners ( GPs ) still prescribe frequently . AIM To assess delayed antibiotic prescribing as a strategy for reducing the unnecessary use of antibiotics for cough in primary care . DESIGN OF STUDY Open r and omised controlled trial of delayed versus immediate prescribing of antibiotics . SETTING One hundred and ninety-one adult patients with uncomplicated cough in 22 Scottish practice s who would have received antibiotics under the GP 's usual practice were r and omised to receive either an immediate prescription ( 92 patients ) or a delayed prescription ( 99 patients ) . METHOD Delayed subjects were asked to wait a week before deciding whether to collect their prescription . Outcome measures included symptom duration , prescription uptake , patient satisfaction , patient enablement , and subsequent consultation rates . The 48 GPs who recruited patients were surveyed six months after the trial to see whether they used delayed prescribing as a part of their normal practice . RESULTS Study and control groups were similar at baseline . Of the subjects in the delayed arm , 55 % did not pick up their prescription . Although most patients were satisfied , more patients in the immediate arm were very satisfied with the treatment ( P = 0.001 ) and the consultation ( P = 0.03 ) . The patients in the immediate arm were also more enabled ( 3.3 versus 2.4 ; P = 0.04 ) , although more of them intended to consult for similar complaints in the future ( 85 % versus 69 % , P = 0.02 ) . We were unable to detect any difference in actual consulting behaviour in the follow-up period ( mean = 15 months [ SD = 5 months ] ) . Subsequently , 68 % of GPs used delayed prescribing at least monthly ; all gave the prescription to the patient . CONCLUSION Delayed prescribing is effective at reducing the use of antibiotics for self-limiting cough ; however , patients are less satisfied and enabled as a result . Patients may be deterred from consulting rather than becoming enabled BACKGROUND The extent of use of antibiotics to treat upper respiratory infections in general practice is an area for concern due to the increasing problem of bacterial resistance . Effective educational strategies to promote rational prescribing are needed . OBJECTIVES We aim ed to examine the effectiveness of prescriber feedback and management guidelines in reducing antibiotics prescribing by GP trainees for undifferentiated upper respiratory tract infection , and in improving the choice of antibiotic for tonsillitis/streptococcal pharyngitis . The research tested a stepwise approach to targeting educational input to high prescribers . METHOD General Practice trainees in New South Wales ( n = 157 ) were r and omly allocated to a treatment group ( n = 78 ) which received an education intervention on antibiotic use , or to a control group ( n = 79 ) which received an intervention on an unrelated topic . Trainees completed three practice activity surveys , each of 110 consecutive patient encounters , with 6-month intervals between surveys . Prescriber feedback and management guidelines on use of antibiotics for URTI and choice of antibiotic for tonsillitis/streptococcal pharyngitis were delivered in a written form between surveys 1 and 2 . An educational outreach visit to high prescribers occurred between surveys 2 and 3 . Outcome measures were the rate of antibiotic prescribing for all indications , for URTI and prescribing of select antibiotics for tonsillitis/streptococcal pharyngitis . RESULTS Antibiotic prescribing by the intervention group declined over three occasions from 25.0 to 23.3 to 19.7 per 100 URTI problems , while the control group increased from 22.0 to 25.0 to 31.7 per 100 URTI problems ( P = 0.002 ) . Prescribing in agreement with accepted guidelines for tonsillitis/streptococcal pharyngitis increased over time in the intervention group from 55.6 to 69.8 to 73.0 per 100 problems , but decreased in the control group from 59.6 to 57.5 to 58.5 ( P = 0.05 ) . CONCLUSION Prescriber feedback and management guidelines were shown to influence antibiotic prescribing for URTI and choice of antibiotic for tonsillitis/streptococcal pharyngitis . This study provides a model for targeting educational input to those prescribers who most need to change their behaviour Abstract Objective : To compare immediate with delayed prescribing of antibiotics for acute otitis media . Design : Open r and omised controlled trial . Setting : General practice s in south west Engl and . Participants : 315 children aged between 6 months and 10 years presenting with acute otitis media . Interventions : Two treatment strategies , supported by st and ardised advice sheets — immediate antibiotics or delayed antibiotics ( antibiotic prescription to be collected at parents ' discretion after 72 hours if child still not improving ) . Main outcome measures : Symptom resolution , absence from school or nursery , paracetamol consumption . Results : On average , symptoms resolved after 3 days . Children prescribed antibiotics immediately had shorter illness ( −1.1 days ( 95 % confidence interval −0.54 to −1.48 ) ) , fewer nights disturbed ( −0.72 ( −0.30 to −1.13 ) ) , and slightly less paracetamol consumption ( −0.52 spoons/day ( −0.26 to −0.79 ) ) . There was no difference in school absence or pain or distress scores since benefits of antibiotics occurred mainly after the first 24 hours — when distress was less severe . Parents of 36/150 of the children given delayed prescriptions used antibiotics , and 77 % were very satisfied . Fewer children in the delayed group had diarrhoea ( 14/150 ( 9 % ) v 25/135 ( 19 % ) , χ2=5.2 , P=0.02 ) . Fewer parents in the delayed group believed in the effectiveness of antibiotics and in the need to see the doctor with future episodes . Conclusion : Immediate antibiotic prescription provided symptomatic benefit mainly after first 24 hours , when symptoms were already resolving . For children who are not very unwell systemically , a wait and see approach seems feasible and acceptable to parents and should substantially reduce the use of antibiotics for acute otitis media OBJECTIVE To explore the experiences and opinions of family physicians and patients regarding the delay of antibiotic prescriptions , to be dispensed if symptoms persist or worsen over time , in treating upper respiratory tract infections . STUDY DESIGN Qualitative study using semistructured interviews conducted in family practice in Auckl and , New Zeal and . POPULATION Thirteen physicians recruited from a study of family physicians ' reported antibiotic prescribing and 13 patients recruited from the intervention arm of a r and omized controlled trial on delayed antibiotic prescribing . OUTCOMES MEASURED Patients ' and physicians ' experiences of delayed antibiotic prescriptions for upper respiratory tract infections . RESULTS The primary themes identified were value judgments of antibiotics , decreased antibiotic use , patient-centered factors , effects on the physician-patient relationship , patient convenience , adverse effects of delaying prescription , and selectivity for use of antibiotics . Many themes were common to both patients and physicians . Physicians valued empowering patients ' decision making about their health care management more highly than did patients . Decreasing antibiotic use was not a key factor for most patients . Both groups acknowledged the value in saving patients time and money . Physicians viewed the strategy as giving patients reassurance and meeting their expectations for antibiotics . Negative implication s included perception of physician incompetence and physician loss of management control . Opinions were mixed regarding which patients , under which conditions , were suitable for delayed antibiotic prescriptions . CONCLUSIONS Although delayed antibiotic prescriptions are effective in decreasing antibiotic use for conditions not clinical ly warranting antibiotics , neither patients nor physicians universally endorsed this strategy . Research to establish formalized recommendations for patient suitability and instructions for use would be of value Two recent review s question ed the routine use of antibiotics in the initial management of acute otitis media . 1 2 My practice partners and I responded to the review s by changing our policy , with the aim of reducing such prescribing in children . We measured the change one year after adopting the new policy . From July 1997 my practice partners and I changed our policy on routine prescription of antibiotics in the initial management of acute otitis media in children . In children who were not particularly ill we gave the parents a h and out that summarised the limited benefit of antibiotics on the basis of the data presented in the Cochrane review .1 We advised parents to give regular paracetamol suspension ; we also offered an antibiotic prescription but asked the parents to keep it for a day or two . They could redeem it at a pharmacy if the child did not got better over this period . A local practice acted as a concurrent control . Both practice s use |
1,944 | 28,075,506 | CONCLUSIONS This systematic review found that chlorhexidine is not significantly effective in reducing the severity of mucositis ( moderate quality of evidence ) nor in preventing the incidence of mucositis ( low quality of evidence ) . | BACKGROUND Oral mucositis occurs in patients undergoing chemoradiation for cancer treatment .
It is believed that colonization of ulcerated mucosa by bacteria , fungi , and virus results in secondary infections .
The effect of chlorhexidine on the incidence and severity of oral mucositis in patients with cancer was evaluated in this review . | Benzydamine hydrochloride rinse was shown to prevent oral mucositis in radiation therapy . Prevention of mucositis allows reduction in morbidity of one of the therapy limiting complications of radiotherapy for cancer therapy OBJECTIVE To assess the microbiological effects of an antiseptic , non-alcohol based mouth-rinse containing chlorhexidine and cetylpyridinium chloride , in patients undergoing radiation therapy for head- and -neck cancer . STUDY DESIGN This was a parallel , double-blind , prospect i ve , r and omized clinical trial , including patients irradiated as part of the therapy of head- and -neck cancer , aged 18 - 75 , with at least 10 teeth , and willing to sign an informed consent . Cancer patients were r and omly assigned to one of the two treatments ( test mouth-rinse or a placebo ) . Three visits were scheduled ( baseline , 14 and 28 days ) . Microbiological findings were evaluated in tongue , mucosa and subgingival sample s , by means of culture . Microbiological variables were assessed by means of the Mann-Whitney , Wilcoxon and chi-square tests . RESULTS 70 patients were screened and 36 were included . The detection of C and ida species in mucosa and tongue sample s showed significant reductions in the test group . Total bacterial counts decreased in both groups from baseline to the 2-week visit , while minor changes occurred between 2 and 4 weeks ( effects on P. gingivalis , P. intermedia , C. rectus , E. corrodens ) . CONCLUSIONS Within the limitations of the small sample size , this study suggests that the use of the tested mouth-rinse may lead to improvements in microbiological parameters in patients irradiated for head- and -neck cancer Patients receiving cytotoxic antineoplastic therapy often have treatment-associated stomatitis . A 0.12 % chlorhexidine digluconate mouthrinse was evaluated ( 15 ml , three times a day ) in a prospect i ve , double-blind r and omized trial as prophylaxis against cytotoxic therapy-induced damage to oral soft tissues . Seventy subjects , forty in patients receiving high-dose chemotherapy and thirty out patients receiving high-dose head and neck radiation therapy , were evaluated . Chlorhexidine mouthrinse significantly reduced the incidence of oral mucositis in the chemotherapy group on day 14 ( p less than 0.02 ) and at 1 week follow-up on day 28 ( p less than 0.002 ) . Mucositis in the patients undergoing chemotherapy who received chlorhexidine also resolved more rapidly . Mucositis severity was significantly less compared to the control chemotherapy group on day 14 ( p less than 0.03 ) , day 21 ( p less than 0.04 ) , and on 1 week follow-up ( p less than 0.02 ) . Concomitant trends in the reduction in oral streptococci and yeast were noted in the chemotherapy group receiving chlorhexidine mouthrinse . Although no differences were observed in oral mucositis between the control and chlorhexidine groups of patients undergoing high-dose radiotherapy , similar reductions of oral microflora to those seen in the chemotherapy population were also noted for patients undergoing radiation therapy who received chlorhexidine . Although generally not significant , some increase in gram-negative bacilli was noted in the chlorhexidine-treated patients in both the chemotherapy and radiotherapy groups , but there was no correlation with increased systemic infection . Prophylactic chlorhexidine mouthrinse reduces oral mucositis and microbial burden in patients with cancer undergoing intensive chemotherapy Oral mucosal ulceration complicating bone marrow transplantation interferes with patients ' comfort , nutrition and may lead to systemic infection derived from the mouth . The mucosal injury results from epithelial damage due to the cytotoxic effects of chemotherapy and radiation conditioning as well as from superficial oropharyngeal infection . Because chlorhexidine gluconate is a broad spectrum topical antimicrobial which has been demonstrably effective in preventing oral infection and gingivitis , we performed a r and omized , placebo controlled , double-blind trial of chlorhexidine as a mouth rinse in BMT recipients to study the severity of oral mucositis and both oral and systemic infectious complications . One hundred patients were r and omly assigned to receive either chlorhexidine gluconate 0.12 % mouth rinse or placebo three times daily from the initiation ( day -8 ) of chemoradiotherapy conditioning until day + 35 post-BMT . Chlorhexidine use result ed in a trend toward improved oral hygiene index ( reduced dental plaque ) ( p = 0.06 ) but did not modify the oral mucositis . Patients using chlorhexidine developed a maximum ulceration of 18 + /- 22 % of their oral mucosa , while placebo patients ulcerated 25 + /- 31 % of the mouth . Ulcerative mucositis was significantly worse in adults compared with children , in individuals who received methotrexate for graft-versus-host disease prophylaxis , and was most prominent on non-keratinized epithelium . Overall , there was no clinical ly demonstrable additional therapeutic advantage to the use of chlorhexidine in either reducing the mucositis , controlling oral pain , facilitating oral nutrition , shortening hospital stay , or reducing oral infection with herpes simplex virus . There was a trend toward diminished oral c and idiasis in chlorhexidine users ( p = 0.06 ) . ( ABSTRACT TRUNCATED AT 250 WORDS PURPOSE To determine whether a chlorhexidine mouthwash could alleviate radiation-induced oral mucositis . PATIENTS AND METHODS Patients scheduled to receive radiation therapy to include greater than one third of the oral cavity mucosa were selected for study . Following stratification , they were r and omized in a double-blind manner to receive a chlorhexidine mouthwash or a placebo mouthwash . Both groups were then similarly evaluated for mucositis and mouthwash toxicity . RESULTS Twenty-five patients were r and omized to receive the chlorhexidine mouthwash , while 27 received the placebo mouthwash . Treatment arms were well balanced . There was a trend for more mucositis and there was substantially more toxicity ( eg , mouthwash-induced discomfort , taste alteration , and teeth staining ) on the chlorhexidine arm . CONCLUSION In contrast to the pre study hypothesis that a chlorhexidine mouthwash might provide benefit for patients receiving radiation therapy to the oral mucosa , this study provides strong evidence suggesting that a chlorhexidine mouthwash is detrimental in this clinical situation PURPOSE / OBJECTIVES To test the effectiveness of a nurse-initiated systematic oral hygiene teaching program-PRO-SELF : Mouth Aware (PSMA)-in conjunction with two mouthwashes ( 0.12 % chlorhexidine or sterile water ) in preventing chemotherapy-induced oral mucositis . DESIGN R and omized , double-blind , placebo-controlled , clinical trial . SETTING S 23 outpatient clinics and office practice s in California . SAMPLE 222 patients who were starting a cycle of mucositis-inducing chemotherapy . METHOD Participants were followed over three chemotherapy cycles . All patients were provided the PSMA program . R and om assignment to a mouthwash occurred prior to the development of oral mucositis . Research ers used the Oral Assessment Guide to assess the patients oral cavities monthly ( with the patients cycles of chemotherapy ) and when patients reported any oral changes between cycles . MAIN RESEARCH VARIABLES Type of mouthwash , incidence , days to onset , and severity of chemotherapy-induced oral mucositis . FINDINGS No significant differences existed between the two mouthwashes in regard to incidence , days to onset , and severity of mucositis . CONCLUSIONS Because chlorhexidine ( S20 per pint ) was no more effective than water , a substantial cost savings can be realized by rinsing with water . Interestingly , the PSMA program appeared to reduce the incidence of mucositis from on a prior estimate of 44 % to less than 26 % . IMPLICATION S FOR NURSING PRACTICE A nursing prescription of a systematic oral hygiene program using water as a mouth rinse is cost efficient and may be effective in preventing oral mucositis The goal of reducing oral complications during chemotherapy and bone marrow transplantation has received attention at several centers . The current r and omized study of 86 adults with leukemia treated with chemotherapy or bone marrow transplantation assessed the potential role of chlorhexidine , nystatin , and saline solution rinses to reduce the findings of oral mucositis , gingivitis , and oral infection . The results of this study did not show a reduction in mucositis with the use of these rinses . However , potential bacterial and fungal pathogens were identified less frequently in the patients using chlorhexidine rinse OBJECTIVE To assess the effects of an antiseptic , non-alcohol based mouth-rinse containing chlorhexidine and cetylpyridinium chloride , in preventing the oral complications associated to radiation therapy in head- and -neck cancer patients . STUDY DESIGN This was a parallel , double blind , prospect i ve , r and omized clinical trial . Cancer patients were r and omly assigned to one of the two treatments ( test mouth-rinse or a placebo ) . Three visits were scheduled ( baseline , 14 and 28 days ) . Different outcome variables were evaluated : mucositis , plaque and gingival indices , stimulated saliva and salivary pH. RESULTS 70 patients were screened and 36 were included . The presence and the degree of mucositis significantly increased in both groups and no significant differences were detected between groups , although the median increase in the placebo group ( 1.81 ) at 2 weeks was higher than in the test group ( 1.20 ) . CONCLUSIONS Within the limitations of the small sample size , this study suggests that the use of the tested mouth-rinse may lead to some improvements in clinical parameters in patients irradiated for head- and -neck cancer AIMS The present study was done to assess the effect of three alcohol-free mouthwashes on radiation-induced oral mucositis in patients with head and neck malignancies . MATERIAL S AND METHODS Eighty patients with head and neck malignancies , scheduled to undergo curative radiotherapy , were r and omly assigned to receive one of the three alcohol-free test mouthwashes ( 0.12 % chlorhexidine , 1 % povidone-iodine , or salt/soda ) or a control . The patients were instructed to rinse with 10 ml of the mouthwash , twice a day , for a period of 6 weeks . Mucositis was assessed at baseline and at weekly intervals during radiation therapy , using the World Health Organization criteria for grading of mucositis . The baseline demography of the four groups was matched for age , sex , stage of cancer , and whether the patient had cancer of oral or extraoral regions . A post hoc test for repeated measures was used to find the difference of mean mucositis scores between the groups at various week intervals . RESULTS Among the 76 patients who completed the study , patients in the povidone-iodine group had significantly lower mucositis scores when compared to the control group from the first week of radiotherapy . Their scores were also significantly lower when compared to the salt/soda and chlorhexidine groups from the fourth and fifth week , respectively , after radiotherapy . CONCLUSIONS This study demonstrates that use of alcohol-free povidone-iodine mouthwash can reduce the severity and delay the onset of oral mucositis due to antineoplastic radiotherapy Conditioning chemoradiotherapy damages the mucosal barrier of the mouth and throat and often produces severe oral inflammation and infection . In a prospect i ve , double-blind , r and omized study , we examined the use of a chlorhexidine digluconate mouthrinse for prophylaxis against oral mucosal complications in 51 bone marrow transplant patients . Use of chlorhexidine mouthrinse produced significant reductions in the incidence and severity of oral mucositis . Mucositis also resolved more quickly in patients receiving chlorhexidine . Concomitant reductions in total oral streptococci ( p less than 0.02-p less than 0.001 ) and oral c and ida ( p less than 0.004 ) were seen in patients using chlorhexidine . Persistent clinical oral c and idiasis ( thrush ) was observed in 15 to 27 control group patients ( 56 % ) , but only transiently in two ( 8 % ) of 24 patients who used chlorhexidine rinse ( p less than 0.001 ) . Five of 27 control group patients ( 19 % ) had c and idemia , while no c and idemia was observed in the chlorhexidine group ( p less than 0.03 ) . Three deaths from disseminated c and idiasis occurred in the placebo group ; none occurred in patients who received chlorhexidine . Prophylactic use of chlorhexidine mouthrinse produces reductions in oral soft tissue disease and oral microbial burden in patients undergoing bone marrow transplantation . The reductions in mucositis and in oral c and ida infections observed with prophylactic chlorhexidine mouthrinse represent a significant advantage for patients undergoing marrow transplantation Mucositis induced by irradiation is the reactive inflammatory-like process of the oropharyngeal mucous membranes following irradiation . Bacteria colonizing the oral tissues are thought to contribute to this inflammatory process . The eradication of Gram-negative bacilli ( selective elimination of oral flora ) in fifteen comparably irradiated head and neck cancer patients was found to be associated with a significant reduction in mucositis compared with two groups of 15 patients receiving either placebo or chlorhexidine rinsing . Criteria used were the extent of local mucositis signs ( mucositis score ) , as well as generalized side-effects such as the need of nasogastric tube feedings following severe feeding problems . Mucositis signs were confined to erythema only in all selectively decontaminated patients . No pseudomembranes were observed and artificial feeding was completely prevented . These promising results need further confirmation in larger ( multicenter ) studies The prophylactic value of twice-daily mouth rinses with a solution of 0.1 % chlorhexidine gluconate in minimizing oral complications during remission-induction chemotherapy was tested in sixteen patients with acute myeloblastic leukemia . The study design was double blind with a placebo control . St and ardized measurement indices were employed to assess the dental plaque levels and the degree of gingivitis and mucositis during remission-induction . The treatment group demonstrated superior oral health on the basis of each of these measurement parameters . A moderate increase in tooth staining was observed in the treatment group . The results also suggested the potential value of chlorhexidine mouth rinses in the prophylaxis of oral c and idiasis in the myelosuppressed patient Immunosuppressive chemotherapy and bone marrow transplantation are increasingly used to treat and , in some cases , cure numerous malignant conditions . The systemic sequelae as a result of these immunosuppressive techniques lead to a host of oral and dental complications . The direct and indirect stomatotoxic effects lead to development of ulcerative , hemorrhagic , or infectious complications that potentially can lead to increased mortality and morbidity . Chlorhexidine was studied to evaluate its broad spectrum antimicrobial properties and to evaluate its effect on immunosuppression-induced mucositis . Our double-blind r and omized study revealed that chlorhexidine versus controls had considerable effect in the bone marrow transplant cohort . Patients who received chlorhexidine while undergoing bone marrow transplantation were found to exhibit fewer and less painful mucositis lesions . This study supports prophylactic use of chlorhexidine in patients who undergo bone marrow transplantation Oral flora is thought to contribute to irradiation mucositis in patients with head and neck cancer . Neglect of oral hygienic care may also contribute to mucositis . The purpose of this prospect i ve , r and omized , placebo-controlled , double-blind study was to evaluate the effect of chlorhexidine 0.1 % mouthrinses on oral flora and irradiation mucositis . This study included 30 patients with head and neck cancer who had comparable irradiation portals . One group ( N = 15 ) rinsed four times daily with chlorhexidine 0.1 % , the other group ( N = 15 ) with a placebo . The oral flora was cultured ( oral washing technique ) twice before and three times per week during the period of radiotherapy . On the same days , the severity of mucositis was determined . The colonization index of viridans streptococci was significantly reduced only after 5 weeks of chlorhexidine 0.1 % treatment . The colonization patterns of C and ida species , Streptococcus faecalis , staphylococci , and Enterobacteriaceae , Pseudomonadaceae , and Acinetobacter species were not influenced by 5 weeks of use of chlorhexidine rinses when compared with the placebo . No differences were seen between the two study groups in the development and severity of mucositis . In conclusion , suppression of oral flora and a lowering of the severity of mucositis by means of disinfecting mouthrinses were not successful |
1,945 | 27,013,238 | The review ed papers collectively support the notion that migraine patients have alterations in serotonergic neurotransmission .
Most likely , migraine patients have a low cerebral serotonin level between attacks , which elevates during a migraine attack . | Background Migraine is one of the most common and disabling of all medical conditions , affecting 16 % of the general population , causing huge socioeconomic costs globally .
Current available treatment options are inadequate .
Serotonin is a key molecule in the neurobiology of migraine , but the exact role of brain serotonergic mechanisms remains a matter of controversy . | Migraine is associated with stimulus hypersensitivity , increased evoked cortical responses , and abnormal 5-HT levels in peripheral blood . We studied cortical auditory evoked potentials ( AEPs ) between attacks in 35 patients suffering from migraine without aura ( MO , n = 25 ) or with aura ( MA , n = 10 ) and in 25 healthy volunteers . Binaural tones were delivered at 40 , 50 , 60 , and 70 dB sensation level ( SL ) in a pseudor and omized order . The intensity dependence of the auditory Nl-P2 component was significantly greater in MO ( p = 0.003 ) and MA ( p = 0.02 ) patients than in healthy controls , result ing in a much steeper amplitudeistimulus intensity function slope . When three sequential blocks of 40 averaged responses were analyzed at the 40- and 70-dB SL intensities , N1–P2 amplitude decreased in second and third blocks at both intensities in controls , but increased in migraineurs , a difference that was significant in both blocks for the 70-dB SL stimulus . The strong interictal dependence of AEPs on stimulus intensity may thus be due to potentiation ( instead of habituation ) of the response during repetition of the high-intensity stimulation . In concordance with previous studies of visual evoked potentials , these results confirm that migraine is characterized between attacks by an abnormality of cortical information processing , which might be a consequence of low 5-HT transmission and favor cortical energy dem and Purpose The tracer 123I-2-([2-({dimethylamino}methyl)phenyl]thio)-5-iodophenylamine ( [123I]ADAM ) has been developed to image serotonin transporters ( SERTs ) with SPECT . Pre clinical studies have shown that [123I]ADAM binds selectively to SERTs . Moreover , initial human studies have shown that [123I]ADAM binding could be blocked by selective serotonin reuptake inhibitors ( SSRIs ) . However , in humans it has not been proven that [123I]ADAM binds selectively to SERTs . Methods We examined the in vivo availability of SERTs in 12 healthy young volunteers 5 h after bolus injection of [123I]ADAM . To evaluate the selectivity of binding , four participants were pretreated ( double-blinded design ) with placebo , four with paroxetine ( 20 mg ) and four with the dopamine/norepinephrine blocker methylpheni date ( 20 mg ) . SPECT studies were performed on a brain-dedicated system ( Neurofocus ) , and the SPECT images were coregistered with individual MR scans of the brain . ADAM binding in SERT-rich brain areas and cerebellar cortex ( representing non-specific binding ) was assessed by drawing regions of interest ( ROIs ) on the individual MR images . Specific to non-specific ratios were used as the outcome measure . Results We found that specific to non-specific ratios were statistically significantly lower in paroxetine-pretreated participants than in placebo- or methylpheni date -pretreated participants . No such difference was found between groups pretreated with placebo or methylpheni date . Conclusion Our preliminary findings suggest that [123I]ADAM binds selectively to SERTs in human brain Identification of a biomarker that can inform on extracellular serotonin ( 5-HT ) levels in the brains of living humans would enable greater underst and ing of the way brain circuits are modulated by serotonergic neurotransmission . Substantial evidence from studies in animals and humans indicates an inverse relationship between central 5-HT tonus and 5-HT type 4 receptor ( 5-HT4R ) density , suggesting that 5-HT4R receptor density may be a biomarker marker for 5-HT tonus . Here , we investigated whether a 3-week administration of a selective serotonin reuptake inhibitor , expected to increase brain 5-HT levels , is associated with a decline in brain 5-HT4R binding . A total of 35 healthy men were studied in a placebo-controlled , r and omized , double-blind study . Participants were assigned to receive 3 weeks of oral dosing with placebo or fluoxetine , 40 mg per day . Brain 5-HT4R binding was quantified at baseline and at follow-up with [11C]SB207145 positron emission tomography ( PET ) . Three weeks of intervention with fluoxetine was associated with a 5.2 % reduction in brain 5-HT4R binding ( P=0.017 ) , whereas placebo intervention did not change 5-HT4R binding ( P=0.52 ) . Our findings are consistent with a model , wherein the 5-HT4R density adjusts to changes in the extracellular 5-HT tonus . Our data demonstrate for the first time in humans that the imaging of central 5-HT4R binding may be used as an in vivo biomarker of the central 5-HT tonus Objective : The 5-HT1B/D agonists ( triptans ) are specific headache medications that have no effect on pain as such . Although they are routinely used in the treatment of acute migraine attacks , the underlying mechanisms of action are still a matter of debate . Methods : Forty-three healthy participants underwent fMRI while receiving trigemino-nociceptive stimulation and control stimuli in a st and ardized fMRI paradigm . Using a crossover , double-blind , placebo-controlled design , 21 participants ( 10 women , mean age 26.9 , range 20–37 years ) received sumatriptan and 22 participants ( 11 women , mean age 25.5 , range 22–32 years ) received acetylsalicylic acid ( ASA ) . Administration of medication and saline was r and omized between participants of each group result ing in half of the participants receiving saline and the other half receiving the respective medication during the first fMRI data acquisition . Results : While mean pain intensity ratings did not differ significantly between control and medication nor between medications , we found a significant blood oxygen level – dependent signal increase in the trigeminal nuclei and the thalamus after sumatriptan treatment compared with placebo or ASA . In addition , we specifically looked for the pharmacologic modulation of functional coupling between trigeminal nuclei and higher brain areas , i.e. , trigemino-cortical pathways , and found a strong coupling during the saline condition , which was altered by sumatriptan but not after ASA administration . Conclusion : These data suggest that a specific functional inhibition of trigemino-cortical projections is one of the reasons that triptans , unlike pain killers , act highly specifically on headache and migraine but not pain as such Background : Altered serotonin ( 5-HT ) neurotransmission has been implicated in the pathophysiology of migraine headache . Objectives : To test this hypothesis in migraine patients in vivo using PET and α-[11C]methyl-l-tryptophan as a surrogate marker of brain 5-HT synthetic rate during different phases of their migraine attack and after acute antimigraine therapy with sumatriptan , and to compare them with normal controls . Methods : Six patients were scanned 1 ) within 6 hours after the onset of a spontaneous migraine attack , 2 ) 2 hours after subcutaneous sumatriptan , and 3 ) interictally when migraine free for at least 3 days . Head pain was rated before each scan , and before and every 15 minutes after sumatriptan . Results : Brain 5-HT synthesis was highest during attacks , lowest after sumatriptan , and intermediate when patients were migraine free . All states were statistically different from the others in virtually all brain regions examined . 5-HT synthetic rates in patients during migraine attacks did not differ from those of age- and sex-matched controls , whereas they were significantly lower after sumatriptan in a majority of regions . Interictally , global brain 5-HT synthetic rate was slightly , albeit not significantly , lower ( −14 % ) in migraine patients than in controls , with specific cortical areas exhibiting proportionally more severe reductions ( −28 % to 31 % ) . Conclusions : These findings point to a low cortical serotonergic tone in migraine patients interictally . Further , they demonstrate widespread increases in brain serotonin ( 5-HT ) synthetic rate in migraine patients during attacks , and that triptans exert a negative feedback regulation of brain 5-HT synthesis concurrently with modulation of pain pathways Objective .—To investigate the effects of fluoxetine in migraine prophylaxis on habituation of visually evoked potentials Abstract Objective : Triptans are highly effective in the treatment of migraine . Both central and peripheral mechanisms of action have been suggested . Until now , firm data about the passage of triptans into the CNS in humans have been lacking . The aim of the current study was to evaluate , using positron emission tomography ( PET ) , the uptake and distribution of zolmitriptan into the CNS after intranasal administration . Subjects and methods : Eight healthy volunteers , five males and three females ( mean ages 23 and 26 years , respectively ) , were included . Radioactive [carbonyl-11C]zolmitriptan was infused intravenously for 5 minutes on two occasions : once alone , and once 30–40 minutes after intranasal administration of unlabelled zolmitriptan 5 mg . PET was used to measure the concentration of labelled zolmitriptan in the brain , from the start of the tracer infusion for 90 minutes . Regional cerebral blood volume was determined with [15O]carbon monoxide . In addition , an MRI scan was performed to obtain anatomical information . The PET images were analysed quantitatively for different areas of the brain , generating [11C]zolmitriptan time-activity data corrected for circulating tracer activity . The rate of uptake of intranasal zolmitriptan into the CNS was estimated by kinetic modelling using the PET data . Results : PET data from this study demonstrate a rapid dose-proportional uptake of [11C]zolmitriptan into the brain . Significant concentrations of [11C]zolmitriptan were found in all brain regions studied . Calculated CNS concentrations after intranasal zolmitriptan administration showed a gradual increase , reaching about 2nM ( 0.5 μg/L ) 30 minutes after administration and 3.5nM ( 1.0 μg/L ) , or one-fifth of the plasma concentration , 1 hour after administration . Five minutes after zolmitriptan administration , the mean CNS concentration had already reached 0.5nM , which is higher than in vitro values for initiation of the agonistic action on 5-HT1B/1D receptors . Conclusion : This study demonstrates by direct measurements that zolmitriptan enters the brain parenchyma in humans , achieving an uptake rate and concentration compatible with a central mode of action As shown in animal studies , 5HT1B/1D agonists can inhibit activity in the trigeminal nucleus caudalis , which may be advantageous for their antimigraine effect . To demonstrate a possible central nervous system ( CNS ) action of these compounds in man we studied their effect on the intensity dependence of the cortical auditory evoked potentials ( IDAPs ) , thought to be inversely related to central serotonergic transmission . An amplitude/stimulus intensity function ( ASF ) slope was computed in healthy volunteers and migraine patients between attacks before and 2 h after oral 311C90 ( zolmitriptan “ Zomig ” ) 10 mg ( n=14 ) , 311C90 5 mg ( n=7 ) , sumatriptan 100 mg ( n=14 ) , dexfenfluramine 15 mg ( n=4 ) , lorazepam 1.25 mg ( n=4 ) and placebo ( n=14 ) . 311C90 10 mg and , to a lesser degree , 5 mg significantly increased the mean ASF slope ( p=0.007 and 0.05 vs placebo ) . There was a significant positive correlation between plasma levels of 311C90 and ASF slope changes . Sumatriptan and lorazepam had little effect , but dexfenfluramine produced a significant ASF slope decrease . 311C90 is able to modify a CNS activity that is modulated by serotonin , i.e. the IDAP . This effect is probably the consequence of its super or lipophilicity compared to sumatriptan and of activation of prejunctional 5HT1B/1D autoreceptors , which lowers central serotonin release and thus the preactivation level of sensory cortices Background : Migraine is frequently associated with nonheadache symptoms before , during , and after the headache . Premonitory symptoms occurring before the attack have not been rigorously studied . Should these symptoms accurately predict headache , there are considerable implication s for the pathophysiology and management of migraine . Methods : Electronic diaries were used in a 3-month multicenter study to record nonheadache symptoms before , during , and after migraine . The authors recruited subjects who reported nonheadache symptoms in at least two of three attacks that they believed predicted headache . Symptoms were entered in the diaries by patient initiation and through prompted entries at r and om times daily . Entries could not be altered retrospectively . Data recorded included nonheadache symptoms occurring during all three phases of the migraine , prediction of the attack from premonitory symptoms , general state of health , and action taken to prevent the headache . Results : One hundred twenty patients were recruited : 97 provided usable data . Patients correctly predicted migraine headaches from 72 % of diary entries with premonitory symptoms . A range of cognitive and physical symptoms was reported at a similar rate through all three phases of the migraine . The most common premonitory symptoms were feeling tired and weary ( 72 % of attacks with warning features ) , having difficulty concentrating ( 51 % ) , and a stiff neck ( 50 % ) . Subjects who functioned poorly in the premonitory phase were the most likely to correctly predict headache . Conclusions : Using an electronic diary system , the authors show that migraineurs who report premonitory symptoms can accurately predict the full-blown headache |
1,946 | 14,583,993 | Therefore it is not possible to confirm whether this increase seen with PI(max ) translates into any measurable clinical benefit .
REVIEW ER 'S CONCLUSIONS Currently there is insufficient evidence to suggest that inspiratory muscle training provides any clinical benefit to patients with asthma . | BACKGROUND In moderate to severe chronic obstructive pulmonary disease there is good evidence of a generalised loss of muscle bulk ( including the respiratory muscles ) .
It is possible that similar loss of respiratory muscle strength occur particularly in more severe asthma related in part to the effects of steroid therapy .
Thus the respiratory muscle function may well be of relevance in asthma and if dysfunctional , may be a suitable target for training .
OBJECTIVES To evaluate the efficacy of inspiratory muscle training with an external resistive device in patients with asthma . | Little information is available about the effects of inspiratory muscle training in patients with cystic fibrosis ( CF ) . In this study the effects of inspiratory-threshold loading in patients with CF on strength and endurance of the inspiratory muscles , pulmonary function , exercise capacity , dyspnoea and fatigue were evaluated . Sixteen patients were assigned to one of two groups using the minimization method : eight patients in the training group and eight patients in the control group . The training was performed using an inspiratory-threshold loading device . Patients were instructed to use the threshold trainer 20 min a day , 5 days a week for 6 weeks . Patients in the training group trained at inspiratory threshold loads up to 40 % of maximal static inspiratory pressure ( Pimax ) and patients in the control group got ' sham ' training at a load of 10 % of Pimax . No significant differences were found among the two groups in gender , age , weight , height , pulmonary function , exercise capacity , inspiratory-muscle strength and inspiratory-muscle endurance before starting the training programme . Mean ( SD ) age in the control group was 19 ( 5.5 ) years , mean ( SD ) age in the training group was 17 ( 5.2 ) years . Mean FEV1 in both groups was 70 % predicted , mean inspiratory-muscle strength in both groups was above 100 % predicted . All patients except one , assigned to the training group , completed the programme . After 6 weeks of training , mean inspiratory-muscle endurance ( % Pimax ) in the control group increased from 50 % to 54 % ( P = 0.197 ) ; in the training group mean inspiratory muscle endurance ( % Pimax ) increased from 49 % to 66 % ( P = 0.003 ) . Statistical analysis showed that the change in inspiratory-muscle endurance ( % Pimax ) in the training group was significantly higher than in the control group ( P = 0.012 ) . After training , in the training group there was a tendency of improvement in Pimax with an increase from 105 to 123 % predicted , which just fell short of statistical significance ( P = 0.064 ) . After training no significant differences were found in changes from baseline in pulmonary function , exercise capacity , dyspnoea and fatigue . It is concluded that low-intensity inspiratory-threshold loading at 40 % of Pimax was sufficient to elicit an increased inspiratory-muscle endurance in patients with CF We examined the effects of ventilatory muscle endurance training on resting breathing pattern in 12 C6-C7 traumatic quadriplegics at least 1 year post-injury . All subjects had complete motor loss below the lesion level . Subjects were r and omly assigned to a training ( N = 6 ) , or a control group ( N = 6 ) . Baseline tests included measurement of resting ventilation and breathing pattern using mercury in rubber strain gauges for 20 minutes in a seated position ; maximum inspiratory mouth pressure ( MIP ) at FRC , and sustainable inspiratory mouth pressure for 10 minutes ( SIP ) ; lung volumes , and arterial blood gases ( ABG 's ) . The training protocol consisted of breathing through an inspiratory resistor equivalent to 85 % SIP for 15 minutes twice daily , 5 days a week for 8 weeks . Both trainers and controls attended the lab every 2 weeks for re assessment of MIP and SIP and the inspiratory resistance was increased in the training group as SIP increased . At the end of 8 weeks , baseline tests were repeated . All subjects had normal ABG 's . There was a significant increase in mean MIP and SIP in both the control group ( 30 % ± 19 % and 31 % ± 18 % respectively ) , and in the training group ( 42 % ± 24 % and 78 % ± 49 % respectively ) . Although the absolute values for both MIP and SIP were greater in the training group than in the control group , the differences were not significant . The alterations in resting breathing pattern were also the same in both groups . Mean frequency decreased significantly in the control group ( 20.2/minute to 16.9/minute ) and , while insignificant , the change in frequency in the training group was the same , 19.4/minute to 16.4/minute . Mean tidal volume ( Vt ) increased 18.2 % of baseline Vt in the control group and 17.0 % baseline in the trainers , result ing in no change in minute ventilation . As MIP and SIP increased similarly in both groups , the data from the control and trainers was pooled and timing changes re-evaluated pre- and post- study . A significant decrease in mean Ti/Ttot was observed , while no change in Vt/ Ti was found . We concluded that the testing procedure itself provided the stimulus result ing in a significant increase in MIP and SIP . The addition of training did not increase MIP and SIP further . The increased MIP and SIP result ed in a slower and deeper breathing pattern and a significantly shorter Ti/Ttot in both trainers and control subjects Whether , and to what extent , beta 2-agonists protect against respiratory muscle overloading and breathlessness during bronchoconstriction remains to be defined in patients with asthma . In a double blind placebo-controlled study , 100 micrograms of fenoterol were administered to six stable asthmatics before a bronchial provocation test , performed by inhaling doubling concentrations of histamine from a Devilbiss 646 nebulizer . We recorded breathing pattern ( tidal volume VT , inspiratory time TI , total time of the respiratory cycle TTOT ) , inspiratory capacity ( IC ) , dynamic pleural pressure swing ( Pplsw ) , total lung resistance ( RL ) and FEV1 . VT was expressed both in actual values and as % of IC . Changes in VT ( % IC ) during histamine inhalation reflected changes in dynamic end-inspiratory lung volume ( EILV ) . Pplsw was expressed as % of maximal ( the most negative in sign ) pleural pressure , obtained under control conditions during a sniff manoeuvre ( Pplsn ) . Pplsw ( % Pplsn ) is an index of inspiratory muscle effort . The test ended when the concentration of histamine which caused a decrease in FEV1 of > or = 40 % post-saline was reached . Dyspnoea rating was scored by a modified Borg scale . At the ultimate degree of bronchoconstriction ( UDB ) with histamine : ( i ) decrease in FEV1 was similar after placebo and fenoterol , while increase in RL was lower after fenoterol ( P < 0.005 ) ; ( ii ) VT(%IC ) increased less after fenoterol ( P < 0.027 ) ; ( iii ) increases in Pplsw ( % Pplsn ) was lower after fenoterol ( P < 0.001 ) ; ( iv ) delta Borg ( from saline ) was lower ( P < 0.01 ) after fenoterol ; ( v ) differences in delta Borg , from placebo to fenoterol , related to concurrent changes in VT(%IC ) ( r2 = 0.67 ) . In conclusion , at UDB 100 micrograms of fenoterol produced a beneficial effect on the degree of inspiratory muscle loading and breathlessness , an effect greater than it would be expected from measuring FEV1 alone BACKGROUND Men and women respond differently to asthma . PATIENTS AND METHODS Maximal inspiratory mouth pressure ( P(Imax ) ) , beta(2)-agonist consumption , and perception of dyspnea ( POD ) were measured in 22 women and 22 men with mild persistent-to-moderate asthma . Next , the women were r and omized into two groups : those who received inspiratory muscle training and those who received sham training . The training ended when the P(Imax ) of the training group was equal to that of the male subjects . POD was then measured once again . RESULTS Baseline P(Imax ) was significantly lower ( p < 0.01 ) while POD and mean daily beta(2)-agonist consumption were significantly higher in the female subjects . P(Imax ) reached the level of the male subjects at the end of the 20th week of training . The increase in the P(Imax ) was associated with a statistically significant decrease in mean daily beta(2)-agonist use and in POD to a similar level as in male subjects . CONCLUSIONS POD and mean daily beta(2)-agonist consumption in asthmatic women are significantly higher , and the P(Imax ) significantly lower , than that of their male counterparts . When the P(Imax ) of female subjects following training is equal to that in male subjects , the differences in POD and mean daily beta(2)-agonist consumption disappear BACKGROUND It is well documented that the perception of dyspnea ( POD ) , subjectively reported by patients , is related to the activity and strength of the inspiratory muscles , and influences the use of ' as needed ' beta2-agonists . STUDY OBJECTIVE To investigate the relationship among the increase in inspiratory muscle strength after specific inspiratory muscle training , beta2-agonist consumption and the POD in patients with persistent , mild to moderate asthma . METHODS Inspiratory muscle strength , daily beta2-agonist consumption and the POD were measured in 30 patients with mild to moderate asthma . Patients were then r and omly assigned to two groups : one group received specific inspiratory muscle training until an increase of more than 20 cm H2O was reached , and one group was a control group and received sham training . Inspiratory muscle strength , the POD and daily beta2-agonist consumption were assessed during and after the training period . RESULTS There was no good correlation between the baseline maximal inspiratory pressure and the POD , or between the baseline maximal inspiratory pressure and the mean daily beta2-agonist consumption . However , there was a significant correlation between the POD and the mean daily beta2-agonist consumption . The increase in inspiratory muscle strength after the inspiratory muscle training was closely correlated with the decrease in the POD ( P<0.001 ) and the decrease in beta2-agonist consumption ( P<0.001 ) . CONCLUSIONS The present study shows that , in patients with mild to moderate , persistent asthma , there is a correlation between the POD and the mean daily beta2-agonist consumption . When the inspiratory muscles are strengthened , there is a significant decrease in the POD and in beta2-agonist consumption In patients with asthma , the respiratory muscles have to overcome the increased resistance while they become progressively disadvantaged by hyperinflation . We hypothesized that increasing respiratory muscle strength and endurance with specific inspiratory muscle training ( SIMT ) would result in improvement in asthma symptoms in patients with asthma . Thirty patients with moderate to severe asthma were recruited into 2 groups ; 15 patients received SIMT ( group A ) and 15 patients were assigned to the control group ( group B ) and got sham training in a double-blind group-comparative trial . The training was performed using a threshold inspiratory muscle trainer . Subjects of both groups trained five times a week , each session consisted of 1/2-h training , for six months . Inspiratory muscle strength , as expressed by the PImax at RV , increased significantly , from 84.0 + /- 4.3 to 107.0 + /- 4.8 cm H2O ( p < 0.0001 ) and the respiratory muscle endurance , as expressed by the relationship between Pmpeak and PImax from 67.5 + /- 3.1 percent to 93.1 + /- 1.2 percent ( p < 0.0001 ) , in patients of group A , but not in patients of group B. This improvement was associated with significant improvements compared with baseline for asthma symptoms ( nighttime asthma , p < 0.05 ; morning tightness , p < 0.05 ; daytime asthma , p < 0.01 ; cough , p < 0.005 ) , inhaled B2 usage ( p < 0.05 ) , and the number of hospital ( p < 0.05 ) and sick-leave ( p < 0.05 ) days due to asthma . Five patients were able to stop taking oral/IM corticosteroids while on training and one in the placebo group . We conclude that SIMT , for six months , improves the inspiratory muscle strength and endurance , and results in improvement in asthma symptoms , hospitalizations for asthma , emergency department contact , absence from school or work , and medication consumption in patients with asthma BACKGROUND It has been known for many years that there are variations between asthmatic patients in terms of their perception of breathlessness during airway obstruction . STUDY OBJECTIVE To investigate the relationship between beta(2)-agonist consumption and the score of perception of dyspnea , in mild asthmatics , and the relationship between the effect of specific inspiratory muscle training ( SIMT ) on the score of perception of dyspnea and beta(2)-agonist consumption in " high perceivers . " METHODS Daily beta(2)-agonist consumption was assessed during a 4-week run-in period in 82 patients with mild asthma . Patients with a mean beta(2)-agonist consumption of > 1 puff/d ( " high consumers " ) then were r and omized into two groups : one group of patients received SIMT for 3 months ; the other group of patients was assigned as a control group and received sham training . Inspiratory muscle strength and perception of dyspnea were assessed before patients entered the study , following the 4-week run-in period , and after completing the training period . RESULTS Following the 4-week run-in period , 23 high-consumer patients ( mean [ + /- SEM ] beta(2)-agonist consumption , 2.7 + /- 0.4 puffs/d ) were detected . The mean Borg score during breathing against resistance was significantly higher ( p < 0.05 ) in the patients with high beta(2)-agonist consumption than in the subjects with low mean beta(2)-agonist consumption . Following SIMT , the mean maximal inspiratory pressure increased significantly from 94.1 + /- 5.1 to 109.7 + /- 5.2 cm H(2)O ( p < 0.005 ) in the training group . The increase in inspiratory muscle strength was associated with a statistically significant decrease in the mean Borg score during breathing against resistance ( p < 0.05 ) as well as in the mean daily beta(2)-agonist consumption . CONCLUSIONS We have shown that patients with mild asthma , who have a high beta(2)-agonist consumption , have a higher perception of dyspnea than those with normal consumption . In addition , SIMT was associated with a decrease in perception of dyspnea and a decrease in beta(2)-agonist consumption This study was design ed to determine whether inspiratory resistive training could improve the exercise performance of patients with severe chronic airflow limitation who had already received optimum conventional therapy with bronchodilators and physiotherapy . Eighteen patients were studied . Ten patients were trained with an inspiratory resistance device for six weeks and eight patients used a placebo device . Psychological factors , likely to influence exercise capacity , were taken into account . Although there was no significant increase in maximum inspiratory pressure in the ten trained subjects , inspiratory muscle endurance was improved . Exercise performance , as assessed by progressive cycle exercise , stair climbing , 12 minute walking distance and treadmill walking did not change significantly in either group . It was concluded that inspiratory muscle training , using a currently available technique , produced no additional improvement in exercise capacity beyond that achieved by conventional bronchodilator and rehabilitation therapy |
1,947 | 22,085,949 | By following these recommendations the incidence of heart failure is reduced to approximately five per cent of treated patients .
CONCLUSION In summary , the favourable effects of trastuzumab are convincing , but cardiotoxicity is a significant challenge in treatment . | BACKGROUND Breast cancer with overexpression of the HER2 receptor is an aggressive type of breast cancer with poor prognosis .
Trastuzumab ( Herceptin ) is a monoclonal antibody that binds to the HER2 receptor on the cell surface blocking the signals that promote cell-growth proliferation .
Trastuzumab treatment has almost halved the risk of relapse , when given as an adjuvant , and has improved the overall survival in metastatic breast cancer .
However , when given alone or in combination with cardiotoxic chemotherapy , especially anthracyclines , trastuzumab may lead to congestive heart failure of varying severity .
RESULTS The cardiotoxic effects of trastuzumab and anthracycline in combination were already reported in the pivotal trials . | Background — Heart failure has an annual mortality rate ranging from 5 % to 75 % . The purpose of the study was to develop and vali date a multivariate risk model to predict 1- , 2- , and 3-year survival in heart failure patients with the use of easily obtainable characteristics relating to clinical status , therapy ( pharmacological as well as devices ) , and laboratory parameters . Methods and Results — The Seattle Heart Failure Model was derived in a cohort of 1125 heart failure patients with the use of a multivariate Cox model . For medications and devices not available in the derivation data base , hazard ratios were estimated from published literature . The model was prospect ively vali date d in 5 additional cohorts totaling 9942 heart failure patients and 17 307 person-years of follow-up . The accuracy of the model was excellent , with predicted versus actual 1-year survival rates of 73.4 % versus 74.3 % in the derivation cohort and 90.5 % versus 88.5 % , 86.5 % versus 86.5 % , 83.8 % versus 83.3 % , 90.9 % versus 91.0 % , and 89.6 % versus 86.7 % in the 5 validation cohorts . For the lowest score , the 2-year survival was 92.8 % compared with 88.7 % , 77.8 % , 58.1 % , 29.5 % , and 10.8 % for scores of 0 , 1 , 2 , 3 , and 4 , respectively . The overall receiver operating characteristic area under the curve was 0.729 ( 95 % CI , 0.714 to 0.744 ) . The model also allowed estimation of the benefit of adding medications or devices to an individual patient 's therapeutic regimen . Conclusions — The Seattle Heart Failure Model provides an accurate estimate of 1- , 2- , and 3-year survival with the use of easily obtained clinical , pharmacological , device , and laboratory characteristics Background — An increase in troponin I soon after high-dose chemotherapy ( HDC ) is a strong predictor of poor cardiological outcome in cancer patients . This finding has important clinical implication s and provides a rationale for the development of prophylactic strategies for preventing cardiotoxicity . Angiotensin-converting enzyme inhibitors slow the progression of left ventricular dysfunction in different clinical setting s , but their role in the prevention of cardiotoxicity has never been investigated . Methods and Results — Of the 473 cancer patients evaluated , 114 ( 72 women ; mean age , 45±12 years ) who showed a troponin I increase soon after HDC were r and omized to receive ( angiotensin-converting enzyme inhibitor group ; 20 mg/d ; n=56 ) or not to receive ( control subjects ; n=58 ) enalapril . Treatment was started 1 month after HDC and continued for 1 year . Cardiological evaluation was performed at baseline and at 1 , 3 , 6 , and 12 months after HDC . The primary end point was an absolute decrease > 10 percent units in left ventricular ejection fraction , with a decline below the normal limit value . A significant reduction in left ventricular ejection fraction and an increase in end-diastolic and end-systolic volumes were observed only in untreated patients . According to the Kaplan-Meier analysis , the incidence of the primary end point was significantly higher in control subjects than in the angiotensin-converting enzyme inhibitor group ( 43 % versus 0 % ; P<0.001 ) . Conclusions — In high-risk , HDC-treated patients , defined by an increased troponin I value , early treatment with enalapril seems to prevent the development of late cardiotoxicity PURPOSE We investigated the incidence of cardiac adverse events in patients with early breast cancer in the Herceptin Adjuvant ( HERA ) trial who were treated with 1 year of trastuzumab after completion of (neo)adjuvant chemotherapy . PATIENTS AND METHODS The HERA trial is a three-group , r and omized trial that compared 1 year or 2 years of trastuzumab with observation in women with human epidermal growth factor receptor-2 ( HER2 ) -positive early breast cancer . Eligible patients had normal left ventricular ejection fraction ( LVEF ; > or= 55 % ) after completion of (neo)adjuvant chemotherapy with or without radiotherapy . Cardiac function was monitored throughout the trial . This analysis considers patients r and omly assigned to 1 year of trastuzumab treatment or observation . RESULTS There were 1,698 patients r and omly assigned to observation and 1,703 r and omly assigned to 1 year of trastuzumab treatment ; 94.1 % of patients had been treated with anthracyclines . The incidence of discontinuation of trastuzumab because of cardiac disorders was low ( 5.1 % ) . At a median follow-up of 3.6 years , the incidence of cardiac end points remained low , though it was higher in the trastuzumab group than in the observation group ( severe CHF , 0.8 % v 0.0 % ; confirmed significant LVEF decreases , 3.6 % v 0.6 % ) In the trastuzumab group , 59 of 73 patients with a cardiac end point reached acute recovery ; of these 59 patients , 52 were considered by the cardiac advisory board ( CAB ) to have a favorable outcome from the cardiac end point . CONCLUSION The incidence of cardiac end points remains low even after longer-term follow-up . The cumulative incidence of any type of cardiac end point increases during the scheduled treatment period of 1 year , but it remains relatively constant thereafter BACKGROUND We present the combined results of two trials that compared adjuvant chemotherapy with or without concurrent trastuzumab in women with surgically removed HER2-positive breast cancer . METHODS The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks ( group 1 ) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel ( group 2 ) . The North Central Cancer Treatment Group trial N9831 compared three regimens : doxorubicin and cyclophosphamide followed by weekly paclitaxel ( group A ) , the same regimen followed by 52 weeks of trastuzumab after paclitaxel ( group B ) , and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel ( group C ) . The studies were amended to include a joint analysis comparing groups 1 and A ( the control group ) with groups 2 and C ( the trastuzumab group ) . Group B was excluded because trastuzumab was not given concurrently with paclitaxel . RESULTS By March 15 , 2005 , 394 events ( recurrent , second primary cancer , or death before recurrence ) had been reported , triggering the first scheduled interim analysis . Of these , 133 were in the trastuzumab group and 261 in the control group ( hazard ratio , 0.48 ; P<0.0001 ) . This result crossed the early stopping boundary . The absolute difference in disease-free survival between the trastuzumab group and the control group was 12 percent at three years . Trastuzumab therapy was associated with a 33 percent reduction in the risk of death ( P=0.015 ) . The three-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1 percent in trial B-31 and 2.9 percent in trial N9831 . CONCLUSIONS Trastuzumab combined with paclitaxel after doxorubicin and cyclophosphamide improves outcomes among women with surgically removed HER2-positive breast cancer . ( Clinical Trials.gov numbers , NCT00004067 and NCT00005970 . PURPOSE The purpose of this analysis was to investigate trastuzumab-associated cardiac adverse effects in breast cancer patients after completion of (neo)adjuvant chemotherapy with or without radiotherapy . PATIENTS AND METHODS The Herceptin Adjuvant ( HERA ) trial is a three-group , multicenter , open-label r and omized trial that compared 1 or 2 years of trastuzumab given once every 3 weeks with observation in patients with HER-2-positive breast cancer . Only patients who after completion of (neo)adjuvant chemotherapy with or without radiotherapy had normal left ventricular ejection fraction ( LVEF > or = 55 % ) were eligible . A repeat LVEF assessment was performed in case of cardiac dysfunction . RESULTS Data were available for 1,693 patients r and omly assigned to 1 year trastuzumab and 1,693 patients r and omly assigned to observation . The incidence of trastuzumab discontinuation due to cardiac disorders was low ( 4.3 % ) . The incidence of cardiac end points was higher in the trastuzumab group compared with observation ( severe congestive heart failure [ CHF ] , 0.60 % v 0.00 % ; symptomatic CHF , 2.15 % v 0.12 % ; confirmed significant LVEF drops , 3.04 % v 0.53 % ) . Most patients with cardiac dysfunction recovered in fewer than 6 months . Patients with trastuzumab-associated cardiac dysfunction were treated with higher cumulative doses of doxorubicin ( 287 mg/m(2 ) v 257 mg/m(2 ) ) or epirubicin ( 480 mg/m(2 ) v 422 mg/m(2 ) ) and had a lower screening LVEF and a higher body mass index . CONCLUSION Given the clear benefit in disease-free survival , the low incidence of cardiac adverse events , and the suggestion that cardiac dysfunction might be reversible , adjuvant trastuzumab should be considered for treatment of breast cancer patients who fulfill the HERA trial eligibility criteria BACKGROUND Trastuzumab , a recombinant monoclonal antibody against HER2 , has clinical activity in advanced breast cancer that overexpresses HER2 . We investigated its efficacy and safety after excision of early-stage breast cancer and completion of chemotherapy . METHODS This international , multicenter , r and omized trial compared one or two years of trastuzumab given every three weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy . RESULTS Data were available for 1694 women r and omly assigned to two years of treatment with trastuzumab , 1694 women assigned to one year of trastuzumab , and 1693 women assigned to observation . We report here the results only of treatment with trastuzumab for one year or observation . At the first planned interim analysis ( median follow-up of one year ) , 347 events ( recurrence of breast cancer , contralateral breast cancer , second nonbreast malignant disease , or death ) were observed : 127 events in the trastuzumab group and 220 in the observation group . The unadjusted hazard ratio for an event in the trastuzumab group , as compared with the observation group , was 0.54 ( 95 percent confidence interval , 0.43 to 0.67 ; P<0.0001 by the log-rank test , crossing the interim analysis boundary ) , representing an absolute benefit in terms of disease-free survival at two years of 8.4 percentage points . Overall survival in the two groups was not significantly different ( 29 deaths with trastuzumab vs. 37 with observation ) . Severe cardiotoxicity developed in 0.5 percent of the women who were treated with trastuzumab . CONCLUSIONS One year of treatment with trastuzumab after adjuvant chemotherapy significantly improves disease-free survival among women with HER2-positive breast cancer . ( Clinical Trials.gov number , NCT00045032 . OBJECTIVES The aim of this study was to determine the protective effect of carvedilol in anthracycline (ANT)-induced cardiomyopathy ( CMP ) . BACKGROUND Despite its broad effectiveness , ANT therapy is associated with ANT-induced CMP . Recent animal studies and experimental observations showed that carvedilol prevented development of CMP due to chemotherapeutics . However , there is no placebo-controlled clinical trial concerning prophylactic carvedilol use in preventing ANT-induced CMP . METHODS Patients in whom ANT therapy was planned were r and omized to administration of carvedilol or placebo . We enrolled 25 patients in carvedilol and control groups . In the carvedilol group , 12.5 mg once-daily oral carvedilol was given during 6 months . The patients were evaluated with echocardiography before and after chemotherapy . Left ventricular ejection fraction ( EF ) and systolic and diastolic diameters were calculated . RESULTS At the end of 6 months of follow-up , 1 patient in the carvedilol group and 4 in the control group had died . Control EF was below 50 % in 1 patient in the carvedilol group and in 5 in the control group . The mean EF of the carvedilol group was similar at baseline and control echocardiography ( 70.5 vs. 69.7 , respectively ; p = 0.3 ) , but in the control group the mean EF at control echocardiography was significantly lower ( 68.9 vs. 52.3 ; p < 0.001 ) . Both systolic and diastolic diameters were significantly increased compared with basal measures in the control group . In Doppler study , whereas E velocities in the carvedilol group decreased , E velocities and E/A ratios were significantly reduced in the control group . CONCLUSIONS Prophylactic use of carvedilol in patients receiving ANT may protect both systolic and diastolic functions of the left ventricle PURPOSE To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial . PATIENTS AND METHODS Patients with HER2-positive operable breast cancer were r and omly assigned to doxorubicin plus cyclophosphamide ( AC ) followed by either weekly paclitaxel ( arm A ) ; paclitaxel then trastuzumab ( arm B ) ; or paclitaxel plus trastuzumab then trastuzumab alone ( arm C ) . Left ventricular ejection fraction ( LVEF ) was evaluated at registration and 3 , 6 , 9 , and 18 to 21 months . RESULTS Of 2,992 patients completing AC , 5.0 % had LVEF decreases disallowing trastuzumab ( decrease below normal : 2.4 % , decrease > 15 % : 2.6 % ) . There were 1,944 patients with satisfactory or no LVEF evaluation who proceeded to post-AC therapy . Cardiac events ( congestive heart failure [ CHF ] or cardiac death [ CD ] ) : arm A , n = 3 ( 2 CHF , 1 CD ) ; arm B , n = 19 ( 18 CHF , 1 CD ) ; arm C , n = 19 ( all CHF ) ; 3-year cumulative incidence : 0.3 % , 2.8 % , and 3.3 % , respectively . Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication . Factors associated with increased risk of a cardiac event in arms B and C : older age ( P < .003 ) , prior/current antihypertensive agents ( P = .005 ) , and lower registration LVEF ( P = .033 ) . Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8 % to 10 % ; LVEF recovered and trastuzumab was restarted in approximately 50 % . CONCLUSION The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm , but by less than 4 % . Older age , lower registration LVEF , and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC BACKGROUND Trastuzumab -- a humanised monoclonal antibody against HER2 - -has been shown to improve disease-free survival after chemotherapy in women with HER2-positive early breast cancer . We investigated the drug 's effect on overall survival after a median follow-up of 2 years in the Herceptin Adjuvant ( HERA ) study . METHODS HERA is an international multicentre r and omised trial that compared 1 or 2 years of trastuzumab treatment with observation alone after st and ard neoadjuvant or adjuvant chemotherapy in women with HER2-positive node positive or high-risk node negative breast cancer . 5102 women participated in the trial ; we analysed data from 1703 women who had been r and omised for treatment with trastuzumab for 1 year and 1698 women from the control group , with median follow-up of 23.5 months ( range 0 - 48 months ) . The primary endpoint of the trial was disease-free survival . Here , we assess overall survival , a secondary endpoint . Analyses were done on an intent-to-treat basis . This trial is registered with the European Clinical Trials Data base , number 2005 - 002385 - 11 . FINDINGS 97 ( 5.7 % ) patients r and omised to observation alone and 58 ( 3.4 % ) patients r and omised to 1 year of treatment with trastuzumab were lost to follow-up . 172 women stopped trastuzumab prematurely . 59 deaths were reported for trastuzumab and 90 in the control group . The unadjusted hazard ratio ( HR ) for the risk of death with trastuzumab compared with observation alone was 0.66 ( 95 % CI 0.47 - 0.91 ; p=0.0115 ) . 218 disease-free survival events were reported with trastuzumab compared with 321 in the control group . The unadjusted HR for the risk of an event with trastuzumab compared with observation alone was 0.64 ( 0.54 - 0.76 ; p<0.0001 ) . INTERPRETATION Our results show that 1 year of treatment with trastuzumab after adjuvant chemotherapy has a significant overall survival benefit after a median follow-up of 2 years . The emergence of this benefit after only 2 years reinforces the importance of trastuzumab in the treatment of women with HER2-positive early breast cancer |
1,948 | 18,580,456 | RESULTS The majority of studies are retrospective in nature , demonstrating good correlation between the full total MPA area-under-the-curve and the risk of acute rejection , but not toxicity .
Free MPA levels may better predict toxicity .
Single-point parameters , in particular trough levels , show poor correlation with the risk of acute rejection and toxicity , and in prospect i ve studies do not improve clinical outcomes .
Limited sampling strategies using sample s from the first few hours postdose allow good prediction of the full area-under-the-curve , and monitoring using these strategies may improve clinical outcomes . | BACKGROUND The use of mycophenolate mofetil ( MMF ) as a primary immunosuppressant after transplantation is increasing .
A number of factors interact to result in variability in blood levels of mycophenolic acid ( MPA ) increasing the risk of toxicity .
This has led to interest in the application of therapeutic drug monitoring to optimize its use . | OBJECTIVE The aim of this study was to investigate the effect of time on pharmacokinetic ( PK ) parameters of mycophenolic acid ( MPA ) in the early post-transplant period in kidney recipients . MPA is the active metabolite of mycophenolate mofetil ( MMF ) , which was introduced into clinical practice ten years ago . METHOD Mycophenolate mofetil was co-administered with cyclosporin ( CsA ) in a subgroup of 23 patients and with tacrolimus ( Tac ) in a subgroup of 10 patients . MPA plasma concentration profiles were measured by a vali date d high performance liquid chromatography method 1 week , 2 and 3 months after transplantation . RESULTS Despite a comparable MMF dose , a large inter-patient variability in both MPA area under the curve ( AUC ) from 0 to 12 h ( range 10.03 - 135.4 microg h/mL ) and in predose concentrations ( 0.31 - 6.09 microg/mL ) was observed . Patients with AUC > 35 microg h/mL showed better ( P < 0.1 ) renal function than patients with AUC < 20 microg h/mL ( mean creatinine concentration 1.48 + /- 0.12 vs. 3.35 + /- 0.4 mg/dL respectively ) . The total MPA trough and AUC did not correlate with biochemical parameters : leucocyte cell count and haematocrit . A higher trough level of the metabolite MPA glucuronide ( MPAG ) in the 1 week after transplantation was found when compared with the 3-month level ( mean 150.1 + /- 146.7 ; range 17.1 to 560 vs. 75.8 + /- 40.0 ; range 27.3 to 174.2 microg/mL ) . The concentration of MPA , and MPA AUC values were significantly lower in patients receiving MMF and CsA than those receiving MMF and Tac during all three periods studied ( P < 0.02 ) . The influence of C(0 ) and MPA AUC values on the risk of graft rejection was investigated using receiver operating characteristic ( ROC ) curve analysis . The area under the ROC curve for AUC was 0.847 , whereas that of C(0 ) was 0.632 . CONCLUSIONS The MPA AUC(0 - 12h ) appeared to be the more effective PK parameter for predicting acute rejection . We recommend that routine MPA and MPAG therapeutic drug level monitoring should be an important part of MMF therapy The pharmacokinetics of mycophenolic acid ( MPA ) was studied after oral administration of mycophenolate mofetil ( MMF ) in 8 liver transplant patients . The mean ( + /- SD ) maximum MPA plasma concentration of 10.6 ( + /- 7.5 ) mg/ml was achieved within 0.5 to 5 hours . The mean ( + /- SD ) steady-state area under the plasma concentration versus time curve ( AUC(0 - 12 ) ) was 40 ( + /- 30.9 ) mg/ml/h . The mean ( + /- SD ) half-life was 5.8 ( + /- 3.8 ) hours . There was poor correlation between trough blood concentrations of tacrolimus ( r = -0.004 ) or serum creatinine ( r = 0.689 ) with MPA AUC , while the serum bilirubin concentrations correlated ( r = 0.743 ) well with MPA AUC , suggesting impairment in MPA conjugation in patients with liver dysfunction . The mean ( + /- SD ) ratio of the AUC of mycophenolic acid glucuronide ( MPAG ) to MPA was 64 ( + /- 84 ) , which correlated significantly with serum creatinine ( r = 0.72 ) but not with serum bilirubin concentrations ( r = 0.309 ) , indicating accumulation of MPAG in patients with renal dysfunction . In 7 primary liver transplant patients on the same dose of MMF , the trough plasma concentrations of MPA during the first week of therapy ranged from < 0.3 to 1.5 microg/ml . The MPA concentrations increased by several folds during the next few weeks , which correlates well with increases in serum albumin concentrations . Changes in albumin appear to partially contribute to the variations in the pharmacokinetics of MPA in liver transplant patients BACKGROUND Significant relationships between the mycophenolic acid ( MPA ) area under the concentration-time curve ( AUC(0 - 12h ) ) and the risks for acute rejection and side effects have been reported . We developed a practical method for estimation of MPA AUCs . Regression equations were developed using repeated cross-validation for r and omly chosen subsets , characterized statistically , and verified for acceptable performance . METHODS Twenty-one renal transplant patients receiving 0.5 or 1.0 g of mycophenolate mofetil twice daily and concomitant tacrolimus provided a total of 50 pharmacokinetic profiles . MPA concentrations were measured by a vali date d HPLC method in 12 plasma sample s collected at predose and at 30 and 60 min ; 2 , 3 , 4 , 6 , 8 , 9 , 10 , 11 , and 12 h ; 1 and 2 weeks ; and 3 months after transplantation . Twenty-six 1- , 2- , or 3- sample estimation models were fit ( r(2 ) = 0.341 - 0.862 ) to a r and omly selected subset of the profiles using linear regression and were used to estimate AUC(0 - 12h ) for the profiles not included in the regression fit , comparing those estimates with the corresponding AUC(0 - 12h ) values , calculated with the linear trapezoidal rule , including all 12 timed MPA concentrations . The 3- sample models were constrained to include no sample s past 2 h. RESULTS The model using c(0h ) , c(0.5h ) , and c(2h ) was superior to all other models tested ( r(2 ) = 0.862 ) , minimizing prediction error for the AUC(0 - 12h ) values not included in the fit ( i.e. , the cross-validation error ) . The regression equation for AUC estimation that gave the best performance for this model was : 7.75 + 6.49c(0h ) + 0.76c(0.5h ) + 2.43c(2h ) . When we applied this model to the full data set , 41 of the 50 ( 82 % ) estimated AUC values were within 15 % of the value of AUC(0 - 12h ) calculated using all 12 concentrations . CONCLUSIONS This limited sampling strategy provides an effective approach for estimation of the full MPA AUC(0 - 12h ) in renal transplant patients receiving concomitant tacrolimus therapy Mycophenolate mofetil ( MMF ) is a prodrug immunosuppressant with a high oral bioavailability . Enterohepatic cycling of a glucuronide derivative of MMF contributes substantially to the bioavailability , but is dependent on bacterial deglucuronidation by intestinal flora . This study aims to determine whether an antibiotic regimen with activity against such organisms reduces the bioavailability of MMF by impairing enterohepatic cycling . In a prospect i ve trial , 6 liver transplant recipients were administered MMF and a 21-day antibiotic regimen for selective bowel decontamination ( SBD ) . Time-concentration profiles of the pharmacologically active metabolite , mycophenolic acid ( MPA ) , were obtained during and after the SBD regimen . The bioavailability of MPA was reduced during compared with after the regimen ( 14.5 + /- 3.5 v 21.1 + /- 9.8 mg . h/mL ; P = .07 ) . The most pronounced contribution to this reduction was observed from 6 hours onward ( 2.4 + /- 1.4 v 5.6 + /- 4.4 mg . h/mL ; P < .05 ) . The presence of secondary maxima in the time-concentration profiles of MPA after , but not during , SBD indicates that enterohepatic cycling may be inhibited during SBD and restored afterward . Enterohepatic cycling may contribute 7 % to 54 % ( mean , 29 % ) of the bioavailability of MPA . We conclude that the bioavailability of MMF may be reduced when SBD is used , and the reduction is likely to result from the interruption of enterohepatic cycling . This mechanism should be taken into consideration not only during SBD , but in any clinical setting combining MMF and broad-spectrum antibiotics BACKGROUND Mycophenolate mofetil ( MMF ) is an effective posttransplantation immunosuppressive agent used in combination with cyclosporin A ( CsA ) or tacrolimus ( Tc ) . An increase in plasma mycophenolic acid ( MPA ) has been shown in patients receiving Tc-MMF combination therapy compared with CsA-MMF combination therapy at the same dose of MMF . The aim of this prospect i ve study was to assess the pharmacokinetic/pharmacodynamic ( PK/PD ) relationship for MPA in kidney transplant patients receiving low-dose MMF ( 500 mg twice a day ) in combination with Tc . METHODS Adult kidney transplant recipients ( n = 51 ) were included . MPA-PK profiles ( blood sampling at 0 , 0.5 , 1 , 2 , 4 , 6 , and 12 h after MMF oral dose ) were obtained within the first 2 weeks after transplantation , 3 months after grafting , and at every adverse clinical event [ side effect or acute rejection ( AR ) ] . All patients received Tc , MMF ( 500 mg twice a day ) , and steroids . RESULTS Thirty patients ( 59 % ) had uneventful outcomes , and 21 patients had 33 episodes of MPA-related side effects ; only 3 patients had AR . A total of 78 MPA-PK profiles were obtained . The following PK parameters were increased in the side-effects group compared with the non-side effects group : mean MPA c(min ) , 2.63 + /- 1.58 vs 1.75 + /- 0.82 mg/L ( P = 0.016 ) ; mean c(30 ) , 10.47 + /- 6.27 vs 7.66 + /- 8.95 mg/L ( P = 0.009 ) ; mean c(60 ) , 9.67 + /- 5.42 vs 5.83 + /- 2.6 mg/L ( P = 0.0002 ) ; mean area under the MPA time-concentration curve from 0 to 12 h [ MPA-AUC((0 - 12 ) ) ] , 48.38 + /- 18.5 vs 36.04 + /- 10.82 mg . h/L ( P = 0.0006 ) ; mean dose-normalized MPA-AUC , 0.16 + /- 0.05 vs 0.12 + /- 0.04 ( mg . h/L)/(mg/m(2 ) ) ( P = 0.0015 ) . For the three AR patients , MPA concentrations obtained at the time of AR revealed MPA c(min ) values of 1.86 , 1.76 , and 3.83 mg/L , respectively , and MPA-AUC((0 - 12 ) ) values of 37.7 , 24.9 , and 104.9 mg . h/L. The threshold of toxicity was 3 mg/L ( sensitivity , 38.7 % ; specificity , 91.5 % ) for c(min ) , 8.09 mg/L for maximum MPA concentration during the first hour ( sensitivity , 77.8 % ; specificity , 67.4 % ) , and 37.6 mg . h/L for MPA-AUC((0 - 12 ) ) ( sensitivity , 83.3 % ; specificity , 59.6 % ) . CONCLUSIONS These results demonstrate the relationship between plasma MPA concentrations and toxicity . High c(min ) , c(30 ) , and c(60 ) values as well as AUC((0 - 12 ) ) are associated with increased risk for side effects . These values may have an importance in a routine monitoring program BACKGROUND HPLC is currently the preferred method for accurate measurement of mycophenolic acid ( MPA ) . This study was design ed to vali date the Emit compared with HPLC in relation to clinical outcome measurements . METHODS Pediatric renal-transplant recipients ( n = 50 ) on an immunosuppressive triple regimen consisting of cyclosporin A , prednisone , and mycophenolate mofetil ( 600 mg/m(2 ) twice per day ) were investigated in an open-label prospect i ve study . Pharmacokinetic profiles over 12 h were obtained at 1 week , 3 weeks , 3 months , and 6 months posttransplant . Plasma MPA was measured by both reversed-phase HPLC and the Emit immunoassay . RESULTS There was an association between the risk of acute rejection episodes and low area under the curve values from t(0 ) to t(12h ) ( AUC(0 - 12 ) ) for MPA ( MPA-AUC(0 - 12 ) ) or predose concentrations of MPA derived from both HPLC and Emit measurements . According to ROC analysis , an AUC value of 33.8 mg x h/L for MPA from t(0 ) to t(12h ) ( MPA-AUC(0 - 12 ) ) determined by HPLC had a diagnostic sensitivity of 80 % and a diagnostic specificity of 57 % . The corresponding value of the Emit was 36.1 mg x h/L. For the predose concentration ( MPA-c(12 ) ) , a concentration of 1.2 mg/L determined by HPLC and 1.4 mg/L determined by Emit gave a sensitivity of 80 % and a specificity of 60 % , respectively . There was no association of any pharmacokinetic variables derived from total MPA measurements with an increased risk of side effects related to mycophenolate mofetil . CONCLUSIONS The Emit assay appears to have a comparable diagnostic efficacy to HPLC for assessing the risk of acute rejection in pediatric renal-transplant recipients . However , because of the cross-reactivity of the antibody used in the Emit assay with the active MPA acyl glucuronide metabolite , the decision thresholds for the Emit were higher than those calculated from HPLC measurements The objective of this study was to investigate the effect of concurrent antibiotic administration on the disposition of mycophenolic acid ( MPA ) and mycophenolic acid glucuronide ( MPAG ) after oral administration of mycophenolate mofetil ( MMF ) in healthy subjects . Eleven healthy subjects were enrolled . The study was divided into 4 treatment periods . Subjects received MMF as a single oral 1-g dose alone and were then r and omized to 3 antibiotic treatment periods . The 3 periods included norfloxacin , metronidazole , and a combination of norfloxacin and metronidazole . Antibiotic treatment was started 3 days prior to each MMF pharmacokinetic study day and was given for a total of 5 days . On day 4 of each antibiotic phase , subjects received a single 1-g oral dose of MMF . Plasma and urine sample s were obtained over 48 hours after the MMF dose in all treatment periods and were quantitatively measured for MPA and MPAG . Pharmacokinetic parameters for MPA and MPAG were determined for all periods . Compared to MMF alone , the area under the plasma concentration versus time curve ( AUC ) of MPA was reduced by an average of 10 % , 19 % , and 33 % when given with norfloxacin , metronidazole , and norfloxacin plus metronidazole , respectively . The AUC of MPAG was also reduced on average by 10 % , 27 % , and 41 % in the corresponding periods . The combination of norfloxacin and metronidazole significantly reduced the AUC of MPA and MPAG in healthy subjects . This likely occurs as a result of reduced enterohepatic recirculation Efficacy and safety of mycophenolate mofetil ( MMF ) may be optimized with individualized doses based on therapeutic monitoring of its active metabolite , mycophenolic acid ( MPA ) . In this 12‐month study , 137 renal allograft recipients from 11 French centers receiving basiliximab , cyclosporine A , MMF and corticosteroids were r and omized to receive either concentration‐controlled doses or fixed‐dose MMF . A novel Bayesian estimator of MPA AUC based on three‐point sampling was used to individualize doses on posttransplant days 7 and 14 and months 1 , 3 and 6 . The primary endpoint was treatment failure ( death , graft loss , acute rejection and MMF discontinuation ) . Data from 65 patients /group were analyzed . At month 12 , the concentration‐controlled group had fewer treatment failures ( p = 0.03 ) and acute rejection episodes ( p = 0.01 ) with no differences in adverse event frequency . The MMF dose was higher in the concentration‐controlled group at day 14 ( p < 0.0001 ) , month 1 ( p < 0.0001 ) and month 3 ( p < 0.01 ) , as were median AUCs on day 14 ( 33.7 vs. 27.1 mg•h/L ; p = 0.0001 ) and at month 1 ( 45.0 vs. 30.9 mg•h/L ; p < 0.0001 ) . Therapeutic MPA monitoring using a limited sampling strategy can reduce the risk of treatment failure and acute rejection in renal allograft recipients 12 months posttransplant with no increase in adverse events The current approach for therapeutic drug monitoring in renal transplant recipients receiving mycophenolate mofetil ( MMF ) is measurement of total mycophenolic acid ( MPA ) concentration . Because MPA is highly bound , during hypoalbuminemia the total concentration no longer reflects the free ( pharmacologically active ) concentration . The authors investigated what degree of hypoalbuminemia causes a significant change in protein binding and thus percentage free MPA . Forty-two renal transplant recipients were recruited for the study . Free and total concentrations of MPA ( predose , and 1 , 3 , and 6 hours post-MMF dose sample s ) and plasma albumin concentrations were determined on day 5 posttransplantation . Six-hour area under the concentration-time curve ( AUC0–6 ) values were calculated for free and total MPA , and percentage free MPA was determined for each patient . The authors found a significant relationship between low albumin concentrations and increased percentage free MPA ( Spearman correlation = −0.54 , P < 0.0001 ) . Receiver operating characteristic ( ROC ) curve analysis was performed on the albumin versus percentage free MPA data . The cutoff value of albumin determined from the ROC analysis that differentiated normal from elevated percentage free MPA ( defined as ≥3 % ) in this patient population was 31 g/L. At this cutoff value albumin was found to be a good predictor of altered free MPA percentage , with a sensitivity and specificity of 0.75 and 0.80 , respectively , and an area under the ROC curve of 0.79 . To rationalize MMF dosing regimens in hypoalbuminemic patients ( plasma albumin ≤ 31 g/L ) , clinicians should consider monitoring the free MPA concentration BACKGROUND Steroids have been shown to induce the hepatic glucuronyltransferase ( GT ) expression enhancing the activity of uridine diphosphate-GT , the enzyme responsible for mycophenolic acid ( MPA ) metabolism . The impact of steroids on MPA pharmacokinetics , however , has not been investigated to date . METHODS As a part of a steroid-sparing clinical trial , we studied the effect of steroids on MPA bioavailability in 26 kidney transplant recipients . RESULTS Despite that the MMF dose did not change significantly with time , dose-normalized MPA AUC0 - 12h was lower during the first month ( triple therapy , high doses of steroids ) than at month 6 post-surgery ( triple therapy , low maintenance dose of steroids ( 32.94 + /- 10.98 vs. 50.87 + /- 22.37 microg/mL. h ; P < 0.01 ) . During the steroid tapering and withdrawal phase ( from month 6 to 21 post-Tx ) , plasma MPA trough and peak concentration as well as AUC0 - 12h progressively increased , while plasma MPA clearance and MPAG ( the major MPA metabolite ) trough levels declined . Renal function was stable throughout . Since cyclosporine A ( CsA ) may interfere with MPA pharmacokinetics , MPA and CsA also were measured in an additional control group of 12 kidney transplant patients at month 21 post-Tx who were still on triple therapy ( MMF , CsA and steroids ) . Despite a similar CsA exposure , the control group had a significantly lower MPA AUC0 - 12h and higher MPAG trough concentration than patients on dual therapy at month 21 post-Tx . CONCLUSION These findings indicate that steroids interfere with MPA bioavailability , and that discontinuation of the drug results in higher MPA exposure , which may compensate at least in part for the lower immunosuppressive level achieved with the remaining dual therapy with CsA and MMF Objectives To investigate the pharmacokinetics of mycophenolic acid ( MPA ) in Chinese adult renal allograft recipients , and to generate the vali date d model equations for estimation of the MPA area under the plasma concentration-time curve from 0 to 12 hours ( AUC12 ) with a limited sampling strategy . Patients and methods The pharmacokinetics in 75 Chinese renal allograft recipients treated with mycophenolate mofetil 2 g/day in combination with Ciclosporin and corticosteroids were determined . The MPA concentration was assayed by high-performance liquid chromatography at pre-dose ( C0 ) and at 0.5 ( C0.5 ) , 1 ( C1 ) , 1.5 ( C1.5 ) , 2 ( C2 ) , 4 ( C4 ) , 6 ( C6 ) , 8 ( C8 ) , 10 ( C10 ) and 12 ( C12 ) hours after dosing on day 14 post-transplant . Patients were r and omly divided into : ( i ) a model group ( n = 50 ) to generate the model equations by multiple stepwise regression analysis for estimation of the MPA AUC by a limited sampling strategy ; and ( ii ) a validation group ( n = 25 ) to evaluate the predictive performance of the model equations . Results The mean MPA AUC12 was 52.97 ± 15.09 mg · h/L , ranging from 24.0 to 102.3 mg · h/L. The patient ’s age and serum albumin level had a significant impact on the MPA AUC12 . The correlation between the pre-dose MPA trough level ( C0 ) and the MPA AUC12 was poor ( r2 = 0.02 , p = 0.33 ) . Model equations 7 ( MPA AUC12 = 14.81 ± 0.80 · C0.5 ± 1.56 · C2 ± 4.80 · C4 , r2 = 0.70 ) and 11 ( MPA AUC12 = 11.29 ± 0.51 · C0.5 ± 2.13 · C2 ± 8.15 · C8 , r2 = 0.88 ) were selected for MPA AUC calculation in Chinese patients , result ing in good agreements between the estimated MPA AUC and the full MPA AUC12 , with a mean prediction error of ±10.1 and ±6.9 mg · h/L , respectively . Conclusion In Chinese renal allograft recipients , MPA pharmacokinetics manifest substantial interindividual variability , and the MPA AUC12 tends to be higher than that in Caucasian patients receiving the same dose of mycophenolate mofetil . Two vali date d model equations with three sampling timepoints are recommended for MPA AUC estimation in Chinese patients Abstract . Objectives : Area under the curve (AUC)-based monitoring of cyclosporin ( CsA ) could help to optimise therapeutic drug monitoring in certain transplant patients in addition to trough concentration monitoring . It is the method of choice for mycophenolic acid ( MPA ) . The objective of this study was to develop a limited sampling strategy for simultaneous estimation of CsA and MPA AUCs in long-term renal transplant patients . Methods : Twenty kidney transplant patients treated with CsA and mycophenolate mofetil were included in a pharmacokinetic study more than 6 months after transplantation . Multilinear regression analyses were performed to develop a model enabling the estimation of both drugs ' AUCs using a limited number of sample s. Dose-normalised data were used throughout the analysis . Results : Trough concentrations of MPA were poorly correlated with AUC , either used alone ( r2=0.232 ) or together with other concentrations . Several models for CsA AUC estimation met the predefined criteria ( r2>0.9 , P<0.05 ) . The AUC of MPA was best estimated by a three-concentration model ( AUC=0.58 C20 min+0.97 C1 h+6.64 C3 h+3.48 ; r2=0.946 ) . These sampling times also applied to CsA AUC ( AUC=1.17 C20 min+0.68 C1 h+5.36 C3 h+4.24 ; r2=0.985 ) . AUCs estimated using these models in our patients using the jack-knife procedure were found to be precise and unbiased as compared with reference trapezoidal AUCs . Conclusion : We were able to develop a multilinear regression model for simultaneous estimation of both CsA and MPA AUCs using only three blood sample s taken up to 3 h post-dosing There are data suggesting an association between mycophenolic acid ( MPA ) levels and acute rejection and toxicity in renal transplant recipients treated with mycophenolate mofetil ( MMF ) , and therefore , knowledge of factors determining MPA levels may aid in accurate adjustment of MMF dosage . A total of 4970 sample s taken 12 hours postdose were analyzed for MPA by immunoassay at regular intervals from the first week posttransplantation in 117 renal transplant patients immunosuppressed with MMF and tacrolimus in a steroid-sparing regimen ( prednisolone for the first 7 days only ) . MPA levels rose in the first 3 months and stabilized thereafter ; dose-normalized MPA levels rose throughout the first 12 months and subsequently stabilized . Multivariate analysis by means of a population -averaged linear regression showed positive associations between MPA level and total daily dose ( P < 0.001 ) but not individual dose or total daily dose corrected for body weight . Positive associations were also seen with serum albumin ( P = 0.01 ) , tacrolimus trough level ( P = 0.01 ) , and female gender ( P = 0.002 ) . The association with tacrolimus levels diminished with time . Negative associations were seen between MPA level and higher estimated creatinine clearance ( P < 0.001 ) , and also with increasing alanine transaminase levels ( P = 0.002 ) , the use of oral antibiotics ( P < 0.001 ) , and infective diarrhea ( P < 0.001 ) . The latter findings may be related to changes in enterohepatic recirculation of MPA . Many clinical variables show associations with trough MPA levels . An underst and ing of these factors may aid therapeutic monitoring of MMF Mycophenolate mofetil , a pro‐drug for mycophenolic acid , reduces the likelihood of allograft rejection after renal transplantation . We studied the relationship between mycophenolic acid pharmacokinetics and the likelihood of rejection in a r and omized concentration‐controlled trial Twenty-seven stable kidney transplant recipients treated with cyclosporine and prednisone were converted to mycophenolate mofetil ( MMF ) and prednisone 1 year after transplantation . After conversion the patients were treated with a st and ard daily dose of 1 g MMF b.i.d . and 10 mg prednisone for 4 months . Thereafter , two MMF dose reductions were performed with a 4-month interval . Mycophenolic acid ( MPA ) trough levels were measured at regular intervals . A relation was found between MPA trough levels and MMF dose . The median MPA trough level for patients treated with 1 g MMF b.i.d . was 4.3 microg/ml ( 0.95 - 15.5 ) and 3.0 microg/ml ( 0.73 - 7.8 ) for patients treated with 750 mg b.i.d . ( P = 0.0002 ) . The MPA trough levels further decreased from 3.0 to 2.3 microg/ml ( 0.6 - 6.63 ) in patients treated with 500 mg MMF b.i.d . ( P = 0.01 ) . Dose reduction of MMF from 1 g to 750 mg b.i.d . could be performed without acute rejections . A further dose reduction to 500 mg b.i.d . elicited 3 rejections . Patients experiencing an acute rejection had a median MPA trough level of 2.3 microg/ml ( 1.26 - 3.38 ) compared to 3.8 microg/ml ( 1.48 - 6.52 ) in patients without an acute rejection ( P = 0.25 ) . We conclude that there is a significant relation between MPA trough levels and MMF dose . MPA trough levels were not predictive of rejection in the present study BACKGROUND Adding a fixed dose of 1 g b.i.d . of mycophenolate mofetil ( MMF ) to an immunosuppressive regimen consisting of cyclosporine and prednisone results in a 50 % reduction in the incidence of acute rejection after kidney transplantation . This study was design ed to investigate the relationship between pharmacokinetic data ( mycophenolic acid area under the curve ; MPA AUC ) and the prevention of rejection after kidney transplantation . METHODS A total of 154 adult recipients of a primary or secondary cadaveric kidney graft were r and omly allocated , in this double-blind trial , to receive MMF treatment aim ed at three predefined target MPA AUC values ( 16.1 , 32.2 , and 60.6 microg x hr/ml ) . During the first 6 months after transplantation , plasma sample s for nine AUCs were collected . After analysis of the sample s , a coded dose adjustment advice was generated using a Bayesian algorithm , maintaining the double blinding . Immunosuppressive therapy further consisted of cyclosporine and prednisone . The primary end point of this study was the occurrence of biopsy-proven acute rejection within the 6-month study period . RESULTS A total of 150 patients were eligible for analysis . Although after day 21 , the mean MMF dose was reduced , the mean MPA AUC gradually increased and target MPA AUC values were exceeded in all three groups . The incidences of biopsy-proven acute rejection in the low , intermediate , and high target MPA AUC groups were 14 of 51 ( 27.5 % ) , 7 of 47 ( 14.9 % ) , and 6 of 52 ( 11.5 % ) , respectively . The incidences of premature withdrawal from the study due to adverse events in the three groups were 4 of 51 ( 7.8 % ) , 11 of 47 ( 23.4 % ) , and 23 of 52 ( 44.2 % ) , respectively . Logistic regression analysis showed a highly statistically significant relationship between median ln(MPA AUC ) and the occurrence of a biopsy-proven rejection ( P<0.001 ) . The logistic regression using median ln(Cpredose ) was also statistically significant for this relationship ( P=0.01 ) , whereas it was not when using mean MMF dose ( P=0.082 ) . In contrast , the logistic regression using mean MMF dose for comparison of patients who successfully completed the study versus patients experiencing premature withdrawal due to adverse events was highly significant ( P<0.001 ) , whereas this was not significant when using median ln(Cpredose ) ( P=0.512 ) or median ln(MPA AUC ) ( P=0.434 ) . CONCLUSION MPA Cpredose and MPA AUC are significantly related to the incidence of biopsy-proven rejection after kidney transplantation , whereas MMF dose is significantly related to the occurrence of adverse events BACKGROUND Interest has recently been expressed in tacrolimus and mycophenolate mofetil ( MMF ) , two potent immunosuppressants , for a variety of transplant indications . The efficacy of this combination was assessed as primary therapy following cardiac transplantation . METHODS Forty-five patients were enrolled ; 15 into Phase I and 30 to Phase II of the study . Intravenous tacrolimus was administered for 2 - 3 days to all patients prior to conversion to oral therapy ; target blood concentrations were 10 - 15 ng/mL. Treatment also consisted of steroids and MMF . During Phase I , a fixed 2 g/day dose of MMF was given whilst doses were adjusted according to mycophenolic acid ( MPA ) plasma levels during Phase II ( target range 2.5 - 4.5 microg/mL ) . Mean follow-up was 696 + /- 62 days and 436 + /- 88 days for Phases I and II , respectively . RESULTS Phase I : Patient survival was 100 % . Rejection was diagnosed in 66.7 % of patients ( mean number of episodes per patient 1.33 + /- 1.18 ) . Retrospective analyses indicated that whereas mean MPA plasma levels > 3.0 microg/mL were not associated with rejection , no correlation was found with tacrolimus blood concentrations . Phase II : A survival rate of 96.7 % was evident , one patient having died from aspergillosis . Diagnoses of rejection were made in 10.0 % of patients ( 0.10 + /- 0.31 episodes per patient ) and confounding factors were present in all 3 cases . MPA trough levels were 1.0 + /- 0.3 microg/mL at this time . Resolution was apparent following pulse steroid therapy . Steroids were successfully withdrawn from all patients who completed 6 months ' treatment . CONCLUSIONS Combination therapy with tacrolimus and MMF is associated with suppression of acute myocardial rejection ; however , this is dependent upon routine therapeutic drug monitoring The aim of this single‐center crossover sub study was to assess pharmacokinetics and pharmacodynamics [ inosine 5′‐monophosphate dehydrogenase ( IMPDH ) activity ] of enteric‐coated mycophenolate sodium ( EC‐MPS ) and mycophenolate mofetil ( MMF ) at steady‐state conditions . Stable maintenance renal transplant patients on 1 g MMF b.i.d . participating in a double‐blind , multicenter study , were r and omized to receive EC‐MPS ( 720 mg b.i.d . ) or continue receiving MMF ( 1000 mg b.i.d . ) for 12 months . Thereafter , all patients ( n = 18 ) received 720 mg EC‐MPS b.i.d . Area under the plasma mycophenolic acid ( MPA ) concentration – time curve with EC‐MPS ( 57.4 ± 15.0 μg h/mL ) fulfilled bioequivalence criteria ( geometric mean 0.98 ( 90 % CI : 0.87–1.11 ) compared to MMF ( 58.4 ± 14.1 μg h/mL ) . Consistent with the delayed release characteristics of EC‐MPS , peak MPA concentration ( geometric mean 0.89 ; 90 % CI : 0.70–1.13 ) occurred approximately 0.5 h later ( p < 0.05 ) and predose MPA levels ( geometric mean 2.10 ; 90 % CI : 1.51–2.91 ) were higher and more variable , not fulfilling bioequivalence criteria . IMPDH activity inversely followed MPA concentrations and was inhibited to a similar degree ( approximately 85 % ) by both formulations . The calculated value for 50 % IMPDH inhibition was identical for both drugs . In conclusion , equimolar doses of EC‐MPS and MMF produce equivalent MPA exposure , while the delayed release formulation of EC‐MPS exhibits more variable predose levels and Tmax . Overall , IMPDH activity reflected MPA pharmacokinetics Mycophenolate mofetil ( MMF ) is given to children in fixed doses based either on body weight or body surface area . There are data indicating mycophenolic acid ( MPA ) blood levels should be monitored in the early period of transplantation . However , there is little information regarding MPA pharmacokinetics ( PK ) in stable pediatric recipients . We evaluated MPA-PK in 20 stable renal transplant children ( 11.7±1.9 years ) under long-term ( 46±31 months ) MMF ( 26.1±7 mg/kg per day or 785±183 mg/m2 per day ) therapy plus prednisone and cyclosporin A ( n=16 ) , tacrolimus ( n=3 ) , or MMF/prednisone ( n=1 ) . Total MPA levels were measured using the EMIT-MPA assay at 0 , 1 , 2 , 3 , 4 , 6 , and 8 h after an oral dose of MMF . The level at 12 h was considered equal to the trough level for AUC0–12 calculation . Mean C0 , Cmax , AUC 0–12 , and Tmax were 3.46±1.32 , 13.5±0.58 μg/ml , 63.2±24.4 μg.h/ml , and 1.3±0.6 h , respectively . Six ( 30 % ) children were considered to have an adequate exposure ( 36–54 μg.h/ml ) to MPA , 11 ( 55 % ) showed an AUC0–12 > 54 μg.h/ml , and 3 ( 15 % ) showed an AUC0–12 < 36 μg.h/ml . A Cmax ≥10 μg/ml was seen in 13 ( 65 % ) children . MMF dose did not correlate with AUC0–12 or Cmax . The combination of variables C0 , C1 , and C4 provided an equation to predict exposure ( r2=0.75 ) where AUC0–12=12.62+(7.78xC0)+(0.90xC1)+(1.30xC2 ) ( P<0.001 ) . The use of MMF without monitoring MPA blood levels may cause unnecessary overexposure to the drug in stable pediatric recipients Mycophenolate mofetil ( MMF ) is commonly used in solid organ transplant recipients . MMF is converted to mycophenolic acid ( MPA ) upon reaching the systemic circulation . Many acidic drugs have altered protein binding in renal failure , and it is possible that MPA protein binding may be decreased . The authors studied 23 renal transplant recipients : 8 transplant patients ( 7 kidney , 1 kidney/pancreas ) with chronic renal insufficiency ( CRI ) and 15 renal transplant patients with preserved renal function . Plasma was obtained for kinetic profiles of total MPA , free MPA , and its glucuronide metabolite ( MPAG ) . Plasma was obtained from 10 hemodialysis patients and 8 healthy control volunteers to assess in vitro differences in MPA protein binding . Average free fraction of MPA in patients with chronic renal insufficiency was more than double that of patients with normal renal function ( 5.8 + /- 2.7 vs. 2.5 + /- 0.4 , p < 0.01 ) . Free MPAAUC was almost doubled in the patients with chronic renal insufficiency versus controls ( 2.04 + /- .08 vs. 1.03 + /- 0.6 , p < 0.01 ) . MPA protein binding is decreased , and free MPA concentrations are increased in patients with chronic renal failure BACKGROUND Mycophenolate mofetil ( MMF ) is widely used in organ transplantation to prevent acute rejection . Because MMF can produce hematologic and /or gastrointestinal toxicity , therapeutic monitoring is becoming m and atory . This study was design ed to investigate the relationship between the clinical events and the pharmacokinetics of mycophenolic acid ( MPA ) in adult renal transplantation . METHODS Thirty-one adult kidney recipients were prospect ively included in the study . MPA pharmacokinetic profiles ( blood sampling at 0 , 0.5 , 1 , 2 , 4 , 6 , and 12 h after MMF oral dose ) were obtained after transplantation ( desired creatinine clearance , 40 mL/min ) , at 3 months after grafting , and at every clinical event ( e.g. , side effect or rejection ) . All patients received a 10-day course of anti-thymocyte globulin , cyclosporine , MMF ( 1 g twice daily ) , and steroids . RESULTS We divided the 31 patients into two groups ( groups 1 and 2 ) . Ten patients ( 32 % ; group 1 ) had uneventful outcomes , and 21 patients ( 68 % ; group 2 ) presented with MPA-related side effects . For groups 1 and 2 , the MPA trough concentrations ( C(min ) ) were 1.63 + /- 1.07 and 2.29 + /- 1.16 mg/L , respectively ( P = 0.06 ) , and the areas under the curve ( AUCs ) for MPA from t(0 ) to t(12 h ) ( MPA-AUC(0 - 12h ) ) were 39.80 + /- 15.29 and 62.10 + /- 21.07 mg . h/L , respectively ( P = 0.0005 , two- sample t-test ) . Three patients experienced acute graft rejection after the oral MMF dose was reduced because of side effects . In this group , the MPA-C(min ) and MPA-AUC were significantly lower by the time acute rejection occurred ( 1.00 + /- 0.45 mg/L and 25.00 + /- 6.20 mg . h/L , respectively ) . At a fixed dose ( 1 g twice per day ) , we compared the pharmacokinetic parameters of MPA [ C(min ) , the MPA concentration 30 min after the oral dose of MMF ( C(30 ) ) , and AUC ] according to the presence or absence of side effects in the two groups . C:(min ) and AUC did not differ between the two groups [ C(min ) = 2.22 + /- 1.13 vs 2.17 + /- 1.13 mg/L ( P = 0.9 ) ; AUC = 66.82 + /- 29.87 vs 55.70 + /- 11.74 mg . h/L ( P = 0.11 ) ] ; and C(30 ) was significantly higher in group 2 than in group 1 ( C(30 ) = 32.99 + /- 12.59 vs 7.45 + /- 5.40 mg/L ; P < 0.0001 ) . CONCLUSIONS Our results demonstrate a pharmacokinetic/pharmacodynamic relationship between MPA and clinical events . At a fixed dose of 2 g/day , a high C(30 ) is associated with increased risk for side effects . This study suggests that dividing the MMF daily oral dose into more than two divided doses might prevent early MPA toxicity OBJECTIVE Mycophenolate mofetil ( MMF ) is routinely used as an immunosuppressant in a fixed daily dose regimen although it shows marked fluctuations in pharmacokinetics , and despite the fact that in regard to the active metabolite , mycophenolic acid ( MPA ) , there is a well-known association between the pharmacokinetic parameters and clinical outcome . METHOD In order to determine the time course and the variability in cellular target of MPA after renal transplantation , we investigated the pharmacodynamic response in 8 patients receiving 1 g MMF for the first time prior to renal transplantation and in 8 stable renal transplant patients maintained on long-term MMF therapy ( 1 g b.i.d . ) for more than 1 year . The pharmacodynamic response was measured using inosine 5'-monophosphate dehydrogenase ( IMPDH ) activity in peripheral mononuclear cells . MPA plasma concentrations were measured in parallel , IMPDH activity in 89 healthy blood donors was used as a control . RESULTS We observed a high interindividual variability in IMPDH activity in the 89 untreated healthy volunteers ( 4.0 - 32.9 nmol/h/mg protein ) , in 8 patients on dialysis ( 5.3 - 18.9 nmol/h/mg protein ) and in 8 renal transplant patients under long-term MMF treatment ( 2.3 - 14.4 nmol/h/mg protein ) . The mean AUC0 - 12h for mycophenolic acid was 2-fold higher in patients receiving long-term treatment with MMF ( 62.2 + /- 16.6 mg x h/ml ) compared to dialysis patients receiving 1 g MMF for the first time ( 31.5 + /- 15.6 mg x h/ml ) . Despite this pharmacokinetic difference there were no statistically significant differences in the cellular pharmacodynamic response . Minimal IMPDH activity ( 1.62 + /- 1.23 vs. 1.77 + /- 1.49 nmol/h/mg protein ) and maximal IMPDH inhibition ( 87.5 + /- 0.08 vs. 77.4 + /- 18.8 % ) during the dosing interval were similar . CONCLUSIONS The considerable interindividual variability in the pharmacokinetics of MMF as well as in the drug target support the use of pharmacodynamic drug monitoring to optimize MMF dosing and to reduce the risk of graft rejection and side effects BACKGROUND Triple drug treatment consisting of mycophenolate mofetil ( MMF ) , in a st and ard dose of 2 g daily , combined with cyclosporine ( CsA ) and prednisone , has become the st and ard immunosuppressive regimen after kidney transplantation in many centers . The need for therapeutic drug monitoring of mycophenolic acid ( MPA ) has not yet been established . Several drug interactions with MMF are known . We investigated the influence of CsA withdrawal on MPA trough levels in renal transplant patients . METHODS Fifty-two patients were treated with 1 g of MMF twice daily , and prednisone and CsA targeted between 125 and 175 ng/ml for 6 months after transplantation . At 6 months after transplantation , 19 patients were r and omized for continuation of triple therapy ( group A ) , 19 patients discontinued CsA ( group B ) , and 14 patients discontinued prednisone ( group C ) . We compared 12-hr fasted MPA trough levels at 6 and 9 months after transplantation within and between these groups . RESULTS MPA trough levels during treatment with CsA , MMF , and prednisone were significantly lower than those during treatment with MMF and prednisone only ( group B ) ; median levels were 1.87 mg/L ( range : 0.56 - 5.27 ) vs. 3.16 mg/L ( range : 0.32 - 7.78 ) , respectively ( P=0.002 ) . MPA trough levels in groups A and C did not change between 6 and 9 months after transplantation ; group A median levels were 1.87 ( range : 0.31 - 4.32 ) vs. 1.53 mg/L ( range : 0.36 - 3.70 ) , and group C median levels were 1.62 ( range : 0.69 - 10.34 ) vs. 1.79 mg/L ( range : 0.54 - 6.00 ) , respectively . At 9 months after transplantation , patients in whom CsA was discontinued had higher MPA trough levels as compared with patients who continued the use of triple therapy ( P=0.001 ) or patients in whom steroids were withdrawn ( P=0.014 ) . CONCLUSION A significant increase of MPA trough levels was found after discontinuation of CsA ( 6 months after transplantation ) , result ing in almost a doubling of MPA trough levels at 9 months after transplantation . This result ed in increased MPA levels in patients without CsA as compared to MPA levels in patients continuing triple therapy or discontinuing prednisone BACKGROUND Mycophenolate mofetil ( MMF ) therapy decreases the incidence of allograft rejection following solid-organ transplantation . Current dosing strategies of MMF are not routinely adjusted based on mycophenolic acid ( MPA ) area under the concentration-time curve ( AUC ) , MPA trough , or free MPA ( fMPA ) AUC values . METHODS To determine the clinical significance of MPA concentrations following orthotopic heart transplantation ( OHT ) , we measured pre-dose MPA trough , MPA free fraction , an estimated MPA AUC using an abbreviated sampling schedule , and fMPA AUC in 38 consecutive patients . We measured MPA concentrations using a vali date d high-performance liquid chromatography method and grade d endomyocardial biopsies based on the International Society for Heart and Lung Transplantation ( ISHLT ) grading system . RESULTS The MPA values for the study group were as follows : MPA trough of 1.2 + /- 0.6 microg/ml ; MPA free fraction of 1.9 + /- 0.4 % ; MPA AUC of 44.5 + /- 16 . 1 microg/hour/ml ; and fMPA AUC of 0.83 + /- 0.30 microg/hour/ml . We compared patients with Grade 0 ( n = 22 ) , Grade 1 ( n = 13 ) , or Grade 2/3 ( n = 3 ) . The MPA AUC values were lower in patients with Grade 2/3 than in patients with Grade 0 ( 26.1 + /- 6.6 vs 42.8 + /- 14.0 microg/hour/ml , p < 0.08 ) or Grade 1 rejection ( 26.1 + /- 6.6 vs 51.7 + /- 17.5 microg/hour/ml , p < 0.05 ) . The fMPA AUC values were lower in patients with Grade 2/3 than with patients with Grade 0 ( 0.49 + /- 0.11 vs 0.81 + /- 0.25 microg/hour/ml , p < 0.05 ) or Grade 1 ( 0.49 + /- 0.25 vs 0.95 + /- 0.34 microg/hour/ml , p < 0.05 ) rejection . We noted a trend in MPA trough concentrations between patients with Grade 2/3 vs 0 ( 0.65 + /- 0.15 vs 1.20 + /- 0.58 microg/ml , p = 0.15 ) and Grade 1 ( 0.65 + /- 0.15 vs 1.24 + /- 0.72 microg/ml , p = 0.14 ) rejection . CONCLUSION These preliminary results suggest that lower MPA AUC and fMPA AUC values are associated with cardiac allograft rejection in heart transplant recipients . Individualizing MMF dosing based on MPA determinations may minimize the risk of rejection following OHT Abstract Background : Therapeutic drug monitoring of mycophenolic acid ( MPA ) may minimise the risk of acute rejection after transplantation . Area under the curve ( AUC ) rather than trough concentration-based monitoring is recommended and models for AUC estimation are needed . Objective : To develop a population pharmacokinetic model suitable for Bayesian estimation of individual AUC in stable renal transplant patients . Patients and methods : The population pharmacokinetics of MPA were studied using nonlinear mixed effects modelling ( NONMEM ) in 60 patients ( index group ) receiving MPA on a twice-daily basis . Ten blood sample s were collected at fixed timepoints from ten patients and four blood sample s were collected at sparse timepoints from 50 patients . Bayesian estimation of individual AUC was made on the basis of three blood concentration measurements and covariates . The predictive performances of the Bayesian procedure were evaluated in an independent group of patients ( test group ) comprising ten subjects in whom ten blood sample s were collected at fixed timepoints . Results : A two-compartment model with zero-order absorption best fitted the data . Covariate analysis showed that bodyweight was positively correlated with oral clearance . However , the weak magnitude of the reduction in variability ( from 34.8 to 28.2 % ) indicates that administration on a per kilogram basis would be of limited value in decreasing interindividual variability in MPA exposure . Bayesian estimation of pharmacokinetic parameters using sample s drawn at 20 minutes and 1 and 3 hours enabled estimation of individual AUC with satisfactory accuracy ( bias 7.7 % , range of prediction errors 0.43–15.1 % ) and precision ( root mean squared error 12.4 % ) as compared with the reference value obtained using the trapezoidal method . Results : This paper reports for the first time population pharmacokinetic data for MPA in stable renal transplant patients , and shows that Bayesian estimation can allow accurate prediction of AUC with only three sample s. This method provides a tool for therapeutic drug monitoring of MPA or for concentration-effect studies . Its application to MPA monitoring in the early period post-transplantation needs to be evaluated There is increasing evidence that monitoring predose plasma levels of mycophenolic acid ( MPA ) is of benefit in renal transplant recipients treated with mycophenolate mofetil ( MMF ) . Concomitant treatment with oral antibiotics leads to a 10 % to 30 % reduction in MPA area under the curve (AUC)0 - 12 , probably by reducing enterohepatic recirculation ( EHR ) . Because of the timing of EHR ( 6 to 12 hours postdose ) , the magnitude of predose MPA level reduction may be disproportionately larger than that of AUC0 - 12 . However , changes in predose MPA levels and the time course over which these changes occur and resolve during antibiotic treatment have not been studied . The purpose of this study was to define the extent and time course of MPA predose level reduction during antibiotic therapy . A total of 64 MMF-treated renal transplant recipients ( with tacrolimus cotherapy ) were prospect ively studied . Clinical ly indicated cotherapy with either oral ciprofloxacin or amoxicillin with clavulanic acid result ed in a reduction in 12 hour predose MPA level to 46 % of baseline within 3 days of antibiotic commencement . No demographic or biochemical variables were associated with the magnitude of MPA level reduction . No further fall in MPA level was seen by day 7 , but MPA levels recovered spontaneously to 79 % of baseline after 14 days of antibiotics . Levels normalized within 3 days of antibiotic cessation . No changes in daily MMF dose ( normalized for body weight ) were made during antibiotic treatment . This data should help the clinician to recognize the extent of MPA predose level reduction during antibiotic therapy , and to avoid inappropriate MMF dose escalation and potential risk of toxicity Mycopehenolate mofetil ( MMF ) is a powerful immunosuppressant that inhibits the proliferation of T and B lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase . MMF has been shown to prevent acute graft rejection in animal experiments and may have an important role in clinical renal transplantation . We conducted a prospect i ve , double-blind , multi-center trial to compare the efficacy and safety of MMF and azathioprine within st and ard immunosuppressive regimen for patients receiving a first or second cadaveric renal graft . A total of 503 patients were r and omized to groups receiving MMF 3 g ( n=164 ) , MMF 2 g ( n=173 ) , or azathioprine ( AZA ) 100 - 150 mg ( n=166 ) daily . All were treated simultaneously with equivalent doses of cyclosporine and oral corticosteroids and followed for 12 months . The primary endpoint was treatment failure , defined as the occurrence of biopsy-proven graft rejection , graft loss , patient death , or discontinuation of the study drug during the first 6 months after transplantation . Treatment failure occurred in 50.% of patients in the AZA group by 6 months after transplantation , compared with 34.8 % in the MMF 3 g group ( P=0.0045 ) and 38.2 % in the MMF 2 g group ( P=0.0287 ) . Biopsy-proven rejection occurred in 15.9 % of patients in the MMF 3 g group and 19.7 % in the MMF2 g group , compared with 35.5 % in the AZA group . Rejection of histologic severity grade II or more developed in 6.1 % , 10.4 % and 19.9 % of patients in the MMF 3 g , MMF 2 g , and AZA groups , respectively . Patients receiving MMF required less frequent and less intensive treatment for acute rejection : 24.4 % of patients on MMF 3 g and 31.0 % on MMF 2 g were tested for acute rejection , compared with 47.5 % on AZA . Only 4.9 % on MMF 3 g and 8.8 % on MMF 2 g required antilymphocyte antibodies for treatment of severe or steroid-resistant rejection , compared with 15.4 % of the patients on AZA . At 1 year after transplantation , graft survival in the MMF groups was marginally superior to that in the AZA group , although this difference was not statistically significant . Gastrointestinal toxicity and tissue-invasive cytomegalovirus infection were more common in the MMF 3 g group . Noncutaneous malignancies occurred in six patients on MMF 3 g , three patients on MMF 2 g , and four patients on AZA . Lymphoproliferative disorders occurred in two patients per MMF group , compared with one patient receiving AZA . MMF appears to be an important advance in prophylaxis following renal transplantation . It is associated with a significantly lower rate of treatment failure compared with AZA during the first 6 months after renal transplantation and produces a clinical ly important reduction in the incidence , severity , and treatment of acute graft rejection . These differences persist throughout the first year of follow-up . Clinical benefit was greatest with a dose of MMF 3 g/day , but gastrointestinal effects , invasive cytomegalovirus infection , and malignancies were slightly more common at that dose . The appropriate dose may lie between 2 g and 3 g per day and may require individualization depending on clinical course or other factors Background . In liver transplantation , mycophenolate mofetil ( MMF ) is habitually administered using fixed doses . We assessed whether mycophenolic acid ( MPA ) monitoring could be advisable in liver transplant patients . Methods . In 15 liver transplant patients receiving tacrolimus , daclizumab and MMF ( 1 g bid , orally ) , we determined the 12-hour plasma MPA pharmacokinetic profile after one dose of MMF at days 6 , 10 , and 16 , and months 3 and 6 . The inhibitory capacity of serum MPA on proliferation of CEM cells , a cell line insensitive to other immunosuppressants , was also determined . Results . A large interindividual variability in MPA profiles was observed at any time . Regardless of a gradual increase in individual MPA AUC and C0 over time following transplantation , a substantial proportion of patients had these parameters below the ranges recommended in other organ transplantations throughout the study . When MPA AUC and C0 were within the recommended ranges , CEM proliferation was inhibited by almost all serum sample s , but when these pharmacokinetic parameters were below the recommended ranges , CEM proliferation was very variable and , therefore , unpredictable . No relationship between MPA pharmacokinetics and the efficacy of MMF could be established ( only one patient developed rejection ) , probably due to the concomitant administration of tacrolimus and daclizumab . Gastrointestinal symptoms were the only adverse events with a significant relationship with MPA levels . Conclusions . During the first postoperative months , exposure to MPA is low in a considerable proportion of liver transplant patients receiving MMF at a fixed dose of 1 g bid . MPA monitoring appears necessary in these patients STUDY OBJECTIVE To develop limited sampling strategies for estimation of mycophenolic acid exposure ( by determining area under the concentration-time curve [ AUC ] ) in lung transplant recipients by using sampling times within 2 hours after drug administration and a maximum of three plasma sample s. DESIGN Prospect i ve , open-label clinical study . SETTING Lung transplant clinic in Vancouver , British Columbia , Canada . PATIENTS Nineteen adult ( mean age 48.3 yrs ) lung transplant recipients who were receiving mycophenolate mofetil therapy along with cyclosporine ( 9 patients ) or tacrolimus ( 10 patients ) . INTERVENTION Eleven blood sample s were collected from each of the 19 patients over 12 hours : immediately before ( 0 hr ) and 0.3 , 0.6 , 1 , 1.5 , 2 , 4 , 6 , 8 , 10 , and 12 hours after administration of mycophenolate mofetil . MEASUREMENTS AND MAIN RESULTS Mycophenolic acid levels in plasma were determined by a high-performance liquid chromatography-ultraviolet detection method . The 19 patients were r and omly divided into index ( 10 patients ) and validation ( 9 patients ) groups . Limited sampling strategies were developed with multiple regression analysis by using data from the index group . Data from the validation group were used to test each strategy . Bias and precision of each limited sampling strategy were determined by calculating the mean prediction error and the root mean square error , respectively . The correlation between AUC and single concentrations was generally poor ( r2= 0.18 - 0.73 ) . Two single-concentration strategies , eight two-concentration strategies , and eight three-concentration strategies matched our criteria . However , the best overall limited sampling strategies ( and their predictive performance ) were the following : log AUC = 0.241 log C0 + 0.406 log C2 + 1.140 ( bias -5.82 % , precision 5.97 % , r2= 0.828 ) and log AUC = 0.202 log C0 + 0.411 log C1.5 + 1.09 ( bias -5.71 % , precision 6.94 % , r2= 0.791 ) , where Cx is mycophenolic acid concentration at time x hours . CONCLUSION Two-concentration limited sampling strategies provided minimally biased and highly precise estimation of mycophenolic acid AUC in lung transplant recipients . These optimal and most clinical ly feasible limited sampling strategies are based collectively on the number of blood sample s required , r2 value , bias , and precision Immunosuppressive regimens including mycophenolate mofetil ( MMF , Cellcept ) were used in a renal transplant transplant program since May 2000 including 67 patients in whom it was the primary drug . Acute rejection ( AR ) occurred in 9 cases ( 13 % ) with 1-year graft survival rate of 96.8 % . Pharmacokinetic ( PK ) studies of mycophenolic acid ( MPA ) were performed in 46 recent patients ( total , 127 times ) . There was no correlation between dose ( mg/kg ) and blood concentration ( AUC0 - 9 : r2= 0.27 ) . AUC0 - 9 was well correlated with AUC0 - 4 ( r2= 0.91 ) , but not with a single timepoint concentration . MPA AUC0 - 9 level was significantly higher among the AR-negative group ( n = 33 ; 34.2 + /- 16.8 ng.hr/mL ) compared with AR-positive group ( n = 3 ; 28.2 + /- 1.9 ng.hr/mL ; P = .04085 ) over the 2 weeks after transplantation . MPA AUC0 - 9 level was higher among the adverse event ( AE-positive ) group ( n = 15 ; 39.2 + /- 22.8 ng.hr/mL ) compared with the negative group ( n = 21 ; 30.1 + /- 8.0 ng.hr/mL ; P = .08772 ) within 2 weeks after transplantation . These results suggest the necessity of measuring AUC for therapeutic drug monitoring ( TDM ) of MMF-containing immunosuppressive therapy . The possible target level of MPA AUC0 - 9 would be approximately 30 ng.hr/mL using the present immunosuppressive regimen Tacrolimus and cyclosporine A have different effects on exposure to concomitantly administered mycophenolate mofetil ( MMF ) , measured as the mycophenolic acid ( MPA ) dose interval area under the plasma concentration versus time curve ( AUC0 - 12 h ) or the plasma MPA predose concentration ( C0 ) . This has led to recommendations in using a 50 % lower dose of MMF in combination with tacrolimus compared to cyclosporin A. At present , no long-term data are available regarding the pharmacokinetics ( PK ) of different dosages of MMF in combination with tacrolimus and the clinical variables that influence the dose-exposure relationship of MPA . A prospect i ve 12-month pharmacokinetic study was performed in 100 de novo renal transplant recipients treated with two different MMF dosages ( 1 g/day vs. 2 g/day ) in combination with tacrolimus and corticosteroids . MPA AUC data were collected 7 days , 6 weeks , and 3 and 12 months posttransplantation , and model-independent PK parameters were calculated . Clinical variables that could possibly influence MPA PK were evaluated . The MPA AUC0 - 12 h significantly increased toward 6 weeks ( p < 0.05 ) but only in the 2-g MMF dosing group . The MPA AUC0 - 12 h in the 1-g MMF group reached its nadir at 3 months , while in the 2-g MMF group , it remained elevated until 3 months , returning to baseline values by 12 months . This differential evolution in exposure was not only inadequately reflected by the corresponding MPA C0 concentrations , but the MPA C0 concentrations also were not significantly different between the two dosing groups at early postgrafting ( day 7 ) and at 12 months . Using multiple stepwise regression analysis , C0 ( r = 0.51 , p < 0.0001 ) and end-of-dose interval MPA plasma concentration ( C12 : r2 = 0.61 , p < 0.0001 ) were found to poorly predict MPA AUC0 - 12 h , while MPA plasma concentrations at 4 hours ( C4 : r2 = 0.85 , p < 0.0001 ) and 6 hours postdosing ( C6 : r2 = 0.83 , p < 0.0001 ) were superior but hampered by a large prediction bias and imprecision . An abbreviated 2-hour AUC measurement ( r2 = 0.78 ) , using three sampling points ( C0 , C40 [ MPA plasma concentration 40 min postdosing ] , C2 ) , provided the best compromise between a monitoring tool that is theoretically ideal and practically feasible . MPA pharmacokinetics were not influenced by recipient age , gender , and body weight or by serum albumin concentrations , allograft function , or corticosteroid or tacrolimus dose . Mild hepatic dysfunction early after grafting did result in significantly reduced MPA exposure ( MPA AUC0 - 12 h , p = 0.01 and C0 , p = 0.03 ) . In this study , it was demonstrated for the first time that the dynamics of long-term MPA pharmacokinetics in combination with tacrolimus differ according to the daily MMF dose and that this effect is not adequately reflected by MPA trough concentrations . Using the latter as a routine measure for therapeutic drug monitoring might mislead clinicians into drawing wrong conclusions in terms of relating questions of efficacy or toxicity to MPA exposure The pharmacokinetics of mycophenolic acid ( MPA ) , the active moiety of the immunosuppressant mycophenolate mofetil ( MMF ) , exhibits large inter-individual variability . Concentration-controlled dosing of MMF based on therapeutic drug monitoring may therefore be advantageous compared to a fixed-dose regimen . Because full AUC0 - 12 monitoring is not practical and predose MPA concentrations correlate only moderately with the corresponding AUC0 - 12 , the estimation of MPA exposure by a limited sampling strategy has been suggested . However , before such an algorithm is transferred to clinical practice , it is compulsory to prospect ively vali date it in a different data set , in order to avoid biased results . The aim of this investigation was therefore to prospect ively vali date an algorithm based on an abbreviated pharmacokinetic ( PK ) profile for the estimation of MPA exposure in 54 pediatric renal transplant recipients ( 169 PK profiles ) on MMF in conjunction with CsA and prednisone on a second data set in a different group of patients with a similar immunosuppressive regimen ( 25 patients , 119 PK profiles ) . An algorithm based on three PK sampling timepoints during the first 2 hours after MMF dosing ( estimated AUC0 - 12 = 18.6 + 4.3 · C0 + 0.54 · C0.5 + 2.15 · C2 ) was able to predict the corresponding MPA-AUC0 - 12 with a low percentage prediction error ( 10.7 % ) and an acceptable coefficient of determination ( r2 = 0.76 ) . The performance of this algorithm was comparable among different pediatric age groups . By ROC curve analysis , the calculated MPA-AUC0 - 12 based on this algorithm was able to differentiate between rejecters and non-rejecters with a comparable prognostic sensitivity ( 66.7 % ) and specificity ( 61.9 % ) as the full-time MPA-AUC0 - 12 . In conclusion , the use of this vali date d algorithm for the estimation of MPA exposure based on a limited sampling strategy during the first 2 hours after MMF dosing has the potential to optimize MMF therapy in pediatric renal transplant recipients Preliminary studies suggested that mycophenolate mofetil ( MMF ) , which inhibits proliferation of T and B cells , may reduce the frequency of acute rejection after renal transplantation . Our r and omised , double-blind , multicentre , placebo-controlled study compared the efficacy and safety of MMF with placebo for prevention of acute rejection episodes after first or second cadaveric renal allograft transplantation . 491 patients were enrolled ; 166 were assigned placebo , 165 MMF 2 g , and 160 MMF 3 g. Patients also received cyclosporin and corticosteroids . Significantly fewer ( p < or = 0.001 ) patients had biopsy-proven rejection or withdrew early from the trial ( for any reason ) during the first 6 months after transplantation with MMF 2 g ( 30.3 % ) or 3 g ( 38.8 % ) than with placebo ( 56.0 % ) . The corresponding percentages for biopsy-proven rejection were 17.0 % , 13.8 % , and 46.4 % . 28.5 % of MMF 2 g and 24.4 % of MMF 3 g patients needed full courses of corticosteroids or antilymphocyte agents for treatment of rejection episodes in the first 6 months , compared with 51.8 % of placebo recipients . By 6 months , 10.2 % , 6.7 % , and 8.8 % of the patients in the placebo , MMF 2 g , and MMF 3 g groups , respectively , had died or lost the graft . Overall , the frequency of adverse events was similar in all treatment groups , although gastrointestinal problems , leucopenia , and opportunistic infections were more common in the MMF groups and there was a trend for more events in the 3 g than the 2 g group . MMF significantly reduced the rate of biopsy-proven rejection or other treatment failure during the first 6 months after transplantation and was well tolerated . The 3 g dose was somewhat less well tolerated Mycophenolic acid ( MPA ) , an effective immunosuppressive drug used in renal transplantation , is extensively glucuroni date d by several uridine diphosphate – glucuronosyltransferases ( UGTs ) into an inactive 7‐O‐glucuronide and , to a lesser extent , into a pharmacologically active acyl‐glucuronide . Experiments using human liver microsomes have shown that T—275A and C—2152 T single‐nucleotide polymorphisms ( SNPs ) of the UGT1A9 promoter region are associated with higher hepatic expression of UGT1A9 and increased in vitro glucuronidation activity for MPA Background Tacrolimus is an efficient primary immunosuppressive drug in renal transplantation but its long-term use is associated with calcineurin-inhibitor-related toxicity . The specific characteristics of the inter-relationship between dose , concentration and clinical (side-)effects for tacrolimus have not yet been identified and extensive long-term pharmacokinetic studies are presently lacking . Objective To establish the characteristics of the long-term pharmacokinetics of tacrolimus , to determine the time-dependent factors that influence the pharmacokinetics within the first critical post-transplant year and to identify a more appropriate way of monitoring drug exposure in clinical practice . Study design A prospect i ve pharmacokinetic study of tacrolimus was conducted in 100 de novo renal allograft recipients during the first year post-transplantation . Methods Area under the concentration-time curve ( AUC ) blood samplings for tacrolimus were performed on days 7 , 42 , 90 , 180 and 360 for all patients . Model-independent pharmacokinetic parameters for tacrolimus were calculated and dose-corrected when appropriate : AUC12 , peak plasma concentration ( Cmax ) , predose trough concentration ( C0 ) , time to Cmax , average steady-state blood concentration , steady-state total body clearance , terminal half-life , volume of distribution and an estimate for tacrolimus bioavailability was derived from additional steady-state intravenous clearance data . The association between tacrolimus pharmacokinetic parameters and different clinical variables was evaluated on days 7,42 , 90 , 180 and 360 . The clinical variables were either donor-related ( e.g. donor age ) , transplantation-related ( e.g. delayed graft function ) , recipient-related ( e.g. bodyweight ) , biochemical ( e.g. serum albumin ) , therapeutic variables ( e.g. corticosteroid dose ) or disease variables ( e.g. liver dysfunction ) . Results Long-term tacrolimus dose-corrected exposure ( AUC12 , Co ) is characterised by a late significant increase towards the end of the first year posttransplantation as the result of a significant increase in tacrolimus bioavailability ( p < 0.05 ) and a slow decrease in tacrolimus steady-state clearance . Consequently , tacrolimus dose-requirements corrected for bodyweight decrease significantly in the first postoperative year ( p < 0.05 ) , in part because of the simultaneous tapering of the corticosteroid dose which significantly affects tacrolimus bioavailability ( p < 0.05 ) . Other clinical variables that significantly influenced tacrolimus administration , exposure and bioavailability in a time-related fashion were identified in this study ( renal allograft function [ p < 0.05 ] , liver dysfunction [ p < 0.05 ] , diarrhoea [ p < 0.05 ] ) , while the clinical relevance of other variables was considerably moderated by our findings ( serum albumin , haematocrit ) . Time-unrelated variables proved to be of significant continuing clinical importance for tacrolimus dose-exposure pharmacokinetics throughout the first post-transplant year ( recipient age [ p < 0.05 ] , gender [ p < 0.01 ] and donor-receptor gender mismatch [ p < 0.05 ] ) , while donor hypotension ( p < 0.05 ) and cold ischaemia time ( p < 0.05 ) also proved significant although at present the reasons for this are unknown . Finally , using multiple stepwise regression analysis we demonstrated that classical assessment of tacrolimus exposure by monitoring pre-dose trough blood concentration ( or any other single concentration sampling timepoint ) is not the most reliable method and that abbreviated AUC measurements may constitute a more accurate clinical tool for ( therapeutic ) monitoring of drug exposure . Conclusion Tacrolimus pharmacokinetics in the first year after renal transplantation are characterised by a specific time-dependent evolution . The identification of clinical variables that determine tacrolimus pharmacokinetics is an important aid in the development of reliable drug monitoring strategies using abbreviated AUC measurements Mycophenolate mofetil ( MMF ) , a new immunosuppressant that selectively inhibits proliferation of T and B lymphocytes , may reduce the frequency and severity of acute graft rejection . Acute graft rejection is the leading cause of graft loss in cadaveric renal transplantation . The purpose of this r and omized , double-blind , multicenter study was to evaluate the efficacy and safety of MMF for the prevention of acute rejection episodes in adult patients during the first 6 months after renal transplantation . A total of 499 patients who were to receive a primary cadaveric renal allograft as their first transplant were r and omized to receive MMF 1.0 g b.i.d . ( MMF 2 g treatment group ) , MMF 1.5 g b.i.d . ( MMF 3 g treatment group ) , or azathioprine 1 - 2 mg/kg/day . CsA , corticosteroids , and antithymocyte globulin ( ATGAM ) were administered as part of a quadruple sequential induction protocol . The primary efficacy endpoint was biopsy-proven rejection or treatment failure ( defined as graft loss , death , or premature withdrawal from the study for any reason ) during the first 6 months after transplant . All enrolled patients were included in the primary analyses of efficacy on the basis of intent to treat . The 495 patients who received study drug were included in the safety and secondary efficacy analyses . Biopsy-proven acute rejection episodes or treatment failure occurred in 47.6 % of patients in the azathioprine group compared with 31.1 % ( P = 0.0015 ) and 31.3 % ( P = 0.0021 ) of patients in the MMF 2 g and 3 g treatment groups , respectively . Time to first biopsy-proven rejection episode or treatment failure was significantly longer for MMF 2 g versus azathioprine ( P = 0.0036 ) and MMF 3 g versus azathioprine ( P = 0.0006 ) . First biopsy-proven rejection alone occurred in 38.0 % of patients who received azathioprine compared with 19.8 % and 17.5 % of patients who received MMF 2 g and 3 g , respectively . Patients in the azathioprine group received a greater number of full courses of antirejection treatment as compared with the MMF 2 g and MMF 3 g groups ( 44.5 % , 24.8 % , and 21.1 % , respectively ) . The use of antilymphocyte agents to treat rejection was greater in the azathioprine group ( 20.1 % ) compared with the MMF 2 g group ( 10.3 % ) and the MMF 3 g group ( 5.4 % ) . At 6 months after transplant , graft and patient survival were similar in all 3 treatment groups . ( ABSTRACT TRUNCATED AT 400 WORDS Eighteen patients with compensated alcoholic cirrhosis participated in a single-dose pharmacokinetic study of oral mycophenolate mofetil ( MMF ) . Participants were divided into groups of 6 patients each with mild , moderate , or severe hepatic oxidative impairment as defined by the aminopyrine breath test ( APBT ) . Clinical ly , hepatic disease was of mild or moderate severity . Six healthy volunteers were included as control subjects . Plasma and urine sample s were collected over 96 hours and assayed for the active metabolite mycophenolic aced ( MPA ) and the glucuronide conjugate , MPAG . Plasma protein binding of MPA also was determined in 6 unrelated patients with cirrhosis . Cirrhosis did not grossly affect plasma pharmacokinetics or plasma binding of MPA . Maximum plasma concentrations ( C(max ) ) and area under the curve ( AUC ) of MPA and MPAG consistently decreased , increased , and then decreased as oxidative impairment declined from normal to severe . Patients with cirrhosis had comparable or greater recovery of administered drug substance in urine than controls , showing that cirrhosis did not affect the extent of MMF absorption . Urine clearance of MPAG was two times higher in the group with severe impairment than in the other groups . Creatinine clearance was similar in all groups . These results suggest progressive impairment of hepatic glucuronidation of MPA and induction of renal glucuronidation in patients with severe hepatic oxidative impairment |
1,949 | 29,982,383 | Conclusion An uninterrupted DOACs strategy for CA of NVAF appears to be as safe as uninterrupted VKA without a significantly increased risk of minor or major bleeding events .
There was a trend favouring DOACs in terms of major bleeding . | Aims To assess the incremental benefit of uninterrupted direct oral anticoagulants ( DOACs ) vs. uninterrupted vitamin K antagonists ( VKA ) for catheter ablation ( CA ) of non-valvular atrial fibrillation ( NVAF ) on three primary outcomes : major bleeding , thrombo-embolic events , and minor bleeding . | Aims VENTURE-AF is the first prospect i ve r and omized trial of uninterrupted rivaroxaban and vitamin K antagonists ( VKAs ) in patients with non-valvular atrial fibrillation ( NVAF ) undergoing catheter ablation ( CA ) . Methods and results Trial size was administratively set at 250 , the protocol -specified target . Events were independently and blindly adjudicated . We r and omly assigned 248 NVAF patients to uninterrupted rivaroxaban ( 20 mg once-daily ) or to an uninterrupted VKA prior to CA and for 4 weeks afterwards . The primary endpoint was major bleeding events after CA . Secondary endpoints included thromboembolic events ( composite of stroke , systemic embolism , myocardial infa rct ion , and vascular death ) and other bleeding or procedure-attributable events . Patients were 59.5 ± 10 years of age , 71 % male , 74 % paroxysmal AF , and had a CHA2DS2-VASc score of 1.6 . The average total heparin dose used to manage activated clotting time ( ACT ) was slightly higher ( 13 871 vs. 10 964 units ; P < 0.001 ) and the mean ACT level attained slightly lower ( 302 vs. 332 s ; P < 0.001 ) in rivaroxaban and VKA arms , respectively . The incidence of major bleeding was low ( 0.4 % ; 1 major bleeding event ) . Similarly , thromboembolic events were low ( 0.8 % ; 1 ischemic stroke and 1 vascular death ) . All events occurred in the VKA arm and all after CA . The number of any adjudicated events ( 26 vs. 25 ) , any bleeding events ( 21 vs. 18 ) , and any other procedure-attributable events ( 5 vs. 5 ) were similar . Conclusion In patients undergoing CA for AF , the use of uninterrupted oral rivaroxaban was feasible and event rates were similar to those for uninterrupted VKA therapy . Name of the Trial Registry Clinical trials.gov trial registration number is NCT01729871 OBJECTIVES The purpose of this study was to evaluate the feasibility and safety of periprocedural dabigatran during atrial fibrillation ( AF ) ablation . BACKGROUND AF ablation requires optimal periprocedural anticoagulation for minimizing bleeding and thromboembolic complications . The safety and efficacy of dabigatran as a periprocedural anticoagulant for AF ablation are unknown . METHODS We performed a multicenter , observational study from a prospect i ve registry including all consecutive patients undergoing AF ablation in 8 high-volume centers in the United States . All patients receiving dabigatran therapy who underwent AF ablation on periprocedural dabigatran , with the dose held on the morning of the procedure , were matched by age , sex , and type of AF with an equal number of patients undergoing AF ablation with uninterrupted warfarin therapy over the same period . RESULTS A total of 290 patients , including 145 taking periprocedural dabigatran and an equal number of matched patients taking uninterrupted periprocedural warfarin , were included in the study . The mean age was 60 years with 79 % being male and 57 % having paroxysmal AF . Both groups had a similar CHADS(2 ) score , left atrial size , and left ventricular ejection fraction . Three thromboembolic complications ( 2.1 % ) occurred in the dabigatran group compared with none in the warfarin group ( p = 0.25 ) . The dabigatran group had a significantly higher major bleeding rate ( 6 % vs. 1 % ; p = 0.019 ) , total bleeding rate ( 14 % vs. 6 % ; p = 0.031 ) , and composite of bleeding and thromboembolic complications ( 16 % vs. 6 % ; p = 0.009 ) compared with the warfarin group . Dabigatran use was confirmed as an independent predictor of bleeding or thromboembolic complications ( odds ratio : 2.76 , 95 % confidence interval : 1.22 to 6.25 ; p = 0.01 ) on multivariate regression analysis . CONCLUSIONS In patients undergoing AF ablation , periprocedural dabigatran use significantly increases the risk of bleeding or thromboembolic complications compared with uninterrupted warfarin therapy INTRODUCTION Stroke can be a life-threatening complication of atrial fibrillation ( AF ) catheter ablation . Uninterrupted warfarin treatment contributes to minimizing the risk of stroke complications . METHODS AND RESULTS This was a prospect i ve , open-label , r and omized , multicenter study assessing the safety and efficacy of apixaban for the prevention of cerebral thromboembolism complicating AF catheter ablation . Two hundred patients with drug-resistant AF were equally assigned to take either apixaban ( 5 mg or 2.5 mg twice daily ) or warfarin ( target international normalized ratio , 2 - 3 ) for at least 1 month before AF ablation . Neither drug regimen was interrupted throughout the operative period . Diffusion-weighted magnetic resonance imaging was performed for all patients to detect silent cerebral infa rct ion ( SCI ) after the ablation . Primary outcomes were defined as the occurrence of stroke , transient ischemic attack , SCI , or major bleeding that required intervention . The secondary outcome was minor bleeding . The groups did not statistically differ in patients ' background s or procedural parameters . During AF ablation , the apixaban group required administration of more heparin to maintain an activated clotting time > 300 seconds than the warfarin group ( apixaban , 14,000 ± 4,000 units ; warfarin , 9,000 ± 3,000 units ) . Three primary outcome events occurred in each group ( apixaban , 2 SCI and 1 major bleed ; warfarin , 3 SCI , P = 1.00 ) , and 3 and 4 secondary outcome events occurred in the apixaban and warfarin groups ( P = 0.70 ) , respectively . CONCLUSION Apixaban has similar safety and effectiveness to warfarin for the prevention of cerebral thromboembolism during the periprocedural period of AF ablation Background Systemic thromboembolism and bleeding remain the two most common and serious complications of catheter ablation of atrial fibrillation . A variety of periprocedure anticoagulation strategies have been proposed to mitigate these risks . Although operators are now routinely administering dabigatran for anticoagulation in this setting , its relative safety and effectiveness compared to warfarin are unknown . Methods and results A total of 202 patients received dabigatran as part of their periprocedural anticoagulation regimen at the time of initial or redo catheter ablation for symptomatic atrial fibrillation . A comparison group of 202 patients treated with warfarin was r and omly selected from patients undergoing atrial fibrillation ( AF ) ablation during the same time period . AF types were paroxysmal in 223 patients , persistent in 158 patients , and longst and ing persistent in 13 patients . Mean age was 60.0 ± 10.5 years , 55 % had a history of hypertension , and mean CHADS-VASc score was 1.7 ± 1.3 . “ Continuous ” warfarin or dabigatran was administered in 80 and 32 % of patients , respectively . Time to first dose of dabigatran post-procedure was 12.2 ± 10.3 h. Two dabigatran and no warfarin-treated patients had systemic thromboembolism ( p = NS ) ; five dabigatran and three warfarin-treated patients had bleeding complications ( p = NS , combined endpoint p = 0.116 ) . One dabigatran patient had severe pericardial bleeding ( 3 L blood loss ) . Conclusions In a retrospective pilot trial comparing the risks of systemic thromboembolism or bleeding complications in patients treated with warfarin or dabigatran anticoagulation , the outcomes were similar . A prospect i ve trial is warranted OBJECTIVES The purpose of this study was to evaluate the feasibility and safety of uninterrupted rivaroxaban therapy during atrial fibrillation ( AF ) ablation . BACKGROUND Optimal periprocedural anticoagulation strategy is essential for minimizing bleeding and thromboembolic complications during and after AF ablation . The safety and efficacy of uninterrupted rivaroxaban therapy as a periprocedural anticoagulant for AF ablation are unknown . METHODS We performed a multicenter , observational , prospect i ve study of a registry of patients undergoing AF ablation in 8 centers in North America . Patients taking uninterrupted periprocedural rivaroxaban were matched by age , sex , and type of AF with an equal number of patients taking uninterrupted warfarin therapy who were undergoing AF ablation during the same period . RESULTS A total of 642 patients were included in the study , with 321 in each group . Mean age was 63 ± 10 years , with 442 ( 69 % ) males and 328 ( 51 % ) patients with paroxysmal AF equally distributed between the 2 groups . Patients in the warfarin group had a slightly higher mean HAS- BLED ( hypertension , abnormal renal/liver function , stroke , bleeding history or predisposition , labile international normalized ratio , elderly , drugs/alcohol concomitantly ) score ( 1.70 ± 1.0 vs. 1.47 ± 0.9 , respectively ; p = 0.032 ) . Bleeding and embolic complications occurred in 47 ( 7.3 % ) and 2 ( 0.3 % ) patients ( both had transient ischemic attacks ) respectively . There were no differences in the number of major bleeding complications ( 5 [ 1.6 % ] vs. 7 [ 1.9 % ] , respectively ; p = 0.772 ) , minor bleeding complications ( 16 [ 5.0 % ] vs. 19 [ 5.9 % ] , respectively ; p = 0.602 ) , or embolic complications ( 1 [ 0.3 % ] vs. 1 [ 0.3 % ] , respectively ; p = 1.0 ) between the rivaroxaban and warfarin groups in the first 30 days . CONCLUSIONS Uninterrupted rivaroxaban therapy appears to be as safe and efficacious in preventing bleeding and thromboembolic events in patients undergoing AF ablation as uninterrupted warfarin therapy Advances in antithrombotic therapy , along with an early invasive strategy , have reduced the incidence of recurrent ischemic events and death in patients with acute coronary syndromes ( ACS ; unstable angina , non – ST-segment – elevation myocardial infa rct ion [ MI ] , and ST-segment – elevation MI).1,–,4 However , the combination of multiple pharmacotherapies , including aspirin , platelet P2Y12 inhibitors , heparin plus glycoprotein IIb/IIIa inhibitors , direct thrombin inhibitors , and the increasing use of invasive procedures , has also been associated with an increased risk of bleeding . Editorial see p 2664 Bleeding complications have been associated with an increased risk of subsequent adverse outcomes , including MI , stroke , stent thrombosis , and death , in patients with ACS and in those undergoing percutaneous coronary intervention (PCI),5,–,10 as well as in the long-term antithrombotic setting .11,12 Thus , balancing the anti-ischemic benefits against the bleeding risk of antithrombotic agents and interventions is of paramount importance in assessing new therapies and in managing patients . Prior r and omized trials comparing antithrombotic agents suggest that a reduction in bleeding events is associated with improved survival.13,14 Because prevention of major bleeding may represent an important step in improving outcomes by balancing safety and efficacy in the contemporary treatment of ACS , bleeding events have been systematic ally identified as a crucial end point for the assessment of the safety of drugs during the course of r and omized clinical trials , and are an important aspect of the evaluation of new devices and interventional therapies.15 Unlike ischemic clinical events ( eg , cardiac death , MI , stent thrombosis ) , for which there is now general consensus on end-point definitions,16,17 there is substantial heterogeneity among the many bleeding definitions currently in use . Lack of st and ardization makes it difficult to optimally organize key clinical trial processes such as adjudication , and even more difficult to interpret relative Purpose Left atrial catheter ablation for patients with atrial fibrillation ( AF ) requires periprocedural anticoagulation to minimize thromboembolic complications . High rates of major bleeding complications using dabigatran etexilate for periprocedural anticoagulation have been reported , raising concerns regarding its safety during left atrial catheter ablation . We sought to evaluate the safety and efficacy of a dabigatran use strategy versus warfarin , at a single high-volume AF ablation center . Methods We performed a retrospective analysis on consecutive patients undergoing left atrial ablation at V and erbilt Medical Center from January 2011 through August 2012 with a minimum follow-up of 3 months . Patient cohorts were divided into two groups , those utilizing dabigatran etexilate pre- and post-ablation and those undergoing ablation on dose-adjusted warfarin , with or without low-molecular-weight heparin bridging . Dabigatran was held 24–30 h pre-procedure and restarted 4–6 h after hemostasis was achieved . We evaluated all thromboembolic and bleeding complications at 3 months post-ablation . Results A total of 254 patients underwent left atrial catheter ablation for atrial fibrillation or left atrial flutter . Periprocedural anticoagulation utilized dabigatran in 122 patients and warfarin in 135 patients . Three late thromboembolic complications occurred in the dabigatran group ( 2.5 % ) , compared with one ( 0.7 % ) in the warfarin group ( p = 0.28 ) . The dabigatran group had similar minor bleeding ( 2.5 vs. 7.4 % , p = 0.07 ) , major bleeding ( 1.6 vs. 0.7 % , p = 0.51 ) , and composite of bleeding and thromboembolic complications ( 6.6 vs. 8.9 % , p = 0.49 ) when compared to warfarin . There were no acute thromboembolic complications in either group ( < 24 h post-ablation ) . Conclusions In patients undergoing left atrial catheter ablation for AF or left atrial flutter , use of periprocedural dabigatran etexilate provides a safe and effective anticoagulation strategy compared to warfarin . A prospect i ve r and omized study is warranted OBJECTIVES This r and omized study compared uninterrupted rivaroxaban therapy with warfarin therapy as prophylaxis against catheter ablation (CA)-induced asymptomatic cerebral infa rct ion ( ACI ) and identified the risk factors of rivaroxaban . BACKGROUND The reported incidence of ACI during CA for atrial fibrillation ( AF ) remains at 10 % to 30 % , and periprocedural oral anticoagulation could affect this incidence . METHODS Patients with nonvalvular AF undergoing radiofrequency CA were r and omly assigned to receive either uninterrupted rivaroxaban or warfarin as periprocedural anticoagulation therapy . CA was performed after at least 1 month of adequate anticoagulation . Cerebral magnetic resonance imaging ( MRI ) was performed within 2 weeks before and 1 day after CA to detect ACI . RESULTS A total 132 patients were enrolled ; 127 ( median : 60.0 years of age ; 83.5 % males ; 64.6 % incidence of paroxysmal AF ) complied with the study protocol and were analyzed ; 64 patients received rivaroxaban , and 63 patients received warfarin . The rates of CA-induced ACI in the rivaroxaban group ( 15.6 % [ 10 of 64 patients ] ) were similar to those in the warfarin group ( 15.9 % [ 10 of 63 patients ] ; p = 1.000 ) . No thromboembolic events developed ; no differences in major or nonmajor bleeding rates were observed between the 2 drug groups ( 3.1 % vs. 1.6 % , respectively , or 18.8 % vs. 19.0 % , respectively ) . Multiple regression analysis indicated that the presence of deep and subcortical white matter hyperintensity ( p = 0.002 ; odds ratio [ OR ] : 5.323 ) and the frequency of cardioversions ( p = 0.016 ; OR : 1.250 ) were associated with the incidence of ACI . CONCLUSIONS No notable differences were found between the incidence of CA-induced ACI in the rivaroxaban group and that in the warfarin group in this r and omized study Background — Catheter ablation of atrial fibrillation is associated with the potential risk of periprocedural stroke , which can range between 1 % and 5 % . We developed a prospect i ve data base to evaluate the prevalence of stroke over time and to assess whether the periprocedural anticoagulation strategy and use of open irrigation ablation catheter have result ed in a reduction of this complication . Methods and Results — We collected data from 9 centers performing the same ablation procedure with the same anticoagulation protocol . We divided the patients into 3 groups : ablation with an 8-mm catheter off warfarin ( group 1 ) , ablation with an open irrigated catheter off warfarin ( group 2 ) , and ablation with an open irrigated catheter on warfarin ( group 3 ) . Outcome data on stroke/transient ischemic attack and bleeding complications during and early after the procedures were collected . Of 6454 consecutive patients in the study , 2488 were in group 1 , 1348 were in group 2 , and 2618 were in group 3 . Periprocedural stroke/transient ischemic attack occurred in 27 patients ( 1.1 % ) in group 1 and 12 patients ( 0.9 % ) in group 2 . Despite a higher prevalence of nonparoxysmal atrial fibrillation and more patients with CHADS2 ( congestive heart failure , hypertension , age > 75 years , diabetes mellitus , and prior stroke or transient ischemic attack ) score > 2 , no stroke/transient ischemic attack was reported in group 3 . Complications among groups 1 , 2 , and 3 , including major bleeding ( 10 [ 0.4 % ] , 11 [ 0.8 % ] , and 10 [ 0.4 % ] , respectively ; P>0.05 ) and pericardial effusion ( 11 [ 0.4 % ] , 11 [ 0.8 % ] , and 12 [ 0.5 % ] ; P>0.05 ) , were equally distributed . Conclusion — The combination of an open irrigation ablation catheter and periprocedural therapeutic anticoagulation with warfarin may reduce the risk of periprocedural stroke without increasing the risk of pericardial effusion or other bleeding complications |
1,950 | 30,510,515 | Conclusion : Concomitant use of PPIs and clopidogrel has been proved not to be associated with elevated cardiovascular risks according to RCTs . | Background : Clopidogrel and proton pump inhibitors ( PPIs ) are metabolized by cytochrome P450 enzymes .
Contradictory results have been reported on possible complications of simultaneous PPI and clopidogrel use .
Our aim was to investigate the clinical relevance of this debate with a systematic review and meta- analysis . | Background —Certain proton pump inhibitors ( PPIs ) interfere with clopidogrel metabolism , potentially attenuating P2Y12 receptor inhibition . Previous observational and r and omized trials report conflicting results regarding the clinical significance of this pharmacological interaction . We examined the interaction between concomitant administration of PPI and clopidogrel on platelet reactivity and clinical outcomes in the large-scale , prospect i ve Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents study . Methods and Results —On-treatment P2Y12 platelet reactivity testing was performed using the VerifyNow assay after clopidogrel loading and successful drug-eluting stent implantation at 11 sites in the United States and Germany . PPIs were prescribed at the discretion of treating physicians ; patients were followed for 2 years . High platelet reactivity was defined as P2Y12 reactivity units > 208 . Of 8582 enrolled patients , 2697 ( 31.4 % ) were taking a PPI at the time of coronary intervention . After adjustment for differences in baseline characteristics , PPI use was independently associated with high platelet reactivity ( odds ratio , 1.38 : 95 % confidence interval , 1.25–1.52 , P=0.0001 ) . A total of 2162 ( 25.2 % ) patients were prescribed a PPI at hospital discharge . In a propensity-adjusted multivariable analysis , discharge PPI use was independently associated with increased risk for postdischarge major adverse cardiac events ( cardiac death , myocardial infa rct ion , or ischemia-driven target lesion revascularization ) at 2-year follow-up ( hazard ratio , 1.21 ; 95 % confidence interval , 1.04–1.42 , P=0.02 ) . Conclusions —In patients treated with clopidogrel after successful drug-eluting stents implantation , the concomitant administration of PPI was associated with high platelet reactivity and a greater rate of adverse outcomes during long-term follow-up . Additional studies are warranted to determine the risk – benefit ratio of PPIs in patients with drug-eluting stents treated with clopidogrel . Clinical Trial Registration —URL : http://www . clinical trials.gov . Unique identifier : NCT00433966 BACKGROUND Omeprazole , usually used in the antiplatelet therapy during percutaneous coronary intervention ( PCI ) in acute coronary syndrome ( ACS ) , has been reported to increase ischemic events in retrospective studies . However , other clinical trials gave paradoxical results . The aim of this study was to assess the effects of omeprazole on clopidogrel efficacy and clinical events . METHODS All patients ( n = 172 ) received aspirin ( loading dose 300 mg and maintenance dose 100 mg/d ) and clopidogrel ( loading dose 600 mg and maintenance dose 75 mg/d ) during the therapy . They were r and omized to receive omeprazole ( 20 mg/d ) or placebo for 30 days . Residual platelet activities in the adenosine 5'-diphosphate ( ADP ) pathway were detected on the fifth day after PCI with thrombelastography (TEG)-mapping . The clinical events were recorded after one month . RESULTS According to the five levels of platelet activities , the frequency distributions of the inhibition rates were significantly different ( P = 0.0062 ) . However , no significant change was seen in the distribution among the highest or the lowest inhibiting levels ( > 95 % and < 30 % inhibition rate ) . And there were no significant differences ( P > 0.05 ) in events incidence , while gastro-intestinal bleeding decreased in co-administration of omeprazole . CONCLUSIONS Omeprazole significantly blunts clopidogrel efficacy while not exacerbates ischemic events in ACS undergoing PCI . Omeprazole even can decrease gastro-intestinal bleeding in those patients Background — The clinical significance of the interaction between clopidogrel and proton pump inhibitors ( PPIs ) remains unclear . Methods and Results — We examined the relationship between PPI use and 1-year cardiovascular events ( cardiovascular death , myocardial infa rct ion , or stroke ) in patients with acute coronary syndrome r and omized to clopidogrel or ticagrelor in a prespecified , nonr and omized subgroup analysis of the Platelet Inhibition and Patient Outcomes ( PLATO ) trial . The primary end point rates were higher for individuals on a PPI ( n=6539 ) compared with those not on a PPI ( n=12 060 ) at r and omization in both the clopidogrel ( 13.0 % versus 10.9 % ; adjusted hazard ratio [ HR ] , 1.20 ; 95 % confidence interval [ CI ] , 1.04–1.38 ) and ticagrelor ( 11.0 % versus 9.2 % ; HR , 1.24 ; 95 % CI , 1.07–1.45 ) groups . Patients on non-PPI gastrointestinal drugs had similar primary end point rates compared with those on a PPI ( PPI versus non-PPI gastrointestinal treatment : clopidogrel , HR , 0.98 ; 95 % CI , 0.79–1.23 ; ticagrelor , HR , 0.89 ; 95 % CI , 0.73–1.10 ) . In contrast , patients on no gastric therapy had a significantly lower primary end point rate ( PPI versus no gastrointestinal treatment : clopidogrel , HR , 1.29 ; 95 % CI , 1.12–1.49 ; ticagrelor , HR , 1.30 ; 95 % CI , 1.14–1.49 ) . Conclusions — The use of a PPI was independently associated with a higher rate of cardiovascular events in patients with acute coronary syndrome receiving clopidogrel . However , a similar association was observed between cardiovascular events and PPI use during ticagrelor treatment and with other non-PPI gastrointestinal treatment . Therefore , in the PLATO trial , the association between PPI use and adverse events may be due to confounding , with PPI use more of a marker for , than a cause of , higher rates of cardiovascular events . Clinical Trial Registration — http://www . clinical trials.gov . Unique identifier : NCT00391872 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 It remains unclear whether concomitant use of omeprazole attenuates platelet function as compared with that of famotidine in patients with acute coronary syndromes ( ACS ) who receive clopidogrel . METHODS AND RESULTS In this prospect i ve study , 130 ACS patients treated with aspirin and clopidogrel who underwent stent implantation were r and omly assigned to receive a Japanese st and ard dose of omeprazole 10 mg daily or famotidine 20 mg daily for at least 4 weeks . Between 14 and 28 days after enrollment , there was no significant difference in the platelet reactivity index ( PRI ) measured with vasodilator-stimulated phosphoprotein phosphorylation assay between the omeprazole group ( n=65 ) and famotidine group ( n=65 ) ( 55±17 % vs. 51±19 % ; P=0.26 ) . The cumulative rate of adverse cardiovascular events at 12 months was similar in the groups ( 13 % vs. 17 % ; P=0.81 ) . The PRI was similar ( 54.9±17.9 % vs. 54.0±17.8 % ; P=0.83 ) in the omeprazole group ( n=33 ) and the famotidine group ( n=39 ) among patients with ST-elevation myocardial infa rct ion ( STEMI ) . However , there was a trend toward a higher PRI ( 55.2±15.9 % vs. 46.4±19.4 % ; P=0.06 ) in the omeprazole group ( n=32 ) as compared with the famotidine group ( n=26 ) among patients without persistent ST-segment elevation ACS . CONCLUSIONS As compared with famotidine , concomitant use of low-dose omeprazole does not significantly attenuate the antiplatelet effects of clopidogrel in patients with ACS , especially in those with STEMI BACKGROUND Gastrointestinal complications are an important problem of antithrombotic therapy . Proton-pump inhibitors ( PPIs ) are believed to decrease the risk of such complications , though no r and omized trial has proved this in patients receiving dual antiplatelet therapy . Recently , concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel . METHODS We r and omly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo , in addition to aspirin . The primary gastrointestinal end point was a composite of overt or occult bleeding , symptomatic gastroduodenal ulcers or erosions , obstruction , or perforation . The primary cardiovascular end point was a composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , revascularization , or stroke . The trial was terminated prematurely when the sponsor lost financing . RESULTS We planned to enroll about 5000 patients ; a total of 3873 were r and omly assigned and 3761 were included in analyses . In all , 51 patients had a gastrointestinal event ; the event rate was 1.1 % with omeprazole and 2.9 % with placebo at 180 days ( hazard ratio with omeprazole , 0.34 , 95 % confidence interval [ CI ] , 0.18 to 0.63 ; P<0.001 ) . The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo ( hazard ratio , 0.13 ; 95 % CI , 0.03 to 0.56 ; P = 0.001 ) . A total of 109 patients had a cardiovascular event , with event rates of 4.9 % with omeprazole and 5.7 % with placebo ( hazard ratio with omeprazole , 0.99 ; 95 % CI , 0.68 to 1.44 ; P = 0.96 ) ; high-risk subgroups did not show significant heterogeneity . The two groups did not differ significantly in the rate of serious adverse events , though the risk of diarrhea was increased with omeprazole . CONCLUSIONS Among patients receiving aspirin and clopidogrel , prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding . There was no apparent cardiovascular interaction between clopidogrel and omeprazole , but our results do not rule out a clinical ly meaningful difference in cardiovascular events due to use of a PPI . ( Funded by Cogentus Pharmaceuticals ; Clinical Trials.gov number , NCT00557921 . ) BACKGROUND Proton pump inhibitors ( PPIs ) are frequently prescribed in combination with clopidogrel , but conflicting data exist as to whether PPIs diminish the efficacy of clopidogrel . We assessed the association between PPI use and clinical outcomes for patients treated with percutaneous coronary intervention ( PCI ) and dual-antiplatelet therapy ( DAPT ) with clopidogrel plus aspirin . METHODS AND RESULTS In the PRODIGY trial , 1,970 patients were r and omized to 6- or 24-month DAPT at 30 days from index procedure . Among them , 738 patients ( 37.5 % ) received PPI ( mainly lansoprazole ; 90.1 % ) at the time of r and omization . Proton pump inhibitor users were older , were most likely to be woman , had a lower creatinine clearance , presented more frequently with acute coronary syndrome , and had a higher CRUSADE bleeding score . After adjustment , the primary efficacy end point ( composite of all-cause death , myocardial infa rct ion , and cerebrovascular accident ) was similar between no PPI and PPI users ( 9.2 % vs 11.5 % , adjusted hazard ratio [ HR ] 1.051 , 95 % CI 0.788 - 1.400 , P = .736 ) . Bleeding rates did not differ between the 2 groups ( Bleeding Academic Research Consortium type 2 , 3 , or 5 : adjusted HR 0.996 , 95 % CI 0.672 - 1.474 , P = .980 ) . Net clinical adverse events were also similar in no PPI and PPI patients ( 12.9 % vs 14.9 % , adjusted HR 0.99 , 95 % CI 0.772 - 1.268 , P = .93 ) . Results remained consistent at sensitivity analysis when focusing on the 548 patients who remained on PPI for the whole study duration . CONCLUSIONS The current findings suggest that the concomitant use of PPIs , when clinical ly indicated , in patients receiving clopidogrel is not associated with adverse clinical outcome BACKGROUND Recent pharmacodynamic and retrospective clinical analyses have suggested that proton pump inhibitors ( PPIs ) may modify the antiplatelet effects of clopidogrel bisulfate . METHODS We conducted a retrospective cohort study of persons enrolled in a multistate health insurance plan with commercial and Medicare clients to evaluate adverse clinical outcomes in patients using clopidogrel plus a PPI compared with clopidogrel alone . Patients who were discharged from the hospital after myocardial infa rct ion ( MI ) or coronary stent placement and treated with clopidogrel plus a PPI ( n = 1033 ) were matched 1:1 ( using propensity scoring ) with patients with similar cardiovascular risk factors treated with clopidogrel alone . Rehospitalizations for MI or coronary stent placement were evaluated for up to 360 days . A sub analysis was conducted to study the impact of pantoprazole sodium , the most used PPI . RESULTS Patients who received clopidogrel plus a PPI had a 93 % higher risk of rehospitalization for MI ( adjusted hazard ratio , 1.93 ; 95 % confidence interval , 1.05 - 3.54 ; P = .03 ) and a 64 % higher risk of rehospitalization for MI or coronary stent placement ( 1.64 ; 1.16 - 2.32 ; P = .005 ) than did patients receiving clopidogrel alone . Increased risk of rehospitalization for MI or coronary stent placement was also observed for the subgroup of patients receiving clopidogrel plus pantoprazole ( adjusted hazard ratio , 1.91 ; 95 % confidence interval , 1.19 - 3.06 ; P = .008 ) . CONCLUSIONS Patients who received clopidogrel plus a PPI had a significantly higher risk of rehospitalization for MI or coronary stent placement than did patients receiving clopidogrel alone . Prospect i ve clinical trials and laboratory analyses of biochemical interactions are warranted to further evaluate the potential impact of PPIs on the efficacy of clopidogrel OBJECTIVE To evaluate the impact of different proton pump inhibitors on the antiplatelet activity of clopidogrel . METHODS A total of 60 hospitalized patients undergoing percutaneous coronary intervention were r and omly assigned to receive omeprazole group 40 mg/d ( 20 patients ) , pantoprazole group 40 mg/d ( 20 patients ) and control group ( 20 patients ) . All patients also received st and ard clopidogrel therapy , continuing 30 days treatments . The percentage clotting inhibition was measured by the use of thrombelastogram and the maximal platelet aggregation rate ( MPAR ) was measured by turbidity method at the first day before admission and 15 or 30 days after treatment . Major adverse cardiac and cerebral events ( MACCE ) and hemorrhagic events within 30 days were recorded . RESULTS The baseline clinical characteristics , angiography and PCI result were compared among the three groups . At the first day before admission and 15 or 30 days after treatment , no significant difference was shown in the percentage clotting inhibition measured by thrombelastogram and the maximal platelet aggregation rate ( MPAR ) measured by turbidity method among the three groups . Though the platelet agglutination inhibition rate measured at 15 and 30 days increased and MPAR measured at 15 and 30 days declined compared with the baseline data ( P < 0.05 ) , no significant difference was found between levels measured at 15 and 30 days ( P > 0.05 ) . The rates of MACCE had no significant difference among the three groups . Compared with control group , the rates of hemorrhagic event were significantly decreased in omeprazole or pantoprazole group ( P < 0.05 ) , but no significant difference was shown between the omeprazole and pantoprazole group . CONCLUSION No significant impact of different proton pump inhibitors on the antiplatelet activity of clopidogrel has been found in patients undergoing coronary stent implantation and short-time combined administration is safe Background Recent studies have suggested that proton pump inhibitors ( PPIs ) attenuate the benefits of clopidogrel . The clinical relevance of this interaction in patients who have undergone percutaneous coronary intervention ( PCI ) is unknown . We hypothesized that post-PCI patients discharged on clopidogrel will have higher cardiovascular events if concomitant PPI therapy is used . Aims To determine whether post-PCI patients discharged on clopidogrel will have higher cardiovascular events if concomitant PPI therapy is used . Methods We review ed the medical records of all the patients discharged on clopidogrel who underwent PCI from January 2003 to August 2004 . The primary outcome studied was a major adverse cardiovascular event ( MACE ) , which was defined as a composite of death , myocardial infa rct ion , and target vessel failure . Results Of the 315 post-PCI patients who were discharged on clopidogrel , 72 were discharged on PPI . During a mean follow-up period of 50 months , patients discharged on concomitant clopidogrel-PPI therapy had a MACE rate of 56 % ( vs. 38 % in the clopidogrel alone group ) ( P = 0.025 ) and had 95 % excess risk of MACE . Conclusion Concomitant use of clopidogrel and PPI in post-PCI patients is associated with a higher risk of MACE . This suggests that PPIs may attenuate clopidogrel ’s beneficial antiplatelet effect , which is crucial after PCI . Prospect i ve r and omized studies are warranted to provide definitive evidence for this interaction OBJECTIVES : Little is known about the efficacy of proton pump inhibitors compared with H2 receptor antagonists in preventing adverse upper gastrointestinal complications in patients with acute coronary syndrome ( ACS ) or ST elevation myocardial infa rct ion ( STEMI ) receiving aspirin , clopidogrel , and enoxaparin or thrombolytics . The objective of this study was to compare the efficacies of esomeprazole and famotidine in preventing gastrointestinal complications . METHODS : A double-blind , r and omized , controlled trial was performed in patients receiving a combination of aspirin , clopidogrel , and either enoxaparin or thrombolytics . Patients received either esomeprazole ( 20 mg nocte ) or famotidine ( 40 mg nocte ) orally for 4–52 weeks , depending on the duration of dual antiplatelet therapy . The primary end point was upper gastrointestinal bleeding ( GIB ) , perforation , or obstruction from ulcer/erosion ( http://www . clinical trials.gov NCT00683111 ) . RESULTS : In all , 311 patients were recruited , with 163 and 148 patients in the esomeprazole and famotidine groups , respectively . Mean ( s.d . ) follow-up was 19.2 ( 17.6 ) and 17.6 ( 18.0 ) weeks , respectively . One ( 0.6 % ) patient in the esomeprazole group and 9 ( 6.1 % ) in the famotidine group reached the primary end point ( log-rank test , P=0.0052 , hazard ratio=0.095 , 95 % confidence interval : 0.005–0.504 ) ; all had upper GIB . CONCLUSIONS : In patients with ACS or STEMI , esomeprazole is superior to famotidine in preventing upper gastrointestinal complications related to aspirin , clopidogrel , and enoxaparin or thrombolytics BACKGROUND & AIMS We performed a prospect i ve , r and omized , controlled study to compare the combination of esomeprazole and clopidogrel vs clopidogrel alone in preventing recurrent peptic ulcers in patients with atherosclerosis and a history of peptic ulcers . We also investigated the effects of esomeprazole on the antiplatelet action of clopidogrel . METHODS From January 2008 to January 2010 , long-term clopidogrel users with histories of peptic ulcers who did not have peptic ulcers at an initial endoscopy examination were assigned r and omly to receive the combination of esomeprazole ( 20 mg/day , before breakfast ) and clopidogrel ( 75 mg/day , at bedtime ) , or clopidogrel alone for 6 months . A follow-up endoscopy examination was performed at the end of the sixth month and whenever severe symptoms occurred . Platelet aggregation tests were performed on days 1 and 28 for 42 consecutive patients who participated in the pharmacodynamic study . RESULTS The cumulative incidence of recurrent peptic ulcer during the 6-month period was 1.2 % among patients given the combination of esomeprazole and clopidogrel ( n = 83 ) and 11.0 % among patients given clopidogrel alone ( n = 82 ) ( difference , 9.8 % ; 95 % confidence interval , 2.6%-17.0 % ; P = .009 ) . In the group given the combination therapy , there were no differences in the percentages of aggregated platelets on days 1 and 28 ( 31.0 % ± 20.5 % vs 30.1 % ± 16.5 % ) . CONCLUSIONS Among patients with atherosclerosis and a history of peptic ulcers , the combination of esomeprazole and clopidogrel reduced recurrence of peptic ulcers , compared with clopidogrel alone . Esomeprazole does not influence the action of clopidogrel on platelet aggregation BACKGROUND Dual antiplatelet therapy ( aspirin plus clopidogrel ) is recommended in patients undergoing percutaneous coronary intervention ( PCI ) . Treatment with proton pump inhibitors ( PPIs ) decreases bleeding rate . Alarming reports have been made that PPIs may decrease the antiplatelet activity of clopidogrel . We sought to determine whether levels of interleukin-6 ( IL-6 ) and transforming growth factor-β1 ( TGF-β1 ) might help distinguish individuals at risk for adverse events . METHODS Thirty-eight patients on aspirin and clopidogrel were enrolled and divided into two groups : group 1 [ patients receiving omeprazole ( n = 18 ) ] and group 2 [ patients not receiving omeprazole ( n = 20 ) ] . Patients underwent PCI and were scheduled for twelve-month clinical follow-up . The major , adverse cardiac and cerebrovascular events ( MACCE ) include death , re-hospitalization for acute coronary syndromes , and stroke . RESULTS Median concentrations of IL-6 were higher in group 1 at 4.7 pg/mL , in comparison with group 2 , 1.65 pg/mL ( p = 0.003 ) . Median concentrations of TGF-β1 were similar in both groups ( p = 0.5 ) . Patients in group 1 had a significantly higher leukocyte count [ 103/mm3 ] ( median 7.5 vs 6.5 ; p = 0.04 ) . There were no deaths during follow-up . The incidence of myocardial infa rct ion was higher in group 1 ( 33.4 % vs 5.0 % ; p = 0.03 ) . MACCE at twelve months were more frequent in group 1 ( 55.6 % vs 20.0 % ; p = 0.02 ) . The cut-off value to predict MACCEs for IL-6 was > 3.6 pg/mL ( sensitivity 64 % , specificity 88 % , positive predictive value 75 % , negative predictive value 81 % ) . INTERPRETATION We show here that concomitant omeprazole use is associated with an increased inflammatory reaction . Drug interactions may reduce the anti-inflammatory effect of clopidogrel . This mechanism maybe responsible for an increased risk of non-fatal , cardiovascular events , following stent placement The capacity of clopidogrel to inhibit ADP-induced platelet aggregation shows wide intersubject variability . To determine whether frequent functional variants of genes coding for c and i date cytochrome P450 ( CYP ) isoenzymes involved in clopidogrel metabolic activation ( CYP2C19 * 2 , CYP2B6 * 5 , CYP1A2 * 1F , and CYP3A5 * 3 variants ) influence the platelet responsiveness to clopidogrel , we conducted a prospect i ve pharmacogenetic study in 28 healthy white male volunteers treated for 7 days with clopidogrel 75 mg/d . We observed that pharmacodynamic response to clopidogrel was significantly associated with the CYP2C19 genotype . Twenty of the subjects were wild-type CYP2C19 ( * 1/*1 ) homozygotes , while the other 8 subjects were heterozygous for the loss-of-function polymorphism CYP2C19 * 2 ( * 1/*2 ) . Baseline platelet activity was not influenced by the CYP2C19 genotype . In contrast , platelet aggregation in the presence of 10 muM ADP decreased gradually during treatment with clopidogrel 75 mg once daily in * 1/*1 subjects , reaching 48.9 % + /- 14.9 % on day 7 ( P < .001 vs baseline ) , whereas it did not change in * 1/*2 subjects ( 71.8 % + /- 14.6 % on day 7 , P = .22 vs baseline , and P < .003 vs * 1/*1 subjects ) . Similar results were found with VASP phosphorylation . The CYP2C19 * 2 loss-of-function allele is associated with a marked decrease in platelet responsiveness to clopidogrel in young healthy male volunteers and may therefore be an important genetic contributor to clopidogrel resistance in the clinical setting OBJECTIVES This trial sought to assess the influence of omeprazole on clopidogrel efficacy . BACKGROUND Clopidogrel has proved its benefit in the treatment of atherothrombotic diseases . In a previous observational study , we found clopidogrel activity on platelets , tested by vasodilator-stimulated phosphoprotein ( VASP ) phosphorylation , to be diminished in patients receiving proton pump inhibitor ( PPI ) treatment . METHODS In this double-blind placebo-controlled trial , all consecutive patients undergoing coronary artery stent implantation received aspirin ( 75 mg/day ) and clopidogrel ( loading dose , followed by 75 mg/day ) and were r and omized to receive either associated omeprazole ( 20 mg/day ) or placebo for 7 days . Clopidogrel effect was tested on days 1 and 7 in both groups by measuring platelet phosphorylated-VASP expressed as a platelet reactivity index ( PRI ) . Our main end point compared PRI value at the 7-day treatment period in the 2 groups . RESULTS Data for 124 patients were analyzed . On day 1 , mean PRI was 83.2 % ( st and ard deviation [ SD ] 5.6 ) and 83.9 % ( SD 4.6 ) , respectively , in the placebo and omeprazole groups ( p = NS ) , and on day 7 , 39.8 % ( SD 15.4 ) and 51.4 % ( SD 16.4 ) , respectively ( p < 0.0001 ) . RESULTS Omeprazole significantly decreased clopidogrel inhibitory effect on platelet P2Y12 as assessed by VASP phosphorylation test . Aspirin-clopidogrel antiplatelet dual therapy is widely prescribed worldwide , with PPIs frequently associated to prevent gastrointestinal bleeding . The clinical impact of these results remains uncertain but merits further investigation OBJECTIVES We assessed the incidence , predictors , and outcomes of gastrointestinal bleeding ( GIB ) in patients with acute coronary syndromes ( ACS ) . BACKGROUND GIB is a potential hemorrhagic complication in patients with ACS treated with antithrombotic and /or antiplatelet medications . The clinical outcomes associated with GIB in this setting have not been systematic ally studied . METHODS In the ACUITY ( Acute Catheterization and Urgent Intervention Triage Strategy ) trial , 13,819 patients with moderate- and high-risk ACS , enrolled at 450 centers in 17 countries between August 2003 and December 2005 , were r and omized to the open-label use of 1 of 3 antithrombin regimens ( heparin plus a glycoprotein IIb/IIIa inhibitor , bivalirudin plus a glycoprotein IIb/IIIa inhibitor , or bivalirudin monotherapy ) . RESULTS GIB within 30 days occurred in 178 patients ( 1.3 % ) . Older age , baseline anemia , longer duration of study drug administration before angiogram , smoking , ST-segment deviation > or=1 mm , and diabetes were identified as independent predictors of GIB . On multivariable analysis , GIB was strongly associated with 30-day all-cause mortality ( hazard ratio [ HR ] : 4.87 [ interquartile range ( IQR ) 2.61 to 9.08 ] , p<0.0001 ) , cardiac mortality ( HR : 5.35 [ IQR 2.71 to 10.59 ] , p<0.0001 ) , and composite ischemia ( HR : 1.94 [ IQR 1.14 to 3.30 ] , p=0.014 ) , as well as with 1-year all-cause mortality ( HR : 3.97 [ IQR 2.64 to 5.99 ] , p<0.0001 ) , cardiac mortality ( HR : 3.77 [ IQR 2.14 to 6.63 ] , p<0.0001 ) , myocardial infa rct ion ( HR : 1.74 [ IQR 1.01 to 3.02 ] , p=0.047 ) , and composite ischemia ( HR : 1.90 [ IQR 1.37 to 2.64 ] , p=0.0001 ) . Patients who experienced GIB had significantly higher rates of stent thrombosis compared with patients without GIB ( 5.8 % vs. 2.4 % , p=0.009 ) . CONCLUSIONS GIB is a serious condition in the scenario of ACS and is independently associated with mortality and ischemic complications |
1,951 | 30,625,165 | Most interventions incorporated lifestyle changes and behavioural strategies such as coping and problem solving skills with family involvement .
The meta-analyses did not show significant effects of the intervention in reducing weight related outcomes when compared with controls .
Meta-analyses of the selected studies did not show significant effects of the interventions on weight related outcomes among overweight and obese schoolchildren when compared with controls . | BACKGROUND Childhood overweight and obesity has emerged as a major public health threat worldwide with challenges in its management .
This review assessed the effectiveness of interventions for childhood overweight and obesity . | Background Screen-based activities , such as watching television ( TV ) , playing video games , and using computers , are common sedentary behaviors among young people and have been linked with increased energy intake and overweight . Previous home-based sedentary behaviour interventions have been limited by focusing primarily on the child , small sample sizes , and short follow-up periods . The SWITCH ( Screen-Time Weight-loss Intervention Targeting Children at Home ) study aim ed to determine the effect of a home-based , family-delivered intervention to reduce screen-based sedentary behaviour on body composition , sedentary behaviour , physical activity , and diet over 24 weeks in overweight and obese children . Methods A two-arm , parallel , r and omized controlled trial was conducted . Children and their primary caregiver living in Auckl and , New Zeal and were recruited via schools , community centres , and word of mouth . The intervention , delivered over 20 weeks , consisted of a face-to-face meeting with the parent/caregiver and the child to deliver intervention content , which focused on training and educating them to use a wide range of strategies design ed to reduce their child ’s screen time . Families were given Time Machine TV monitoring devices to assist with allocating screen time , activity packages to promote alternative activities , online support via a website , and monthly newsletters . Control participants were given the intervention material on completion of follow-up . The primary outcome was change in children ’s BMI z-score from baseline to 24 weeks . Results Children ( n = 251 ) aged 9 - 12 years and their primary caregiver were r and omized to receive the SWITCH intervention ( n = 127 ) or no intervention ( controls ; n = 124 ) . There was no significant difference in change of z BMI between the intervention and control groups , although a favorable trend was observed ( -0.016 ; 95 % CI : -0.084 , 0.051 ; p = 0.64 ) . There were also no significant differences on secondary outcomes , except for a trend towards increased children ’s moderate intensity physical activity in the intervention group ( 24.3 min/d ; 95 % CI : -0.94 , 49.51 ; p = 0.06 ) . Conclusions A home-based , family-delivered intervention to reduce all leisure-time screen use had no significant effect on screen-time or on BMI at 24 weeks in overweight and obese children aged 9 - 12 years . Trial registration Australian New Zeal and Clinical Trials RegistryWebsite : http://www.anzctr.org.auTrial registration number : BACKGROUND AND OBJECTIVE : Clinic-based programs for childhood obesity are not available to a large proportion of the population . The purpose of this study was to evaluate the efficacy of a guided self-help treatment of pediatric obesity ( GSH-PO ) compared with a delayed treatment control and to evaluate the impact of GSH-PO 6-months posttreatment . METHODS : Fifty overweight or obese 8- to 12-year-old children and their parents were r and omly assigned to immediate treatment or to delayed treatment . The GSH-PO includes 12 visits over 5 months and addresses key components included in more intensive clinic-based programs . Children and parents in the immediate treatment arm were assessed at time 1 ( T1 ) , participated in GSH-PO between T1 and T2 , and completed their 6-month posttreatment assessment at T3 . Children and parents in the delayed treatment arm were assessed at T1 , participated in GSH-PO between T2 and T3 , and completed their 6-month posttreatment assessment at T4 . The main outcome measures were BMI , BMI z score , and percentage overweight ( % OW ) . RESULTS : Children in the immediate treatment GSH-PO arm decreased their BMI significantly more than did the delayed treatment arm ( BMI group × time = −1.39 ; P < .001 ) . Similar results were found for BMI z score and % OW . At the 6-month posttreatment assessment , changes result ing from GSH-PO were maintained for BMI z score and % OW but not BMI ( BMI time effect = −0.06 , not significant ; BMI z score time effect = −0.10 , P < .001 ; % OW time effect = −4.86 , P < .05 ) . CONCLUSIONS : The GSH-PO showed initial efficacy in decreasing BMI for children in this study . Additional efficacy and translational studies are needed to additionally evaluate GSH-PO OBJECTIVE Maintaining weight loss results in childhood obesity treatment is difficult to achieve . Self-management techniques such as self-monitoring are associated with increased weight loss and maintenance . This study analyzes whether self-monitoring of lifestyle behaviours through a short message service maintenance treatment ( SMSMT ) via mobile phones with personalized feedback positively effects weight , lifestyle behaviours and psychological well-being in obese children . METHODS After 3 months of behavioural lifestyle treatment , 141 overweight and obese children ( 7 - 12 years ) were r and omly assigned to an intervention group receiving SMSMT for 9 months ( n = 73 ) or to the control group ( n = 68 ) . The intervention group sent weekly self-monitoring data on exercise and eating behaviour and their mood via mobile phones . In return , they received tailored feedback messages . Primary treatment outcomes were weight , eating behaviour and psychological well-being , i.e. competence , self-esteem and quality of life . Secondary outcome was adherence to the SMSMT . Data were analyzed with mixed modelling . RESULTS SMSMT did not improve treatment outcomes . Controls gained temporarily in physical health scores ( P = 0.01 ) . SMSMT completers sent on average every 2 weeks an SMS . Children who had greater weight loss during the first 3 months of lifestyle treatment sent more SMSs ( P = 0.04 ) . CONCLUSIONS We did not find a positive effect of SMSMT on weight , eating behaviour or psychological well-being in obese children . SMSMT seems to be a feasible method of treatment delivery . Future research should study variations of SMSMT to investigate how SMSMT can be more effective OBJECTIVES . Television viewing and physical inactivity increase the risk of obesity in youth . Thus , identifying new interventions that increase physical activity and reduce television viewing would be helpful in the prevention and treatment of pediatric obesity . This study evaluated the effects of open-loop feedback plus reinforcement versus open-loop feedback alone on physical activity , targeted sedentary behavior , body composition , and energy intake in youth . METHODS . Thirty overweight or obese 8- to 12-year-old children were r and omly assigned to an intervention ( n = 14 ) or control group ( n = 16 ) . Participants wore accelerometers every day for 8 weeks and attended biweekly meetings to download the activity monitors . For children in the open-loop feedback plus reinforcement ( intervention ) group , accumulating 400 counts of physical activity on pedometers earned 1 hour of television/VCR/DVD time , which was controlled by a Token TV electronic device . Open-loop feedback control subjects wore activity monitors but had free access to targeted sedentary behavior . RESULTS . Compared with controls , the open-loop feedback plus reinforcement group demonstrated significantly greater increases in daily physical activity counts ( + 65 % vs + 16 % ) and minutes per day of moderate-to-vigorous physical activity ( + 9.4 vs + 0.3 ) and greater reductions in minutes per day spent in television viewing ( −116.1 vs + 14.3 ) . The intervention group also showed more favorable changes in body composition , dietary fat intake , and energy intake from snacks compared with controls . Reductions in sedentary behavior were directly related to reductions in BMI , fat intake , snack intake , and snack intake while watching television . CONCLUSIONS . Providing feedback of physical activity in combination with reinforcing physical activity with sedentary behavior is a simple method of modifying the home environment that may play an important role in treating and preventing child obesity Objective : The aim of the study was to compare the efficacy of group treatment stressing a health-promoting lifestyle with routine counseling in the treatment of childhood obesity . Design and subjects : Seventy obese children ( weight for height 115–182 % ) aged 7–9 years were r and omized either to routine counseling ( two appointments for children ) or to family-based group treatment ( 15 separate sessions for parents and children ) . These sessions included nutrition education , physical activity education and behavioral therapy . Outcome measures : Children 's weights and heights were measured at baseline , after the 6-month intervention and after the 6-month follow-up . The change of weight for height based on Finnish growth charts was used as the primary , and changes in body mass index ( BMI ) and BMI st and ard deviation scores ( BMI -SDS ) as secondary outcome measures . Results : Children attending the group treatment lost more weight for height ( 6.8 % ) than children receiving routine counseling ( 1.8 % ) ( P=0.001 ) . The difference was significant when the data were analyzed in four groups by the cut-off limits of 0 , −5 and −10 % for the change in weight for height . The respective decreases in BMI were 0.8 vs 0.0 ( P=0.003 ) and in BMI -SDS 0.3 vs 0.2 ( P=0.022 ) . The results remained similar in adjusted analyses . Both group and routine programs were feasible with a high , 87–99 % , participation rate in sessions and appointments and very low , 3 % or less , attrition rate from the programs . Six months after the intervention , beneficial effects were partly lost , but for changes in weight for height and BMI , the differences between the two treatment programs still were significant , and for BMI -SDS , there was a trend . Conclusions : Family-based group treatment that stresses a health-promoting lifestyle and is given separately for parents and children , offers an effective mode of therapy to treat obese school-aged children The purpose of this study was to assess the effects of a six-months ’ nutrition program , delivered and taught by classroom teachers with in-service nutrition training , on the prevention of overweight and obesity among children in grade s 1 to 4 . In this r and omized trial , four hundred and sixty four children from seven elementary schools were allocated to a nutrition educational program delivered by their own teachers . Intervened teachers had 12 sessions of three hours each with the research ers throughout six months , according to the topics nutrition and healthy eating , the importance of drinking water and healthy cooking activities . After each session , teachers were encouraged to develop activities in class focused on the learned topics . Sociodemographic , anthropometric , dietary , and physical activity assessment s were performed at baseline and at the end of the intervention . In the intervention group the increase in Body Mass Index ( BMI ) z-score was significantly lower than in the control group ( p = 0.009 ) ; fewer proportion of children became overweight in the intervened group compared with the control ( 5.6 % vs. 18.4 % ; p = 0.037 ) . Our study provides further support to decrease the overweight epidemic , involving classroom teachers in a training program and making them dedicated interventionists A strategy is needed on how to treat the growing number of obese children with the limited re sources available . We compared the long-term ( 24 months ) effectiveness of therapist-led groups ( TLG ) v. self-help groups ( SHG ) for parents on changes in children 's adiposity and dietary intake . The study included ninety-nine children ( forty-eight girls ) who were referred to obesity treatment ( 7–12 years , BMI z-scores ≥ 2 , attendance of at least one parent ) . Parents ( ninety-one mothers , fifty-four fathers ) were r and omised to TLG aim ed at increasing parents ' competence to accomplish lifestyle changes ( n 47 ) , or SHG ( n 52 ) , both with fifteen sessions . All children participated in children 's groups , and all families attended individual counselling by a clinical dietitian and physiotherapist . Percentage of body fat ( BF ) was measured by dual-energy X-ray absorptiometry , BMI z-score was calculated by international reference values and dietary intake was calculated from 4 d estimated food records at baseline and after 6 and 24 months . No significant between-group differences were detected in the children 's changes in adiposity or dietary intake after 6 and 24 months . BF , BMI z-scores and energy intake were significantly decreased after 6 months ( P < 0·05 ) in both intervention groups , and this persisted throughout 24 months without compromising the diet macronutrient composition . In conclusion , the TLG and SHG intervention groups appear to be equally effective in improving long-term adiposity and dietary intake in obese children . Further research should be performed to clarify whether the SHG should be preferred to parental group treatment for similar children with obesity OBJECTIVE : We evaluated the efficacy of family-based , behavioral weight control in the management of severe pediatric obesity . METHODS : Participants were 192 children 8.0 to 12.0 years of age ( mean ± SD : 10.2 ± 1.2 years ) . The average BMI percentile for age and gender was 99.18 ( SD : 0.72 ) . Families were assigned r and omly to the intervention or usual care . Assessment s were conducted at baseline , 6 months , 12 months , and 18 months . The primary outcome was percent overweight ( percent over the median BMI for age and gender ) . Changes in blood pressure , body composition , waist circumference , and health-related quality of life also were evaluated . Finally , we examined factors associated with changes in child percent overweight , particularly session attendance . RESULTS : Intervention was associated with significant decreases in child percent overweight , relative to usual care , at 6 months . Intent-to-treat analyses documented that intervention was associated with a 7.58 % decrease in child percent overweight at 6 months , compared with a 0.66 % decrease with usual care , but differences were not significant at 12 or 18 months . Small significant improvements in medical outcomes were observed at 6 and 12 months . Children who attended ≥75 % of intervention sessions maintained decreases in percent overweight through 18 months . Lower baseline percent overweight , better attendance , higher income , and greater parent BMI reduction were associated with significantly greater reductions in child percent overweight at 6 months among intervention participants . CONCLUSIONS : Intervention was associated with significant short-term reductions in obesity and improvements in medical parameters and conferred longer-term weight change benefits for children who attended ≥75 % of sessions BACKGROUND Parental obesity reduces the likelihood of a multidisciplinary childhood obesity program to succeed , suggesting that special family-based interventions should be constructed for obese children from obese families . AIM To examine the effects of an intense combined 3-month familial dietary-behavioral-physical activity intervention for a subgroup of obese children ( BMI > 95th percentile ) from obese families ( parental BMI > 27 kg/m2 ) compared to a control group of obese children and obese parents who did not participate in the combined intervention . CHILDREN Twenty-two obese children were r and omly assigned to the intervention ( n = 11 ) or control ( n = 11 ) group . Anthropometric measurements , body composition , dietary and activity habits and fitness levels were measured before and at the end of a 3-month intervention . RESULTS The intervention led to a significant difference in change in body weight ( -0.2 + /- 0.3 vs 1.7 + /- 0.6 kg ; p < 0.05 ) , BMI percentiles ( -1.4 + /- 0.5 vs -0.1 + /- 0.2 % ; p < 0.05 ) , and to a decrease in screen ( television and computer ) time ( -2.2 + /- 0.6 vs 0.1 + /- 0.3 h/day ; p < 0.05 ) in the intervention group compared to the controls . In addition , the intervention led to a significant improvement in fitness level determined by endurance time ( 181 + /- 30 vs 26 + /- 63 seconds in the intervention vs control group , respectively ; p < 0.05 ) . CONCLUSION Obese children from obese families pose a therapeutic challenge to health care providers . Intense family-oriented multidisciplinary weight management intervention should be design ed for treatment in this unique population BACKGROUND Interactive technologies have the potential to increase the reach and frequency of practical clinical interventions that assist the parents of overweight and at-risk children to promote healthy lifestyle behaviors for their families . DESIGN A practical RCT evaluated the relative effectiveness of three interventions to support parents of overweight or at-risk children to change the home environment to foster more healthful child eating and activity behaviors , thereby reducing child BMI and BMI z-scores . A secondary purpose was to determine the patterns of use and potential dose effect for the highest-intensity intervention . SETTING / PARTICIPANTS Parent- and -child ( aged 8 - 12 years ) dyads ( N=220 ) who received care from Kaiser Permanente Colorado were assigned r and omly to one of the three Family Connections ( FC ) interventions : FC-workbook , FC-group , or FC-interactive voice response ( IVR ) counseling . MAIN OUTCOME MEASURES Child BMI z-scores , as well as symptoms of eating disorders and body image , were assessed at baseline , 6 months , and 12 months . RESULTS The BMI z-scores of children assigned to the FC-IVR intervention were the only ones that decreased from baseline to 6 months ( 0.07 SD ) and from baseline to 12 months ( 0.08 SD , p<0.05 ) . Children whose parents completed at least six of the ten FC-IVR counseling calls had decreased BMI z-scores to a greater extent than children in the FC-workbook or FC-group interventions at both 6 months ( p<0.05 ) and 12 months ( p<0.01 ) . No intervention increased child symptoms of eating disorders or body dissatisfaction at any time point . CONCLUSIONS This trial demonstrated that automated telephone counseling can support the parents of overweight children to reduce the extent to which their children are overweight . TRIAL REGISTRATION NCT00433901 The aim of this study was to evaluate the effectiveness of the Mind , Exercise , Nutrition , Do it ( MEND ) Program , a multicomponent community-based childhood obesity intervention ( www.mend central .org ) . One hundred and sixteen obese children ( BMI > or= 98 th percentile , UK 1990 reference data ) were r and omly assigned to intervention or waiting list control ( 6-month delayed intervention ) . Parents and children attended eighteen 2-h group educational and physical activity sessions held twice weekly in sports centers and schools , followed by a 12-week free family swimming pass . Waist circumference , BMI , body composition , physical activity level , sedentary activities , cardiovascular fitness , and self-esteem were assessed at baseline and at 6 months . Children were followed up 12 months from baseline ( 0 and 6 months postintervention for the control and intervention group , respectively ) . Participants in the intervention group had a reduced waist circumference z-score ( -0.37 ; P < 0.0001 ) and BMI z-score ( -0.24 ; P < 0.0001 ) at 6 months when compared to the controls . Significant between-group differences were also observed in cardiovascular fitness , physical activity , sedentary behaviors , and self-esteem . Mean attendance for the MEND Program was 86 % . At 12 months , children in the intervention group had reduced their waist and BMI z-scores by 0.47 ( P < 0.0001 ) and 0.23 ( P < 0.0001 ) , respectively , and benefits in cardiovascular fitness , physical activity levels , and self-esteem were sustained . High-attendance rates suggest that families found this intensive community-based intervention acceptable . Further larger controlled trials are currently underway to confirm the promising findings of this initial trial BACKGROUND Few studies have examined correlates of re source empowerment among parents of children with overweight or obesity . METHODS We studied baseline data of 721 parent-child pairs participating in the Connect for Health r and omized trial being conducted at six pediatric practice s in Massachusetts . Parents completed the child weight management subscale ( n = 5 items ; 4-point response scale ) of the Parent Re source Empowerment Scale ; items were averaged to create a summary empowerment score . We used linear regression to examine the independent effects of child ( age , sex , and race/ethnicity ) , parent/household characteristics ( age , education , annual household income , BMI category , perceived stress , and their ratings of their healthcare quality ) , and neighborhood median household income , on parental re source empowerment . RESULTS Mean ( SD ) child age was 7.7 years ( 2.9 ) and mean ( SD ) BMI z-score was 1.9 ( 0.5 ) ; 34 % of children were white , 32 % black , 22 % Hispanic , 5 % Asian , and 6 % multiracial/other . The mean parental empowerment score was 2.95 ( SD = 0.56 ; range = 1 - 4 ) . In adjusted models , parents of older children [ β -0.03 ( 95 % CI : -0.04 , -0.01 ) ] , Hispanic children [ -0.14 ( -0.26 , -0.03 ) ] , those with annual household income less than $ 20,000 [ -0.16 ( -0.29 , -0.02 ) ] , those with BMI ≥30.0 kg/m2 [ -0.17 ( -0.28 , -0.07 ) ] , and those who reported receiving lower quality of obesity-related care [ -0.05 ( -0.07 , -0.03 ) ] felt less empowered about re sources to support their child 's healthy body weight . CONCLUSIONS Parental re source empowerment is influenced by parent and child characteristics as well as the quality of their obesity-related care . These findings could help inform equitable , family-centered approaches to improve parental re source empowerment CONTEXT Few r and omized controlled trials ( RCTs ) of interventions for the treatment of childhood obesity have taken place outside the Western world . AIM To test whether a good practice intervention for the treatment of childhood obesity would have a greater impact on weight status and other outcomes than a control condition in Kuala Lumpur , Malaysia . METHODS Assessor-blinded RCT of a treatment intervention in 107 obese 7- to 11-year olds . The intervention was relatively low intensity ( 8 hours contact over 26 weeks , group based ) , aim ing to change child sedentary behavior , physical activity , and diet using behavior change counselling . Outcomes were measured at baseline and six months after the start of the intervention . Primary outcome was BMI z-score , other outcomes were weight change , health-related quality of life ( Peds QL ) , objective ly measured physical activity and sedentary behavior ( Actigraph accelerometry over 5 days ) . RESULTS The intervention had no significant effect on BMI z score relative to control . Weight gain was reduced significantly in the intervention group compared to the control group ( + 1.5 kg vs. + 3.5 kg , respectively , t-test p < 0.01 ) . Changes in health-related quality of life and objective ly measured physical activity and sedentary behavior favored the intervention group . CONCLUSIONS Treatment was associated with reduced rate of weight gain , and improvements in physical activity and quality of life . More substantial benefits may require longer term and more intensive interventions which aim for more substantive lifestyle changes BACKGROUND . Parenting-skills training may be an effective age-appropriate child behavior-modification strategy to assist parents in addressing childhood overweight . OBJECTIVE . Our goal was to evaluate the relative effectiveness of parenting-skills training as a key strategy for the treatment of overweight children . DESIGN . The design consisted of an assessor-blinded , r and omized , controlled trial involving 111 ( 64 % female ) overweight , prepubertal children 6 to 9 years of age r and omly assigned to parenting-skills training plus intensive lifestyle education , parenting-skills training alone , or a 12-month wait-listed control . Height , BMI , and waist-circumference z score and metabolic profile were assessed at baseline , 6 months , and 12 months ( intention to treat ) . RESULTS . After 12 months , the BMI z score was reduced by ∼10 % with parenting-skills training plus intensive lifestyle education versus ∼5 % with parenting-skills training alone or wait-listing for intervention . Waist-circumference z score fell over 12 months in both intervention groups but not in the control group . There was a significant gender effect , with greater reduction in BMI and waist-circumference z scores in boys compared with girls . CONCLUSION . Parenting-skills training combined with promoting a healthy family lifestyle may be an effective approach to weight management in prepubertal children , particularly boys . Future studies should be powered to allow gender sub analysis Abstract Introduction : Obesity has become the most common modern pediatric chronic disease . Early prevention and treatment of childhood and adolescent obesity is m and ated . Severe obesity [ body mass index ( BMI ) percentile > 98 % ] reduces the likelihood of the multidisciplinary childhood obesity program to succeed , suggesting , most probably , that a more intense program is needed to treat severely obese children . Objective and methods : To prospect ively examine the effects of an intense , 3-month , combined dietary-behavioral-physical activity intervention on anthropometric measures , leisure time activity patterns , and fitness in prepubertal severely obese ( BMI percentile > 98 % ) children ( n=22 ) compared to age , gender , and obesity matched controls ( n=18 ) . Results : At 3 months , there were significant differences ( p<0.05 ) in changes in body weight ( –0.5±2.4 vs. 1.7±1.9 kg ) , BMI ( –0.9±1.2 vs. 0.4±1.0 kg/m2 ) , BMI percentile ( 0.39±0.39 % vs. –0.04±0.32 % ) , sum skinfolds ( –3.1±8.1 vs. 1.1±4.7 mm ) , total habitual physical activity ( 25.4±10.8 vs. 0.3±10.1 Mets ) , and fitness ( 142±72 vs. –8±88 s ) in the intervention vs. control participants . Conclusions : Our data demonstrate the beneficial , short-term effects of an intense combined dietary-behavioral-physical activity intervention on anthropometric measures , activity patterns , and fitness in severely obese children . However , despite the encouraging results , the modest effect on BMI percentiles emphasizes the difficulty of treating severely obese children using the conventional nutritional-behavioral-physical activity approach |
1,952 | 28,375,448 | Alginates are more effective than placebo or antacids for treating GERD symptoms | In patients with gastroesophageal reflux disease ( GERD ) and erosive esophagitis , treatment with proton pump inhibitors ( PPIs ) is highly effective .
However , in some patients , especially those with nonerosive reflux disease or atypical GERD symptoms , acid-suppressive therapy with PPIs is not as successful .
Alginates are medications that work through an alternative mechanism by displacing the postpr and ial gastric acid pocket .
This study performed a systematic review and meta- analysis to examine the benefit of alginate-containing compounds in the treatment of patients with symptoms of GERD . | AIM To assess the efficacy and safety of a compound containing alginic acid plus antacid ( Topaal ) compared to equal-strength antacid ( Nacid ) in patients with endoscopy-negative reflux disease ( ENRD ) . METHODS A total of 121 patients with ENRD were r and omized to receive Topaal ( 65 patients ) or Nacid ( 56 patients ) for 6 weeks , with a consultation every 3 weeks . The primary end-point assessment was the change in the severity of heartburn as evaluated using a visual analog scale ( VAS ) at 6 weeks . The secondary end-point assessment s were the VAS at 3 weeks , the change of frequency of the reflux symptom , the change of quality of life and the adverse effects . RESULTS Demographics of r and omized subjects in each treatment group were comparable except that the Topaal group included more males . The baseline characteristics between the groups were similar . After 6 weeks of treatment , the reduction of VAS of heartburn was more prominent in the Topaal group ( -6.29 cm vs -4.11 cm ) . At the 3rd week , Topaal group showed greater reduction of VAS for heartburn ( P=0.0016 ) , regurgitation ( P=0.0006 ) , vomiting ( P=0.0373 ) , and belching ( P<0.0001 ) . The patients of the Topaal group had lower frequency of heartburn ( P=0.0015 ) and pain ( P=0.0163 ) at the end of the 6-week treatment period . From the doctor 's point of view , the Topaal group also showed significant reduction in the severity of heartburn ( P=0.0020 ) , regurgitation ( P=0.0081 ) , vomiting ( P=0.0182 ) , and belching ( P=0.0018 ) at the end of the treatment . The improvement of the quality of life was more remarkable in the Topaal group at the end of the 6-week treatment period ( P<0.0001 ) . For the adverse effect , there was no difference in both the groups . CONCLUSION Topaal is more effective than Nacid for the treatment of symptoms presented by patients with ENRD Abstract Three r and omised groups of 20 patients with gastro-œsophageal reflux were studied using 15-hour recordings of lower œsophageal pH , before and after two weeks ' treatment , either with an alginate/antacid compound ( ' Gaviscon ' ) , antacids alone , or a placebo tablet . Significant reduction in the number of reflux episodes and percentage time during which the lower œsophageal pH was acid was noted in the gaviscon group after treatment , whereas no significant changes occurred in the other two groups . Symptoms reported by patients during the second test were fewer after gaviscon treatment than after antacid alone The aims of the present study were to compare effects of sodium alginate and the antacid magaldrate anhydrous in adults with gastroesophageal reflux ( GOR ) symptoms . Patients with heartburn and /or acid regurgitation for at least 3 days in the week before the study started ( n=203 ) were r and omized to receive a single dose of sodium alginate or magaldrate anhydrous at the onset of symptoms during a 3-day run-in period . Patients with symptoms during the run-in ( n=191 ) were rer and omized to receive a 14-day treatment with either drug given as four daily doses . A speed of action ≤30 min was significantly more frequent among patients in the alginate group ( 49.4 % vs. 40.4 % ; P=0.0074 ) . A trend toward a more prolonged duration of action ( median : 16.5 vs. 12.7 hr ) and a greater sum of the symptom intensity difference ( median : 40.0 vs. 31.0 ) was observed in the sodium alginate group . Total disappearance of symptoms was reported in 81.6 % and 73.9 % of patients in the sodium alginate group and magaldrate group , respectively . We conclude that sodium alginate was faster than magaldrate in relieving GRO symptoms and showed a tendency toward a more prolonged duration of action and a higher level of efficacy Background Medical management of GERD mainly uses proton pump inhibitors . Alginates also have proven efficacy . The aim of this trial was to compare short-term efficacy of an alginate ( Gaviscon ® , 4 × 10 mL/day ) and omeprazole ( 20 mg/day ) on GERD symptoms in general practice . Methods A 14-day multicentre r and omised double-blind double-dummy non-inferiority trial compared Gaviscon ® ( 4 × 10 mL/day ) and omeprazole ( 20 mg/day ) in patients with 2 - 6 day heartburn episodes weekly without alarm signals . The primary outcome was the mean time to onset of the first 24-h heartburn-free period after initial dosing . Secondary outcomes were the proportion of patients without heartburn by D7 , pain relief by D7 , and reduction in pain intensity by D7 and D14 . Results 278 patients were recruited ; 120 were included in the Gaviscon ® group and 121 in the omeprazole group for the per protocol non-inferiority analysis . The mean time to onset of the first 24-h heartburn-free period after initial dosing was 2.0 ( ± 2.2 ) days for Gaviscon ® and 2.0 ( ± 2.3 ) days for omeprazole ( p = 0.93 ) ; mean intergroup difference was 0.01 ± 1.55 days ( 95 % CI = -0.41 to 0.43 ) : i.e. , less than the lower limit of the 95 % CI of -0.5 days predetermined to demonstrate non-inferiority . The mean number of heartburn-free days by D7 was significantly greater in the omeprazole group : 3.7 ± 2.3 days vs. 3.1 ± 2.1 ( p = 0.02 ) . On D7 , overall quality of pain relief was slightly in favour of omeprazole ( p = 0.049 ) . There was no significant difference in the reduction in pain intensity between groups by D7 ( p = 0.11 ) or D14 ( p = 0.08 ) . Tolerance and safety were good and comparable in both groups . Conclusion Gaviscon ® was non-inferior to omeprazole in achieving a 24-h heartburn-free period in moderate episodic heartburn , and is a relevant effective alternative treatment in moderate GERD in primary care . Trial registration IS RCT N62203233 Many patients who present with dyspepsia are prescribed antacid/alginates as their first line and often mainstay therapy . This multicentre study was design ed to assess whether early introduction of acid inhibition is an effective strategy in dyspepsia management To assess the efficacy and tolerance of sodium alginate compared to cisapride in patients suffering from reflux symptoms , without severe oesophagitis Nonerosive reflux disease ( NERD ) is the most common form of gastroesophageal reflux disease . Patients with NERD have a lower response rate to proton pump inhibitors ( PPIs ) than patients with erosive esophagitis when gauged from relief of heartburn . Sodium alginate decreases the acidity of refluxate and protects the esophageal mucosa . However , whether the addition of sodium alginate to PPI therapy can improve NERD symptoms remains unknown . Accordingly , the aim of this study was to evaluate the efficacy of adding sodium alginate to basal PPI therapy for NERD . Patients who had experienced heartburn on at least 2 days per week during the 1-month period before entering the study and had no endoscopic mucosal breaks ( grade M or N according to Hoshihara 's modification of the Los Angeles classification ) were r and omized to one of two treatments for 4 weeks : omeprazole ( 20 mg once daily ) plus sodium alginate ( 30 mL four times a day ) ( group A ) or omeprazole ( 20 mg once daily ) alone ( group B ) . Eighty-seven patients were enrolled , and 76 patients were r and omly assigned to group A ( n = 36 ) or group B ( n = 40 ) . Complete resolution of heartburn for at least 7 consecutive days by the end of treatment was significantly more common in group A ( 56.7 % ) than in group B ( 25.7 % ) . One patient from group A had mild drug-related diarrhea that was not clinical ly serious . In conclusion , omeprazole combined with sodium alginate was better than omeprazole alone in Japanese patients with NERD The aim of this study was to compare the efficacy of the sodium alginate preparation , Gaviscon Advance , with placebo in the relief of symptoms of reflux oesophagitis . This was a r and omised , double-blind , parallel-group , multicentre study conducted at 13 GP centres in the UK . Patients aged between 18 and 70 years , who had experienced symptoms of reflux oesophagitis within the previous 24 h , and on two other occasions within the previous week , were recruited into the study . Patients were evaluated at baseline , and then reassessed after two and four weeks of treatment with sodium alginate or placebo , for symptoms of reflux oesophagitis in the previous 24 h. Patients were required to fill out a diary card twice daily , from which frequency and severity of symptoms were assessed , and the percentage of symptom-free days and nights calculated . Of the 100 patients recruited into the study , 98 received medication ( safety population ; placebo , n = 50 ; sodium alginate , n = 48 ) and 94 were eligible for inclusion in the intention-to-treat ( ITT ) population ( placebo , n = 48 ; sodium alginate , n = 46 ) . For this population , sodium alginate was assessed as significantly superior by both investigators and patients at week two ( p < 0.001 and p = 0.004 , respectively ) and at week four ( p = 0.001 and p < 0.001 , respectively ) . Significantly more patients in the safety population on placebo withdrew from the study ( 40 % ) compared with sodium alginate ( 21 % ; p = 0.04 ) , due primarily to lack of effect and adverse events . The sodium alginate preparation demonstrated a superior efficacy compared with placebo , which was achieved in a more acceptable volume of medication than a previous st and ard preparation , Liquid Gaviscon . The reduced dosage volume of the ' new ' preparation ( Gaviscon Advance ) may be expected to improve patient compliance , and thereby increase treatment efficacy BACKGROUND & AIMS Alginate rafts ( polysaccharide polymers that precipitate into a low-density viscous gel when they contact gastric acid ) have been reported to form at the acid pocket , an unbuffered pool of acid that floats on top of ingested food and causes postpr and ial acid reflux . We studied the location of an alginate formulation in relation to the acid pocket and the corresponding effects on reflux parameters and acid pocket positioning in patients with gastroesophageal reflux disease ( GERD ) . METHODS We r and omly assigned patients with symptomatic GERD and large hiatal hernias to groups who were given either (111)In-labeled alginate-antacid ( n = 8 , Gaviscon Double Action Liquid ) or antacid ( n = 8 , Antagel ) after a st and ard meal . The relative positions of labeled alginate and acid pocket were analyzed for 2 hours by using scintigraphy ; reflux episodes were detected by using high-resolution manometry and pH-impedance monitoring . RESULTS The alginate-antacid label localized to the acid pocket . The number of acid reflux episodes was significantly reduced in patients receiving alginate-antacid ( 3.5 ; range , 0 - 6.5 ; P = .03 ) compared with those receiving antacid ( 15 ; range , 5 - 20 ) , whereas time to acid reflux was significantly increased in patients receiving alginate-antacid ( 63 minutes ; range , 23 - 92 ) vs those receiving antacid ( 14 minutes ; range , 9 - 23 ; P = .01 ) . The acid pocket was located below the diaphragm in 71 % of patients given alginate-antacid vs 21 % of those given antacid ( P = .08 ) . There was an inverse correlation between a subdiaphragm position of the acid pocket and acid reflux ( r = -0.76 , P < .001 ) . CONCLUSIONS In a study of 16 patients with GERD , we observed that the alginate-antacid raft localizes to the postpr and ial acid pocket and displaces it below the diaphragm to reduce postpr and ial acid reflux . These findings indicate the importance of the acid pocket in GERD pathogenesis and establish alginate-antacid as an appropriate therapy for postpr and ial acid reflux Forty-four patients with symptoms of gastro-oesophageal reflux were r and omly assigned in a crossover trial to treatment for 15-day periods with Liquid Gaviscon ( a reflux suppressant ) or an antacid gel containing magnesium and aluminium hydroxide . Good relief of symptoms was reported by 84 % of patients during therapy with Liquid Gaviscon compared to only 23 % during antacid therapy . Relief of symptoms was obtained within 15 minutes by 68 % of patients during therapy with Liquid Gaviscon compared to only 9 % during antacid treatment . The beneficial effect lasted for more than 4 hours in 75 % of patients during treatment with Liquid Gaviscon compared to only 23 % of patients obtaining long-term relief during antacid therapy In a double-blind trial in 26 patients with symptomatic gastro-oesophageal reflux , the alginate/effervescent/antacid compound ' Gaviscon ' was compared with antacid containing placebo similarly formulated . Retrosternal pain after meals and at night was significantly reduced whilst patients were taking ' Gaviscon ' and the beneficial effects lasted for many weeks after discontinuation of the active preparation Summary Twenty-eight patients with hiatus hernia and severe symptoms of oesophageal reflux completed a double-blind cross-over trial in which compounds design ed to float on gastric contents were administered . Each patient received an alginate/antacid compound ( ‘ Gaviscon ’ ) , alginate without antacid and ‘ placebo ’ inr and omized order for periods of two weeks . Significant relief of both regurgitation and heartburn was achieved with the alginate I antacid compound despite its low antacid content . The mode of action of alginate is discussed and , as alginate without antacid is only marginally better than placebo , it seems probable that it facilitates placement of antacid in the upper stomach and lower oesophagus . † ‘ Gaviscon ’ is a trade mark of Reckitt and Colman Limited |
1,953 | 25,914,908 | Overall , as demonstrated also by the Bayesian nomograms , which enable readers to calculate post-test probabilities for any target condition prevalence , the EUS accuracy can be considered clinical ly useful to guide physicians in the locoregional staging of people with gastric cancer .
Moreover , we must emphasize that the analysis of positive and negative likelihood values revealed that EUS diagnostic performance can not be considered optimal either for disease confirmation or for exclusion , especially for the ability of EUS to distinguish T1a ( mucosal ) versus T1b ( submucosal ) cancers and positive versus negative lymph node status .
By analyzing the data from the largest series ever considered , we found that the diagnostic accuracy of EUS might be considered clinical ly useful to guide physicians in the locoregional staging of people with gastric carcinoma .
Moreover , physicians should be warned that EUS performance is lower in diagnosing superficial tumors ( T1a versus T1b ) and lymph node status ( positive versus negative ) . | BACKGROUND Endoscopic ultrasound ( EUS ) is proposed as an accurate diagnostic device for the locoregional staging of gastric cancer , which is crucial to developing a correct therapeutic strategy and ultimately to providing patients with the best chance of cure .
However , despite a number of studies addressing this issue , there is no consensus on the role of EUS in routine clinical practice .
OBJECTIVES To provide both a comprehensive overview and a quantitative analysis of the published data regarding the ability of EUS to preoperatively define the locoregional disease spread ( i.e. , primary tumor depth ( T-stage ) and regional lymph node status ( N-stage ) ) in people with primary gastric carcinoma . | Summary AIM : The aim of our study was to evaluate the accuracy of preoperative TNM staging with endoscopic ultrasound ( EUS ) in gastric cancer patients in comparison with the pathohistological stage of the resected specimen , and to determine the possible implication s of EUS for individualized treatment of gastric cancer patients at our institution . PATIENTS AND METHODS : The study included 82 patients operated for resectable gastric cancer between January 1st 2001 and July 1st 2003 at the Maribor Teaching Hospital Department of Abdominal and General Surgery . The EUS stage was assessed preoperatively at the Endoscopical Unit , and the pathohistological stage in the resected specimen was determined postoperatively at the Department of Pathologic Morphology according to recommended st and ards . RESULTS : Comparison of EUS and pathohistological assessment s revealed accuracy of EUS staging for locoregional tumor infiltration ( category T ) in 68 % of patients . The accuracy of EUS staging was 68 % for T1 , 69 % for T2 , 69 % for T3 and 60 % for T4 . Lymph nodes ( category N ) were correctly staged with EUS in 57 % of cases . The EUS stage was correct for lymph nodes with no metastases ( N− ) in 40 % of cases , and for lymph nodes with metastases ( N+ ) in 90 % . There was no significant difference in accuracy of EUS staging with regard to tumor site ( P = 0.768 ) or tumor size ( P = 0.766 ) . CONCLUSIONS : According to our results the accuracy of EUS staging matched pathohistological staging with regard to tumor infiltration and lymph node stage in 68 % and 57 % of cases respectively . Underestimation of the final T2 and T3 stages as T1 stage by EUS presents a problem regarding the consistency of EUS examination at our institution , particularly with respect to individual treatment for early gastric cancer . The present uncertainty in EUS stage reliability makes it necessary to have a strategy of radical resection with D2 lymphadenectomy in patients within EUS stages T1–T3 , with additional CT examinations in more advanced EUS stages in order to visualize the circumstances of tumor growth . Nevertheless , EUS provides an opportunity for the surgeon to gain more insight into the loco-regional circumstances of the gastric tumor process . For development of individual modes of treatment based on EUS staging , a more reliable assessment of EUS stage is m and atory BACKGROUND / AIMS Endoscopic ultrasonography is expected to be useful for invasion depth staging of early gastric cancer . A prospect i ve blind study of the staging characteristics of endoscopy and endoscopic ultrasonography for early gastric cancer was performed . METHODS Findings of endoscopy and endoscopic ultrasonography using a 20 MHz thin ultrasound probe were independently review ed and the results of 52 early gastric cancer lesions analysed . RESULTS The overall accuracy rates in invasion depth staging of early gastric cancer were 63 % for endoscopy and 71 % for endoscopic ultrasonography . No statistically significant differences were observed in overall accuracy . Endoscopic ultrasonography tended to overstage , and lesions that were classified as mucosal cancer by endoscopic ultrasonography were very likely ( 95 % ) to be limited to the mucosa on histological examination . All 16 lesions staged as mucosal cancer independently but coincidentally by both methods were histologically limited to the mucosa . CONCLUSIONS Endoscopic ultrasonography is expected to compensate for the understaging of lesions with submucosal invasion that are endoscopically staged as mucosal cancer BACKGROUND AND STUDY AIMS This study aim ed to compare the diagnostic accuracy of endoscopic ultrasonography ( EUS ) with that of conventional endoscopy for staging depth of invasion ( T staging ) in early gastric cancer . PATIENTS AND METHODS A total of 955 patients with suspected early gastric cancer were prospect ively registered . EUS staging was carried out prospect ively by a single endoscopist using either miniprobe or radial EUS depending on the endoscopic appearance of the tumor . Conventional endoscopy staging was performed retrospectively by consensus between two endoscopists who were blinded to the EUS staging . Conventional endoscopy staging was conducted on the basis of endoscopic features such as surface nodularity and fold convergence . Patients underwent either surgical ( n = 586 ) or endoscopic resection ( n = 369 ) with curative intent . The staging accuracy of each test was compared with the pathological staging of the resected specimen . RESULTS The presence of a T1 m tumor was histologically confirmed in 644 cases ( 67.4 % ) and that of a T1sm tumor in 311 cases ( 32.6 % ) . The overall accuracy of EUS staging was 67.4 % ( 644 / 955 ) and that of conventional endoscopy staging was 73.7 % ( 704 / 955 ) ( P < 0.001 ) . The accuracy of miniprobe EUS was significantly higher than that of radial EUS ( 79.5 % vs. 59.6 % , P < 0.001 ) , but did not differ significantly from that of conventional endoscopy ( 79.0 % ) . CONCLUSIONS EUS does not substantially impact on pretreatment T staging of patients with early gastric cancer compared with conventional endoscopy . Therefore , EUS may not be necessary routinely , and conventional endoscopy may be sufficient for determining the optimal therapeutic strategy , especially in relation to endoscopic resection for early gastric cancer Background Endoscopic ultrasonography ( EUS ) is an integrated part of the pretherapeutic evaluation program for patients with upper gastrointestinal ( GI ) tract cancer . Whether the clinical impact of EUS differs between surgeons from different countries is unknown . The same applies to the potential clinical influence of EUS misinterpretations . The aim of this study was to evaluate the interobserver agreement on predefined treatment strategies between surgeons from four different countries , with and without EUS , and to evaluate the clinical consequences of EUS misinterpretations . Methods One hundred patients with upper GI tract cancer were r and omly selected from all upper GI tract cancer patients treated at Odense University Hospital between 1997 and 2000 . Based on patient records and EUS data base results , a case story was created with and without the EUS result for each patient . Four surgeons were asked to select the relevant treatment strategy in each case , at first without knowledge of the EUS and thereafter with the EUS result available . Interobserver agreement and impact of EUS misinterpretations were evaluated using the actual final treatment of each patient as reference . Results Three of four or all four surgeons agreed on the same treatment strategy for nearly 60 % of the patients with and without the EUS results . Treatment decisions were changed in 34 % based on the EUS results , and the majority of these changes were toward nonsurgical and palliative treatments ( 85 % ) . Interobserver agreement was relatively low , but overall EUS increased kappa values from 0.16 ( “ poor ” ) to 0.33 ( “ fair ” ) , thus indicating increased overall agreement after the EUS results were available . EUS conclusion regarding stage or resectability was wrong in 17 % of the cases , but only one serious event would have been the clinical result of EUS misinterpretations . Conclusion Despite being used in different ways by different surgeons , EUS did change patient management in one third of the cases . The impact of EUS misinterpretations seemed very low , and this study confirmed one of the strongest clinical possibilities of EUS , i.e. , the ability to detect nonresectable cases . EUS is an important imaging modality for oncosurgeons from different countries Background Early gastric cancer ( EGC ) with undifferentiated histology has not been generally accepted as an indication for endoscopic treatment . This study was design ed to evaluate the outcomes and clinicopathological factors associated with the complete resection of undifferentiated EGC using endoscopic submucosal dissection ( ESD ) . Methods A retrospective analysis of prospect ively collected data was performed on consecutive patients who underwent ESD . Among the 456 EGCs treated using ESD at the Seoul National University Hospital , Seoul , Korea , between April 2005 and June 2008 , 60 lesions ( 13.2 % ) were diagnosed as undifferentiated gastric cancer ( poorly differentiated adenocarcinoma or signet ring cell carcinoma ) . Results En bloc resection was performed in all lesions without significant complications . The size discrepancy between the pretreatment endoscopy and the resected specimen was significantly higher in undifferentiated EGCs than differentiated EGCs ( p = 0.002 ) . The complete resection rate was significantly lower for undifferentiated EGC ( 55 % ) cases than differentiated EGC cases ( 84.1 % ; p < 0.001 ) . Independent risk factors for incomplete resection of undifferentiated EGC included tumor size > 20 mm , submucosal invasion , and presence of ulceration . During a mean observation time of 16 months , no recurrence developed in any of the patients with undifferentiated EGCs thought to be completely resected by ESD . Conclusions ESD might be considered an alternative treatment modality in carefully selected cases of undifferentiated EGC Conventional imaging studies are often not sensitive enough to allow accurate preoperative staging of intra-abdominal tumour spread . Laparoscopy and laparoscopic ultrasound appear to be suitable to improve staging of gastrointestinal tumors . Within a 10-month period 40 patients with upper GI tract cancer underwent laparoscopy for intra-abdominal staging . Additionally laparoscopic ultrasound was performed on 20 of these patients using a flexible echo-endoscope equipped with a curved array transducer ( 5/7.5 MHz ) . By laparoscopy additional information compared to conventional staging was obtained in 16 patients ( 40 % ) . Laparoscopy revealed peritoneal carcinomatosis and liver metastases in seven and four patients , respectively . M1-lymph nodes were detected in four patients . Laparoscopic ultrasound was able to image otherwise inaccessible regions of the abdominal cavity and induced a change of staging in seven of 20 patients in whom laparoscopy was uneventful . Ultrasound also proved to be valuable for localization of M1-lymph nodes . In summary , combination of laparoscopy and laparoscopic ultrasound improved staging in 23 of 40 patients ( 57 % ) . Consequently surgery was ab and oned in 16 patients due to incurable or non-resectable disease , while down-staging occurred in seven patients , who subsequently underwent resection . Laparoscopy is capable of improving staging of intra-abdominal malignancy by detection and subsequent biopsy of small lesions . Laparoscopic ultrasound can replace the lack of tactile sensitivity in laparoscopy , thus enabling the detection of non-superficial lesions Background : Local and multimodal therapeutic strategies for tumours of the oesophagus and gastric cardia , require precise preoperative staging . Endosonography is considered the most accurate staging method , while computed tomography ( CT ) has limitations especially in the evaluation of local infiltration . Macroscopic endoscopic evaluation was reported to be accurate in selected series , but no study has yet compared all three staging modalities . Methods : One hundred and seventeen unselected patients with tumours of the oesophagus and gastric cardia were prospect ively staged first by the endoscopic macroscopic appearance and then by endosonography . All patients had preoperative CT scans , however , only the 36 patients receiving the scans at our institution were included in the study . The preoperative staging results were then compared to postoperative histology which was available as the gold st and ard in all included patients . Kappa statistics were used to exclude chance agreement of the clinical staging results with the pathohistological findings . Differences between the result ing ĸ values for the different staging modalities were analysed with a jack-knife test . Results : Endoscopic macroscopic staging and endosonography ( accuracy 67 and 69 % , weighted ĸ 0.78 and 0.84 ) were significantly more accurate than CT ( accuracy 33 % , weighted ĸ 0.44 ) for determination of the T category ( p = 0.006 and p = 0.001 ) . After exclusion of tumours of the cardia ( n = 33 ) , the accuracy of macroscopic and endosonographic staging ( accuracy 72 and 75 % , weighted ĸ 0.86 and 0.88 ) increased and remained more accurate than CT ( accuracy 50 % , weighted ĸ 0.62 ) . The main pitfall in our series in staging the T category was the overestimation of T2 tumours in the cardia as T3 or even as T4 tumours due to the inability to visualise the serosa . The accuracy of predicting lymph node metastasis was 68 % for macroscopic endoscopic , 79 % for endosonographic , and 67 % for CT staging . Only endosonographic staging was significantly different from chance agreement with histology ( weighted ĸ = 0.56 ) . Endosonographic staging was significantly more accurate than endoscopic macroscopic and CT staging ( p = 0.03 ) . Conclusions : Endosonography is the most accurate staging modality for overall preoperative staging of oesophageal and cardial tumours . Endoscopic macroscopic staging allows a reasonably accurate assessment of the T category BACKGROUND AND STUDY AIMS Endosonography ( EUS ) has been shown to be more accurate than incremental computed tomography ( CT ) in the local ( T ) and regional ( N ) staging of gastric carcinoma ; however , EUS has never been compared with helical CT ( HCT ) . The fifth edition of the TNM classification changed the guidelines for N-staging of gastric carcinoma . The accuracy of imaging methods in this new system remains unknown . PATIENTS AND METHODS Staging accuracy of EUS and HCT were compared prospect ively with pathological or intraoperative findings in 88 gastric carcinoma patients . Staging was done according to the fourth and fifth editions of the TNM classification . EUS was done with a radial echo endoscope , and HCT with a scanner with two rows of detectors ( two-phase contrast-enhanced scanning of a water-filled stomach ) . RESULTS The T-staging accuracy of EUS ( 63 % , CI 52 - 73 % ) was superior to the accuracy of HCT ( 44 % , CI 34 - 55 % ; P = 0.021 ) . N-staging accuracy of both methods was similar when the fourth edition of the TNM classification was used ( EUS 47 % , CI 34 - 60 % ; HCT 52 % , CI 38 - 65 % ) . However , HCT was more accurate than EUS when the fifth edition of the classification was applied ( EUS 30 % , CI 18 - 43 % , HCT 47 % , CI 34 - 60 % ; P = 0.044 ) . The accuracy of detection of lymph node metastases was similar for both methods ( EUS 67 % , CI 54 - 78 % ; HCT 77 % , CI 64 - 86 % ) . CONCLUSIONS EUS is more accurate than HCT in the T-staging of gastric carcinoma . Both methods are comparable for N-staging , when this is done according to the older , fourth edition of the TNM classification . If the fifth edition is used , EUS is less accurate than HCT BACKGROUND Endoscopic ultrasound ( EUS ) is the most accurate locoregional staging tool for gastroesophageal junction ( GEJ ) adenocarcinoma , and it may allow pretreatment risk stratification . The purpose of this study was to compare preoperative EUS staging with postoperative pathologic staging and to assess the ability of EUS to predict survival after resection for GEJ adenocarcinoma . STUDY DESIGN Patients with GEJ adenocarcinoma , who had preoperative staging with EUS followed by resection , were identified from a prospect ively maintained data base . Patients receiving neoadjuvant therapy were excluded . EUS stage was compared with pathologic stage . Survival analyses were performed in patients who underwent complete gross resection . RESULTS From 1985 through 2003 , 209 patients underwent preoperative EUS followed by surgery without neoadjuvant therapy for GEJ adenocarcinoma . EUS correlated with pathologic T stage in 128 of 209 ( 61 % ) patients and with pathologic nodal stage in 154 of 206 ( 75 % ) patients . EUS accurately stratified patients into " early " ( T0 - 2 N0 ) or " advanced " ( T3 - 4 or N1 ) disease categories in 173 ( 83 % ) patients . Curative ( R0 ) resection was performed in 184 patients : EUS " early " ( n=84 ) and " advanced " ( n=122 ) stages were associated with R0 rates of 100 % and 82 % , respectively ( p=0.001 ) . EUS " early " versus " advanced " stage was highly predictive of outcomes ( p < 0.0001 ) . The 5-year disease-specific survival for EUS " early " patients was 65 % compared with 34 % for EUS " advanced " stage . CONCLUSIONS EUS accurately predicts pathologic stage . In addition , EUS is predictive of outcomes after complete gross resection without neoadjuvant treatment for GEJ adenocarcinoma and identifies a high-risk population that might benefit from preoperative therapy BACKGROUND There is a need to assess the sensitivity , specificity , and predictive value of endoscopic ultrasonography ( EUS ) in the diagnosis and staging of gastric cancer and lymphoma . METHODS A prospect i ve study was performed on 86 patients with endoscopic gross appearance suspicious for cancer or lymphoma . Biopsies with endoscopic forceps were always carried out before EUS . All patients underwent laparotomy for final diagnosis , staging , and eventually treatment . The results of EUS were correlated with the histologic findings of the resected specimens , when possible , or with the surgical findings . There were 42 gastric cancers and 44 primary gastric lymphomas . RESULTS EUS made a correct diagnosis of cancer in 35 of 42 patients , with a sensitivity of 83 % . Positive predictability was 87 % , specificity was 97 % , and negative predictability was 96 % . Diagnostic accuracy was 95 % . In the evaluation of cancer depth invasion , EUS was correct in 91 % of cases . EUS displayed perigastric metastatic lymph nodes in 14 of 25 patients , with a sensitivity of 56 % . Positive predictive value was 93 % , specificity was 93 % , and negative predictive value was 54 % . Diagnostic accuracy was 69 % . EUS made a correct diagnosis of lymphoma in 39 of 44 patients , with a sensitivity of 89 % . Positive predictability was 87 % , specificity was 97 % , and negative predictability was 97 % . Diagnostic accuracy was 95 % . In the evaluation of lymphoma depth invasion , EUS was correct in 92 % of cases . EUS displayed metastatic perigastric lymph nodes in 8 of 18 patients , with a sensitivity of 44 % . Positive predictability was 100 % , specificity was 100 % , and negative predictability was 72 % . Diagnostic accuracy was 77 % . CONCLUSIONS From these data it appears that in these diseases EUS has demonstrated specific ultrasonographic features that allow correct diagnosis and staging in the majority of patients . In difficult cases EUS may help to achieve the correct diagnosis . EUS also appear to be a useful tool for staging of gastric cancer and lymphoma . It shows not only tumor depth and local spread but also the passage from a pathologic to a normal wall and lymph node metastasis . With this accurate noninvasive staging procedure , in the near future many patients will no longer undergo exploratory laparotomy for surgical staging . Thanks to EUS , the choice of conservative or surgical treatment can be strongly affected . In case of surgery , EUS can orient the kind of surgical approach . Moreover , the use of EUS for evaluation of therapy during follow-up will probably become of major importance PURPOSE In the West , curative ( R0 ) resection is achieved in approximately 50 % of patients with localized gastric carcinoma , and more than 60 % die of cancer following an R0 resection . A multi-institutional study of preoperative chemoradiotherapy was done to assess the R0 resection rate , pathologic complete response ( pathCR ) rate , safety , and survival in patients with resectable gastric carcinoma . PATIENTS AND METHODS Operable patients with localized gastric adenocarcinoma were eligible . Staging also included a laparoscopy and endoscopic ultrasonography ( EUS ) . Patients received up to two 28-day cycles of induction chemotherapy of fluorouracil , leucovorin , and cisplatin , followed by 45 Gy of radiation plus concurrent fluorouracil . Patients were then staged and surgery was attempted . RESULTS Thirty-four patients were registered at three institutions . One ineligible patient was excluded . Most patients had a promixal cancer and EUST3N1 design ation . Twenty-eight ( 85 % ) of 33 patients underwent surgery . The R0 resection rate was 70 % and pathCR rate was 30 % . A pathologic partial response ( < 10 % residual carcinoma in the primary ) occurred in eight patients ( 24 % ) . EUS T plus N and postsurgery T plus N correlation showed significant downstaging ( P = < .01 ) . The median survival time for 33 patients was 33.7 months . Patients achieving a pathCR or pathPR had a significantly longer median survival time ( 63.9 months ) than those achieving less than pathPR ( 12.6 months ; P = .03 ) . There were two treatment-related deaths . CONCLUSION Our data suggest that the three-step strategy of preoperative induction chemotherapy followed by chemoradiotherapy result ed in substantial pathologic response that result ed in durable survival time . This strategy is worthy of a direct comparison with postoperative adjuvant chemoradiotherapy Diagnosis is a critical component of health care , and clinicians , policymakers , and patients routinely face a range of questions regarding diagnostic tests . They want to know whether testing improves outcome ; what test to use , purchase , or recommend in practice guidelines ; and how to interpret test results . Well- design ed diagnostic test accuracy studies can help in making these decisions , provided that they transparently and fully report their participants , tests , methods , and results as facilitated , for example , by the STARD ( St and ards for Reporting of Diagnostic Accuracy ) statement ( 1 ) . That 25-item checklist was published in many journals and is now adopted by more than 200 scientific journals worldwide . As in other areas of science , systematic review s and meta- analysis of accuracy studies can be used to obtain more precise estimates when small studies addressing the same test and patients in the same setting are available . Review s can also be useful to establish whether and how scientific findings vary by particular subgroups , and may provide summary estimates with a stronger generalizability than estimates from a single study . Systematic review s may help identify the risk for bias that may be present in the original studies and can be used to address questions that were not directly considered in the primary studies , such as comparisons between tests . The Cochrane Collaboration is the largest international organization preparing , maintaining , and promoting systematic review s to help people make well-informed decisions about health care ( 2 ) . The Collaboration decided in 2003 to make preparations for including systematic review s of diagnostic test accuracy in their Cochrane Data base of Systematic Review s. To enable this , a working group ( Appendix ) . was formed to develop methodology , software , and a h and book The first diagnostic test accuracy review was published in the Cochrane Data base in October 2008 . In this paper , we review recent method ological developments concerning problem formulation , location of literature , quality assessment , and meta- analysis of diagnostic accuracy studies by using our experience from the work on the Cochrane H and book . The information presented here is based on the recent literature and up date s previously published guidelines by Irwig and colleagues ( 3 ) . Definition of the Objectives of the Review Diagnostic test accuracy refers to the ability of a test to distinguish between patients with disease ( or more generally , a specified target condition ) and those without . In a study of test accuracy , the results of the test under evaluation , the index test , are compared with those of the reference st and ard determined in the same patients . The reference st and ard is an agreed-on and accurate method for identifying patients who have the target condition . Test results are typically categorized as positive or negative for the target condition . By using such binary test outcomes , the accuracy is most often expressed as the test 's sensitivity ( the proportion of patients with positive results on the reference st and ard that are also positive on the index test ) and specificity ( the proportion of patients with negative results on the reference st and ard that are also negative on the index test ) . Other measures have been proposed and are in use ( 46 ) . It has long been recognized that test accuracy is not a fixed property of a test . It can vary between patient subgroups , with their spectrum of disease , with the clinical setting , or with the test interpreters and may depend on the results of previous testing . For this reason , inclusion of these elements in the study question is essential . In order to make a policy decision to promote use of a new index test , evidence is required that using the new test increases test accuracy over other testing options , including current practice , or that the new test has equivalent accuracy but offers other advantages ( 79 ) . As with the evaluation of interventions , systematic review s need to include comparative analyses between alternative testing strategies and should not focus solely on evaluating the performance of a test in isolation . In relation to the existing situation , 3 possible roles for a new test can be defined : replacement , triage , and add-on ( 7 ) . If a new test is to replace an existing test , then comparing the accuracy of both tests on the same population and with the same reference st and ard provides the most direct evidence . In triage , the new test is used before the existing test or testing pathway , and only patients with a particular result on the triage test continue the testing pathway . When a test is needed to rule out disease in patients who then need no further testing , a test that gives a minimal proportion of falsenegative results and thus a relatively high sensitivity should be used . Triage tests may be less accurate than existing ones , but they have other advantages , such as simplicity or low cost . A third possible role of a new test is add-on . The new test is then positioned after the existing testing pathway to identify false-positive or false-negative results after the existing pathway . The review should provide data to assess the incremental change in accuracy made by adding the new test . An example of a replacement question can be found in a systematic review of the diagnostic accuracy of urinary markers for primary bladder cancer ( 10 ) . Clinicians may use cytology to triage patients before they undergo invasive cystoscopy , the reference st and ard for bladder cancer . Because cytology combines high specificity with low sensitivity ( 11 ) , the goal of the review was to identify a tumor marker with sufficient accuracy to either replace cytology or be used in addition to cytology . For a marker to replace cytology , it has to achieve equally high specificity with improved sensitivity . New markers that are sensitive but not specific may have roles as adjuncts to conventional testing . The review included studies in which the test under evaluation ( several different tumor markers and cytology ) was evaluated against cystoscopy or histopathology . Included studies compared 1 or more of the markers , cytology only , or a combination of markers and cytology . Although information on accuracy can help clinicians make decisions about tests , good diagnostic accuracy is a desirable but not sufficient condition for the effectiveness of a test ( 8) . To demonstrate that using a new test does more good than harm to patients tested , r and omized trials of test- and -treatment strategies and review s of such trials may be necessary . However , with the possible exception of screening , in most cases , such r and omized trials are not available and systematic review s of test accuracy may provide the most useful evidence available to guide clinical and health policy decision making and use as input for decision and cost-effectiveness analysis ( 12 ) . Identification and Selection of Studies Identifying test accuracy studies is more difficult than search ing for r and omized trials ( 13 ) . There is not a clear , unequivocal keyword or indexing term for an accuracy study in literature data bases comparable with the term r and omized , controlled trial . The Medical Subject Heading sensitivity and specificity may look suitable but is inconsistently applied in most electronic bibliographic data bases . Furthermore , data on diagnostic test accuracy may be hidden in studies that did not have test accuracy estimation as their primary objective . This complicates the efficient identification of diagnostic test accuracy studies in electronic data bases , such as MEDLINE . Until indexing systems properly code studies of test accuracy , search ing for them will remain challenging and may require additional manual search es , such as screening reference lists . In the development of a comprehensive search strategy , review authors can use search strings that refer to the test(s ) under evaluation , the target condition , and the patient description or a subset of these . For tests with a clear name that are used for a single purpose , search ing for publications in which those tests are mentioned may suffice . For other review s , adding the patient description may be necessary , although this is also often poorly indexed . A search strategy in MEDLINE should contain both Medical Subject Headings and free text words . A search strategy for articles about tests for bladder cancer , for example , should include as many synonyms for bladder cancer as possible in the search strategy , including neoplasm , carcinoma , transitional cell , and hematuria . Several method ological electronic search filters for diagnostic test accuracy studies have been developed , each attempting to restrict the search to articles that are most likely to be test accuracy studies ( 1316 ) . These filters rely on indexing terms for research methodology and text words used in reporting results , but they often miss relevant studies and are unlikely to decrease the number of articles one needs to screen . Therefore , they are not recommended for systematic review s ( 17 , 18 ) . The incremental value of search ing in language s other than English and in the gray literature has not yet been fully investigated . In systematic review s of intervention studies , publication bias is an important and well-studied form of bias in which the decision to report and publish studies is linked to their findings . For clinical trials , the magnitude and determinants of publication bias have been identified by tracing the publication history of cohorts of trials review ed by ethics committees and research boards ( 19 ) . A consistent observation has been that studies with significant results are more likely to be published than studies with nonsignificant findings ( 19 ) . Investigating publication bias for diagnostic tests is problematic , because many studies are done without ethical review or study registration ; therefore , identification of cohorts of studies from registration to final publication status Background In esophageal cancer patients preoperative staging will determine the type of surgical procedure and use of neoadjuvant therapy . Tumor location and lymph node status play a pivotal role in this tailored strategy . The aim of the present study was to prospect ively evaluate the accuracy of preoperative assessment of tumor location according to the Siewert classification and lymph node status per station with endoscopy/endoscopic ultrasound ( EUS ) and computed tomography ( CT ) . Methods In 50 esophagectomy patients with adenocarcinoma of the gastroesophageal junction ( GEJ ) , tumor location according to Siewert and N-stage per nodal station as determined preoperatively by endoscopy/EUS and CT were compared with the histopathologic findings in the resection specimen . Results Overall accuracy in predicting tumor location according to the Siewert classification was 70 % for endoscopy/EUS and 72 % for CT . Preoperative data could not be compared with the pathologic assessment in 11 patients ( 22 % ) , as large tumors obscured the l and mark of the gastric folds . The overall accuracy for predicting the N-stage in 250 lymph node stations was 66 % for EUS and 68 % for CT . The accuracy was good for those stations located high in the thorax , but poor for celiac trunk nodes . Conclusions Given the frequent discrepancy between the endoscopic and pathologic location of the GEJ and the common problem of advanced tumors obscuring the l and marks used in the assessment of the Siewert classification , its usefulness is limited . The overall accuracy for EUS and CT in predicting the N-stage per station was moderate BACKGROUND Preoperative assessment of gastro-esophageal junction ( GEJ ) adenocarcinoma stage and its location according to Siewert are essential for planning the therapeutic approach . The present study was aim ed at analyzing the utility of endoscopic ultrasonography ( EUS ) in evaluating GEJ adenocarcinoma stage and whether this modality added to EGD improves assessment of Siewert type . METHODS The results of 51 patients studied by EGD plus EUS ( EGD/EUS group ) were compared with the results of 54 patients studied by EGD only ( EGD group ) . RESULTS A differentiation of pT1 tumors was attempted by measurement of the tumor length using 4 cm as a criterion . This goal was not achieved because of a high rate of advanced tumors less than 4 cm ( sensitivity and specificity were 81.3 % and 34.2 % , respectively ) . Conversely EUS ability in pT1 assessment was very reliable ( 92 % ) . The accuracy in defining the Siewert type was 72.5 % and 64.8 % for EGD/EUS and EGD groups , respectively ( P = 0.394 ) . Some difficulties in distinguishing between type II and III tumors were observed in both groups with an extremely low specificity ( 44 % ) in classifying type II tumors by EGD group . CONCLUSIONS EUS seems to be essential in differentiating pT1 from advanced tumors . It shows an accuracy in defining the Siewert type of 72.5 % , with some difficulties in distinguishing from type II and III tumors Prospect i ve controlled data of lymph node evaluation by endoscopic ultrasound in esophageal , gastric and pancreatic cancer is presented . Lymph node pattern , changes of boundaries and echogenicity were considered . Preoperative findings of endoscopic ultrasound were classified according to TNM staging . Only those cases with subsequent histologic examination of the resected specimen were entered into the study . Sensitivity of endoscopic ultrasonography ( EUS ) was 90 % for esophageal and 87 % for gastric cancer . The specificity was 72 % and 88 % , respectively . In spite of the overall satisfactory results of EUS in evaluation of lymph nodes , further improvement in detection and differentiation of benign and malignant nodes is required BACKGROUND The majority of newly diagnosed patients with gastric cancer have disease that is not resectable because of local extension or metastatic ( M1 ) disease . Laparoscopy is a recommended staging evaluation to identify occult peritoneal metastatic disease . We determined if endoscopic ultrasound ( EUS ) could improve the selection of patients for laparoscopy . STUDY DESIGN Gastric cancer patients being screened for a preoperative chemotherapy clinical trial were prospect ively examined . Patients underwent st and ard preoperative assessment . Those without obvious metastatic disease were referred for EUS and laparoscopy . EUS divided patients into risk categories for metastatic disease : low risk ( T1 - 2 , N0 ) and high risk ( T3 - 4 , N+ , or both ) . Laparoscopy categories were M1 and M0 . The ability of EUS to predict subradiographic peritoneal metastatic disease was evaluated . RESULTS Ninety-four patients were studied . The majority were EUS high risk ( 72 % ) . Occult metastatic disease was identified in 19 patients , 18 of whom had high-risk EUS stage . The yields of identifying M1 disease by laparoscopy in EUS high- and low-risk patients were 25 % ( 95 % CI , 15 % to 37 % ) and 4 % ( 95 % CI , 0.1 % to 20 % ) , respectively . The negative predictive value of low-risk EUS for laparoscopy and pathologic M0 was 96 % ( exact 95 % CI , 80 % to 100 % ) . CONCLUSIONS This study suggested that laparoscopy can be avoided in patients with EUS early-stage gastric cancer . Patients with more advanced disease are at higher risk of occult peritoneal disease and require laparoscopy . Validation with greater numbers is warranted , but , based on these data , we propose a new staging algorithm allowing EUS low-risk patients to proceed directly to resection From 1986 to 1990 a prospect i ve comparative study was undertaken to compare the relative accuracy of computed tomography , endogastric ultrasonography , and intraoperative surgical assessment in evaluating the depth of invasion ( T category ) and involvement of lymph nodes ( N category ) of patients with gastric carcinoma . One hundred and eight consecutive patients , who were treated by total gastrectomy and previously evaluated with computed tomography , endogastric ultrasonography , and intraoperative surgical assessment , entered the study . Results ( T and N category ) were compared with those of histopathological staging ( pT and pN category ) . T categories were correctly staged in 43 % of cases with computed tomography , 86 % with endogastric ultrasonography , and 56 % with intraoperative surgical assessment . Computed tomography scanning correctly staged 51 % of all N1 and N2 lymph nodes compared with 74 % for endogastric ultrasonography and 54 % for intraoperative surgical assessment . In general , computed tomography was more accurate for advanced stages of cancer and showed a tendency to overstage the T category and understage N category of gastric tumours . By contrast , endogastric ultrasonography was equally accurate for all T categories and showed an understaging for N categories . Intraoperative surgical assessment overstaged early T stages , understaged T4 tumours , and was equally accurate for all grade s of N categories . Computed tomography scanning and intraoperative surgical assessment of T and N categories were of little value in staging of gastric carcinoma . Endogastric ultrasonography is more accurate than computed tomography scanning and intraoperative surgical assessment . Therefore endogastric ultrasonography should be introduced in the preoperative assessment of patients with gastric carcinoma INTRODUCTION AND OBJECTIVE Oesophago-gastric carcinoma is associated with a poor prognosis despite advances in diagnosis and treatment . Accurate preoperative staging of gastro-oesophageal carcinoma is , therefore , essential in order to determine patient selection for potentially curative resection . The aim of this study was to evaluate and compare the role of computerised tomography ( CT ) , laparoscopic ultrasound ( LapUS ) and endoscopic ultrasound ( EUS ) in the staging of oesophago-gastric carcinoma . METHODS AND PATIENTS Thirty-six patients with histologically proven carcinoma of the oesophagus or stomach who were considered fit for surgical resection were identified from a prospect ively collected data base . All patients underwent spiral CT , LapUS and EUS as part of their preoperative staging investigations . RESULTS from the staging modalities were compared retrospectively with final histopathology where available and to intraoperative findings where the tumour was irresectable . RESULTS Locally advanced tumours ( T3/T4 ) were accurately identified by CT in 15/16 ( 94 % ) and by EUS in 14/16 ( 88 % ) . LapUS was unable to detect 11 tumours ( of which five were T3/T4 ) because they were above the diaphragm , but in the locally advanced cases where the tumour could be seen the accuracy was 10/12 ( 83 % ) . EUS was the best modality for assessing early tumours and locoregional nodal involvement with accuracies of 8/13 ( 62 % ) and 21/29 ( 72 % ) , respectively . EUS accuracies rose to 64 , 92 and 83 % for T1/T2 , T3/T4 and N staging with the exclusion of those patients ( n=6 ) in whom strictures prevented full assessment . LapUS had a specificity of 100 % , compared to 90 % for CT and was more accurate than CT for assessing distant metastases ( accuracy of 26/32 ( 81 % ) compared to 23/32 ( 72 % ) for CT ) . CONCLUSIONS Although this study is small it has confirmed that CT , EUS and LapUS act in a complimentary manner to provide the most complete preoperative staging for patients with oesophago-gastric cancer Background : Preoperative staging of tumour extent in upper gastrointestinal malignancy greatly facilitates planning of therapy . The present study was undertaken to see whether preoperative endoscopic ultrasonography ( EUS ) accurately predicts the tumour stage in gastric carcinoma Background Endoscopic ultrasonography ( EUS ) is a st and ard procedure in the preoperative staging of patients with gastric carcinomas . Herein we present our experience with EUS and discuss the results and their implication s for surgical therapy . Methods A total of 116 patients with histologically confirmed gastric adenocarcinoma were referred to EUS and classified prospect ively by the TNM system . The results of the preoperative endosonographic staging were compared with the definitive histopathological results after the operation . Results The overall accuracy of EUS for determination of the T stage was 78 % . The accuracy for the T1 and T2 stages was 80 % and 63 % , respectively . With 20 % and 30 % , there was a relatively high rate of overstaging in these cases . The accuracy for T3 and T4 tumors was 95 % and 83 % , respectively . The accuracy of EUS for determination of the N stage was 77 % , with a sensitivity of 91 % and a specificity of 84 % . Resectability was predicted correctly with a sensitivity of 94 % and a specificity of 83 % . Conclusions Generally accepted st and ards for the therapy of advanced gastric carcinomas do not exist . In cases where the therapeutic strategy is surgical exploration , no preoperative staging is necessary . In cases with differentiated treatment strategies , the accuracy of EUS is not sufficient for the selection of patients for endoscopic resection . Its accuracy for submucosal cancer invasion and for the detection of lymph node metastases needs to be further enhanced . If only multimodal therapy is considered , EUS staging seems to be absolutely m and atory . Patients classified preoperatively as T1 to T3 can be operated on primarily with sufficient security . In patients where radical resection of the tumor seems doubtful , we recommend that a diagnostic laparoscopy be performed to confirm the diagnosis PURPOSE To prospect ively compare diagnostic parameters of a newly developed endoluminal MRI ( endo-MRI ) concept with endoscopic ultrasound ( EUS ) and hydro-computer tomography ( Hydro-CT ) in T-staging of gastric carcinoma on one patient collective . MATERIAL AND METHODS 28 consecutive patients ( 11 females , 17 males , age range 46 - 87 years , median 67 years ) referred for surgery due to a gastric malignancy were included . Preoperative staging by EUS was performed in 14 cases and by Hydro-CT in 14 cases within a time frame of 2 weeks . Ex vivo endo-MRI examination of gastric specimens was performed directly after gastrectomy within a time interval of 2 - 3h . EUS data were acquired from the clinical setting whereas Hydro-CT and endo-MRI data were evaluated in blinded fashion by two experienced radiologists and one surgeon well experienced in EUS on gastric carcinomas . RESULTS Histopathology result ed in 4 pT1 , 17 pT2 , 3 pT3 and 2 pT4 carcinomas with 2 gastric lymphomas which were excluded . Overall accuracy for endo-MRI was 75 % for T-Staging of the 26 carcinomas . EUS achieved 42.9 % accuracy ; endo-MRI in this subgroup was accurate in 71.4 % . Hydro-CT was correct in 28.6 % , accuracy for endo-MRI in this subgroup was 71.4 % . CONCLUSION The direct comparison of all three modalities on one patient collective shows that endo-MRI is able to achieve adequate staging results in comparison with clinical ly accepted methods like EUS and Hydro-CT in classifying the extent of tumor invasion into the gastric wall . However the comparison is limited as we compared in vivo routine clinical data with experimental ex vivo data . Future investigations need to show if the potential of endo-MRI can be transferred into a clinical in vivo setting We performed a prospect i ve study from November 1989 to December 1996 to assess the accuracy of endoscopic ultrasonography ( EUS ) in the locoregional staging and resectability of patients with gastric carcinoma . One hundred and nineteen patients with gastric cancer who received preoperative assessment by EUS underwent subsequent surgery . The endosonographic tumor-node-metastasis ( TNM ) classification was used for comparison with the histopathologic findings of the resected specimens . The ability of EUS to accurately predict the T stage ( depth of tumor invasion ) and N stage ( involvement of lymph node ) was 70 % and 65 % , respectively . EUS displayed a tendency to overestimate T stage and underestimate N state . The differentiation of early gastric cancer from advanced gastric cancer showed a concordance rate of 89 % and underestimation rate of 8 % and underestimation rate of 3 % . The accuracy of EUS in predicting the stage T1 to T3 , which correspond to D0 resectability ( no macroscopic or microscopic tumor remains ) , was 91 % . In conclusion , these results revealed EUS as a valuable tool for evaluating the local staging and resectability of gastric cancer . We suggest that EUS should be introduced in the preoperative assessment of patients with gastric cancer BACKGROUND AND AIM The development of endoscopic treatment , such as endoscopic submucosal dissection , extends the indications for endoscopic resection in patients with early gastric cancer ( EGC ) . Endoscopic ultrasonography ( EUS ) is the first-choice imaging modality for determining the depth of invasion of gastric cancer . The aim of the present study was to prospect ively assess the accuracy of EUS for determining the depth of EGC , according to the accepted/extended indications . METHODS We prospect ively included a total of 181 lesions in 178 patients , with an endoscopic diagnosis of EGC , who underwent EUS for staging the depth of tumor invasion using a 20-MHz catheter probe . We investigated the accuracy of EUS for determining the depth of endoscopically-suspected EGC and then analyzed the difference in the accuracy of EUS according to the accepted/extended indications . RESULTS Of the 178 patients , five patients were dropped because of the absence of final histological results . For the 176 lesions in 173 patients , the accuracy of EUS assessment for the depth of tumor invasion was 80.7 % ( 142 of 176 lesions ) . The accuracy of EUS for the lesions with accepted indications and with extended indications was 97.6 % ( 40 of 41 lesions ) and 83.6 % ( 46 of 57 lesions ) , respectively ( P = 0.040 ) . Of the lesions with extended indications , the accuracy of EUS decreased especially for the lesions with ulceration and those with minute submucosal invasion ( 79.2 % and 42.9 % , respectively ) . CONCLUSIONS The accuracy of EUS for the lesions with the extended indications was lower than that for the lesions with the accepted indications . In particular , lesions with ulceration and minute submucosal invasion should be carefully considered prior to endoscopic treatment by pretreatment EUS staging Abstract . Background : To evaluate the diagnostic accuracy of endosonography ( ES ) in a prospect i ve series of cancer of the cardia . Methods : Thirty-five patients with cancer of the cardia were investigated by ES ; 29 underwent surgery . ES staging for the surgery patients was compared with histopathologic findings . Tumors were staged according to the 1987 TNM classification . Results : ES had a diagnostic accuracy of 79 % for the T category , 79 % for the N category , 89 % for the M category , and 72 % for prognostic TNM staging . Conclusion : ES is an excellent para clinical modality for the staging of local – regional spread of cancer of the cardia and a useful complement to computed tomography for evaluation of these tumors The objective of the current study was to assess the staging accuracy and prognostic role of preoperative endoscopic ultrasound ( EUS ) and computed tomography ( CT ) in patients with locally advanced gastric cancer ( LAGC ) after neoadjuvant chemotherapy BACKGROUND AND OBJECTIVE Publication bias and other sample size effects are issues for meta-analyses of test accuracy , as for r and omized trials . We investigate limitations of st and ard funnel plots and tests when applied to meta-analyses of test accuracy and look for improved methods . METHODS Type I and type II error rates for existing and alternative tests of sample size effects were estimated and compared in simulated meta-analyses of test accuracy . RESULTS Type I error rates for the Begg , Egger , and Macaskill tests are inflated for typical diagnostic odds ratios ( DOR ) , when disease prevalence differs from 50 % and when thresholds favor sensitivity over specificity or vice versa . Regression and correlation tests based on functions of effective sample size are valid , if occasionally conservative , tests for sample size effects . Empirical evidence suggests that they have adequate power to be useful tests . When DORs are heterogeneous , however , all tests of funnel plot asymmetry have low power . CONCLUSION Existing tests that use st and ard errors of odds ratios are likely to be seriously misleading if applied to meta-analyses of test accuracy . The effective sample size funnel plot and associated regression test of asymmetry should be used to detect publication bias and other sample size related effects OBJECTIVE to determine the diagnostic precision of endoscopic ultrasounds ( EUS ) and magnetic resonance imaging ( MRI ) in the preoperative staging of gastric cancer . METHODS a prospect i ve , blind study was carried out in 17 patients diagnosed with gastric cancer ( GC ) using endoscopic biopsy from November 2002 to June 2003 . Patients underwent preoperative MRI and EUS . The reference test used was pathology , and laparotomy for non-resectable cases . RESULTS MRI ( 53 % ) was better than EUS in the assessment of gastric wall infiltration ( 35 % ) . MRI ( 50 % ) was also superior to EUS ( 42 % ) for N staging . After pooling stages T1-T2 and T3-T4 together , results improved for both MRI ( 67 and 87.5 % , respectively ) and EUS ( 67 and 62.5 % , respectively ) ( p < 0.05 ) . N staging -- lymph node invasion-- results were correct in 50 % for MRI as compared to EUS ( 42 % ) . In classifying positive and negative lymph nodes EUS was superior to MRI ( 73 versus 54 % ) . CONCLUSIONS MRI was the best method in the assessment of gastric wall infiltration . EUS was superior to MRI for T1 staging , and in the assessment of lymph node infiltration To assess the accuracy and limitations of endoscopic ultrasonography ( EUS ) in the preoperative staging of esophageal and gastric carcinoma , we performed a prospect i ve controlled study over a five year period . Data from 63 patients with esophageal cancer and 147 patients with gastric cancer who underwent surgery were available for comparison of the endosonographic TNM classification to the histophathological findings of the resected specimens . The overall accuracy of EUS in the assessment of tumor infiltration depth was 85.7 % and 78 % in esophageal and gastric cancer , respectively . The sensitivity of EUS in the detection of regional lymph node metastases was 90 % in esophageal and 87 % in gastric carcinoma . The most frequent causes of misdiagnoses by endosonography were microscopic tumor invasion and peritumorous inflammatory changes . The inability to traverse a tumor stenosis restricted the endosonographic evaluation in 31.6 and 14 % of the cases with esophageal and gastric cancer , respectively The aim of the study was to evaluate the usefulness of and problems associated with a new endoscopically guided ultrasound miniprobe , used for pre-operative staging of gastric cancers . 59 cases of gastric cancer were prospect ively examined with a 15 MHz ultrasound miniprobe . The results of the ultrasound imaging were compared with the histological findings of the resected specimens . The accuracy of the miniprobe for depth of invasion ( T category ) was 61 % for all tumours , and 72 % and 40 % , respectively , for T1 and T2 to T4 lesions . If indeterminate cases due to ultrasound attenuation were excluded , the accuracy was improved to 82 % for T1 and 57 % for T2 to T4 tumours , respectively . The accuracy of the miniprobe for nodal staging ( N category ) was 69 % overall , and 86 % , 25 % and 14 % for stages N0 , N1 and N2 , respectively . In tumours classified on the basis of endoscopic types , the miniprobe staged early type gastric cancers ( T category = 73 % , N category = 80 % ) significantly ( p < 0.01 ) more accurately than advanced ones ( T category = 21 % , N category = 36 % ) . This study suggests that the miniprobe is indicated for pre-operative TN staging when endoscopy reveals an early gastric cancer Background Endoscopic ultrasonography ( EUS ) is considered valuable for preoperative staging of gastric cancer and defining patient eligibility for enrollment in neoadjuvant protocol s. The aim of this study was to correlate EUS staging with pathologic evaluation and outcome in patients undergoing curative R0 resection for gastric cancer . Methods All patients who underwent preoperative clinical assessment of T/N stage with EUS and subsequent R0 resection for gastric adenocarcinoma between 1993 and 2003 were identified from a prospect i ve data base . Patients who received neoadjuvant chemotherapy were excluded . Clinical staging results from preoperative EUS were compared with postoperative pathologic staging results and correlated with clinical outcome . Results Two hundred twenty-five patients with gastric cancer underwent EUS followed by R0 resection , without preoperative chemotherapy . The accuracy of the individual EUS T stage was 57 % ( 127 of 223 ) and was 50 % for N stage ( 110 of 218 ) . Although EUS was less able to predict outcome according to individual T stage , patients with lesions ≤T2 on EUS had a significantly better outcome than patients with lesions ≥T3 . Preoperative assessment of risk was not predicted by EUS N stage alone . Patients identified as high risk on EUS and those with a combination of serosal invasion and nodal disease had both the highest concordance with pathology and a significantly worse outcome ( P = .02 ) . Conclusions The concordance between EUS and pathologic results was lower than expected for individual T and N stages . Patients with lesions ≤T2 had a significantly better prognosis than patients with more advanced lesions . Individual EUS N stage has limited value in preoperative risk assessment . Combined assessment of serosal invasion and nodal positivity on EUS identifies 77 % of patients at risk for death from gastric cancer after curative resection BACKGROUND Electronic 270 degrees transverse-array EUS ( TA-EUS ) provides high- quality cross-sectional images but can not guide FNA . Linear EUS ( L-EUS ) provides longitudinal images of malignancies and the ability to guide FNA . OBJECTIVE We conducted a prospect i ve r and omized comparison of TA-EUS and L-EUS for the staging of upper-GI ( UGI ) malignancies . DESIGN Forty-three patients underwent L-EUS immediately followed by TA-EUS ( N = 27 , 63 % ) or TA-EUS immediately followed by L-EUS ( N = 16 , 37 % ) . PATIENTS Forty-three subjects ( mean age , 64 years ; 37 men ) with an UGI malignancy ( 4 stomach and 38 esophageal ) were evaluated with both TA-EUS and L-EUS . INTERVENTIONS Abnormal lymph nodes were sample d by FNA for cytology . RESULTS There was agreement on the T stage by linear and radial techniques in 38 of 43 subjects ( 88 % ) . Twenty-seven of 43 patients ( 63 % ) had abnormal lymph nodes by linear or transverse-array imaging . L-EUS demonstrated 66 abnormal lymph nodes in 27 subjects ( average of 2.4 nodes/subject ) . TA-EUS demonstrated 90 abnormal lymph nodes in 27 subjects ( average of 3.3 nodes/subject , P = .009 , compared with L-EUS ) . In 16 of the 27 subjects , an FNA was performed , which was positive in 13 cases ( 81 % ) and negative in 3 cases ( 10 % ) for malignancy . CONCLUSIONS TA-EUS and L-EUS provide similar results of T staging of UGI malignancies . However , the number of abnormal lymph nodes detected by TA-EUS was more than by L-EUS . These findings suggest that radial or transverse-array EUS imaging should be the primary method for staging of UGI malignancies PURPOSE To determine the accuracy of double contrast-enhanced ultrasound ( DCEUS ) , in which intravenous microbubbles are used together with an oral contrast agent , in the preoperative T staging of advanced gastric cancer . MATERIAL S AND METHODS This prospect i ve , ethics committee-approved study recruited 350 patients who gave informed consent . All had gastric cancer proved by endoscopic biopsy and underwent preoperative ultrasound staging using the TNM classification ( UICC 2002 ) . The results of DCEUS were compared with postoperative pathologic findings . The staging accuracy of oral contrast-enhanced ultrasound ( OCEUS ) and DCEUS were compared to each other . Sensitivity and specificity for assessing serosal involvement by DCEUS were evaluated , and the concordance of this method was analyzed using Kappa statistics . RESULTS The accuracies of OCEUS and DCEUS in determining the T stage of advanced gastric cancer were 75.1 % ( 70.4 % for T2 , 79.5 % for T3 , 68.1 % for T4 ) and 87.4 % ( 83.3 % for T2 , 89.7 % for T3 , 87.2 % for T4 ) , respectively , and the difference between the two methods was statistically significant ( χ2 = 17.364 , p < 0.001 ) . The performance of DCEUS for staging lesions in the cardia ( 69.81 % ) , fundus ( 85.71 % ) and body ( 85.56 % ) had lower accuracy than that of other parts ( 93.94 % for antrum ; 92.11 % for pylorus ) . Sensitivity and specificity for assessing serosal involvement by DCEUS were 98.76 % and 83.33 % respectively . The reliability was almost perfect with Kappa values of 0.89 ( p < 0.001 ) for intra-observer and 0.82 ( p < 0.001 ) for inter-observer agreement . CONCLUSION DCEUS could be considered as an accurate , non-invasive , and reliable diagnostic method for preoperative staging of advanced gastric cancer BACKGROUND / AIMS To assess the accuracy and limitation of endoscopic ultrasonography in preoperative staging of gastric cancer , we performed a prospect i ve study on 99 patients . MATERIAL AND METHODS Ninety-nine patients with gastric cancer had preoperative staging with endoscopic ultrasound ( EUS ) and CT . RESULTS The depth of infiltration ( T parameter ) was correctly defined by EUS in 58/65 patients ( 89 % ) . The lymph node involvement ( N parameter ) was correctly classified in 44/65 patients ( 68 % ) , the sensitivity was 74 % and the specificity was 54 % . The most frequent cause of understaging T parameter was microscopic tumor invasion , whereas overstaging was due to peri-tumor inflammation . CONCLUSIONS We believe that EUS is a reliable method , superior to all diagnostic tools , in the evaluation of locoregional extension of gastric cancer UNLABELLED The aim of the study was to analyze epidemiologic parameters , treatment-related data and prognostic factors in the management of gastric cancer patients of a university surgical center under conditions of routine clinical care before the onset of the era of multimodal therapies . By analyzing our data in relation with multi-center quality assurance trials [ German Gastric Cancer Study - GGCS ( 1992 ) and East German Gastric Cancer Study - EGGCS ( 2004 ) ] we aim ed at providing an instrument of internal quality control at our institution as well as a base for comparison with future analyses taking into account the implementation of evolving ( multimodal ) therapies and their influence on treatment results . MATERIAL AND METHODS Retrospective analysis of prospect ively gathered data of gastric cancer patients treated at a single institution during a defined 10-year time period with multivariate analysis of risk factors for early postoperative outcome . RESULTS From 04/01/1993 through 03/31/2003 , a total of 328 gastric cancer patients were treated . In comparison with the EGGCS cohort there was a larger proportion of patients with locally advanced and proximally located tumors . 272 patients ( 82.9 % ) underwent surgery with curative intent ; in 88.4 % of these an R0 resection was achieved ( EGGCS/GGCS : 82.5%/71.5 % ) . 68.2 % of patients underwent preoperative endoluminal ultrasound ( EUS ) ( EGGCS : 27.4 % ) ; the proportion of patients undergoing EUS increased over the study period . Diagnostic accuracy of EUS for T stage was 50.6 % ( EGGCS : 42.6 % ) . 77.2 % of operated patients with curative intent underwent gastrectomy ( EGGCS/GGCS : 79.8%/71.1 % ) . Anastomotic leaks at the esophagojejunostomy occurred slightly more frequently ( 8.8 % ) than in the EGGCS ( 5.9 % ) and GGCS ( 7.2 % ) ; however , postoperative morbidity ( 36.1 % ) and early postoperative mortality ( 5.3 % ) were not increased compared to the multi-center quality assurance study results ( EGGCS morbidity , 45 % ) ; EGGCS/GGCS mortality , 8%/8.9 % ) . D2 lymphadenectomy was performed in 72.6 % of cases ( EGGCS : 70.9 % ) . Multivariate analysis revealed splenectomy as an independent risk factor for postoperative morbidity and ASA status 3 or 4 as an independent risk factor for early postoperative mortality . The rate of splenectomies performed during gastric cancer surgery decreased substantially during the study period . CONCLUSIONS Preoperative diagnostics were able to accurately predict resectability in almost 90 % of patients which is substantially more than the corresponding results of both the EGGCS and the GGCS . In the future , more wide-spread use of EUS will play an increasing role as stage-dependent differentiation of therapeutic concepts gains acceptance . However , diagnostic accuracy of EUS needs to be improved . Our early postoperative outcome data demonstrate that the quality st and ard of gastric cancer care established by the EGGCS is being fulfilled at our institution in spite of distinct characteristics placing our patients at higher surgical risk . Besides being a valuable instrument of internal quality control , our study provides a good base for comparison with ongoing analyses on future developments in gastric cancer therapy BACKGROUND The usefulness of and problems associated with an ultrasound catheter probe in the pretreatment staging of endoscopically early gastric cancer remain unexplored . METHODS Endoscopic ultrasonography using a 15 MHz catheter probe of 2.6 mm diameter was performed in a prospect i ve study to determine the pretherapy staging of endoscopically early gastric cancer in 78 patients . The results of the ultrasound images were compared with the histologic findings of the specimens obtained by endoscopic mucosal resection or surgical resection . RESULTS The accuracy of the catheter probe for depth of invasion of endoscopically early gastric cancers was 67 % ( 52 of 78 patients ) . The accuracy in determining depth of invasion in relation to endoscopic type was significantly higher for the elevated type ( 91 % ) than for the depressed type of early cancer ( 56 % ) ( p < 0.01 ) . The staging accuracy classified by histologic type was significantly higher for differentiated ( 86 % ) than for undifferentiated ( 18 % ) cancer ( p < 0.01 ) . Staging accuracy decreased as tumor size increased . The accuracy , sensitivity , and specificity for nodal staging were 80 % , 17 % , and 90 % , respectively . CONCLUSIONS A 15 MHz ultrasound catheter probe is most useful for determining depth of invasion when the tumor is histologically differentiated and endoscopically of the small elevated type early gastric cancer , but it is unreliable in the diagnosis of metastatic lymph nodes |
1,954 | 28,992,741 | Results : Meta-analyses indicated lower IQ , memory and executive function in both violent schizophrenia and antisocial personality disorder groups compared to healthy controls .
The degree of deficit was consistently larger in violent schizophrenia .
Both antisocial personality disorder and violent schizophrenia groups had difficulties in aspects of facial affect recognition , although theory of mind results were less conclusive .
Psychopathic traits related positively to experiential emotion deficits across the two disorders .
Conclusion : There are qualitatively similar , but quantitatively different , neuropsychological and emotion processing deficits in violent individuals with schizophrenia and antisocial personality disorder which could be developed into transdiagnostic treatment targets for violent behaviour . | Objectives : To assess whether there are shared or divergent ( a ) cognitive and ( b ) emotion processing characteristics among violent individuals with antisocial personality disorder and /or schizophrenia , diagnoses which are commonly encountered at the interface of mental disorder and violence .
Cognition and emotion processing are incorporated into models of violence , and thus an underst and ing of these characteristics within and between disorder groups may help inform future models and therapeutic targets . | BACKGROUND Social cognition difficulties in schizophrenia are seen as a barrier to recovery . Intervention tackling problems in this domain have the potential to facilitate functioning and recovery . Social Cognition and Interaction Training ( SCIT ) is a manual-based psychological therapy design ed to improve social functioning in schizophrenia . AIMS The aim of this study is to evaluate the feasibility and acceptability of a modified version of SCIT for inpatient forensic wards . The potential benefits of the intervention were also assessed . METHOD This study is a r and omized single blind controlled design , with participants r and omized to receive SCIT ( N = 21 ) or treatment as usual ( TAU ; N = 15 ) . SCIT consisted of 8-week therapy sessions twice per week . Participants were assessed at week 0 and one week after the intervention on measures of social cognition . Feasibility was assessed through group attendance and attrition . Participant acceptability and outcome was evaluated through post-group satisfaction and achievement of social goals . RESULTS The intervention was well received by all participants and the majority reported their confidence improved . The SCIT group showed a significant improvement in facial affect recognition compared to TAU . Almost all participants agreed they had achieved their social goal as a result of the intervention . CONCLUSIONS It is feasible to deliver SCIT in a forensic ward setting ; however , some adaptation to the protocol may need to be considered in order to accommo date for the reduced social contact within forensic wards . Practice of social cognition skills in real life may be necessary to achieve benefits to theory of mind and attributional style Background There is a broad literature suggesting that cognitive difficulties are associated with violence across a variety of groups . Although neurocognitive and social cognitive deficits are core features of schizophrenia , evidence of a relationship between cognitive impairments and violence within this patient population has been mixed . Methods We prospect ively examined whether neurocognition and social cognition predicted inpatient violence amongst patients with schizophrenia and schizoaffective disorder ( n = 89 ; 10 violent ) over a 12 month period . Neurocognition and social cognition were assessed using the MATRICS Consensus Cognitive Battery ( MCCB ) . Results Using multivariate analysis neurocognition and social cognition variables could account for 34 % of the variance in violent incidents after controlling for age and gender . Scores on a social cognitive reasoning task ( MSCEIT ) were significantly lower for the violent compared to nonviolent group and produced the largest effect size . Mediation analysis showed that the relationship between neurocognition and violence was completely mediated by each of the following variables independently : social cognition ( MSCEIT ) , symptoms ( PANSS Total Score ) , social functioning ( SOFAS ) and violence proneness ( HCR-20 Total Score ) . There was no evidence of a serial pathway between neurocognition and multiple mediators and violence , and only social cognition and violence proneness operated in parallel as significant mediators accounting for 46 % of the variance in violent incidents . There was also no evidence that neurocogniton mediated the relationship between any of these variables and violence . Conclusions Of all the predictors examined , neurocognition was the only variable whose effects on violence consistently showed evidence of mediation . Neurocognition operates as a distal risk factor mediated through more proximal factors . Social cognition in contrast has a direct effect on violence independent of neurocognition , violence proneness and symptom severity . The neurocognitive impairment experienced by patients with schizophrenia spectrum disorders may create the foundation for the emergence of a range of risk factors for violence including deficits in social reasoning , symptoms , social functioning , and HCR-20 risk items , which in turn are causally related to violence Individuals with antisocial personality disorder ( ASPD ) are impulsive and show impairment in reinforcement processing . There is increasing evidence for a neurobiological basis of psychopathy , which shares some of the characteristics of ASPD , but research on the neuronal correlates of neuropsychological processes in ASPD remains limited . Furthermore , no research has examined the effects of serotonergic manipulation on brain activations in antisocial groups . In this study , 25 male participants with ASPD ( mean age 42.1 ) and 32 male control participants ( mean age 30.5 ; 25 participants providing usable scans ) were r and omly allocated to receive the 5-HT(2C)-agonist mCPP or placebo . Participants were scanned using functional magnetic resonance imaging ( fMRI ) during a behavioural inhibition ( Go/NoGo ) and a reward task . In comparison to healthy controls the ASPD group showed reduced task related activations in the dorsolateral prefrontal cortex ( DLPFC ) but increased signal in the pre/subgenual anterior cingulate cortex ( ACC ) in the Go/No-Go task and increased activation in OFC in the reward task . mCPP modulated brain responses in both tasks in the whole group . Interactions between group and drug occured in bilateral OFC , cau date and ventral pallidum during the reward task but no significant interactions were found in the Go/No-Go task . This suggests that ASPD involves altered serotonin modulation of reward , but not motor inhibition pathways . These findings suggest that ASPD involves altered DLPFC , ACC and OFC function . Altered serotonergic modulation of reward pathways seen in the ASPD group raises the possibility that targeting serotonin systems may be therapeutic Objective : There is a need to find effective treatments for individuals with antisocial and borderline personality disorder who are known to be difficult to engage and treat . Many of these individuals share considerable overlap with symptoms of ADHD , hence this study aim ed to evaluate the Reasoning and Rehabilitation ADHD program ( R&R2 ADHD ) among patients with severe personality disorder . Method : A total of 31 males detained in a “ dangerous and severe personality disorder ” unit completed question naires at baseline and post treatment to assess social problem solving , violent attitudes , anger , ADHD symptoms , emotional control , and social functioning . A total of 16 patients participated in the group condition , and their scores were compared with 15 waiting-list controls who received treatment as usual . Results : In all , 76 % of group participants completed the program . In contrast to controls , they showed significant improvements in scores with mainly medium effect sizes . Conclusion : R&R2 ADHD was effective in a small sample of severely personality-disordered offenders The role of mentalizing abilities ( or theory of mind ) and empathic abilities in violent behavior were studied in 24 hospitalized males with paranoid schizophrenia ( ICD-10 ) . Patients were divided into violent and nonviolent groups based on their history of committing violent acts against others . To examine these abilities , patients heard a series of 12 short scenarios depicting social situations followed by questions that require making mental state or empathic inferencing . Our results show that violent patients have more difficulties than nonviolent patients in tasks involving empathic inferencing , and better abilities in inferring cognitive-mental states in others . In addition , violence seems to be associated with a history of alcohol and drug abuse , young age , and the hostility component of the Brief Psychiatric Rating Scale . Logistic regression analyses suggest that violence is associated with the combination of hostility towards others , good mentalizing abilities and poor empathy . These results are discussed in light of recent theories on violent behavior in psychiatric population Cognitive remediation has proven efficacy for improving neurocognition in people with schizophrenia . The current study evaluated the benefits of cognitive remediation on neurocognition , functioning , psychotic symptoms , and aggression in a sample of forensic and mental health patients . Care recipients with schizophrenia or schizoaffective disorder ( N = 78 ) receiving services in the forensic and mental health units of a state hospital were r and omized to participate in cognitive remediation versus computer games control activities . Participants ' neurocognition , functional capacity , experiential recovery , psychotic symptoms , and aggression incidents were assessed at baseline and posttreatment . Cognitive remediation was associated with improvements in several neurocognitive domains and circumscribed domains of functional capacity . People assigned to cognitive remediation experiences greater reductions in negative symptoms , agitation/excitement , and verbal and physical aggression . In addition to improving neurocognition in long-term hospitalized forensic and mental health patients , cognitive remediation may enhance efforts at reducing negative symptoms , emotion dysregulation , and aggression incidents . Forensic setting s may represent a new frontier for the clinical dissemination of cognitive remediation Cognitive Behavioral Social Skills Training ( CBSST ) is a 24-session weekly group therapy intervention to improve functioning in people with schizophrenia . In our prior r and omized clinical trial comparing treatment as usual ( TAU ) with TAU plus group CBSST ( Granholm , E. , McQuaid , J.R. , McClure , F.S. , Ausl and er , L. , Perivoliotis , D. , Pedrelli , P. , Patterson , T. , Jeste , D.V. , 2005 . A r and omized controlled trial of cognitive behavioral social skills training for middle-aged and older out patients with chronic schizophrenia . Am . J. Psychiatry 162 , 520 - 529 . ) , participants with schizophrenia in CBSST showed significantly better functional outcome than participants in TAU . The present study was a secondary analysis of neuropsychological predictors of functional outcome in our prior CBSST trial . We examined ( 1 ) whether neuropsychological impairment at baseline moderated functional outcome in CBSST relative to TAU , and ( 2 ) whether improvement in neuropsychological abilities mediated improvement in functional outcome in CBSST . Attention , verbal learning/memory , speed of processing , and executive functions were assessed at baseline , end of treatment , and 12-month follow-up . Greater severity of neuropsychological impairment at baseline predicted poorer functional outcome for both treatment groups ( nonspecific predictor ) , but the interaction between severity of neuropsychological impairment and treatment group was not significant ( no moderation ) . Effect sizes for the difference between treatment groups on functional outcome measures at 12-month follow-up were similar for participants with relatively mild ( d=.44-.64 ) and severe ( d=.29-.60 ) neuropsychological impairment . Results also did not support the hypothesis that improvement in neuropsychological abilities mediated improvement in functioning in CBSST . Adding CBSST to st and ard pharmacologic care , therefore , improved functioning relative to st and ard care alone , even for participants with severe neuropsychological impairment , and this improvement in functioning was not related to improvement in neuropsychological abilities in CBSST |
1,955 | 27,214,762 | No significant differences were noted in rates of medication adherence or adverse events between OD and MD dosing .
With regard to mesalamine suppository , no significant differences were noted for comparisons between dosing regimens and adverse events for induction of remission .
OD dose of mesalamine is as effective and safe as MD doses for the induction and maintenance treatment of mild to moderate UC .
OD mesalamine given as a suppository can attain the same effect and safety as MD mesalamine in inducing remission of mild to moderate ulcerative colitis | AIM 5-Aminosalicylic acid is the first-line drug for mild to moderate ulcerative colitis ( UC ) .
The most commonly used 5-aminosalicylic acid is mesalamine .
Several systematic review s have demonstrated that mesalamine is effective in inducing and maintaining remission . | Objectives : To determine the therapeutic equivalence and safety of once daily ( OD ) versus three times daily ( TID ) dosing of a total daily dose of 3 g Salofalk ( mesalazine ) granules in patients with active ulcerative colitis . Design : A r and omised , double-blind , double-dummy , parallel group , multicentre , international , phase III non-inferiority study . Setting : 54 centres in 13 countries . Patients : 380 patients with confirmed diagnosis of established or first attack of ulcerative colitis ( clinical activity index (CAI)>4 and endoscopic index ⩾4 at baseline ) were r and omised and treated . Interventions : 8-week treatment with either 3 g OD or 1 g TID mesalazine granules . Main outcome measures : Clinical remission ( CAI⩽4 ) at study end . Results : 380 patients were evaluable for efficacy and safety by intention-to-treat ( ITT ) ; 345 for per protocol ( PP ) analysis . In the ITT population , 79.1 % in the OD group ( n = 191 ) and 75.7 % in the TID group ( n = 189 ) achieved clinical remission ( p<0.0001 for non-inferiority ) . Significantly more patients with proctosigmoiditis achieved clinical remission in the OD group ( 86 % ; n = 97 ) versus the TID group ( 73 % ; n = 100 ; p = 0.0298 ) . About 70 % of patients in both treatment groups achieved endoscopic remission , and 35 % in the OD group and 41 % in the TID group achieved histological remission . About 80 % of all patients preferred OD dosing . Similar numbers of adverse events occurred in 55 patients ( 28.8 % ) in the OD group and in 61 patients ( 32.3 % ) in the TID group , indicating that the two dosing regimens were equally safe and well tolerated . Conclusions : OD 3 g mesalazine granules are as effective and safe as a TID 1 g schedule . With respect to the best possible adherence of patients to the treatment , OD dosing of mesalazine should be the preferred application mode in active ulcerative colitis . Clinical Trials.gov Identifier : Background and Aims Multiple studies have demonstrated the efficacy of aminosalicylates in maintaining remission in ulcerative colitis ( UC ) . A newer formulation of mesalamine can be administered once daily . We aim ed to examine the efficacy and tolerability of pH-dependent mesalamine for long-term maintenance , and compare the rates of medication consumption between groups over a prolonged period . Methods Subjects whose UC had been quiescent for at least 4 months , and who had been receiving mesalamine for maintenance only , were r and omized to once daily or conventional dosing for 12 months . Disease activity and medication consumption was assessed every 3 months . The primary endpoint was the percentage of those with quiescent disease at 12 months . Results We enrolled 20 patients , 12 to once daily and 8 to conventional dosing . Six of the 12 patients ( 50 % ) in the once daily group compared with 5 of the 8 patients ( 62.5 % ) in the conventional group experienced a flare ( p = 0.31 ) . Only 5 of the 12 ( 42 % ) patients in the once daily group were adherent compared with 3 of 8 patients ( 37.5 % ) in the conventional dosing group ( p = NS ) . Median amount consumed in the once daily group was 63 % ( range 0%–100 % ) and in the conventional group 55 % ( range 0%–100 % ) , ( p > 0.5 ) . None of the adherent subjects in the once daily group experienced a flare , while 6 out of 7 ( 86 % ) who were non-adherent experienced a flare ( p < 0.01 ) . In the conventional dosing group , 1 in 3 adherent patients ( 33 % ) experienced a flare compared with 4 out of 5 ( 80 % ) in the non-adherent group ( p < 0.01 ) . Conclusion Adherence , rather than medication regimen , appeared to be important in disease outcome at 12 months Background : Mesalazine ( Asacol ) is still widely prescribed in divided doses for ulcerative colitis ( UC ) , despite evidence that adherence is improved by once‐daily ( OD ) prescribing . We aim ed to investigate whether OD Asacol was as effective as three times ( TDS ) daily dosing , and to evaluate the role of treatment adherence . Methods : An investigator‐blind r and omized trial was undertaken comparing OD Asacol ( three 800 mg tablets ) versus one 800 mg TDS in maintenance of remission of UC over 1 year . The primary endpoint was relapse rate , and noninferiority would be concluded if the lower limit of the two‐sided 95 % confidence interval ( CI ) of the difference in proportions relapsing ( TDS‐OD ) exceeded −10 % . Adherence was measured by tablet counts and self‐reported adherence . A subgroup of patients used a bottle cap that recorded all bottle opening events . Results : In all , 213 patients were r and omized . In the intention‐to‐treat ( ITT ) population , relapse rates were 31 % ( 95 % CI 22%–40 % ) in the OD and 45 % ( 95 % CI 35%–54 % ) in the TDS group . Primary analysis confirmed the noninferiority of OD dosing . Two of the study population s , ITT and per‐ protocol ( PP ) , showed potential superiority of OD dosing . All measures of adherence showed that it was significantly better in the OD group . Multivariate analysis , however , showed OD dosing was associated with lower relapse risk independently of adherence . Conclusions : OD dosing with Asacol 2.4 g is as safe and effective as TDS dosing , and secondary analysis confirmed significantly reduced relapse rates . The benefit , however , was clinical ly borderline and may relate in part to ease of adherence . ( Inflamm Bowel Dis 2012 BACKGROUND & AIMS SPD476 ( MMX mesalamine ) , a novel , once-daily mesalamine formulation , uses MMX Multi Matrix System ( MMX ) technology to delay and extend delivery of active drug throughout the colon . We performed a r and omized , double-blind , parallel-group , placebo-controlled , multicenter phase III study in patients with mild to moderately active ulcerative colitis . METHODS Two hundred eighty patients with mild to moderately active ulcerative colitis received MMX mesalamine 2.4 g/day given twice daily ( n = 93 ) , 4.8 g/day given once daily ( n = 94 ) , or placebo ( n = 93 ) for 8 weeks . The primary end point was the percentage of patients in clinical and endoscopic remission ( modified ulcerative colitis disease activity index score of < or = 1 , with a score of 0 for rectal bleeding and stool frequency , and at least a 1-point reduction in sigmoidoscopy score ) at week 8 . Patients with mucosal friability were not considered to have achieved this end point . RESULTS Clinical and endoscopic remission at week 8 was achieved by 34.1 % and 29.2 % of patients receiving MMX mesalamine 2.4 g/day given twice daily and MMX mesalamine 4.8 g/day given once daily , respectively , versus 12.9 % receiving placebo ( P < .01 ) . MMX mesalamine was generally well-tolerated . CONCLUSIONS MMX mesalamine given once or twice daily is well-tolerated and , compared with placebo , demonstrated efficacy for the induction of clinical and endoscopic remission in mild to moderately active ulcerative colitis BACKGROUND & AIMS This study was conducted to assess , in a small sample , the short-term outcomes of once-daily mesalamine versus conventional dosing in maintaining quiescent ulcerative colitis ( UC ) and to assess adherence rates with both regimens . METHODS Consecutive patients were r and omly assigned to either a once-daily regimen , or they continued current conventional regimen ( twice daily or 3 times daily ) . Patients were assessed at 3 months and 6 months . At each point , a clinical symptom disease score was obtained using patient question naires , and medication rates via pharmacy data . Adherence was defined as consumption of > 80 % of prescribed medication . Information was collected by an investigator blinded to treatment regimen . RESULTS Twenty-two patients were enrolled in the study , 12 in the once-daily group ( QD ) and 10 in the conventional group ( CD ) . At 3 months , no patients had experienced a relapse . All of the patients in the QD group and 70 % of patients in the CD group were adherent ( P = 0.04 ) . The average amount of medication consumed in the QD group was significantly higher than in the CD group ( 90 % vs. 75 % , P = 0.02 ) . At 6 months , 2 patients ( 1 patient from each group ) experienced a clinical relapse ( P = 0.76 ) . Seventy-five percent vs. 70 % of patients were adherent ( P = 0.8 ) ; the amount of medication taken approached significance ( 90 % vs. 76 % , P = 0.07 ) . All patients in the QD group reported being either " very satisfied " or " satisfied " with their regimen . CONCLUSIONS In this r and omized pilot trial , patients taking once-daily mesalamine had outcomes similar to those for patients on conventional regimens . A larger trial is warranted to assess whether true differences between regimens exist BACKGROUND & AIMS The practice of dosing mesalamines in divided doses for the treatment of ulcerative colitis ( UC ) began with sulfasalazine and was driven by sulfapyridine toxicity . This convention and the assumption that dosing multiple times a day is necessary to treat UC had not been challenged until recently . This study was conducted to determine the efficacy and safety of once-daily dosing of delayed-release mesalamine ( Asacol 400-mg tablets ) compared with twice-daily dosing for maintaining remission in UC patients . METHODS A multicenter , r and omized , investigator-blinded , 12-month , active-control trial was conducted to assess the noninferiority of delayed-release mesalamine 1.6 - 2.4 g/day administered once daily compared with twice daily in patients with mild-to-moderate UC currently in clinical remission . The primary end point was maintenance of clinical remission at month 6 . RESULTS A total of 1023 patients were r and omized and dosed . The primary objective of noninferiority was met . At month 6 , 90.5 % of patients receiving once-daily dosing had maintained clinical remission , compared with 91.8 % of patients receiving twice-daily dosing ( 95 % confidence interval for twice daily - once daily , -2.3 to 4.9 ) . At month 12 , 85.4 % of patients receiving once-daily dosing had maintained clinical remission , compared with 85.4 % of patients receiving twice-daily dosing ( 95 % confidence interval for twice daily - once daily , -4.6 to 4.7 ) . Both regimens had low rates of withdrawals as a result of adverse events and serious adverse events . CONCLUSIONS Once-daily dosing of delayed-release mesalamine at doses of 1.6 - 2.4 g/day was shown to be as effective as twice-daily dosing for maintenance of clinical remission in patients with UC Background : Ulcerative colitis ( UC ) , a chronic , relapsing , and remitting inflammatory bowel disease , requires long-term treatment to maintain remission . In this study , the long-term safety and tolerability of mesalamine granules ( MG ) therapy was evaluated in the maintenance of UC remission . Previous prospect i ve studies evaluating different oral mesalamine formulations have not exceeded a duration of 14 months . Methods : A phase 3 , multicenter , 24-month , open-label extension study evaluating MG 1.5 g once daily in patients who achieved previous remission from mild to moderate UC was performed . Eligible patients had successfully participated in 1 of 2 previous 6-month double-blind , placebo-controlled trials or were new patients in remission . Safety assessment s included monitoring of adverse events ( AEs ) and clinical laboratory tests . Risk of UC recurrence was assessed by the occurrence of UC-related AEs . Results : Of the 393 patients enrolled ( 280 from the double-blind studies ; 113 new patients ) , 388 were included in the safety population . The most common AEs included nasopharyngitis ( 13.9 % ) , headache ( 11.6 % ) , and diarrhea ( 10.8 % ) , and the incidence of these events was generally lower in the MG group versus historical placebo group from the double-blind studies . Pancreatic , renal , and hepatic AEs occurred in 23 patients ( 5.9 % ) . The risk of UC-related AEs was low and was maintained for 24 months during the open-label study . Conclusions : Once-daily MG has a favorable safety profile for the maintenance of remission for up to 2 years in patients with UC BACKGROUND & AIMS SPD476 ( LIALDA in the US ; MEZAVANT in the EU ; otherwise known as MMX mesalamine ; Shire Pharmaceuticals Inc. , Wayne , PA , under license from Giuliani SpA , Milan , Italy ) is a novel , once-daily , high-strength ( 1.2 g/tablet ) formulation of mesalamine , utilizing MMX Multi Matrix System ( MMX ) technology design ed to deliver the active drug throughout the colon . We performed a double-blind , multicenter study , comparing MMX mesalamine vs placebo for the treatment of active ulcerative colitis . A delayed-release oral mesalamine ( ASACOL ; Procter & Gamble , Cincinnati , OH ) reference arm was included . METHODS Three hundred forty-three patients with active , mild-to-moderate ulcerative colitis received MMX mesalamine 2.4 g/day or 4.8 g/day given once daily , ASACOL 2.4 g/day given in 3 divided doses , or placebo for 8 weeks . The primary end point was the proportion of patients in clinical and endoscopic remission ( modified ulcerative colitis disease activity index of < or = 1 with rectal bleeding and stool frequency scores of 0 , no mucosal friability , and a > or = 1-point reduction in sigmoidoscopy score from baseline ) . RESULTS A significantly greater proportion of patients receiving MMX mesalamine 2.4 g/day given once daily ( 40.5 % ; P = .01 ) and 4.8 g/day given once daily ( 41.2 % ; P = .007 ) achieved clinical and endoscopic remission at week 8 , vs placebo ( 22.1 % ) . The clinical and endoscopic remission rate for ASACOL ( 32.6 % ; P = .124 ) was not significantly superior to placebo . All active treatments were well-tolerated . CONCLUSIONS Once-daily MMX mesalamine was efficacious and well-tolerated for the induction of clinical and endoscopic remission . MMX mesalamine offers effective and convenient mesalamine therapy , potentially improving treatment compliance Background : Ulcerative proctitis ( UP ) usually presents as fresh rectal bleeding . Successful treatment using topical mesalamine 5‐aminosalicyclic acid ( 5‐ASA ) 500 mg BID suppository led to developing a once‐a‐day formulation that could contribute to better acceptability and ease of use by patients . The objective of this r and omized trial , conducted in 18 centers , was to compare efficacy of 2 modes of treatment with 5‐ASA suppositories . Methods : Ninety‐nine patients with mild or moderate UP limited to 15 cm of the anal margin , evidence d by a disease activity index ( DAI ) between 4 and 11 , were r and omized to 5‐ASA 500 mg suppository ( Canasa ; Axcan Pharma ) BID or 1 g at bedtime ( HS ) for 6 weeks . The study used a noninferiority hypothesis based on the mean difference in DAI values after 6 weeks of treatment on an intent‐to‐treat basis using analysis of covariance . DAI was derived from a composite of the measures of stool frequency , rectal bleeding , mucosal visualization at endoscopy , and general well being . Results : There was no difference between groups at baseline for demographic and clinical parameters . Mean DAIs fell from 6.6 ± 1.5 ( SD ) to 1.6 ± 2.3 in the 500 mg BID group ( n = 48 ) and from 6.1 ± 1.5 to 1.3 ± 2.2 in the 1 g HS group ( n = 39 ) . There was no significant difference ( P = 0.74 ) in mean DAI at week 6 between the 2 groups . Both groups showed a significant reduction ( P < 0.0001 ) in DAI over the course of the 6 weeks . Both formulations showed effectiveness in reducing each individual component of the DAI . There was no significant difference between treatments in adverse events , and both groups had an overall drug compliance of greater than 95 % . Conclusion : This study showed that 1 g HS and 500 mg BID mesalamine suppository treatments of UP patients were equivalent in all facets of efficacy , safety , and compliance in a 6‐week trial Background : Mesalazine preparations are widely used to treat mild to moderately severe ulcerative colitis ( UC ) . We compared once-daily administration of oral mesalazine in patients with quiescent UC with the established 3-times-daily prescription , assessing the efficacy and safety of each method in maintaining remission for 52 weeks . Methods : This was a double-blind , double-dummy , r and omized , multicenter noninferiority study in which 301 patients with quiescent UC were r and omly assigned to treatment groups and administered prolonged-release oral mesalazine at doses of 1.5 to 2.25 g/d once daily ( QD ) or 3 times daily ( TID ) for 52 weeks . The primary endpoint was whether remission was maintained after 52 weeks of administration or until the time of discontinuation , as represented by the Ulcerative Colitis Disease Activity Index score . Results : The proportion of patients still in remission after 52 weeks of administration was 79.4 % in the QD group and 71.6 % in the TID group . The between-group difference was 7.8 % ( 2-tailed 95 % confidence interval [ CI ] : −2.2 % to 17.8 % ) , and the noninferiority of QD administration to TID administration was verified with a noninferiority margin of −10 % . In the safety analysis , the incidence of adverse events in each group was 72.4 % for the QD group and 76.5 % for the TID group , showing no statistically significant difference between the 2 groups ( P = 0.4305 ) . Conclusions : This double-blind parallel-group comparison verified for the first time the noninferiority of QD administration of oral mesalazine 1.5 to 2.25 g/d to TID administration in terms of maintaining remission in patients with UC A r and omized , 2-way , crossover study was conducted in 30 volunteers to compare the pharmacokinetic profile of a new once-daily dosing regimen of mesalazine ( 1 x 4 g/d ) with the current twice-daily dosage ( 2 x 2 g/d ) used in many European countries . The 2 dosages were administrated orally for 8 days , separated by a 2-week washout . Plasma concentrations of mesalazine and N-acetyl-mesalazine were determined on days 1 and 8 by a vali date d high-performance liquid chromatography method and C(max ) , t(max ) , and AUCs calculated . The bioequivalence was obtained for a 90 % confidence interval of the AUC(0 - 24h ) ratio ( test/reference ) for mesalazine and N-acetyl-mesalazine on days 1 and 8 , within the range of 0.80 to 1.25 . The bioequivalence was demonstrated on day 1 for mesalazine and N-acetyl-mesalazine and on day 8 for mesalazine . As it is desirable to offer patients a preparation with a less frequent administration to enhance compliance , this once-daily regimen may be an attractive dosing option OBJECTIVES : Treatment with mesalamine to maintain endoscopic remission ( mucosal healing ) of ulcerative colitis ( UC ) has been shown to reduce the risk of relapse and is the recommended first-line maintenance therapy . To improve treatment adherence , a mesalamine formulation that can be administered once-daily , MMX ® mesalamine ( Lialda ; Shire Pharmaceuticals LLC , Wayne , PA ) , was developed . This study was conducted to determine the efficacy and safety of once-daily MMX mesalamine compared with twice-daily delayed-release mesalamine ( Asacol ; Warner Chilcott , Dublin , Irel and ) for maintaining endoscopic remission in patients with UC . METHODS : A multicenter , r and omized , double-blind , 6-month , active-control trial was conducted to assess the non-inferiority of once-daily MMX mesalamine 2.4 g/day compared with twice-daily delayed-release mesalamine at a total daily dose of 1.6 g/day in patients with UC in endoscopic remission . The primary end point was maintenance of endoscopic remission at month 6 in the per- protocol ( PP ) population . RESULTS : Overall , 826 patients were r and omized and dosed . The primary objective ( non-inferiority ) was met . At month 6 , 83.7 and 77.8 % of patients receiving MMX mesalamine in the PP and intent-to-treat ( ITT ) population s , respectively , had maintained endoscopic remission compared with 81.5 % ( PP ) and 76.9 % ( ITT ) of patients receiving delayed-release mesalamine ( 95 % confidence interval for difference : –3.9 % , 8.1 % ( PP ) ; –5.0 % , 6.9 % ( ITT ) ) . Time to relapse was not significantly different between the two treatment groups ( log-rank test , P=0.5116 ( PP ) ; P=0.5455 ( ITT ) ) . The proportion of patients with adverse events was 37.1 and 36.0 % in patients receiving MMX mesalamine and delayed-release mesalamine , respectively . CONCLUSIONS : Once-daily dosing of MMX mesalamine 2.4 g/day was shown to be well tolerated and non-inferior to twice-daily dosing with delayed-release mesalamine 1.6 g/day for maintenance of endoscopic remission in patients with UC Mesalazine suppositories at 500 mg b.d . are a safe and effective treatment for patients with ulcerative proctitis or distal proctosigmoiditis . Recently a mesalazine 1 g suppository ( Pentasa ) has been developed BACKGROUND & AIMS Oral mesalamine ( 5-aminosalicylate ) is the current st and ard of care for mild-to-moderate ulcerative colitis . We investigated the efficacy and safety of once daily administration of prolonged-release mesalamine granules in maintenance of remission in patients with quiescent ulcerative colitis , compared with the well established twice daily dosing regimen . METHODS In this multicenter , r and omized , single blind , noninferiority trial , 362 patients with quiescent ulcerative colitis were r and omly assigned ( 1:1 ) to groups that were given oral mesalamine 2 g , once daily , or 1 g , twice daily , for 12 months . The primary objective was to compare remission rates at 1 year , based on the ulcerative colitis disease activity index score , using Kaplan-Meier methodology . RESULTS At 1 year , 70.9 % of the group given 2 g mesalamine once daily remained in remission vs 58.9 % of the group given 1 g mesalamine twice daily ; this difference was statistically significant ( P = .024 ) , indicating the increased efficacy of once daily , compared with twice daily , dosing . Self-reported adherence to therapy , measured by visual analog scale score after 4 , 8 , and 12 months , was significantly greater in the group given 2 g mesalamine once daily , compared with twice daily , at all but 1 study visit ( P < .05 ) . Compliance measured by medication taken was not significantly different between the groups . The difference between the 2 groups in overall incidence of adverse events was not statistically significant ( P = .23 ) . CONCLUSIONS Patients with ulcerative colitis given prolonged-release oral mesalamine 2 g once daily had better remission rates , acceptability , and self-reported adherence to therapy compared with patients given oral mesalamine 1 g twice daily Background : Mesalamine suppositories are first‐line therapy in active ulcerative proctitis ; the st and ard regime still recommends multiple doses per day . The primary objective of this study was to show the noninferiority of once‐daily administration of a novel 1 g mesalamine suppository versus thrice‐daily administration of the 0.5 g mesalamine suppository . Methods : This was a single‐blind ( investigator‐blinded ) , r and omized , multicenter , comparative , Phase III clinical trial . Patients with mild to moderately active ulcerative proctitis inserted either one mesalamine 1 g suppository at bedtime or one mesalamine 0.5 g suppository thrice daily over a 6‐week period . The primary endpoint was rate of remission ( Disease Activity Index below 4 ) . Results : In all , 354 patients were evaluable for safety and per‐ protocol analysis . The new regimen demonstrated noninferiority : The percentage of patients with remission was 87.9 % for the once‐daily 1 g mesalamine suppository and 90.7 % for the thrice‐daily 0.5 g mesalamine suppository . Each regimen result ed in prompt cessation of clinical symptoms ( e.g. , median time to ≤3 stools per day ( all without blood ) : 5 days in the 1 g mesalamine once‐daily and 7 days in the 0.5 g mesalamine thrice‐daily group ) . Patients preferred applying suppositories once a day . Conclusions : In active ulcerative proctitis the once‐daily administration of a 1 g mesalamine suppository is as effective and safe , yet considerably more convenient , than the st and ard thrice‐daily administration of a 0.5 g mesalamine suppository . ( Inflamm Bowel Dis 2010 |
1,956 | 26,431,122 | High- quality studies mainly assessed factors related to disease functions and structures . | BACKGROUND Characterization of the prognostic variables for persistent neuropathic pain ( PNP ) remains incomplete despite multiple articles addressing this topic .
To provide more insight into the recovery and prognosis of neuropathic pain , high- quality data are required that provide information about the predictors that contribute to the development of PNP .
OBJECTIVE To determine the method ological quality of studies about predictors for PNP and to summarize findings of predictors found in high- quality studies . | Abstract We studied the prevalence of chronic pain and long term sensory changes after cosmetic augmentation mammoplasty and the effects of a single i.v . preoperative dose of methylprednisolone 125 mg ( n = 74 ) , parecoxib 40 mg ( n = 71 ) , or placebo ( n = 74 ) . A question naire was mailed 6 weeks and 1 year after surgery . Response rate after 1 year was 80 % . At 1 year non‐evoked pain was present in 13 % , and evoked pain was present in 20 % with no statistically significant differences between the groups . Methylprednisolone was associated with reduced odds for hyperesthesia at 1 year ( OR 0.3 , 95 % CI 0.1–0.6 ) , and significantly reduced the prevalence of hyperesthesia ( 30 % ) compared with placebo ( 56 % , P < 0.01 ) and parecoxib ( 51 % , P < 0.04 ) . Factors associated with increased odds for pain at 1 year were intensity of pain during the first 6 days after surgery ( OR 1.3 , 95 % CI 1.1–1.6 ) , pain at 6 weeks ( OR 18.4 , 95 % CI 6.9–49.3 ) , hyperesthesia at 6 weeks ( OR 2.3 , 95 % CI 1.1–5.1 ) and present hyperesthesia ( OR 3.1 , 95 % CI 1.4–6.7 ) . We conclude that persistent pain and sensory changes are common after augmentation mammoplasty , and that patients having pain at 6 weeks most likely will have pain also at 1 year . Acute postoperative pain , hyperesthesia at 6 weeks , and the presence of hyperesthesia increased the odds for pain at 1 year . Preoperative methylprednisolone result ed in significantly less hyperesthesia compared with both parecoxib and placebo , but did not significantly reduce the prevalence of persistent spontaneous or evoked pain Background : Sympathetic blockade with local anesthetics is used frequently in the management of complex regional pain syndrome type 1(CRPS-1 ) , with variable degrees of success in pain relief . The current study investigated which signs or symptoms of CRPS-1 could be predictive of outcome . The incidence of side effects and complications of sympathetic blockade also were determined prospect ively . Methods : A prospect i ve observational study was done of 49 patients with CRPS-1 in one extremity only and for less than 1-yr duration who had severe pain and persistent functional impairment with no response to st and ard treatment with medication and physical therapy . Results : Fifteen ( 31 % ) patients had good or moderate response . The response rate was not different in patient groups with cold or warm type CRPS-1 or in those with more or less than 1.5 ° C differential increase in skin temperature after sympathetic blockade . Allodynia and hypoesthesia were negative predictors for treatment success in CRPS-1 . There were no symptoms or signs of CRPS-1 that positively predicted treatment success . A majority of patients ( 84 % ) experienced transient side effects such as headache , dysphagia , increased pain , backache , nausea , blurred vision , groin pain , hoarseness , and hematoma at the puncture site . No major complications were reported . Conclusions : The presence of allodynia and hypoesthesia are negative predictors for treatment success . The selection of sympathetic blockade as treatment for CRPS-1 should be balanced carefully between potential success and side effect ratio . The procedure is as likely to cause a transient increase in pain as a decrease in pain . Patients should be informed accordingly BACKGROUND Spinal cord stimulation ( SCS ) has proven to be an effective however an invasive and relatively expensive treatment of chronic Complex Regional Pain Syndrome type 1(CRPS-1 ) . Furthermore , in one third of CRPS-1 patients , SCS treatment fails to give significant pain relief and 32 - 38 % of treated patients experience complications . The aim of the current study was to develop effective prognostic factors for prediction of successful outcome of SCS . METHODS AND RESULTS The study population consisted of 36 chronic CRPS patients enrolled in a r and omized controlled trial of SCS efficacy . We analyzed various prognostic factors in the group of patients treated with SCS and compared baseline values of possible predictors of outcome in the successfully treated and the not successfully treated group . Success was defined as Patient Global Perceived Impression of Change score of at least " much improved " and pain reduction of at least 2.5 on a visual-analogue scale ( VAS score 0 - 10 ) . Univariate analyses showed that patient age , duration of the disease , localization of the disease , intensity of the pain , and the presence of mechanical hypoesthesia did not predict SCS success . The mean and maximum value of brush-evoked allodynia proved to be statistically significant predictors of outcome . Using Receiver-Operating Characteristic ( ROC ) curve analyses of maximum allodynia values , the diagnostic sensitivity for successful SCS was 0.75 and the specificity 0.81 . CONCLUSION Brush-evoked allodynia may be a significant negative prognostic factor of SCS treatment outcome after 1 year in chronic CRPS-1 Background Herpes zoster ( HZ ) is a common disease , characterized by rash-associated localized pain . Its main complication , post-herpetic neuralgia ( PHN ) , is difficult to treat and may last for months to years in the wake of rash resolution . Uncertainties remain as to the knowledge of predictors of HZ-related pain , including the role of antiviral therapy in preventing PHN in ordinary clinical practice . This prospect i ve cohort study was aim ed at investigating pain intensity at HZ presentation and its correlates , as well as the incidence of PHN and its predictors . Methods Patients diagnosed with HZ were consecutively enrolled by a network of Italian General Practitioners and Hospital Units in the health district of Pescara , Italy , over two years . Uncertain cases were referred for microbiological investigation . Data were collected through electronic case report form ( e-CRFs ) at enrolment and at 1 , 3 , 6 and 12 months after enrolment . Pain intensity was coded on a five-degree semi-quantitative scale at each time point . PHN was defined as pain of any intensity during follow-up and quantified using an area-under-the-curve ( AUC ) method . Results Four hundred and forty-one patients composed the final sample . Mean age was 58.1 years ( SD = 20.4 years ) ; 43.5 % of patients were males ; 7.9 % did not receive prescription of antivirals . Intense/very intense pain at presentation was reported by 25.2 % of patients and was significantly associated with female gender , older age , cigarette smoking , trauma and /or surgery at HZ site ( logistic regression ) . PHN was diagnosed in 51.2 % of patients at one month and in 30.0 % of patients at three months . PHN was significantly associated with pain intensity at presentation , age , smoking , trauma and missed antiviral prescription ( generalized estimating equations model ) . The same factors were also independent predictors of the overall pain burden as described by the AUC method ( linear regression ) . Conclusions Smoking , traumas and surgery at the HZ site emerged as new predictors of both HZ-related pain intensity and persistence , opening new perspectives in the prevention of HZ-related pain . An independent line of evidence was provided for the efficacy of antiviral therapy in preventing PHN and reducing total pain burden Summary Despite early diagnosis and treatment with antiviral agents , many herpes zoster patients report persistent pain and marked long‐term reduction in health‐related quality of life . Abstract Underst and ing the effect of herpes zoster and zoster‐related pain should inform care to improve health‐related quality of life in elderly patients . A 12‐month , longitudinal , prospect i ve , multicenter observational study conducted in primary care in France enrolled patients aged ⩾50 years with acute eruptive herpes zoster . Patient‐reported zoster‐related pain was assessed by vali date d question naires ( Douleur Neuropathique en 4 Questions [ DN4 ] , Zoster Brief Pain Inventory [ ZBPI ] , and Neuropathic Pain Symptom Inventory [ NPSI ] ) on days 0 and 15 , and at months 1 , 3 , 6 , 9 , and 12 . Health‐related quality of life was assessed by the 12‐item short‐form health survey ( SF‐12 ) and the Hospital Anxiety and Depression scale on day 0 and at months 3 , 6 , and 12 . Of 1358 patients included , 1032 completed follow‐up . Mean ± st and ard deviation age was 67.7 ± 10.7 ( range , 50–95 ) years ; 62.2 % were women . Most patients ( 94.1 % ) were prescribed antiviral drugs . The prevalence of zoster‐related pain on day 0 and at months 3 , 6 , 9 , and 12 was 79.6 % , 11.6 % , 8.5 % , 7.4 % , and 6.0 % , respectively . Patients with persistent pain had lower scores on the physical and mental component summaries of the SF‐12 and the ZBPI interference score than those without pain . By logistic regression analysis , main predictive factors on day 0 for postherpetic neuralgia at month 3 were age , male sex , ZBPI interference score , Physical Component Summary score of the SF‐12 , and neuropathic quality of pain ( DN4 score ⩾4 ) . Despite early diagnosis and treatment with antiviral agents , many patients with herpes zoster experience persistent pain and marked long‐term reduction in health‐related quality of life Background : Women scheduled to undergo hysterectomy for benign indications frequently have preoperative pelvic pain , but it is largely unknown why pain in some cases persists or even develops after surgery . This nationwide question naire and data base study describes pain and identifies risk factors for chronic postsurgical pain 1 yr after hysterectomy for benign indications . Methods : A pain question naire was mailed to 1,299 women 1 yr after hysterectomy . The response rate was 90.3 % , and the presence of persistent pain was correlated to indication for surgery , surgical procedure , type of anesthesia , and other perioperative data . Results : Pain was reported by 31.9 % 1 yr after hysterectomy ( chronic pain ) , and 13.7 % had pain more than 2 days a week . Pain was not present before surgery in 14.9 % of women with chronic postsurgical pain . Risk factors for chronic pain were preoperative pelvic pain ( odds ratio [ OR ] , 3.25 ; 95 % confidence interval [ CI ] , 2.40–4.41 ) , previous cesarean delivery ( OR , 1.54 ; CI , 1.06–2.26 ) , pain as the main indication for surgery ( OR , 2.98 ; CI , 1.54–5.77 ) , and pain problems elsewhere ( OR , 3.19 ; CI , 2.29–4.44 ) . Vaginal hysterectomy versus total abdominal hysterectomy was not significantly associated with a lower risk of chronic pain ( OR , 0.70 ; CI , 0.46–1.06 ) . Importantly , spinal versus general anesthesia was associated with less chronic pain ( OR , 0.42 ; CI , 0.21–0.85 ) . Conclusions : Thirty-two percent had chronic pain after hysterectomy , and risk factors were comparable to those seen in other operations . Interestingly , spinal anesthesia was associated with a lower frequency of chronic pain , justifying prospect i ve study of spinal anesthesia for patients with a high risk for development of chronic postsurgical pain Objectives : To identify risk factors for postherpetic neuralgia ( PHN ) using a vali date d definition of this chronic neuropathic pain syndrome , to determine combinations of risk factors that identify patients with a high risk of developing PHN , and to examine the characteristics of patients with subacute herpetic neuralgia , that is , pain that persists beyond the acute phase of herpes zoster but that resolves before PHN can be diagnosed . Methods : The authors examined baseline and follow-up data from 965 herpes zoster patients enrolled within 72 hours of rash onset in two clinical trials of famciclovir . Results : Univariate and multivariate analyses indicated that older age , female sex , presence of a prodrome , greater rash severity , and greater acute pain severity made independent contributions to identifying which patients developed PHN . Patients with subacute herpetic neuralgia who did not develop PHN were significantly younger and had less severe acute pain than PHN patients but were significantly more likely to have severe and widespread rash than patients without persisting pain . Conclusions : The independent contributions to the prediction of PHN made by older age , female sex , presence of a prodrome , greater rash severity , and greater acute pain severity suggest that these risk factors reflect different mechanisms that each contribute to the development of PHN . Subacute herpetic neuralgia that does not progress to PHN may reflect peripheral tissue damage and inflammation caused by a particularly severe or widespread rash Seventy-one patients presenting with acute herpes zoster ophthalmicus were followed up for six months for a prospect i ve analysis of the natural history of the disease . Acute and chronic ocular complications , nasociliary nerve involvement , age , sex , rash , and pain were assessed , and the results are presented . Acute pain was measured by a visual analogue scale . Postherpetic neuralgia ( PHN ) was more likely in patients over 80 and in those who scored their pain highly at presentation . Duration of rash was longer in patients who developed PHN . No other associations between the parameters studied were found . Nasociliary nerve involvement was associated with subsequent ocular disease Acute neuritis and persistent pain are the most significant clinical manifestations of herpes zoster and are end points for clinical trials therapy . In an acyclovir and prednisone study , patients were categorized according to pain severity and number of lesions at presentation . Risk categories were defined according to the magnitude of risk ratios ( RRs ) and a comparison of Kaplan-Meier survival estimates . For acute neuritis and zoster-associated pain , RRs defined rate of resolution . Patients who presented with severe or incapacitating pain and a large number of lesions were less likely to achieve resolution of both acute neuritis and zoster-associated pain ( RR , 18.0 ; 95 % confidence interval [ CI ] , 6 . 6 - 48.6 , and RR , 5.3 ; 95 % CI , 4.2 - 17.2 , respectively ) . These analyses identify the subgroups of patients for whom aggressive interventions are most strongly indicated Chronic pain following thoracic surgery is common and associated with neuropathic symptoms , however , the proportion of patients with neuropathic pain in the immediate postoperative period is unknown . We aim ed to determine the proportion of patients who have neuropathic symptoms and signs immediately after , and at three months following thoracic surgery . The study was design ed as a prospect i ve observational cohort study . We identified patients with pain of predominantly neuropathic origin using the Leeds Assessment of Neuropathic Symptoms and Signs ( LANSS ) score in the immediate postoperative period and the self-report LANSS ( S-LANSS ) version three months after surgery . One hundred patients undergoing video assisted thoracic surgery ( VATS ) or thoracotomy completed LANSS scores preoperatively and in the immediate postoperative period . Eighty-seven percent completed three months S-LANSS follow-up scores . Eight percent of patients had positive LANSS scores in the immediate postoperative period ; 22 % of patients had positive S-LANSS scores three months following surgery . There was a significant association between positive scores in the acute and chronic periods ( relative risk ( RR ) 3.5 , [ 95 % confidence interval ( CI ) 1.7 - 7.2 ] ) . Identifying pain of predominantly neuropathic origin in the postoperative period with a simple pain score can help identify those at risk of developing chronic pain with these features following thoracic surgery Although patients with chronic pain are often psychologically distressed , it has been difficult to determine whether this distress is an antecedent of chronic pain or whether it is caused by the experience of living with chronic pain . The aim of this investigation was to develop a method that would allow individuals who are at risk for the development of chronic pain to be studied before their pain has become chronic . Patients with acute herpes zoster were assessed with demographic , medical , pain , and psychosocial measures . Pain was assessed in follow-up interviews at 6 weeks and 3 , 5 , 8 , and 12 months after these initial assessment s. There were no significant differences between patients who developed short-term herpes zoster pain and patients who did not develop short-term pain for any of the measures at the initial assessment , except for one measure of pain intensity . Patients who developed chronic herpes zoster pain , however , had significantly greater pain intensity , higher state and trait anxiety , greater depression , lower life satisfaction , and greater disease conviction at the initial assessment than patients who did not develop chronic pain . In discriminant analyses , disease conviction , pain intensity , and state anxiety each made a unique contribution to discriminating patients who did and who did not develop chronic pain . This study demonstrates the feasibility of investigating psychosocial antecedents of the development of chronic pain by prospect ively examining the longitudinal course of herpes zoster & NA ; Post‐herpetic neuralgia ( PHN ) is a neuropathic pain state that is often difficult to treat . Although frequently discussed in the clinical literature , little is known about the impact of pain on daily function and the extent to which psychosocial factors , in particular pain coping strategies , influence adaptation to this chronic illness . In the context of a crossover pharmacological trial , 68 patients with PHN completed a battery of psychological measures during a first drug‐free baseline period . Following discontinuation of approximately 8 weeks of treatment , 49 of these patients completed data collection during a second drug‐free assessment prior to beginning a second drug phase . Twice‐weekly telephone pain ratings were combined with question naire measures of perceived interference due to pain , overall activity level , depressive symptoms , and pain coping strategies . Cross‐sectional hierarchical regression analyses indicated that catastrophizing correlated with depressive symptoms but not pain , and coping self‐statements were correlated with higher levels of overall activity . Prospect i ve hierarchical regression analyses indicated that catastrophizing at baseline predicted level of pain 8 weeks later , an effect that was independent of baseline pain and depressive symptoms . Patients who reported increasing their activity in response to pain also reported more perceived interference due to pain 8 weeks later . Higher levels of ignoring pain sensations at baseline were prospect ively correlated with more depressive symptoms 8 weeks later . These findings support a role for the continued investigation of cognitive‐behavioral factors affecting the adaptation of elderly individuals experiencing PHN Objective : To investigate the effects of IV lidocaine on spontaneous and evoked pain ( allodynia and hyperalgesia ) due to peripheral nerve injury ( postherpetic neuralgia or nerve trauma ) using quantitative sensory testing . Method : The authors r and omized 22 patients to receive lidocaine 5 mg/kg IV during 30 minutes or placebo in a double-blind crossover design and 16 patients subsequently received mexiletine on an open basis titrated from 400 to 1,000 mg per day ( mean 737 mg/day ) . Results : Lidocaine induced a significant decrease in ongoing pain for up to 6 hours with a peak effect 60 to 120 minutes postinjection . The drug also decreased mechanical dynamic allodynia and static ( punctate ) mechanical allodynia/hyperalgesia , but not thermal allodynia and hyperalgesia . The effects of lidocaine and mexiletine on spontaneous pain intensity were significantly higher in patients with concomitant mechanical allodynia in comparison with those without allodynia . Conclusions : These data indicate modality-specific antihyperalgesic effects of IV lidocaine in patients with peripheral nerve injury . Patients with mechanical allodynia may be good c and i date s for treatment with local anesthetic-like drugs and possibly with other sodium-channel blockers The incidence of post-herpetic neuralgia following shingles and the factors that are known to predict it were examined in a prospect i ve observational community study of patients with acute shingles presenting to their family doctors . The detection of viral DNA in the blood at presentation as a prognostic indicator for pain was also evaluated . Patients were followed for one year and the persistence of pain following rash assessed . Among 165 patients who had completed 6 months , and 139 one-year follow-up , the prevalence of post herpetic neuralgia was 30 % at 6 weeks 27 % at 12 weeks , 15.9 % at 6 months , and 9 % at one year . Age and severity of pain were significantly associated with the persistence of pain beyond 3 months . Viremia at presentation was detected in 66 % of patients and was significantly associated with the presence of pain at six months or beyond . Antiviral agents were administered to only 50 % of those at highest risk of post-herpetic neuralgia ( PHN ) mainly because of presentation longer than 72 hours after the onset of rash . Few patients were prescribed the more potent prodrugs , Valaciclovir and Famciclovir . In conclusion , treatment of acute shingles in this observational community-based study was suboptimal in 50 % of cases . More accurate prediction of which subset of elderly patients are most at risk of PHN may enable targeted prescribing of the most potent drugs to those most likely to benefit ABSTRACT Neurotoxicity represents a major complication of oxaliplatin . This study aim ed to identify early clinical markers of oxaliplatin neurotoxicity , in comparison with cisplatin , and detect predictors of chronic neuropathy . Forty‐eight patients with mainly colorectal cancer were evaluated prospect ively before oxaliplatin ( n = 28 ) or cisplatin ( n = 20 ) administration and then 2 weeks after the third ( C3 ) , sixth ( C6 ) and ninth ( C9 ) cycles . Eighteen oxaliplatin patients were re‐assessed at 12 ± 2 months . Evaluation included quantitative sensory testing , i.e. , detection/pain thresholds for mechanical , vibration , cold and heat stimuli ; pain induced by suprathreshold cold ( 5–25 ° C ) and heat ( 38–48 ° C ) stimuli and quantified assessment of symptoms ( neuropathic pain symptom inventory ) . Symptoms of oxaliplatin neurotoxicity ( cold‐triggered dysesthesia of the h and s ; 96 % of the cases ) were reversible between cycles for up to C6 . In contrast , thermal testing identified sustained ( irreversible between cycles ) neurotoxicity two weeks after C3 in the oxaliplatin group only , characterized by hyperalgesia to cold ( 5–25 ° C ) ( F = 11.4 ; p = 0.0002 relative to cisplatin patient responses in the h and ) and heat stimuli ( 38–48 ° C ) ( F = 4.1 ; p = 0.049 for the h and ) . Cold‐evoked symptoms lasting 4 days or more after C3 predicted chronic neuropathy ( OR : 22 ; 95 % CI : 1.54–314.74 ; p = 0.02 ) whereas enhanced pain in response to cold ( 20 ° C stimulus on the h and ) predicted severe neuropathy ( OR : 39 ; 95 % CI : 1.8–817.8 p = 0.02 ) . Thermal hyperalgesia is a relevant clinical marker of early oxaliplatin neurotoxicity and may predict severe neuropathy Acyclovir treatment of acute herpes zoster speeds rash healing and decreases pain and ocular complications . The limited oral bioavailability of acyclovir necessitates frequent dosing . Valaciclovir , the l-valyl ester of acyclovir , is rapidly and almost completely converted to acyclovir in vivo and gives three- to fivefold increases in acyclovir bioavailability . In a r and omized , double-blind , multicenter study , the safety and efficacy of oral valaciclovir given at a dosage of 1,000 mg three times daily for 7 or 14 days and oral acyclovir given at a dosage of 800 mg five times daily for 7 days were compared in immunocompetent adults aged > or = 50 years with herpes zoster . Patients were evaluated for 6 months . The intent-to-treat analysis ( 1,141 patients ) showed that valaciclovir for 7 or 14 days significantly accelerated the resolution of herpes zoster-associated pain ( P = 0.001 and P = 0.03 , respectively ) compared with acyclovir ; median pain duration s were 38 and 44 days , respectively , versus 51 days for acyclovir . Treatment with valaciclovir also significantly reduced the duration of postherpetic neuralgia and decreased the proportion of patients with pain persisting for 6 months ( 19.3 versus 25.7 % ) . However , there were no differences between treatments in pain intensity or quality -of-life measures . Cutaneous manifestations resolved at similar rates in all groups . Adverse events were similar in nature and prevalence among groups , and no clinical ly important changes occurred in hematology or clinical chemistry parameters . Thus , in the management of immunocompetent patients > or = 50 years of age with localized herpes zoster , valaciclovir given at 1,000 mg three times daily for 7 days accelerates the resolution of pain and offers simpler dosing , while it maintains the favorable safety profile of acyclovir UNLABELLED The results of previous studies using retrospective methods or small sample s have suggested that there may be psychosocial risk factors for postherpetic neuralgia ( PHN ) . We conducted a prospect i ve study in which 110 patients with herpes zoster were assessed within the first month after rash onset with measures of acute pain and five broad domains of psychosocial functioning-physical , role , social , and emotional functioning , and stress and social support . Twenty of the 102 patients with follow-up data were diagnosed with PHN , defined as pain that had persisted for 4 months after rash onset . Measures of role functioning , personality disorder symptoms , and disease conviction during herpes zoster each made independent contributions to predicting either presence or intensity of PHN in logistic and linear regression analyses that controlled for relevant demographic and clinical variables , including age and acute pain intensity . These findings indicate that psychosocial variables are risk factors for the development of PHN . PERSPECTIVE The results of this prospect i ve study of patients with herpes zoster suggest that future research on the mechanisms and prevention of PHN should consider psychosocial as well as neurobiologic processes A study was carried out to assess the factors predisposing to chronic post-treatment pain in the breast area and in the ipsilateral arm in patients treated for breast cancer using two multivariate models . In the study 509 patients with non-metastasized breast cancer who were treated during 1988 - 1994 completed the question naire about pain in the operated breast and in the ipsilateral arm 10 - 58 months after surgery . The factors included in the analysis were : age , type of operation , size of the tumour , number of lymph nodes removed , involvement of lymph nodes , complications of surgery , intensity of the acute postoperative pain remembered by the patient , number of doses of analgesics , number of months from surgery , adjuvant radiotherapy , chemotherapy and endocrine treatment . The most important factors included in the models of chronic pain were : intensity of the acute postoperative pain , the type of operation , involvement of regional lymph nodes and radiotherapy Abstract Postherpetic neuralgia ( PHN ) is the most frequent complication of herpes zoster ( HZ ) and difficult to treat . Timely identification of high‐risk HZ‐ patients enables physicians to focus on PHN prevention . To assess which simple to measure factors are independent predictors of PHN , and whether psychosocial and serological/virological parameters have additional predictive value , a prospect i ve cohort study in primary care was conducted . We included 598 elderly ( > 50 years ) consecutive patients with acute HZ ( rash < 7 days ) below sixth cervical dermatome . At baseline demographic , clinical ( e.g. , duration and severity of pain and rash ) , psychological ( Pain Cognition List [ PCL ] and Spielberger ’s Anxiety Inventory ) , serological ( VZV‐antibodies ) and virological ( viremia presence ) variables were measured . Blood tests were performed in a r and om subset of 218 patients . Primary outcome was significant pain ( VAS > 30 on 0–100 scale ) after three months . The final prediction model obtained from multivariable logistic regression was ( internally ) vali date d using bootstrapping techniques , and adjusted for optimism . Forty‐six ( 7.7 % ) patients developed PHN . Independent predictors were age ( odds ratio [ OR ] = 1.08 per year ) , acute pain severity ( OR = 1.02 per unit ) , presence of severe rash ( OR = 2.31 ) , and rash duration before consultation ( OR = 0.78 per day ) : area under receiver‐operating‐characteristic curve [ ROC area ] = 0.77 ( 95 % CI : 0.71–0.82 ) . Of the five PCL scores , only factor V ( ‘ trust in healthcare ’ ) was an additional predictor ( OR = 1.01 per unit ) , though it increased the ROC area with only 0.01 to 0.78 . The Spielberger ’s anxiety scores and serological and virological variables were no additional predictors . Thus , four simple variables can help physicians to timely identify elderly HZ‐ patients at risk of PHN Post-herpetic neuralgia ( PHN ) following acute herpes zoster remains a significant cause of neuropathic pain especially in the elderly . Early treatment of the zoster rash with antiviral agents , such as aciclovir remains one of the few measures proven to reduce the incidence and duration of PHN albeit only in a subset of patients . It is therefore crucial that the physician who first sees a case of zoster identifies those patients who are most likely to develop long-term pain and treats them accordingly . In particular , prodrugs such as famciclovir and valaciclvoir may be more beneficial in reducing PHN than the shorter acting aciclovir , but can be more expensive . Measures that could be used to predict patients likely to develop PHN would also facilitate the evaluation of early use of antiepileptic , anti-inflammatory and analgesic agents in the prevention of PHN . In a prospect i ve study of 280 herpes zoster ( HZ ) cases seen by the general practitioner ( GP ) we evaluated the predictive value of five clinical factors identified in clinical trials as associated with a higher likelihood of PHN . A visual analogue score ( VAS ) over 5 and /or age over 50 correctly identified all subjects with PHN at 3 and 6 months , respectively . However , the specificity of this prediction was low because as many as 81 % and 85 % of those aged over 50 recovered within 3 and 6 months , respectively . Better methods are needed to identify patients over 50 at most risk of PHN that enable GPs to better allocate their re sources with respect to HZ treatment UNLABELLED Anxiety , depression , and catastrophizing are generally considered to be predictive of chronic postoperative pain , but this may not be the case after all types of surgery , raising the possibility that the results depend on the surgical model . We assessed the predictive value of these factors for chronic postsurgical pain in 2 different surgical models : total knee arthroplasty for osteoarthritis ( 89 patients , 65 % women , age = 69 ± 9 years , baseline pain intensity = 4.7 ± 2.1 ) and breast surgery for cancer ( 100 patients , 100 % women , age = 55 ± 12 years , no preoperative pain ) . Data were collected before surgery , then 2 days and 3 months after surgery . Anxiety , depression , and catastrophizing were measured with the Spielberger State-Trait Anxiety Inventory , Beck Depression Inventory , and Pain Catastrophizing Scale , respectively . Pain was assessed with the Brief Pain Inventory . Neuropathic pain was detected with the DN4 question naire . Multivariate logistic regression analyses for the total knee arthroplasty and breast surgery models considered together indicated that the presence of clinical ly meaningful chronic pain at 3 months ( pain intensity ≥3/10 ) was predicted independently by age ( P = .04 ) , pain intensity on day 2 ( P = .009 ) , and state anxiety ( P = .001 ) . Linear regression models also showed that pain magnification , one of the dimensions of catastrophizing , independently predicted chronic pain intensity ( P = .04 ) . These results were not affected by the surgical model or by the neuropathic characteristics of the pain . Thus , state anxiety and pain magnification seem to constitute psychological risk factors for chronic postsurgical pain relevant in all surgical models . PERSPECTIVE This prospect i ve study performed in patients with total knee arthroplasty or breast surgery for cancer shows that state anxiety , amplification of pain , and acute postoperative pain independently predict postsurgical pain at 3 months and that this does not depend on the surgical model Sensory loss and allodynia are hallmark signs of postherpetic neuralgia ( PHN ) . We set out to investigate how frequently these signs are present in patients with acute herpes zoster ( HZ ) and what their prognostic value might be . We assessed pain , mechanical allodynia , and sensitivity to pinprick in 113 immunocompetent patients with HZ of a median duration of 5 days . Follow-up visits took place at 2 weeks , 6 weeks , 3 months , and 6 months . When first seen , 87 ( 77 % ) patients reported ongoing pain and 48/107 ( 45 % ) had allodynia . Twenty-eight ( 25 % ) patients had pain at 3 months ( and were considered to have developed PHN ) , while 14 ( 12 % ) patients had pain at 6 months . Allodynia tended to subside quickly in most patients . Reduced sensitivity to pinprick was less common . Mechanical allodynia and pinprick hypesthesia were strongly associated with the development of PHN . They merit addition to the list of potential risk factors for PHN although they can not be used as a predictive rule for an individual patient . By contrast , lack of allodynia in the early stages of HZ predicts good recovery by three months UNLABELLED To characterise predisposition to post herpetic neuralgia following herpes zoster . DESIGN Late follow up of patients originally admitted with acute zoster to a double blind r and omised placebo controlled study of oral acyclovir over 60 years of age . SETTING Two UK cities of 1.5 million population . RESULTS 158 of the 298 patients from the original study were available for evaluation at a mean follow up of 9 years . Thirty four ( 21 % ) described experiencing pain from the zoster within the previous 12 months . Pain at follow up was associated with characteristics at the time of acute zoster of : moderate or severe acute pain ( p = 0.006 ) , prodromal pain > 72 h before rash ( p = 0.006 ) , severity of rash ( p = 0.033 ) and female gender ( p = 0.046 ) . There was no association between pain at 9 year follow up and use of placebo or aciclovir nor with the presence or absence of pain at the point of discharge from the original study . Further analysis of 17 of the 34 patients with long term pain who have full data available , the median pain score was 4 out of 10 and more than 50 % described persistent pain and interference with sleep . CONCLUSION Long term pain in the elderly following zoster is associated with identifiable characteristics during the acute illness Summary Acute neuropathic characteristics and secondary hyperalgesia are independent , additive factors predictive of chronic postsurgical pain after iliac crest bone harvest . ABSTRACT Nerve lesions and secondary hyperalgesia may both be present after surgery , and their relative contributions to chronic postsurgical neuropathic pain ( CPSNP ) remain unclear . This prospect i ve study explored the roles of these factors in the development of CPSNP after iliac crest bone harvest . CPSNP was defined as pain in the area of hypoesthesia , with a positive Douleur neuropathique 4 question naire ( DN4 ) score 3 months after iliac crest bone harvest . The location , intensity , and neuropathic characteristics of pain were evaluated in 82 patients who were followed for 6 months . Neuropathic characteristics were assessed by clinical examination and DN4 question naire . The area of secondary hyperalgesia was evaluated 48 h and 1 month after surgery . The area of mechanical hypoesthesia , detection , and mechanical pain threshold were evaluated at 48 h and at 1 and 3 months . Nineteen patients ( 23 % ) had CPSNP at 3 months . The patients who developed CPSNP had a larger area of secondary hyperalgesia at 48 h ( 88 cm2 vs 33 cm2 ; P = .001 ) , higher pain intensity ( numerical rating scale 6.7 vs 4.7 ; P = .02 ) , and higher neuropathic characteristics score on the DN4 question naire ( 4.3 vs 2.3 ; P = .001 ) . However , neither the area nor the severity of hypoesthesia differed significantly between patients with and without CPSNP . Two independent , additive predictors of CPSNP were identified : area of secondary hyperalgesia ( odds ratio 1.02 ; P = .004 ) and DN4 score ( odds ratio 1.94 ; P = .001 ) . These findings suggest that both nerve lesions and central sensitization are involved in CPSNP development and could be seen as early warning signs Three hundred and one patients with acute herpes zoster treated early with oral acyclovir were enrolled in an open , prospect i ve study design ed to evaluate painful and neurologic disorders over a 6-month period . Age , initial pain severity , and occurrence of a neurologic deficit influenced the incidence of postherpetic neuralgia . No relationship was found between initial rash severity and either pain incidence or neurologic deficit . NEUROLOGY 1995;45(Suppl 8) : Study Design . In this prospect i ve study , a cohort of 2077 workers free of sciatic pain and another cohort of 327 workers with severe sciatic pain were followed up for 1 year . Objective . To evaluate the effects of different risk factors on the incidence and persistence of sciatic pain . Summary of Background Data . Sciatic pain seems to differ from other types of low back pain in terms of etiology , occurrence , and prognosis . Yet only a few studies of sciatic pain exist . The role of individual characteristics , occupational loading , and participation in different sports has rarely been assessed in a study with a prospect i ve design among a working population . Methods . The subjects of this study , Finnish forest industry workers , replied to a modified version of the Nordic Question naire at the baseline of this study and after 1 year . The effects of the predictors on the 1-year incidence and persistence of sciatic pain were studied with multivariable logistic regression modeling . Results . Greater age , mental stress , smoking of long duration , and work-related twisting of the trunk increased the risk of incidental sciatic pain . Joggers had a lower risk for incidental sciatic pain , but a higher risk for persistent symptoms . Walking was positively associated with the risk of incidental pain . Greater age , mental stress , former smoking , jogging , and poor job satisfaction increased the risk for persistent severe sciatic pain . Conclusions . The findings from this study suggest that mental stress and smoking are independent risk factors for incidental sciatic pain . Overall physical exercise and most of the sports activities , except jogging and walking , had no effect on sciatic pain . Physical workload factors seemed to be more involved in the onset of sciatic pain , whereas psychosocial factors were related to the persistence of symptoms Summary Classification of neuropathic pain has been based on disease entities , anatomical localization , or histological observations . Over the past decade , there has been an explosion in our underst and ing of the basic mechanisms of neuropathic pain . The exciting advances in basic science are paralleled by the recognition from clinical investigations that neuropathic pain is not a monolithic entity , but instead presents as a composite of pain and other sensory symptoms . Attempts are under way to supplement the traditional classification with a classification that links pain and sensory symptoms with neurobiological mechanisms . This mechanism- or symptom-based classification takes both negative and positive sensory symptoms into account . By using a battery of several st and ardized quantitative sensory tests , the characteristic profile of sensory symptoms can be eluci date d in each patient . Moreover , in question naires the verbal descriptors can depict the quality and intensity of the individual pain . The approach of classifying and subgrouping patients with neuropathic pain on the basis of symptoms or signs opens up new possibilities for stratifying patients in clinical trials . First , in clinical proof-of-concept trials the study population can be enriched prospect ively on the basis of entry criteria defined a priori . This enrichment with patients who potentially require a specific treatment should increase the likelihood for positive trial outcomes . Second , in clinical practice it becomes possible to establish an individualized therapy — that is , to identify the particular patients who require a specific treatment option Abstract Cognitive‐behavioral factors are considered important in the development of chronic disability and pain in patients with low back pain . In a prospect i ve cohort study of 277 patients undergoing surgery for lumbosacral radicular syndrome , the predictive value of preoperatively measured cognitive‐behavioral factors ( fear of movement/(re)injury , passive pain coping , and negative outcome expectancies ) for disability and pain intensity at 6 weeks and 6 months after surgery was investigated , taking into account the effect of possible confounding variables . Higher levels of cognitive‐behavioral factors were found to be associated with a worse outcome at both 6 weeks and 6 months . These associations remained significant after controlling for possible confounding variables ( preoperative disability and pain intensity , age , gender , educational level , duration of complaints , neurological deficits , and intake of analgesics ) and pain intensity 3 days postoperatively . In multiple regression analyses , the cognitive‐behavioral factors independently predicted different outcomes . Fear of movement/(re)injury predicted more disability and more severe pain at 6 weeks and more severe pain at 6 months ; passive pain‐coping strategies predicted more disability at 6 months ; and negative outcome expectancies predicted more disability and more severe pain at both 6 weeks and 6 months . The findings support the potential utility of preoperative screening measures that include cognitive‐behavioral factors for predicting surgical outcome , as well as studies to examine the potential benefits of cognitive‐behavioral treatment to improve surgical outcome AIM OF THE STUDY An observational study with valaciclovir was conducted to assess clinical outcome in herpes zoster , especially pain and associated neurological signs and symptoms in relation to a series of demographic and disease characteristics discernible at presentation . The safety and acceptability of valaciclovir for treatment of zoster was assessed in a wide variety of primary care and clinic referral setting s. METHODS In total , 1897 immunocompetent adults with clinical ly diagnosed , localized acute herpes zoster were enrolled in this international , open-label study of valaciclovir . All subjects received treatment with oral valaciclovir ( 1000 mg three times daily ) for 7 days from entry to the study and were asked to record the presence of zoster-associated pain and abnormal sensations throughout treatment and 6 months ' follow-up . They were seen frequently in clinic to verify subjective assessment s and for evaluation of rash healing . Safety and tolerability were assessed by adverse event monitoring . RESULTS Overall , 1191 subjects ( 63 % ) were aged > or = 50 years , and 203 ( 11 % ) had ophthalmic zoster . Cessation of zoster-associated pain was significantly faster in the younger age group ; median times to loss of zoster-associated pain were 23 days and 9 days in the > or = 50 and < 50 years age groups , respectively . Similarly , abnormal sensations resolved significantly more rapidly in the younger subjects ; the median duration of abnormal sensations was 31 days in the > or = 50 year olds and 16 days in those aged < 50 years . In cases of ophthalmic zoster , the rate of pain resolution was not different from those with zoster in other dermatomes ( median duration of pain 18 vs. 16 days ) . However , abnormal sensations persisted significantly longer in subjects with ophthalmic zoster than in those with zoster at other sites ( 47 vs. 22 days ) . In addition to advancing age , subjects suffering moderate to severe prodromal pain or acute pain during the rash phase were at significantly greater risk of zoster-associated pain and abnormal sensations persisting for longer . Subjects with concomitant neurological disorders were also more likely to develop prolonged abnormal sensations . Valaciclovir treatment was well tolerated , and adverse events were rare and generally mild . CONCLUSION This study confirmed the prognostic importance of advancing age and the intensity of prodromal or acute pain as risk factors for prolonged zoster-associated pain and persisting abnormal sensations in the affected dermatome . Ophthalmic zoster and pre-existing neurological disorders are also identified as highly significant risk factors for prolonged abnormal sensations in herpes zoster Study Design . Prospect i ve design in which 102 patients were evaluated with a battery of psychological assessment tests 1–2 weeks before surgery , and outcome was assessed 6 months and 1 year after surgery . Objectives . The study examined whether three aspects of psychological distress ( depression , anxiety , and hostility ) predict several surgical outcomes ( employment status , subjective pain change ratings , and changes in functional abilities ) . Summary of Background Data . Surgery for back pain has been shown to yield poor results in 15–45 % of patients . Tools are needed to identify those “ at risk ” for poor outcome . Aspects of emotional distress , including anxiety , depression , and hostility , have been found to be relevant to various illness outcomes ( e.g. , cancer , heart disease ) , but their influence has not been prospect ively evaluated for back pain surgical outcome . Methods . Study patients completed measures of distress before surgery , including the Spielberger Trait Anxiety Inventory , Zung Depression Scale , Modified Somatic Perception Question naire , and Cook – Medley Hostility Scale . At 1-year follow-up , patients completed pain change ratings , functional abilities measure ( Dallas Pain Question naire ) , and questions about employment status . Results . Multivariate regression analyses , controlling for significant demographic variables , found that failure to return to work was predicted by presurgical anxiety ( P < 0.001 ) and depression ( P < 0.01 ) ; failure to report improvement in pain was predicted by presurgical somatic anxiety ( P < 0.01 ) and depression ( P < 0.058 ) ; and failure to report improved functional abilities was predicted by presurgical somatic anxiety ( P < 0.01 ) and depression ( P < 0.05 ) . Hostility did not predict any outcome . Regression analyses found a strong predictor to be a combination of the Zung Depression Scale and Modified Somatic Perception Question naire , known as the Distress and Risk Assessment Method ( DRAM ) . Conclusions . These results indicate that screening for presurgical distress is likely to identify those patients at risk for poor outcome . Studies to evaluate whether presurgical psychological treatment improves outcome are warranted & NA ; Sciatica caused by a lumbar disk herniation is a frequently diagnosed disorder with a favorable natural course . While most prognostic studies focus on good outcome , patients might experience unsatisfactory results . Female gender has been found to be associated with chronic pain in other musculoskeletal disorders . Our aim is to quantify the relationship between gender and ( 1 ) rate of recovery and ( 2 ) outcome at one year . Recovery was registered on a 7‐point Likert scale for 283 patients with 6–12 weeks of persistent sciatica who participated in a r and omized trial to investigate timing of surgery . Complete and near complete recovery were considered good outcomes . Function and pain were registered by the Rol and Disability Question naire ( RDQ ) and a visual analogue scale ( VAS ) . A univariate Cox model was used to study the influence of variables on rate of recovery while a univariate and multivariate logistic regression analysis evaluated variables predicting unsatisfactory outcome at 12 months . At one year unsatisfactory outcome was registered for 17 % of patients , 11 % of all males and 28 % of all females ( p < 0.001 ) . Patients with an unsatisfactory outcome had worse RDQ and VAS scores compared to those who recovered satisfactorily ( p < 0.001 ) . Women had a slower rate of recovery : HR 0.76 ( 95 % CI 0.59–0.99 ) and xbfnkbsdkvbated with an unsatisfactory outcome represented by an unadjusted odds ratio of 3.3 ( 95 % CI 1.7–6.3 ) compared to males . Besides a slower recovery rate , female gender was a strong predictor of unsatisfactory outcome at one year for patients with sciatica |
1,957 | 18,043,264 | ( 1 ) Many of the significant advances in cancer management in recent years have centered on the development and introduction of molecularly targeted therapies , such as monoclonal antibodies and tyrosine kinase inhibitors.(2 ) Despite targeted therapy that has clearly benefited and even cured certain patients ( eg , imatinib , trastuzumab ) , the ultimate goal of curing cancer , and the more immediate goal of replacing non-targeted chemotherapies with less toxic , targeted agents has yet to be achieved for most cancer patients .(3 ) Based on a systematic review of r and omized controlled trials , examples of significant benefits in selected cancers are provided:(a ) Non-Hodgkin 's lymphoma ( NHL ) - A large meta- analysis and several individual r and omised , controlled trials ( RCTs ) report that rituximab plus chemotherapy has a major survival advantage over chemotherapy alone in patients with NHL ; an overview of six clinical trials supports the survival benefit of rituximab plus chemotherapy.(b ) Renal cell carcinoma ( RCC ) - Temsirolimus or sunitinib has a significant survival benefit relative to interferon-alpha , and sorafenib carries such a benefit in patients resistant to st and ard therapy.(c ) Colorectal cancer ( CRC ) - An overview of three RCTs in metastatic CRC revealed that bevacizumab plus 5-fluorouracil/leucovorin possesses a significant survival advantage over 5-fluorouracil/leucovorin and irinotecan/5-fluorouracil/leucovorin.(d ) Non-small-cell lung cancer ( NSCLC ) - In refractory NSCLC , erlotinib significantly prolongs survival , particularly in nonsmokers , and gefitinib may have some utility in patients of Asian ethnicity.(e ) Head and neck squamous-cell carcinoma ( HNSCC ) - Cetuximab plus radiotherapy ( versus radiotherapy alone ) significantly improves locoregional control and survival ( hazard ratio [ HR ] 0.68 ; p = 0.005 ) without worsening radiotherapy-related toxicity | null | null |
1,958 | 26,186,528 | Subgroup and sensitively analyses showed consistent results .
Conclusion Little evidence from published cohort studies supports the statement that total fat , saturated fat or unsaturated fat intake increases the risk for Pca or advanced stage Pca | Background Since the late 1960s , the average global supply of fat has increased by 20 g per capita per day .
While fat intake has been considered a potential risk factor for prostate cancer ( Pca ) , the hypothesis from previous epidemiologic studies remained equivocal . | Prostate cancer incidence was prospect ively studied among 7999 men of Japanese ancestry who were first examined between 1965 and 1968 and then followed through 1986 . During this surveillance period , 174 incident cases of prostate cancer were recorded . Prostate cancer was not associated with any measure of socioeconomic status , including amount of education , type of occupation , and type of residence . There was also no relationship with the number of children , as a surrogate measure of sexual activity . Increased consumption of rice and tofu were both associated with a decreased risk of prostate cancer , while consumption of seaweeds was associated with an increased risk of prostate cancer . There was no relationship between prostate cancer and the intake of various nutrients , including total fat and total protein . Etiological implication s of these associations are discussed , but more research is needed on these dietary factors and the subsequent development of prostate cancer before any firm conclusions can be drawn Abstract Background : Calcium , phosphorus , fructose , and animal protein are hypothesized to be associated with prostate cancer risk , potentially via their influence on 1,25-dihydroxyvitamin D3 . We examined these nutrients and overall diet and prostate cancer risk in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study ( ATBC Study ) . Material s and methods : The ATBC Study was a r and omized 2 × 2 trial of alpha-tocopherol and beta-carotene on lung cancer incidence conducted among Finnish male smokers ; 27,062 of the men completed a food-use question naire at baseline , and comprise the current study population . There were 184 incident clinical ( stage 2–4 ) prostate cancer cases diagnosed between 1985 and 1993 . We used Cox proportional hazards models to examine associations between dietary intakes and prostate cancer . Results : We did not observe significant independent associations for calcium and phosphorus and prostate cancer risk . However , men with lower calcium and higher phosphorus intake had a multivariate relative risk of 0.6 ( 95 % CI 0.3–1.0 ) compared to men with lower intakes of both nutrients , adjusting for age , smoking , body mass index , total energy , education , and supplementation group . Of the other foods and nutrients examined , none was significantly associated with risk . Discussion : This study provides , at best , only weak evidence for the hypothesis that calcium and phosphorus are independently associated with prostate cancer risk , but suggests that there may be an interaction between these nutrients BACKGROUND Findings from early observational studies have suggested that the intake of dietary fat might be a contributing factor in the etiology of prostate cancer . However , the results from more recent prospect i ve studies do not support this hypothesis , and the possible association between different food sources of fat and prostate cancer risk also remains unclear . OBJECTIVE The objectives were to assess whether intakes of dietary fat , subtypes of fat , and fat from animal products were associated with prostate cancer risk . DESIGN This was a multicenter prospect i ve study of 142,520 men in the European Prospect i ve Investigation into Cancer and Nutrition ( EPIC ) . Dietary fat intake was estimated with the use of country-specific vali date d food question naires . The association between dietary fat and risk of prostate cancer was assessed by using Cox regression , stratified by recruitment center and adjusted for height , weight , smoking , education , marital status , and energy intake . RESULTS After a median follow-up time of 8.7 y , prostate cancer was diagnosed in 2727 men . There was no significant association between dietary fat ( total , saturated , monounsaturated , and polyunsaturated fat and the ratio of polyunsaturated to saturated fat ) and risk of prostate cancer . The hazard ratio for prostate cancer for the highest versus the lowest quintile of total fat intake was 0.96 ( 95 % CI : 0.84 , 1.09 ; P for trend = 0.155 ) . There were no significant associations between prostate cancer risk and fat from red meat , dairy products , and fish . CONCLUSION The results from this large multicenter study suggest that there is no association between dietary fat and prostate cancer risk itamin E supplements could V reduce prostate-cancer incidence and mortality by one-third in men who smoke , according to the results of a large primary -prevention trial in Finnish men . Prostate cancer is the fourth most common male cancer . As part of the Alpha-Tocopherol , Beta-Carotene ( ATBC ) study ( US National Cancer Institute and University of Helsinki , Finl and ) , more than 29 000 male smokers aged 50 - 69 years were r and omly assigned to receive 50 mg atocopherol , 20 mg P-carotene , both , or placebo daily for up to 8 years . At the end of the study , 246 new cases of prostate cancer and 62 deaths from the disease had occurred . Incidence was 32 % lower , and mortality 41 % lower , in men taking a-tocopherol , with or without P-carotene , than in those not taking the vitamin Nad Cancer Znst 1998 ; 90 : 440 - 46 ) . Men taking P-carotene had a 23 % . amin supplementation can be diffihigher incidence of , and 15 % higher cult to interpret , especially when mortality from , prostate cancer than there are multiple endpoints and no those not taking it . But these differences were not statistically significant . In addition , the investigators found that p-carotene nonsignificantly reduced the risk of prostate cancer in nondrinkers and increased the risk in drinkers , the risk rising with increasing strong a priori hypothesis . “ If the effect of a vitamin supplement is examined at , say , 20 cancer sites ” , says Franceschi , “ it is likely to appear protective at one site purely by chance . ” “ Studies with vitamin supplements are not a good basis for dietary advice ” , consumpDeserves further High dietary intakes of calcium and dairy products have been hypothesized to enhance prostate cancer risk , but available prospect i ve data regarding these associations are inconsistent . We examined dietary intakes of calcium and dairy products in relation to risk of prostate cancer in the Alpha-Tocopherol , Beta-Carotene ( ATBC ) Cancer Prevention Study , a cohort of 29,133 male smokers aged 50 - 69 years at study entry . Dietary intake was assessed at baseline using a vali date d 276-item food use question naire . Cox proportional hazards regression was used to adjust for known or suspected risk factors for prostate cancer . During 17 years of follow-up , we ascertained 1,267 incident cases of prostate cancer . High versus low intake of dietary calcium was associated with a marked increase in prostate cancer risk . The multivariate relative risk ( RR ) of prostate cancer for > or = 2,000 mg/day compared to < 1,000 mg/day of calcium intake was 1.63 ( 95 % confidence interval ( CI ) , 1.27 - 2.10 ; p trend < 0.0001 ) . Total dairy intake was also positively associated with risk of prostate cancer . The multivariate RR of prostate cancer comparing extreme quintiles of intake was 1.26 ( 95 % CI , 1.04 - 1.51 ; p trend = 0.03 ) . However , no association with total dairy intake remained after we adjusted for calcium ( p trend = 0.17 ) . Findings were similar by stage and grade of prostate cancer . The results from this large prospect i ve study suggest that intake of calcium or some related component contained in dairy foods is associated with increased prostate cancer risk BACKGROUND Prostate cancer is a disease with a complex etiology . Oxidative stress has been implicated in its pathogenesis ; however , few prospect i ve studies have investigated the association between an oxidative stress/balance score and risk of prostate cancer . METHODS We investigated associations between an oxidative balance score , calculated as the summation of individual scores obtained from five pro-oxidative and eight anti-oxidative exposures , as well as each individual constituent of the score and risks of prostate cancer overall , and by clinical characteristics , in a case-cohort study ( 661 cases and 1864 subcohort ) nested within the Canadian Study of Diet , Lifestyle , and Health cohort . Men in the lowest quintiles of each pro-oxidant exposure received a score of four ( the highest score ) , while those in the highest quintile received a score of zero ( the lowest score ) . In contrast , scoring for all anti-oxidants was performed in the opposite way . Total oxidative balance score was calculated by summating all individual scores of pro- and anti-oxidative variables , with higher values indicating a higher antioxidant status . RESULTS The average oxidative balance score was similar between prostate cancer cases and men in the subcohort : 25.2 and 25.3 , respectively . There was no association between oxidative balance score and overall risk of prostate cancer with hazard ratios ( HRs ) of 1.00 , 1.02 , 1.03 , 0.97 and 1.01 for increasing quintiles of the score ( p-trend=0.71 ) . There were also no associations for non-advanced or advanced disease , or when analysis was restricted to incident cases that arose after two years of follow-up ( n=508 ) . In general constituents of the score were not associated with prostate cancer , except for red meat intake ( HR=1.44 ; 95%CI 1.06 - 1.95 comparing Q5 vs. Q1 ) and lycopene ( HRs of 0.7 - 0.8 for increasing quintiles ) . CONCLUSION Our findings do not support an association between oxidative balance score and risks of overall prostate cancer or advanced disease BACKGROUND The strong correlation between national consumption of fat and national rate of mortality from prostate cancer has raised the hypothesis that dietary fat increases the risk of this malignancy . Case-control and cohort studies have not consistently supported this hypothesis . PURPOSE We examined prospect ively the relationship between prostate cancer and dietary fat , including specific fatty acids and dietary sources of fat . We examined the relationship of fat consumption to the incidence of advanced prostate cancer ( stages C , D , or fatal cases ) and to the total incidence of prostate cancer . METHODS We used data from the Health Professionals Follow-up Study , which is a prospect i ve cohort of 51529 U.S. men , aged 40 through 75 , who completed a vali date d food-frequency question naire in 1986 . We sent follow-up question naires to the entire cohort in 1988 and 1990 to document new cases of a variety of diseases and to up date exposure information . As of January 31 , 1990 , 300 new cases of prostate cancer , including 126 advanced cases , were documented in 47855 participants initially free of diagnosed cancer . The Mantel-Haenszel summary estimator was used to adjust for age and other potentially confounding variables . Multiple logistic regression was used to estimate relative risks ( RRs ) when controlling simultaneously for more than two covariates . RESULTS Total fat consumption was directly related to risk of advanced prostate cancer ( age- and energy-adjusted RR = 1.79 , with 95 % confidence interval [ CI ] = 1.04 - 3.07 , for high versus low quintile of intake ; P [ trend ] = .06 ) . This association was due primarily to animal fat ( RR = 1.63 ; 95 % CI = 0.95 - 2.78 ; P [ trend ] = .08 ) , but not vegetable fat . Red meat represented the food group with the strongest positive association with advanced cancer ( RR = 2.64 ; 95 % CI = 1.21 - 5.77 ; P = .02 ) . Fat from dairy products ( with the exception of butter ) or fish was unrelated to risk . Saturated fat , monounsaturated fat , and alpha-linolenic acid , but not linoleic acid , were associated with advanced prostate cancer risk ; only the association with alpha-linolenic acid persisted when saturated fat , monounsaturated fat , linoleic acid , and alpha-linolenic acid were modeled simultaneously ( multivariate RR = 3.43 ; 95 % CI = 1.67 - 7.04 ; P [ trend ] = .002 ) . CONCLUSION The results support the hypothesis that animal fat , especially fat from red meat , is associated with an elevated risk of advanced prostate cancer . IMPLICATION S These findings support recommendations to lower intake of meat to reduce the risk of prostate cancer . The potential roles of carcinogens formed in cooking animal fat and of alpha-linolenic acid in the progression of prostate cancer need to be explored CONTEXT The most recent summary of the European Association of Urology ( EAU ) guidelines on prostate cancer ( PCa ) was published in 2011 . OBJECTIVE To present a summary of the 2013 version of the EAU guidelines on screening , diagnosis , and local treatment with curative intent of clinical ly organ-confined PCa . EVIDENCE ACQUISITION A literature review of the new data emerging from 2011 to 2013 has been performed by the EAU PCa guideline group . The guidelines have been up date d , and levels of evidence and grade s of recommendation have been added to the text based on a systematic review of the literature , which included a search of online data bases and bibliographic review s. EVIDENCE SYNTHESIS A full version of the guidelines is available at the EAU office or online ( www.uroweb.org ) . Current evidence is insufficient to warrant widespread population -based screening by prostate-specific antigen ( PSA ) for PCa . Systematic prostate biopsies under ultrasound guidance and local anesthesia are the preferred diagnostic method . Active surveillance represents a viable option in men with low-risk PCa and a long life expectancy . A biopsy progression indicates the need for active intervention , whereas the role of PSA doubling time is controversial . In men with locally advanced PCa for whom local therapy is not m and atory , watchful waiting ( WW ) is a treatment alternative to and rogen-deprivation therapy ( ADT ) , with equivalent oncologic efficacy . Active treatment is recommended mostly for patients with localized disease and a long life expectancy , with radical prostatectomy ( RP ) shown to be superior to WW in prospect i ve r and omized trials . Nerve-sparing RP is the approach of choice in organ-confined disease , while neoadjuvant ADT provides no improvement in outcome variables . Radiation therapy should be performed with ≥ 74 Gy in low-risk PCa and 78 Gy in intermediate- or high-risk PCa . For locally advanced disease , adjuvant ADT for 3 yr results in superior rates for disease-specific and overall survival and is the treatment of choice . Follow-up after local therapy is largely based on PSA and a disease-specific history , with imaging indicated only when symptoms occur . CONCLUSIONS Knowledge in the field of PCa is rapidly changing . These EAU guidelines on PCa summarize the most recent findings and put them into clinical practice . PATIENT SUMMARY A summary is presented of the 2013 EAU guidelines on screening , diagnosis , and local treatment with curative intent of clinical ly organ-confined prostate cancer ( PCa ) . Screening continues to be done on an individual basis , in consultation with a physician . Diagnosis is by prostate biopsy . Active surveillance is an option in low-risk PCa and watchful waiting is an alternative to and rogen-deprivation therapy in locally advanced PCa not requiring immediate local treatment . Radical prostatectomy is the only surgical option . Radiation therapy can be external or delivered by way of prostate implants . Treatment follow-up is based on the PSA level OBJECTIVES The results of epidemiologic and animal studies support the role of a low-fat diet supplemented with omega-3 fatty acids contained in fish oil in preventing the development and progression of prostate cancer . As a first step in study ing the role of a low-fat , fish oil-supplemented ( LF/FOS ) diet in a clinical setting , we conducted a prospect i ve study in men with untreated prostate cancer to evaluate whether a 3-month dietary intervention affects the ratio of omega-3 to omega-6 fatty acids in plasma and gluteal fat . In addition , we evaluated the feasibility of study ing cyclooxygenase-2 ( COX-2 ) expression in serial prostate needle biopsy specimens before and after the diet . METHODS Nine men with untreated prostate cancer consumed an LF/FOS diet for 3 months . Plasma , gluteal adipose tissue , and prostate needle biopsy specimens were obtained from each patient before and after the intervention . The fatty acid compositions of the plasma and gluteal adipose tissue were determined by gas-liquid chromatography , and the COX-2 expression in the prostatic tissue specimens was determined by semiquantitative reverse transcriptase-polymerase chain reaction ( RT-PCR ) . RESULTS Short-term intervention with an LF/FOS diet caused a significant increase in the omega-3/omega-6 fatty acid ratio in plasma ( P = 0.002 ) and gluteal adipose tissue ( P = 0.002 ) in men with prostate cancer . The COX-2 expression in prostatic tissue was quantitated by RT-PCR in 7 of 9 patients , and COX-2 expression decreased in 4 of these 7 patients . CONCLUSIONS A short-term dietary intervention in men with prostate cancer leads to a significant increase in the omega-3/omega-6 fatty acid ratios in plasma and adipose tissue . The potential for this diet to prevent the development and progression of prostate cancer by way of altered COX-2 expression and prostagl and in production in prostatic tissue requires further study |
1,959 | 22,742,642 | There is insufficient evidence at present to advocate the use of these agents , although some studies suggest that some antiseptics may have equal efficacy compared to clindamycin or metronidazole . | Background The study objective was to assess the available data on efficacy and tolerability of antiseptics and disinfectants in treating bacterial vaginosis ( BV ) . | ABSTRACT To compare the frequencies , concentrations , and antimicrobial susceptibilities of vaginal microbes isolated from women with bacterial vaginosis ( BV ) before and after therapy , 119 nonpregnant women aged 18 to 45 with clinical and Gram stain evidence of BV were r and omized to receive intravaginal clindamycin or metronidazole . Vaginal swabs were collected at baseline and 7 to 12 days , 35 to 45 days , and 70 to 90 days following therapy for quantitative vaginal culture . For the 99 women completing all four visits , statistical analyses were performed comparing differences in vaginal microflora between the two treatment arms and between visits in the same treatment group . Antimicrobial susceptibility testing using the agar dilution method was performed for anaerobic gram-negative rods . Although both therapies result ed in decreased colonization by Gardnerella vaginalis and Mycoplasma hominis , only metronidazole treatment result ed in a significant decrease in the frequency and concentration of Prevotella bivia and black-pigmented Prevotella species . Of the 865 anaerobic gram-negative rods evaluated for susceptibility , only 3 ( 0.3 % ) were resistant to metronidazole , whereas clindamycin resistance increased significantly for P. bivia and black-pigmented anaerobic gram-negative rods persisting following clindamycin therapy . Clindamycin-resistant sub population s of P. bivia and black-pigmented Prevotella species emerged 7 to 12 days after therapy even among women colonized initially by clindamycin-susceptible strains . These resistant sub population s persisted at high frequencies ( 42 to 50 % ) 70 to 90 days following therapy . The two topical agents for treatment of BV have differing microbiologic effects on the vaginal microflora . The emergence of clindamycin-resistant anaerobic gram-negative rods following therapy is of concern SUMMARY Objective : We evaluated the efficacy and tolerability of a new chlorhexidine-based bioadhesive vaginal gel ( Clomirex * ) in women with vaginal infections . Study design and subjects : A total of 90 non-pregnant women with vaginal infections of both bacterial ( bacterial vaginosis : BV ) or fungal ( vaginal c and idiasis VC ) origin , were enrolled in the study : a r and omised , controlled , 4-week , multicentre trial . Patients were r and omly treated with either chlorhexidine 0.5 % vaginal gel ( CHX-VG ) , 2.5 g or with metronidazole vaginal tablets 500 mg ( M ) or clotrimazole ( CL ) vaginal cream , depending on aetiology of the infection , daily for 7 days ( treatment phase ) in a 2:1 ratio . A total of 45 women had a diagnosis of BV and 45 a diagnosis of VC . Sixty women were treated with CHX-VG , 15 with M and 15 with CL . All patients were followed for an additional 3 weeks without treatments ( follow-up phase ) . For women with BV , clinical cure rate was defined as the disappearance of the following signs and symptoms : homogenous vaginal discharge ; presence of ≥ 2 or more clue cells at the wet mount microscopy ; a vaginal pH > 4.7 and a positive whiff test . For women with VC , clinical cure rate was defined as a resolution of signs and symptoms plus absence of hyphae , pseudohyphae and blastospores on 10 % KOH wet mount microscopy . Clinical cure rate was assessed at the end of the study ( week 4 ) by an investigator unaware of the patient 's treatment allocation . Results : At week 4 , in women with BV , 28 out of 30 ( 93 % ) women in the CHX-VG group were clinical ly cured in comparison with 11 out of 15 ( 74 % ) in the M group ( p = 0.3 ) . In women with VC , 26 out of 30 ( 86.6 % ) women in the CHX-VG group were clinical ly cured in comparison with 13 out of 15 ( 86 % ) in the CL group ( p = 0.5 ) . Tolerability was good and very good in 90 % of the CHX-VG patients . Six women ( 10 % ) complained of a mild transient burning sensation after CHX-VG vaginal application . No serious adverse events were observed during the trial in all treated groups . No women presented with vaginal discharge after treatment . Conclusion : These results demonstrate that in the short term , this CHX-VG is an effective treatment for both bacterial and mycotic vaginal infections . Further clinical trials are warranted to evaluate the efficacy and tolerability profile of this new chlorhexidine vaginal gel on a long-term basis and in reducing recurrency rate of vaginal infections In a study of 100 women with non-specific vaginitis , characterised by a vaginal discharge which was malodorous and pruritic in most cases and caused dyspareunia and dysuria in some , Gardnerella vaginalis was isolated in 46 % of patients . When present , G vaginalis was significantly associated with Mycoplasma hominis and Bacteroides species . Isolation of G vaginalis was unrelated to the presenting symptoms . Treatment with povidone-iodine pessaries for two weeks produced no pronounced benefit , either clinical ly or microbiologically , compared with a placebo . Nevertheless , 68 % of all patients followed reported improvement four weeks after the start of treatment . The findings suggest that G vaginalis is one cause of non-specific vaginitis , which is more likely to be seen in women using oral contraceptives and is usually cured spontaneously Bacterial vaginosis ( BV ) is a common cause of abnormal malodorous vaginal discharge and can be frustrating to manage in its recurrent form . Metronidazole is the st and ard treatment , but is unacceptable to many women when given repeatedly . Results of treating recurrent BV using a single vaginal washout with 3 % hydrogen peroxide are analysed . A total of 30 symptomatic women with clinical ly confirmed recurrent BV in the absence of other genital infections were recruited after informed consent . Hydrogen peroxide ( 3 % ) was instilled into the vagina , left for 3 minutes and drained . Re assessment was at 3 weeks after treatment . A total of 23 women completed the study . Symptoms cleared completely in 78 % ( 18/ 23 ) , improved in 13 % ( 3/23 ) and remained unchanged in 9 % ( 2/23 ) . All the 3 women with improved symptoms had a mild vaginal discharge , but only one of them was still able to perceive the malodour . The amine test was negative in all 23 women including the 2 ( 9 % ) who felt no change in their symptoms following treatment . Mixed anaerobes isolated in all women before treatment were not re-isolated , and microscopy did not show ' clue cells ' in the vaginal discharge following treatment . Vaginal acidity was restored to normal in all but one ( 96 % ) . No side-effects were observed in the treated women . Hydrogen peroxide ( 3 % ) used as a single vaginal wash was as effective as any other agent in current use in clearing the vaginal malodour of bacterial vaginosis at 3 weeks after treatment OBJECTIVE This study was undertaken to evaluate antimicrobial susceptibility of vaginal anaerobic bacteria before and after treatment of bacterial vaginosis . STUDY DESIGN A r and omized clinical trial of 119 nonpregnant women with bacterial vaginosis receiving either intravaginal metronidazole for 5 days or clindamycin for 3 days was performed . Women had 1 baseline and 3 follow-up visits at which quantitative vaginal cultures were performed . Anaerobic isolates underwent antimicrobial susceptibility testing . RESULTS Complete susceptibility data was available on 95 women ( 47 metronidazole and 48 clindamycin ) . Of 1059 anaerobic bacterial isolates , less than 1 % demonstrated resistance to metronidazole . In contrast , 17 % demonstrated baseline clindamycin resistance , and 53 % demonstrated resistance to clindamycin after therapy . Women exposed to clindamycin ( but not metronidazole ) had high frequencies ( 80 % ) of clindamycin-resistant anaerobic bacteria that persisted for 90 days after treatment . CONCLUSION Treatment of bacterial vaginosis with clindamycin is associated with marked evidence of antimicrobial resistance among vaginal anaerobic bacteria . This may increase the vaginal reservoir of macrolide-resistant bacteria This r and omised , double-blind , multicentric clinical study compared the efficacy and tolerability of the two vaginal antiseptics , 10 mg dequalinium chloride ( CAS 522 - 51 - 0 , Fluomycin N ) and 200 mg povidone iodine ( CAS 25655 - 41 - 8 ) , in a parallel-group design . A total of 180 patients with vaginal infections of varying etiology participated in this study ( bacterial vaginosis , fluor vaginalis , vulvo-vaginal c and idiasis , trichomoniasis ) . Patients were r and omly allocated to one of the two treatment groups and were treated once per day for 6 days . Control examinations took place 5 to 7 days after the end of treatment , and 3 to 4 weeks after the first control examination . The total symptoms score , a summary score for the clinical symptoms , discharge , burning , pruritus , redness of vulva/vagina , was defined as primary efficacy parameter . The treatments at the first control examination were compared in the full analysis set using the Wilcoxon-Mann-Whitney U-test , 2-sided , thereby proving equivalence of both treatments at the 5 % level . Both treatments strongly improved the symptoms of vaginal infections both on short-term and long-term follow-up . Descriptive analysis of the secondary parameters , vaginal pH , degree of purity of the vaginal flora , and number of lactobacilli in the wet mounts , supported the comparable efficacy of both therapies to restore the vaginal milieu . Analysis of the diagnostic subgroups indicated that irrespective of the diagnosis , both treatments improved the efficacy criteria as observed for the entire population . The global assessment of the therapeutic efficacy by investigators and patients supported the results of the efficacy analysis with good to very good ratings in 70 - 90 % of the cases . A good tolerability of both preparations was observed in this study with a low number of adverse events in the test group ( 5.8 % ) OBJECTIVE At the present the clinical treatment of choice of bacterial vaginosis ( BV ) is the use of systemic or local metronidazole or clindamycin . Aim of the study was to evaluate the efficacy and tolerability of a single dose of gynaecologic solution , Polyhexamethylene Biguanide ( PHMB ) , Monogin , in the treatment of BV in comparison to a 7-days treatment with clindamycin vaginal cream . STUDY DESIGN This multicenter , r and omized , single-blind , parallel-group study enrolled 740 patients with BV infections . Treatment consisted of either a single intravaginal dose of PHMB or 7 daily doses of Clindamycin . Efficacy and safety were assessed 21 - 30 days after the start of treatment . The efficacy endpoints were Investigator Cure , Clinical Cure ( a composite of all 4 Amsel 's criteria and investigator Cure ) , Nugent Cure ( Nugent score < 4 ) , and therapeutic cure ( a composite of clinical cure and Nugent Cure ) . Resolution of individual Amsel 's criteria was also evaluated . Any adverse event of the treatment has been monitored throughout the study . RESULTS No significant differences has been reported in cure rates between the PHMB and Clindamycin treatment groups in Investigator Cure ( P = 0.702 ) , Clinical Cure ( P = 0.945 ) , Nugent Cure ( P = 0.788 ) , or Therapeutic Cure ( P = 0.572 ) . Results were also similar for 3 of 4 and 2 of 4 Amsel 's criteria and for each individual Amsel 's criterion ( all P-values > 0.200 ) . Ninety-five percent confidence intervals for each endpoint were consistent with equivalence between the 2 products . There was no significant difference between the treatment groups in the incidence of treatment-emergent adverse events ( P = 0.386 ) . CONCLUSIONS A single dose , of PHMB gynaecologic solution ( Monogin ) is equivalent in safety and efficacy to a 7-dose regimen of Clindamycin vaginal cream in the treatment of bacterial vaginosis . Futhermore the compliance as been reported to be higher for the single-dose treatment with PHMB than with 7-days treatment with Clindamycin Povidone-iodine pessaries ( Betadine vaginal pessaries ) containing 200 mg of povidone-iodine ( PVP-I ) in a water soluble base , are a widely used gynaecological preparation for treatment of vaginitis . We conducted a study on PVP-I pessaries at the reduced dose of one pessary daily for 7 days to suit conditions in Macau where patients are eager for a simple , short treatment course with confirmed clinical efficacy benefiting their professional and household essential requirements . Thirty-eight cases were selected for this particular clinical trial . These consisted of housewives , factory workers and professional girls ( a sexually high risk group ) who were suffering from vaginitis and complaining of vaginal discharge and irritation due to trichomonas , c and ida or non-specific vaginitis . After routine examination , including the collection of sample s for microbiology , patients were treated with PVP-I pessaries 200 mg once a day for 7 days . The second microbiology sample s were collected after the 7 day treatment period . Among the 38 cases , we had 30 cases with a complete record to allow us to make a summary and analysis of the trial . There were 14 cases of vaginitis due to yeasts and fungi infection , 3 cases of protozoa ( trichomonas ) , and 13 cases due to non-specific pathogenic infections . 73.3 % of cases had a complete symptomatic and microbiological cure and a further 16.7 % had a microbiological cure with a good improvement in symptoms . No complications or side effects were found in the 7 days consecutive treatment course and inflammation quickly subsided during the course of treatment . PVP-I pessaries , used once daily for 7 days , seem to be an ideal treatment for cases who are likely to be unable to follow a longer treatment course OBJECTIVE To compare the effectiveness of single hydrogen peroxide vaginal douching and a single oral dose of metronidazole for the treatment of bacterial vaginosis . METHOD A r and omized trial was performed at the outpatient clinic in King Chulalongkorn Memorial Hospital . 142 patients diagnosed as having bacterial vaginosis were r and omly allocated into two groups . The subjects in the first group were douched with 20 milliliters of 3 per cent hydrogen peroxide and received an oral placebo . The subjects in the second group received oral metronidazole 2 grams orally and were douched with a placebo . The cure rate in each group was assessed using Amsel 's criteria 2 weeks after treatment . RESULT The cure rate in the subjects treated with hydrogen peroxide douching was lower than the cases who received oral metronidazole ( 62.5 % versus 78.6 % , p-value = 0.036 ) . Rate of gastrointestinal side effects in metronidazole group was higher than in the hydrogen peroxide group ( 48.6 % versus 13.9 % , p-value < 0.001 ) . CONCLUSION Single hydrogen peroxide vaginal douching was less effective than a single oral dose of metronidazole in the treatment of bacterial vaginosis In a double-blind r and omized study we evaluated the efficacy of povidone-iodine in the treatment of clue cell-positive discharge ( CCPD ) . Vaginal pessaries ( 200 mg povidone-iodine or placebo ) were taken twice daily for five consecutive days . Although the regimen was reasonably well accepted , ' messiness ' was reported by 13 of 33 women ( 39 % ) . Of 44 women enrolled , treatment efficacy was evaluated in 28 women who had both follow-up visits . There was no significant difference in the efficacy of povidone-iodine and placebo pessaries , at either the first or the second follow-up visit ( p values 0.46 and 1 respectively ) . It is concluded that the use of povidone-iodine pessaries , at least in the regimen described , can not be regarded as an effective therapy for CCPD A prospect i ve , r and omized clinical trial was performed to study the efficacy of povidone iodine ( Betadine ® ) suppositories for the treatment of bacterial vaginosis ( BV ) in comparison to capsules containing lactobacilli ( Döderlein Med ® ) . Seventy patients with BV included in the study were r and omly assigned to be either treated with povidone iodine suppositories or lactobacilli . Patients were treated once a day for 5 days . Initial examinations took place on the first day of the study with follow-up examinations on days 8 and 15 . The examinations included clinical parameters , patient evaluation , secretion screens , and quantitative and qualitative microbiological tests of vaginal flora . Both treatment groups showed improvement of clinical parameters , condition of secretions and subjective state of health . At day 15 there was a trend towards a better efficacy of the treatment with povidone iodine but this was not significant . However , patients with acute BV treated with povidone iodine had significantly better scores after 15 days . Both treatments were well tolerated . The microbiological examinations showed an increase of the mean number of lactobacilli in the vagina on day 8 after initiation of treatment with lactobacilli , but a decrease on day 15 . Contrary to that the lactobacilli counts from patients treated with povidone iodine suppositories decreased after the first week but increased in the second one . Potentially pathogenic germs , e.g. Gardnerella , Bacteroides and Enterobacteria were reduced in a higher extent and with a longer lasting effect after treatment with povidone iodine suppositories than with capsules containing lactobacilli . The results of this study show that native lactobacilli rapidly re-colonize after the antiseptic treatment with povidone iodine . Therefore , there is no need to use lactobacilli in addition The authors report the results achieved in a controlled clinical study carried out for evaluating the efficacy of some topical preparations in the treatment of the so-called non-specific cervicovaginitis . The best results have been observed in 55 patients treated with a 0.1 % benzydamine solution , whose efficacy was found to be significantly greater than that of povidone-iodine vaginal suppositories or a 0.2 % aluminium acetate solution that were used in an additional 45 patients suffering from non-specific vulvovaginitis and exocervicitis , according to a fully r and omized experimental study protocol . The results obtained in the non-selected population of the present study confirm the usefulness of benzydamine vaginal douches in the therapy of non-specific inflammations involving the lower female genital apparatus |
1,960 | 24,796,491 | Obstacles in implementation are the mirror image of these : for example , when people fail to prepare , have insufficient capacity for implementation or when the setting is resistant to change , then care quality is at risk , and patient safety can be compromised . | BACKGROUND Getting greater levels of evidence into practice is a key problem for health systems , compounded by the volume of research produced .
Implementation science aims to improve the adoption and spread of research evidence .
A linked problem is how to enhance quality of care and patient safety based on evidence when care setting s are complex adaptive systems .
Our research question was : according to the implementation science literature , which common implementation factors are associated with improving the quality and safety of care for patients ? | Objective To explore the causes of failure to activate the rapid response system ( RRS ) . The organisation has a recognised incidence of staff failing to act when confronted with a deteriorating patient and leading to adverse outcomes . Design A multi- method study using the following : a point prevalence survey to determine the incidence of abnormal simple bedside observations and activation of the rapid response team by clinical staff ; a prospect i ve audit of all patients experiencing a cardiac arrest , unplanned intensive care unit admission or death over an 8-week period ; structured interviews of staff to explore cognitive and sociocultural barriers to activating the RRS . Setting Southern Health is a comprehensive healthcare network with 570 adult in-patient beds across four metropolitan teaching hospitals in the south-eastern sector of Melbourne . Measurements Frequency of physiological instability and outcomes within the in-patient hospital population . Qualitative data from staff interviews were thematically coded . Results The incidence of physiological instability in the acute adult population was 4.04 % . Nearly half of these patients ( 42 % ) did not receive an appropriate clinical response from the staff , despite most ( 69.2 % ) recognising their patient met physiological criteria for activating the RRS , and being ‘ quite ’ , or ‘ very ’ concerned about their patient ( 75.8 % ) . Structured interviews with 91 staff members identified predominantly sociocultural reasons for failure to activate the RRS . Conclusions Despite an organisational commitment to the RRS , clinical staff act on local cultural rules within the clinical environment that are usually not explicit . Better underst and ing of these informal rules may lead to more appropriate activation of the RRS Background Increasing dem and s on general practice to manage chronic disease may warrant organisational change at the practice level . Staff 's readiness for organisational change can act as a facilitator or barrier to implementing interventions aim ed at organisational change . Objectives To explore general practice staff readiness for organisational change and its association with staff and practice s characteristics . Methods This is a cross-sectional study of practice s in three Australian states involved in a r and omised control trial on the effectiveness of an intervention to enhance the role of non-general practitioner staff in chronic disease management . Readiness for organisational change , job satisfaction and practice characteristics were assessed using question naires . Results 502 staff from 58 practice s completed question naires . Practice characteristics were not associated with staff readiness for change . A multilevel regression analysis showed statistically significant associations between staff readiness for organisational change ( range 1 to 5 ) and having a non- clinical staff role ( vs general practitioner ; B=−0.315 ; 95 % CI −0.47 to −0.16 ; p<0.001 ) , full-time employment ( vs part-time ; B=0.175 , 95 % CI 0.06 to 0.29 ; p<0.01 ) and lower job satisfaction ( B=−0.277 , 95 % CI −0.40 to −0.15 ; p<0.001 ) . Conclusions The results suggest that different approaches are needed to facilitate change which addresses the mix of practice staff . Moderately low job satisfaction may be an opportunity for organisational change BACKGROUND Surgery has become an integral part of global health care , with an estimated 234 million operations performed yearly . Surgical complications are common and often preventable . We hypothesized that a program to implement a 19-item surgical safety checklist design ed to improve team communication and consistency of care would reduce complications and deaths associated with surgery . METHODS Between October 2007 and September 2008 , eight hospitals in eight cities ( Toronto , Canada ; New Delhi , India ; Amman , Jordan ; Auckl and , New Zeal and ; Manila , Philippines ; Ifakara , Tanzania ; London , Engl and ; and Seattle , WA ) representing a variety of economic circumstances and diverse population s of patients participated in the World Health Organization 's Safe Surgery Saves Lives program . We prospect ively collected data on clinical processes and outcomes from 3733 consecutively enrolled patients 16 years of age or older who were undergoing noncardiac surgery . We subsequently collected data on 3955 consecutively enrolled patients after the introduction of the Surgical Safety Checklist . The primary end point was the rate of complications , including death , during hospitalization within the first 30 days after the operation . RESULTS The rate of death was 1.5 % before the checklist was introduced and declined to 0.8 % afterward ( P=0.003 ) . Inpatient complications occurred in 11.0 % of patients at baseline and in 7.0 % after introduction of the checklist ( P<0.001 ) . CONCLUSIONS Implementation of the checklist was associated with concomitant reductions in the rates of death and complications among patients at least 16 years of age who were undergoing noncardiac surgery in a diverse group of hospitals Background Service development innovation in health technology and practice is viewed as a pressing need within the field of mental health yet is relatively poorly understood . Macro-level theories have been criticised for their limited explanatory power and they may not be appropriate for underst and ing local and fine-grained uncertainties of services and barriers to the sustainability of change . This study aim ed to identify context ual influences inhibiting or promoting the acceptance and integration of innovations in mental health services in both National Health Service ( NHS ) and community setting s. Methods A comparative study using qualitative and case study data collection methods , including semi-structured interviews with key stakeholders and follow-up telephone interviews over a one-year period . The analysis was informed by learning organisation theory . Drawn from 11 mental health innovation projects within community , voluntary and NHS setting s , 65 participants were recruited including service users , commissioners , health and non-health professionals , managers , and caregivers . The methods deployed in this evaluation focused on process- outcome links within and between the 11 projects . Results Key barriers to innovation included resistance from corporate departments and middle management , complexity of the innovation , and the availability and access to re sources on a prospect i ve basis within the host organisation . The results informed the construction of a proposed model of innovation implementation within mental health services . The main components of which are context , process , and outcomes . Conclusions The study produced a model of conducive and impeding factors drawn from the composite picture of 11 innovative mental health projects , and this is discussed in light of relevant literature . The model provides a rich agenda to consider for services wanting to innovate or adopt innovations from elsewhere . The evaluation suggested the importance of study ing innovation with a focus on context , process , and outcomes Background Despite recent high- quality evidence for their cost-effectiveness , thiazides are underused for controlling hypertension . The goal of this study was to design and test a practice -based intervention aim ed at increasing the use of thiazide-based antihypertensive regimens . Methods This quasi-experimental study was carried out in general medicine ambulatory practice s of a large , academically-affiliated Veterans Affairs hospital . The intervention group consisted of the practitioners ( 13 staff and 215 trainees ) , nurses , and patients ( 3,502 ) of the teaching practice ; non-r and omized concurrent controls were the practitioners ( 31 providers ) and patients ( 18,292 ) of the non-teaching practice s. Design of the implementation intervention was based on Rogers ' Diffusion of Innovations model . Over 10.5 months , intervention teams met weekly or biweekly and developed and disseminated informational material s among themselves and to trainees , patients , and administrators . These teams also review ed summary electronic-medical-record data on thiazide use and blood pressure ( BP ) goal attainment . Outcome measures were the proportion of hypertensive patients prescribed a thiazide-based regimen , and the proportion of hypertensive patients attaining BP goals regardless of regimen . Thirty-three months of time-series data were available ; statistical process control charts , change point analyses , and before-after analyses were used to estimate the intervention 's effects . Results Baseline use of thiazides and rates of BP control were higher in the intervention group than controls . During the intervention , thiazide use and BP control increased in both groups , but changes occurred earlier in the intervention group , and primary change points were observed only in the intervention group . Overall , the pre-post intervention difference in proportion of patients prescribed thiazides was greater in intervention patients ( 0.091 vs. 0.058 ; p = 0.0092 ) , as was the proportion achieving BP goals ( 0.092 vs. 0.044 ; p = 0.0005 ) . At the end of the implementation period , 41.4 % of intervention patients were prescribed thiazides vs. 30.6 % of controls ( p < 0.001 ) ; 51.6 % of intervention patients had achieved BP goals vs. 44.3 % of controls ( p < 0.001 ) . Conclusion This multi-faceted intervention appears to have result ed in modest improvements in thiazide prescribing and BP control . The study also demonstrates the value of electronic medical records for implementation research , how Rogers ' model can be used to design and launch an implementation strategy , and how all members of a clinical microsystem can be involved in an implementation effort Background The Promoting Action on Research Implementation in Health Services framework , or PARIHS , is a conceptual framework that posits key , interacting elements that influence successful implementation of evidence -based practice s. It has been widely cited and used as the basis for empirical work ; however , there has not yet been a literature review to examine how the framework has been used in implementation projects and research . The purpose of the present article was to critically review and synthesize the literature on PARIHS to underst and how it has been used and operationalized , and to highlight its strengths and limitations . Methods We conducted a qualitative , critical synthesis of peer- review ed PARIHS literature published through March 2009 . We synthesized findings through a three-step process using semi-structured data abstract ion tools and group consensus . Results Twenty-four articles met our inclusion criteria : six core concept articles from original PARIHS authors , and eighteen empirical articles ranging from case reports to quantitative studies . Empirical articles generally used PARIHS as an organizing framework for analyses . No studies used PARIHS prospect ively to design implementation strategies , and there was generally a lack of detail about how variables were measured or mapped , or how conclusions were derived . Several studies used findings to comment on the framework in ways that could help refine or vali date it . The primary issue identified with the framework was a need for greater conceptual clarity regarding the definition of sub-elements and the nature of dynamic relationships . Strengths identified included its flexibility , intuitive appeal , explicit acknowledgement of the outcome of ' successful implementation , ' and a more expansive view of what can and should constitute ' evidence . ' Conclusions While we found studies reporting empirical support for PARIHS , the single greatest need for this and other implementation models is rigorous , prospect i ve use of the framework to guide implementation projects . There is also need to better explain derived findings and how interventions or measures are mapped to specific PARIHS elements ; greater conceptual discrimination among sub-elements may be necessary first . In general , it may be time for the implementation science community to develop consensus guidelines for reporting the use and usefulness of theoretical frameworks within implementation studies Objective Implementation of a surgical checklist depends on many organisational factors and on socio-cultural patterns . The objective of this study was to identify barriers to effective implementation of a surgical checklist and to develop a best use strategy . Setting 18 cancer centres in France . Design The authors first assessed use compliance and completeness rates of the surgical checklist on a r and om sample of 80 surgical procedures performed under general or loco-regional anaesthesia in each of the 18 centres . They then developed a typology of the organisational and cultural barriers to effective checklist implementation and defined each barrier 's contents using data from collective and semi-structured individual interviews of key staff , the results of an email question naire sent to the 18 centres , and direct observations over 20 h in two centres . Results The study consisted of 1440 surgical procedures , 1299 checklists , and 28 578 items . The mean compliance rate was 90.2 % ( 0 , 100 ) . The mean completion rate was 61 % ( 0 , 84 ) . 11 barriers to effective checklist implementation were identified . Their incidence varied widely across centres . The main barriers were duplication of items within existing checklists ( 16/18 centres ) , poor communication between surgeon and anaesthetist ( 10/18 ) , time spent completing the checklist for no perceived benefit , and lack of underst and ing and timing of item checks ( 9/18 ) , ambiguity ( 8/18 ) , unaccounted risks ( 7/18 ) and a time-honoured hierarchy ( 6/18 ) . Conclusions Several of the barriers to the successful implementation of the surgical checklist depended on organisational and cultural factors within each centre . The authors propose a strategy for change for checklist design , use and assessment , which could be used to construct a feedback loop for local team organisation and national initiatives Background Data of the German Competence Network for Community-Acquired Pneumonia showed a gap between the recommendations of the national guideline for management of community-acquired pneumonia ( CAP ) and the routine care . We developed and evaluated an implementation strategy to improve the quality of care of patients with CAP . Method A prospect i ve , r and omised , controlled trail was conducted within CAPNETZ . In four local clinical centres ( LCC ) , the guideline was implemented by different strategies . The other four LCC served as control group . Indicators for guideline adherence comprised initial site of treatment , initial antibiotic treatment and duration of antibiotic treatment . As patient-related factors , we assessed the effect of guideline implementation on 30-day mortality and length of hospital stay . Results Active guideline implementation yielded an increased proportion of guideline adherence to the length of antibiotic treatment in out patients ( + 9.2 % ) , the recommended antibiotic treatment ( + 5.6 % ) and duration of antibiotic treatment in in patients ( + 5.0 % ) compared with baseline . In contrast , the proportion of patients in the control group , treated according to the guideline , decreased in the same period by 7.9 % , 2.9 % and 4.7 % , respectively . None of these results was statistically significant . Decrease of CAP-related mortality was higher in the intervention group compared with the control group ( 2.9 % vs 0.5 % , ns ) . Conclusion This study showed improvements in the process of care after implementation of a guideline for treating CAP . Further strategies , such as quality improvement cycles and medical practice audits , may enhance this effect Objective Daily interruption of sedation ( DIS ) has multiple proven benefits , but implementation is erratic . Past research on sedative interruption utilisation focused on individual clinicians , ignoring the role of organisations in shaping practice . The authors test the hypothesis that specific hospital organisational characteristics are associated with routine use of DIS . Design and setting National , mailed survey to a stratified r and om sample of US hospitals in 2009 . Respondents were the lead infection control professionals at each institution . Methods Survey items enquired about DIS use , institutional structure , and organisational culture . Multivariable analysis was used to evaluate the independent association of these factors with DIS use . Results A total of 386 hospitals formed our final analytic sample ; the response rate was 69.4 % . Hospitals ranged in size from 25 to 1359 beds . 26 % of hospitals were associated with a medical school . Almost 80 % reported regular use of DIS for ventilated patients . While 75.4 % of hospitals reported having leadership focus on safety culture , only 42.7 % reported that their staff were receptive to changes in practice . In a multivariable logistic regression model , structural characteristics such as size and academic affiliation were not associated with use of DIS . However , leadership emphasis on safety culture ( p=0.04 ) , staff receptivity to change ( p=0.02 ) and involvement in an infection prevention collaborative ( p=0.04 ) were significantly associated with regular DIS use . Conclusions Several elements of hospital organisational culture were associated with regular use of DIS in US hospitals . These findings emphasise the importance of combining specific administrative approaches with strategies to encourage receptivity to change among bedside clinicians in order to successfully implement complex evidence -based practice s in the intensive care setting Aim This paper describes key factors that shaped implementation of prospect i ve targeted injury-detection systems ( TIDS ) for adverse drug events ( ADEs ) and nosocomial pressure ulcers ( PrU ) . Methods Using case- study methodology , the authors conducted semistructured interviews with implementation champions and TIDS users at five hospitals . Interviews focused on implementation experiences , assessment of TIDS ' effectiveness and utility , and plans for sustainability . The authors used content analysis techniques to compare implementation experiences within and across organisations and triangulated data for explanation and confirmation of common themes . Findings Participating hospitals were more successful in implementing the low-complexity PrU-TIDS , as compared with high-complexity ADE-TIDS . This pattern reflected the greater complexity of ADE-TIDS , its higher costs and poorer alignment with existing workflows . Complexity affected the innovations ' perceived usability , the time needed to learn and install the trigger systems , and their costs . Local factors affecting implementation and sustainability of both innovations included turnover affecting champions and other staff , shifting organisational priorities , changing information infrastructures , and institutional constraints on adapting existing IT to the electronic TIDS . Conclusions To facilitate implementation of complex healthcare innovations such as ADE-TIDS , staff in adopting organisations should give high priority to innovation implementation ; allocate sufficient re sources ; effectively communicate with and involve local champions and users ; and align innovations with workflows and information systems . In addition , they should monitor local factors , such as changes in organisational priorities and IT , availability of implementation staff and champions , and external regulations and constraints that may pose barriers to innovation implementation and sustainability BACKGROUND In the 10 years since publication of the Institute of Medicine 's report To Err Is Human , extensive efforts have been undertaken to improve patient safety . The success of these efforts remains unclear . METHODS We conducted a retrospective study of a stratified r and om sample of 10 hospitals in North Carolina . A total of 100 admissions per quarter from January 2002 through December 2007 were review ed in r and om order by teams of nurse review ers both within the hospitals ( internal review ers ) and outside the hospitals ( external review ers ) with the use of the Institute for Healthcare Improvement 's Global Trigger Tool for Measuring Adverse Events . Suspected harms that were identified on initial review were evaluated by two independent physician review ers . We evaluated changes in the rates of harm , using a r and om-effects Poisson regression model with adjustment for hospital-level clustering , demographic characteristics of patients , hospital service , and high-risk conditions . RESULTS Among 2341 admissions , internal review ers identified 588 harms ( 25.1 harms per 100 admissions ; 95 % confidence interval [ CI ] , 23.1 to 27.2 ) [ corrected ] . Multivariate analyses of harms identified by internal review ers showed no significant changes in the overall rate of harms per 1000 patient-days ( reduction factor , 0.99 per year ; 95 % CI , 0.94 to 1.04 ; P=0.61 ) or the rate of preventable harms . There was a reduction in preventable harms identified by external review ers that did not reach statistical significance ( reduction factor , 0.92 ; 95 % CI , 0.85 to 1.00 ; P=0.06 ) , with no significant change in the overall rate of harms ( reduction factor , 0.98 ; 95 % CI , 0.93 to 1.04 ; P=0.47 ) . CONCLUSIONS In a study of 10 North Carolina hospitals , we found that harms remain common , with little evidence of widespread improvement . Further efforts are needed to translate effective safety interventions into routine practice and to monitor health care safety over time . ( Funded by the Rx Foundation . ) Objective : To evaluate clinical and cost effectiveness of implementing evidence -based guidelines for the prevention of stroke . Design : Cluster-r and omised trial Setting : Three primary care organisations in the North of Engl and covering a population of 400 000 . Participants : Seventy six primary care teams in four clusters : North , South & West , City I and City II . Intervention : Guidelines for the management of patients with atrial fibrillation and transient ischaemic attack ( TIA ) were developed and implemented using a multifaceted approach including evidence -based recommendations , audit and feedback , interactive educational sessions , patient prompts and outreach visits . Outcomes : Identification and appropriate treatment of patients with atrial fibrillation or TIA , and cost effectiveness . Results : Implementation led to 36 % increase ( 95 % CI 4 % to 78 % ) in diagnosis of atrial fibrillation , and improved treatment of TIA ( odds ratio of complying with guidelines 1.8 ; 95 % CI 1.1 to 2.8 ) . Combined analysis of atrial fibrillation and TIA estimates that compliance was significantly greater ( OR 1.46 95 % CI 1.10 to 1.94 ) in the condition for which practice s had received the implementation programme . The development and implementation of guidelines cost less than £ 1500 per practice . The estimated costs per quality -adjusted life year gained by patients with atrial fibrillation or TIA were both less than £ 2000 , very much less than the usual criterion for cost effectiveness . Conclusions : Implementation of evidence -based guidelines improved the quality of primary care for atrial fibrillation and TIA . The intervention was feasible and very cost effective . Key components of the model include context ual analysis , strong professional support , clear recommendations based on robust evidence , simplicity of adoption , good communication and use of established networks and opinion leaders |
1,961 | 19,560,860 | Pooled analyses suggest that MET with alpha-blockers or calcium channel blockers augments stone expulsion rates , reduces the time to stone expulsion , and lowers analgesia requirements for ureteral stones with and without ESWL for stones < or = 10 mm .
There is some evidence that a combination of alpha-blockers and corticosteroids might be more effective than treatment with alpha-blockers alone .
Renal stones after ESWL also seem to profit from MET . | CONTEXT Medical expulsive therapy ( MET ) for urolithiasis has gained increasing attention in the last years .
It has been suggested that the administration of alpha-adrenoreceptor antagonists ( alpha-blockers ) or calcium channel blockers augments stone expulsion rates and reduces colic events .
OBJECTIVE To evaluate the efficacy and safety of MET with alpha-blockers and calcium channel blockers for upper urinary tract stones with and without prior extracorporeal shock wave lithotripsy ( ESWL ) . | OBJECTIVES In delayed extracorporeal shock wave lithotripsy ( ESWL ) treatment , increasing stone impaction is associated with delayed stone clearance . Whether colic patients treated by rapid ESWL have the same time to stone clearance as noncolic patients , which supports the thesis that stones in both groups are nonimpacted , has not been investigated yet , and was the objective of this study . METHODS A total of 82 patients were prospect ively enrolled and treated with piezoelectric ESWL for a solitary proximal ureteral stone . Of these , 56 patients experienced at least one colic episode compared with 26 noncolic patients . Hydronephrosis has been assessed with the use of ultrasound and intravenous urography ( IVU ) . Time to stone clearance after the first ESWL and stone-free rates after a follow-up period of 3 mo were recorded . RESULTS In colic and noncolic patients , mean stone size was 7.8 mm ( p=0.7 ) . Ultrasound-detected hydronephrosis was present in 88 % versus 39 % ( p<0.0001 ) , whereas IVU-detected hydronephrosis was present in 60 % versus 7.7 % ( p=0.0001 ) . Mean number of impulses applied was 8000+/-4000 versus 6700+/-3400 ( p=0.1 ) . Mean time to stone clearance was 9.5+/-12.1 d versus 4.6+/-3.8 d ( p=0.1 ) . Colic and noncolic patients were considered as treatment success in 83 % and 81 % after 3 mo of follow-up ( p=0.9 ) . CONCLUSIONS Treatment outcome and time to stone clearance after rapid ESWL in colic patients compared with noncolic patients is comparable and independent of concomitant hydronephrosis . This finding suggests an absence of significant impaction in proximal ureteral stones treated within 24h after a first colic episode , enforcing the concept of performing rapid ESWL in patients harbouring proximal ureteral stones PURPOSE We evaluated the effect of the alpha-blocker tamsulosin on stone clearance , analgesic requirements and steinstrasse in shock wave lithotripsy for solitary renal and ureteral calculus . MATERIAL S AND METHODS A prospect i ve , double-blind , r and omized placebo controlled study was performed during 1 year involving 60 patients with a solitary renal or ureteral calculus undergoing shock wave lithotripsy . The control group ( 30 ) received 0.4 mg tamsulosin and the study group ( 30 ) received placebo daily until stone clearance or for a maximum of 30 days . An oral preparation of dextropropoxyphene hydrochloride and acetaminophen was the analgesic used on an on-dem and basis . The parameters assessed were stone size , position , clearance time , effect on steinstrasse and analgesic requirement . RESULTS The overall clearance rate was 96.6 % ( 28 of 29 ) in the study group and 79.3 % ( 23 of 29 ) in the control group ( p = 0.04 ) . With larger stones 11 to 24 mm the difference in the clearance rate was significant ( p = 0.03 ) but not so with the smaller stones 6 to 10 mm ( p = 0.35 ) . The average dose of analgesic used was lower with tamsulosin than with controls , without statistical significance . Steinstrasse resolved spontaneously in the tamsulosin group whereas 25 % ( 2 of 8) required intervention in the placebo group . There was no difference between the 2 groups with regard to age , stone size or location . CONCLUSIONS The alpha-blocker tamsulosin seemed to facilitate stone clearance , particularly with larger stones during shock wave lithotripsy for renal and ureteral calculus . It also appeared to improve the outcome of steinstrasse . Tamsulosin may have a potential role in routine shock wave lithotripsy Background : Alpha – 1 blockers decrease the tension and release the spasm of smooth muscles and thus lessen the obstruction and irritation symptoms in the lower urinary tract ( LUTS ) . They make a faster passing of calculi from the terminal part of the ureters possible . Objectives : The goal of this study was to objective ly assess the improvement of difficulties caused by obstructions in ureterolithiasis localized in the lower part of the ureters of 104 r and omly chosen patients ( pts . ) in a double-blind study . Methods : During a period of 2 and half years ( June 1999–January 2002 ) 104 pts . suffering from ureterolithiasis of the lower urinary tract were treated and observed . Patients were divided into two groups : A ( n:53 ; later only 51 were evaluated ) which was subjected to st and ard treatment and group B ( n:51 ) where the st and ard treatment was supplemented by the alpha – 1 blocker . As alpha – 1 blocker one capsule of Tamsulosin /OMNIC 0.4 / was administered daily . Results : With alpha – 1 blocker , we have registered a more speedy passing of calculi from the terminal parts of ureters in 17.6 % of pts . Recurrence of renal colics was less frequent and occurred in one of eight pts . as compared with group A ( without the alpha – 1 blocker ) where a recurrence of the renal colic was observed in about every fifth pts . In group A ( n:51 ) , 62.8 % of the pts . passed the calculi , whereas in group B ( n:51 ) , where st and ard treatment was supplemented by the administration of the alpha – 1 blocker Tamsulosin , this percentage increased to 80.4 % . Conclusion : The treatment by alpha – 1 blockers considerably decreased not only LUTS but also helped to accelerate the passing of minor calculi from the terminal parts of the ureters of 80.4 % of pts . It seems that alpha – 1 blockers potentiate the spasmoanalgetic action of drugs used in st and ard methods of treatment OBJECTIVES To design a r and omized , no-treatment , controlled , prospect i ve study to determine whether the administration of tamsulosin , as adjunctive medical therapy , increases the efficacy of one extracorporeal shock wave lithotripsy ( ESWL ) session to treat renal stones and decreases the use of analgesic drugs after the procedure . METHODS A total of 130 patients underwent a single ESWL session to treat solitary radiopaque renal stones 4 to 20 mm in diameter . After treatment , all patients were r and omly assigned to receive our st and ard medical therapy alone ( controls ) or in association with 0.4 mg tamsulosin daily for a maximum of 12 weeks . All 130 patients were followed up for 3 months or until an alternative treatment was given . RESULTS Of the 130 patients , 78.5 % of those receiving tamsulosin and 60 % of controls had achieved clinical success at 3 months ( P = 0.037 ) . When we stratified patients according to stone size , for those with a stone size larger than 10 mm , the success rate was significantly greater in the tamsulosin group ( P = 0.028 ) . Renoureteral colic occurred in 76.9 % of patients treated with st and ard therapy but in only 26.1 % of those receiving tamsulosin ( P < 0.001 ) . The mean cumulative diclofenac dose was 375 mg per patient in the tamsulosin group and 675 mg per patient in the control group ( P < 0.001 ) . CONCLUSIONS The results of our study have demonstrated that tamsulosin therapy , as an adjunctive medical therapy after ESWL , is more effective than lithotripsy alone for the treatment of patients with large renal stones and is equally safe . In addition , our results also indicated that adjunctive treatment with tamsulosin could decrease the use of analgesic drugs after ESWL Extracorporeal shock wave lithotripsy ( ESWL ) is currently considered one of the main treatments for ureteral stones . Some studies have reported the effectiveness of pharmacologic therapies ( calcium antagonists or alpha-blockers ) in facilitating ureteral stone expulsion after ESWL . We prospect ively evaluated the efficacy , after ESWL , of nifedipine on upper-middle ureteral stones , and tamsulosin on lower ureteral stones , both associated to ketoprofene as anti-edema agent . From January 2003 to March 2005 we prospect ively evaluated 113 patients affected by radiopaque or radiolucent ureteral stones . Average stone size was 10.16 ± 2.00 mm ( range 6–14 mm ) . Thirty-seven stones were located in the upper ureter , 27 in the middle ureter , and 49 in the lower ureter . All patients received a single session of ESWL ( mean number of shock waves : 3,500 ) by means of a Dornier Lithotripter S ( mean energy power for each treatment : 84 % ) . Both ultrasound and X-ray were used for stone scanning . After treatment , 63 of 113 patients were su bmi tted to medical therapy to aid stone expulsion : nifedipine 30 mg/day for 14 days administered to 35 patients with upper-middle ureteral stones ( group A1 ) and tamsulosin 0.4 mg/day for 14 days administered to 28 patients with stones located in the distal ureter ( group A2 ) . The remaining 50 patients were used as a control group ( 29 upper – middle ureteral stones — B1— and 21 lower ureteral stones — B2— ) , receiving only pain-relieving therapy . No significant difference in stone size between the groups defined was observed . Stone clearance was assessed 1 and 2 months after ESWL by means of KUB , ultrasound scan and /or excretory urography . A stone-free condition was defined as complete stone clearance or the presence of residual fragments smaller than 3 mm in diameter . The stone-free rates in the expulsive medical therapy group were 85.7 and 82.1 % for the nifedipine ( A1 ) and tamsulosin ( A2 ) groups respectively ; stone-free rates in the control groups were 51.7 and 57.1 % ( B1 and B2 , respectively ) . Five patients ( 14.3 % ) in group A1 , 5 ( 17.8 % ) in group A2 , 14 ( 48.3 % ) in group B1 and 9 ( 42.8 % ) in group B2 were not stone-free after a single ESWL session and required ESWL re-treatment or an endoscopic treatment . Medical therapy following ESWL to facilitate ureteral stone expulsion results in increased 1- and 2-month stone-free rates and in a lower percentage of those needing re-treatment . The efficacy of nifedipine for the upper-mid ureteral tract associated with ketoprofene makes expulsive medical therapy suitable for improving overall outcomes of ESWL treatment for ureteral stones Drugs are increasingly being used to promote stone passage in renal colic . Diclofenac , nifedipine and tamsulosin cause ureteric smooth muscle relaxation in vitro ; however , in clinical trials nifedipine and tamsulosin promote stone passage whereas diclofenac has no apparent benefit . We adapted a ureteric pressure transducer catheter in an attempt to compare the human ureteric response to these drugs in vivo . The catheter was inserted into the contralateral ureter following ureteroscopy for stone disease . Contraction frequency , pressure and velocity measurements were recorded at 24 h. Each patient was r and omly allocated to receive oral diclofenac , nifedipine or tamsulosin . Measurements were taken following drug administration . Eighteen patients ( mean age 50 years ) were recruited . Two patients were excluded intraoperatively and three required early removal of the catheter . Prior to drug administration , the mean number of contractions recorded was 0–4.1/min and the peak contraction pressure ranged from 11 to 35 mmHg . Conduction velocity ranged from 1.5 to 2.6 cm/s . Ureteric peristalsis persisted in all patients despite these drugs . Diclofenac and nifedipine produced inconsistent ureteric pressure responses but had little effect on contraction frequency . Tamsulosin significantly reduced ureteric pressure but had no effect on contraction frequency . There are many limitations associated with the use of ureteric catheters , however , they may provide some useful information when used to record the response to an intervention in the same patient . These preliminary results suggest a reduction in pressure generation may be the essential factor in the promotion of stone passage . More work is required but these drugs may work by preventing the increased , uncoordinated muscular activity seen in renal colic whilst maintaining peristalsis , thereby promoting stone passage PURPOSE To evaluate the efficacy of the addition of tamsulosin to our st and ard expulsive pharmacologic therapy for the treatment of distal-ureteral stones . PATIENTS AND METHODS A series of 96 patients referred to our department for the management of symptomatic distal-ureteral calculi were r and omly divided into group 1 ( N = 46 ) who received diclofenac ( 100 mg/daily ) plus aescin ( 80 mg/daily ) and group 2 ( N = 50 ) who received the same therapy plus tamsulosin ( 0.4 mg/daily ) for a maximum of 2 weeks . There were no differences between the groups with respect to age , sex , or stone size . The primary endpoint was the expulsion rate . Expulsion time , need for analgesics , need for hospitalization , and drug side effects were the secondary endpoints . RESULTS The expulsion rate was significantly higher in group 2 ( 90 % ) than in group 1 ( 58.7 % ; P = 0.01 ) , and group 2 achieved stone passage in a shorter time ( mean 4.4 v 7.5 days , respectively ; P = 0.005 ) . Lower analgesic use was found in group 2 ( P = 0.003 ) , as well as significantly fewer hospitalizations for recurrent colic ( P = 0.01 ) . Both groups experienced few side effects associated with expulsive therapy . CONCLUSIONS A conservative approach should be considered as an option in the management of uncomplicated distal-ureteral stones . Even if the best pharmacologic expulsive regimen remains to be established , the use of the selective alpha-blocker tamsulosin is recommended in this setting PURPOSE We evaluated the efficacy of alfuzosin as medical expulsive therapy for distal ureteral stone passage . MATERIAL S AND METHODS A total of 76 patients with a distal ureteral calculus provided consent for the study . Patients were r and omized between placebo and study medication , and investigators and patients were blinded to the r and omization scheme . Followup was done on a weekly basis and continued until the patient was rendered stone-free . The patient blood pressure , discomfort level , stone position on imaging , number of remaining pills and any adverse events were assessed . Statistical analysis was performed with the Student t test with p < 0.05 considered significant . RESULTS The overall spontaneous stone passage rate was 75 % , including 77.1 % for placebo and 73.5 % for alfuzosin ( p = 0.83 ) . Mean + /- SD time needed to pass the stone was 8.54 + /- 6.99 days for placebo vs 5.19 + /- 4.82 days for alfuzosin . ( p = 0.003 ) . There was no difference in the size or volume of stones that passed spontaneously between the placebo and alfuzosin arms , as measured on baseline computerized tomography ( 4.08 + /- 1.17 and 3.83 + /- 0.95 mm , p = 0.46 ) and by a digital caliper after stone expulsion ( 3.86 + /- 1.76 and 3.91 + /- 1.06 mm , respectively , p = 0.57 ) . When comparing the improvement from the baseline pain score , the alfuzosin arm experienced a greater decrease in pain score in the days after the initial emergency department visit to the date of stone passage ( p = 0.0005 ) . CONCLUSIONS Alfuzosin improves the patient discomfort associated with stone passage and decreases the time to distal ureteral stone passage but it does not increase the rate of spontaneous stone passage OBJECTIVES To evaluate whether alpha1-blockers have any impact on stone clearance in patients with lower ureteral stones who underwent either shock wave lithotripsy ( SWL ) or were followed up with st and ard hydration , analgesics , and anti-inflammatory treatment . METHODS A total of 78 patients ( 56 men and 22 women ) who had lower ureteral stones located at the distal 5 cm of the ureter were divided into four groups . The first group consisted of 30 patients ( 38.5 % ) with stones less than 5 mm ( range 3 to 5 ) who were r and omly divided into two subgroups . Group 1 consisted of 15 patients ( 19.2 % ) who were followed up with oral hydration and diclofenac sodium . Group 2 consisted of 15 patients ( 19.2 % ) who received tamsulosin 0.4 mg daily in addition to the st and ard regimens . The second two groups consisted of 48 patients ( 61.5 % ) with stones greater than 5 mm ( range 6 to 15 ) who underwent SWL . These patients were also r and omly divided between those who did not ( group 3 , n = 24 ) and those who did ( group 4 , n = 24 ) receive tamsulosin 0.4 mg daily . All patients were re-evaluated with plain abdominal x-rays and helical computed tomography 15 days after the beginning of treatment . RESULTS Of the 78 patients , 36 ( 46.2 % ) became stone free . The stone-free rate was 20 % , 53.3 % , 33.3 % , and 70.8 % for group 1 , 2 , 3 , and 4 , respectively . The best results were achieved in those who underwent SWL plus tamsulosin treatment ( group 4 ) . The differences between the stone-free rates for groups 3 versus 4 ( P = 0.019 ) and the tamsulosin versus control groups ( P = 0.0015 ) were statistically significant . CONCLUSIONS The addition of tamsulosin to conventional treatment seemed beneficial in terms of stone clearance of lower ureteral stones , and this effect was more evident for larger stones , especially when combined with SWL OBJECTIVE To evaluate the efficacy of alpha1-adrenergic antagonist in the medical management of lower ureteral stone with extracorporeal shock wave lithotripsy ( ESWL ) . METHODS A total of 80 patients with stone located in lower ureter were r and omly divided into two groups . Group 1 served as control and group 2 received tamsulosin ( 0.4 mg , once daily ) after ESWL . All patients were observed for 2 weeks and asked to compile a diary about renal colic , stone expulsion , use of analgesic drugs , and side effects of medical therapy . RESULTS During 2 weeks , stones were expulsed in 18 patients ( 45.0 % ) of group 1 and in 31 patients ( 77.5 % ) of group 2 . The expulsion rate between group 1 and group 2 was significantly different ( P < 0.01 ) . Eight patients ( 20.0 % ) in group 1 and 2 patients ( 5.0 % ) in group 2 experienced renal colic relapse within 2 weeks and were administered with analgesics ( P < 0.05 ) . No side effect in group 1 was reported , except that 2 patients in group 2 complained of slight dizziness . CONCLUSIONS Tamsulosin ( alpha1-adrenergic antagonist ) can improve the stone-free rate of lower ureteral stones after ESWL and reduce the relapse of renal colic . As a safe and effective agent , it can be regarded as an auxiliary clearance method after ESWL for lower ureteral stones Low-dose ( 0.2 mg/day ) and st and ard-dose ( 0.4 mg/day ) tamsulosin were studied in a r and omized controlled trial of 75 out patients with distal ureteroliths in Thail and . Group 1 ( n = 25 ; control ) received oral sodium diclofenac 50 mg twice a day for 10 days ; group 2 ( n = 25 ) received oral sodium diclofenac 50 mg twice a day for 10 days , with oral tamsulosin 0.2 mg once a day up to 28 days ; and group 3 ( n = 25 ) received oral sodium diclofenac 50 mg twice a day for 10 days , with oral tamsulosin 0.4 mg once a day up to 28 days . For groups 1 , 2 and 3 , respectively , the expulsion rates were 4 % , 40 % and 68 % ( significantly different for group 1 vs group 2 , and for group 1 vs group 3 ) and mean expulsion times were 23.00 , 9.30 and 10.76 days . Both doses of tamsulosin increased stone expulsion rate and decreased expulsion time in comparison with the control , and have been shown to be safe and effective in Asian patients PURPOSE Recent studies show the interesting efficacy of different drug combinations for the spontaneous expulsion of distal ureteral stones . We performed a r and omized , prospect i ve study to assess and compare the efficacy of 3 drugs as medical expulsive therapy for distal ureteral calculi . MATERIAL S AND METHODS A total of 210 symptomatic patients with distal ureteral calculi greater than 4 mm were r and omly allocated to home treatment with phloroglucinol , tamsulosin or nifedipine ( groups 1 to 3 , respectively ) . Each group was given a corticosteroid drug and antibiotic prophylaxis with an injectable nonsteroidal anti-inflammatory drug was also used on dem and . The primary end point was the expulsion rate and the secondary end points were expulsion time , analgesic use , need for hospitalization and endoscopic treatment as well as the number of workdays lost , quality of life and drug side effects RESULTS The expulsion rate was significantly higher in group 2 ( 97.1 % ) than in groups 1 ( 64.3 % , p < 0.0001 ) or 3 ( 77.1 % , p < 0.0001 ) . Group 2 significantly achieved stone passage in a shorter time than the other 2 groups and showed a significantly decreased number of hospitalizations as well as a better decrease in endoscopic procedures performed to remove the stone . The control of renal colic pain was significantly superior in group 2 compared with the other groups , result ing in fewer workdays lost . Group 3 showed lower analgesic use and decreased workdays lost compared with group 1 . No difference in side effects was observed among the groups . CONCLUSIONS Medical expulsive therapy should be considered for distal ureterolithiasis without complications before ureteroscopy or extracorporeal lithotripsy . The use of tamsulosin in this treatment regimen produced stone expulsion in almost all cases in a short time , allowing complete home patient treatment PURPOSE To evaluate the clinical role of an alpha(1a-1d)-specific blocker in the medical expulsive therapy of symptomatic lower ureteral stones . MATERIAL S AND METHODS This prospect i ve study was carried out from May 2005 to December 2006 and involved 95 patients . All patients , who had symptomatic lower ureteral stones < 10 mm diameter , were enrolled in this prospect i ve study , and were r and omly divided into three groups using the statistical software programs Plus 1.0 and Plus 2.10 . Group 1 ( 32 patients ) received tamsulosin ( 0.4 mg daily ) , group 2 ( 32 patients ) received terazosin ( 2 mg daily ) , group 3 ( 31 patients ) acted as controls . All patients were diagnosed with x-rays of the kidneys , ureters , and bladder , urinary ultrasonography , and intravenous urography . All patients received the same analgesic regimen and sublingual buprenorphine on dem and . The number of colic episodes , lower urinary tract symptoms , analgesic dosages , and the number of days required for spontaneous passage of the stones were all recorded in a diary . RESULTS Expulsion was observed in 26 of 32 patients in group 1 ( 81 % ) , 25 of 32 in group 2 ( 78 % ) , and 17 of 31 in group 3 ( 55 % ) . The average expulsion time for groups 1 , 2 , and 3 were 6.3 , 6.3 , and 10.1 days , respectively . Mean analgesic dosage per patient in groups 1 , 2 , and 3 were 231 , 256 , and 347 mg , respectively . A statistically significant difference was observed between groups 1 and 2 with respect to group 3 for all three of these parameters . Adverse effects were also seen in 5 of 32 patients in group 2 ( 16 % ) , a statistically significant difference with regard to groups 1 and 3 . CONCLUSIONS Medical treatment with alpha(1a-1d)-blocker proved to be safe and effective as demonstrated by the increased stone expulsion rate and reduced expulsion time , as well as the need for analgesics OBJECTIVES To investigate the relationship between delay in extracorporeal shock wave lithotripsy ( ESWL ) after a first colic and subsequent time to complete stone clearance . METHODS This prospect i ve , non-r and omized study included 94 patients treated with ESWL for unilateral solitary proximal ureteral stones after at least one episode of colic pain . Time between the first onset of colic pain and ESWL and stone clearance was recorded . The pretherapeutic degree of hydronephrosis has been assessed using ultrasound . RESULTS Mean stone size was 7.9 + /- 2.3 mm and mean time before ESWL after a first colic was 93.4 + /- 143.5 h. At 3 months , 3 patients were lost to follow-up . In 76.9 % of patients stones were completely cleared and a further 3.3 % harbored residual fragments < or =3 mm . Delay in treatment after a first colic correlated with subsequent time to stone clearance ( p < 0.0001 ) . Mean time to stone clearance in patients treated within 24h was 6.4 + /- 6.3 days compared with 16.0 + /- 17.8 days for those treated later ( p = 0.008 ) . Maximum stone diameter correlated with time to stone clearance ( p = 0.031 ) , but the degree of hydronephrosis did not . CONCLUSIONS Rapid ESWL after a first onset of colic pain result ed in accelerated stone clearance independent of the degree of hydronephrosis but had no impact on the need for auxiliary procedures Our study aim ed to define the position of tamsulosin as adjunctive therapy in patients with stones of the distal ureter who had undergone extracorporeal shock wave lithotripsy ( ESWL ) . In total , 61 consecutive patients ( 38 men and 23 women ) with single distal radiopaque ureteral stone of ≥6 mm of diameter were enrolled . After ESWL patients were r and omized in two groups . Non-steroidal anti-inflammatory drug ( supp . diclofenac 50 mg ) was given to both groups upon dem and . In group B , all patients ( 30 ) received additionally tamsulozin 0.4 mg every day . Follow-up visits were performed 1 , 2 , 3 and 4 weeks after ESWL . Evaluation included a KUB plain film and an ultrasound examination . Efficacy was evaluated in terms of success rate , stone-free rate , expulsion time of the fragments and use of diclofenac . Two patients from the tamsulosin group experienced dizziness and one was withdrawn . The success rate was 58.06 and 66.66 % for the control and the tamsulosin group , respectively , while the corresponding values for stone-free rate were 51.6 and 63.33 % , respectively . The mean expulsion time of the fragments was 13.22 days for group A and 12.95 days for group B. These results did not achieve statistically significant difference ( P > 0.05 ) . The mean diclofenac dose was 118.9 mg in group A and 56.9 mg in group B. This difference was statistically significant ( P = 0.02 ) . Despite the relatively small number of patients , our data indicate that the use of tamsulosin after ESWL in this specific subgroup of patients does not result in improved success and stone-free rate and expulsion time . In contrast , a significantly reduced need for analgesics was found We have conducted a double-blind , r and omized , placebo-controlled trial with oral diclofenac to study the prophylactic effect on renal colic recurrence and spontaneous stone expulsion rate . Forty-one patients were given 50 mg oral diclofenac 3 times a day for 7 days after being discharged for a colic episode from Oslo Emergency Hospital ( < 24 h stay ) and 39 patients were given matching placebo tablets . The number of new renal colic episodes per accumulated patient treatment days was 64/287 in the diclofenac group and 119/273 in the placebo group ( p < 0.01 ) . This difference was greatest during the first 4 treatment days . A similar trend was found for pain intensity ( 0 - 10 cm VAS ) with the greatest difference on day 1 ( 4.3 vs. 2.8 , p = 0.05 ) . Side effects , mainly gastrointestinal , were reported for 14 % of the treatment days in both treatment groups . Stone expulsion rate was almost identical ( 28 vs. 29 days ) , regardless of stone size . Readmission rate to Oslo Emergency Hospital/other hospitals were 10 and 67 % ( p < 0.001 ) . In conclusion , oral treatment with diclofenac was effective as short-term prophylaxis of new colic episodes , especially during the first 4 days , and reduces the number of hospital readmissions significantly . The stone passage rate appears not to be affected OBJECTIVES To increase the success rate of the first treatment of ureteral stones through extracorporeal shock wave lithotripsy ( ESWL ) , we tested the efficacy of a medical therapy with nifedipine and deflazacort administered to patients who had undergone ESWL for ureteral stones . METHODS This prospect i ve study lasted from October 1998 to September 2000 and involved 80 patients . All the patients underwent ESWL with Sonolith 4000 + . The patients were r and omly divided into two groups : 40 patients ( group 1 ) received an " adjunctive " treatment with oral medical therapy ( nifedipine and deflazacort ) ; the other 40 patients ( group 2 ) were used as the control group . RESULTS Complete fragment expulsion occurred in 30 ( 75 % ) of the 40 patients of group 1 and in 20 ( 50 % ) of the 40 patients of group 2 at the endpoint . A statistically significant difference was observed in the stone-free rate ( P = 0.02 ) . Concerning the symptomatic therapy , the average diclofenac use was 37.5 mg per patient in group 1 and 86.25 mg per patient in group 2 ( P = 0.02 ) . CONCLUSIONS The results of this study have shown the role that adjunctive medical therapy with nifedipine and deflazacort given after an ESWL procedure can play in increasing the success rate of ureteral stone treatment . Furthermore , these results would suggest that adjunctive medical therapy can reduce total analgesic consumption after the ESWL procedure OBJECTIVES To evaluate whether tamsulosin , as an alpha(1)-blocker , was effective for the treatment of steinstrasse in the lower ureter after shock wave lithotripsy . METHODS A total of 67 patients ( 43 men and 24 women ) with steinstrasse in the lower portion of the ureters were r and omly divided into two groups . Only hydration and tenoxicam ( 20 mg orally once daily ) was given to group 1 ( 35 patients ) . Group 2 ( 32 patients ) , was also given tamsulosin ( 0.4 mg daily ) . All patients were reevaluated and question ed about the number of episodes and severity of ureteral colic and the rates of spontaneous resolution of steinstrasse 6 weeks after beginning treatment . They were asked to score the severity of pain according to a visual analog scale . RESULTS In 23 ( 65.7 % ) of 35 patients in group 1 and in 24 ( 75 % ) of 32 patients in group 2 , steinstrasse resolved during the first 6 weeks . The resolution rates were not significantly different ( P > 0.05 ) between groups 1 and 2 . Group 1 had more ureteral colic episodes than did group 2 while passing their stones . This difference was statistically significant ( P < 0.01 ) . Group 1 patients reported significantly greater ( P < 0.001 ) visual analog scale scores than did group 2 patients . CONCLUSIONS The addition of tamsulosin to conservative treatment seemed to be beneficial in terms of the reduced number of ureteral colic episodes and the severity of pain in the patients who developed steinstrasse after shock wave lithotripsy OBJECTIVES To compare two treatment regimens in patients with ureteral calculi . One regimen ( control arm ) used routine drugs , and the second regimen ( treatment arm ) used the same routine drugs plus uncommonly used drugs . METHODS Between February and October 1998 , 70 consecutive patients were evaluated for symptomatic ureteral calculi . Thirty-five patients were r and omized to a control arm and received ketorolac , oxycodone , and acetaminophen combination tablets and prochlorperazine suppositories . Thirty-five patients were r and omized to the treatment arm and received the same medications plus nifedipine XL , prednisone , and trimethoprim/sulfa combination tablets and plain acetaminophen . Stone passage rates , work days lost , emergency room visits , surgical interventions , and possible side effects of the drugs were recorded . RESULTS The treatment arm ( addition of nifedipine XL , prednisone , trimethoprim/sulfa , and plain acetaminophen ) had higher ( 86 % versus 56 % ) stone passage rates and fewer lost work days ( mean 1.76 versus 4.9 ) , emergency room visits ( 1 versus 4 ) , and surgical interventions ( 2 versus 15 ) . Both arms exhibited similar potential drug side effects . CONCLUSIONS The addition of a calcium channel blocking agent , steroids , antibiotics , and more acetaminophen effected a higher stone passage rate and fewer lost work days , emergency room visits , and surgical interventions OBJECTIVES To assess the clinical role of corticosteroids in the medical expulsive therapy of symptomatic distal ureteral stones . METHODS Between January 2004 and September 2005 , 114 patients with symptomatic distal ureteral stones with a > /=5 mm diameter were enrolled in this prospect i ve study and divided into four groups based on the urologist ( of four ) who treated them in the emergency unit . Group A ( 33 patients ) received tamsulosin ( 0.4 mg daily ) , group B ( 24 patients ) received deflazacort ( 30 mg daily ) , group C ( 33 patients ) received both ( 0.4 mg tamsulosin+30 mg deflazacort daily ) , and control group D ( 24 patients ) received only analgesics . The treatment duration was 10 d to prevent the side-effects of prolonged corticosteroid therapy . The end points were the expulsion rate , analgesic consumption , number of ureteroscopies , and safety . RESULTS The groups were comparable in terms of age , sex , and stone location . The stone diameter was 5.96+/-0.33 mm for group A , 5.83+/-0.4 mm for group B , 5.88+/-0.23 mm for group C , and 5.71+/-0.5 mm ( p>0.05 ) for group D. The rates of expulsion for the four groups were 60 % , 37.5 % , 84.8 % , and 33.3 % , respectively . There was a significant difference between group C and the other groups ( p<0.001 ) . The mean analgesic consumption was 42.5+/-0.4 mg for group A , 50+/-0.3 mg for group B , 27.3+/-0.5 mg for group C , and 81+/-0.33 mg for group D , with a significant difference between group C and the other groups ( p<0.001 ) . During the treatment period , only two cases of drug side-effects related to tamsulosin ( without any drop-outs ) were recorded . CONCLUSION When the medical expulsive therapy for symptomatic distal ureteral stones is considered , the use of steroids ( deflazacort ) proves efficient only when administered together with alpha(1)-blockers ( tamsulosin ) . In addition , tamsulosin used on its own as a medical expulsive therapy can be considered as an alternative treatment for those patients who are not suitable for steroid therapy , as it is generally efficient OBJECTIVES To evaluate the activity of the therapeutic agents ( tamsulosin and /or tolterodine ) used to accelerate the expulsion of stones and to reduce the probable complications during observation of the medical treatment of distal ureteral stones to allow spontaneous passage . METHODS A total of 120 patients with distal ureteral stones were included in the study . Patients with stones less than 10 mm and allowing urinary flow were included in the study . The patients were studied in four r and omly divided groups . Group 1 patients received tamsulosin 0.4 mg/day , group 2 patients received tamsulosin 0.4 mg/day plus tolterodine 2 mg ( twice a day ) , group 3 patients received tolterodine 2 mg ( twice a day ) , and group 4 patients did not receive any medical treatment ( control group ) . RESULTS Differences among the four groups in patient age and stone dimension were not statistically significant ( P > 0.05 ) . The stone expulsion rates were greater ( P < 0.05 ) in groups 1 and 2 than in groups 3 and 4 . A significant variation ( P < 0.05 ) regarding the time to stone expulsion was observed in groups 1 and 2 . CONCLUSIONS In our study , the use of tamsulosin for the expulsion of distal ureteral stones was effective ; however , the use of tolterodine provided no additional advantages OBJECTIVES To evaluate the effectiveness of medical therapy during watchful waiting in patients with distal ureter stones . METHODS Ninety-six patients with radiopaque stones located in the distal tract of the ureter and with stone sizes of 1 cm or smaller were involved in the study . The patients were r and omly divided into two groups . Group A ( n = 48 ) received oral treatment with 30 mg of deflazacort daily ( maximum 10 days ) plus 30 mg of slow-release nifedipine daily ( maximum 4 weeks ) . Group B ( n = 48 ) underwent a wait- and -watch approach . Both groups of patients were allowed to use diclofenac on dem and . Statistical analyses were carried out using Student 's t test , the chi-square test , and Fisher 's exact test . RESULTS The average stone size was 5.8 + /- 1.8 mm for group A and 5 . 5 + /- 1.4 mm for group B. No statistically significant difference was found in stone size . Stone expulsion was observed in 38 ( 79 % ) of 48 patients in group A and in 17 ( 35 % ) of 48 patients in group B. The average expulsion time was 7 days ( range 2 to 10 ) for group A and 20 days ( range 10 to 28 ) for group B. A statistically significant difference was observed in both the expulsion rate and the expulsion time ( P < 0.05 ) . The mean amount of sodium diclofenac used was 15 mg per patient for group A and 105 mg per patient for group B ( P < 0.05 ) . CONCLUSIONS The medical treatment proved to be effective and safe , as demonstrated by the increased stone expulsion rate , decreased expulsion time , and reduced need for analgesic therapy Expulsive medical therapy of ureteral stones is not well established . To test the efficacy of a calcium antagonist ( nifedipine ) associated with a corticosteroid ( methylprednisolone ) in facilitating ureteral stone passage , we studied 86 patients with a unilateral ureteral radiopaque stone not larger than 15 mm . in maximum diameter , confirmed in each case by drop excretory urography . Patients were r and omly treated for a maximum of 45 days under double-blind conditions with 16 mg . methylprednisolone plus 40 mg . nifedipine daily ( group 1 - 13 women and 30 men , mean age 45 + /- 14 years , st and ard deviation ) and with 16 mg . methylprednisolone plus placebo daily ( group 2 - 18 women and 25 men , mean age 43 + /- 14 years ) . All patients also received 2 l. of low mineral content water daily . The average maximum diameter of the stones was 6.7 + /- 3.0 mm . in group 1 and 6.8 + /- 2.9 mm . in group 2 ( not significant ) . Partial ureteral obstruction was present in approximately half of the patients in both groups . Four patients in group 1 and 6 in group 2 dropped out of the study . In group 1 , 34 patients had successful results ( stone passage without surgical manipulation ) and 5 failed ( success rate 87 % ) , compared to 24 and 13 , respectively , in group 2 ( success rate 65 % ) . This difference was significant ( p = 0.021 , Fisher 's exact test ) . No difference was present in the maximum stone diameter among the successful cases in groups 1 and 2 ( 6.4 + /- 2.8 and 5.3 + /- 2.2 mm . , respectively , not significant ) . In both groups the maximum diameter of the stone was larger in the failed than in the successful cases ( group 1 - 10.4 + /- 3.0 versus 6.4 + /- 2.8 mm . , p = 0.005 , and group 2 - 9.3 + /- 2.5 versus 5.3 + /- 2.2 mm . , p = 0.0001 ) . In group 1 the mean interval for stone passage in the successful cases was 11.2 + /- 7.5 days , compared to 16.4 + /- 11.0 days in group 2 ( p = 0.036 , Student 's t test ) . We conclude that nifedipine associated with methylprednisolone is effective in facilitating ureteral stone passage Alpha1-adrenoblocker tamsulosin reduces muscle spasm in the ureteric wall , decreases peristalsis below and raises pressure above the stone thus facilitating stone passage . Patients on tamsulosin had spontaneous stone passage in 73.8 % cases while only 22.4 % patients on routine therapy became stone free . Tamsulosin also shortens hospital stay . Use of tamsulosin 0.4 mg daily in patients with distal ureteric stones is pathogenetically vali date d , is highly clinical ly and cost effective OBJECTIVE We evaluated the efficacy of low dose tamsulosin after extracorporeal shock wave lithotripsy ( ESWL ) in Japanese male patients with ureteral stone . METHODS One hundred and two Japanese male patients with ureteral stones who underwent ESWL were r and omly divided into three groups . Group A ( 38 patients ) was given tamsulosin ( 0.2 mg/day ) ; group B ( 30 patients ) was given c horeito , a herbal medicine ( 7.5 g/day ) ; and group C ( 34 patients ) received no medication . Stone clearance was assessed at 1 , 7 , 14 , and 28 days after ESWL using plain abdominal radiography and abdominal ultrasonography . After 28 days , stone delivery was checked every 2 weeks . RESULTS The stone-free rate was 84.21 % , 90 % , and 88.24 % for groups A , B , and C , respectively ( P = 0.3425 ) . The mean expulsion time was 15.66 + /- 6.14 days in group A , 27.74 + /- 25.36 days in group B , and 35.47 + /- 53.70 days in group C. The expulsion time of group A was significantly shorter than that of groups B ( P = 0.0116 ) and C ( P = 0.0424 ) . CONCLUSIONS The addition of tamsulosin to conservative treatment appeared to be effective in shortening the stone expulsion time OBJECTIVE To determine the efficacy of terazosin as a facilitator agent for the passage of lower ureteral stones . METHODS Since February 2004 to December 2004 , 64 patients with lower ureteral stones who came to the emergency department were enrolled in this study . Exclusion criteria were the presence of urinary tract infection , severe hydronephrosis , elevated serum creatinine , hypertension , history of peptic ulcer disease and history of spontaneous stone passage . Patients were r and omized into 2 groups of 32 . Group 1 patients received terazosin tablets , 10 mg daily and analgesic ( indomethacin capsules ) for a maximum of 4 weeks , but patients in Group 2 received only analgesic . In cases of incomplete pain control , intravenous pethidine was administered . The 2 groups were compared with regard to stone passage rate , time to stone passage , the amount of received pethidine and the need for intervention . Statistical analysis was performed by student t-test . RESULTS The mean age of Group 1 was 44 years and Group 2 was 39 years . The median stone size was 6.9 + /- 2.3 mm in Group 1 and 6.6 + /- 3.1 mm in Group 2 , which was not significantly different . Stone expulsion rate was 90.62 % in Group 1 and 62.5 % in Group 2 , with a significant statistical difference ( p=0.041 ) . The mean expulsion time was 76.3 + /- 60 hours and 141 + /- 64 hours in Groups 1 and 2 , ( p=0.001 ) . Extra analgesic ( pethidine ) requirement averaged 34.4 + /- 12.7 mg and 62.1 + /- 10.5 mg in Groups 1 and 2 ( p=0.036 ) . Seven patients in Group 1 and 15 patients in Group 2 required ureteroscopy after 4 weeks due to lack of the stone passage . CONCLUSION Terazosin is a safe and effective treatment for lower ureteral stones . By using this medication , stone passage rate increases and the time of stone passage and the need for intervention decreases It has recently been demonstrated that specific adrenoceptors subtypes ( α1A/α1D ) are prevalent in the distal part of the ureter , a finding supporting the interesting results obtained by different groups with the use of tamsulosin in the treatment of distal ureteral calculi . We performed a prospect i ve r and omized study to evaluate the effects of the addition of tamsulosin on our st and ard pharmacological therapy for the treatment of selected ureteral stones . A total of 64 patients referred to our department for the management of symptomatic ureteral calculi were considered . Patients were r and omly divided into two treatment groups : group A ( n=32 ) who received diclofenac ( 100 mg/daily ) plus aescin ( 80 mg/daily ) and group B ( n=32 ) who received the same therapy plus tamsulosin ( 0.4 mg/daily ) for a maximum of 2 weeks . No significant differences were found between the groups for age , gender distribution and mean stone size measured in the single largest dimension at presentation . The stone expulsion rate was 60 % ( 19/32 patients ) for group A and 88 % for ( 28/32 ) for group B with a mean expulsion time of 7.4±2.2 ( range 3.5–12 ) and 4.8±2.7 days ( range 1.8–10.5 ) , respectively . Group B showed a significant advantage in terms of both expulsion rate ( P=0.01 ) and expulsion time ( P=0.005 ) . Different analgesics from those used in the st and ard treatment regimen were required in ten patients in group A ( 31 % ) but only three patients in group B ( 9 % ) . This difference was significant ( P=0.003 ) . Hospitalization for recurrent colic was needed in 21 % of patients in group A ( 7/32 ) and in 9 % in group B ( 3/32 ) ( P=0.01 ) . Only two patients in each group ( 6 % ) experienced minor side effects associated with the expulsive therapy . Our data confirm the efficacy of tamsulosin in the treatment of distal ureteral stones up to 1 cm . This selective α-blocker should therefore be included in the pharmacological regimen of patients when a conservative approach is considered in the treatment of ureteral lithiasis OBJECTIVES To assess the clinical efficacy of the addition of a corticosteroid drug to tamsulosin in the medical-expulsive therapy of distal ureterolithiasis . METHODS Sixty consecutive patients with a symptomatic distal ureteral stone were included in our study and r and omized to one of two home treatment groups . Group 1 patients ( n = 30 ) received tamsulosin ( 0.4 mg daily ) , and group 2 patients ( n = 30 ) were treated with a corticosteroid drug ( deflazacort , 30 mg daily ) plus tamsulosin . The treatment duration was until stone expulsion or 28 days , whichever came first . The primary endpoint of the study was the stone expulsion rate . The secondary endpoints were the expulsion time ; use of analgesics ; number of emergency room admissions , hospitalizations , and workdays lost ; drug side effects ; and quality of life of the patients ( EuroQol question naire , EQ-5D ) during treatment . RESULTS The two groups had a similar expulsion rate ( 90 % for group 1 and 96.7 % for group 2 ; P = 0.612 ) , but the expulsion time was significantly reduced in group 2 patients ( P = 0.036 ) . During the treatment period , we did not observe significant differences between the two groups in the number of emergency room visits or hospitalizations , analgesic use , number of workdays lost , or incidence of drug side effects . The quality of life of the patients during therapy , as determined using the EQ-5D , was similar in both groups . CONCLUSIONS The use of a corticosteroid drug in association with tamsulosin seemed to induce more rapid stone expulsion . In addition , tamsulosin alone as medical-expulsive therapy for distal ureteral calculi had excellent expulsive effectiveness Objective . To evaluate the potential role of tamsulosin in the medical treatment of distal ureteral stones . Material and methods . Ninety patients with symptomatic distal ureteral calculi were enrolled . They were r and omly divided into two groups : Group A ( n=45 ) received diclofenac 100 mg on dem and for 4 weeks plus levofloxacin 250 mg daily for the first week and were well hydrated ; and Group B ( n=45 ) received the same therapy plus tamsulosin 0.4 mg/daily for 4 weeks . Abdominal ultrasound scans and KUB X-rays were performed weekly . Stone expulsion rates , time to expulsion , pain episodes and analgesic usage were determined . Intervention by means of shock-wave lithotripsy ( SWL ) or ureteroscopy was evaluated . Results . The stone expulsion rate was 51.1 % for Group A , compared to 88.9 % for Group B ( p=0.001 ) . The average time to expulsion was 12.53±2.12 days for Group A and 7.32±0.78 days for Group B ( p=0.04 ) . The number of pain episodes was significantly lower in Group B and mean use of analgesics was lower for Group B ( 0.14±0.5 vials ) than Group A ( 2.78±2.7 vials ) . Twenty-two patients in Group A failed to pass their stones after 4 weeks but only five in Group B. Of the patients who were not stone-free , 19 were treated with SWL and eight underwent ureteroscopy . Conclusion . Our study reveals the efficacy of tamsulosin for the treatment of distal ureteral stones . Tamsulosin should be added to the st and ard medical approach for treating these stones OBJECTIVES To evaluate the role of tamsulosin in the clearance of fragments after extracorporeal shock wave lithotripsy ( ESWL ) to treat renal calculi . METHODS In this open-label prospect i ve r and omized study conducted at our institute from 2006 to 2007 , 139 patients with normal renal function and a single radiopaque renal calculus , 5 - 20 mm , undergoing ESWL were enrolled . All patients underwent ESWL every 3 weeks until success or for < or=3 months , whichever was earlier . They were r and omly assigned to 2 groups with respect to whether they had received tamsulosin , 0.4 mg/d . The primary endpoint was the success rate , and the secondary endpoints were clearance time , sessions required for clearance , pain intensity , incidence of steinstrasse , and the need for auxiliary procedures . RESULTS Of the 139 patients , 51 in group 1 and 65 in group 2 completed the requisite follow-up . The demographic profile of both groups was comparable . The success rate after 1 , 2 , and 3 ESWL sessions was greater in group 1 than in group 2 ( 52.9 % , 78.4 % , and 94.1 % vs 30.8 % , 52.3 % , and 75.4 % ; P = .016 , P = .004 , and P = .007 , respectively ) . The total days required for success ( 35.53 + /- 19.47 vs 47.22 + /- 23.64 ; P = .006 ) , total ESWL sessions required for success ( 1.66 vs 2.16 ; P = .005 ) , and the pain experienced ( visual analog scale score 28.67 + /- 20.35 vs 47.30 + /- 24.98 , respectively ; P = .0001 ) were significantly less in group 1 . Two patients in group 1 and 9 in group 2 developed steinstrasse ( P = .10 ) ; conservative management was successful in 1 patient in each group ( P = .345 ) . Three patients in group 1 and 10 in group 2 required auxiliary procedures ( P = .14 ) . CONCLUSIONS The results of our study have shown that tamsulosin facilitates earlier clearance of fragments after ESWL to renal calculi and helps reduce the severity of the pain . It tended to facilitate spontaneous clearance of steinstrasse ; however , this requires additional evaluation |
1,962 | 25,192,224 | Oocyte vitrification compared to slow freezing probably increases clinical pregnancy rates in women undergoing assisted reproduction . | BACKGROUND Oocyte cryopreservation is a technique with considerable potential in reproductive medicine , including fertility preservation , as a way of delaying childbearing and as part of oocyte donation programs .
Although the technique was relatively ineffective at first more recently numerous modifications have led to higher success rates .
OBJECTIVES To compare the effectiveness and safety of vitrification and slow freezing as oocyte cryopreservation techniques for fertility outcomes in women undergoing assisted reproduction . | Background Oocyte cryopreservation is an important method used in a number of human fertility circumstances . Here , we compared the survival , in vitro maturation , fertilization , and early embryonic development rates of frozen-thawed human immature oocytes using two different cryopreservation methods . Methods A total of 454 failed-matured oocytes [ germinal vesicle ( GV ) and metaphase I ( MI ) stages ] were collected from 135 patients ( mean age 33.84 + /- 5.0 y ) who underwent intracytoplasmic sperm injection ( ICSI ) cycles between February 2009 and December 2009 and r and omly divided into a slow freezing group [ 1.5 mol/L-1 , 2-propanediol ( PROH ) + 0.2 mol/l sucrose ] and vitrification group [ 20 % PROH + 20 % ethylene glycol ( EG ) + 0.5 mol/l sucrose ] . Results The vitrification protocol yielded a better survival rate than the slow freezing protocol at each maturation stage assessed . Regardless of the maturation stage ( GV + MI ) , the slow freezing protocol had a significantly lower survival rate than the vitrification protocol ( p < 0.001 ) . In addition , a significant difference was found in the survival rates between GV and MI oocytes regardless of the protocol used ( 90.1 vs. 64.7 % , respectively ; p < 0.01 ) . We also found that the maturation rates of GV and MI oocytes from the slow freezing and vitrification groups were 16.7 vs. 24.4 % and 50.8 vs. 55.4 % , respectively . Regardless of the protocol used , the GV oocytes had significantly lower viability than MI oocytes after 36 h of in vitro maturation ( 21.2 vs. 54.0 % , respectively ; p < 0.01 ) . In addition , the GV and MI oocytes from the slow freezing group had a markedly lower maturation rate than those from the vitrification group ( 33.6 vs. 43.1 % , respectively ) , but no statistical difference was found between the two groups ( P > 0.05 ) . For the GV-matured oocytes , no fertilized eggs were obtained in the slow-freezing group , while a 19.0 % ( 4/21 ) fertilization rate was observed in the vitrification group . For the MI-matured oocytes , fertilization rates for the slow freezing and vitrified groups were 36 % and 61.1 % , respectively , but no significant difference was found between the two groups ( PIn the Methods section in the MS , all procedures were compliant with ethical guidelines , i.e. approved by the Ethical Committee of our university and Informed Consent signed by each patient . > 0.05 ) . In the GV vitrification group , no embryo formed ; however , in the MI slow freezing group , 12 oocytes were fertilized , but only two achieved cleavage and were subsequently blocked at the 2-cell stage . In the MI vitrification group , a total of 22 embryos were obtained , five of which developed to the blastocyst stage . Conclusions Vitrification is superior to the slow freezing method in terms of the survival and developmental rates for the cryopreservation of human failed-matured oocytes . In addition , GV oocytes appeared to be more resistant than MI oocytes to the low temperature and cryoprotectant used during cryopreservation BACKGROUND An efficient oocyte cryopreservation method is m and atory to establish a successful egg-banking programme . Although there are increasing reports showing good clinical outcomes after oocyte cryopreservation , there is still a lack of large controlled studies evaluating the effectiveness of oocyte cryo-banking . In this study , we aim ed to compare the outcome of vitrified-banked oocytes with the gold st and ard procedure of employing fresh oocytes . METHODS A r and omized , prospect i ve , triple-blind , single-centre , parallel-group controlled- clinical trial ( NCT00785993 ) , including 600 recipients ( alpha = 0.05 and power of 80 % for sample -size calculation ) selected among 1032 eligible patients from November 2008 to September 2009 , was design ed to compare the outcome of vitrified-banked oocytes with the gold st and ard procedure of employing fresh oocytes . The study was design ed to establish the superiority of the ongoing pregnancy rate ( OPR ) of fresh oocytes over that of vitrified oocytes , by performing a likelihood ratio test in a logistic regression analysis expressed as odds ratio ( OR ) with 95 % confidence interval ( CI ) . A limit of 0.66 for OR of vitrified versus fresh groups was defined to set up a possible conversion from superiority to non-inferiority . R and omization was performed 1:1 based on a computer r and omization list in vitrification ( n = 300 ) or fresh groups ( n = 300 ) . The primary end-point was the OPR per r and omized patient i.e. intention-to-treat population ( ITT ) . Secondary end-points were clinical pregnancy ( CPR ) , implantation ( IR ) and fertilization rates , respectively . Additionally , embryo developmental characteristics were recorded . RESULTS There were no differences in donor ovarian stimulation parameters , demographic baseline characteristics for donors and recipients , ovum donation indications or male factor distribution between groups ( NS ) . The OPR per ITT was 43.7 and 41.7 % in the vitrification and fresh groups , respectively . The OR of OPR was 0.921 in favour of the vitrification group . Nevertheless , the 95 % CI was 0.667 - 1.274 , thus the superiority of fresh group with respect to OPR was not proven ( P = 0.744 ) . Non-inferiority of the vitrified group compared with the fresh group was shown with a margin of 0.667 , which was above the pre-established non-inferiority limit of 0.66 . CPR per cycle ( 50.2 versus 49.8 % ; P = 0.933 ) or per embryo-transfer ( 55.4 versus 55.6 % ; P = 0.974 ) , and IR ( 39.9 versus 40.9 % ; P = 0.745 ) were similar for patients receiving either vitrified or fresh oocytes . The proportion of top- quality embryos obtained either by inseminated oocyte ( 30.8 versus 30.8 % for Day-2 ; and 36.1 versus 37.7 % for Day-3 , respectively ) or by cleaved embryos ( 43.6 versus 43.8 % for Day-2 and 58.4 versus 60.7 % for Day-3 , respectively ) was similar between groups ( NS ) . CONCLUSIONS This controlled-r and omized , clinical trial confirmed the effectiveness of oocyte cryo-storage in an ovum donation programme , failing to demonstrate the superiority of using fresh oocytes with respect to the use of vitrified egg-banked ones in terms of OPR . Instead , the non-inferiority of vitrified oocytes was confirmed . These findings involve highly relevant issues that may open a new range of possibilities in ART STUDY QUESTION How does vitrification affect oocyte viability ? SUMMARY ANSWER Vitrification does not affect oocyte viability in oocyte donation cycles . WHAT IS KNOWN ALREADY Oocyte vitrification is performed routinely and successfully in IVF and oocyte donation programs . STUDY DESIGN , SIZE , DURATION This is a prospect i ve study performed between June 2009 and February 2012 to compare ongoing pregnancy rates and other indices of viability between fresh and vitrified oocytes . A total of 99 donations with more than 16 oocytes ( MII ) in which oocytes were allocated both to a synchronous recipient ( fresh oocytes ) and to an asynchronous recipient ( vitrified oocytes ) were included . PARTICIPANTS / MATERIAL S , SETTING , METHODS The participants were consenting couples ( donors and recipients ) from the oocyte donation program . On the day of retrieval , the oocytes allocated to the synchronous recipient were inseminated and those allocated for banking were denuded of cumulus and vitrified . Vitrified oocytes were microinjected with spermatozoa 2 h after warming . Embryo transfer was performed on Day 2 of development in both groups , and the remaining embryos were cryopreserved on Day 3 . Clinical pregnancy was defined by a positive fetal heartbeat at 6 weeks . MAIN RESULTS AND ROLE OF CHANCE A total of 989 oocytes were warmed and 85.6 % survived . No significant differences were observed between fresh and vitrified oocytes : fertilization rate ( 80.7 versus 78.2 % ) , ongoing embryo rate ( 71.0 versus 68.2 % ) or good- quality embryo rate ( 54.1 versus 49.8 % ) . The mean number of embryos transferred was similar in both groups ( 1.82 ± 0.44 versus 1.90 ± 0.34 ) . The implantation rate ( 33.3 versus 34.0 % ) and the multiple pregnancy rate ( 27.7 versus 20.8 ) were also similar between both groups ( P > 0.05 ) . The live birth rate per cycle was 38.4 % in the recipients of fresh oocytes and 43.4 % in the recipients of vitrified oocytes ( P > 0.05 ) . Eighty five frozen embryo transfers were also evaluated . Comparing embryos from fresh and vitrified oocytes there were no significant differences in the embryo survival rate ( 70.1 versus 65.8 % ) , clinical pregnancy rate ( 40.8 versus 33.3 % ) or implantation rate ( 21.8 versus 26.8 % ) . LIMITATIONS , REASONS FOR CAUTION The oocytes were donated by healthy , young women ( ≤35 years ) and these results can not be extrapolated to other population s. WIDER IMPLICATION S OF THE FINDINGS Outcomes obtained with vitrified oocytes are as good as with fresh oocytes and the use of vitrification can be extended to new applications , e.g. accumulation of oocytes from successive stimulations for preimplantation genetic diagnosis , for patients at risk of ovarian hyperstimulation syndrome or in patients needing to preserve their fertility . STUDY FUNDING /COMPETING INTEREST(S ) This work was done under the auspices of the Càtedra d'Investigació en Obstetrícia i Ginecologia of the Universitat Autònoma de Barcelona Accumulation of oocytes from several ovarian stimulation cycles is currently possible using novel vitrification technologies . This strategy could increase the inseminated cohort , creating a similar situation to normoresponders . This study included 242 low-responder ( LR ) patients ( 594 cycles ) whose mature oocytes were accumulated by vitrification and inseminated simultaneously ( LR-Accu-Vit ) and 482 patients ( 588 cycles ) undergoing IVF/embryo transfer with fresh oocytes in each stimulation cycle ( LR-fresh ) . Drop-out rate in the LR-fresh group was > 75 % . The embryo-transfer cancellation per patient was significantly lower in the LR-Accu-Vit group ( 9.1 % ) than the LR-fresh group ( 34.0 % ) . Live-birth rate (LBR)/patient was higher in the LR-Accu-Vit group ( 30.2 % ) than the LR-fresh group ( 22.4 % ) . Cumulative LBR/patient was statistically higher in the LR-Accu-Vit group ( 36.4 % ) than the LR-fresh group ( 23.7 % ) and a similar outcome was observed among patients aged ⩾40years ( LR-Accu-Vit 15.8 % versus LR-fresh 7.1 % ) . The LR-Accu-Vit group had more cycles with embryo cryopreservation ( LR-Accu-Vit 28.9 % versus LR-fresh 8.7 % ) . Accumulation of oocytes by vitrification and simultaneous insemination represents a successful alternative for LR patients , yielding comparable success rates to those in normoresponders and avoiding adverse effects of a low response . The accumulation of oocytes from several ovarian stimulation cycles is currently possible with the aid of novel vitrification technologies . This strategy could be useful for low-responder patients , contributing to increase the inseminated cohort and creating a similar situation as in normal responders . According to the results presented herein ( higher live-birth rate per patient treated ) , this strategy represents a successful alternative for low-responder patients , yielding comparable success rates to those in normal responders and avoiding the adverse effects of a low response OBJECTIVE To compare the survival , fertilization , early embryonic development , and meiotic spindle assembly and chromosome alignment in frozen-thawed human oocytes after slow-freezing and vitrification . DESIGN A r and omized study . SETTING A university-affiliated assisted reproductive center . PATIENT(S ) Donated extra eggs from women undergoing assisted reproduction treatment . INTERVENTION(S ) A total of 605 mature oocytes were divided into a slow-freezing group and a vitrification group for cryopreservation . MAIN OUTCOME MEASURE(S ) After frozen-thawing , the oocyte survival rate , spindle assembly , and chromosome alignment were compared . The surviving oocytes were inseminated by intracytoplasmic sperm injection , and the rate of fertilization and embryo development were also compared in two groups . RESULT ( S ) The oocyte survival rate was statistically significantly lower in the slow-freezing group ( 75 out of 123 , 61.0 % ) than the vitrification group ( 268 out of 292 , 91.8 % ) . The fertilization rate was the same for both groups , but the cleavage rate of zygotes was statistically significantly different between two groups : ( slow-freezing , 25/46 ( 54.4 % ) versus vitrification , 142 out of 182 ( 78.0 % ) . There was a considerable difference in the percentage of high- quality embryos between slow-freezing and vitrification groups : 6 out of 25 ( 24.0 % ) versus 60 out of 142 ( 42.3 % ) , respectively . The percentage of blastocyst development was statistically significantly higher in the vitrification group ( 47 out of 60 , 33.1 % ) than in the slow-freezing group ( 3 out of 25 , 12.0 % ) . There was a much higher percentage of oocyte abnormalities in terms of spindle assembly and chromosome alignment in the slow-freezing group ( 25 out of 64 , 39.1 % ) compared with the vitrification group ( 11 out of 62 , 17.7 % ) . CONCLUSION ( S ) Vitrification is superior to the slow-freezing method , leading to improved oocyte survival rate , fertilization , and embryonic development in vitro . These results may be related to vitrified human oocytes incurring less damage to spindle integrity and chromosome alignment OBJECTIVE To compare cryopreservation of mature human oocytes with slow-rate freezing and vitrification and determine which is most efficient at establishing a pregnancy . DESIGN Prospect i ve r and omized . SETTING Academically affiliated , private fertility center . PATIENT(S ) Consenting patients with concerns about embryo cryopreservation and more than nine mature oocytes at retrieval were r and omized to slow-rate freezing or vitrification of supernumerary ( more than nine ) oocytes . INTERVENTION(S ) Oocytes were frozen or vitrified , and upon request oocytes were thawed or warmed , respectively . MAIN OUTCOME MEASURE(S ) Oocyte survival , fertilization , embryo development , and clinical pregnancy . RESULT ( S ) Patient use has result ed in 30 thaws and 48 warmings . Women 's age at time of cryopreservation was similar . Oocyte survival was significantly higher following vitrification/warming ( 81 % ) compared with freezing/thawing ( 67 % ) . Fertilization was more successful in oocytes vitrified/warmed compared with frozen/thawed . Fertilized oocytes from vitrification/warming had significantly better cleavage rates ( 84 % ) compared with freezing/thawing ( 71 % ) and result ed in embryos with significantly better morphology . Although similar numbers of embryos were transferred , embryos result ing from vitrified oocytes had significantly enhanced clinical ( 38 % ) pregnancy rates compared with embryos result ing from frozen oocyte ( 13 % ) . Miscarriage and /or spontaneous abortion rates were similar . CONCLUSION ( S ) Our results suggest that vitrification/warming is currently the most efficient means of oocyte cryopreservation in relation to subsequent success in establishing pregnancy OBJECTIVE To evaluate the outcome of a newly established oocyte vitrification program in women undergoing in vitro fertilization ( IVF ) within a short timeframe by simultaneously evaluating embryos derived from vitrified and fresh oocytes from the same stimulated cycle . DESIGN Cohort prospect i ve controlled trial and case-control study . SETTING University-based tertiary fertility center . PATIENT(S ) Fourteen women who fulfilled the inclusion criteria underwent controlled ovarian hyperstimulation and Intracytoplasmic sperm injection ( ICSI ) treatment . INTERVENTION(S ) Oocyte vitrification . MAIN OUTCOME MEASURE(S ) The primary outcome measures were oocyte survival , fertilization and cleavage rate , and subsequent embryo development , compared between vitrified and fresh oocytes . Secondary outcomes were implantation , clinical pregnancy , miscarriage and live birth rates using embryos derived from the vitrified oocytes for transfer . This was compared with age-matched controls who met similar inclusion criteria as the study patients and who underwent IVF during the same time period . Neonatal data on all newborns was also collected . RESULTS From October 2009 until November 2010 , a total of 17 patients were enrolled in this study ( mean age 31.9 + /- 2.9 years ) . Three subjects withdrew prior to retrieval and one subject did not have a transfer from vitrified oocytes . A total of 164 metaphase II ( MII ) oocytes were retrieved ( mean 11.7 + /- 3.7 ) , 83 were vitrified with 86.7 % survival . Fertilization rate was similar between vitrified and fresh oocytes ( 69.4 vs 78.2 % , P = 0.8 ) . Cleavage on day two , however , was lowerin the vitrified oocytes ( 88 % vs 100 % , P = 0.004 ) . Implantation rate ( IR ) was 25 % ( 7/28 ) with a mean number of 2.0 + /- 0.5 embryos transferred . Live birth rate/embryo transfer ( ET ) was 46.1 % ( 6/13 ) after transferring embryos derived only from vitrified oocytes , ( six live births , seven babies , one set of twins ) . One additional ongoing pregnancy has been established after transfer of a cryopreserved blastocyst derived from a vitrified oocyte ( combined pregnancy rate/ ET : 50 % ; 7/14 ) . CONCLUSIONS This study provides a viable model to quickly assess the efficacy of a newly established egg vitrification program following American Society for Reproductive Medicine ( ASRM ) guidelines in an investigational protocol . Embryos result ing from oocyte vitrification result ed in optimal live birth and implantation rate . The lower cleavage rate noted in this study may indicate a possible detrimental effect of the vitrification process , which may be overcome with additional experience and refinement of the technique OBJECTIVE To evaluate the outcome of oocyte vitrification using the Cryotop method , observed in an egg donation program by simultaneously evaluating embryos derived from vitrified and fresh oocytes coming from the same stimulated cycle . DESIGN Cohort prospect i ve r and omized study . SETTING Instituto Valenciano de Infertilidad ( IVI ) Valencia , Spain . PATIENT(S ) Thirty oocyte donors and 30 recipients with informed consents . INTERVENTION(S ) Vitrification by the Cryotop method . Warming 1 hour after vitrification . Microinjection of surviving MII and fresh oocytes , evaluation of fertilization , embryo development , and clinical results . MAIN OUTCOME MEASURE(S ) Survival , fertilization , and cleavage rate . Embryo quality , pregnancy rate ( PR ) , and implantation rate . RESULT ( S ) Survival rate observed was 96.7 % . There was no difference in fertilization rates ( 76.3 % and 82.2 % ) , day 2 cleavage ( 94.2 % and 97.8 % ) , day 3 cleavage ( 80.8 % and 80.5 % ) , and blastocyst formation ( 48.7 % and 47.5 % ) for vitrified and fresh oocytes , respectively . Embryo quality on day 3 and on day 5 - 6 were similar for vitrification and fresh oocyte group ( 80.8 % vs. 80.5 % and 81.1 % vs. 70 % , respectively ) . A total of 23 embryo transfers were carried out in the vitrification group . Pregnancy rates , implantation rates , miscarriage rates , and ongoing PR were 65.2 % , 40.8 % , 20 % , and 47.8 % , respectively . CONCLUSION ( S ) The Cryotop method preserves the potential of vitrified oocytes to fertilize and further develop , which is similar , when evaluated simultaneously , to fresh counterparts . Excellent clinical outcome indicates the possible use of this technology for egg donation programs , as well as a high potential for establishing oocyte banking The aim of the this study was to compare the in vitro developmental competence of parthenogenetically activated oocytes cryopreserved with slow-freezing or vitrification . Supernumerary metaphase II oocytes obtained during in vitro fertilization procedures were r and omized to slow freezing or vitrification procedure . After thawing or devitrification , oocytes were parthenogenetically activated and cultured . Survival , activation , development rate , and cell number during culture were compared . The 2 groups showed no significant differences between the rates of parthenogenetic activation , development , good quality parthenotes and blastomere number on day 2 of culture . However , parthenotes from the devitrified oocytes continued cleaving till day 3 in a significantly low proportion ( 27 % vs. 42 % ) . On day 3 , the mean number of blastomeres was also lower in vitrification group compared to slow-freezing ( 4.8 + 1.9 vs. 5.8 + 1.7 ) . In conclusion , parthenogenesis highlights a reduced potential of vitrified oocytes to cleave on day 3 compared with oocytes from slow-freezing |
1,963 | 22,607,694 | Effective interventions tended to be higher in intensity , provide dairy foods and were delivered across a variety of setting s to a range of primary targets .
The number of behaviour change techniques used did not differentiate effective and ineffective interventions , but the use of taste exposure and prompting practice appeared to be important for effective intervention .
Interventions that target an increase in children 's dairy food or Ca intake could potentially increase children 's dairy food intake by about one serving daily .
The review has identified some promising strategies likely to be part of effective interventions for improving dairy and Ca intakes in countries where children 's intake is insufficient | OBJECTIVE Strategies are needed to address the shortfall in children 's dairy food and Ca intakes .
The present review identified interventions targeting an increase in children 's dairy food or Ca intakes , and determined characteristics associated with successful intervention . | OBJECTIVE The objective was to compare targeting increased eating of healthy foods vs. reducing intake of high energy-dense foods within the context of a family-based behavioral weight control program . METHODS AND PROCEDURES Forty-one 8 - 12 year-old children > 85th BMI percentile were r and omly assigned to a 24-month family-based behavioral treatment that targeted increasing fruits and vegetables and low-fat dairy vs. reducing intake of high energy-dense foods . RESULTS Children in the increase healthy food group showed greater reduction in z BMI compared to children in the reduce high energy-dense food group at 12- ( -0.30 z BMI units vs. -0.15 z BMI units , P = 0.01 ) and 24- ( -0.36 z BMI units vs -0.13 z BMI units , P = 0.04 ) month follow-up . Parents in the increase healthy food group showed greater reductions in concern about child weight ( P = 0.007 ) , and these changes were associated with child z BMI change ( P = 0.008 ) . Children in the reduce high energy-dense group showed larger sustained reductions in high energy-dense foods ( P < 0.05 ) . Baseline levels of high energy-dense foods ( P < 0.05 ) , parent food restraint ( P = 0.01 ) , parent concern over parent weight ( P = 0.01 ) and parent acceptance of the child ( P < 0.05 ) moderated child z BMI change , with greater sustained reductions in z BMI for children in the increase healthy food group for each measure . Parent z BMI change followed the same pattern as child changes , and parent and child z BMI changes were correlated ( P < 0.001 ) . DISCUSSION Focusing on healthy food choices within an energy restricted diet may be useful in family-based weight control programs Background . Prevention of cardiovascular disease through diet and lifestyle change is strongly advocated in adults and is initiated preferably during childhood . The Dietary Intervention Study in Children ( DISC ) was a multicenter , collaborative , r and omized trial in 663 preadolescent children ( 363 boys and 301 girls ) with elevated low-density lipoprotein cholesterol , design ed to test the efficacy and safety of a dietary intervention to lower saturated-fat and cholesterol intake while also advocating a healthy eating pattern . DISC results have been published extensively . This ancillary study reports new data regarding changes in eating patterns among this cohort . Objective . We set out to compare children 's self-selected eating patterns and approaches to achieving adherence to the DISC fat-reduced diet intervention with children in the usual-care group . Methods . An ancillary study was conducted to develop a detailed food-grouping system and report new analyses on dietary adherence to the recommended eating pattern . Every food in the nutrient data base was ranked by its saturated-fat and cholesterol content and classified within its relevant food group as a “ go ” ( less atherogenic ) or “ whoa ” ( more atherogenic ) food . Results . At baseline , go foods contributed ∼57 % of total energy intake and 12.4 % to 13.1 % total fat energy intake in both groups . At 3 years , go foods contributed 67.4 % and 13.7 % of total and fat energy intake , respectively , in the intervention group versus 56.8 % and 12.8 % in the usual-care group . Differences between the 2 treatment groups were significant for changes in consumption of dairy foods , desserts , and fats/oils , with the intervention group reporting a 0.2- to 0.3-serving-per-day greater increase in go foods than the usual-care group . The intervention group also reported a 0.2- to 0.8-serving-per-day greater decrease in whoa foods than the usual-care group for breads/grains , dairy , fats/oils , meat/fish/poultry , snacks , and vegetables . Overall , snack foods , desserts , and pizza contributed approximately one third of total daily energy intake in both groups at 3 years . Conclusions . Children in the intervention group reported consuming more servings per day of go grains , dairy , meats , and vegetable foods compared with children in the usual-care group , but intake of fruits and vegetables was low in both groups . Discovering that snacks , desserts , and pizza actively contribute so heavily to the diets of this age group , even among children who were part of this intervention , offers valuable insights regarding the need for more aggressive , innovative , and realistic approaches for additional dietary counseling BACKGROUND During the nutrition transition in Chile , dietary changes were marked by increased consumption of high-energy , nutrient-poor products , including sugar-sweetened beverages ( SSBs ) . Obesity is now the primary nutritional problem in posttransitional Chile . OBJECTIVE We conducted a r and omized controlled trial to examine the effects on body composition of delivering milk beverages to the homes of overweight and obese children to displace SSBs . DESIGN We r and omly assigned 98 children aged 8 - 10 y who regularly consumed SSBs to intervention and control groups . During a 16-wk intervention , children were instructed to drink 3 servings/d ( approximately 200 g per serving ) of the milk delivered to their homes and to not consume SSBs . Body composition was measured by dual-energy X-ray absorptiometry . Data were analyzed by multiple regression analysis according to the intention-to-treat principle . RESULTS For the intervention group , milk consumption increased by a mean ( + /- SEM ) of 452.5 + /- 37.7 g/d ( P < 0.0001 ) , and consumption of SSBs decreased by -711.0 + /- 33.7 g/d ( P < 0.0001 ) . For the control group , milk consumption did not change , and consumption of SSBs increased by 71.9 + /- 33.6 g/d ( P = 0.04 ) . Changes in percentage body fat , the primary endpoint , did not differ between groups . Nevertheless , the mean ( + /- SE ) accretion of lean body mass was greater ( P = 0.04 ) in the intervention ( 0.92 + /- 0.10 kg ) than in the control ( 0.62 + /- 0.11 kg ) group . The increase in height was also greater ( P = 0.01 ) in the intervention group ( 2.50 + /- 0.21 cm ) than in the control group ( 1.77 + /- 0.20 cm ) for boys but not for girls . CONCLUSION Replacing habitual consumption of SSBs with milk may have beneficial effects on lean body mass and growth in children , despite no changes in percentage body fat . This trial was registered at clinical trials.gov as NCT00149695 Background A two-year , community-based , group-r and omized trial to promote bone mass gains among 9–11 year-old girls through increased intake of calcium-rich foods and weight-bearing physical activity was evaluated . Methods Following baseline data collection , 30 5th- grade Girl Scout troops were r and omized to a two-year behavioral intervention program or to a no-treatment control group . Evaluations were conducted at baseline , one year , and two years . Measures included bone mineral content , density , and area ( measured by DXA ) , dietary calcium intake ( 24-hour recall ) , and weight-bearing physical activity ( physical activity checklist interview ) . Mixed-model regression was used to evaluate treatment-related changes in bone mineral content ( g ) for the total body , lumbar spine ( L1-L4 ) , proximal femur , one-third distal radius , and femoral neck . Changes in eating and physical activity behavioral outcomes were examined . Results Although the intervention was implemented with high fidelity , no significant intervention effects were observed for total bone mineral content or any specific bone sites . Significant intervention effects were observed for increases in dietary calcium . No significant intervention effects were observed for increases in weight-bearing physical activity . Conclusion Future research needs to identify the optimal dosage of weight-bearing physical activity and calcium-rich dietary behavior change required to maximize bone mass gains in pre-adolescent and adolescent girls The purpose was to study if serving milk or water with the lunch at preschool influenced 6- to 7-year-old children 's preferences for and later choice between milk and water at lunch in elementary school later . Children ( n = 147 ) at 12 daycare centres were usually served water at lunch but , for 3 months , six r and omly chosen centres served milk at lunch ( Intervention group ) and six matched centres continued serving water ( Control group ) . The groups did not differ with respect to preferences for seven types of beverages ( including water and four varieties of milk ) either before or after the intervention . Four and 12 months later , their choice of lunch drink ( milk or water ) at school was studied for two 5-week periods . At the 4-month assessment , the children in the Intervention group chose milk at lunch significantly more often than did those in the Control group ( 92 % vs. 81 % of the days ) , while there were no significant differences at 12 months ( 85 % vs. 81 % ) . Since there were no demonstrable effects on preferences , one interpretation of the results is that children tend to associate the type of drink regularly served at a meal with that specific meal Objectives : To examine if and how ready-to-eat cereals ( RTEC ) contribute to the quality of the diet of children , adolescents and young adults in a Mediterranean setting . Methods : A r and om sample of 3534 subjects aged 2 to 24 years in Spain was studied . Food and nutrient intakes were determined by a 24 hour recall . RTEC consumption was assessed by a quantitative food frequency question naire . Additional questions on socioeconomic level and nutritional knowledge were administered . Cereal consumption was classified into non-consumers and daily intakes between 1 and 20 g , 21 and 40 g , and more than 40 g . After excluding the underreporters the final sample consisted of 2852 individuals . Results : About half of the population ( 49.8 % ) reported eating RTEC . Macronutrient profile improved with increasing cereal consumption . Intakes of thiamine , riboflavin and vitamin B6 increased significantly with increasing consumption of RTEC in all age-sex groups , whereas niacin and folate intake improved in almost all groups and calcium , iron and vitamin D in at least half of the groups . Except for magnesium , vitamin B12 and vitamin E in males , consumption of RTEC was significantly associated with increased coverage of the daily nutrient requirements for all micronutrients studied . Higher levels of RTEC consumption was associated with a greater consumption of dairy products , and related to better breakfast quality . Conclusions : Level of RTEC consumption is associated with a better nutritional profile in the diets of Spanish children , adolescents and young adults and a lower risk for inadequate micronutrient intakes . RTEC consumers have better quality breakfasts , in terms of both food choices as well as energy and nutrient content BACKGROUND This paper describes the impact of the Eat Smart School Nutrition Program , the food service component of the Child and Adolescent Trial for Cardiovascular Health ( CATCH ) , on the percentage of calories from total fat and saturated fat and the sodium content of school breakfasts . METHODS Fifty-nine of the 96 CATCH schools offered breakfast . We collected 5 consecutive days of school breakfast menu , recipe , and vendor product information at three periods to assess the nutrient content of the school menus as offered . RESULTS At baseline ( Fall 1991 ) , intervention school breakfasts provided 28 % of calories from total fat and control schools 30 % . Decreases occurred over time in both groups , but no significant differences were attributable to the intervention ( adjusted mean difference = -0.4 ; P = 0.77 ) . Saturated fat exceeded the Eat Smart goal at baseline in all schools and by follow-up ( Spring 1994 ) , the reduction in mean percentage of calories from saturated fat was greater in intervention than in control schools ( adjusted mean difference = -1.6 % ; P = 0.052 ) . Sodium goals were not achieved . Mean calorie levels were maintained at or above Eat Smart goals throughout the study in both groups . Differences over time in other dietary variables ( percentage of calories from protein and carbohydrate and mean levels of protein , carbohydrate , calcium , iron , vitamin A value , vitamin C , total sugars , and dietary fiber ) were not statistically significant between groups . No significant reductions in student participation in the School Breakfast Program ( SBP ) occurred . CONCLUSIONS The Eat Smart food service intervention improved school breakfast composition , but not significantly more so than in control schools . Fat and saturated fat in school breakfasts were lowered while maintaining calories , other essential nutrient levels , and student participation in the SBP . Secular trends and also the possibility that control schools were affected by the Eat Smart intervention may account for these findings BACKGROUND Poor nutrition and inactivity are widespread and contribute to the epidemic problem of childhood obesity . This study examined the effectiveness of a school-based pilot program to improve nutrition and activity in elementary ( ES ) and high school ( HS ) students . METHODS The Improving Meals and Physical Activity in Children and Teens ( IMPACT ) school-based curriculum used a train-the-trainer model to improve activity and nutrition . Nine students were recruited from one rural North Carolina high school and trained in the IMPACT curriculum and leadership skills . Four 4th grade classes at a neighboring elementary school were r and omized to receive the IMPACT curriculum delivered by the HS students over 12 weeks ( two classrooms , 38 students ) versus the st and ard curriculum ( two classrooms , 37 students ) . Pre- and post-intervention surveys were used to assess program effectiveness . RESULTS ES students in the intervention classes reported increased fruit and vegetable intake ( + 0.85 servings/day compared with controls ; p < 0.05 ) and improved knowledge of the food group in which to eat the most servings ( p < 0.01 ) . ES students who participated in the IMPACT curriculum also reported increased intake of calcium-rich foods and grains , though these results were not statistically significant . Similar though nonsignificant improvements in diet behaviors were reported by the HS students who assisted in delivering the 4th grade curriculum . LIMITATIONS Study limitations include small sample size , risk of cross-contamination , and short program duration . CONCLUSIONS ES students who participated in the IMPACT curriculum reported improved dietary behaviors and knowledge . School-based curricula such as IMPACT may help improve nutrition among ES students Objective : We have reported that a lifestyle intervention with mothers improved calcium intake and physical activity in both mothers and their children . In this study , we aim ed to describe the strategies and approaches used by these mothers to improve their children 's calcium intake and physical activity . Design : A qualitative study using semistructured interviews . Setting : Population -based convenience sample .Subjects : A sub sample of 39 mothers were taken from a population -based r and om sample of 354 mothers who had participated in the original osteoporosis-prevention trial . Results : Mothers described specific dietary changes they made to increase their children 's calcium intake . They also described strategies for improving calcium intake and physical activity such as raising awareness of the importance of calcium ; ensuring calcium-rich foods were accessible ; assessing their children 's likes and dislikes and working within these ; role modelling ; information provision ; taking a balanced approach to attempting behaviour change ; and encouraging activities that they could do with their children . Mothers emphasized the general importance of a balanced diet and lifestyle , rather than just focussing on lifestyle factors specific to osteoporosis prevention . Conclusion : Even without specific guidance , mothers are adept at developing strategies to apply to changing lifestyle behaviours in their children and identifying barriers to change . These results provide information , which could be incorporated into future interventions for lifestyle change in children and also provide further support for considering parent-focused approaches to this problem Purpose . To test effects of parent/child training design ed to increase calcium intake , bone-loading physical activity ( PA ) , and bone density . Design . Two-group r and omized controlled trial . Setting . Family-based intervention delivered at research center . Subjects . 117 healthy children aged 10–13 years ( 58.1 % female , 42.7 % Hispanic , 40.2 % White ) . Ninety-seven percent of participants had at least one parent graduate from high school and 37.2 % had at least one parent graduate from a 4-year university . Intervention . Children and parents were r and omly assigned to diet and exercise ( experimental ) or injury prevention ( control ) interventions . Children were taught in eight weekly classes how to engage in bone-loading PA and eat calcium-rich foods or avoid injuries . Parents were taught behavior management techniques to modify children 's behaviors . Measures . Measures at baseline and at 3 , 9 , and 12 months included 24-hour diet and PA recalls , and bone mineral density ( BMD ) by dual-energy x-ray absorptiometry . Analysis . Analysis of variance and generalized estimating equations ( GEE ) assessed group by time differences . Comparisons were conducted separately for boys and girls . Results . For boys , cross-sectional differences between experimental and control groups were achieved for 3- and 9-month calcium intake ( 1352 vs. 1052 mg/day , 1298 vs. 970 mg/day , p < .05 ) . For girls , marginal cross-sectional differences were achieved for high-impact PA at 12 months ( p < .10 ) . For calcium intake , a significant group by time interaction was observed from pretest to posttest for the full sample ( p = .008 ) and for girls ( p = .006 ) but not for boys . No significant group by time differences in calcium were observed across the follow-up period . No group by time differences were observed for high-impact PA . Among boys , longitudinal group by time differences reached significance for total hip BMD ( p = .045 ) and femoral neck BMD ( p = .033 ) , even after adjusting for skeletal growth . Similar differential increases were observed among boys for bone mineral content ( BMC ) at the hip ( p = .068 ) and total body ( p = .054 ) regions . No significant group by time interaction effects were observed for girls at any bone site for BMD . For BMC , control girls showed a significant increase ( p = .03 ) in spine BMC compared to intervention girls . Conclusion . This study demonstrated that parent/preteen training can increase calcium intake and attenuate the decline in high-impact PA . Results suggest that more powerful interventions are needed to increase activity levels and maximize bone mineral accrual during preadolescent years OBJECTIVE To determine if after-school nutrition workshops conducted in public libraries were related to lasting changes in food choice . METHODS " Snack Smart " workshops , based on Social Cognitive Theory , were conducted in 8 branch libraries ( 49 ethnically diverse children , ages 9 to 14 ) to assess changes in consumption of targeted food items by pretest , posttest , and follow-up food frequency question naires . Results were analyzed using the Friedman test for repeated measures and Wilcoxon signed rank test . RESULTS Intake of milk , vegetables , and water significantly increased at 3-week posttest ( P < .05 ) , but only water intake showed a significant change from pretest to follow-up 3 months later . CONCLUSIONS AND IMPLICATION S This low-intensity program did not produce lasting behavior change , as measured by changes in food frequency at 3 months post- intervention . The study supports the need to critically evaluate out-of-school nutrition programs for lasting impact BACKGROUND The Child and Adolescent Trial for Cardiovascular Health ( CATCH ) tested the effectiveness of a multilevel intervention aim ed at promoting a healthful school environment and positive eating and physical activity behaviors in children . The CATCH Eat Smart Program targeted the school food service staff and aim ed to lower the total fat , saturated fat , and sodium content of school meals . METHODS The Eat Smart intervention was conducted in 56 intervention schools over a 2(1/2)-year period.+Five consecutive days of school menu , recipe , and vendor product information were collected from intervention and control schools at three intervals , Fall 1991 , Spring 1993 , and Spring 1994 , to assess the nutrient content of school menus as offered . RESULTS There was a significantly greater mean reduction in the percentage of calories from total fat ( adjusted mean difference -4.1 % ; P < 0.0001 ) and saturated fat ( adjusted mean difference -1.3 % ; P = 0.003 ) in intervention compared with control schools from baseline to follow-up . Although the sodium content of school lunches increased in both conditions , the mean increase was significantly lower in intervention schools ( adjusted mean difference -89 mg ; P = 0.034 ) . There were no statistically significant differences for total amounts of cholesterol , carbohydrate , protein , dietary fiber , total sugars , calcium , iron , vitamin A value , and vitamin C. Average total calories decreased significantly ; however , the mean total calories ( 683 kcal ) for intervention schools remained above one-third of the Recommended Dietary Allowances for this age group . CONCLUSIONS The CATCH Eat Smart intervention successfully lowered the total fat and saturated fat content of school lunches as offered , while maintaining recommended amounts of calories and essential nutrients OBJECTIVE To compare treatment , sex , and visit differences in beverage choice and calcium intake in the Dietary Intervention Study in Children , to compare the relationship of other beverages to milk consumption , and document whether or not the dietary intervention affected choice of beverage and milk type over time . DESIGN Data from the Dietary Intervention Study in Children , a r and omized , controlled , multicenter , clinical trial with five sets of three 24-hour recalls . SUBJECTS Six hundred fifty-three children from six clinics started the study at age 8 to 10 years . Participants had serum low-density lipoprotein cholesterol levels between the 80th and 98th percentiles of age , and were followed for a median of 7.3 years . INTERVENTION Children were r and omized to a total fat- and saturated fat-modified dietary intervention or usual care . MAIN OUTCOME MEASURES Volume and percent of total energy from soft drinks , fruit-flavored drinks , fruit juice , and milk , calcium intake in milligrams and per 1,000 kcal , and percent reduced-fat and skim milk consumed . STATISTICAL ANALYSES General Estimating Equations methodology was used to adjust for treatment , sex , and visit differences . RESULTS The intervention group consumed more reduced-fat or skim milk than the usual care group . The intervention group also reported a greater increase in calcium per 1,000 kcal than those in the usual care group due to nonbeverage sources . Consumption of soft drinks increased over the course of the study , whereas total milk consumption decreased sharply . CONCLUSIONS With nutrition education , children can make changes in the type of milk consumed , and in the quantity of dietary calcium consumed |
1,964 | 29,075,970 | Conclusions The TAP block using a short-acting anesthetic had a significant effect on the postoperative pain outcome in the early ( 0–2 h ) and late ( 24 h ) period at movement .
However , it did not have a significant effect on the postoperative pain outcome in the early ( 0–2 h ) and late ( 24 h ) periods at rest after laparoscopic surgery | Background Transversus abdominis plane ( TAP ) block using a short-acting local anesthetic as part of multimodal analgesia is efficient in various abdominal surgeries , including laparoscopic surgery .
However , information regarding its use in laparoscopic colorectal surgery is still limited and sometimes controversial .
Therefore , we conducted a systematic review and meta- analysis to determine whether TAP block using a short-acting anesthetic has a positive postoperative analgesic outcome in patients who have undergone laparoscopic colorectal surgery . | Background : Ultrasound-guided transversus abdominis plane ( TAP ) block has recently come up as a modality to take care of postoperative pain . It can somewhat avoid the use of intravenous opioid analgesics and hence to avoid its complications . We have performed a prospect i ve , double-blinded , r and omized study to assess the analgesic effect of adding dexmedetomidine to local ropivacaine on TAP block for patients undergoing lower abdominal surgeries . Aim : The aim is to assess whether addition of dexmedetomidine to ropivacaine may bring some improvements to the analgesic efficacy of TAP blocks in patients undergoing lower abdominal surgeries . Material s and Methods : The study was conducted on forty patients undergoing lower abdominal surgeries under general anesthesia . The patients were divided into two groups : one receiving plain ropivacaine ( Group 1 ) and other receiving ropivacaine with dexmedetomidine ( Group 2 ) during TAP block . The patients in the two groups were compared for age , sex , body mass index , incidence of postoperative nausea , and vomiting and pain as measured on visual analog scale ( VAS ) . Results : There was significantly lower pain score on VAS at 1 , 3 , 6 , 12 , and 18 h in Group 2 than in Group 1 . Conclusion : The addition of dexmedetomidine to ropivacaine during TAP block improves analgesic effect of TAP block and prolongs the duration of analgesia as well BACKGROUND : Superior early pain control has been suggested with transversus abdominis plane blocks , but evidence -based recommendations for transversus abdominis plane blocks and their effects on patient outcomes are lacking . OBJECTIVE : The aim of this study was to determine whether transversus abdominis plane blocks improve early postoperative outcomes in patients undergoing laparoscopic colorectal resection already on an optimized enhanced recovery pathway . DESIGN : This study is based on a prospect i ve , r and omized , double-blind controlled trial . SETTING S : The trial was conducted at a tertiary referral center . PATIENTS : Patients undergoing elective laparoscopic colorectal resection were selected . INTERVENTIONS ( S ) : Patients were r and omly assigned to receive either a transversus abdominis plane block or a placebo placed intraoperatively under laparoscopic guidance . All followed a st and ardized enhanced recovery pathway . Patient demographics , perioperative procedures , and postoperative outcomes were collected . MAIN OUTCOME MEASURES : Postoperative pain and nausea/vomiting scores in the postanesthesia care unit and department , opioid use , length of stay , and 30-day readmission rates were measured . RESULTS : The trial r and omly assigned 41 patients to the transversus abdominis plane block group and 38 patients to the control group . Demographic , clinical , and procedural data were not significantly different . In the postanesthesia care unit , the transversus abdominis plane block group had significantly lower pain scores ( p < 0.01 ) and used fewer opioids ( p < 0.01 ) than the control group ; postoperative nausea/vomiting scores were comparable ( p = 0.99 ) . The transversus abdominis plane group had significantly lower pain scores on postoperative day 1 ( p = 0.04 ) and throughout the study period ( p < 0.01 ) . There was no significant difference between groups in postoperative opioid use ( p = 0.65 ) or nausea/vomiting ( p = 0.79 ) . The length of stay ( median , 2 days experimental , 3 days control ; p = 0.50 ) and readmission rate ( 7 % experimental , 5 % control , p = 0.99 ) was similar across cohorts . LIMITATIONS : This study was conducted a single center . CONCLUSIONS : Transversus abdominis plane blocks improved immediate short-term opioid use and pain outcomes . Pain improvement was durable throughout the hospital stay . However , the blocks did not translate into less overall narcotic use , shorter length of stay , or lower readmission rates Background The transversus abdominis plane block is recently described peripheral block to providing analgesia to the anterior abdominal wall . The goal of this study is to evaluate the analgesic efficacy of the ultrasound-guided transversus abdominis plane block ( US-TAP block ) in patients undergoing gynecologic surgery via a transverse lower abdominal skin incision . Methods Thirty-two patients undergoing gynecologic surgery were r and omized to undergo st and ard care such as PCA , or to receive additional US-TAP block with st and ard care . After general anesthesia induction , a bilateral US-TAP block was performed using 0.375 % ropivacaine 20 ml on each side . Postoperative dem and of rescue analgesics in PACU and ward were recorded . Each patient was assessed postoperatively by a blinded investigator in the postanesthesia care unit ( PACU ) and at 2 , 6 , 10 , 24 , 48 hr postoperatively to investigate pain , drowsiness , nausea and itch . Results The US-TAP block reduced pain intensity compared to st and ard care in the PACU ( 5.2 ± 3.1 vs 8.4 ± 1.3 ) and at 2 , 24 postoperative hours ( 3.0 ± 2.4 vs 5.2 ± 2.4 , 0.9 ± 1.5 vs 2.2 ± 1.9 ) . Fentanyl requirements in PACU was reduced ( 20.3 ± 20.9 vs 62.5 ± 35.4 µg , P < 0.05 ) . In ward , pethidine requirements was reduced ( 21.9 ± 28.7 vs 56.3 ± 34.8 mg , P < 0.05 ) . Conclusions The US-TAP block with st and ard care provide more effective analgesia after gynecologic surgery via a transverse lower abdominal skin incision Background Although enhanced recovery pathways ( ERPs ) may permit early recovery and discharge after laparoscopic colorectal surgery ( LC ) , most publications report that the mean hospital stay is 4 and 6 days . This study evaluates the addition of a transversus abdominis plane ( TAP ) block to the st and ard ERP . Methods In this study , 35 consecutive elective patients received a TAP block at the end of LC . The patients were matched by operation , diagnosis , age , gender , and body mass index ( BMI ) with 35 recent cases and followed in a prospect i ve institutional review board (IRB)-approved data base . All the patients were managed with a st and ardized ERP . The surgeon placed TAP blocks under laparoscopic guidance that infiltrated 15 ml of 0.5 % Marcaine on both sides of the abdomen . Results The cases included 8 low pelvic anastomoses , 4 proctectomies with or without an ileal pouch anal anastomosis , 5 sigmoid/left colectomies , 13 ileocolic/right colectomies , 1 total colectomy , and 5 others . The mean age was 59 years for the TAP group and 64.1 years for the control group ( p = 0.21 ) . The mean hospital stay was 2 days for the TAP patients and 3 days for the control patients ( p = 0.000013 ) . Of the 35 TAP patients , 13 went home on postoperative day ( POD ) 1 ( 37 % ) , 12 on POD 2 ( 34 % ) , 8 on POD 3 ( 23 % ) , and the remainder on POD 4 . Of the 35 control patients , 1 went home on POD 1 ( 3 % ) , 10 on POD 2 ( 29 % ) , 10 on POD 3 ( 29 % ) , 11 on POD 4 ( 31 % ) , and the remainder on POD 5 to 8 . The TAP patients required fewer narcotics postoperatively than the control patients ( respective mean morphine equivalents , 31.08 vs. 85.41 ; p = 0.01 ) . Discussion A bilateral TAP block significantly improved the results of an established ERP for patients undergoing LC . Surgeon-administered TAP blocks may be an economical and efficient method for improving the results of LC INTRODUCTION Opioid sparing in postoperative pain management appears key in colorectal enhanced recovery . Transversus abdominis plane ( TAP ) blocks offer such an effect . This study aim ed to quantify this effect on pain , opioid use and recovery of bowel function after laparoscopic high anterior resection . METHODS This was a retrospective analysis of prospect i ve data on 68 patients . Patients received an epidural ( n=24 ) , intravenous morphine patient controlled analgesia ( PCA , n=22 ) or TAP blocks plus PCA ( n=22 ) determined by anaesthetist preference . Outcome measures were numerical pain scores ( 0 - 3 ) , cumulative intravenous morphine dose and time to recovery of bowel function ( passage of flatus or stool ) . RESULTS There were no differences in patient characteristics , complications or extraction site . The TAP block group had lower pain scores ( 0.7 vs 1.36 , p<0.001 ) and morphine requirements ( 8 mg vs 15 mg , p=0.01 ) than the group receiving PCA alone at 12 hours and 24 hours . Earlier passage of flatus ( 2.0 vs 2.7 vs 3.4 days , p=0.002 ) , stool ( 3.1 vs 4.1 vs 5.5 days , p=0.04 ) and earlier discharge ( 4 vs 5 vs 6 days , p=0.02 ) were also seen . CONCLUSIONS Use of TAP blocks was found to reduce pain and morphine use compared with PCA , expedite recovery of bowel function compared with PCA and epidural , and expedite hospital discharge compared with epidural Background The increasing use of laparoscopic techniques for colorectal resections means that the issue of postoperative analgesia needs to be reassessed . This nonr and omized comparative study aim ed to assess the efficacy of the transversus abdominis plane ( TAP ) block in laparoscopic colorectal resections . Methods Prospect ively collected data from consecutive patients undergoing laparoscopic colorectal resections were used . Analgesia usage and outcome data for patients who had a TAP block and a postoperative morphine patient-controlled analgesia pump ( PCA ) were compared with those for patients who had a PCA alone . Results Data for 74 patients were used in the final analysis ( 40 TAP/PCA and 34 PCA alone ) . There was a significant reduction in overall intravenous opiate use in the TAP/PCA group ( 31.3 vs. 51.8 mg ; P = 0.03 ) . The TAP/PCA group showed a slight trend toward a shorter hospital stay ( 3 vs. 4 days ; P = 0.17 ) but no difference in postoperative complications or any other outcome measure . There was no procedure-related morbidity relating to the use of TAP blocks . Conclusions It appears that TAP blocks reduce postoperative analgesia use of patients undergoing laparoscopic colorectal resections within an enhanced recovery program , and this may have an impact on their postoperative hospital length of stay Background Although h and -assisted laparoscopic surgery ( HALS ) offers patients smaller surgical incisions , they still experience pain . Currently , there is no consensus on the optimal analgesic package for patients undergoing HALS . The aim of this prospect i ve , r and omized , double-blinded , placebo-controlled clinical trial was to evaluate the effect of transversus abdominis plane ( TAP ) block on postoperative pain control ( pain score and analgesic use ) and other outcomes in colon cancer patients undergoing h and -assisted laparoscopic left hemicolectomy . Methods Sixty-four patients with colon cancer scheduled for an elective colon resection were enrolled in this study . Patients were r and omized into two groups to receive either TAP block using 20 mL of 0.375 % ropivacaine ( TAP block group : 32 patients ) or 20 mL of 0.9 % normal saline infusion ( placebo group : 32 patients ) . Anaesthetic and surgical techniques were st and ardized . Twenty-four-hour postoperative analgesia was maintained by continuous infusion of 0.1–0.9 µg/kg/h fentanyl and intravenous injection of ketorolac . The primary outcome of the study was postoperative pain control ( pain score and analgesic use ) . Pain was assessed using numeric rating scale at 2 , 4 , 8 , 12 , and 24 h after surgery at rest and during movement . Secondary outcomes included the time to resumption of intestinal function and the length of hospital stay . The data of the two groups were compared using Mann – Whitney U test . All statistical tests were two-tailed at a significance level of 0.05 . Results The patients ’ mean age was 60.50 ± 6.77 years , and 68.75 % of patients were males . The mean body mass index was 26.23 ± 4.83 kg/m2 . The TAP block group had lower pain scores after surgery at 2 , 4 , and 12 h at rest ( p < 0.05 ) , at 2 and 4 h during movement ( p < 0.01 ) and used less fentanyl and ketorolac than the placebo group ( p < 0.01 ) . The mean time to resumption of intestinal function was shorter in the TAP block group than that in the placebo group ( p < 0.0001 ) . The mean length of hospital stay was by 2.7 days shorter in the TAP block group than in the placebo group ( p = 0.001 ) . Conclusions The ultrasound-guided TAP block given during h and -assisted laparoscopic colon surgery as part of a multimodal analgesic regimen is a feasible and effective technique for postoperative analgesia in colon cancer patients and significantly reduces both pain experienced by patients and short-term postoperative analgesic use and promotes early ambulation . Future studies are needed to determine the efficacy and costs/ benefits of the ultrasound-guided TAP block in HALS Background Despite the laparoscopic approach becoming the st and ard in colorectal surgery , postoperative pain management for minimally invasive surgery is still mainly based on strategies that have been established for open surgical procedures . Patient-controlled epidural and intravenous analgesia are considered st and ard postoperative analgesia regimens in colorectal surgery . Epidural analgesia provides excellent analgesia , but is increasingly scrutinized in laparoscopic surgery since postoperative pain after the laparoscopic approach is significantly reduced . Moreover , epidural analgesia can be associated with numerous complications . Therefore , epidural analgesia is no longer recommended for the management of postoperative pain in laparoscopic colorectal surgery . Likewise , patient-controlled intravenous analgesia is subject to significant side effects . Given these important limitations of the traditional strategies for postoperative analgesia , effective and efficient alternatives in patients undergoing laparoscopic colorectal surgery are needed . Both the transversus abdominis plane block and systemically administered lidocaine have already been reported to effectively reduce pain after laparoscopic colorectal surgery . We hypothesize that the transversus abdominis plane block is superior to perioperative intravenous lidocaine . Methods / design One hundred and twenty five patients undergoing laparoscopic colorectal surgery will be included in this prospect i ve , r and omized , double-blind controlled clinical trial . Patients will be r and omly allocated to three different postoperative strategies : postoperative patient-controlled intravenous analgesia with morphine ( control group , n = 25 ) , a transversus abdominis plane block with ropivacaine 0.375 % at the end of surgery plus postoperative patient-controlled intravenous analgesia with morphine ( TAP group , n = 50 ) , or perioperative intravenous lidocaine plus postoperative patient-controlled intravenous analgesia with morphine ( LIDO group , n = 50 ) . As the primary outcome parameter , we will evaluate the opioid consumption during the first 24 postoperative hours . Secondary endpoints include the Numeric Rating Scale , time to return of intestinal function , time to mobilization , inflammatory response , incidence of postoperative nausea and vomiting , length of hospital stay and postoperative morbidity as assessed with the Clavien-Dindo classification . Discussion Recognizing the importance of a multimodal approach for perioperative pain management , we aim to investigate whether a transversus abdominis plane block delivers superior pain control in comparison to perioperative intravenous lidocaine and patient-controlled intravenous analgesia with morphine alone . Trial registration EudraCT Identifier : 2014 - 001499 - 73 ; 31 July 2014 Background The lumbar transversus abdominis plane ( TAP ) block has become an optional part of multimodal analgesia following several abdominal surgeries . There remains a lack of consensus regarding the extent of dermatomal blockade following lumber TAP block , as well as the optimal local anesthetic volumes and concentrations . The objectives of this pilot trial were to assess the feasibility of conducting a similar full-scale trial and gather information on relevant clinical outcomes , namely whether greater local anesthetic volumes would lead to more cephalad dermatomal blockade . Methods The study was a prospect i ve , double-blinded pilot r and omized controlled trial ( RCT ) with three arms , each representing different local anesthetic volumes : 20 ml 0.5 % ropivacaine , 30 ml 0.33 % ropivacaine , and 40 ml 0.25 % ropivacaine . We planned to recruit 30 females undergoing total abdominal hysterectomy for non-malignant pathology , who would then receive bilateral ultrasound-guided midaxillary TAP blocks at the completion of surgery . R and omized patients would be followed for 48 h post-block and would receive multimodal analgesia . The primary outcomes were measurements of patient recruitment and safety , to inform the feasibility of a larger trial . The main secondary outcome was the clinical ly pertinent endpoint of dermatomal blockade , which was assessed by loss of sensation to ice and pinprick . Results Our target sample size was reached in 8 months , and the recruitment rate was 52 % ( 31/60 ) . A total of 58 TAP blocks were performed among 29 patients . All but one of the patients who received interventions were successfully followed and assessed up to 48 h. No patient safety-related adverse events were reported during the study period . The mean highest dermatome blocked in each group at any time point was T8 . The 20 ml 0.5 % ropivacaine group achieved a T9–L1 block that lasted for 48 h. The 30 ml 0.33 % ropivacaine group had a sensory block from T9–L1 that regressed to T10–T12 between 24 and 48 h. The 40 ml 0.25 % ropivacaine group reported an initial sensory block from T9–T12 that regressed by 24 h to include only the T12 dermatome . Conclusions This pilot study demonstrated that the study design is feasible and safe to be carried to a full-scale RCT . The preliminary clinical findings showed that increasing the volume , while maintaining a constant dose , of local anesthetic does not appear to extend the height of dermatomal blockade following midaxillary TAP block . This finding needs to be confirmed in future studies .Trial registration Clinical Trials.gov registration is : NCT01307215 BACKGROUND Transversus abdominis plane ( TAP ) block has been used as a component of multimodal analgesia after abdominal operation . We introduced a new laparoscope-assisted TAP ( LTAP ) block technique using intraperitoneal injection and compared its analgesic effect with that of an ultrasound-guided TAP ( UTAP ) block in terms of postoperative pain control . STUDY DESIGN A prospect i ve , r and omized , single-blinded non-inferiority clinical trial was conducted with patients undergoing elective laparoscopic colectomy for colon cancer . Eighty patients were r and omly assigned ( 1:1 ratio ) to the UTAP and LTAP groups . At the end of the operation , opioid consumption and numeric rating scores ( NRS ; 0 [ no pain ] to 10 [ worst pain ] ) of pain were recorded at 2 , 6 , 24 , and 48 hours postoperatively and were compared between the groups . The primary end point was pain NRS during rest at 24 hours after operation . RESULTS Thirty-eight patients in the LTAP group and 35 patients in the UTAP group completed the study protocol . We found no significant difference in mean ± SD pain NRS during rest at 24 hours between the LTAP group ( 3.90 ± 1.7 ) and the UTAP group ( 4.5 ± 1.9 ) . The mean difference in pain NRS during rest at 24 hours was 0.57 ( 95 % CI -0.26 to 1.41 ) . Because the lower boundary of a 95 % CI for the differences in pain NRS was > -1 , non-inferiority was established . There was no significant difference between the groups in NRS pain during rest , NRS pain on movement , and postoperative morphine consumption during the 48 hours after operation . CONCLUSIONS These results show our new LTAP block technique was non-inferior to the ultrasound-guided technique in providing a TAP block after laparoscopic colorectal operation Background Although laparoscopic colorectal surgery decreases postoperative pain and facilitates a speedier recovery compared with laparotomy , postoperative pain at trocar insertion sites remains a clinical concern . The objective of this study was to assess the effects of a preoperative ultrasound-guided transversus abdominis plane ( TAP ) block on pain after laparoscopic surgery for colorectal cancer . Methods In total , 58 patients scheduled to undergo laparoscopic surgery following a diagnosis of colorectal cancer were included in this study . The patients were r and omized into TAP and control groups ; the TAP group patients received a preoperative ultrasound-guided bilateral TAP block with 0.5 mL/kg of 0.25 % bupivacaine , while the control patients received the block with an equal amount of saline . Pain on coughing and at rest was assessed during postanesthetic recovery ( PAR ; 1 h after surgery ) and on postoperative days ( PODs ) 1 ( 24 h ) , 2 ( 48 h ) , and 3 ( 72 h ) by an investigator blinded to group allocations using the numeric rating scale ( NRS ) . The primary outcome was pain on coughing on postoperative day ( POD ) 1 . Results Fifty-five patients were included in the final analysis , including 28 in the TAP and 27 in the control groups . The pain intensity on coughing and at rest during PAR and on PODs 1 , 2 , and 3 showed no significant differences between groups . Furthermore , there was no significant difference in postoperative opioid consumption , sedation scores , nausea scores at the four time points , complication rates , and length of hospital stay between groups . Conclusions In colorectal cancer patients undergoing laparoscopic colorectal surgery , a TAP block did not offer enough benefit for clinical efficacy in terms of postoperative pain or analgesic consumption BACKGROUND Current knowledge on local anesthetic dosage for the TAP block in pediatric patients is very limited . OBJECTIVE To evaluate the effect of two escalating local anesthetic doses on postsurgical analgesic outcomes in children receiving a TAP block . METHODS The study was a prospect i ve , r and omized , double-blinded , clinical trial . Children ( < 8 years ) were r and omized to one of the two intervention groups : TAP block with bupivacaine at a dose of 2.5 mg · kg(-1 ) or 1.25 mg · kg(-1 ) . Analgesic outcomes included pain scores in the postanesthesia care unit ( PACU ) , time to analgesic requirement and total number of analgesic requirements . RESULTS Thirty-six patients were recruited in the study . Pain scores in PACU were not different between study groups . The total number of analgesic dosage required in 24 h after surgery was higher in the lower dose group , median ( IQR ) of 4 ( 3 to 5 ) compared to 2.5 ( 1.5 to 3 ) in the greater dose group , P = 0.03 . There was a clinical ly but not statistically significant difference in the time to first analgesic requirement in the 2.5 mg · kg(-1 ) group , median ( IQR ) of 248 ( 130 to 367 ) minutes compared to 146 ( 95 to 261 ) minutes in the 1.25 mg · kg(-1 ) dose group , P = 0.15 . CONCLUSIONS The use of higher local anesthetic doses for the TAP block in children does not provide benefits on early pain scores but seems to improve analgesic duration and decrease the need for additional analgesics over 24 h after surgery . The use of higher , but yet safe , local anesthetic dosages for TAP blocks is a viable strategy to improve analgesia in children Background Optimal analgesia following laparoscopic colorectal resection is yet to be determined ; however , recent studies have question ed the role of postoperative epidural anaesthesia , suggesting other analgesic modalities may be preferable . The aim of this r and omised controlled trial was to assess the effect of transversus abdominis plane ( TAP ) blocks on opioid requirements in patients undergoing laparoscopic colorectal resection . Methods After appropriate trial registration ( www . clinical trials.gov NCT 00830089 ) and local medical ethics review board approval ( REC 09/H0407/10 ) , all adult patients who were to undergo laparoscopic colorectal surgery at a single centre were r and omised into the intervention group receiving bilateral TAP blocks or the control group ( no TAP block ) . The blocks were administered prior to surgery after the induction of a st and ardised anaesthetic by an anaesthetist otherwise uninvolved with the case . The patient , theatre anaesthetist , surgeon , and ward staff were blinded to treatment allocation . All patients received postoperative analgesia of paracetamol and morphine as a patient-controlled analgesia ( PCA ) . Cumulative opioid consumption and pain scores were recorded at 2 , 4 , 6 , and 24 h postoperatively and compared between the groups as were clinical outcomes and length of stay . Results The intervention ( TAP block ) group ( n = 33 ) and the control group ( n = 35 ) were comparable with respect to characteristics , specimen pathology , and type of procedure . The TAP block group ’s median cumulative morphine usage ( 40 mg [ IQR = 25–63 ] ) was significantly less than that of the control group ( 60 mg [ IQR = 39–81 ] ) . Pain scores and median length of stay ( LOS ) were similar between the two groups . Conclusion Preoperative TAP blocks in patients undergoing laparoscopic colorectal resection reduced opioid use in the first postoperative day in this study Background Few data are available on TAP block in laparoscopic colorectal surgery and ERAS program . The aim of this prospect i ve study was to evaluate local wound infiltration plus TAP block compared to local wound infiltration in the management of postoperative pain , nausea and vomiting , ileus and use of opioids in the context of laparoscopic colorectal surgery and ERAS program . Methods From March 2014 to March 2015 , 48 patients were treated by laparoscopic resection and ERAS program for colorectal cancer and diverticular disease at the Division of General and Hepatobiliary Surgery , University of Verona Hospital Trust . Among these , 24 patients received local wound infiltration plus TAP block ( TAP block group ) and 24 patients received local wound infiltration ( control group ) . Results No differences were observed in baseline patient characteristics , clinical variables and surgical procedures between the two groups . Local wound infiltration plus TAP block allowed to achieve pain control despite a reduced use of opioid analgesics ( P = 0.009 ) . The adoption of TAP block result ed beneficial on the prevention of postoperative nausea ( P = 0.002 ) and improvement of essential outcomes of ERAS program as recovery of bowel function ( P = 0.005 ) , urinary catheter removal ( P = 0.003 ) and capability to tolerate oral diet ( P = 0.027 ) . Conclusions TAP block plus local wound infiltration in the setting of laparoscopic colorectal surgery and ERAS program guarantees a reduced use of opioid analgesics and good pain control allowing the improvement of essential items of enhanced recovery pathways Introduction Adequate postoperative analgesia is essential for recovery following colorectal surgery . Transversus abdominis plane ( TAP ) blocks have been found to be beneficial in improving pain following a variety of abdominal operations . The objective of this study was to determine if TAP blocks are useful in improving postoperative recovery following laparoscopic colorectal surgery . Material s and methods A prospect i ve double-blind r and omized clinical trial , involving 226 consecutive patients having laparoscopic colorectal surgery , was performed by a university colorectal surgical department . Patients were r and omized to either TAP blockade using ultrasound guidance , or control , with the primary outcome being postoperative pain , as measured by analgesic consumption . Secondary outcomes assessed were pain visual analogue score ( VAS ) , respiratory function , time to return of gut function , length of hospital stay , postoperative complications , and patient satisfaction . Results A total of 142 patients were followed up to trial completion ( 74 controls , 68 interventions ) . Patients were well matched with regard to demographics . No complications occurred as a result of the intervention of TAP blockade . There was no difference between groups with regards to analgesic consumption ( 161 mEq morphine control vs 175 mEq morphine TAP ; p = 0.596 ) . There was no difference between the two groups with regards to the secondary outcomes of daily VAS , respiratory outcome , time to return of gut function , length of hospital stay , postoperative complications , and patient satisfaction . Conclusion We conclude that TAP blockade appears to be a safe intervention but confers no specific advantage following laparoscopic colorectal surgery BACKGROUND A key point in pathways for optimal rehabilitation and enhanced recovery is an effective postoperative multimodal pain treatment regimen . OBJECTIVE To investigate the analgesic effects of transversus abdominis plane ( TAP ) block in conjunction with paracetamol and ibuprofen in patients undergoing laparoscopic colonic resection . DESIGN R and omised placebo-controlled double-blind study . SETTING Herlev University Hospital , Copenhagen , Denmark , from March 2010 to February 2013 . PATIENTS Eighty adult patients scheduled for elective laparoscopic colectomy . INTERVENTIONS Bilateral TAP block with 20 ml of either ropivacaine or isotonic saline . MAIN OUTCOME MEASURES Visual analogue scale ( VAS ) pain scores ( 0 to 100 mm ) while coughing at 6 h after surgery ( primary outcome ) . Secondary outcomes were area under the curve pain scores ( 2 to 24 h ) at rest and while coughing , 24-h morphine consumption and incidence of nausea and vomiting . RESULTS VAS pain scores at 6 h while coughing was not different between groups ( median , interquartile range ) , TAP , 27 ( 11 to 45 ) mm vs. placebo , 33 ( 20 to 49 ) mm ( P = 0.20 ) . Total 24-h morphine consumption was reduced in the TAP block group vs. placebo group , 30 ( 15 to 41 ) mg vs. 43 ( 30 to 67 ) mg , respectively ( P = 0.008 ) . This difference was most pronounced in the first postoperative hours . The remaining outcomes did not differ between groups . CONCLUSION TAP block used in combination with paracetamol and ibuprofen did not reduce pain after laparoscopic colonic surgery . However , we found a 30 % reduction in opioid use , most marked in the early postoperative period . TRIAL REGISTRATION www . clinical trials.gov ( NCT01418144 ) The transversus abdominis plane block has been used as a component of postoperative analgesia after hysterectomy and open abdominal surgery . This block involves the injection of anesthetic between the internal oblique and transversus abdominis muscles . We demonstrate an improved method by the use of laparoscopic guidance for transversus abdominis plane blocks . Transversus abdominis plane blocks are performed at the conclusion of an elective laparoscopic procedure by an experienced colorectal surgeon . With the use of direct visualization with a laparoscope , a Braun Stimuplex A insulated needle is passed through the skin at the level of the midaxillary line , midway between the iliac crest and the costal margin . The needle is inserted further until 2 distinct “ pops ” are felt , indicating the correct needle position between the internal oblique and transversus abdominis muscle . The laparoscope confirms a bulge , which signifies the injectate covered by the transversus abdominis muscle . The procedure is performed at a second injection site on the same side and bilaterally . The transversus abdominis plane block is useful as an adjunct to reduce postoperative analgesia in patients undergoing laparoscopic colorectal surgery . Our method for transversus abdominis plane blocks with the use of laparoscopy is easily performed at the conclusion of any laparoscopic procedure . Prospect i ve r and omized trials are necessary to assess the significance of these blocks in postoperative pain control , length of stay , and cost benefit Background and Objectives The ability of transversus abdominis plane ( TAP ) blocks to anesthetize the upper abdomen remains debatable . We aim ed to describe the local anesthetic distribution following ultrasound-guided TAP blocks with repeated magnetic resonance imaging investigations and to relate this to the result ing dermatomal anesthesia . Methods Eight volunteers were included in a r and omized , observer-blinded study . Sixty milliliters of ropivacaine 0.375 % was administered : 1 injection of 30 mL as a lateral classic TAP block , followed by a sham upper intercostal TAP block , and on the contralateral side , 2 separate 15-mL injections at the upper intercostal and lateral classic TAP plexuses , respectively . The primary outcome measure was magnetic resonance imaging – assessed area expansion of all injectates over a 6-hr period . Dermatomal anesthesia and sequential serum ropivacaine levels were recorded at the same time intervals . Results All injectate areas exp and ed in a statistically significant manner in the anterior abdominal wall . Lateral classic TAP blocks with 30-mL injectates did not extend into the upper intercostal TAP plexus . The dual 15-mL injectates on the other hemiabdomen remained within the upper intercostal and lateral classic TAP compartments and result ed in significantly ( P < 0.018 ) more widespread dermatomal anesthesia . Measured serum ropivacaine concentrations were below the potential level of toxicity . Conclusions Magnetic resonance imaging analysis revealed a significant time-dependent expansion of injectates . Magnetic resonance imaging and the degree of dermatomal anesthesia confirmed that the upper and lateral TAP compartments do not appear to communicate . Separate injections at the upper intercostal and lateral classic TAP plexuses are necessary to block the entire abdominal wall BACKGROUND The safety and short-term efficacy of laparoscopic surgery for rectal cancer after preoperative chemoradiotherapy has not been demonstrated . The aim of the r and omised Comparison of Open versus laparoscopic surgery for mid and low REctal cancer After Neoadjuvant chemoradiotherapy ( COREAN ) trial was to compare open surgery with laparoscopic surgery for mid or low rectal cancer after neoadjuvant chemoradiotherapy . METHODS Between April 4 , 2006 , and Aug 26 , 2009 , patients with cT3N0 - 2 mid or low rectal cancer without distant metastasis after preoperative chemoradiotherapy were enrolled at three tertiary-referral hospitals . Patients were r and omised 1:1 to receive either open surgery ( n=170 ) or laparoscopic surgery ( n=170 ) , stratified according to sex and preoperative chemotherapy regimen . Short-term outcomes assessed were involvement of the circumferential resection margin , macroscopic quality of the total mesorectal excision specimen , number of harvested lymph nodes , recovery of bowel function , perioperative morbidity , postoperative pain , and quality of life . Analyses were based on the intention-to-treat population . Patients continue to be followed up for the primary outcome ( 3-year disease-free survival ) . This study is registered with Clinical Trials.gov , number NCT00470951 . FINDINGS Two patients ( 1.2 % ) in the laparoscopic group were converted to open surgery , but were included in the laparoscopic group for analyses . Estimated blood loss was less in the laparoscopic group than in the open group ( median 217.5 mL [ 150.0 - 400.0 ] in the open group vs 200.0 mL [ 100.0 - 300.0 ] in the laparoscopic group , p=0.006 ) , although surgery time was longer in the laparoscopic group ( mean 244.9 min [ SD 75.4 ] vs 197.0 min [ 62.9 ] , p<0.0001 ) . Involvement of the circumferential resection margin , macroscopic quality of the total mesorectal excision specimen , number of harvested lymph nodes , and perioperative morbidity did not differ between the two groups . The laparoscopic surgery group showed earlier recovery of bowel function than the open surgery group ( time to pass first flatus , median 38.5 h [ 23.0 - 53.0 ] vs 60.0 h [ 43.0 - 73.0 ] , p<0.0001 ; time to resume a normal diet , 85.0 h [ 66.0 - 95.0 ] vs 93.0 h [ 86.0 - 121.0 ] , p<0.0001 ; time to first defecation , 96.5 h [ 70.0 - 125.0 ] vs 123 h [ 94.0 - 156.0 ] , p<0.0001 ) . The total amount of morphine used was less in the laparoscopic group than in the open group ( median 107.2 mg [ 80.0 - 150.0 ] vs 156.9 mg [ 117.0 - 185.2 ] , p<0.0001 ) . 3 months after proctectomy or ileostomy takedown , the laparoscopic group showed better physical functioning score than the open group ( 0.501 [ n=122 ] vs -4.970 [ n=128 ] , p=0.0073 ) , less fatigue ( -5.659 [ n=122 ] vs 0.098 [ n=129 ] , p=0.0206 ) , and fewer micturition ( -2.583 [ n=122 ] vs 4.725 [ n=129 ] , p=0.0002 ) , gastrointestinal ( -0.400 [ n=122 ] vs 4.331 [ n=129 ] , p=0.0102 ) , and defecation problems ( 0.535 [ n=103 ] vs 5.327 [ n=99 ] , p=0.0184 ) in repeated measures analysis of covariance , adjusted for baseline values . INTERPRETATION Laparoscopic surgery after preoperative chemoradiotherapy for mid or low rectal cancer is safe and has short-term benefits compared with open surgery ; the quality of oncological resection was equivalent Posterior transversus abdominis plane blocks have been reported to be an effective method of providing analgesia after lower abdominal surgery . We compared the efficacy of a novel technique of providing continuous transversus abdominis plane analgesia with epidural analgesia in patients on an enhanced recovery programme following laparoscopic colorectal surgery . A non‐inferiority comparison was used . Adult patients undergoing elective laparoscopic colorectal surgery were r and omly assigned to receive continuous transversus abdominis plane analgesia ( n = 35 ) vs epidural analgesia ( n = 35 ) , in addition to a postoperative analgesic regimen comprising regular paracetamol , regular diclofenac and tramadol as required . Sixty‐one patients completed the study . The transversus group received four‐quadrant transversus abdominis plane blocks and bilateral posterior transversus abdominis plane catheters that were infused with levobupivacaine 0.25 % for 48 h. The epidural group received an infusion of bupivacaine and fentanyl . The primary outcome measure was visual analogue scale pain score on coughing at 24 h after surgery . We found no significant difference in median ( IQR [ range ] ) visual analogue scores during coughing at 24 h between the transversus group 2.5 ( 1.0–3.0 [ 0–5.5 ] ) and the epidural group 2.5 ( 1.0–5.0 [ 0–6.0 ] ) . The one‐sided 97.5 % CI was a 0.0 ( ∞–1.0 ) difference in means , establishing non‐inferiority . There were no significant differences between the groups for tramadol consumption . Success rate was 28/30 ( 93 % ) in the transversus group vs 27/31 ( 87 % ) in the epidural group . Continuous transversus abdominis plane infusion was non‐inferior to epidural infusion in providing analgesia after laparoscopic colorectal surgery Background : The goals of this study are threefold : ( 1 ) to determine what effect epinephrine has on the duration of bupivacaine finger block anesthesia ; ( 2 ) to see whether the duration of action of bupivacaine on digital pain relief is the same duration as numbness to touch/pressure ; and ( 3 ) to assess the fingertip temperature changes that result from bupivacaine digital blocks . Methods : The ring fingers of both h and s of 44 volunteers were r and omized to injection of bupivacaine with or without 1:200,000 epinephrine . The duration s of time for digits to return to normal pain , touch , pressure sensation , and fingertip temperature were measured and recorded . Results : There were three main findings : ( 1 ) the pain block of bupivacaine lasts only half as long ( 15 hours ) as the return to normal sensation ( 30 hours ) ; ( 2 ) the effect of adding epinephrine to bupivacaine prolongs the duration of pain relief in a finger block for only an additional 1.5 hours ; ( 3 ) in addition to pain relief , bupivacaine finger blocks cause fingertip hyperemia with consistent significant fingertip temperature elevation that lasts 15 hours . Conclusions : The duration of bupivacaine pain relief is the clinical ly important factor that needs to be reported in bupivacaine trials . Patients should be informed that the return of pain will occur much sooner than the return of normal sensation . Adding epinephrine to bupivacaine does not add a clinical ly significant length of time to pain relief . Bupivacaine finger blocks provide prolonged hyperemia and pain block to fingertips , which may be useful in the treatment of acute frostbite . CLINICAL QUESTION /LEVEL OF EVIDENCE : Therapeutic , |
1,965 | 30,463,836 | Computer-assisted cognitive rehabilitation was effective in improving cognitive function .
Specific technology types have been found to be effective for some outcomes ( eg , telephone and remote medication monitoring for adherence to treatment ) , while other types of telehealth technologies ( eg , delivery of patient education using computers ) had no benefit over traditional nurse-based methods and were less acceptable to patients . | BACKGROUND People with severe mental illness ( SMI ) must receive early interventions to prevent mental health deterioration or relapse .
Telecommunications and other technologies are increasingly being used to assist in health care delivery using " telehealth , " which includes telephones and mobile phones , computers , remote sensors , the internet , and other devices , to provide immediate real-time information to service users to improve the management of chronic health conditions .
Some initial findings have suggested that technology could improve the quality of life of people with SMI .
OBJECTIVE In this systematic review , we aim ed to identify the various uses and efficacy of telehealth technology for SMI .
CONCLUSIONS A growing variety of telehealth technologies are being used to support the management of SMI . | An emerging body of research has shown that computer-assisted cognitive remediation , consisting of training in attention , memory , language and /or problem-solving , produces improvement in neurocognitive function that generalizes to untrained neurocognitive tests and may also impact symptoms and work functioning in patients with schizophrenia . The active ingredient of these interventions , however , remains unknown as control groups in these studies have typically included few , if any , of the elements of these complex behavioral treatments . This study compared the effects of an extended ( 12-month ) , st and ardized , computer-assisted cognitive remediation intervention with those of a computer-skills training control condition that consisted of many of the elements of the experimental intervention , including hours spent on a computer , interaction with a clinician and non-specific cognitive stimulation . Forty-two patients with schizophrenia were r and omly assigned to one of two conditions and were assessed with a comprehensive neuropsychological test battery before and after treatment . Results revealed that cognitive-remediation training produced a significant improvement in working memory , relative to the computers-skills training control condition , but that there was overall improvement in both groups on measures of working memory , reasoning/executive-function , verbal and spatial episodic memory , and processing speed . Taken together , these findings suggest that specific practice in neurocognitive exercises targeted at attention , memory and language , produce improvements in neurocognitive function that are not solely attributable to non-specific stimulation associated with working with a computer , interacting with a clinician or cognitive challenge , but that non-specific stimulation has a salutary effect on neurocognition as well CONTEXT Despite the availability of efficacious treatments , the long-term course of bipolar disorder is often unfavorable . OBJECTIVE To test the effectiveness of a multicomponent intervention program to improve the quality of care and long-term outcomes for persons with bipolar disorder . DESIGN R and omized controlled trial with allocation concealment and blinded outcome assessment . SETTING Mental health clinics of a group-model prepaid health plan . PATIENTS Of 785 patients in treatment for bipolar disorder who were invited to participate , 509 attended an evaluation appointment , 450 were found eligible to participate , and 441 enrolled in the trial . INTERVENTIONS Participants were r and omly assigned to a multicomponent intervention program or to continued care as usual . Three nurse care managers provided a 2-year systematic intervention program , including the following : a structured group psychoeducational program , monthly telephone monitoring of mood symptoms and medication adherence , feedback to treating mental health providers , facilitation of appropriate follow-up care , and as-needed outreach and crisis intervention . MAIN OUTCOME MEASURES In-person blinded research interviews every 3 months assessed mood symptoms using the Longitudinal Interval Follow-up Examination . Health plan administrative records were used to assess the use and cost of mental health services . RESULTS Intent-to-treat analyses demonstrated that the intervention significantly reduced the mean level of mania symptoms ( z = 2.09 , P = .04 ) and the time with significant mania symptoms ( 19.2 vs 24.7 weeks ; F(1 ) = 6.0 , P = .01 ) . There was no significant intervention effect on mean level of depressive symptoms ( z = 0.19 , P = .85 ) or time with significant depressive symptoms ( 47.6 vs 50.7 weeks ; F(1 ) = 0.56 , P = .45 ) . Benefits of the intervention were found only in a subgroup of 343 persons with clinical ly significant mood symptoms at the baseline assessment . The incremental cost ( adjusted ) of the intervention was 1251 dollars ( 95 % confidence interval , 55 - 2446 dollars ) , including approximately 800 dollars for the intervention program services and an approximate 500 dollars increase in the costs of other mental health services . CONCLUSIONS Population -based systematic care programs can significantly reduce the frequency and severity of mania in bipolar disorder , and cost increases are modest considering the clinical gains . The incorporation of more specific cognitive and behavioral content or more effective medication regimens may be necessary to significantly reduce the symptoms of depression BACKGROUND Patient-clinician communication is central to mental healthcare but neglected in research . AIMS To test a new computer-mediated intervention structuring patient-clinician dialogue ( DIALOG ) focusing on patients ' quality of life and needs for care . METHOD In a cluster r and omised controlled trial , 134 keyworkers in six countries were allocated to DIALOG or treatment as usual ; 507 people with schizophrenia or related disorders were included . Every 2 months for 1 year , clinicians asked patients to rate satisfaction with quality of life and treatment , and request additional or different support . Responses were fed back immediately in screen displays , compared with previous ratings and discussed . Primary outcome was subjective quality of life , and secondary outcomes were unmet needs and treatment satisfaction . RESULTS Of 507 patients , 56 were lost to follow-up and 451 were included in intention-to-treat analyses . Patients receiving the DIALOG intervention had better subjective quality of life , fewer unmet needs and higher treatment satisfaction after 12 months . CONCLUSIONS Structuring patient-clinician dialogue to focus on patients ' views positively influenced quality of life , needs for care and treatment satisfaction Nonadherence to medication is a widespread problem in schizophrenia and is associated with poor clinical outcomes and inappropriate management and utilization of re sources . The aim of the current investigation was to assess the impact of telemonitoring of medication adherence on symptomatology and service use in patients with schizophrenia . A total of 108 schizophrenia patients were r and omized into three equal groups according to the approaches used to assess medication adherence ; self-report , pill counting , and telemonitoring . Telementoring was achieved through an innovative new platform called @HOME . This platform offers clinicians early warnings about impeding nonadherence as well as information about the pattern of medication taking . Patient 's adherence was observed over an 8-week period , during which patient 's clinical status and service use were recorded . In comparison to the other two groups , patients using @HOME showed improvement in the Global Clinical Impression Scale and a significant reduction in emergency visits and medical appointments . The @HOME platform was highly acceptable by patients , caregivers , and professionals , and required minimal training for implementation . The results of the study suggest that the use of telemonitoring in psychiatric setting s was both feasible and acceptable and may be associated with significant clinical and service related benefits INTRODUCTION Schizophrenic patients present cognitive dysfunctions which are regarded to be one of endophenotypical markers predisposing to schizophrenia . Currently , schizophrenia can be treated as a neurodegenerative and neurodeveloping disease with genetic background . OBJECTIVE Assessment of the possible positive effect of neuropsychological rehabilitation in schizophrenia , in patients presenting cognitive dysfunctions . An additional aim was to verify the hypothesis that some genetic polymorphisms can be a prognostic factor for success in neuropsychological rehabilitation . MATERIAL AND METHODS 41 participants and 40 control subjects were r and omly selected . Both groups had the diagnosis of paranoid schizophrenia . Cognitive functions were checked with the Wisconsin Card Sorting Test , Trail Making Test , and Stroop Test at the beginning and end of the experiment . In the research group , each patient trained with the rehabilitation programme RehaCom , whereas the control group did not receive such training . Genes COMT rs4680 and BDNF rs6265 were analysed in the genetic part of study . RESULTS RehaCom procedures appear to be useful in the neuropsychological rehabilitation of cognitive dysfunctions in patients diagnosed with schizophrenia . The research group showed a moderate improvement in the training programmes . Analysis of parameters obtained in the neuropsychological tests showed a slight improvement in both groups . At the present time , analysis of the polymorphisms of genes can not be treated as a prognostic factor for the success of neuropsychological rehabilitation because statistical analyses showed few dependences with little statistical significance . CONCLUSIONS Cognitive rehabilitation produces moderate improvement in cognitive functioning Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more OBJECTIVE There is considerable interest in cognitive remediation for schizophrenia . Our study aim ed to evaluate , in a large sample of patients with schizophrenia , the interest of a computer-assisted cognitive remediation program on cognitive performances of patients as well as in clinical and functional outcome . METHOD Seventy-seven patients with remitted schizophrenia were r and omly assigned to 14 2-hours individual sessions of computer-assisted cognitive remediation ( n=39 ) or a control condition ( n=38 ) . Remediation was performed using RehaCom ® software . Four procedures were chosen to train four cognitive functions involved in different stages of the information processing : attention/concentration , working memory , logic , and executive functions . Primary outcomes were remediation exercise metrics , neuropsychological composites ( episodic memory , working memory , attention , executive functioning , and processing speed ) , clinical and community functioning measures . RESULTS Cognitive performances concerning Attention/vigilance , verbal working memory and verbal learning memory and reasoning/problem solving improved significantly in the remediation condition when no difference was reported in the control condition between the 2 assessment s. However , there were no significant benefits of cognitive remediation on non-verbal working memory and learning and speed of processing or functional outcome measures . CONCLUSIONS Cognitive remediation for people with schizophrenia was effective in improving performance , but the benefits of training did not generalize to functional outcome measures . Long term follow-up studies are needed to confirm the maintenance of such improvements Computerized cognitive remediation has result ed in improved executive function in schizophrenia , whereas results with regard to verbal memory were inconsistent . In the present study , 42 in patients with schizophrenia were r and omly assigned to a computerized cognitive remediation group or to a treatment-as-usual ( TAU ) control group . The remediation group received 15 sessions of computerized cognitive training ( Cogpack ) over a 3-week period . Neurocognitive functions were assessed at the beginning and end of this period . Compared to the control condition , remediation training result ed in improvements in verbal learning , processing speed and executive function ( verbal fluency ) . The results indicate that cognitive remediation may lead to improvements beyond those of executive function Abstract Objective . Adherence to prescribed antipsychotic medication is a major factor in achieving optimal long-term clinical outcomes . The aim of this study was to evaluate the impact of a telephone-based strategy provided by a nurse on adherence to antipsychotic treatment among patients with schizophrenia . Methods . A total of 928 clinical ly stable out patients with schizophrenia were r and omized to receive a monthly telephone call by a nurse or routine clinical care . Telephone calls were performed at weeks 4 , 8 , and 12 , consisting of a st and ardized interview to detect and assess therapeutic adherence and subjective attitude towards medication . Patients were followed for 4 months . A cut-point of ≥ 60 % of prescribed dose was used to classify patients as being adherent . Results . At week 16 , a significantly higher percentage of patients who received a telephone-based follow-up ( 96.7 % , n = 410 ) were classified as adherent compared to the control group ( 91.2 % , n = 402 ) ( P = 0.0007 ) . Patients in the intervention group were significantly more likely to be adherent than control group ( adjusted OR = 3.3 95 % CI 1.6–6.6 , P = 0.0001 ) . Conclusions . Telephone-based nursing strategy showed a significant improvement in adherence to antipsychotic drugs . Further studies are necessary to confirm if this kind of intervention could be a complementary strategy to optimize adherence in patients with schizophrenia Although social skills training ( SST ) is an effective approach for improving social skills for schizophrenia , the motivational deficit attenuates its efficacy . Virtual reality ( VR ) applications have allowed individuals with mental disabilities to enhance their motivation for rehabilitation . We compared SST using VR role-playing ( SST-VR ) to SST using traditional role-playing ( SST-TR ) . This r and omized , controlled trial included 91 in patients with schizophrenia who were assigned to either SST-VR ( n=46 ) or SST-TR ( n=45 ) . Both groups were administered over 10 semiweekly group sessions . An experienced , blinded rater assessed vocal , nonverbal and conversational skills . We also obtained data on motivation for SST and various social abilities . Throughout the 10 sessions , the SST-VR group ( n=33 ) showed greater interest in SST and generalization of the skills than the SST-TR group ( n=31 ) . After SST , the SST-VR group improved more in conversational skills and assertiveness than the SST-TR group , but less in nonverbal skills . The VR application in role-plays of SST for schizophrenia may be particularly beneficial in terms of improving the conversational skills and assertiveness , possibly through its advantages in enhancing motivation for SST and generalization of the skills , and thus it may be a useful supplement to traditional SST Deprivation of liberty ( DL ) in psychiatric inpatient care is common worldwide . As liberty is a central element of patients ’ rights , there is a need to develop most effective methods supporting patients ’ personal liberty . The article presents initial results from a study to determine the effectiveness of an information technology (IT)-based patient education programme on patients ’ experiences of being deprived of their liberty during their in-hospital stay . An overall sample of 311 patients with schizophrenia spectrum psychosis was r and omized into three groups : an intervention group with needs-based computerized patient education , a patient education group with conventional education and a control group with st and ard care . Data on the general experience of DL were collected at baseline and during the patient discharge process . In general , all patients experienced less DL at the time of their discharge . The change in patients ’ experiences of their DL did not differ statistically between the three groups . Male patients in the st and ard care group were significantly more likely to drop out of the study than female patients . Although technology-based patient education was not found to be superior to other approaches , we did not find any reason to inhibit its utilization in patient care among persons with severe mental health problems . From the healthcare organizations ’ perspective , a cost-effectiveness analysis is needed , as the IT education was slightly more time-consuming BACKGROUND Deficits in social cognition and neurocognition are believed to underlie schizophrenia disability . Attempts at rehabilitation have had circumscribed effects on cognition , without concurrent improvement in broad aspects of behavior and adjustment . OBJECTIVE To determine the differential effects of cognitive enhancement therapy ( a recovery-phase intervention ) on cognition and behavior compared with state-of-the-art enriched supportive therapy . DESIGN A 2-year , r and omized controlled trial with neuropsychological and behavioral assessment s completed at baseline and at 12 and 24 months . SETTING An outpatient research clinic housed in a medical center 's comprehensive care service for patients with severe mental illness . PATIENTS A total of 121 symptomatically stable , non-substance-abusing but cognitively disabled and chronically ill patients with schizophrenia or schizoaffective disorder . INTERVENTIONS Cognitive enhancement therapy is a multidimensional , developmental approach that integrates computer-assisted training in neurocognition with social cognitive group exercises . Enriched supportive therapy fosters illness management through applied coping strategies and education . MAIN OUTCOME MEASURES Six highly reliable summary measures --Processing Speed , Neurocognition , Cognitive Style , Social Cognition , Social Adjustment and Symptoms -- were tested using analysis of covariance and linear trend analysis . RESULTS At 12 months , robust cognitive enhancement therapy effects were observed on the Neurocognition and Processing Speed composites ( P<.003 ) , with marginal effects observed on the behavioral composites . By 24 months , differential cognitive enhancement therapy effects were again observed for the 2 neuropsychological composites and for Cognitive Style ( P=.001 ) , Social Cognition ( P=.001 ) , and Social Adjustment ( P=.01 ) . As expected , no differences were observed on the residual Symptoms composite . Effects were unrelated to the type of antipsychotic medication received . Enriched supportive therapy also demonstrated statistically significant within-group effect sizes , suggesting that supportive psychotherapy can also have positive , although more modest , effects on cognitive deficits . CONCLUSION Many cognitive deficits and related behaviors of patients with stable schizophrenia are improved when sufficient exposure to relevant rehabilitation is provided OBJECTIVE To examine the effect of the adapted virtual reality cognitive training program in older adults with chronic schizophrenia . METHODS Older adults with chronic schizophrenia were recruited from a long-stay care setting and were r and omly assigned into intervention ( n = 12 ) and control group ( n = 15 ) . The intervention group received 10-session of VR program that consisted of 2 VR activities using IREX . The control group attended the usual programs in the setting . RESULTS After the 10-session intervention , older adults with chronic schizophrenia preformed significantly better than control in overall cognitive function ( p .000 ) , and in two cognitive subscales : repetition ( p .001 ) and memory ( p .040 ) . These participants engaged in the VR activities volitionally . No problem of cybersickness was observed . CONCLUSIONS The results of the current study indicate that engaging in the adapted virtual reality cognitive training program offers the potential for significant gains in cognitive function of the older adults with chronic schizophrenia Objective To evaluate an individually tailored multicomponent nonadherence treatment protocol using a telehealth delivery approach in adolescents with inflammatory bowel disease . Methods Nine participants , age 13.71±1.35 years , completed a brief treatment online through Skype . Medication nonadherence , severity of disease , and feasibility/acceptability data were obtained . Results Adherence increased markedly from 62 % at baseline to 91 % for mesalamine ( & dgr;=0.63 ) , but decreased slightly from 61 % at baseline to 53 % for 6-mercaptopurine /azathioprine . The telehealth delivery approach result ed in cost savings of $ 100 in mileage and 4 h of travel time/patient . Treatment session attendance was 100 % , and the intervention was rated as acceptable , particularly in terms of treatment convenience . Conclusion Individually tailored treatment of nonadherence through telehealth delivery is feasible and acceptable . This treatment shows promise for clinical efficacy to improve medication adherence and reduce costs . Large-scale testing is necessary to determine the impact of this intervention on adherence and health outcomes BACKGROUND Despite the availability of efficacious medications and psychotherapies , care of bipolar disorder in everyday practice is often deficient . This trial evaluated the effectiveness of a multi-component care management program in a population -based sample of people with bipolar disorder . METHOD Four hundred and forty-one patients treated for bipolar disorder during the prior year were r and omly assigned to continued usual care or usual care plus a systematic care management program including : initial assessment and care planning , monthly telephone monitoring including brief symptom assessment and medication monitoring , feedback to and coordination with the mental health treatment team , and a structured group psychoeducational program -- all provided by a nurse care manager . Blinded quarterly assessment s generated week-by-week ratings of severity of depression and mania symptoms using the Longitudinal Interval Follow-Up Evaluation . RESULTS Participants assigned to the intervention group had significantly lower mean mania ratings averaged across the 12-month follow-up period ( Z= 2.44 , p=0.015 ) and approximately one-third less time in hypomanic or manic episode ( 2.59 weeks v. 1.69 weeks ) . Mean depression ratings across the entire follow-up period did not differ significantly between the two groups , but the intervention group showed a greater decline in depression ratings over time ( Z statistic for group-by-time interaction = 1.98 , p = 0.048 ) . CONCLUSIONS A systematic care program for bipolar disorder significantly reduces risk of mania over 12 months . Preliminary results suggest a growing effect on depression over time , but longer follow-up will be needed Purpose . To evaluate the effectiveness of the Information Technology-Aided Program of Re lapse Prevention in Schizophrenia ( ITAREPS ) . Methods . Relapse-prone out patients with schizophrenia or schizoaffective disorder were r and omized to the active ( n=75 ) or control group ( n=71 ) . In the active arm , according to the protocol , investigators were prompted to increase the antipsychotic dose upon occurrence of a pharmacological inter vention requiring event ( PIRE ) detected by ITAREPS . Results . Intention-to-treat ( ITT ) analysis found no between-group difference in the hospitalization-free survival rate at 12 months . However , the trial suffered from high non-adherence of investigators in the active group , with no antipsychotic dose increase in 61 % of PIREs . Furthermore , Cox regression analysis showed a 11-fold increased risk of hospitalization in the absence of pharmacological intervention following a PIRE ( hazard ratio [HR]=10.8 ; 95 % confidence interval [ CI ] 1.4–80.0 ; p=0.002 ) . Therefore , a post-hoc as-treated analysis was performed , which demonstrated a nine-fold reduction in the risk of hospitalization in ITAREPS Algorithm-Adherers ( IAAs , n=25 ) compared with the ITAREPS Non-interventional group ( INIs , n=70 ; Kaplan-Meier survival analysis , HR=0.11 , 95 % CI 0.05–0.28 , p=0.009 ; number needed to treat [NNT]=4 , 95 % CI 3–10 ) . A significant difference in favor of the IAA group was seen in the number of inpatient days ( p<0.05 ) and costs ( p<0.05 ) . Conclusion . Future ITAREPS trials should target the underlying mechanisms that cause low investigator adherence to the program . Trial registration : Clinical Trials NCT00712660 ( Journal of Psychiatric Practice 2012;18:269–280 OBJECTIVES To examine the comparative effectiveness of an online psychoeducation program for people diagnosed with bipolar disorder within the previous 12 months , completed alone or with adjunctive peer support , on symptoms and perceived control over the illness . METHOD Participants were r and omly allocated to an eight-week online psychoeducation program ( n=139 ) , a psychoeducation program plus online peer support ( n=134 ) or an attentional control condition ( n=134 ) . RESULTS Increased perceptions of control , decreased perceptions of stigmatisation and significant improvements in levels of anxiety and depression , from pre- to post-intervention were found across all groups . There were no significant differences between groups on outcome measures , although a small clinical difference was found between the supported and unsupported conditions in depression symptoms and in functional impairment at the six-month follow-up . Adherence to the treatment program was significantly higher in the supported intervention than in the unsupported program . Gender and age were also significant predictors of adherence , with females and those over the age of 30 showing greater adherence . LIMITATIONS Mood state at study entry was measured by self-report rather than by clinical interview . CONCLUSIONS The pattern of outcomes suggests a primary influence of non-specific or common therapeutic factors across all three intervention groups . A personally tailored intervention may be more suitable for individuals recently diagnosed with bipolar disorder , and longer term coaching may increase program adherence and long-term improvement in symptoms and functioning This study evaluated the impact of a cognitive retraining intervention design ed to enhance the attention skills of schizophrenia patients . The dependent variables included measures of perceptual sensitivity and sustained vigilance derived from a visual continuous performance test , as well as visual span of apprehension and world-list recall . Sixteen subjects received approximately 15 hours of repeated practice with computer-mediated vigilance tasks . Seventeen subjects were assigned to a no-treatment control group . All subjects were rated on measures of negative and positive symptoms before treatment . Despite improved performance on the training tasks , no significant changes on the outcome measures were observed following treatment . Thus , it is suggested that cognitive rehabilitation interventions with schizophrenia patients stress the teaching of behavioral strategies that bypass deficits , rather than remediating deficiencies in basic abilities , such as attention OBJECTIVES The efficacy of cognitive remediation interventions in schizophrenia has been demonstrated in several experimental studies . However , the effectiveness of such treatments in the usual setting of care of schizophrenia and a direct comparison of different modalities of interventions have not been systematic ally analyzed . The aim of the study was to assess the effectiveness of the cognitive subprograms of Integrated Psychological Therapy ( IPT-cog ) and of a computer-assisted cognitive remediation ( CACR ) method on symptomatological , neuropsychological and functional outcome measures in schizophrenia . METHODS Ninety patients with schizophrenia were assigned to IPT-cog , CACR or usual rehabilitative interventions ( REHAB ) in a naturalistic setting of care . Clinical , neuropsychological , and functional outcome variables were assessed at baseline and after 24 weeks of treatment . RESULTS Both the IPT-cog and CACR groups improved more than the comparison group with respect to all outcome variables . The more responsive cognitive domains were speed of processing and working memory . The effectiveness of the 2 remediation methods on the outcome dimensions considered was comparable . However , IPT-cog , but not CACR , was more effective than REHAB on speed of processing , and the CACR group had better outcome than both the REHAB and the IPT-cog groups when the Health of the Nation Outcome Scale was considered . Few correlations between neurocognitive and functional outcome changes were found . CONCLUSIONS The study demonstrates the effectiveness , although nongeneralized , of IPT-cog and CACR in schizophrenia when applied within a psychiatric and psychosocial treatment regimen representative of the usual setting and modality of care , with no evident superiority of any of the methods , and indicates that the changes in functional outcome during treatment are modestly mediated by improvement in specific cognitive domains BACKGROUND Small studies suggest that telemonitoring may improve heart-failure outcomes , but its effect in a large trial has not been established . METHODS We r and omly assigned 1653 patients who had recently been hospitalized for heart failure to undergo either telemonitoring ( 826 patients ) or usual care ( 827 patients ) . Telemonitoring was accomplished by means of a telephone-based interactive voice-response system that collected daily information about symptoms and weight that was review ed by the patients ' clinicians . The primary end point was readmission for any reason or death from any cause within 180 days after enrollment . Secondary end points included hospitalization for heart failure , number of days in the hospital , and number of hospitalizations . RESULTS The median age of the patients was 61 years ; 42.0 % were female , and 39.0 % were black . The telemonitoring group and the usual-care group did not differ significantly with respect to the primary end point , which occurred in 52.3 % and 51.5 % of patients , respectively ( difference , 0.8 percentage points ; 95 % confidence interval [ CI ] , -4.0 to 5.6 ; P=0.75 by the chi-square test ) . Readmission for any reason occurred in 49.3 % of patients in the telemonitoring group and 47.4 % of patients in the usual-care group ( difference , 1.9 percentage points ; 95 % CI , -3.0 to 6.7 ; P=0.45 by the chi-square test ) . Death occurred in 11.1 % of the telemonitoring group and 11.4 % of the usual care group ( difference , -0.2 percentage points ; 95 % CI , -3.3 to 2.8 ; P=0.88 by the chi-square test ) . There were no significant differences between the two groups with respect to the secondary end points or the time to the primary end point or its components . No adverse events were reported . CONCLUSIONS Among patients recently hospitalized for heart failure , telemonitoring did not improve outcomes . The results indicate the importance of a thorough , independent evaluation of disease-management strategies before their adoption . ( Funded by the National Heart , Lung , and Blood Institute ; Clinical Trials.gov number , NCT00303212 . ) Thirty-four-day treatment program clients diagnosed with schizophrenia or schizoaffective disorder were r and omly assigned to a computer-assisted cognitive rehabilitation ( CACR ) group or a wait-list Control group . CACR clients received 16 CACR sessions over an 8-week period . Measures of cognitive functioning , negative symptoms and self-esteem were administered at the beginning and end of this period . CACR clients showed greater improvement in cognitive functioning ( verbal memory and attention ) and negative symptoms . Symptom reduction was not mediated by raised self-esteem . CACR 's effects may go beyond cognitive remediation to include some of the most disabling and refractory clinical features of schizophrenia We studied the efficacy and feasibility of using computer-based instruction to provide medication information to hospitalized patients with acute psychotic conditions . Patients were r and omly assigned to receive computer-based ( n = 21 ) or personal instruction ( n = 21 ) ; for the final analyses the computer group was exp and ed to include 13 patients from a pilot study . Outcome measures were knowledge retention ( indicated by changes in test scores ) and compliance with medication regimens after discharge ( indicated by telephone follow-up at one week , one month , and three months ) . The subjects reacted positively to the computer program . Knowledge retention and compliance were similar in the computer and control groups . We conclude that psychiatric in patients admitted for acute care can participate in , and learn from , computerized medication instruction BACKGROUND The true benefit of pharmacologic intervention to improve cognition in schizophrenia may not be evident without regular cognitive enrichment . Clinical trials assessing the neurocognitive effects of new medications may require engagement in cognitive remediation exercises to stimulate the benefit potential . However , the feasibility of large-scale multisite studies using cognitive remediation at clinical trials sites has not been established . METHOD 53 adult patients with DSM-IV schizophrenia from 9 university-affiliated sites were r and omized to a cognitive remediation condition that included the Posit Science Brain Fitness auditory training program with weekly Neuropsychological and Educational Approach to Remediation ( NEAR ) " bridging groups " or a control condition of computer games and weekly healthy lifestyles groups . Patients were expected to complete 3 to 5 one-hour sessions weekly for 40 sessions or 12 weeks , whichever came first . The primary outcomes were feasibility results as measured by rate of enrollment , retention , and completion rate of primary outcome measures . The study was conducted from July 2009 through January 2010 . RESULTS During a 3-month enrollment period , 53 ( of a projected 54 ) patients were enrolled , and 41 ( 77 % ) met criteria for study completion . Thirty-one patients completed all 40 sessions , and all patients completed all primary outcome measures . Preliminary efficacy results indicated that , after 20 sessions , patients in the cognitive remediation condition demonstrated mean MATRICS Consensus Cognitive Battery composite score improvements that were 3.7 ( 95 % CI , 0.05 - 7.34 ) T-score points greater than in patients in the computer-games control group ( F(1,46 ) = 4.16 , P = .047 ) . At the end of treatment , a trend favoring cognitive remediation was not statistically significant ( F(1,47 ) = 2.26 , P = .14 ) . CONCLUSION Multisite clinical trials of cognitive remediation using the Posit Science Brain Fitness auditory training program with the NEAR method of weekly bridging groups at traditional clinical sites appear to be feasible . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00930150 Abstract Objectives : To compare use , effect , and cost of personalised computer education with community psychiatric nurse education for patients with schizophrenia . Design : R and omised trial of three interventions . Modelling of costs of alternatives . Participants : 112 patients with schizophrenia in contact with community services ; 67 completed the intervention . Interventions : Three interventions of five educational sessions : ( a ) computer intervention combining information from patient 's medical record with general information about schizophrenia ; ( b ) sessions with a community psychiatric nurse ; ( c ) “ combination ” ( first and last sessions with nurse and remainder with computer ) . Main outcome measures : Patients ' attendance , opinions , change in knowledge , and psychological state ; costs of interventions and patients ' use of NHS community services ; modelling of costs for these three , and alternative , interventions . Results : Rates of completion of intervention did not differ significantly ( 71 % for combination intervention , 61 % for computer only , 46 % for nurse only ) . Computer sessions were shorter than sessions with nurse ( 14 minutes v 60 minutes ) . More patients given nurse based education thought the information relevant . Of 20 patients in combination group , 13 preferred the sessions with the nurse and seven preferred the computer . There were no significant differences between groups in psychological outcomes . Because of the need to transport patients to the computer for their sessions , there was no difference between interventions in costs , but computer sessions combined with other patient contacts would be substantially cheaper . Conclusions : The computer based patient education offered no advantage over sessions with a community psychiatric nurse . Investigation of computer use combined with other health service contacts would be worth while . What is already known on this topic Education of patients with schizophrenia has limited but positive outcomes Computer based approaches have not been thoroughly evaluated What this study adds A computer based method of education for patients with schizophrenia , which personalised the information with details from each patient 's medical record , was acceptable and as effective as educational sessions given by a community psychiatric nurse However , because of the need to provide transport for patients to attend their sessions , the computer based intervention was as costly as the nurse based one Investigating the addition of computer based education to other routine patient contacts would be Objective To examine the costs and cost effectiveness of telehealth in addition to st and ard support and treatment , compared with st and ard support and treatment . Design Economic evaluation nested in a pragmatic , cluster r and omised controlled trial . Setting Community based telehealth intervention in three local authority areas in Engl and . Participants 3230 people with a long term condition ( heart failure , chronic obstructive pulmonary disease , or diabetes ) were recruited into the Whole Systems Demonstrator telehealth trial between May 2008 and December 2009 . Of participants taking part in the Whole Systems Demonstrator telehealth question naire study examining acceptability , effectiveness , and cost effectiveness , 845 were r and omised to telehealth and 728 to usual care . Interventions Intervention participants received a package of telehealth equipment and monitoring services for 12 months , in addition to the st and ard health and social care services available in their area . Controls received usual health and social care . Main outcome measure Primary outcome for the cost effectiveness analysis was incremental cost per quality adjusted life year ( QALY ) gained . Results We undertook net benefit analyses of costs and outcomes for 965 patients ( 534 receiving telehealth ; 431 usual care ) . The adjusted mean difference in QALY gain between groups at 12 months was 0.012 . Total health and social care costs ( including direct costs of the intervention ) for the three months before 12 month interview were £ 1390 ( € 1610 ; $ 2150 ) and £ 1596 for the usual care and telehealth groups , respectively . Cost effectiveness acceptability curves were generated to examine decision uncertainty in the analysis surrounding the value of the cost effectiveness threshold . The incremental cost per QALY of telehealth when added to usual care was £ 92 000 . With this amount , the probability of cost effectiveness was low ( 11 % at willingness to pay threshold of £ 30 000 ; > 50 % only if the threshold exceeded about £ 90 000 ) . In sensitivity analyses , telehealth costs remained slightly ( non-significantly ) higher than usual care costs , even after assuming that equipment prices fell by 80 % or telehealth services operated at maximum capacity . However , the most optimistic scenario ( combining reduced equipment prices with maximum operating capacity ) eliminated this group difference ( cost effectiveness ratio £ 12 000 per QALY ) . Conclusions The QALY gain by patients using telehealth in addition to usual care was similar to that by patients receiving usual care only , and total costs associated with the telehealth intervention were higher . Telehealth does not seem to be a cost effective addition to st and ard support and treatment . Trial registration IS RCT N43002091 BACKGROUND Bipolar Disorder ( BD ) is a severe mental health problem . Psychological interventions are recommended by the National Institute for Health and Care Excellence ( NICE ) but patients experience severe inequalities in access . This study assessed the feasibility and potential effectiveness of a recovery informed web-based self-management intervention for people with BD . METHODS An online r and omised controlled trial ( n=122 ) compared treatment as usual ( TAU ) plus the ' Living with Bipolar ' ( LWB ) intervention with a waiting list control ( WLC ) group . RESULTS The study recruited to target and the retention rates were high . Participants engaged with the approach . Compared with the WLC , those receiving LWB showed the most robust improvement in psychological and physical domains of quality of life , wellbeing and recovery at the end of the intervention . LIMITATIONS The trial was not definitive and requires further investigation . CONCLUSIONS There is preliminary evidence that a web-based treatment approach in BD is feasible and potentially effective . Such interventions could form part of the Improving Access to Psychological Therapy ( IAPT ) initiative in severe mental health Cognitive impairment is a core symptom in schizophrenia that has a significant impact on psychosocial function , but shows a weak response to pharmacological treatment . Consequently , a variety of cognitive remediation strategies have been evaluated to improve cognitive function in schizophrenia . The efficacy of computer-based cognitive remediation as a st and -alone intervention on general measures of neuropsychological function remains unclear . We tested the effectiveness of biweekly training using computerized cognitive remediation programs on neuropsychological and event-related potential outcome measures . Schizophrenia patients were r and omly assigned to cognitive remediation training ( N=17 ) , active control ( TV-watching ; N=17 ) , or treatment-as-usual ( N=10 ) groups for ten weeks and run in parallel . Cognitive and ERP measures revealed no differential improvement over time in the cognitive remediation group . Practice effects might explain change over time on several cognitive measures for all groups , consistent with studies indicating task-specific improvement . Computer-assisted cognitive remediation alone may not be sufficient for robust or generalized effects on cognitive and electrophysiological measures in schizophrenia patients Employment provides schizophrenic patients with a positive identity and hope . Cognitive impairments have been suggested to slow down the progress in work rehabilitation . The purpose of this study was to investigate the efficacy and effectiveness of VR as a cognitive intervention for enhancing vocational outcomes . 95 in patients with schizophrenia were r and omly assigned to a virtual reality-based vocational training group ( VRG ) , a therapist-administered group ( TAG ) and a conventional group ( CG ) . Twenty-five of them in each group had completed the study . Their performances were evaluated , before and after interventions , by Brief Neuropsychological Cognitive Examination , Digit Vigilance Test , Rivermead Behavioural Memory Test , Wisconsin Card Sorting Test ( WCST ) and Vocational Cognitive Rating Scale . Patients in the VRG were found to perform better than patients in the TAG and CG in cognitive functioning , as shown by the WCST-percentage of error ( F ( 2 , 72)=7.146 , p<0.001 ) and the WCST-percentage of conceptual level response ( F ( 2 , 72)=8.722 , p<0.001 ) . The post-hoc test revealed that the VRG showed a better performance than both the TAG ( p=0.03 ) and the CG ( p<0.001 ) in the WCST-percentage of error . The VRG also showed a better performance than patients in both the TAG ( p=0.01 ) and the CG ( p<0.001 ) in the WCST-percentage of conceptual level response . The VRG also showed a better self-efficacy score than CG . Both VRG and TAG showed a better work performance as reflected by the on-site tests . Further studies on the use of VR in schizophrenia rehabilitation and for vocational success are discussed Objective : An intervention to structure patient – key worker communication has been tested in a r and omized controlled trial . The aim of this paper was to investigate effectiveness of the intervention in terms of moderators of effectiveness Cognitive dysfunction is a chronically disabling feature of schizophrenia , associated with limits in obtaining rehabilitation improvements . The purpose of this study is to assess the effectiveness of intensive computer-aided cognitive remediation treatment ( CRT ) added to a st and ard rehabilitation treatment ( SRT ) , in enhancing neuropsychological performances and daily functioning in patients with schizophrenia . A 12-week , r and omized , controlled , single-blind trial of neurocognitive remediation was carried out on 86 patients with clinical ly stabilized DSM-IV schizophrenia . Patients were assessed on cognitive and daily functioning before and after either CRT or placebo training that had been added to their SRT . After 3 months the repeated measure ANOVA showed a significant time x treatment interaction for executive function and attention performances and in daily functioning assessment in favour of patients in the SRT+CRT treatment . Results confirmed that cognitive remediation added to the SRT of schizophrenia enhanced its neuropsychological effects and increased the effects of a long-term rehabilitation programme in terms of functional outcomes |
1,966 | 31,455,279 | Most of the vaccinated individuals had previous immunity for at least one serotype , which generated safety concerns in individuals without previous immunity .
Conclusions Compared with other commercially available vaccines , the dengue vaccine showed poor efficacy | Background Dengue is an arbovirus that has rapidly spread worldwide , and the incidence of dengue has greatly increased in recent decades .
The actual numbers of dengue cases are underreported , and many cases are not classified correctly .
Recent estimates indicate that 390 million dengue infections occur per year ( 95 % CI , 284–528 million ) , of which 96 million ( 67–136 million ) are symptomatic infections of any severity .
One of the goals of the World Health Organization is to reduce dengue mortality by 50 % by the year 2020 .
The use of a vaccine can be an important strategy to achieve this goal .
Vaccines for dengue are in various stages of development ; in Brazil , only one commercial formulation is available ( CYD-TDV ) , which was developed by Sanofi Pasteur . | BACKGROUND In light of the increasing rate of dengue infections throughout the world despite vector-control measures , several dengue vaccine c and i date s are in development . METHODS In a phase 3 efficacy trial of a tetravalent dengue vaccine in five Latin American countries where dengue is endemic , we r and omly assigned healthy children between the ages of 9 and 16 years in a 2:1 ratio to receive three injections of recombinant , live , attenuated , tetravalent dengue vaccine ( CYD-TDV ) or placebo at months 0 , 6 , and 12 under blinded conditions . The children were then followed for 25 months . The primary outcome was vaccine efficacy against symptomatic , virologically confirmed dengue ( VCD ) , regardless of disease severity or serotype , occurring more than 28 days after the third injection . RESULTS A total of 20,869 healthy children received either vaccine or placebo . At baseline , 79.4 % of an immunogenicity subgroup of 1944 children had seropositive status for one or more dengue serotypes . In the per- protocol population , there were 176 VCD cases ( with 11,793 person-years at risk ) in the vaccine group and 221 VCD cases ( with 5809 person-years at risk ) in the control group , for a vaccine efficacy of 60.8 % ( 95 % confidence interval [ CI ] , 52.0 to 68.0 ) . In the intention-to-treat population ( those who received at least one injection ) , vaccine efficacy was 64.7 % ( 95 % CI , 58.7 to 69.8 ) . Serotype-specific vaccine efficacy was 50.3 % for serotype 1 , 42.3 % for serotype 2 , 74.0 % for serotype 3 , and 77.7 % for serotype 4 . Among the severe VCD cases , 1 of 12 was in the vaccine group , for an intention-to-treat vaccine efficacy of 95.5 % . Vaccine efficacy against hospitalization for dengue was 80.3 % . The safety profile for the CYD-TDV vaccine was similar to that for placebo , with no marked difference in rates of adverse events . CONCLUSIONS The CYD-TDV dengue vaccine was efficacious against VCD and severe VCD and led to fewer hospitalizations for VCD in five Latin American countries where dengue is endemic . ( Funded by Sanofi Pasteur ; Clinical Trials.gov number , NCT01374516 . ) Background : The dengue virus is a member of the Flavivirus ( FV ) genus , which also includes the yellow fever virus . Dengue disease is caused by any 1 of 4 dengue virus serotypes and is a serious public health concern in Latin America . This study evaluated the safety and immunogenicity of a c and i date recombinant , live-attenuated , tetravalent dengue vaccine ( CYD-TDV ) in 9–16 year olds in Latin America . Methods : In this r and omized , blinded , controlled study , volunteers received either 3 doses of CYD-TDV ( n = 401 ) or placebo as first and second injection and tetanus/diphtheria/acellular pertussis vaccine as third injection ( n = 199 ) at 0 , 6 and 12 months . Adverse events were documented . Plaque reduction neutralization test antibody titers against the 4 CYD-TDV parental strains were measured before and 28 days after each dose . Seropositivity was defined as antibody titers ≥10 1/dil . Results : The number of adverse reactions decreased after each successive CYD-TDV dose . After each CYD-TDV dose , antibody titers against all 4 serotypes were higher than baseline and respective predose titers . After the third dose of CYD-TDV , 100 % , 98.6 % and 93.4 % of participants were seropositive for at least 2 , at least 3 or all 4 serotypes , respectively . Higher antibody titers were observed in participants in the CYD-TDV group who were FV-seropositive at baseline compared with those who were FV-seronegative . Conclusions : CYD-TDV had a favorable safety profile and elicited antibody responses against all 4 dengue virus serotypes in 9–16 year olds in Latin America . These findings support the continued development of CYD-TDV Immunogenicity and safety of a recombinant , live-attenuated , tetravalent dengue disease vaccine ( CYD-TDV ) was evaluated in children/adolescents in Brazil . In this observer-blind , placebo-controlled , phase II single-center study , children/adolescents ( ages 9–16 years ) were r and omized to receive CYD-TDV or placebo at 0 , 6 , and 12 months . Immunogenicity was assessed using a 50 % plaque neutralization test . Overall , 150 participants were enrolled ( CYD-TDV : N = 100 ; placebo : N = 50 ) . Injection site pain and headache were the most common solicited injection site and systemic reactions . Unsolicited adverse events ( AEs ) and serious AEs were similar between groups . No serious AEs were vaccine-related . Geometric mean titers against all dengue virus serotypes increased with CYD-TDV vaccination and were 267 , 544 , 741 , and 432 1/dil for serotypes 1–4 , respectively , after dose 3 , representing a mean fold increase from baseline of 5 , 6 , 6 , and 20 , respectively . CYD-TDV vaccination elicited a neutralizing antibody response against serotypes 1–4 and was well-tolerated in children/adolescents in a dengue-endemic region BACKGROUND Roughly half the world 's population live in dengue-endemic countries , but no vaccine is licensed . We investigated the efficacy of a recombinant , live , attenuated tetravalent dengue vaccine . METHODS In this observer-masked , r and omised , controlled , monocentre , phase 2b , proof-of-concept trial , healthy Thai schoolchildren aged 4 - 11 years were r and omly assigned ( 2:1 ) to receive three injections of dengue vaccine or control ( rabies vaccine or placebo ) at months 0 , 6 , and 12 . R and omisation was by computer-generated permuted blocks of six and participants were assigned with an interactive response system . Participants were actively followed up until month 25 . All acute febrile illnesses were investigated . Dengue viraemia was confirmed by serotype-specific RT-PCR and non-structural protein 1 ELISA . The primary objective was to assess protective efficacy against virologically confirmed , symptomatic dengue , irrespective of severity or serotype , occurring 1 month or longer after the third injection ( per- protocol analysis ) . This trial is registered at Clinical Trials.gov , NCT00842530 . FINDINGS 4002 participants were assigned to vaccine ( n=2669 ) or control ( n=1333 ) . 3673 were included in the primary analysis ( 2452 vaccine , 1221 control ) . 134 cases of virologically confirmed dengue occurred during the study . Efficacy was 30·2 % ( 95 % CI -13·4 to 56·6 ) , and differed by serotype . Dengue vaccine was well tolerated , with no safety signals after 2 years of follow-up after the first dose . INTERPRETATION These data show for the first time that a safe vaccine against dengue is possible . Ongoing large-scale phase 3 studies in various epidemiological setting s will provide pivotal data for the CYD dengue vaccine c and i date . FUNDING Sanofi Pasteur BACKGROUND A c and i date tetravalent dengue vaccine is being assessed in three clinical trials involving more than 35,000 children between the ages of 2 and 16 years in Asian-Pacific and Latin American countries . We report the results of long-term follow-up interim analyses and integrated efficacy analyses . METHODS We are assessing the incidence of hospitalization for virologically confirmed dengue as a surrogate safety end point during follow-up in years 3 to 6 of two phase 3 trials , CYD14 and CYD15 , and a phase 2b trial , CYD23/57 . We estimated vaccine efficacy using pooled data from the first 25 months of CYD14 and CYD15 . RESULTS Follow-up data were available for 10,165 of 10,275 participants ( 99 % ) in CYD14 and 19,898 of 20,869 participants ( 95 % ) in CYD15 . Data were available for 3203 of the 4002 participants ( 80 % ) in the CYD23 trial included in CYD57 . During year 3 in the CYD14 , CYD15 , and CYD57 trials combined , hospitalization for virologically confirmed dengue occurred in 65 of 22,177 participants in the vaccine group and 39 of 11,089 participants in the control group . Pooled relative risks of hospitalization for dengue were 0.84 ( 95 % confidence interval [ CI ] , 0.56 to 1.24 ) among all participants , 1.58 ( 95 % CI , 0.83 to 3.02 ) among those under the age of 9 years , and 0.50 ( 95 % CI , 0.29 to 0.86 ) among those 9 years of age or older . During year 3 , hospitalization for severe dengue , as defined by the independent data monitoring committee criteria , occurred in 18 of 22,177 participants in the vaccine group and 6 of 11,089 participants in the control group . Pooled rates of efficacy for symptomatic dengue during the first 25 months were 60.3 % ( 95 % CI , 55.7 to 64.5 ) for all participants , 65.6 % ( 95 % CI , 60.7 to 69.9 ) for those 9 years of age or older , and 44.6 % ( 95 % CI , 31.6 to 55.0 ) for those younger than 9 years of age . CONCLUSIONS Although the unexplained higher incidence of hospitalization for dengue in year 3 among children younger than 9 years of age needs to be carefully monitored during long-term follow-up , the risk among children 2 to 16 years of age was lower in the vaccine group than in the control group . ( Funded by Sanofi Pasteur ; Clinical Trials.gov numbers , NCT00842530 , NCT01983553 , NCT01373281 , and NCT01374516 . ) |
1,967 | 31,581,205 | Early mobilization appears to decrease the incidence of ICU-AW , improve the functional capacity , and increase the number of ventilator-free days and the discharged-to-home rate for patients with a critical illness in the ICU setting | BACKGROUND Physical therapy can prevent functional impairments and improve the quality of life of patients after hospital discharge .
However , the effect of early mobilization on patients with a critical illness remains unclear .
This study was performed to assess the evidence available regarding the effect of early mobilization on critically ill patients in the intensive care unit ( ICU ) . | Purpose Cognitive impairment after critical illness is common and debilitating . We developed a cognitive therapy program for critically ill patients and assessed the feasibility and safety of administering combined cognitive and physical therapy early during a critical illness . Methods We r and omized 87 medical and surgical ICU patients with respiratory failure and /or shock in a 1:1:2 manner to three groups : usual care , early once-daily physical therapy , or early once-daily physical therapy plus a novel , progressive , twice-daily cognitive therapy protocol . Cognitive therapy included orientation , memory , attention , and problem-solving exercises , and other activities . We assessed feasibility outcomes of the early cognitive plus physical therapy intervention . At 3 months , we also assessed cognitive , functional , and health-related quality of life outcomes . Data are presented as median ( interquartile range ) or frequency ( % ) . Results Early cognitive therapy was a delivered to 41/43 ( 95 % ) of cognitive plus physical therapy patients on 100 % ( 92–100 % ) of study days beginning 1.0 ( 1.0–1.0 ) day following enrollment . Physical therapy was received by 17/22 ( 77 % ) of usual care patients , by 21/22 ( 95 % ) of physical therapy only patients , and 42/43 ( 98 % ) of cognitive plus physical therapy patients on 17 % ( 10–26 % ) , 67 % ( 46–87 % ) , and 75 % ( 59–88 % ) of study days , respectively . Cognitive , functional , and health-related quality of life outcomes did not differ between groups at 3-month follow-up . Conclusions This pilot study demonstrates that early rehabilitation can be extended beyond physical therapy to include cognitive therapy . Future work to determine optimal patient selection , intensity of treatment , and benefits of cognitive therapy in the critically ill is needed Purpose : The purpose of this review is to evaluate the literature related to mobilization of the critically ill patient with an emphasis on functional outcomes and patient safety . Methods : We search ed the electronic data bases of PubMed , CINAHL , Medline ( Ovid ) , and The Cochrane Library for a period spanning 2000‐2011 . Articles used in this review included r and omized and nonr and omized clinical trials , prospect i ve and retrospective analyses , and case series in peer review ed journals . Sackett 's Levels of Evidence were used to classify the current literature to evaluate the strength of the outcomes reported . Results : Fifteen studies met inclusion criteria and were review ed . According to Sackett 's Levels of Evidence , 9 studies were level 4 evidence , one study was level 3 , 4 studies were level 2 , and one study was level one evidence . Ten studies pertained to patient safety/feasibility and 10 studies pertained to functional outcomes with 5 fitting into both categories . Conclusion : A search of the scientific literature revealed a limited number of studies that examined the mobilization of critically ill patients in the intensive care unit . However , literature that does exist supports early mobilization and physical therapy as a safe and effective intervention that can have a significant impact on functional outcomes Objectives : To investigate whether a daily exercise session , using a bedside cycle ergometer , is a safe and effective intervention in preventing or attenuating the decrease in functional exercise capacity , functional status , and quadriceps force that is associated with prolonged intensive care unit stay . A prolonged stay in the intensive care unit is associated with muscle dysfunction , which may contribute to an impaired functional status up to 1 yr after hospital discharge . No evidence is available concerning the effectiveness of an early exercise training intervention to prevent these detrimental complications . Design : R and omized controlled trial . Setting : Medical and surgical intensive care unit at University Hospital Gasthuisberg . Patients : Ninety critically ill patients were included as soon as their cardiorespiratory condition allowed bedside cycling exercise ( starting from day 5 ) , given they still had an expected prolonged intensive care unit stay of at least 7 more days . Interventions : Both groups received respiratory physiotherapy and a daily st and ardized passive or active motion session of upper and lower limbs . In addition , the treatment group performed a passive or active exercise training session for 20 mins/day , using a bedside ergometer . Measurements and Main Results : All outcome data are reflective for survivors . Quadriceps force and functional status were assessed at intensive care unit discharge and hospital discharge . Six-minute walking distance was measured at hospital discharge . No adverse events were identified during and immediately after the exercise training . At intensive care unit discharge , quadriceps force and functional status were not different between groups . At hospital discharge , 6-min walking distance , isometric quadriceps force , and the subjective feeling of functional well-being ( as measured with “ Physical Functioning ” item of the Short Form 36 Health Survey question naire ) were significantly higher in the treatment group ( p < .05 ) . Conclusions : Early exercise training in critically ill intensive care unit survivors enhanced recovery of functional exercise capacity , self-perceived functional status , and muscle force at hospital discharge Introduction The purpose of this trial was to investigate the effectiveness of an exercise rehabilitation program commencing during ICU admission and continuing into the outpatient setting compared with usual care on physical function and health-related quality of life in ICU survivors . Methods We conducted a single-center , assessor-blinded , r and omized controlled trial . One hundred and fifty participants were stratified and r and omized to receive usual care or intervention if they were in the ICU for 5 days or more and had no permanent neurological insult . The intervention group received intensive exercises in the ICU and the ward and as out patients . Participants were assessed at recruitment , ICU admission , hospital discharge and at 3- , 6- and 12-month follow-up . Physical function was evaluated using the Six-Minute Walk Test ( 6MWT ) ( primary outcome ) , the Timed Up and Go Test and the Physical Function in ICU Test . Patient-reported outcomes were measured using the Short Form 36 Health Survey , version 2 ( SF-36v2 ) and Assessment of Quality of Life ( AQoL ) Instrument . Data were analyzed using mixed models . Results The a priori enrollment goal was not reached . There were no between-group differences in demographic and hospital data , including acuity and length of acute hospital stay ( LOS ) ( Acute Physiology and Chronic Health Evaluation II score : 21 vs 19 ; hospital LOS : 20 vs 24 days ) . No significant differences were found for the primary outcome of 6MWT or any other outcomes at 12 months after ICU discharge . However , exploratory analyses showed the rate of change over time and mean between-group differences in 6MWT from first assessment were greater in the intervention group . Conclusions Further research examining the trajectory of improvement with rehabilitation is warranted in this population .Trial registration The trial was registered with the Australian New Zeal and Clinical Trials Registry ACTRN12605000776606 ABSTRACT Objective : To evaluate the effects that passive cycling exercise , in combination with conventional physical therapy , have on peripheral muscle strength , duration of mechanical ventilation , and length of hospital stay in critically ill patients admitted to the ICU of a tertiary care university hospital . Methods : This was a r and omized clinical trial involving 38 patients ( ≥ 18 years of age ) on mechanical ventilation who were r and omly divided into two groups : control ( n = 16 ) , receiving conventional physical therapy ; and intervention ( n = 22 ) , receiving conventional physical therapy and engaging in passive cycling exercise five days per week . The mean age of the patients was 46.42 ± 16.25 years , and 23 were male . The outcomes studied were peripheral muscle strength , as measured by the Medical Research Council scale , duration of mechanical ventilation , and length of hospital stay . Results : There was a significant increase in peripheral muscle strength ( baseline vs. final ) in both groups ( control : 40.81 ± 7.68 vs. 45.00 ± 6.89 ; and intervention : 38.73 ± 11.11 vs. 47.18 ± 8.75 ; p < 0.001 for both ) . However , the range of increase in strength was higher in the intervention group than in the control group ( 8.45 ± 5.20 vs. 4.18 ± 2.63 ; p = 0.005 ) . There were no significant differences between the groups in terms of duration of mechanical ventilation or length of hospital stay . Conclusions : The results suggest that the performance of continuous passive mobilization on a cyclical basis helps to recover peripheral muscle strength in ICU patients . ( Clinical Trials.gov Identifier : NCT01769846 [ http://www . clinical trials.gov/ ] Background : Systematic review s of early rehabilitation within intensive care units have highlighted the need for robust multi‐centre r and omised controlled trials with longer term follow up . This trial aims to explore the feasibility of earlier and enhanced rehabilitation for patients mechanically ventilated for ≥5 days and to assess the impact on possible long term outcome measures for use in a definitive trial . Methods : Patients admitted to a large UK based intensive care unit and invasively ventilated for ≥5 days were r and omised to the rehabilitation intervention or st and ard care on a 1:1 basis , stratified by age and SOFA score . The rehabilitation intervention involved a structured programme , with progression along a functionally based mobility protocol according to set safety criteria . Results : 103 out of 128 eligible patients were recruited into the trial , achieving an initial recruitment rate of 80 % . Patients in the intervention arm mobilized significantly earlier ( 8 days vs 10 days , p = 0.035 ) , at a more acute phase of illness ( SOFA 6 vs 4 , p < 0.05 ) and reached a higher level of mobility at the point of critical care discharge ( MMS 7 vs 5 , p < 0.01 ) . Conclusion : We have demonstrated the feasibility of introducing a structured programme of rehabilitation for patients admitted to critical care . HighlightsThe introduction of an earlier and enhanced rehabilitation was feasible for patients ' ventilated ≥5 daysWhen introduced , patients were mobilised earlier and in a more acute phase of their illness , Earlier mobilisation led to patients achieving higher levels of mobility at the point of critical care dischargeThis positive impact was seen despite the previous successful implementation of a quality improvement project in the BACKGROUND muscle wasting is associated with a detrimental outcome in older people . Muscle strength measurements could be useful as part of a clinical evaluation of oldest old patients to determine who are most at risk of accelerated decline in the near future . OBJECTIVE this study aim ed to assess if h and grip strength predicts changes in functional , psychological and social health among oldest old . DESIGN the Leiden 85-plus Study is a prospect i ve population -based follow-up study . SUBJECTS five-hundred fifty-five , all aged 85 years at baseline , participated in the study . METHODS h and grip strength was measured with a h and grip strength dynamometer . Functional , psychological and social health were assessed annually . Baseline data on chronic diseases were obtained from the treating physician , pharmacist , electrocardiogram and blood sample analysis . RESULTS at age 85 , lower h and grip strength was correlated with poorer scores in functional , psychological and social health domains ( all , P < 0.001 ) . Lower baseline h and grip strength predicted an accelerated decline in activities of daily living ( ADL ) and cognition ( both , P < or= 0.001 ) , but not in social health ( P > 0.30 ) . CONCLUSION poor h and grip strength predicts accelerated dependency in ADL and cognitive decline in oldest old . Measuring h and grip strength could be a useful instrument in geriatric practice to identify those oldest old patients at risk for this accelerated decline BACKGROUND Immobilisation predicts adverse outcomes in patients in the surgical intensive care unit ( SICU ) . Attempts to mobilise critically ill patients early after surgery are frequently restricted , but we tested whether early mobilisation leads to improved mobility , decreased SICU length of stay , and increased functional independence of patients at hospital discharge . METHODS We did a multicentre , international , parallel-group , assessor-blinded , r and omised controlled trial in SICUs of five university hospitals in Austria ( n=1 ) , Germany ( n=1 ) , and the USA ( n=3 ) . Eligible patients ( aged 18 years or older , who had been mechanically ventilated for < 48 h , and were expected to require mechanical ventilation for ≥24 h ) were r and omly assigned ( 1:1 ) by use of a stratified block r and omisation via restricted web platform to st and ard of care ( control ) or early , goal -directed mobilisation using an inter-professional approach of closed-loop communication and the SICU optimal mobilisation score ( SOMS ) algorithm ( intervention ) , which describes patients ' mobilisation capacity on a numerical rating scale ranging from 0 ( no mobilisation ) to 4 ( ambulation ) . We had three main outcomes hierarchically tested in a prespecified order : the mean SOMS level patients achieved during their SICU stay ( primary outcome ) , and patient 's length of stay on SICU and the mini-modified functional independence measure score ( mmFIM ) at hospital discharge ( both secondary outcomes ) . This trial is registered with Clinical Trials.gov ( NCT01363102 ) . FINDINGS Between July 1 , 2011 , and Nov 4 , 2015 , we r and omly assigned 200 patients to receive st and ard treatment ( control ; n=96 ) or intervention ( n=104 ) . Intention-to-treat analysis showed that the intervention improved the mobilisation level ( mean achieved SOMS 2·2 [ SD 1·0 ] in intervention group vs 1·5 [ 0·8 ] in control group , p<0·0001 ) , decreased SICU length of stay ( mean 7 days [ SD 5 - 12 ] in intervention group vs 10 days [ 6 - 15 ] in control group , p=0·0054 ) , and improved functional mobility at hospital discharge ( mmFIM score 8 [ 4 - 8 ] in intervention group vs 5 [ 2 - 8 ] in control group , p=0·0002 ) . More adverse events were reported in the intervention group ( 25 cases [ 2·8 % ] ) than in the control group ( ten cases [ 0·8 % ] ) ; no serious adverse events were observed . Before hospital discharge 25 patients died ( 17 [ 16 % ] in the intervention group , eight [ 8 % ] in the control group ) . 3 months after hospital discharge 36 patients died ( 21 [ 22 % ] in the intervention group , 15 [ 17 % ] in the control group ) . INTERPRETATION Early , goal -directed mobilisation improved patient mobilisation throughout SICU admission , shortened patient length of stay in the SICU , and improved patients ' functional mobility at hospital discharge . FUNDING Jeffrey and Judy Buzen Purpose : To investigate whether passive tilting added to a st and ardized rehabilitation therapy improved strength at Intensive Care Unit ( ICU ) discharge . Material and methods : This single‐center trial included patients admitted to an adult surgical ICU and ventilated for at least 3 days . Patients were r and omized to daily st and ardized rehabilitation therapy alone or with tilting on a table for at least 1 h. The primary outcome was the Medical Research Council ( MRC ) sum score at ICU discharge . Muscular recovery was a secondary outcome . Results : Of 145 included patients , 125 received mobilization , 65 in the Tilt group and 60 in the Control group . Total mobilization duration ( median [ 25th–75th percentiles ] ) in the Tilt group was 1020 [ 580–1695 ] versus 1340 [ 536–2775 ] minutes in the Control group ( p = 0.313 ) . MRC sum scores at ICU discharge were not significantly different between groups ( Tilt , 50 [ 45–56 ] versus 48 [ 45–54 ] ; p = 0.555 ) . However , the number of patients with weakness was higher in the Tilt group at baseline ( Tilt : 60/65 versus 48/60 , p = 0.045 ) and muscular recovery was better in the Tilt group ( p = 0.004 ) . Conclusions : Passive tilting added to a st and ardized rehabilitation therapy did not improve muscle strength at ICU discharge in surgical patients even if a faster recovery with tilting is suggested . Clinical Trials.gov identifier : NCT02047617 . HIGHLIGHTSTilting intensive care unit patients has been advocated to minimize acute weaknessPassive tilting plus early physiotherapy was compared to physiotherapy aloneTilting added to early physiotherapy affords a faster recovery of muscle BACKGROUND : Chair-sitting may allow for more readily activated scalene , sternocleidomastoid , and parasternal intercostal muscles , and may raise and enlarge the upper thoracic cage , thereby allowing the thoracic cage to be more easily compressed . OBJECTIVE : To evaluate the effect of chair-sitting during exercise training on respiratory muscle function in mechanically ventilated patients . METHODS : We r and omized 16 patients to a control group and 18 patients to a chair-sitting group . The patients in the chair-sitting group were transferred by 2 intensive care unit nurses from bed to armchair and rested for at least 30 min , based on the individual patient 's tolerance . We measured heart rate , blood pressure , SpO2 , and respiratory rate . In the treatment group , before transferring the patient from bed to armchair , and 30 min after the completion of chair-sitting we measured respiratory muscle function variables , including the ratio of respiratory rate ( f ) to tidal volume ( VT ) , SpO2 , maximum inspiratory pressure ( PImax ) and maximum expiratory pressure ( PEmax ) . In the control patients we took those same measurements while the patient was in semirecumbent position , before and after treatments , for at least 6 days or until the patient was discharged from the intensive care unit or died . RESULTS : The 2 groups did not significantly differ in age , sex , or clinical outcomes . Respiratory rate , VT , f/VT , SpO2 , PImax , and PEmax were not significantly better in the chair-sitting group . The study period significantly improved respiratory rate , VT , PImax , and PEmax ( all P < .001 ) , but not f/VT . CONCLUSIONS : Six days of chair-sitting exercise training did not significantly improve respiratory muscle function in mechanically ventilated patients Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more OBJECTIVE To analyze the outcomes achieved by motor physical therapy in critically ill patients admitted to intensive care units . METHODS A systematic literature review was performed , and clinical trials published between 2002 and 2011 were included in the study . The search involved the LILACS , SciELO , MedLine , EMBASE and Cochrane data bases , using the keywords " intensive care unit " , " physiotherapy " , " physical therapy " , " mobility " , " mobilization " and " r and omized controlled trials . " Two research ers screened the articles independently and included works that addressed the effect of physical therapy on critically ill patients . RESULTS From an initial analysis of 67 potentially relevant articles , only 8 met the selection criteria and addressed the outcomes of electrostimulation , cycle ergometry and kinesiotherapy techniques . The sample sizes ranged from 8 to 101 subjects , with mean ages between 52 and 79 years . All patients were undergoing invasive mechanical ventilation . Among the analyzed articles , 6 reported significant benefits of motor physical therapy , such as improvement in peripheral muscle strength , respiratory capacity and functionality , in critically ill patients . CONCLUSION With this systematic review , it is possible to conclude that motor physical therapy is a feasible and safe therapy for critically ill patients and can minimize the deleterious effects of prolonged immobilization . Approaches involving electrostimulation , cycle ergometry and kinesiotherapy showed positive responses in patients under intensive care . Available evidence regarding the impact of motor physical therapy on length of stay in intensive care units and on mortality is still scarce , and further study in this area is warranted STUDY OBJECTIVE To compare the effects of active limb mobilization ( ALM ) with or without electrical stimulation ( ES ) on muscle strength , respiratory rate ( RR ) , heart rate , oxygen saturation , and time needed to transfer from bed to chair in two groups of patients with COPD . DESIGN R and omized , controlled study . SETTING Respiratory high-dependency care unit . PATIENTS Twenty-four bed-bound patients with chronic hypercapnic respiratory failure due to COPD who were receiving mechanical ventilation , with marked peripheral muscle hypotonia and atrophy . METHODS Patients were r and omly assigned either to ALM alone or to ALM plus ES ( ALM/ES ) . ES was applied using square-wave alternate , symmetric , and compensated impulses for 30 min bid . The duration of treatment was 28 days for all patients . RESULTS Muscle strength improved significantly in the overall group of patients ( from 1.75 + /- 0.73 to 3.44 + /- 0.65 , p < 0.05 ) . Comparing the change ( end minus beginning ) of the analyzed variables , ALM/ES significantly improved muscle strength ( 2.16 + /- 1.02 vs 1.25 + /- 0.75 , p = 0.02 ) and RR ( - 1.91 + /- 1.72 vs 0.41 + /- 1.88 , p = 0.004 ) , and decreased the number of days needed to transfer from bed to chair ( 10.75 + /- 2.41 days vs 14.33 + /- 2.53 days , p = 0.001 ) . CONCLUSION In bed-bound patients with COPD receiving mechanical ventilation , with marked peripheral muscle hypotonia and atrophy , application of ES in addition to classical ALM significantly improved muscle strength and decreased the number of days needed to transfer from bed to chair Background and Purpose . Patients requiring prolonged mechanical ventilation ( PMV ) are frequently deconditioned because of respiratory failure precipitated by the underlying disease , the adverse effects of medications , and a period of prolonged immobilization . The effects of 6 weeks of physical training on the strength of respiratory and limb muscles , on ventilator-free time , and on functional status in patients requiring PMV were examined . Subjects . Thirty-nine patients with PMV were initially enrolled in the study and were assigned to either a treatment group ( n=20 ) or a control group ( n=19 ) . Three subjects in the treatment group and 4 subjects in the control group died during the 6-week intervention period and thus their data were excluded from the final analysis . Methods . Subjects in the treatment group received physical training 5 days a week for 6 weeks . Strength of respiratory and limb muscles , ventilator-free time , and functional status , which was measured by the Barthel Index of Activities of Daily Living ( BI ) and Functional Independence Measure ( FIM ) , were examined at baseline and at the third and sixth weeks of the study period . Results . Respiratory and limb muscle strength improved significantly at the third and sixth weeks in the treatment group compared with baseline measurements . Total BI and FIM scores increased significantly in the treatment group and remained unchanged in the control group . Effect sizes of the BI and FIM scores were 2.02 and 1.93 , respectively , at the sixth week . Discussion and Conclusion . The results show that a 6-week physical training program may improve limb muscle strength and ventilator-free time and thus improve functional outcomes in patients requiring PMV Rationale Survivors of sepsis syndromes have poor outcomes for physical and cognitive function . No investigations of early physical rehabilitation in the intensive care unit have specifically targeted patients with sepsis syndromes . Objective To determine whether early physical rehabilitation improves physical function and associated outcomes in patients with sepsis syndromes . Methods Fifty critically ill adults admitted to a general intensive care unit with sepsis syndromes were recruited into a prospect i ve double-blinded r and omised controlled trial investigating early physical rehabilitation . Measurements Primary outcomes of physical function ( acute care index of function ) and self-reported health-related quality of life were recorded at ICU discharge and 6 months post-hospital discharge , respectively . Secondary measures included inflammatory biomarkers ; Interleukin-6 , Interleukin-10 and tumour necrosis factor-α , blood lactate , fat-free muscle mass , exercise capacity , muscle strength and anxiety . Main results A significant increase in patient self-reported physical function ( 81.8 ± 22.2 vs. 60.0 ± 29.4 ) , p = 0.04 ) and physical role ( 61.4 ± 43.8 vs. 17.1 ± 34.4 , p = 0.005 ) for the SF-36 at 6 months was found in the exercise group . Physical function scores were not significantly different between groups . Muscle strength scores were ( 51.9 ± 10.5 vs. 47.3 ± 13.6 , p = 0.24 ) with the st and ard care mean Medical Research Council Muscle Score ( MRC ) < 48/60 . The mean change of Interleukin-10 increased and was significantly higher in the exercise group ( 1.8 pg/ml , 180 % vs. 0.9 pg/ml , 90 % , p = 0.04 ) . There was no significant difference between groups for lactate , Interleukin-6 , tumour necrosis factor-α , muscle strength , exercise capacity , fat-free mass or hospital anxiety . Conclusion Implementation of early physical rehabilitation can improve self-reported physical function and induce systemic anti-inflammatory effects Acute myopathy is a cause of weakness and additional morbidity in a variety of critically ill patients , including transplant recipients . We report the incidence of and risk factors associated with acute myopathy after orthotopic liver transplantation ( OLTx ) . One hundred consecutive adult patients were prospect ively assessed for muscle weakness after OLTx . Electrodiagnostic studies and muscle biopsies were performed on consenting affected patients . Potential risk factors for myopathy were evaluated in patients with myopathy versus control subjects . Seven patients developed acute persistent weakness after OLTx . Electrodiagnostic studies were consistent with a necrotizing myopathy . Histopathologic evaluation in five revealed a necrotizing myopathy with loss of myosin thick filaments . A higher initial index of illness severity , dialysis requirement , and higher doses of glucocorticoids were associated with development of myopathy . Patients with myopathy subsequently remained in the intensive care unit ( ICU ) longer than unaffected patients . In conclusion , acute substantial weakness was a source of additional morbidity in 7 % of patients after OLTx . Most had myopathy with loss of myosin thick filaments . Patients with greater severity of illnesses and renal failure requiring dialysis were more likely to be affected . The effect of reducing exposure to corticosteroids in high-risk patients warrants further investigation Background : Poor muscular strength has been shown to be associated with increased morbidity and mortality in diverse sample s of middle-aged and elderly people . However , the oldest old population ( i.e. , over 85 years ) is underrepresented in such studies . Our objective was to assess the association between muscular strength and mortality in the oldest old population . Methods : We included 555 participants ( 65 % women ) from the Leiden 85-plus study , a prospect i ve population -based study of all 85-year-old inhabitants of Leiden , Netherl and s. We measured the h and grip strength of participants at baseline and again at age 89 years . We collected baseline data on comorbidities , functional status , levels of physical activity , and adjusted for potential confounders . During the follow-up period , we collected data on mortality . Results : During a follow-up period of 9.5 years ( range 8.5–10.5 years ) , 444 ( 80 % ) participants died . Risk for all-cause mortality was elevated among participants in the lowest tertile of h and grip strength at age 85 years ( hazard ratio [ HR ] 1.35 , 95 % confidence interval [ CI ] 1.00–1.82 , p = 0.047 ) and the lowest two tertiles of h and grip strength at age 89 years ( HR 2.04 , CI 1.24–3.35 , p = 0.005 and HR 1.73 , CI 1.11–2.70 , p = 0.016 ) . We also observed significantly increased mortality among participants in the tertile with the highest relative loss of h and grip strength over four years ( HR 1.72 , CI 1.07–2.77 , p = 0.026 ) . Interpretation : H and grip strength , a surrogate measurement of overall muscular strength , is a predictor of all-cause mortality in the oldest old population and may serve as a convenient tool for prognostication of mortality risk among elderly people OBJECTIVE Pulmonary rehabilitation has been shown to be of benefit to clinical ly stable patients with chronic obstructive pulmonary disease ( COPD ) . This study examined the effect of pulmonary rehabilitation on some physiologic variables in COPD patients recovering from an episode of acute respiratory failure . DESIGN A prospect i ve , r and omized study . SETTING A respiratory intensive care unit ( RICU ) . PATIENTS Eighty COPD patients recovering from an episode of acute respiratory failure were r and omized in a 3:1 fashion to receive stepwise pulmonary rehabilitation ( group A , n=60 patients ) or st and ard medical therapy ( group B , n=20 patients ) . MAIN OUTCOME MEASURES Improvements in exercise tolerance , sense of breathlessness , respiratory muscle function , and pulmonary function test values were measured , respectively , by exercise capacity ( 6-minute walking distance [ 6MWD ] ) , dyspnea score ( Visual Analog Scale [ VAS ] ) , maximal inspiratory pressure ( MIP ) , forced expiratory volume in 1 second ( FEV1 ) , and forced vital capacity ( FVC ) . INTERVENTIONS Group A received pulmonary rehabilitation that consisted of passive mobilization ( step I ) , early deambulation ( step II ) , respiratory and lower skeletal muscle training ( step III ) , and if the patients were able , complete lower extremity training on a treadmill ( step IV ) . Group B received st and ard medical therapy plus a basic deambulation program . RESULTS Sixty-one of 80 patients were mechanically ventilated at admission to the unit and most of them were bedridden . Twelve of the 60 group A patients and 4 of the 20 group B patients died during their RICU stay , and 9 patients required invasive mechanical ventilation at home after their discharge . The total length of RICU stay was 38+/-14 days for patients in group A versus 33.2+/-11 days for those in group B. Most patients from both groups regained the ability to walk , either unaided or aided . At discharge , 6 MWD results were significantly improved ( p < .001 ) in Group A only . MIP improved in Group A only ( p < .05 ) , while VAS scores improved in both groups , but the improvement was more marked in group A ( p < .001 ) than in group B ( p < .05 ) . CONCLUSIONS COPD patients who were admitted to a RICU in critical condition after an episode of acute respiratory failure and who , in most cases , required mechanical ventilation benefited from comprehensive early pulmonary rehabilitation , compared with patients who received st and ard medical therapy and progressive ambulation IMPORTANCE Physical rehabilitation in the intensive care unit ( ICU ) may improve the outcomes of patients with acute respiratory failure . OBJECTIVE To compare st and ardized rehabilitation therapy ( SRT ) to usual ICU care in acute respiratory failure . DESIGN , SETTING , AND PARTICIPANTS Single-center , r and omized clinical trial at Wake Forest Baptist Medical Center , North Carolina . Adult patients ( mean age , 58 years ; women , 55 % ) admitted to the ICU with acute respiratory failure requiring mechanical ventilation were r and omized to SRT ( n=150 ) or usual care ( n=150 ) from October 2009 through May 2014 with 6-month follow-up . INTERVENTIONS Patients in the SRT group received daily therapy until hospital discharge , consisting of passive range of motion , physical therapy , and progressive resistance exercise . The usual care group received weekday physical therapy when ordered by the clinical team . For the SRT group , the median ( interquartile range [ IQR ] ) days of delivery of therapy were 8.0 ( 5.0 - 14.0 ) for passive range of motion , 5.0 ( 3.0 - 8.0 ) for physical therapy , and 3.0 ( 1.0 - 5.0 ) for progressive resistance exercise . The median days of delivery of physical therapy for the usual care group was 1.0 ( IQR , 0.0 - 8.0 ) . MAIN OUTCOMES AND MEASURES Both groups underwent assessor-blinded testing at ICU and hospital discharge and at 2 , 4 , and 6 months . The primary outcome was hospital length of stay ( LOS ) . Secondary outcomes were ventilator days , ICU days , Short Physical Performance Battery ( SPPB ) score , 36-item Short-Form Health Surveys ( SF-36 ) for physical and mental health and physical function scale score , Functional Performance Inventory ( FPI ) score , Mini-Mental State Examination ( MMSE ) score , and h and grip and h and held dynamometer strength . RESULTS Among 300 r and omized patients , the median hospital LOS was 10 days ( IQR , 6 to 17 ) for the SRT group and 10 days ( IQR , 7 to 16 ) for the usual care group ( median difference , 0 [ 95 % CI , -1.5 to 3 ] , P = .41 ) . There was no difference in duration of ventilation or ICU care . There was no effect at 6 months for h and grip ( difference , 2.0 kg [ 95 % CI , -1.3 to 5.4 ] , P = .23 ) and h and held dynamometer strength ( difference , 0.4 lb [ 95 % CI , -2.9 to 3.7 ] , P = .82 ) , SF-36 physical health score ( difference , 3.4 [ 95 % CI , -0.02 to 7.0 ] , P = .05 ) , SF-36 mental health score ( difference , 2.4 [ 95 % CI , -1.2 to 6.0 ] , P = .19 ) , or MMSE score ( difference , 0.6 [ 95 % CI , -0.2 to 1.4 ] , P = .17 ) . There were higher scores at 6 months in the SRT group for the SPPB score ( difference , 1.1 [ 95 % CI , 0.04 to 2.1 , P = .04 ) , SF-36 physical function scale score ( difference , 12.2 [ 95 % CI , 3.8 to 20.7 ] , P = .001 ) , and the FPI score ( difference , 0.2 [ 95 % CI , 0.04 to 0.4 ] , P = .02 ) . CONCLUSIONS AND RELEVANCE Among patients hospitalized with acute respiratory failure , SRT compared with usual care did not decrease hospital LOS . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00976833 Objective : Survivors of severe critical illness frequently develop substantial and persistent physical complications , including muscle weakness , impaired physical function , and decreased health-related quality of life . Our objective was to determine the longitudinal epidemiology of muscle weakness , physical function , and health-related quality of life and their associations with critical illness and ICU exposures . Design : A multisite prospect i ve study with longitudinal follow-up at 3 , 6 , 12 , and 24 months after acute lung injury . Setting : Thirteen ICUs from four academic teaching hospitals . Patients : Two hundred twenty-two survivors of acute lung injury . Interventions : None . Measurements and Main Results : At each time point , patients underwent st and ardized clinical evaluations of extremity , h and grip , and respiratory muscle strength ; anthropometrics ( height , weight , mid-arm circumference , and triceps skin fold thickness ) ; 6-minute walk distance , and the Medical Outcomes Short-Form 36 health-related quality of life survey . During their hospitalization , survivors also had detailed daily evaluation of critical illness and related treatment variables . Over one third of survivors had objective evidence of muscle weakness at hospital discharge , with most improving within 12 months . This weakness was associated with substantial impairments in physical function and health-related quality of life that persisted at 24 months . The duration of bed rest during critical illness was consistently associated with weakness throughout 24-month follow-up . The cumulative dose of systematic corticosteroids and use of neuromuscular blockers in the ICU were not associated with weakness . Conclusions : Muscle weakness is common after acute lung injury , usually recovering within 12 months . This weakness is associated with substantial impairments in physical function and health-related quality of life that continue beyond 24 months . These results provide valuable prognostic information regarding physical recovery after acute lung injury . Evidence -based methods to reduce the duration of bed rest during critical illness may be important for improving these long-term impairments OBJECTIVE To evaluate the effects of an early mobilization protocol on respiratory and peripheral muscles in critically ill patients . METHODS A r and omized controlled clinical trial was conducted with 59 male and female patients on mechanical ventilation . The patients were divided into a conventional physical therapy group ( control group , n=14 ) that received the sector 's st and ard physical therapy program and an early mobilization group ( n=14 ) that received a systematic early mobilization protocol . Peripheral muscle strength was assessed with the Medical Research Council score , and respiratory muscle strength ( determined by the maximal inspiratory and expiratory pressures ) was measured using a vacuum manometer with a unidirectional valve . Systematic early mobilization was performed on five levels . RESULTS Significant increases were observed for values for maximal inspiratory pressure and the Medical Research Council score in the early mobilization group . However , no statistically significant improvement was observed for maximal expiratory pressure or MV duration ( days ) , length of stay in the intensive care unit ( days ) , and length of hospital stay ( days ) . CONCLUSION The early mobilization group showed gains in inspiratory and peripheral muscle strength BACKGROUND For patients in intensive care unit ( ICU ) , mechanical ventilation is an effective treatment to survive from acute illness and improve survival rates . However , long periods of bed rest and restricted physical activity can result in side effects . This study aim ed to investigate the feasibility of early rehabilitation therapy in patients with mechanical ventilation . METHODS A r and omized controlled trial was carried out . Sixty patients , with tracheal intubation or tracheostomy more than 48 hours and less than 72 hours , were admitted to the ICU of the Affiliated Hospital of Medical College , Qingdao University , from May 2010 to May 2012 . These patients were r and omly divided into a rehabilitation group and a control group . In the rehabilitation group , rehabilitation therapy was performed twice daily , and the training time and intensity were adjusted according to the condition of the patients . Early rehabilitation therapy included heading up actively , transferring from the supine position to sitting position , sitting at the edge of the bed , sitting in chair , transferring from sitting to st and ing , and ambulating bedside . The patient 's body mass index , days to first out of bed , duration of mechanical ventilation , length of ICU stay , APACHE II score , highest FiO2 , lowest PaO2/FiO2 and hospital mortality of patients were all compared between the rehabilitation group and the control group . The differences between the two groups were compared using Student 's t test . RESULTS There was no significant difference in body mass index , APACHE II score , highest FiO2 , lowest PaO2/FiO2 and hospital mortality between the rehabilitation group and the control group ( P>0.05 ) . Patients in the rehabilitation group had shorter days to first out of bed ( 3.8±1.2 d vs. 7.3±2.8 d ; P=0.00 ) , duration of mechanical ventilation ( 5.6±2.1 d vs. 12.7±4.1 d ; P=0.005 ) and length of ICU stay ( 12.7±4.1 d vs. 15.2±4.5 d ; P=0.01 ) compared with the control group . CONCLUSION Early rehabilitation therapy was feasible and effective in improving the outcomes of patients with mechanical ventilation CONTEXT Although electrophysiologic and histologic neuromuscular abnormalities are common in intensive care unit ( ICU ) patients , the clinical incidence of ICU-acquired neuromuscular disorders in patients recovering from severe illness remains unknown . OBJECTIVES To assess the clinical incidence , risk factors , and outcomes of ICU-acquired paresis ( ICUAP ) during recovery from critical illness in the ICU and to determine the electrophysiologic and histologic patterns in patients with ICUAP . DESIGN Prospect i ve cohort study conducted from March 1999 to June 2000 . SETTING Three medical and 2 surgical ICUs in 4 hospitals in France . PARTICIPANTS All consecutive ICU patients without preexisting neuromuscular disease who underwent mechanical ventilation for 7 or more days were screened daily for awakening . The first day a patient was considered awake was day 1 . Patients with severe muscle weakness on day 7 were considered to have ICUAP . MAIN OUTCOME MEASURES Incidence and duration of ICUAP , risk factors for ICUAP , and comparative duration of mechanical ventilation between ICUAP and control patients . RESULTS Among the 95 patients who achieved satisfactory awakening , the incidence of ICUAP was 25.3 % ( 95 % confidence interval [ CI ] , 16.9%-35.2 % ) . All ICUAP patients had a sensorimotor axonopathy , and all patients who underwent a muscle biopsy had specific muscle involvement not related to nerve involvement . The median duration of ICUAP after day 1 was 21 days . Mean ( SD ) duration of mechanical ventilation after day 1 was significantly longer in patients with ICUAP compared with those without ( 18.2 [ 36.3 ] vs 7.6 [ 19.2 ] days ; P = .03 ) . Independent predictors of ICUAP were female sex ( odds ratio [ OR ] , 4.66 ; 95 % CI , 1.19 - 18.30 ) , the number of days with dysfunction of 2 or more organs ( OR , 1.28 ; 95 % CI , 1.11 - 1.49 ) , duration of mechanical ventilation ( OR , 1.10 ; 95 % CI , 1.00 - 1.22 ) , and administration of corticosteroids ( OR , 14.90 ; 95 % CI , 3.20 - 69.80 ) before day 1 . CONCLUSIONS Identified using simple bedside clinical criteria , ICUAP was frequent during recovery from critical illness and was associated with a prolonged duration of mechanical ventilation . Our findings suggest an important role of corticosteroids in the development of ICUAP We investigated the effects of early rehabilitation therapy on prolonged mechanically ventilated patients after coronary artery bypass surgery (CABG).A total of 106 patients who underwent CABG between June 2012 and May 2015 were enrolled and r and omly assigned into an early rehabilitation group ( 53 cases ) and a control group ( 53 cases ) . The rehabilitation therapy consisted of 6 steps including head up , transferring from supination to sitting , sitting on the edge of bed , sitting in a chair , transferring from sitting to st and ing , and walking along a bed . The patients received rehabilitation therapy in the intensive care unit ( ICU ) after CABG in the early rehabilitation group . The control group patients received rehabilitation therapy after leaving the ICU.The results showed that the early rehabilitation therapy could significantly decrease the duration of mechanical ventilation ( early rehabilitation group : 8.1 ± 3.3 days ; control group : 13.9 ± 4.1 days , P < 0.01 ) , hospital stay ( early rehabilitation group : 22.0 ± 3.8 days ; control group : 29.1 ± 4.6 days , P < 0.01 ) , and ICU stay ( early rehabilitation group : 11.7 ± 3.2 days ; control group : 18.3 ± 4.2 days , P < 0.01 ) for patients requiring more than 72 hours prolonged mechanical ventilation . The results of Kaplan-Meier analysis showed that the proportions of patients remaining on mechanical ventilation in the early rehabilitation group were larger than that in the control group after 7 days of rehabilitation therapy ( logrank test : P < 0.01 ) . The results provide evidence for supporting the application of early rehabilitation therapy in patients requiring prolonged mechanical ventilation after CABG OBJECTIVE To vali date the feasibility and tolerance of an intensive rehabilitation protocol initiated during the postoperative period in an intensive care unit ( ICU ) in liver transplant recipients . DESIGN Prospect i ve r and omized study . SETTING ICU . PARTICIPANTS Liver transplant recipients over a period of 1 year ( N=40 ) . INTERVENTIONS The " usual treatment group " ( n=20 ) , which benefited from the usual treatment applied in the ICU ( based on physician prescription for the physiotherapist , with one session a day ) , and the experimental group ( n=20 ) , which followed a protocol of early and intensive rehabilitation ( based on a written protocol vali date d by physicians and an evaluation by physiotherapist , with 2 sessions a day ) , were compared . MAIN OUTCOME MEASURES Our primary aims were tolerance , assessed from the number of adverse events during rehabilitation sessions , and feasibility , assessed from the number of sessions discontinued . RESULTS The results revealed a small percentage of adverse events ( 1.5 % in the usual treatment group vs 1.06 % in the experimental group ) that were considered to be of low intensity . Patients in the experimental group sat on the edge of their beds sooner ( 2.6 vs 9.7d ; P=.048 ) and their intestinal transit resumed earlier ( 5.6 vs 3.7d ; P=.015 ) than patients in the usual treatment group . There was no significant difference between the 2 arms regarding length of stay ( LOS ) , despite a decrease in duration in the experimental group . CONCLUSIONS The introduction of an intensive early rehabilitation program for liver transplant recipients was well tolerated and feasible in the ICU . We noted that the different activities proposed were introduced sooner in the experimental group . Moreover , there is a tendency to decreased LOS in the ICU for the experimental group . These results now need to be confirmed by studies on a larger scale IMPORTANCE Survivors of critical illness demonstrate skeletal muscle wasting with associated functional impairment . OBJECTIVE To perform a comprehensive prospect i ve characterization of skeletal muscle wasting , defining the pathogenic roles of altered protein synthesis and breakdown . DESIGN , SETTING , AND PARTICIPANTS Sixty-three critically ill patients ( 59 % male ; mean age : 54.7 years [ 95 % CI , 50.0 - 59.6 years ] ) with an Acute Physiology and Chronic Health Evaluation II score of 23.5 ( 95 % CI , 21.9 - 25.2 ) were prospect ively recruited within 24 hours following intensive care unit ( ICU ) admission from August 2009 to April 2011 at a university teaching and a community hospital in Engl and . Patients were recruited if older than 18 years and were anticipated to be intubated for longer than 48 hours , to spend more than 7 days in critical care , and to survive ICU stay . MAIN OUTCOMES AND MEASURES Muscle loss was determined through serial ultrasound measurement of the rectus femoris cross-sectional area ( CSA ) on days 1 , 3 , 7 , and 10 . In a subset of patients , the fiber CSA area was quantified along with the ratio of protein to DNA on days 1 and 7 . Histopathological analysis was performed . In addition , muscle protein synthesis , breakdown rates , and respective signaling pathways were characterized . RESULTS There were significant reductions in the rectus femoris CSA observed at day 10 ( −17.7 % [ 95 % CI , −25.9 % to 8.1 % ] ; P < .001 ) . In the 28 patients assessed by all 3 measurement methods on days 1 and 7 , the rectus femoris CSA decreased by 10.3 % ( 95 % CI , 6.1 % to 14.5 % ) , the fiber CSA by 17.5 % ( 95 % CI , 5.8 % to 29.3 % ) , and the ratio of protein to DNA by 29.5 % ( 95 % CI , 13.4 % to 45.6 % ) . Decrease in the rectus femoris CSA was greater in patients who experienced multiorgan failure by day 7 ( −15.7 % ; 95 % CI , −27.7 % to 11.4 % ) compared with single organ failure ( −3.0 % ; 95 % CI , −5.3 % to 2.1 % ) ( P < .001 ) , even by day 3 ( −8.7 % [ 95 % CI , −59.3 % to 50.6 % ] vs −1.8 % [ 95 % CI , −12.3 % to 10.5 % ] , respectively ; P = .03 ) . Myofiber necrosis occurred in 20 of 37 patients ( 54.1 % ) . Protein synthesis measured by the muscle protein fractional synthetic rate was depressed in patients on day 1 ( 0.035%/hour ; 95 % CI , 0.023 % to 0.047%/hour ) compared with rates observed in fasted healthy controls ( 0.039%/hour ; 95 % CI , 0.029 % to 0.048%/hour ) ( P = .57 ) and increased by day 7 ( 0.076 % [ 95 % CI , 0.032%-0.120%/hour ] ; P = .03 ) to rates associated with fed controls ( 0.065%/hour [ 95 % CI , 0.049 % to 0.080%/hour ] ; P = .30 ) , independent of nutritional load . Leg protein breakdown remained elevated throughout the study ( 8.5 [ 95 % CI , 4.7 to 12.3 ] to 10.6 [ 95 % CI , 6.8 to 14.4 ] μmol of phenylalanine/min/ideal body weight × 100 ; P = .40 ) . The pattern of intracellular signaling supported increased breakdown ( n = 9 , r = −0.83 , P = .005 ) and decreased synthesis ( n = 9 , r = −0.69 , P = .04 ) . CONCLUSIONS AND RELEVANCE Among these critically ill patients , muscle wasting occurred early and rapidly during the first week of critical illness and was more severe among those with multiorgan failure compared with single organ failure . These findings may provide insights into skeletal muscle wasting in critical illness Objectives : As the catabolic state induced by septic shock together with the physical inactivity of patients lead to the rapid loss of muscle mass and impaired function , the purpose of this study was to test whether an early physical therapy during the onset of septic shock regulates catabolic signals and preserves skeletal muscle mass . Design : R and omized controlled trial . Setting : Tertiary mixed ICU . Patients : Adult patients admitted for septic shock within the first 72 hours . Interventions : Patients were assigned r and omly into two groups . The control group benefited from manual mobilization once a day . The intervention group had twice daily sessions of both manual mobilization and 30-minute passive/active cycling therapy . Measurements and Main Results : Skeletal muscle biopsies and electrophysiology testing were performed at day 1 and day 7 . Muscle biopsies were analyzed for histology and molecular components of signaling pathways regulating protein synthesis and degradation as well as inflammation markers . Hemodynamic values and patient perception were collected during each session . Twenty-one patients were included . Three died before the second muscle biopsy . Ten patients in the control and eight in the intervention group were analyzed . Markers of the catabolic ubiquitin-proteasome pathway , muscle atrophy F-box and muscle ring finger-1 messenger RNA , were reduced at day 7 only in the intervention group , but without difference between groups ( muscle atrophy F-box : –7.3 % ± 138.4 % in control vs –56.4 % ± 37.4 % in intervention group ; p = 0.23 and muscle ring finger-1 : –30.8 % ± 66.9 % in control vs –62.7 % ± 45.5 % in intervention group ; p = 0.15 ) . Muscle fiber cross-sectional area ( µm2 ) was preserved by exercise ( –25.8 % ± 21.6 % in control vs 12.4 % ± 22.5 % in intervention group ; p = 0.005 ) . Molecular regulations suggest that the excessive activation of autophagy due to septic shock was lower in the intervention group , without being suppressed . Markers of anabolism and inflammation were not modified by the intervention , which was well tolerated by the patients . Conclusions : Early physical therapy during the first week of septic shock is safe and preserves muscle fiber cross-sectional area Purpose : To compare the effects of adding a progressive multimodal rehabilitation program to usual care ( MRP + UC ) versus UC alone on 1 ) functional mobility , strength , endurance and 2 ) ventilator weaning and discharge status of patients with ICU‐acquired weakness ( ICUAW ) receiving prolonged mechanical ventilation ( PMV ) . Methods : R and omized pilot trial of an individualized MRP + UC versus UC in middle‐aged and older ICU survivors with ICUAW receiving PMV . Outcomes compare changes in strength , mobility , weaning success and discharge home from a long‐term acute care hospital ( LTACH ) between the groups . Results : Eighteen males and 14 females ( age 60.3 ± 11.9 years ) who received PMV for ≥14 days were enrolled . Despite no significant differences between groups in the changes in h and grip , gait speed , short physical performance battery or 6‐min walk distance after treatment , the MRP + UC group had greater weaning success ( 87 % vs. 41 % , p < 0.01 ) , and more patients discharged home than UC ( 53 vs. 12 % , p = 0.05 ) . Post hoc analyses , combining patients based on successful weaning or discharge home , demonstrated significant improvements in strength , ambulation and mobility . Conclusion : The addition of an MRP that improves strength , physical function and mobility to usual physical therapy in LTACH patients with ICUAW is associated with greater weaning success and discharge home than UC alone . HighlightsA multimodal rehabilitation program for ICU survivors is feasible and well tolerated . Adding a multimodal rehabilitation program to usual care results in improved clinical outcomes .Improvements in mobility are associated with successful weaning and discharge home Importance Early in-bed cycling and electrical muscle stimulation may improve the benefits of rehabilitation in patients in the intensive care unit ( ICU ) . Objective To investigate whether early in-bed leg cycling plus electrical stimulation of the quadriceps muscles added to st and ardized early rehabilitation would result in greater muscle strength at discharge from the ICU . Design , Setting , and Participants Single-center , r and omized clinical trial enrolling critically ill adult patients at 1 ICU within an 1100-bed hospital in France . Enrollment lasted from July 2014 to June 2016 and there was a 6-month follow-up , which ended on November 24 , 2016 . Interventions Patients were r and omized to early in-bed leg cycling plus electrical stimulation of the quadriceps muscles added to st and ardized early rehabilitation ( n = 159 ) or st and ardized early rehabilitation alone ( usual care ) ( n = 155 ) . Main Outcomes and Measures The primary outcome was muscle strength at discharge from the ICU assessed by physiotherapists blinded to treatment group using the Medical Research Council grading system ( score range , 0 - 60 points ; a higher score reflects better muscle strength ; minimal clinical ly important difference of 4 points ) . Secondary outcomes at ICU discharge included the number of ventilator-free days and ICU Mobility Scale score ( range , 0 - 10 ; a higher score reflects better walking capability ) . Functional autonomy and health-related quality of life were assessed at 6 months . Results Among 314 r and omized patients , 312 ( mean age , 66 years ; women , 36 % ; receiving mechanical ventilation at study inclusion , 78 % ) completed the study and were included in the analysis . The median global Medical Research Council score at ICU discharge was 48 ( interquartile range [ IQR ] , 29 to 58 ) in the intervention group and 51 ( IQR , 37 to 58 ) in the usual care group ( median difference , −3.0 [ 95 % CI , −7.0 to 2.8 ] ; P = .28 ) . The ICU Mobility Scale score at ICU discharge was 6 ( IQR , 3 to 9 ) in both groups ( median difference , 0 [ 95 % CI , −1 to 2 ] ; P = .52 ) . The median number of ventilator-free days at day 28 was 21 ( IQR , 6 to 25 ) in the intervention group and 22 ( IQR , 10 to 25 ) in the usual care group ( median difference , 1 [ 95 % CI , −2 to 3 ] ; P = .24 ) . Clinical ly significant events occurred during mobilization sessions in 7 patients ( 4.4 % ) in the intervention group and in 9 patients ( 5.8 % ) in the usual care group . There were no significant between-group differences in the outcomes assessed at 6 months . Conclusions and Relevance In this single-center r and omized clinical trial involving patients admitted to the ICU , adding early in-bed leg cycling exercises and electrical stimulation of the quadriceps muscles to a st and ardized early rehabilitation program did not improve global muscle strength at discharge from the ICU . Trial Registration Clinical Trials.gov Identifier : Purpose Abstract Muscle weakness in long-stay ICU patients contributes to 1-year mortality . Whether electrophysiological screening is an alternative diagnostic tool in unconscious/uncooperative patients remains unknown . We aim ed to determine the diagnostic properties of abnormal compound muscle action potential ( CMAP ) , sensory nerve action potential ( SNAP ) , and spontaneous electrical activity ( SEA ) for Medical Research Council (MRC)-defined weakness and their predictive value for 1-year mortality . Methods Data were prospect ively collected during the EPaNIC trial ( Clinical Trials.gov : NCT00512122 ) . First , sensitivity , specificity , positive ( PPV ) and negative predictive values ( NPV ) of abnormal CMAP , SNAP , and SEA for weakness were determined . Subsequently , association between 1-year mortality and abnormal findings on electrophysiological screening was assessed by univariate and multivariate analyses correcting for weakness and other risk factors and the prediction model involved only a development phase . Results A total of 730 patients were electrophysiologically screened of whom 432 were tested for weakness . On day 8 , normal CMAP excluded weakness with a high NPV ( 80.5 % ) . By day 15 , abnormal SNAP and the presence of SEA had a high PPV ( 91.7 and 80.0 % , respectively ) . Only a reduced CMAP on day 8 was associated with higher 1-year mortality [ 35.6 vs 15.2 % ( p < 0.001 ) ] . This association remained significant after correction for weakness and other risk factors [ OR 2.463 ( 95 % CI 1.113–5.452 ) , p = 0.026 ] . Also among conscious/cooperative patients without weakness , reduced CMAP was independently associated with a higher likelihood of death occurring during 1 year [ HR 2.818 ( 95 % CI 1.074–7.391 ) , p = 0.035 ] . Conclusions The diagnostic properties of electrophysiological screening vary over time . Abnormal CMAP documented early during critical illness carries information about longer-term outcome , which should be further investigated mechanistically Introduction Neuromuscular weakness result ing in severe functional impairment is common in critical care survivors . This study aim ed to evaluate effects of an early progressive rehabilitation intervention in mechanically ventilated adults at risk . Methods This was a parallel , two-arm , assessor-blinded , r and omised controlled trial with 6-months follow-up that was conducted in a mixed ICU of an academic centre in Switzerl and . Previously independent , mechanically ventilated , critically ill adults with expected critical care stay ≥72 hours ( n = 115 ) were r and omised to a control group receiving st and ard physiotherapy including early mobilisation or to an experimental group with early endurance and resistance training combined with mobilisation . Primary endpoints were functional capacity ( 6-Minute Walk Distance ) and functional independence ( Functional Independence Measure ) at hospital discharge . Secondary endpoints including muscle strength were assessed at critical care discharge . Safety was monitored closely by st and ard monitoring and predefined adverse events . Results Physiotherapy started within 48 hours of critical care admission while 97 % of participants were still ventilated and 68 % on inotropes . Compared to the control group ( n = 57 ) , the experimental group ( n = 58 ) received significantly more physiotherapy ( sessions : 407 vs 377 , p<0.001 ; time/session : 25min vs 18min , p<0.001 ) and had less days with sedation ( p<0.001 ) . Adverse events were rare ( 0.6 % ) and without consequences . There were no significant between-group differences in 6-Minute Walk Distance ( experimental 123 m ( IQR 25–280 ) vs control 100 m ( IQR 0–300 ) ; p = 0.542 ) or functional independence ( 98 ( IQR 66–119 ) vs 98 ( IQR 18–115 ) ; p = 0.308 ) . Likewise , no differences were found for the secondary outcomes , except a trend towards improved mental health in the experimental group after 6 months ( 84 ( IQR 68–88 ) vs 70 ( IQR 64–76 ) ; p = 0.023 ) . Conclusions Early endurance and resistance training in mechanically ventilated , intensive care patients does not improve functional capacity or independence at hospital discharge compared to early st and ard physiotherapy but may improve mental health 6-months after critical care discharge . Trial registration German Clinical Trials Register ( DRKS ) : DRKS00004347 , registered on 10 September 2012 Introduction Acute rehabilitation in critically ill patients can improve post-intensive care unit ( post-ICU ) physical function . In-bed cycling early in a patient ’s ICU stay is a promising intervention . The objective of this study was to determine the feasibility of recruitment , intervention delivery and retention in a multi centre r and omised clinical trial ( RCT ) of early in-bed cycling with mechanically ventilated ( MV ) patients . Methods We conducted a pilot RCT conducted in seven Canadian medical-surgical ICUs . We enrolled adults who could ambulate independently before ICU admission , within the first 4 days of invasive MV and first 7 days of ICU admission . Following informed consent , patients underwent concealed r and omisation to either 30 min/day of in-bed cycling and routine physiotherapy ( Cycling ) or routine physiotherapy alone ( Routine ) for 5 days/week , until ICU discharge . Our feasibility outcome targets included : accrual of 1–2 patients /month/site ; > 80 % cycling protocol delivery ; > 80 % outcomes measured and > 80 % blinded outcome measures at hospital discharge . We report ascertainment rates for our primary outcome for the main trial ( Physical Function ICU Test-scored ( PFIT-s ) at hospital discharge ) . Results Between 3/2015 and 6/2016 , we r and omised 66 patients ( 36 Cycling , 30 Routine ) . Our consent rate was 84.6 % ( 66/78 ) . Patient accrual was ( mean ( SD ) ) 1.1 ( 0.3 ) patients /month/site . Cycling occurred in 79.3 % ( 146/184 ) of eligible sessions , with a median ( IQR ) session duration of 30.5 ( 30.0 , 30.7 ) min . We recorded 43 ( 97.7 % ) PFIT-s scores at hospital discharge and 37 ( 86.0 % ) of these assessment s were blinded . Discussion Our pilot RCT suggests that a future multicentre RCT of early in-bed cycling for MV patients in the ICU is feasible . Trial registration number NCT02377830 Objectives : To determine if the early goal -directed mobilization intervention could be delivered to patients receiving mechanical ventilation with increased maximal levels of activity compared with st and ard care . Design : A pilot r and omized controlled trial . Setting : Five ICUs in Australia and New Zeal and . Participants : Fifty critically ill adults mechanically ventilated for greater than 24 hours . Intervention : Patients were r and omly assigned to either early goal -directed mobilization ( intervention ) or to st and ard care ( control ) . Early goal -directed mobilization comprised functional rehabilitation treatment conducted at the highest level of activity possible for that patient assessed by the ICU mobility scale while receiving mechanical ventilation . Measurements and Main Results : The ICU mobility scale , strength , ventilation duration , ICU and hospital length of stay , and total inpatient ( acute and rehabilitation ) stay as well as 6-month post-ICU discharge health-related quality of life , activities of daily living , and anxiety and depression were recorded . The mean age was 61 years and 60 % were men . The highest level of activity ( ICU mobility scale ) recorded during the ICU stay between the intervention and control groups was mean ( 95 % CI ) 7.3 ( 6.3–8.3 ) versus 5.9 ( 4.9–6.9 ) , p = 0.05 . The proportion of patients who walked in ICU was almost doubled with early goal -directed mobilization ( intervention n = 19 [ 66 % ] vs control n = 8 [ 38 % ] ; p = 0.05 ) . There was no difference in total inpatient stay ( d ) between the intervention versus control groups ( 20 [ 15–35 ] vs 34 [ 18–43 ] ; p = 0.37 ) . There were no adverse events . Conclusions : Key Practice Points : Delivery of early goal -directed mobilization within a r and omized controlled trial was feasible , safe and result ed in increased duration and level of active exercises PURPOSE To determine whether frailty can be measured within 4 days prior to hospital discharge in older intensive care unit ( ICU ) survivors of respiratory failure and whether it is associated with post-discharge disability and mortality . MATERIAL S AND METHODS We performed a single-center prospect i ve cohort study of 22 medical ICU survivors age 65 years or older who had received noninvasive or invasive mechanical ventilation for at least 24 hours . Frailty was defined as a score of ≥3 using Fried 's 5-point scale . We measured disability with the Katz Activities of Daily Living . We estimated unadjusted associations between Fried 's frailty score and incident disability at 1-month and 6-month mortality using Cox proportional hazard models . RESULTS The mean ( SD ) age was 77 ( 9 ) years , mean Acute Physiology and Chronic Health Evaluation II score was 27 ( 9.7 ) , mean frailty score was 3.4 ( 1.3 ) , and 18 ( 82 % ) were frail . Nine subjects ( 41 % ) died within 6 months , and all were frail . Each 1-point increase in frailty score was associated with a 90 % increased rate of incident disability at 1-month ( rate ratio : 1.9 , 95 % CI 0.7 - 4.9 ) and a threefold increase in 6-month mortality ( rate ratio : 3.0 , 95 % CI 1.4 - 6.3 ) . CONCLUSIONS Frailty can be measured in older ICU survivors near hospital discharge and is associated with 6-month mortality in unadjusted analysis . Larger studies to determine if frailty independently predicts outcomes are warranted RATIONALE ICU-acquired paresis ( ICUAP ) is common in survivors of critical illness . There is significant associated morbidity , including prolonged time on the ventilator and longer hospital stay . However , it is unclear whether ICUAP is independently associated with mortality , as sicker patients are more prone and existing studies have not adjusted for this . OBJECTIVES To test the hypothesis that ICUAP is independently associated with increased mortality . Secondarily , to determine if h and grip dynamometry is a concise measure of global strength and is independently associated with mortality . METHODS A prospect i ve multicenter cohort study was conducted in intensive care units ( ICU ) of five academic medical centers . Adults requiring at least 5 days of mechanical ventilation without evidence of preexisting neuromuscular disease were followed until awakening and were then examined for strength . MEASUREMENTS AND MAIN RESULTS We measured global strength and h and grip dynamometry . The primary outcome was in-hospital mortality and secondary outcomes were hospital and ICU-free days , ICU readmission , and recurrent respiratory failure . Subjects with ICUAP ( average MRC score of < 4 ) had longer hospital stays and required mechanical ventilation longer . H and grip strength was lower in subjects with ICUAP and had good test performance for diagnosing ICUAP . After adjustment for severity of illness , ICUAP was independently associated with hospital mortality ( odds ratio [ OR ] , 7.8 ; 95 % confidence interval [ CI ] , 2.4 - 25.3 ; P = 0.001 ) . Separately , h and grip strength was independently associated with hospital mortality ( OR , 4.5 ; 95 % CI , 1.5 - 13.6 ; P = 0.007 ) . CONCLUSIONS ICUAP is independently associated with increased hospital mortality . H and grip strength is also independently associated with poor hospital outcome and may serve as a simple test to identify ICUAP . Clinical trial registered with www . clinical trials.gov ( NCT00106665 ) RATIONALE Early physical therapy ( PT ) interventions may benefit patients with acute respiratory failure by preventing or attenuating neuromuscular weakness . However , the optimal dosage of these interventions is currently unknown . OBJECTIVES To determine whether an intensive PT program significantly improves long-term physical functional performance compared with a st and ard-of-care PT program . METHODS Patients who required mechanical ventilation for at least 4 days were eligible . Enrolled patients were r and omized to receive PT for up to 4 weeks delivered in an intensive or st and ard-of-care manner . Physical functional performance was assessed at 1 , 3 , and 6 months in survivors who were not currently in an acute or long-term care facility . The primary outcome was the Continuous Scale Physical Functional Performance Test short form ( CS-PFP-10 ) score at 1 month . MEASUREMENTS AND MAIN RESULTS A total of 120 patients were enrolled from five hospitals . Patients in the intensive PT group received 12.4 ± 6.5 sessions for a total of 408 ± 261 minutes compared with only 6.1 ± 3.8 sessions for 86 ± 63 minutes in the st and ard-of-care group ( P < 0.001 for both analyses ) . Physical function assessment s were available for 86 % of patients at 1 month , for 76 % at 3 months , and for 60 % at 6 months . In both groups , physical function was reduced yet significantly improved over time between 1 , 3 , and 6 months . When we compared the two interventions , we found no differences in the total CS-PFP-10 scores at all three time points ( P = 0.73 , 0.29 , and 0.43 , respectively ) or in the total CS-PFP-10 score trajectory ( P = 0.71 ) . CONCLUSIONS An intensive PT program did not improve long-term physical functional performance compared with a st and ard-of-care program . Clinical trial registered with www . clinical trials.gov ( NCT01058421 ) |
1,968 | 18,677,782 | This review indicates that participation in RCTs is associated with similar outcomes to receiving the same treatment outside RCTs . | BACKGROUND Some people believe that patients who take part in r and omised controlled trials ( RCTs ) face risks that they would not face if they opted for non-trial treatment .
Others think that trial participation is beneficial and the best way to ensure access to the most up-to- date physicians and treatments .
This is an up date d version of the original Cochrane review published in Issue 1 , 2005 .
OBJECTIVES To assess the effects of patient participation in RCTs ( ' trial effects ' ) independent both of the effects of the clinical treatments being compared ( ' treatment effects ' ) and any differences between patients who participated in RCTs and those who did not .
We aim ed to compare similar patients receiving similar treatment inside and outside of RCTs . | We did a prospect i ve study of women with singleton viable pregnancies at 10 - 13 weeks ' gestation who requested first-trimester fetal karyotyping because of advanced maternal age , parental anxiety , or family history of chromosomal abnormality . Women were counselled as to the available options of non-invasive screening or invasive testing by mid-trimester amniocentesis , early amniocentesis ( EA ) , or chorionic villus sampling ( CVS ) , or r and omisation to EA or CVS at 10 - 13 weeks . EA was done in 731 patients ( 493 by choice and 238 by r and omisation ) and CVS in 570 ( 320 by choice and 250 by r and omisation ) . Both procedures were done by transabdominal ultrasound-guided insertion of a 20-gauge needle . The rate of successful sampling was the same for both procedures ( 97.5 % ) . Spontaneous loss ( intrauterine or neonatal death ) was significantly higher after EA ( total group mean = 5.3 % , 95 % CI 3.8 - 7.2 ; r and omised subgroup mean = 5.9 % , 3.3 - 9.7 ) than after CVS ( total group : mean = 2.3 % , 1.2 - 3.9 ; r and omised subgroup : mean = 1.2 % , 0.3 - 3.5 ) . The gestation at delivery and birthweight of the infants after EA and CVS were similar . In the EA group the incidence of talipes equinovarus ( 1.63 % ) , was higher than in the CVS group ( 0.56 % ) , but this difference was not significant BACKGROUND Acute rejection episodes after renal transplantation are an important clinical challenge , despite use of multidrug immunosuppressive regimens . We did a prospect i ve , multicentre , r and omised , double-blind trial to investigate the impact of the addition of sirolimus , compared with azathioprine , to a cyclosporin and prednisone regimen . METHODS 719 recipients of primary HLA-mismatched cadaveric or living-donor renal allografts who displayed initial graft function were r and omly assigned , after transplantation , sirolimus 2 mg daily ( n=284 ) or 5 mg daily ( n=274 ) , or azathioprine ( n=161 ) . We assessed the primary composite endpoint of efficacy failure , occurrence of biopsy-confirmed acute rejection episodes , graft loss , or death , and various secondary endpoints that characterise these episodes at 6 months and 12 months . Analyses were done by intention to treat . FINDINGS The rate of efficacy failure at 6 months was lower in the two sirolimus groups ( 2 mg 18.7 % , p=0.002 ; 5 mg 16.8 % , p<0.001 ) than in the azathioprine group ( 32.3 % ) . The frequency of biopsy-confirmed acute rejection episodes was also lower ( 2 mg 16.9 % , p=0.002 ; 5 mg 12.0 % , p<0.001 ; azathioprine 29.8 % ) . At 12 months , survival was similar in all groups for grafts ( 97.2 % , 96.0 % , and 98.1 % ) and patients ( 94.7 % , 92.7 % , and 93.8 % ) . Patients on sirolimus showed a delay in the time to first acute rejection episode and decreased frequency of moderate and severe histological grade s of rejection episodes and related antibody treatment , compared with the azathioprine group . Rates of infection and malignant disorders were similar in all groups . INTERPRETATION Use of sirolimus reduced occurrence and severity of biopsy-confirmed acute rejection episodes with no increase in complications . Further studies are needed to establish the optimum doses for the combined regimen OBJECTIVES To compare the clinical - and cost-effectiveness of minimally invasive direct coronary artery bypass grafting ( MIDCAB ) and percutaneous transluminal coronary angioplasty ( PTCA ) with or without stenting in patients with single-vessel disease of the left anterior descending coronary artery ( LAD ) . DESIGN Multi-centre r and omised trial without blinding . The computer-generated sequence of r and omised assignments was stratified by centre , allocated participants in blocks and was concealed using a central ised telephone facility . SETTING Four tertiary cardiothoracic surgery centres in Engl and . PARTICIPANTS Patients with ischaemic heart disease with at least 50 % proximal stenosis of the LAD , suitable for either PTCA or MIDCAB , and with no significant disease in another vessel . INTERVENTIONS Patients r and omised to PTCA had local anaesthetic and underwent PTCA according to the method preferred by the operator carrying out the procedure . Patients r and omised to MIDCAB had general anaesthetic . The chest was opened through an 8 - 10-cm left anterior thoracotomy . The ribs were retracted and the left internal thoracic artery ( LITA ) harvested . The pericardium was opened in the line of the LAD to confirm the feasibility of operation . The distal LITA was anastomosed end-to-side to an arteriotomy in the LAD . All operators were experienced in carrying out MIDCAB . MAIN OUTCOME MEASURES The primary outcome measure was survival free from cardiac-related events . Relevant events were death , myocardial infa rct ion , repeat coronary revascularisation and recurrence of symptomatic angina or clinical signs of ischaemia during an exercise tolerance test at annual follow-up . Secondary outcome measures were complications , functional outcome , disease-specific and generic quality of life , health and social services re source use and their costs . RESULTS A total of 12,828 consecutive patients undergoing an angiogram were logged at participating centres from November 1999 to December 2001 . Of the 1091 patients with proximal stenosis of the LAD , 127 were eligible and consented to take part ; 100 were r and omised and the remaining 27 consented to follow-up . All r and omised participants were included in an intention-to-treat analysis of survival free from cardiac-related events , which found a non-significant benefit from MIDCAB . Cumulative hazard rates at 12 months were estimated to be 7.1 and 9.2 % for MIDCAB and PTCA , respectively . There were no important differences between MIDCAB and PTCA with respect to angina symptoms or disease-specific or generic quality of life . The total NHS procedure costs were 1648 British pounds and 946 British pounds for MIDCAB and PTCA , respectively . The costs of re sources used during 1 year of follow-up were 1033 British pounds and 843 British pounds , respectively . CONCLUSIONS The study found no evidence that MIDCAB was more effective than PTCA . The procedure costs of MIDCAB were observed to be considerably higher than those of PTCA . Given these findings , it is unlikely that MIDCAB represents a cost-effective use of re sources in the reference population . Recent advances in cardiac surgery mean that surgeons now tend to carry out off-pump bypass grafting via a sternotomy instead of MIDCAB . At the same time , cardiologists are treating more patients with multi-vessel disease by PTCA . Future primary research should focus on this comparison . Other small trials of PTCA versus MIDCAB have now finished and a more conclusive answer to the original objective could be provided by a systematic review The Emory Angioplasty versus Surgery Trial ( EAST ) showed that multivessel patients eligible for both percutaneous transluminal coronary angioplasty ( PTCA ) and coronary bypass surgery ( CABG ) had equivalent 3-year outcomes regarding survival , myocardial infa rct ion , and major myocardial ischemia . Patients eligible for the trial who were not r and omized because of physician or patient refusal were followed in a registry . This study compares the outcomes of the r and omized and registry patients . Of the 842 eligible patients , 450 did not enter the trial . Their baseline features closely resembled those of the r and omized patients and follow up was performed using the same methods . In the registry there was a bias toward selecting CABG in patients with 3-vessel disease ( 84 % ) and PTCA in patients with 2-vessel disease ( 54 % ) . Three-year survival for the registry patients was 96.4 % , which was better than the r and omized patients , 93.4 % ( p = 0.044 ) . Angina relief in the registry was equal for CABG and PTCA patients and was better for the PTCA registry ( 12.4 % ) than PTCA r and omized patients ( 19.6 % ) ( p = 0.079 ) . Thus , the registry confirms that EAST is representative of all eligible patients and does not represent a low-risk subgroup . Since baseline differences were small , improved survival in the registry may be due to treatment selection . Physician judgment , even in patients judged appropriate for clinical trials , remains a potentially important predictor of outcomes OBJECTIVES This study was done to compare characteristics and outcomes of patients with acute myocardial infa rct ion participating in two thrombolysis trials with those of nontrial patients at study hospitals and external hospitals . BACKGROUND Preferential recruitment of lower risk patients into r and omized trials of thrombolysis has been suggested by earlier studies . However , to date there has not been a definitive population -based comparison of characteristics and outcomes for thrombolysis trial participants and non participants . METHODS Population -based data on hospital admissions and mortality from acute myocardial infa rct ion for all hospitals in Ontario from 1989 to 1992 were linked to data on trial participants in two distinct thrombolysis studies ( GUSTO I and LATE ) . Included were 1,304 patients entered into GUSTO , 12,657 non participants at GUSTO hospitals , 249 patients entered into LATE , 5,997 non participants at LATE hospitals and 12,299 patients at external hospitals . The main outcomes were differences in age , gender , comorbidity scores , coronary revascularization and survival to hospital discharge . RESULTS Patients in both GUSTO and LATE were significantly more likely to be < 70 years old ( odds ratio [ OR ] 2.8 and 3.2 , respectively ) , to be male ( OR 2.0 and 2.1 , respectively ) , to have low comorbidity scores ( OR 2.0 and 2.3 , respectively ) and , for GUSTO alone , to undergo coronary revascularization ( OR 2.4 ) . Nontrial patients were similar between trial hospitals and external hospitals . In-hospital mortality rates for GUSTO and LATE patients were lower ( 6.9 % and 6.6 % , respectively ) than for non participants at study hospitals ( 16.8 % and 19.7 % , respectively ; p<0.001 for both comparisons ) . Survival to hospital discharge remained higher among GUSTO ( OR 1.9 ) and LATE patients ( OR 2.0 ) than non participants at study hospitals even after adjustment for age , gender , revascularization and comorbidity scores . CONCLUSIONS Compared with nontrial patients , thrombolysis trial participants are younger , more often male , undergo more revascularization and have less comorbid disease . Even after adjustment for these factors , participants have a survival advantage over non participants that is larger than expected from thrombolysis alone . These findings are not attributable to inferior care or skewed population s at hospitals that did not join these major trials . Further study of these selection biases may guide future trial design and deepen our underst and ing of why thrombolytics have been underused for high risk patients in routine practice The Coronary Artery Surgery Study ( CASS ) includes 780 patients with mild or moderate stable angina pectoris or asymptomatic survivors of a myocardial infa rct ion who were r and omized to either medical or surgical therapy and 1,319 patients who were eligible for r and omization but were not r and omized ( r and omizable patients ) . There were no substantial aggregate differences observed in any of the survival comparisons after 10 years of follow-up study between the r and omized and r and omizable patients assigned to the medical ( 79 % versus 80 % ) or surgical ( 82 % versus 81 % ) groups or in patient subgroups stratified according to coronary artery disease extent and left ventricular ejection fraction . Cox regression analyses were done with independent variables known to be predictors of survival , including surgical versus medical therapy and r and omized versus r and omizable group , to test the null hypothesis of a mortality difference between medical versus surgical assignment according to group assignment ( r and omized versus r and omizable ) . In no case did the initial group category enter as a significant predictor of survival . The results in the r and omizable group reinforce those in the r and omized group with respect to the medical versus surgical comparison . Two subgroups are identified with a significant surgical advantage : 1 ) patients with proximal left anterior descending coronary artery stenosis greater than or equal to 70 % and an ejection fraction less than 0.50 , and 2 ) patients with three vessel coronary artery disease and an ejection fraction less than 0.50 . In both groups , coronary bypass surgery had a statistically significant beneficial effect on survival ( p less than 0.05 ) . After a decade of follow-up , the CASS r and omizable patients confirm conclusions reached on the basis of the CASS r and omized trial Abstract The drop-out problem was studied in a r and omly selected population sample of men invited to a primary preventive trial against coronary heart disease among middle-aged men . Participants and non- participants in the intervention group were compared with regard to mortality , causes of death , autopsy findings , morbidity and sobriety . The non-participation group was characterized by a somewhat higher prevalence of chronic diseases and alcoholic problems . These features were more pronounced in subjects who died during the follow-up compared to still living subjects . Mortality , total as well as cause-specific , was considerably higher among non- participants . The death rate was higher in the non-participation group irrespective of duration of sick leave . The amount of coronary atherosclerosis , evaluated post-mortem , was essentially the same in those who died in the participation and non-participation groups . The difference in characteristics between participants and non- participants affects the possibilities of generalization to the total population under study . Similar differences between participants and non- participants are certainly present in other studies too Abstract Background : In the early 1980s breast preservation was a rarely applied therapeutic modality in the primary treatment of breast cancer in the Federal Republic of Germany . Reports coming from retrospective studies as well as preliminary results from r and omized trials made it desirable to introduce breast preservation in the form of a controlled clinical trial . Study design : In stage pT1 N0 M0 breast cancer , mastectomy as the st and ard treatment was to be compared with radiotherapy of the remaining breast tissue . The study design originally planned as a r and omized trial had to be changed into a prospect i ve observation study due to the low r and omization rate . Univariate analysis of prognostic variables was the first step to a valid treatment comparison . Those factors determined as being significant were included together with the treatment effects in a multivariate analysis . A high therapeutic st and ard was guaranteed by quality control . Results : 1036 out of 1119 recruited patients are evaluable . After a median follow-up of 48 months the following preliminary results can be reported . With the exception of death without recurrence from breast cancer , the 143 events are evenly distributed among the two treatment groups . Locoregional recurrence of the whole patient population was 5 % . Out of all prognostic factors examined only tumor size and grading are significant in regard to recurrent disease . Recurrence-free survival decreased in cases with ‘ uncertain ’ tumor margins , whereas the width of the margin had no influence on recurrent disease . There was no significant difference in quality of life between the two treatment groups . Conclusions : The four-year results of this study are in accordance with those of other breast preservation trials : There is no significant difference between the two treatment groups in the occurrence of locoregional failure . Incomplete tumorectomy has a negative influence on recurrence . Quality of life seems more dependent on the acceptance of the therapy by the patient than on the therapeutic modality itself . Breast preservation can also be performed appropriately in smaller institutions if the therapeutic st and ard is guaranteed by quality control BACKGROUND There is a mismatch between the wish of a patient with depression to have counselling and the prescription of antidepressants by the doctor . AIMS To determine whether counselling is as effective as antidepressants for depression in primary care and whether allowing patients to choose their treatment affects their response . METHOD A partially r and omised preference trial , with patients r and omised to either antidepressants or counselling or given their choice of either treatment . The treatment and follow-up were identical in the r and omised and patient preference arms . RESULTS There were 103 r and omised and 220 preference patients in the trial . We found : no differences in the baseline characteristics of the r and omised and preference groups ; that the two treatments were equally effective at 8 weeks , both for the r and omised group and when the r and omised and patient preference groups for a particular treatment were combined ; and that expressing a preference for either treatment conferred no additional benefit on outcome . CONCLUSIONS These data challenge several assumptions about the most appropriate treatment for depression in a primary care setting Patients who are treated within clinical trials may have a survival benefit dependent on being a trial participant . A number of factors may produce such beneficial outcome including more rigorous adherence to a peer review ed trial protocol , management by an experienced treatment team , being treated in a specialist centre etc . The current investigation compared patients treated on and off trial with the same st and ard arm treatment regimen . The results could then be interpreted without the confounding factors of differing treatment regimens , treatment teams or treatment hospitals . The results demonstrated given these circumstances that survival was no different for patients participating in a r and omised trial compared with a group of patients similarly treated who were not eligible for trial entry or who declined r and omisation . These results were obtained by the rigorous adherence to a defined protocol with the invaluable assistance of design ated lung cancer staff BACKGROUND Plantar fasciitis is a common foot disorder that may be resistant to nonoperative treatment . This study evaluated the use of electrohydraulic high-energy shock waves in patients who failed to respond to a minimum of six months of antecedent nonoperative treatment . METHODS A r and omized , placebo-controlled , multiply blinded , crossover study was conducted . Phase 1 consisted of twenty patients who were nonr and omized to treatment with extracorporeal shock waves to assess the phase-2 study protocol . In phase 2 , 293 patients were r and omized and an additional seventy-one patients were nonr and omized . Following ankle-block anesthesia , each patient received 100 grade d shocks starting at 0.12 to 0.22 mJ/mm(2 ) , followed by 1400 shocks at 0.22 mJ/mm(2 ) with use of a high-energy electrohydraulic shock-wave device . Patients in the placebo group received minimal subcutaneous anesthetic injections and nontransmitted shock waves by the same protocol . Three months later , patients were given the opportunity to continue without further treatment or have an additional treatment . This allowed a patient in the active treatment arm to receive a second treatment and a patient who received the placebo to cross over to the active treatment arm . Patients were followed at least one year after the final treatment . RESULTS Treatment was successful in seventeen of the twenty phase-1 patients at three months . This improved to nineteen ( 95 % ) of twenty patients at one year and was maintained at five years . In phase 2 , three months after treatment , sixty-seven ( 47 % ) of the 144 actively treated patients had a completely successful result compared with forty-two ( 30 % ) of the 141 placebo-treated patients ( p = 0.008 ) . At one year , sixty-five of the sixty-seven actively treated , r and omized patients maintained a successful result . Thirty-six ( 71 % ) of the remaining fifty-one nonr and omized patients had a successful result at three months . For all 289 patients who had one or more actual treatments , 222 ( 76.8 % ) had a good or excellent result . No patient was made worse by the procedure . CONCLUSIONS The application of electrohydraulic high-energy shock waves to the heel is a safe and effective noninvasive method to treat chronic plantar fasciitis , lasting up to and beyond one year Cocaine-abusing patients r and omly assigned to day-hospital or inpatient rehabilitation were compared with patients who self-selected these treatment setting s to examine differences in substance use and psychosocial outcomes under experimental and nonexperimental design s. There was little evidence of setting or assignment effects or Setting x Assignment interactions over the 12-month follow-up period . However , Assignment x Time interactions were obtained with 2 measures of cocaine use and measures of family-social and psychiatric problem severity . These interactions indicated greater problem severity at intake among the r and omized patients coupled with greater improvements by the 3-month follow-up relative to the nonr and omized patients . Findings suggest that r and omized studies of treatment for cocaine abuse may produce somewhat larger estimates of improvement than what is observed in more typical treatment situations PURPOSE To vali date a computerized expert system evaluating visual fields in a prospect i ve clinical trial , the Ischemic Optic Neuropathy Decompression Trial ( IONDT ) . To identify the pattern and within-pattern severity of field defects for study eyes at baseline and 6-month follow-up . DESIGN Humphrey visual field ( HVF ) change was used as the outcome measure for a prospect i ve , r and omized , multicenter trial to test the null hypothesis that optic nerve sheath decompression was ineffective in treating nonarteritic anterior ischemic optic neuropathy and to ascertain the natural history of the disease . METHODS An expert panel established criteria for the type and severity of visual field defects . Using these criteria , a rule-based computerized expert system interpreted HVF from baseline and 6-month visits for patients r and omized to surgery or careful follow-up and for patients who were not r and omized . RESULTS A computerized expert system was devised and vali date d. The system was then used to analyze HVFs . The pattern of defects found at baseline for patients r and omized to surgery did not differ from that of patients r and omized to careful follow-up . The most common pattern of defect was a superior and inferior arcuate with central scotoma for r and omized eyes ( 19.2 % ) and a superior and inferior arcuate for nonr and omized eyes ( 30.6 % ) . Field patterns at 6 months and baseline were not different . For r and omized study eyes , the superior altitudinal defects improved ( P = .03 ) , as did the inferior altitudinal defects ( P = .01 ) . For nonr and omized study eyes , only the inferior altitudinal defects improved ( P = .02 ) . No treatment effect was noted . CONCLUSIONS A novel rule-based expert system successfully interpreted visual field defects at baseline of eyes enrolled in the IONDT The objective was to study the generalizability of trial results by comparing r and omized patients to eligible but nonr and omized patients who received the same management . Implementation of trial results is only justifiable when the results can be generalized to the total domain population . The design was a multicentre r and omized controlled trial on the effect of early screening and treatment with ventilation tubes on infants with otitis media with effusion . R and omized ( n = 187 ) and nonr and omized eligible patients ( n = 133 ) were followed up . The study population comprised children who were detected by auditory screening at the age of 9 - 12 months and who were subsequently diagnosed with persistent bilateral otitis media with effusion for 4 - 6 months . A significant difference was found in the distribution of some prognostic factors : more r and omized children had older siblings , did not attend day care and had mothers with a lower educational level than the nonr and omized children . These factors , however , did not modify the outcome . No differences were found in mean hearing levels between the r and omized and nonr and omized children : in both the r and omized and nonr and omized children ventilation tubes improved the hearing level , especially after 6 months . However , in the long term ( 12 months ) , the hearing levels were equal again . The results of the r and omized and nonr and omized patients were comparable . The results of this trial appear to be generalizable to the total domain population . The procedure of following up both r and omized and nonr and omized patients is recommended when there is concern about selective participation and reduced generalizability PURPOSE This study was conducted to assess the comparative values of allogeneic bone marrow transplantation ( BMT ) and autologous bone marrow transplantation ( ABMT ) with sequential postremission chemotherapy ( SPC ) in children with acute myelogenous leukemia ( AML ) in first remission . PATIENTS AND METHODS From March 1987 to March 1990 , 161 assessable patients younger than 15 years of age with newly diagnosed AML were treated uniformly with two courses of daunorubicin and st and ard-dose cytarabine . After initial consolidation with a course of daunorubicin , cytarabine , and thioguanine ( DAT ) , patients in complete remission ( CR ) were r and omized to receive either ABMT or SPC , except for those with an HLA-matched sibling who were assigned to undergo BMT . SPC consisted of three additional courses of DAT , followed by three pairs of drugs administered sequentially for a total of six cycles . RESULTS Overall , 127 of 161 patients attained CR ( 79 % ) . The estimated probabilities of survival and event-free survival ( EFS ) at 5 years for all patients were 42 % and 25 % , respectively ( median follow-up , 28 months ) . For the 127 complete responders , the 5-year probability of disease-free survival ( DFS ) was 31 % , with a cumulative risk of relapse of 64 % . For the purpose of this study , all complete responders were evaluated for analysis of disease outcome according to the intent-to-treat principle , regardless of whether they actually received the intended therapy . The 5-year DFS was 51 % for the BMT group ( n = 24 ) , significantly higher ( P = .03 ) than that observed for the other cohorts : 21 % for ABMT ( n = 35 ) , 27 % for SPC ( n = 37 ) , and 34 % for a group of 31 nonr and omized ( NR ) patients . Bone marrow relapse was the most frequent cause of postremission failure in all therapeutic subgroups , including the BMT cohort , in which no deaths attributable to the toxicity of the procedure were recorded . CONCLUSION The results of this study show that BMT is more effective than ABMT or SPC in preventing leukemia relapse and extending DFS duration in children with AML in first remission This was a prospect i ve study in 1,492 women with singleton viable pregnancies undergoing chorion villus sampling ( CVS ) or early amniocentesis ( EA ) at 10 - 13 weeks of gestation because of advanced maternal age , parental anxiety or family history of chromosomal abnormality in the absence of parental chromosomal rearrangement . They were offered the option of having CVS or EA , or to be r and omised into one of the two tests . CVS was performed in 652 cases ( 375 by choice and 277 by r and omisation ) and EA was performed in 840 cases ( 562 by choice and 278 by r and omisation ) . Both procedures were carried out by transabdominal ultrasound-guided insertion of a needle ( 20 gauge ) using a free-h and technique . The two techniques were similar in providing a sample ( CVS 99.3 % , EA 100 % ) and in giving a non-mosaic cytogenetic result ( CVS 97.5 % , EA 97.9 % ) . Spontaneous loss ( intrauterine or neonatal death ) after EA ( total group 4.9 % , r and omised subgroup 5.8 % ) was significantly higher than after CVS ( total group 2.1 % , r and omised subgroup 1.8 % ; difference 2.8 % , 95 % CI 1.3 - 4.3 % , and difference 4 % , 95 % CI 1.3 - 6.7 % ) . The gestation at delivery and birth weight of the infants after EA and CVS were similar . In the EA group the incidence of talipes equinovarus ( 1.66 % ) was higher than in the CVS group ( 0.48 % ) , but this difference was not significant Background Laparoscopic cholecystectomy is now considered the first option for gallbladder surgery . However , 20 % to 30 % of cholecystectomies are completed as open operations often on elderly and fragile patients . The external validity of r and omised trials comparing mini-laparotomy cholecystectomy and laparoscopic cholecystectomy has not been studied . The aim of this study is to analyse characteristics , procedures , and outcomes for all patients who underwent cholecystectomy without being included in such a trial . Methods Characteristics ( age , sex , co-morbidity , and ASA-score ) , operation time , hospital stay , and mortality were compared for patients who underwent cholecystectomy outside and within a r and omised controlled trial comparing mini-laparotomy and laparoscopic cholecystectomy . Results During the inclusion period 1719 patients underwent cholecystectomy . 726 patients were r and omised and 724 of them completed the trial ; 993 patients underwent cholecystectomy outside the trial . The non-r and omised patients were older – and had more complications from gallstone disease , higher co-morbidity , and higher ASA – score when compared with trial patients . They were also more likely to undergo acute surgery and they had a longer postoperative hospital stay , with a median 3 versus 2 days ( p < 0.001 for all comparisons ) . St and ardised mortality ratio within 90 days of operation was 3.42 ( mean ) ( 95 % CI 2.17 to 5.13 ) for non-r and omised patients and 1.61 ( mean ) ( 95%CI 0.02 to 3.46 ) for trial patients . For non-r and omised patients , operation time did not differ significantly between mini-laparotomy and open cholecystectomy in multivariate analysis . However , the operation for laparoscopic cholecystectomy lasted 20 minutes longer than open cholecystectomy . Hospital stay was significantly shorter for both mini-laparotomy and laparoscopic cholecystectomy compared to open cholecystectomy . Conclusion Non-r and omised patients were older and more sick than trial patients . The assignment of healthier patients to trials comparing mini-laparotomy cholecystectomy and laparoscopic cholecystectomy limits the external validity of conclusions reached in such trials We studied the effects of enteral supplements on protein and energy intakes , body composition , energy expenditure , and gastrointestinal histology in 49 subjects with human immunodeficiency virus-associated weight loss ( 12.7 + /- 0.9 % of body wt ) . We also determined whether a stable-isotope mass spectrometric measurement at baseline might predict the short-term response of fat-free mass ( FFM ) measured by bioelectrical impedance analysis . Thirty-nine subjects completed the study after being r and omly assigned to receive either a whole-protein-based ( n = 22 ) or a peptide-based ( n = 17 ) formula . A nonsupplemented , nonr and omly assigned group ( n = 13 ) was followed concurrently . Both formulas were well tolerated . Voluntary intakes of energy and protein from nonsupplement sources decreased significantly during supplementation [ by 819 - 1638 kJ ( 196 - 382 kcal)/d and 5.6 - 14.4 g protein/d , respectively ; P < 0.01 ] but to a lesser extent than the intake from the supplement [ 2300 - 2510 kJ(550 - 600 kcal)/d and 19 - 28 g protein/d , respectively ] , so that net increases in intakes of protein and energy ( P < 0.03 ) , as well as of several vitamins and trace elements were increased . Nevertheless , the mean FFM did not increase for the group as a whole , although there was considerable interindividual heterogeneity . Changes in FFM at 6 wk were significantly inversely correlated ( r = 0.65 , P < 0.01 ) with baseline synthesis of fat ( de novo hepatic lipogenesis ) , but not with other potential measures of energy intake ( insulin-like growth factor 1 or its binding protein ) or inflammation ( soluble tumor necrosis factor receptors I or II ) . The prospect i ve identification of FFM response by measurement of de novo hepatic lipogenesis supported the hypothesis that the subset of wasting patients whose FFM is unresponsive to nutrient supplementation have altered nutrient metabolism HYPOTHESIS P53 and Ki-67 status will predict response to treatment , organ preservation , and survival in patients with advanced squamous cell cancers of the head and neck treated with chemoradiotherapy ( CRT ) . STUDY DESIGN Retrospective analysis of p53 and Ki-67 status from the CRT arm of a r and omized , controlled trial ( n = 50 ) and from patients receiving the same treatment but not enrolled in the trial ( n = 55 ) . METHODS P53 and Ki-67 status were established from archived tissue sample s using immunohistochemical ( IHC ) staining . Tumors were positive for p53 ( p53 + ) when more than 2 % of cells stained for p53 and were positive for Ki-67 ( Ki-67 + ) when any cell stained for Ki-67 . End points were tumor response , tumor recurrence , survival status , and organ preservation at last follow-up , and time to events . Predictive models were calculated for each outcome . RESULTS Neither marker predicted tumor response to treatment . P53 + status was associated with tumor recurrence ( P = .003 ) and locoregional recurrence ( P = .003 ) . Adjusting for time to event , p53 + status was significantly related to a lower recurrence-free survival ( P = .004 ) , lower disease-specific survival ( P = .04 ) , lower overall survival with primary site preservation ( P = .03 ) , and lower disease-specific survival with primary site preservation ( P = .003 ) . Multivariate analysis revealed that p53 + status was significantly related to a lower recurrence-free survival ( P = .01 , risk ratio [ RR ] = 3.65 ) and lower disease-specific survival with organ preservation ( P = .02 , RR = 3.41 ) . Ki-67 + status was not related to any variables . However , multivariate analysis revealed that Ki-67 + was significantly related to a lower overall survival ( P = .05 , RR = 2.03 ) . The combination of both markers negative ( p53-/Ki-67- ) was associated with a lower incidence of tumor recurrence ( P = .02 ) , lower locoregional recurrence ( P = .01 ) , and fewer second primary lesions ( P = .04 ) . Adjusting for time to event , p53-/Ki-67- status was significantly related to a higher recurrence-free survival ( P = .02 ) , higher disease-specific survival with primary site preservation ( P = .02 ) , and higher overall survival with primary site preservation ( P = .02 ) . Multivariate analysis revealed that p53-/Ki-67- status was significantly related to a higher overall survival with site preservation ( P = .01 , RR = 2.78 ) . CONCLUSIONS P53 and Ki-67 status appear to be related to the various survival end points considered in this study . However , this relation does not seem to be sufficient to warrant treatment modifications . Closer follow-up may be justified in both p53 + and Ki67 + patients to detect recurrence or a second primary at an earlier stage , possibly improving survival Background . Sirolimus ( Rapamune ; SRL ) in combination with cyclosporine ( CsA ) reduces the incidence of acute rejection episodes in renal allograft recipients . This study evaluated whether renal function could be improved by elimination of CsA from an SRL-based regimen . Methods . This phase 2 , open-label , controlled , r and omized study was conducted at 17 centers in the United States and Europe . Two hundred forty-six first cadaveric renal allograft recipients were enrolled , and 197 were r and omized to full-dose CsA ( microemulsion ) plus fixed-dose SRL ( 2 mg/day ; group A , n=97 ) or reduced-dose CsA plus concentration-controlled SRL ( troughs 10–20 ng/mL ; group B , n=100 ) . Most patients with acute tubular necrosis-delayed graft function that resolved later than posttransplantation day 7 were not r and omized but were assigned to a third group ( nonr and omized , n=49 ) and received up to 5 mg per day of SRL as part of their individualized treatment regimen . All patients received st and ard doses of corticosteroids . At the end of posttransplantation month 2 , eligible patients ( those not treated for rejection within 3 weeks ) in group B had CsA tapered and eliminated over the subsequent 4 to 6 weeks . Results . At 12 months after transplantation , renal function was significantly better in the CsA-elimination arm . In patients who were on therapy and who had not experienced an acute rejection episode before month 6 , serum creatinine level was significantly lower ( 1.38 mg/dL vs. 1.82 mg/dL , P < 0.001 ) and calculated glomerular filtration rate ( Nankivell method ) was significantly higher ( 73.5 mL/min vs. 57.1 mL/min , P < 0.001 ) in group B than in group A. In the intention-to-treat population , rates of biopsy-confirmed acute rejection at 12 months were similar between groups A and B ( 18.6 % vs. 22.0 % , respectively;P = 0.598 ) . In addition , graft survival ( 92.8 % and 95.0 % ) and patient survival ( 96.9 % and 96.0 % ) rates at 12 months were not significantly different between groups A and B , respectively . Furthermore , there were no significant differences between black and nonblack recipients within treatment groups in terms of rejection rates and graft survival at 12 months . Black recipients in group B had better serum creatinine levels at 12 months compared with black recipients in group A ( 1.55 mg/dL vs. 2.69 mg/dL , respectively , P = 0.011 ) , as did nonblack recipients in group B compared with nonblack recipients in group A ( 1.53 mg/dL vs. 1.75 mg/dL , respectively , P = 0.055 ) . Black patients in group A had higher mean serum creatinine levels ( 2.69 mg/dL ) than nonblack patients in group A ( 1.75 mg/dL , P = 0.028 ) . Hypertension , edema , hypomagnesemia , and dyspnea were reported significantly less frequently in patients r and omly assigned to undergo CsA elimination compared with patients in group A ( P < 0.05 ) ; group B patients had a significantly greater ( P < 0.05 ) incidence of abnormal liver function tests , diarrhea , hypokalemia , and thrombocytopenia . Conclusion . Concentration-controlled SRL with early elimination of CsA is safe and results in improved renal function . Reduced exposure to CsA does not result in a clinical ly significant increase in the incidence of acute rejection episodes . This is true for both black and nonblack recipients . SRL may be used to reduce the exposure of renal allograft recipients to the nephrotoxic effects of & NA ; Acupuncture is widely used by patients with neck pain , but there is a lack of information about its effectiveness in routine medical care . The aim was to investigate the effectiveness of acupuncture in addition to routine care in patients with chronic neck pain compared to treatment with routine care alone . We performed a r and omized controlled multicentre trial plus non‐r and omized cohort in general practice s in Germany . 14,161 patients with chronic neck pain ( duration > 6 months ) . Patients were r and omly allocated to an acupuncture group or a control group receiving no acupuncture . Patients in the acupuncture group received up to 15 acupuncture sessions over three months . Patients who did not consent to r and omization received acupuncture treatment . All subjects were allowed to receive usual medical care in addition to study treatment . Neck pain and disability ( NPAD Scale by Wheeler ) after three months . Of 14,161 patients ( mean age 50.9 ± 13.1 years , 68 % female ) 1880 were r and omized to acupuncture and 1886 to control , and 10,395 included into the non‐r and omized acupuncture group . At three months , neck pain and disability improved by 16.2 ( SE : 0.4 ) to 38.3 ( SE : 0.4 ) ; and by 3.9 ( SE : 0.4 ) to 50.5 ( SE : 0.4 ) , difference 12.3 ( p < 0.001 ) in the acupuncture and control group , respectively . Treatment success was essentially maintained through six months . Non‐r and omized patients had more severe symptoms at baseline and showed higher neck pain and disability improvement compared to r and omized patients . Treatment with acupuncture added to routine care in patients with chronic neck pain was associated with improvements in neck pain and disability compared to treatment with routine care alone OBJECTIVE To compare the cost-effectiveness of generic psychological therapy ( counseling ) with routinely prescribed antidepressant drugs in a naturalistic general practice setting for a follow-up period of 12 months . METHODS Economic analysis alongside a r and omized clinical trial with patient preference arm . Comparison of depression-related health service costs at 12 months . Cost-effectiveness analysis of bootstrapped trial data using net monetary benefits and acceptability curves . RESULTS No significant difference between the mean observed costs of patients r and omized to antidepressants or to counseling ( 342 pounds sterling vs 302 pounds sterling , p = .56 [ t test ] ) . If decision makers are not willing to pay more for additional benefits ( value placed on extra patient with good outcome , denoted by K , is zero ) , then we find little difference between the treatment modalities in terms of cost-effectiveness . If decision makers do place value on additional benefit ( K > 0 pounds sterling ) , then the antidepressant group becomes more likely to be cost-effective . This likelihood is in excess of 90 % where decision makers are prepared to pay an additional 2,000 pounds sterling or more per additional patient with a good global outcome . The mean values for incremental net monetary benefits ( INMB ) from antidepressants are substantial for higher values of K ( INMB = 406 pounds sterling when K = 2,500 pounds sterling ) . CONCLUSION For a small proportion of patients , the counseling intervention ( as specified in this trial ) is a dominant cost-effective strategy . For a larger proportion of patients , the antidepressant intervention ( as specified in this trial ) is the dominant cost-effective strategy . For the remaining group of patients , cost-effectiveness depends on the value of K. Since we can not observe K , acceptability curves are a useful way to inform decision makers PURPOSE To report mortality of patients who were eligible for enrollment in the Collaborative Ocular Melanoma Study ( COMS ) clinical trials of medium-sized choroidal melanoma or large-sized choroidal melanoma but chose to defer treatment or receive no melanoma treatment . DESIGN Prospect i ve nonr and omized multicenter cohort study as an adjunct to the COMS r and omized clinical trials . METHODS Patient follow-up procedures included examinations , correspondence , telephone contacts , and National Death Index search es . Primary outcome was patient death measured by all-cause mortality . Secondary outcomes were melanoma treatment and melanoma metastasis . RESULTS Of 77 patients eligible for the COMS clinical trials who chose to defer or receive no melanoma treatment , 61 were appropriate c and i date s and 45 ( 74 % ) enrolled in the natural history study . Forty-two patients ( 42 eyes ) had medium melanoma , and median follow-up was 5.3 years ( range , 4 - 10.7 years ) . Twenty-two patients ( 52 % ) had subsequent melanoma treatment , and 20 ( 48 % ) had no melanoma treatment . For the 42 patients , the Kaplan-Meier estimate of 5-year mortality was approximately 30 % ( 95 % confidence interval [ CI ] , 18%-47 % ) . For the COMS medium melanoma trial , 5-year mortality was 18 % ( 95 % CI , 16 % -20 % ) , not statistically significantly different from the natural history study patients . After adjusting for differences in age and longest basal diameter , the 5-year risk of death for natural history study patients vs COMS trial patients was 1.54 ( 95 % CI , 0.93 - 2.56 ) . Three patients had large melanoma . Melanoma metastasis was confirmed or suspected in eight ( 42 % ) of 19 deaths . CONCLUSION Greater mortality and higher risk of death for natural history study patients are probative but not conclusive evidence of a beneficial , life-extending effect of medium melanoma treatment BACKGROUND Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome . We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients . METHODS Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter , r and omized trial . The trial compared traditional ventilation treatment , which involved an initial tidal volume of 12 ml per kilogram of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration ( plateau pressure ) of 50 cm of water or less , with ventilation with a lower tidal volume , which involved an initial tidal volume of 6 ml per kilogram of predicted body weight and a plateau pressure of 30 cm of water or less . The primary outcomes were death before a patient was discharged home and was breathing without assistance and the number of days without ventilator use from day 1 to day 28 . RESULTS The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes ( 31.0 percent vs. 39.8 percent , P=0.007 ) , and the number of days without ventilator use during the first 28 days after r and omization was greater in this group ( mean [ + /-SD ] , 12+/-11 vs. 10+/-11 ; P=0.007 ) . The mean tidal volumes on days 1 to 3 were 6.2+/-0.8 and 11.8+/-0.8 ml per kilogram of predicted body weight ( P<0.001 ) , respectively , and the mean plateau pressures were 25+/-6 and 33+/-8 cm of water ( P<0.001 ) , respectively . CONCLUSIONS In patients with acute lung injury and the acute respiratory distress syndrome , mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use Although subjects r and omized into clinical trials tend to have different mortality experiences from those not r and omized , few studies have examined how baseline characteristics may explain these differences . We used the recruitment experience of the Physicians ' Health Study ( PHS ) to describe and compare subgroups of subjects ultimately r and omized - or not - into the PHS . A total of 112528 male physicians ages 40 - 84 years responded to letters of invitation and baseline question naires sent to 261248 subjects . Baseline information was collected on eligibility criteria , plus lifestyle and clinical risk factors . Total , cardiovascular , cancer , and other mortality were determined through the National Death Index after a mean follow-up of 5.39 years . Respondents had 19 and 19 % lower total and cardiovascular mortality rates than nonrespondents . Similarly , willing respondents were 19 and 16 % less likely to die than unwilling respondents . However , much of this difference in mortality was explained by disease and lifestyle factors . Respondents who were eligible for the PHS had significantly lower age-adjusted relative risks ( RRs ) that were attenuated but remained substantially below 1 upon multivariate adjustment in models for total ( RRs from 0.48 to 0.79 ) , cardiovascular ( from 0.40 to 0.85 ) , and cancer mortality ( from 0.55 to 0.87 ) . Finally , a nearly halving in the age-adjusted risk of total and cause-specific mortality among men completing a run-in and r and omized into PHS compared with those not r and omized was nominally altered upon adding all covariates into multivariate models . In conclusion , a difference in mortality rates according to willingness to participate in a trial was explained by disease and lifestyle factors . In contrast , diseases and risk factors explain some , but not all , of the lower mortality rates of physicians based on eligibility status and their ability to complete a run-in phase The use of disodium ethane-1 hydroxy-1 , 1-diphosphonate ( EHDP ) therapy for Paget 's disease of bone was examined in 75 affected patients . Forty-eight patients received r and omly assigned oral doses of either 0 , 2.5 , 5 , 10 , or 20 mg/kg/day in a controlled , double-blind protocol , and the remainder received either 10 or 20 mg/kg/day in a non-r and om protocol . The clinical status of the patients and appropriate laboratory tests were evaluated before treatment and at frequent intervals during a six-month period of initial therapy . There were no significant changes in either urinary hydroxyproline or serum alkaline phosphatase in those patients receiving placebos , while both these parameters decreased significantly at all dose levels of EHDP , with the greatest decline noted in the highest dose group . However , statistical analysis of the data related to changes in symptoms in the double-blind study revealed that patients receiving the higher dose of EHDP ( 10 or 20 mg/kg/day ) had less favorable outcomes than those receiving the lower doses ( 2.5 or 5 mg/kg/day ) . The high does group had a relatively lower rate of symptom improvement and a relatively greater rate of deterioration than did the low dose group . Twenty-one of forty-nine patients followed for at least 18 months have shown a sustained suppression of their serum alkaline phosphatase and urinary hydroxyproline values for 12 months following cessation of EHDP , while therapy has been reinstituted for the other 28 patients because of increases in these measurements , with or without accompanying symptomatic deterioration . Eight patients sustained fractures through Pagetic bone during the period of study and all of these were treated with higher doses of EHDP . On the basis of the biochemical and clinical data in this study it appears that initial therapy of Paget 's disease of bone with 5 mg EHDP/kg/day maximizes benefits while minimizing possible adverse effects PURPOSE A German multicenter r and omized trial ( ARO 95 - 6 ) compared hyperfractionated accelerated radiotherapy ( RT ) alone ( to a total radiation dose of 77.6 Gy ) with hyperfractionated accelerated radiochemotherapy ( to 70.6 Gy ) using concurrent mitomycin C and 5-fluorouracil . We analyzed the baseline patient characteristics and the influence of physician selection bias on treatment outcome for patients who were and were not enrolled in the r and omized Phase III trial , with the therapies administered according to the trial protocol s. METHODS AND MATERIAL S Between February 1996 and May 2000 at Tübingen University , 42 on- study patients and 41 off- study patients with Stage III-IV nonmetastatic squamous cell carcinoma of the head and neck were treated . The median follow-up for patients at risk ( living at last evaluation ) was 44 months , with a minimal follow-up of 2 years . RESULTS The 4-year rate of overall survival , disease-specific survival , and locoregional tumor control was 25 % , 40 % , and 54 % , respectively , for all 83 patients . Among patients enrolled in the study , the 4-year rate of overall survival for those receiving accelerated hyperfractionated radiochemotherapy was 33 % , and that for patients receiving accelerated hyperfractionated RT alone was 18 % ( p = 0.25 ) ; among off- study patients , the comparable rates were 48 % and 0 % ( p = 0.004 ) . The 4-year rate of disease-specific survival among on- study patients receiving radiochemotherapy and RT alone was 41 % and 36 % , respectively ( p = 0.5 ) ; among off- study patients the respective rates were 58 % and 0 % ( p = 0.2 ) . The rate of 4-year locoregional tumor control associated with radiochemotherapy and RT , respectively , was 51 % and 54 % among on- study patients and 72 % and 23 % among off- study patients ( p = 0.08 ) . CONCLUSION Patients with advanced head- and -neck cancer who were entered into the r and omized trial did not have statistically significantly different survival than patients treated according to the same protocol but outside the trial . Also , outside the trial , the physicians ' selection bias in determining which patient received which treatment showed a much greater benefit from combined modality treatment than that found in the r and omized trial A multicenter , prospect i ve r and omized trial was conducted to determine if the addition of rifampin to a combination therapy of an antipseudomonal beta-lactam agent and aminoglycoside improves the outcome of patients with Pseudomonas aeruginosa bacteremia . The Zelen protocol for r and omized-consent design was used . Consent was sought only from patients r and omized to the experimental therapy ( rifampin+ ) . If the experimental therapy was refused , the patient would then receive the st and ard combination therapy ( control ) ; however , when outcome was evaluated , all patients r and omized to the rifampin+ group , including those that declined rifampin , were compared with the control group . One hundred twenty-one consecutive hospitalized patients with positive blood cultures for P. aeruginosa were enrolled . Entry was stratified for prior use of empiric antipseudomonal antibiotics , neutropenia , severity of illness , and presence of pneumonia . Fifty-eight patients were r and omized to receive rifampin ( 600 mg orally every 8 h for the first 72 h and then every 12 h for a total of 10 days ) plus a beta-lactam agent plus an aminoglycoside . Sixty-three received the st and ard therapy of a beta-lactam plus an aminoglycoside agent ( control ) . Bacteriologic cure occurred significantly more frequently in patients r and omized to the rifampin+ regimen . Breakthrough or relapsing bacteremias occurred in 2 % of the three-drug ( rifampin+ ) group , compared with 14 % for the two-drug ( st and ard therapy ) group . Despite this favorable trend in bacteriological response , no significant differences in survival were seen for the two treatment groups . Rifamycin derivatives warrant further clinical study as antipseudomonal agents . The Zelen protocol appears well suited for comparative trials of antimicrobial agents Background The objective of this report is to describe the methods used to develop and vali date a computerized system to analyze Humphrey visual fields obtained from patients with non-arteritic anterior ischemic optic neuropathy ( NAION ) and enrolled in the Ischemic Optic Neuropathy Decompression Trial ( IONDT ) . The IONDT was a multicenter study that included r and omized and non-r and omized patients with newly diagnosed NAION in the study eye . At baseline , r and omized eyes had visual acuity of 20/64 or worse and non-r and omized eyes had visual acuity of better than 20/64 or were associated with patients refusing r and omization . Visual fields were measured before treatment using the Humphrey Field Analyzer with the 24 - 2 program , foveal threshold , and size III stimulus . Methods We used visual fields from 189 non-IONDT eyes with NAION to develop the computerized classification system . Six neuro-ophthalmologists ( " expert panel " ) described definitions for visual field patterns defects using 19 visual fields representing a range of pattern defect types . The expert panel then used 120 visual fields , classified using these definitions , to refine the rules , generating revised definitions for 13 visual field pattern defects and 3 levels of severity . These definitions were incorporated into a rule-based computerized classification system run on Excel ® software . The computerized classification system was used to categorize visual field defects for an additional 95 NAION visual fields , and the expert panel was asked to independently classify the new fields and subsequently whether they agreed with the computer classification . To account for test variability over time , we derived an adjustment factor from the pooled short term fluctuation . We examined change in defects with and without adjustment in visual fields of study participants who demonstrated a visual acuity decrease within 30 days of NAION onset ( progressive NAION ) . Results Despite an agreed upon set of rules , there was not good agreement among the expert panel when their independent visual classifications were compared . A majority did concur with the computer classification for 91 of 95 visual fields . Remaining classification discrepancies could not be resolved without modifying existing definitions . Without using the adjustment factor , visual fields of 63.6 % ( 14/22 ) patients with progressive NAION and no central defect , and all ( 7/7 ) patients with a para central defect , worsened within 30 days of NAION onset . After applying the adjustment factor , the visual fields of the same patients with no initial central defect and 5/7 of the patients with a para central defect were seen to worsen . Conclusion The IONDT developed a rule-based computerized system that consistently defines pattern and severity of visual fields of NAION patients for use in a research setting A prior report suggested that active-duty pregnant women are at increased risk for low-birth weight infants and a higher perinatal mortality rate . The present double-blind investigation was design ed to prospect ively evaluate that risk and to test the efficacy of 17 alpha-hydroxyprogesterone caproate to prevent reported complications . Three groups of active-duty women were studied , beginning between 16 and 20 weeks ' gestation . They were similar for parity , previous abortion , race , cigarette smoking , and marital status . Of these , 80 were given 17 alpha-hydroxyprogesterone caproate , 88 received placebo , and 78 declined to participate in the protocol . There was no significant differences in the three groups when comparisons were made for low-birth weight infants and for perinatal mortality . However , when comparison was made to a military dependent population , they had a significantly worse outcome with regard to both perinatal mortality ( p = 0.001 ) and infants with a birth weight less than 2,500 gm ( p = 0.01 ) . We concluded that pregnant military personnel were at increased risk for adverse pregnancy outcome , but that this risk was not altered by therapy with 17 alpha-hydroxyprogesterone caproate Of 90 patients with intermediate or high- grade sarcoma eligible for a r and omized trial of adjuvant doxorubicin ( Adriamycin , Adria Laboratories , Columbus , Ohio ) , 48 were not entered : 24 ( 27 % ) by physician 's choice and 24 refused r and omization . Sixty-five percent of lower stage patients were r and omized compared with 37 % of those with higher stage ( P = .02 ) . Patients with extremity lesions were more frequently offered participation in the study ( P = .07 ) . Patients with lower stage lesions accepted r and omization more readily than those with higher stage lesions ( P = .01 ) . As predicted by the higher stage and percentage of central lesions , the disease-free survival of nonr and omized patients was inferior to that of r and omized patients ( P = .15 ) . Thus , patients at high risk appeared to avoid r and omization and adjuvant doxorubicin in this trial , result ing in an inferior disease-free survival for the nonr and omized control group . Important questions generally require r and omized trials that reliably determine relative treatment differences . If , however , the patients in a clinical trial are not representative of the entire patient population because of patient and physician selection biases , the generalizability of the results to the entire patient population may be compromised . For example , the prognosis of the general population can not necessarily be inferred from the selected group in the study . In this study , the r and omized and nonr and omized series yielded differing conclusions regarding treatment efficacy , even when an adjustment was made for known prognostic facts Combined proximal left anterior descending and proximal left circumflex , or " left main equivalent " ( LMEQ ) , disease defines a prognostic angiographic high-risk patient population . We assessed the effect of coronary bypass surgery compared with medical therapy in 903 patients with LMEQ disease by stratified life table and Cox regression analysis . The 5 year survival rates of the 639 and 264 patients who received surgical vs medical therapy was 85 % vs 55 % , respectively ( p less than .001 ) . Analysis of patient subsets stratified by age , angina class , right coronary disease , and ejection fraction revealed a significant survival benefit for surgically treated patients in most strata . Cox regression analysis revealed improved survival for surgically treated patients after adjustment for important baseline variables known to influence prognosis . Surgically treated patients had significantly less angina and need for antianginal drugs compared with the medically treated group . When the Coronary Artery Surgery Study r and omized and r and omizable LMEQ patients were analyzed , coronary bypass surgery improved 5 year survival when preoperative ejection fraction was under 0.50 but not when ejection fraction was 0.50 or higher . Thus coronary bypass surgery prolongs and improves quality of life ( as defined by angina status and need for antianginal drugs ) in most patients with LMEQ disease but does not appear to improve 5 year survival in a small subset of LMEQ patients who are asymptomatic after myocardial infa rct ion or who have mild chronic stable angina and are under age 65 with well-preserved left ventricular function Abstract Objective : To determine the efficacy of adjuvant psychological therapy in patients with testicular cancer and to compare the characteristics and psychosocial outcomes of men who agreed to participate with those who declined to participate in a r and omised trial of psychological intervention . Design : Newly diagnosed patients were asked to participate in a r and omised trial of psychological support compared with st and ard medical care . Participants and non- participants completed self assessment question naires at baseline and at 2 , 4 and 12 months . Setting : Testicular Tumour Unit of the Royal Marsden Hospital . Subjects : 73 of 184 ( 40 % ) eligible patients agreed to enter the r and omised trial ( participants ) and 81 ( 44 % ) declined to participate but agreed to complete further assessment s ( non- participants ) . 30 patients wanted no further contact with the research ers . Outcome measures : Hospital anxiety and depression scale , psychosocial adjustment to illness scale , Rotterdam symptom checklist , mental adjustment to cancer scale . Only scores on the hospital anxiety and depression scale are reported for evaluating treatment efficacy . Results : 111 of 184 ( 60 % ) eligible men declined to participate in the trial . Patients with stage I disease were most likely to refuse to participate . A patient was less likely to participate if he had low volume disease and was receiving no further treatment . Likelihood of participation was associated with stage of disease and with type of primary treatment ( P<0.001 for heterogeneity ) . Patients with early stage disease ( P<0.001 ) and fewer physical symptoms ( P<0.001 ) were less likely to participate . Psychosocial factors associated with participation included anxious preoccupation regarding disease ( P=0.01 ) . There were no differences in outcome between participants and non- participants during follow up . Patients seemed to gain little benefit from adjuvant psychological therapy . At 2 months change from baseline favoured the treated group in the anxiety subscale ( mean difference between groups −1.41 ( 95 % confidence interval −2.86 to 0.03 ) ) . This was not sustained when adjusted for factors related to the disease . By 12 months change from baseline seemed to favour the control group ( mean difference between groups 1.66 ( −0.18 to 3.50 ) ) . Conclusions : Patients with testicular cancer seem to have considerable coping abilities . Those who declined to participate in the trial differed from those who participated . Those who agreed to participate may comprise the clinical group who perceive a need for psychological support . No evidence was found to indicate a need for routinely offering adjuvant psychological therapy . Key messages Counselling for patients with cancer is widely advocated , although its effectiveness has not been fully evaluated No study of patients with cancer has evaluated a psychological intervention in young men or in a group of patients with a disease with an excellent prognosis Most patients with testicular cancer declined to participate in this r and omised trial of adjuvant psychological therapy , and those who participated had more psychosocial dysfunction No evidence of benefit was observed after treatment with adjuvant psychological therapy in this group of patients There were no consistently significant differences in psychosocial outcome over one year between those who agreed to participate and those who declined to A variety of factors may influence outcome measures in longitudinal studies , including placebo , Hawthorne , or natural history effects . Quality of life ( QoL ) measures are particularly subject to these phenomena . This 2-month postal survey was set up to examine the extent of nonspecific effects in a treatment ( vitamin supplementation ) group ( n = 180 ) , a placebo group ( n = 180 ) , as part of a stratified , r and omized controlled trial , and two control groups ( n = 768 each ) . Quality of life was measured using the SF36 . The placebo effect had a significant impact on improving physical , mental , and pain dimensions ( p = 0.02 to 0.04 ) , and the Hawthorne effect was significant ( p = 0.03 to 0.009 ) for psychological dimensions . Although the impact of natural history was not significant , it tended to worsen all QoL dimensions . Vitamin supplementation had no effect on QoL. These results demonstrate the importance of placebo and Hawthorne effects and suggest that they may be responsible for misleading results or reductions in the power of controlled trials Sixty-two patients with resectable but poor-prognosis gastric carcinoma were r and omized to either no surgical adjuvant therapy or treatment with 5-fluorouracil ( 15 mg/kg by rapid intravenous injection X 3 ) plus radiation ( 3,750 rad in 24 fractions ) initiated 3 1/2 to six weeks postoperatively . Informed consent was obtained after r and omization and only from the 39 r and omized to treatment . Ten patients refused their treatment assignment . The five-year survival rate for patients r and omized to treatment was 23 % , and for those r and omized to no treatment , 4 % ( P less than .05 ) . Both the survival distributions and the alive-without-recurrence distributions were significantly different for the two groups ( P = .024 ) and favored treatment assignment . When the treatment assignment group was broken down to those patients actually receiving treatment and those refusing , five-year survival rates were : treated , 20 % ; treatment refusal , 30 % ; controls , 4 % ; the three survival distributions were not significantly different . Thirty-nine percent of patients actually treated had a local-regional component of first clinical recurrence compared with 54 % of those who received no treatment . This study does not establish 5-fluorouracil plus radiation as effective surgical adjuvant therapy for gastric cancer but suggests this approach as a possible fruitful area for continued research . This study also illustrates the potential problems that may be encountered in interpreting results when patients are r and omized to a study before consent is obtained BACKGROUND High-dose chemoradiotherapy combined with autologous bone marrow transplantation can cure patients with disseminated , aggressive non-Hodgkin 's lymphoma in whom first-line chemotherapy has failed . In contrast , cure is rare with second-line chemotherapy . It has been suggested that patients with slow responses to the initial phase of first-line chemotherapy are at high risk for relapse . Therefore , such patients are potential c and i date s for early bone marrow transplantation . METHODS To investigate whether patients with slow responses , defined as only a partial response after three courses of cyclophosphamide , doxorubicin , vincristine , and prednisone ( CHOP ) , would benefit from early transplantation , we conducted a prospect i ve , r and omized trial . The early application of high-dose chemoradiotherapy and autologous bone marrow transplantation was compared with the continuation of CHOP therapy for another five courses . Patients with complete responses after three courses of CHOP ( fast responses ) and patients who responded partially but still had tumor-positive marrow continued with another five courses of CHOP . The study end points were the response rate , overall survival , disease-free survival , and event-free survival . RESULTS Of 286 patients who could be evaluated for the rapidity of their response after three courses of CHOP , 38 percent had fast responses , 47 percent had slow responses , and 15 percent had no response . Among 106 patients with slow responses who had lymphoma-negative marrow , 69 patients ( 65 percent ) were r and omized . Seventy-four percent of the CHOP group and 68 percent of the transplantation group had complete remissions ( P = 0.54 ) . At four years the rates of overall , disease-free , and event-free survival were 85 , 72 , and 53 percent , respectively , in the CHOP group and 56 , 60 , and 41 percent in the transplantation group ( P > 0.10 ) . The disease-free survival in both groups did not differ significantly from that of nonr and omized patients with fast responses ( 54 percent at four years ) . CONCLUSIONS The early application of high-dose , marrow-ablative chemoradiotherapy with autologous bone marrow transplantation does not improve the outcome in patients with aggressive non-Hodgkin 's lymphoma that responds slowly to first-line CHOP chemotherapy The Multicenter Australian Study of Epidural Anesthesia and Analgesia in Major Surgery ( The MASTER Trial ) was design ed to evaluate the possible benefit of epidural block in improving outcome in high-risk patients . The trial began in 1995 and is scheduled to reach the planned sample size of 900 during 2001 . This paper describes the trial design and presents data comparing 455 patients r and omized in 21 institutions in Australia , Hong Kong , and Malaysia , with 237 patients from the same hospitals who were eligible but not r and omized . Nine categories of high-risk patients were defined as entry criteria for the trial . Protocol s for ethical review , informed consent , r and omization , clinical anesthesia and analgesia , and perioperative management were determined following extensive consultation with anesthesiologists throughout Australia . Clinical and research information was collected in participating hospitals by research staff who may not have been blind to allocation . Decisions about the presence or absence of endpoints were made primarily by a computer algorithm , supplemented by blinded clinical experts . Without unblinding the trial , comparison of eligibility criteria and incidence of endpoints between r and omized and nonr and omized patients showed only small differences . We conclude that there is no strong evidence of important demographic or clinical differences between r and omized and nonr and omized patients eligible for the MASTER Trial . Thus , the trial results are likely to be broadly generalizable PURPOSE To compare the clinical outcome of pterygium surgery combining intraoperative mitomycin C ( MMC ) with a free conjunctival autograft , with three other methods of pterygium surgery , including intraoperative MMC alone , conjunctival autograft alone , and bare sclera without adjunctive treatment . DESIGN Interventional , r and omized and in part nonr and omized , prospect i ve , comparative study . METHODS setting : A university medical center department of ophthalmology . STUDY POPULATION One hundred and twenty patients underwent pterygium excision surgery . These patients were divided into four treatment groups . INTERVENTION In group 1 ( 30 patients ) , MMC , 0.2 mg/ml , was applied for three minutes . In group 2 ( 30 patients ) , conjunctival autografting was performed . Group 3 ( 30 patients ) received sodium chloride 0.9 % only , and group 4 ( 30 patients ) underwent conjunctival autografting combined with one minute application of MMC , 0.2 mg/ml . MAIN OUTCOME MEASURE Recurrence rates and complications . RESULTS Pterygium recurred in two patients ( 6.6 % ) in group 1 , in four patients ( 13.3 % ) in group 2 , in 14 patients ( 46.6 % ) in group 3 , and in none of the patients in group 4 . chi(2 ) analysis revealed a significantly lower recurrence rate in group 4 compared with group 2 ( P = .038 ) and with group 3 ( P < .0001 ) . Epithelialization of the wounds was complete within 14 days of surgery . No complications were demonstrated in any of the study groups except for one case of minor melting of the flap in group 4 . CONCLUSIONS This study indicates that pterygium excision with a free conjunctival autograft combined with intraoperative low-dose MMC is a safe and effective technique in pterygium surgery BACKGROUND The aim of this study was to evaluate a model of routine pre-IVF counselling focusing on the narrative capacities of couples . The acceptability of counselling , the effects on emotional factors and the participants ' assessment s were considered . METHODS The study included 141 consecutive childless couples preparing for their first IVF . R and omization was carried out through sealed envelopes attributing participants to counselled and non-counselled groups and was accepted by 100 couples . Another 12 couples refused r and omization because they wanted counselling and 29 because they did not . Question naires including the State-Trait Anxiety Inventory , the Beck Depression Inventory and assessment s of help were mailed to couples before IVF and counselling , and after the IVF outcome . RESULTS Counselling was accepted by 79 % ( 112/141 ) of couples . There was no significant effect of counselling on anxiety and depression scores which were within normal ranges at both times . Counselling provided help for 86 % ( 75/87 ) of initially non-dem and ing subjects and 96 % ( 25/26 ) of those initially requesting a session . Help was noted in areas of psychological assistance , technical explanations and discussing relationships . CONCLUSIONS This model of routine counselling centred on the narrative provides an acceptable form of psychological assistance for pre-IVF couples The patient characteristics and outcomes were studied in the 318 patients who survived open label drug titration in the Cardiac Arrhythmia Suppression Trial ( CAST ) and who were not r and omized to double-blind therapy and in 942 patients , who were r and omized to double-blind placebo therapy . The patients r and omized to placebo therapy had a lower total mortality or resuscitated cardiac arrest rate ( 4 % vs. 8.5 % ) . However , at baseline , nonr and omized patients were dissimilar from patients r and omized to placebo in the following ways : older ; lower left ventricular ejection fraction ; greater use of digitalis , diuretic drugs and antihypertensive agents ; lesser use of beta-adrenoceptor blocking agents and more frequent prior cardiac problems , including runs of ventricular tachycardia and left bundle branch block . A matched comparison that took these inequities into account showed no significant differences in mortality or rate of resuscitation from cardiac arrest between nonr and omized patients and clinical ly equivalent patients r and omized to placebo . Cox regression analysis indicated that two factors significantly increased the hazard ratio for arrhythmic death or resuscitated cardiac arrest in the nonr and omized patients : female gender ( 4.7 , p less than 0.05 ) and electrocardiographic events ( ventricular tachycardia , proarrhythmia , widened QRS complex , heart block , bradycardia ) during open label titration ( 7.0 , p less than 0.005 ) . However , some potentially important differences between men and women were not included in the Cox regression model . Of the nonr and omized patients , approximately 70 % were not r and omized because of lack of suppression of ventricular premature depolarizations or adverse events , or both , and the remaining 30 % because of patient or private physician request with no indication of another reason . ( ABSTRACT TRUNCATED AT 250 WORDS In 1970 - 3 313 children were diagnosed as having nephroblastoma in Great Britain . From the start of the first Medical Research Council nephroblastoma study in October 1970 until the end of 1973 , 98 children ( 57 % of all eligible children ) were included in the trial . Of the 313 children , 288 ( 92 % ) had a nephrectomy , 248 ( 79 % ) received a course of radiotherapy , and 267 ( 85 % ) were given at least four days ' chemotherapy . The three-year survival rate was 58 % ; the rate among children in the trial ( 77 % ) was significantly better than that among children who were eligible for the trial but not included ( 58 % ) . Children who had nephrectomies at specialised children 's and teaching hospitals had a higher survival rate than those treated elsewhere . All children with nephroblastoma should be treated according to well-defined protocol s which take into account the age of the child and the stage of the tumour and include a full course of maintenance chemotherapy In a r and omized controlled trial plus a nonr and omized cohort , the authors investigated the effectiveness and costs of acupuncture in addition to routine care in the treatment of chronic low back pain and assessed whether the effects of acupuncture differed in r and omized and nonr and omized patients . In 2001 , German patients with chronic low back pain were allocated to an acupuncture group or a no-acupuncture control group . Persons who did not consent to r and omization were included in a nonr and omized acupuncture group . All patients were allowed to receive routine medical care in addition to study treatment . Back function ( Hannover Functional Ability Question naire ) , pain , and quality of life were assessed at baseline and after 3 and 6 months , and cost-effectiveness was analyzed . Of 11,630 patients ( mean age=52.9 years ( st and ard deviation , 13.7 ) ; 59 % female ) , 1,549 were r and omized to the acupuncture group and 1,544 to the control group ; 8,537 were included in the nonr and omized acupuncture group . At 3 months , back function improved by 12.1 ( st and ard error ( SE ) , 0.4 ) to 74.5 ( SE , 0.4 ) points in the acupuncture group and by 2.7 ( SE , 0.4 ) to 65.1 ( SE , 0.4 ) points among controls ( difference=9.4 points ( 95 % confidence interval 8.3 , 10.5 ) ; p<0.001 ) . Nonr and omized patients had more severe symptoms at baseline and showed improvements in back function similar to those seen in r and omized patients . The incremental cost-effectiveness ratio was euro10,526 ( euros ) per quality -adjusted life year . Acupuncture plus routine care was associated with marked clinical improvements in these patients and was relatively cost-effective Background . Although not much research comparing the emotional distress following medical and surgical abortion is available , few studies have compared psychological sequelae following both methods of abortion early in the first trimester of pregnancy . The aim of this review was to assess the psychological sequelae and emotional distress following medical and surgical abortion at 10–13 weeks gestation In clinical research , r and omized trials are widely accepted as the definitive method of evaluating the efficacy of therapies . The r and om assignment of patients to their treatment ensures the internal validity of the comparison of new treatments with controls . An assessment of the external validity of trial results can best be achieved by comparing the study population to the population of patients who met the eligibility criteria but did not consent to r and omization . A part of the data of the Coronary Artery Surgery Study ( CASS ) , in which coronary artery bypass surgery is compared to conventional medical therapy in patients with coronary artery disease , is used to illustrate a strategy of multivariate analysis of r and omized and nonr and omized patients which allows an investigation of both internal and external validity . The method used Cox 's proportional hazards regression model with inclusion of covariates for r and omization status and corresponding interactions in addition to the usual covariates for treatment and the important prognostic factors In a study design ed to maximize the effectiveness of treatment by allowing participants to select the target of treatment , 40 depressed older adults were r and omly assigned to a waiting-list control condition or to conditions in which the target of treatment was either chosen or assigned . All participants received self-management therapy and the choice was between changing behavior or changing cognition . It was found that individually administered self-management therapy was effective in treating depression for older adults . There were no differences in outcome between versions of self-management therapy that targeted behavioral or cognitive change . Among those who completed treatment , there were no differences in outcome between those who received a choice and those who did not . Individuals who were given a choice of treatment options , however , were less likely to drop out of treatment prematurely OBJECTIVE To investigate whether a buprenorphine opiate detoxification regimen can be considered to be at least as clinical ly effective as a lofexidine regimen . DESIGN An open-label r and omized controlled trial ( RCT ) using a non-inferiority approach . Non-inferiority is demonstrated if , within a 95 % confidence interval , buprenorphine performs within a preset tolerance limit of clinical ly acceptable difference in outcomes and completion rates between the two treatments . METHODS Individuals ready for heroin detoxification were given information about the trial and invited to participate . Consenting participants ( n = 210 ) were then r and omized to one of the two treatments . Detoxification was undertaken in a specialist out-patient clinic according to predefined protocol s. The primary outcome was whether or not an individual completed the detoxification . Abstinence at 1-month follow-up was used as a secondary outcome measure . Additional secondary outcome measures were substance use , dependence , psychological health , social satisfaction , and treatment satisfaction . Data were also collected for individuals who declined r and omization and instead chose their treatment ( n = 271 ) . RESULTS A total of 46 % of those on lofexidine and 65 % of those on buprenorphine completed detoxification . Of these , 35.7 % of the lofexidine and 45.9 % of the buprenorphine groups reported abstinence at 1 month . Of those not completing detoxification abstinence was reported at 27.5 % and 29.0 % , respectively ; 271 individuals who opted not to be allocated r and omly and instead chose one of the two treatments produced similar results CONCLUSIONS Buprenorphine is at least as effective as lofexidine detoxification treatment . Whether or not individuals were r and omized to , or chose , a treatment appeared not to affect the study 's outcome Objective To compare the acceptability of microwave endometrial ablation using a local anaesthesia/sedation regime or general anaesthesia . To compare recovery following treatment with each type of anaesthetic It has been suggested that wound infection rates after colorectal operations are influenced more by the presence of adequate tissue levels of antimicrobials at the time of contamination than by the extent of bacterial colonization of the intestinal lumen . There are , however , theoretical grounds for the belief that both levels are important . The authors therefore conducted a r and om control trial in 119 consecutive patients undergoing elective colorectal operations , comparing the results in a group receiving purely parenteral antimicrobial prophylaxis with those in one having a combined oral and parenteral regimen . The results in 83 contemporary nonr and omized patients , all of whom had the combined prophylactic regimen , are also reported . Oral bowel preparation result ed in a significantly smaller number of operation cultures showing growth of fecal gram-negative aerobes and anaerobes than did the purely parenteral regimen . There were more isolations of enterococci in the combined group but the excess did not achieve statistical significance . The rates of infective complications were higher in the parenteral than in the combined group , the difference in wound infection rates being statistically significant ; the figures were 27.6 percent and 13.9 percent , respectively ( P=.04 ) . It is concluded that , in colorectal operations , it is advisable not only to ensure adequate tissue levels of antimicrobials but also to reduce the risk of endogenous bacterial infection by partially decontaminating the bowel PURPOSE Women with breast cancer were provided with an audiotape of their primary adjuvant treatment consultation , and the following patient outcomes were measured at 12 weeks postconsultation : perceived degree of information provision , audiotape satisfaction and use , communication satisfaction with oncologist , mood state , and cancer-specific quality of life . PATIENTS AND METHODS Participants included 628 women newly diagnosed with breast cancer and 40 oncologists from six cancer centers in Canada . The patients were block r and omized to one of four consultation groups : st and ard care control , not audiotaped ; audiotaped , no audiotape given ; audiotaped , patient given audiotape ; and audiotaped , patient offered choice of receiving audiotape or not . RESULTS Patients receiving the consultation audiotape had significantly better recall of having discussed side effects of treatment than patients who did not receive the audiotape . Audiotape benefit was not significantly related to patient satisfaction with communication , mood state , or quality of life at 12 weeks postconsultation , and was not significantly affected by choice of receiving the audiotape . Patients rated the audiotape intervention positively , with an average score of 83.9 of 100 . CONCLUSION Audiotape provision benefits patients by facilitating their perception of being informed about treatment side effects , but does not significantly influence patient satisfaction with communication , mood state , or quality of life CONTEXT Carcinoma of the esophagus traditionally has been treated by surgery or radiation therapy ( RT ) , but 5-year overall survival rates have been only 5 % to 10 % . We previously reported results of a study conducted from January 1986 to April 1990 of combined chemotherapy and RT vs RT alone when an interim analysis revealed significant benefit for combined therapy . OBJECTIVE To report the long-term outcomes of a previously reported trial design ed to determine if adding chemotherapy during RT improves the survival rate of patients with esophageal carcinoma . DESIGN R and omized controlled trial conducted 1985 to 1990 with follow-up of at least 5 years , followed by a prospect i ve cohort study conducted between May 1990 and April 1991 . SETTING Multi-institution participation , ranging from tertiary academic referral centers to general community practice s. PATIENTS Patients had squamous cell or adenocarcinoma of the esophagus , T1 - 3 N0 - 1 M0 , adequate renal and bone marrow reserve , and a Karnofsky score of at least 50 . Interventions Combined modality therapy ( n = 134 ) : 50 Gy in 25 fractions over 5 weeks , plus cisplatin intravenously on the first day of weeks 1 , 5 , 8 , and 11 , and fluorouracil , 1 g/m2 per day by continuous infusion on the first 4 days of weeks 1 , 5 , 8 , and 11 . In the r and omized study , combined therapy was compared with RT only ( n = 62 ) : 64 Gy in 32 fractions over 6.4 weeks . MAIN OUTCOME MEASURES Overall survival , patterns of failure , and toxic effects . RESULTS Combined therapy significantly increased overall survival compared with RT alone . In the r and omized part of the trial , at 5 years of follow-up the overall survival for combined therapy was 26 % ( 95 % confidence interval [ CI ] , 15%-37 % ) compared with 0 % following RT . In the succeeding nonr and omized part , combined therapy produced a 5-year overall survival of 14 % ( 95 % CI , 6%-23 % ) . Persistence of disease ( despite therapy ) was the most common mode of treatment failure ; however , it was less common in the groups receiving combined therapy ( 34/130 [ 26 % ] ) than in the group treated with RT only ( 23/62 [ 37 % ] ) . Severe acute toxic effects also were greater in the combined therapy groups . There were no significant differences in severe late toxic effects between the groups . However , chemotherapy could be administered as planned in only 89 ( 68 % ) of 130 patients ( 10 % had life-threatening toxic effects with combined therapy vs 2 % in the RT only group ) . CONCLUSION Combined therapy increases the survival of patients who have squamous cell or adenocarcinoma of the esophagus , T1 - 3 N0 - 1 M0 , compared with RT alone Spontaneous resolution of acute hepatitis C virus infection can not be predicted , and chronic evolution of the disease occurs in a majority of cases . To assess the efficacy and safety of peginterferon alpha-2b administered for 8 , 12 , or 24 weeks in patients with acute hepatitis C virus infection a total of 161 patients were identified with acute hepatitis C virus infection . Of these , 30 patients refused treatment but were retained in the study as a nonr and omized comparison group . Of the 131 patients who consented to treatment , 29 patients spontaneously resolved , leaving 102 patients r and omly assigned to peginterferon alpha-2b ( 1.5 microg/kg ) for 8 weeks ( group A ; n=34 ) , 12 weeks ( group B ; n=34 ) , and 24 weeks ( group C ; n=34 ) . The primary end point was sustained virologic response . An intent-to-treat analysis was used for efficacy and safety end points . Sustained virologic response was achieved in 23/34 ( 67.6 % ) , 28/34 ( 82.4 % ) , and 31/34 ( 91.2 % ) of patients in groups A , B , and C , respectively ; all had undetectable hepatitis C virus RNA 48 weeks after the end of therapy . Treatment for 8 or 12 weeks was effective in genotypes 2 , 3 , and 4 , whereas genotype 1 required 24 weeks of therapy . The 8- and 12-week regimens were associated with fewer adverse events compared with the 24-week regimen . In conclusion , peginterferon alpha-2b effectively induces high sustained virologic response rates in patients with acute hepatitis C virus infection , thus preventing development of chronic hepatitis C. Duration of treatment should be further optimized based on genotype and rapid virologic response at week 4 To examine whether written informed consent might influence the results of clinical trials the effect of placebo when given with or without informed consent to patients suffering from insomnia was studied . The study was a single blind observer blinded trial , and patients were paired according to sex , age , and hospital environment . R and omisation assigned the first patient of each pair to the control group ( without informed consent ) or the group to give informed consent . Of the 56 patients , 26 refused to give informed consent , and the age and sex distribution of these differed significantly ( p less than 0.02 ) from the 30 pairs of patients ultimately enrolled into the study . In this " biased " sample , the hypnotic activity of placebo was significantly higher in the control group ( p less than 0.05 ) . It is concluded that the informed consent procedure biases the results of clinical trials and might affect their general applicability BACKGROUND In many countries , surgical uterine evacuation is the st and ard treatment for women with a miscarriage , but expectant management has been advocated as an alternative . The choice between the two options can not be based on published evidence alone , because r and omized clinical trials are scarce while generalizability of findings to patients with a strong preference for either management options is unclear . METHODS In a r and omized controlled trial , the complications and efficacy of either expectant or surgical management for miscarriages were compared , and the results in patients who refused r and omization and were managed according to their own preference were studied . In total , 122 patients were r and omized and 305 were managed according to their choice . RESULTS No differences were found in the number of emergency curettages and complications between expectant and surgical management . Efficacy at 6 weeks was 30/64 ( 47 % ) in women allocated to expectant management , and 55/58 ( 95 % ) in women allocated to surgical evacuation . After 7 days , 37 % of expectantly managed women had a spontaneous complete miscarriage . After 6 weeks , intention-to-treat analysis including cross-overs showed similar effectiveness ( 92 % versus 100 % ) . Results in the preference groups were comparable with those in the r and omized groups . CONCLUSION In our experience a waiting period of 7 days after diagnosis may prevent 37 % of surgical procedures OBJECTIVE To study characteristics of importance for participation in a diet and physical exercise prevention programme . SETTING Primary Health Care , Sollentuna , and the Karolinska Hospital , Stockholm , Sweden . SUBJECTS A sample of 187 men , aged 35 - 60 , with increased risk factors for CHD , were invited to a 6-month prevention programme . Participants ( n = 158 ) were r and omized into a diet group , a physical exercise group , a diet and physical exercise group , and a control group . Twenty-seven men , who declined participation , formed the group of non participants . DESIGN Participants and non participants were compared with respect to health beliefs , health knowledge , CHD risk factors , demographic and personality factors . MAIN OUTCOME MEASURES Characteristics of men participating and not participating in the intervention trial . RESULTS Non participants , compared with participants , believed less in the benefits of dietary change and perceived the health threat of stroke and myocardial infa rct ion as less serious . Non participants had a better knowledge of a number of risk factors for cardiovascular disease . CONCLUSION Belief in treatment efficacy and perceived health threat , rather than health knowledge , predicted initial participation in a non-pharmacological intervention trial BACKGROUND Stereotactic breast biopsy has been developed as a less invasive means of performing biopsy for mammographic abnormalities . METHODS From July 1994 through June 1995 , 103 women with mammographic abnormalities requiring biopsy were prospect ively evaluated . RESULTS Fifty-one women had open biopsy , and 52 women had stereotactic biopsy . The average age in both groups was 60 years . Pathology revealed malignancy in 12 % of stereotactic biopsies and 13 % of open biopsies . Complications occurred in 6 % of the open biopsies and 4 % of the stereotactic biopsies and were limited to hematomas or seromas . The average cost was $ 2400 for open biopsy and $ 650 for stereotactic biopsy ( P < 0.01 ) . One hundred and one patients returned for a follow-up mammogram within 6 months , and 1 patient in each group required a second biopsy , which revealed benign pathology . A Patient Satisfaction Survey revealed no significant differences in patient satisfaction between the two types of procedures . CONCLUSION There were no differences between open and stereotactic biopsies in regards to diagnostic accuracy , complications , or patient satisfaction . A significant difference was noted in charges during the time frame of our study PURPOSE To determine whether estrogen replacement therapy ( ERT ) alters the development of new or recurrent breast cancer in women previously treated for localized breast cancer . PATIENTS AND METHODS Potential participants ( n = 319 ) in a trial of ERT after breast cancer were observed prospect ively for at least 2 years whether they enrolled onto the r and omized trial or not . Of 319 women , 39 were given estrogen and 280 were not given hormones . Tumor size , number of lymph nodes , estrogen receptors , menopausal status at diagnosis , and disease-free interval at the initiation of the observation period were comparable for the trial participants ( n = 62 ) versus non participants ( n = 257 ) and for women on ERT ( n = 39 ) versus controls ( n = 280 ) . Cancer events were ascertained for both groups . RESULTS Patient and disease characteristics were comparable for the trial participants versus non participants , as well as for the women on ERT versus the controls . One patient in the ERT group developed a new lobular estrogen receptor-positive breast cancer 72 months after the diagnosis of a ductal estrogen receptor-negative breast cancer and 27 months after initiation of ERT . In the control group , there were 20 cancer events : 14 patients developed new or recurrent breast cancer at a median time of 139.5 months after diagnosis and six patients developed other cancers at a median time of 122 months . CONCLUSION ERT does not seem to increase breast cancer events in this subset of patients previously treated for localized breast cancer . Results of r and omized trials are needed before any changes in current st and ards of care can be proposed BACKGROUND Reporting of pharmaceutical-industry-sponsored r and omised clinical trials often result in biased findings , either due to selective reporting of studies with non-equivalent arms or publication of low- quality papers , wherein unfavourable results are incompletely described . A r and omised trial should be conducted only if there is substantial uncertainty about the relative value of one treatment versus another . Studies in which intervention and control are thought to be non-equivalent violates the uncertainty principle . METHODS We examined the quality of 136 published r and omised trials that focused on one disease category ( multiple myeloma ) and adherence to the uncertainty principle . To evaluate whether the uncertainty principle was upheld , we compared the number of studies favouring experimental treatments over st and ard ones . We analysed data according to the source of funding . FINDINGS Trials funded solely or in part by 35 profit-making organisations had a trend toward higher quality scores ( mean 2.94 [ SD 1.3 ] ; median 3 ) than r and omised trials supported by 95 governmental or other non-profit organisations ( 2.4 [ 0.8 ] ; 2 ; p=0.06 ) . Overall , the uncertainty principle was upheld , with 44 % of r and omised trials favouring st and ard treatments and 56 % innovative treatments ( p=0.17 ) ; mean and median preference evaluation scores were 3.7 ( 1.0 ) and 4 . However , when the analysis was done according to the source of funding , studies funded by non-profit organisations maintained equipoise favouring new therapies over st and ard ones ( 47 % vs 53 % ; p=0.608 ) to a greater extent than r and omised trials supported solely or in part by profit-making organisations ( 74 % vs 26 % ; p=0.004 ) . INTERPRETATION The reported bias in research sponsored by the pharmaceutical industry may be a consequence of violations of the uncertainty principle . Sponsors of clinical trials should be encouraged to report all results and to choose appropriate comparative controls BACKGROUND Questions about the generalizability of r and omized trial results to clinical practice have arisen because the overall mortality rate is generally lower in trials , potentially because patients who are at lower risk are enrolled . However , little is known about the characteristics of patients included in clinical trials versus those who are not included . METHODS The Thrombolysis In Myocardial Infa rct ion ( TIMI ) 9 Registry prospect ively evaluated patients with ST-elevation myocardial infa rct ion at 20 hospitals during the TIMI 9 trial , which compared hirudin versus heparin with fibrinolysis . We compared the characteristics , treatment , and outcomes of patients enrolled in TIMI 9B ( n = 3002 ) with other fibrinolytic-eligible patients not enrolled in TIMI 9B ( n = 296 ) and with those not eligible for fibrinolysis by American College of Cardiology/American Heart Association criteria , at the same centers ( n = 282 ) , with the latter groups divided by use of reperfusion therapy . RESULTS Across the groups , ranging from those in the TIMI 9 trial to those ineligible for fibrinolysis , we observed a gradient of higher-risk baseline characteristics , lower use of reperfusion therapy , and higher mortality rates ( P < .001 ) . In addition , comparing fibrinolytic-eligible patients in TIMI 9B versus those not enrolled in the trial , the use of aspirin , beta-blockers , and angiotensin-converting enzyme inhibitors was significantly higher in the TIMI 9B trial . Ineligible patients not treated with reperfusion therapy had much lower rates of use of these medications and the highest inhospital mortality rate ( 24 % , adjusted odds ratio 2.8 , P < .0001 ) CONCLUSIONS In this prospect i ve registry , patients not enrolled in a clinical trial had higher risk characteristics and worse outcomes ; however , they also were treated less frequently with guideline -recommended medications , which may have contributed to their higher mortality rates Our objective was to characterize and evaluate pregnancy outcome in women who declined participation in a trial on ultrasound screening in the second trimester . Between 1985 and 1987 , 8768 women were recruited for a trial on ultrasound screening . By r and omization , 4997 women were assigned to either a screening or a non-screening group . Of the 1414 excluded women , data were retrieved from 1211 ( 86 % ) . Participation was declined by 526 of these 1211 women , either because of anxiety regarding harmful effects of ultrasound or because they could see no benefits of ultrasound scanning . Non- participants and participants were compared . The non- participants were older , had a higher birth/pregnancy ratio , were less often smokers , and had fewer ultrasound examinations than the participants . There was a longer mean pregnancy length , an increased number of post-term deliveries , more suspicions of small-for-gestational-age fetuses and later detections of multiple pregnancies among non- participants as compared with the screening group . No differences in neonatal morbidity were found except for a greater number of mild respiratory disorders in the non-participant group . The non-participant women were more obstetrically experienced and showed indications of a healthier lifestyle in comparison with participants . The differences found in pregnancy outcome could be explained by the ultrasound screening procedure . There were no major differences in neonatal morbidity between the groups This report presents baseline clinical and angiographic data from the Bypass Angioplasty Revascularization Investigation ( BARI ) , a multicenter international trial assessing the relative efficacy of percutaneous transluminal coronary angioplasty ( PTCA ) versus coronary artery bypass graft surgery ( CABG ) in selected patients with multivessel coronary artery disease . PTCA is commonly performed in patients with multivessel coronary artery disease , yet its long-term efficacy in comparison to CABG is unknown . From August 1988 through August 1991 , 1,829 qualifying patients with multivessel disease suitable for either procedure were r and omized to PTCA or CABG ; sample size estimates were based on anticipated 5-year mortality . Two registry population s were also defined for follow-up : ( 1 ) 2,013 patients eligible for r and omization but not r and omized ; and ( 2 ) 422 patients considered by angiography as unsuitable for r and omization . Patients r and omized in BARI were at relatively high risk for subsequent cardiac events : 39 % were > or = 65 years old , 55 % had prior myocardial infa rct ion , 69 % presented with unstable angina or non-Q wave myocardial infa rct ion , and 43 % had 3-vessel coronary artery disease . Patients r and omized to PTCA and CABG were equally matched in all the important baseline variables . The r and omized and the eligible but not r and omized groups were similar in most respects . However , the nonr and omized group had a higher proportion with college education ; fewer with a history of myocardial infa rct ion , heart failure , diabetes , and smoking ; and a somewhat better average ejection fraction . At the 3-month follow-up , PTCA had been performed more commonly in the nonr and omized eligible patients , especially those with 2-vessel disease . ( ABSTRACT TRUNCATED AT 250 WORDS Background : The conventional view that participants in r and omised controlled trials sacrifice themselves for the good of future patients is challenged by increasing evidence to suggest that individual patients benefit from participation in trials . Objective : To test the hypothesis that trial participants receive higher quality care and , as a consequence , have better outcomes than patients receiving guideline driven routine care . Methods : Retrospective comparative study of 408 women with pre-eclampsia all managed according to a strict protocol . Trial participants were 86 women who participated in a multicentre r and omised controlled trial of magnesium sulphate for the treatment of pre-eclampsia ( Magpie Trial ) ; 322 non- participants formed the control group . Indicators of the process of care and clinical outcomes were compared between the two groups . Results : Trial participants were significantly more likely to have received daily blood tests ( odds ratio ( OR ) 6.82 , 95 % CI 1.62 to 28.72 ) and had their respiration rate measured hourly ( OR 3.42 , 95 % CI 1.69 to 6.92 ) than control patients . There were no significant differences in other markers of clinical process and no significant difference in clinical outcomes . Conclusion : This study shows minor differences in process markers and no difference in clinical outcomes between patients in a clinical trial and patients receiving protocol driven care . The benefits of improved clinical care that have previously been associated with being in a trial may be explained by the use of clear clinical protocol s. In routine practice , patients may be well advised to insist on treatment as part of a protocol BACKGROUND The aim of the study was to compare satisfaction with medical and surgical abortion and to identify potential confounders affecting satisfaction . METHODS 1033 women with gestational age ( GA ) < or = 63 days had either a medical ( 600 mg mifepristone followed by 1 mg gemeprost ) or a surgical abortion ( vacuum aspiration in general anaesthesia ) . The procedure was determined either by r and omization ( n = 111 ) or by choice ( n = 922 ) . Data on satisfaction , side effects and expectations were collected from question naires 2 and 8 weeks after termination . RESULTS More women were very satisfied or satisfied after a surgical than a medical abortion both after choosing method ( 92 % vs 82 % , P < 0.0001 ) , and after r and omization ( 94 % vs 68 % , P < 0.001 ) . Satisfaction was higher after choosing a medical procedure than after r and omization to the same procedure ; 82 % and 68 % , respectively , P < 0.05 . Satisfaction with the medical procedure was inversely correlated with GA and the intensity of pain , nausea , vomiting and dizziness , while satisfaction with the surgical procedure was unaffected by these side effects . Fewer women with a failed medical than a failed surgical abortion were satisfied ( 17 % vs 62 % ) , P < 0.05 . CONCLUSIONS Satisfaction with both medical and surgical abortions is high , although higher with the surgical than the medical procedure , and higher after choosing method than after r and omization Levels of serum antibody to Bacillus Calmette-Guérin ( BCG ) were determined by solid-phase radioimmunoassays in 48 normal donors and 60 patients with bladder cancer . Of 57 patients enrolled in a r and omized prospect i ve controlled trial of BCG immunotherapy , 47 were followed for up to 30 months , thus permitting comparisons of tumor recurrence , delayed cutaneous hypersensitivity responses to purified protein derivative ( PPD ) , and serum BCG antibody levels at specific intervals during the clinical course . Sera from normal donors and cancer patients prior to BCG therapy had equally low levels of BCG antibody . AFter administration of intravesical and percutaneous BCG , significant rises of serum BCG antibody levels were detected in 23 of 24 r and omized BCG immunotherapy patients . Skin test responses to PPD and serum BCG antibody levels had a close correlation as immune response indicators in 14 of 24 BCG therapy patients , while rises in serum BCG antibody levels were a better response indicator than PPD skin test reactions in the other 10 patients . Eleven of the 23 patients r and omized into the non-BCG treatment group had tumor recurrence , although tumors recurred in only six of the 24 r and omized patients in the BCG therapy group . Two additional nonr and omized BCG-treated patients had tumor recurrence . All eight BCG-treated patients with tumor recurrence had documented increases in serum BCG antibody levels after BCG therapy . Only three of these eight patients had conversion of PPD skin test responses from negative to positive ; three were positive before immunotherapy and two remained negative after BCG therapy . Levels of antibodies reactive with human adenovirus type 5 and with Escherichia coli antigens were similar in sera from normal donors and from the r and omized bladder cancer patients in both the BCG and non-BCG treatment groups . These results suggest that serum BCG antibody responses are as useful as PPD skin tests in identifying immunological responses to the immunoadjuvant BCG during immunotherapy trials in cancer patients OBJECTIVES To test the effect of adenoidectomy in connection with tympanostomy compared with tympanostomy only in preventing otitis media in children younger than 2 years . DESIGN Prospect i ve trial with r and omized and nonr and omized arms . SETTING Primary care study clinics . PARTICIPANTS AND INTERVENTIONS The study participants were selected from 2497 children who had been enrolled in the Finnish Otitis Media Vaccine Trial at the age of 2 months . A total of 306 children , aged 1 to 2 years , who had experienced recurrent episodes of otitis media were r and omized into 2 treatment groups : tympanostomy with or without adenoidectomy . Of the 306 children , 137 were operated on according to r and om basis ( r and omized trial ) . The 169 children whose parents declined participation in the r and omized trial were operated on according to the parents ' preferences ( nonr and omized trial ) . All children were followed up until 2 years of age . The mean follow-up time was 7 months . MAIN OUTCOME MEASURE The rate of acute otitis media episodes . RESULTS The average reduction in the rate of all acute otitis media episodes in the adenoidectomy group was 19 % ( 95 % confidence interval [ CI ] , -14 % to 43 % ) among children enrolled in the r and omized trial and 25 % ( 95 % CI , -13 % to 50 % ) in the nonr and omized trial . The reduction in the r and omized trial was mainly due to reduction in the rate of pneumococcal otitis media ( 58 % , 95 % CI , 16%-79 % ) . CONCLUSION In children younger than 2 years , concurrent adenoidectomy during the insertion of tympanostomy tubes does not seem to have a major advantage over the insertion of tympanostomy tubes alone in preventing otitis media Background Newly diagnosed insulin-dependent diabetes mellitus is characterised by a temporary recovery of endogeneous insulin ( " remission " ) after the beginning of medical treatment with subcutaneous insulin injections . Although most diabetologists think , that insulin reserve is related to reduced occurrence of diabetic long-term complications , such as eye , nerve and kidney disease , there is only one prospect i ve controlled clinical study ( the DCCT ) addressing this question , however as secondary hypothesis . Methods / Design Therefore , we composed a trial consisting of two cohorts with two therapeutic options within each cohort ( conventional versus intensive therapy ) and a three-year follow-up . In one group the patients are r and omly assigned to the treatment regimes to test the statistical alternative hypothesis if variable insulin dosage is superior to fixed insulin injection in preserving insulin reserve measured by C-peptide in serum . Another group includes patients who prefer one of the two therapies , decline r and omisation , but consent to follow-up . Apart from the determination of insulin reserve as a biological parameter a second primary endpoint was defined as ' therapeutic failure ' according to the criteria of the European Association for the Study of Diabetes . Patients pass a training program to help them self-manage diabetes . A st and ardised protocol is being set up to minimize centre effects and bias of health care providers . Potential patient dependent bias will be investigated by question naires measuring psychic coping processes of people with diabetes . Management of visit date s is directly navigated by the data base . Automated visit-reminders are mailed to patients and caregivers to optimise the number of visits on schedule . Data quality is regularly monitored and centres are informed on the results of continuous data management OBJECTIVES --To assess women 's preferences for , and the acceptability of , medical abortion and vacuum aspiration in the early first trimester . DESIGN --Patient centred , partially r and omised trial . Medical abortion was performed with mifepristone 600 mg followed 48 hours later by gemeprost 1 mg vaginal pessary . Vacuum aspiration was performed under general anaesthesia . SETTING --Teaching hospital in Scotl and . PATIENTS --363 women undergoing legal induced abortion at less than nine weeks ' gestation . MAIN OUTCOME MEASURES --Women 's preferences for method of abortion before abortion ; acceptability judged two weeks after abortion by recording the method women would opt to undergo in future and by semantic differential rating technique . RESULTS --73 ( 20 % ) women preferred to undergo medical abortion , and 95 ( 26 % ) vacuum aspiration ; 195 ( 54 % ) were willing to undergo either method , and were allocated at r and om . Both procedures were highly acceptable to women with preferences . Gestation had a definite effect on acceptability in r and omised women ; at less than 50 days there were no differences , but between 50 and 63 days vacuum aspiration was significantly more acceptable . CONCLUSIONS --Women who wish to use a particular method should be allowed their choice , regardless of gestation . Women of 50 - 63 days ' gestation without preferences for a particular method are likely to find vacuum aspiration more acceptable . A patient centred , partially r and omised trial design may be a useful tool in pragmatic research Background About two thirds of adults suffer from backpain at some time during their life . In the emergency room many patients with acute back pain are treated with intravenous non-steroidal analgesics . Whether this treatment is superior to oral administration of non-steroidal analgesics is unknown . Intravenous administration , however , requires considerable amounts of re sources and accounts for high workload in busy clinics . In the further course central ly acting muscle relaxants are prescribed but the effectiveness remains unclear . The objective of this study is on the one h and to compare the effectiveness of intravenous with oral non-steroidal analgesics for acute treatment and on the other h and to compare the effectiveness of a central ly active muscle relaxant with placebo given for three days after presentation to the ED ( emergency department ) . Methods / Design This study is intended as a r and omised controlled factorial trial mainly for two reasons : ( 1 ) the sequence of treatments resembles the actual proceedings in every-day clinical practice , which is important for the generalisability of the results and ( 2 ) this design allows to take interactions between the two sequential treatment strategies into account . There is a patient preference arm included because patients preference is an important issue providing valuable information : ( 1 ) it allows to assess the interaction between desired treatment and outcome , ( 2 ) results can be extrapolated to a wider group while ( 3 ) conserving the advantages of a fully r and omised controlled trial . Conclusion We hope to shed more light on the effectiveness of treatment modalities available for acute low back pain BACKGROUND Tamoxifen reduces the risk of breast cancer in women at high risk for the disease but increases the risk for endometrial tumors and venous thromboembolisms , possibly in a dose-dependent fashion . We compared the effects of tamoxifen at 1 mg/day and 5 mg/day with those of the st and ard dose of 20 mg/day on breast cancer proliferation using a surrogate endpoint marker ( Ki-67 expression ) and blood biomarkers associated with breast cancer , cardiovascular disease , and bone fracture risk . METHODS We r and omly assigned 120 women with estrogen receptor (ER)-positive breast cancer to tamoxifen at 1 , 5 , or 20 mg/day for 4 weeks . Expression of the tumor proliferation marker Ki-67 and of biomarkers of breast cancer ( insulin-like growth factor-I , sex hormone-binding globulin ) , cardiovascular disease ( cholesterol , triglycerides , ultrasensitive C-reactive protein , fibrinogen , antithrombin-III ) , and bone fracture ( type I collagen C-telopeptide ) risk were determined before ( baseline ) and after treatment . All levels were compared with those in two nonr and omized control groups ( 34 women with ER-negative breast cancer and 29 additional women with ER-positive breast cancer ) . Data were analyzed by analysis of covariance . All statistical tests were two-sided . RESULTS Expression of Ki-67 decreased in all three tamoxifen groups , with no difference in the magnitude of reduction among groups ( P = .81 ) . Relative to baseline , Ki-67 expression decreased by a median of 15.0 % ( 95 % confidence interval = 0.0 % to 24.1 % ) among the tamoxifen groups but increased by 12.8 % ( 95 % confidence interval = 0.0 % to 19.6 % ) among the nonr and omized control groups . Several blood biomarkers showed dose-response relationships with tamoxifen , including decreased insulin-like growth factor-I , increased sex hormone-binding globulin , and decreased low-density lipoprotein-cholesterol , ultrasensitive C-reactive protein , fibrinogen , and antithrombin-III levels . CONCLUSIONS The effects on Ki-67 expression of lower doses of tamoxifen were comparable to those achieved with the st and ard dose , although the effects on blood biomarkers were variable . The effects of lower doses of tamoxifen should be assessed further in r and omized trials A r and omised trial of adjuvant chemotherapy vs placebo in operable stomach cancer recruited 249 patients from the West Midl and s Region between 1976 - 1980 . A Cancer Registry survey identified a further 1261 suitable concurrent cases . Trial patients were compared with the 960 non-trial cases from participating Districts . Only 493 ( 51 % ) non-trial cases passed all of the prospect i ve trial selection criteria for entry . Stage and fitness caused the majority of exclusions and were also highly prognostic . A univariate analysis comparing eligible patients with the trial showed the two groups to be balanced for the significant independent prognostic factors of the trial . However , differences in patient age and the surgery performed indicate that recruitment may have been influenced by unknown selection factors . This survey highlights the difficulty of retrospective selection and confirms the need for r and omised controls . Data available from specialist Registries may be used to help develop new protocol s and to verify and extend trial results The tricyclic antidepressant drug amitriptyline was evaluated as a short-term treatment of anorexia nervosa patients . In a 5-week double-blind , placebo-controlled study 11 patients were given amitriptyline and 14 received placebo . In addition , 18 patients who refused to participate in the drug trial and received only psychosocial treatment were used as an additional comparison group . Overall , patients in the three groups showed little improvement . No statistically significant differences favoring amitriptyline were found in any of the outcome variables . Plasma levels varied widely among patients receiving similar doses . No association was found between plasma levels and improvement in either psychiatric symptomatology or weight . Amitriptyline patients did not manifest any tendency for a reduction of depressive symptomatology . In addition , amitriptyline treatment was associated with substantial discomfort and adverse affects & NA ; The thoracodorsal vessels have been the st and ard recipient vessels for the majority of surgeons performing free transverse rectus abdominis musculocutaneous ( TRAM ) flap reconstructions . Recently , the internal mammary vessels have been recommended as the first‐choice recipient vessels for microvascular breast reconstruction . This approach requires a shorter pedicle length , allows for central placement of flap tissue , and avoids axillary scarring . The use of the internal mammary vessels may provide for a shorter operative time and a higher‐ quality aesthetic reconstruction . The authors performed a prospect i ve trial examining the differences in operative and aesthetic outcomes between each recipient site . A prospect i ve trial of 108 consecutive free‐tissue transfers was conducted in 100 patients . The first 60 TRAM flap patients were r and omized so that 30 flaps were anastomosed to the internal mammary vessels and 30 were anastomosed to the thoracodorsal vessels , whereas the recipient vessels for the remaining 40 patients were left to the discretion of the surgeon . Of the 10 nonr and omized patients , 10 patients underwent reconstruction using the internal mammary vessels and 30 patients underwent reconstruction using the thoracodorsal vessels . The patients ' medical history and hospital course were noted . To evaluate aesthetic outcome , a group of five blinded nonmedical observers and three blinded plastic surgeons grade d the reconstructions in the 60 TRAM flap patients for symmetry and overall aesthetic result on a scale of 1 to 5 . Blinded practitioners administered postoperative question naires to patients regarding recovery time and satisfaction with the aesthetic result . Forty‐three flaps were transferred to the internal mammary vessels and 65 were transferred to the thoracodorsal vessels . No significant differences existed between groups with regard to age of preoperative risk factors . Average operative time was 6 hours in each group . Average hospital stay was 5.8 days in each group . Conversion from initial recipient vessel to a secondary recipient site occurred in 12.5 percent of internal mammary reconstructions and 7 percent of thoracodorsal reconstructions . All converted internal mammary cases occurred in left‐sided reconstructions and were attributable to problems with the veins . Overall , 20 percent of left‐sided internal mammary reconstructions were found to have an inadequate recipient vein . Unusable thoracodorsal vessels were found only in delayed reconstructions , at a rate of 15 percent in the delayed setting . All flaps from converted procedures survived without complications . Average follow‐up was 20 months , during which time there was one flap loss in the thoracodorsal group . There were no significant differences in complication rates between groups . Average aesthetic grade was 3.6 in each group . Postoperative recovery time and overall patient satisfaction were not significantly different between groups . Either recipient site can provide for a safe and acceptable result ; however , surgeons should be aware of conversion rates and plan appropriately if recipient vessels appear unusable for free‐tissue transfer . ( Plast . Reconstr . Surg . 111 : 1876 , 2003 . Alcoholic patients r and omly assigned to day hospital or inpatient rehabilitation were compared with patients who self-selected these treatment setting s to examine differences in substance use and psychosocial outcomes under experimental and nonexperimental design s. Patients who self-selected treatment did not have better outcomes than those who were r and omly assigned , and there were no significant differences between day hospital patients and in patients on any of the 11 outcome measures . Significant interactions between treatment setting and assignment were found with only 2 outcome measures . Therefore , the comparisons between day hospital and inpatient treatment yielded similar outcomes under both " scientific " conditions and the conditions that more closely approximate the experiences of most patients . Implication s for the use of nonr and omized participants in alcoholism treatment research and limitations of the study were also discussed Twenty-four cancer patients with diffuse interstitial pneumonitis ( DIP ) were r and omized to undergo an open lung biopsy ( OLB ) within 8 hours of presentation ( 12 patients ) or to receive empiric antimicrobial therapy ( ET ) with trimethoprim-sulfamethoxazole ( TMP-SMX ) erythromycin for a minimum of 4 days ( 12 patients ) . Patients whose condition deteriorated underwent an OLB on day 4 . Eight of 12 patients ( 67 % ) having OLB survived versus 10 of 12 ( 83 % ) receiving ET ( P = .64 ) . Morbidity occurred in nine of 12 ( 75 % ) having OLB versus eight of 12 ( 67 % ) receiving ET ( P = 1.0 ) . Concurrently , there were 14 additional cancer patients with DIP who were not r and omized ( nine refused , three had a coagulopathy contraindicating surgery , two were excluded by primary care physicians ) and who were comparable demographically to the r and omized group . Two received OLB and 12 ET . Combining the r and omized and nonr and omized groups , eight of 14 ( 57 % ) having an initial OLB survived versus 18 of 24 ( 75 % ) of ET-treated patients ( P2 = .19 ) . Results of the OLB were seven Pneumocystis carinii pneumonia ( PCP ) , five nonspecific pneumonitis ( NSP ) , one cytomegalovirus , and one lymphoma . Results of OLB led to discontinuation of antibiotics in three patients . Of the 24 ET patients , eight failed to improve by day 4 and had an OLB . Results were two NSP , two PCP , two cancer , one blastomycosis , and one C and ida pneumonia . Complications were seen in 10 of 14 ( 72 % ) initial OLB patients versus 14 of 24 ( 58 % ) patients on the ET arm ( P = .65 ) . When the complication rate between patients receiving only empiric antibiotics was compared with all patients having an OLB ( initially or on day 4 ) , the difference was greater in patients undergoing OLB ( 37 % v 72 % , respectively ) ( P2 = .14 ) . ET with TMP-SMX plus erythromycin and broad spectrum antibiotics in granulocytopenic patients appeared to be as successful and potentially less toxic than an OLB in this study . Although the number of patients in this study was small , these data suggest that a trial of empiric antibiotic management may be reasonable in cancer patients presenting with DIP , especially if they are nonneutropenic Eligible participants and decliners in a r and omized study of inpatient , intense outpatient , and st and ard outpatient treatments for alcoholics were compared and contrasted on a series of demographic , social stability , psychological , legal , drug use , problem severity , and treatment history variables . Among 302 individuals meeting eligibility requirements , those agreeing to participate , compared with decliners , were more likely to be unemployed , be residentially less stable , have legal problems , use other drugs , have a more severe alcohol problem , have a recent treatment history , and were less likely to have problems with violence . Participants also were more likely to be male and non-white , although gender and racial effects were not significant when other variables were controlled for . The implication s of these findings for generalizing the results of inpatient-outpatient studies are discussed , and the need for routine reporting of decliner characteristics in research reports is stressed Five hundred four shunt procedures have been done at Emory University Hospitals between 1971 and 1981 to decompress bleeding esophageal varices . This paper review s how far the experiences of a prospect i ve r and omized study ( 55 patients ) of distal splenorenal shunts against total shunts is supported by the nonr and omized experience ( 449 patients ) , and outlines our current methods of management dictated by this experience . The overall operative mortality for 348 selective shunts is 4.1 % , and for 156 nonselective shunts , 14.1 % . The five-year survival following selective shunt is 59 % , and following nonselective shunt is 49 % : more than half the selective shunt patients are alive , in contrast to the median survival of 44.5 months for patients having nonselective shunts . Following selective shunt , the survival in nonalcoholic patients is significantly better than the median survival of alcoholic patients of 57 months . Encephalopathy , reported at three years after surgery in the r and omized patients was significantly ( p < 0.001 ) lower after selective shunt ( 12 % ) compared to nonselective shunt ( 52 % ) : in the same population at seven years , all patients with patent nonselective shunts have clinical or sub clinical encephalopathy , but only 30 % of the selective shunt patients have sub clinical encephalopathy . Shunt patency , immediately after surgery , is 93 % following selective shunt , with only two documented late thromboses : nine of nine patients , at a mean of seven years , retain patency in the r and omized study . Shunt occlusion increases with time after interposition nonselective shunts : seven of 13 are occluded at a mean follow-up of seven years in the r and omized study . Portal venous perfusion is retained in 93 % of patients seven to ten days after selective shunt , but in no patient with a patent nonselective shunt . Late portal perfusion is maintained in nine of the eleven patients in the r and omized group studied at a mean of seven years after selective shunt . Restoration of portal perfusion has led to clearing of encephalopathy and improvement in hepatic function in six patients . The following conclusions are made ; ( 1 ) selective shunts can be done with low operative mortality , and long-term patency with excellent control of bleeding ; ( 2 ) hepatic portal venous perfusion has been maintained after selective shunt for ten years , and this is vital for preventing encephalopathy and maintaining hepatic function ; ( 3 ) long-term survival after selective shunt is better than any reported series for nonselective shunt ; and ( 4 ) selective shunts are the operative procedure of choice for variceal decompression and nonselective shunts should rarely be performed for elective decompression Summary We first compared glomerular charge selectivity index in two matched groups of Type 1 ( insulin-dependent ) diabetic patients with micro and normoalbuminuria respectively , and secondly , investigated prospect ively in a r and omized clinical trial , the influence of improved metabolic control on selectivity index in diabetic patients with microalbuminuria . In Study 1 , 27 patients with microalbuminuria ( albumin excretion > -15 μg/min in at least two out of three overnight urine sample s ) were matched ( age , diabetes duration , mean 1-year HbA1c , gender ) with normoalbuminuria patients ( n=24 ) , and in Study 2 , 23 microalbuminuric patients were r and omly allocated to either intensive ( continuous subcutaneous insulin infusion ) or conventional treatment . Glomerular charge selectivity index was measured as IgG/IgG4 selectivity index , i.e. total IgG/IgG4 clearance ratio in timed overnight urine sample s. The microalbuminuric patients had a significantly reduced selectivity index compared to the normoalbuminuric patients : 1.20 ( 0.92–1.40 ) vs 1.68 ( 1.22–2.21 ) , median and 95 % confidence interval ( p<0.01 ) . In Study 2 , the HbA1c improved in the intensive-treatment group compared to the conventional-treatment group : at 2 , 6 and 12 months the difference in mean percentage HbA1c between the groups was 1.1 , 1.2 and 1.4 , respectively ( p<0.01 ) . A sharp 50 % increment in IgG/IgG4 selectivity index was seen in the intensive-treatment group during the first 6 months ( p<0.05 compared to the conventional group ) . We conclude that adolescents and young adults in an early stage of diabetic nephropathy have reduced glomerular charge selectivity , which may be improved by reducing the mean blood glucose level Between 1974 and 1982 , 273 patients with epithelial cancer of the ovary ( International Federation of Gynaecology and Obstetrics Stages III and IV ) were r and omized in four therapeutic trials . In Trial I Adriamycin plus cisplatin versus cisplatin alone versus thiotepa plus methotrexate was tested . The superiority of Adriamycin plus cisplatin in producing the best response rate led to its use as the reference arm in subsequent trials . All investigational arms included cisplatin plus other drugs ( cyclophosphamide , Adriamycin , hexamethylmelamine , and thiotepa ) in various combinations . Eligibility for second look required complete clinical remission and completion of at least 10 cycles of chemotherapy . To date , 73 second-look operations have been performed on r and omized patients . An additional 43 nonr and omized patients underwent second-look procedures and are analyzed separately . Between 40 % and 46 % of patients treated with cisplatin regimens had no disease at second look . Cell differentiation and volume of postoperative disease did not influence response A total of 83 patients with nonorgan-confined bladder cancer with or without lymph node metastases ( tumor stages pT3b , pT4a and /or pN1 , pN2 ) was evaluated in November 1993 for relapse-free and overall survival . All patients underwent radical cystectomy between 1987 and 1991 , 38 underwent adjuvant polychemotherapy with methotrexate , vinblastine and cisplatin plus doxorubicin ( M-VAC ) or epirubicin ( M-VEC ) . Of the 83 patients 49 had entered a prospect i ve r and omized trial comparing adjuvant to no adjuvant treatment . The protocol was activated in May 1987 . Patient recruitment was concluded in December 1990 because an interim analysis of the 49 r and omized patients revealed a significant prognostic advantage in favor of the 26 patients r and omized to the chemotherapy group compared to 23 in the control group ( p = 0.0015 , log-rank test for relapse-free survival curves ) . Preliminary data were published in 1992 . Of the 26 patients r and omized for adjuvant chemotherapy 18 were treated with M-VAC or M-VEC , 7 refused chemotherapy before or during cycle 1 and 1 received chemotherapy without cisplatin because of impaired renal function . The up date of patient followup obtained in November 1993 continues to demonstrate a significant improvement in progression-free survival in favor of patients r and omized for adjuvant chemotherapy ( p = 0.0005 ) . Followup of patients living free of disease ranged from 38 to 78 months . In a second analysis of actual treatment , the total collective of 83 patients treated from 1987 to 1991 was review ed : 38 who had actually undergone adjuvant M-VAC/M-VEC ( 18 during the prospect i ve trial and 20 in 1991 as the routinely recommended therapy ) were compared with 45 without adjuvant M-VAC/M-VEC ( 7 refused to participate in the adjuvant trial , 8 r and omized for but did not undergo adjuvant M-VAC/M-VEC , 23 belonged to the control group of the trial , and 7 underwent cystectomy in 1991 and remained without adjuvant treatment ) . This analysis again revealed a significant prognostic advantage in favor of the patients treated with adjuvant M-VAC/M-VEC . We conclude that adjuvant chemotherapy with M-VAC/M-VEC leads to a significant prolongation of relapse-free survival and to an improvement of the definitive cure rates after radical cystectomy for locally advanced transitional cell carcinoma of the bladder BACKGROUND Patient preferences for treatment can pose problems for the conduct of r and omised controlled trials : patients with a preference may refuse participation and thereby potentially compromise external validity . Moreover , r and omising patients with a preference may affect treatment efficacy and threaten internal validity . AIMS This study compared baseline characteristics and short-term psychological outcomes of patients who selected their treatment and those who agreed to r and om allocation . METHODS Men participating in the prostate testing for cancer and treatment ( ProtecT ) study and who were r and omised to active monitoring ( n=138 ) were compared with those who had refused r and omisation and selected this management ( n=180 ) . Socio-demographic data were collected at baseline , and anxiety and depression data were collected at baseline and six month follow-up . Socio-demographic characteristics were compared across these two groups in univariable analyses , and then linear regression was used to compare levels of anxiety and depression at follow-up with adjustments for confounders . RESULTS Participants who selected active monitoring were more affluent ( based on occupation details ) and had less anxiety at baseline than those who were r and omised . There were no differences with respect to age and marital status . Levels of anxiety and depression at six months follow-up were similar across the two groups of men . CONCLUSIONS This study found some differences at baseline between the socio-demographic and psychological status of those r and omised and self- selecting treatment , but no psychological differences at short-term follow-up . Further empirical evidence is required to assess whether preferences impact upon the process and outcome of r and omised controlled trials In parallel with a r and omized study of the ' starting again ' rehabilitation program for cancer patients , a group of 73 non- participants were monitored ( another 20 patients declined monitoring ) . In comparison with participants ( intervention + control ) , gender , diagnosis , and 10 out of 18 dependent measures differed significantly at baseline . The non- participants group included more men , mostly with cancer of the prostate and irrespective of gender , they showed lower problem levels than participants throughout . Thus , the wish to participate seems to be an indicator of the need for assistance in the rehabilitation process . Social validation of effects was performed by comparing the non- participants with the intervention group . The rationale for this comparison is that non- participants presumably felt so well that they were in no need of rehabilitation . Effects on three variables were socially vali date d : patients ' appraisal of having received sufficient information , physical strength and fighting spirit . No negative effects on outcome variables result ing from being r and omized to the control condition ( resentful demoralization ) were detected when non- participants were compared with controls over one year . Further analysis showed that although a few patients in the control group may have experienced resentful demoralization , this did not significantly affect the outcome variables Twenty-nine patients with cystic fibrosis received either cefsulodin or a reference agent ( tobramycin or ticarcillin ) in a r and omized manner for treatment of pulmonary infections associated with Pseudomonas aeruginosa . Patients ranged in age from 12 to 30 years . Their infections were classified as mild ( six ) , moderate ( 16 ) , or severe ( seven ) . Fourteen patients received cefsulodin , 14 patients were treated with tobramycin , and one patient received ticarcillin . Significant clinical improvement was noted in the majority of patients in both groups . Adverse effects and development of laboratory abnormalities were uncommon in both groups . P. aeruginosa was not permanently eradicated from the sputum of any of the patients . Resistance as measured by disk susceptibility testing may have developed during and immediately after therapy in the cefsulodin group but not in those treated with reference agents . However , this did not appear to affect the clinical outcome . Results of the nonr and omized portion of this multicenter study , in which 46 patients were treated with cefsulodin , were similar to those for the r and omized group . Thus , cefsulodin was shown to be as clinical ly effective as the reference agents in the treatment of lower respiratory tract infections due to Pseudomonas aeruginosa in patients with cystic fibrosis PURPOSE One of the goals of study AMA-BFM-87 was to test prospect ively in acute myelogenous leukemia ( AML ) patients if cranial irradiation could be replaced by late intensification therapy with high-dose cytarabine ( Ara-C ) and etoposide ( VP-16 ) . PATIENTS AND METHODS Patients with a low risk of CNS relapses ( ie , no initial CNS disease , WBC count at diagnosis < or = 70.000/microL ) were r and omized for irradiation ( group A , 31 patients ) . In 25 patients ( group B ) , r and omization was refused . As interim results showed no increase of CNS relapses in nonirradiated patients , prophylactic irradiation was discontinued after 2 1/2 years to prevent unnecessary CNS toxicity . Forty-four patients ( group C ) entered the study after r and omization had been stopped . RESULTS In all patients with a low risk of CNS recurrences ( n = 100 ) , a significantly higher probability of relapse-free interval ( pRFI ) of 5 years was found in irradiated patients ( pRFI = .78 ) compared with nonirradiated patients ( pRFI = .41 ) ( P = .007 ) . Moreover , a slightly higher incidence of CNS relapses was observed in nonirradiated patients . Due to the small number of patients , this was not observed when r and omized patients only were analyzed . In accordance with these findings , the favorable outcome of low-risk patients in the preceding study , AML-BFM-83 ( pRFI > .80 ) , could only be reproduced in study AML-BFM-87 in patients who had received cranial irradiation . CONCLUSION These results indicate that cranial irradiation should be an integral part of the treatment of all AML patients not undergoing bone marrow transplantation . Residual blasts in the CNS may escape systemic chemotherapy and lead to recurrence of the initial disease not only in the CNS , but also in the bone marrow OBJECTIVE --To investigate the rate of recruitment to early breast cancer trials and eluci date the reasons for in eligibility and refusal to participate among patients otherwise suitable for these trials . DESIGN -- Prospect i ve study of one year 's cohort of patients referred to a breast unit with special reference to the subgroup suitable for conservation management and to the proportion eligible for and ( after informed consent ) ultimately r and omised within the Scottish early breast cancer trials . SETTING --The breast unit , Longmore Hospital , Edinburgh , during 1988 . PATIENTS --All 3054 patients referred to the breast unit during the year . 324 Found to have invasive breast cancer and 147 initially thought suitable for conservation management . RESULTS --63 Patients were treated by mastectomy , 19 of whom requested mastectomy rather than conservation management . 84 Patients were excluded from trials , and of the 63 eligible patients , 40 gave informed consent . Most of the 23 patients who refused the trials requested a specific adjuvant treatment after discussion of their management and the trials . CONCLUSIONS --Recruitment to prospect i ve trials in which informed consent is required before r and omisation may be slower than predicted because of a high proportion of exclusions and also refusal by patients . Trials may therefore take longer to complete and give distorted results by virtue of the unpredictable nature of the selection of patients From May 1964 to December 1965 , a controlled field trial of the effectiveness of cholera and cholera El Tor vaccines was conducted in Negros Occidental , Philippines . Some people did not volunteer for vaccination , and of those who did some received cholera vaccine and others a control ( typhoid ) vaccine . After analysing he incidence of cholera among these three groups it was found that the morbidity and mortality rates were significantly higher in the unvaccinated group than in either the control vaccine group or the cholera vaccine group . This would indicate that the unvaccinated group is basically different from the vaccinated control group . The clinical course of the disease was the same whether the patient had been vaccinated or not . The reasons for non-vaccination were investigated and should be taken into account by public health agencies when immunization programmes are being planned The safety of the combined oligosaccharide conjugate Haemophilus influenzae ( Hib ) type b ( HbOC ) and whole cell diphtheria-tetanus toxoids-pertussis ( DTP ) vaccine ( Tetramune$ , HbOC-DTP ; Lederle ) in infancy was evaluated in 6644 recipients of this vaccine and compared with 3914 recipients of separate injections of whole cell DTP and HbOC vaccines when given as a three dose regimen to infants at 2 , 4 and 6 months of age in each group . Of the total number of infants in the study , a subset of 1435 were enrolled into the study and then r and omly assigned to recieve either the Hib-DPT combined vaccine or the separate components . This subset was used to assess local and systemic side effects which were evaluated utilizing telephone interviews 48 to 72 hours after vaccine . The remaining children in the study population were enrolled in a nonr and omized manner . For these children parents were offered the experimental Hib-DPT vaccine and refusers were given HbOC and DTP . Both of these groups of children as well as the r and omized subset described above were used to assess rates of episodes of hospitalization , emergency room utilization and sudden infant death syndrome in HbOC-DTP recipients and children who received HbOC and DTP separately . Immunogenicity was evaluated in 123 children by collection of a single serum sample 30 days after the third dose of HbOC-DTP . The observed immunogenicity was comparable to that observed in other recent studies for HbOC and DTP component antigens . The profile of local and systemic side effects observed was virtually identical to that observed after DTP plus HbOC given separately . In initial analyses the Hib-DPT children appeared to have a higher rate of hospitalization for pneumonia than the children with separate shots . After further analyses including chart review , review of chest radiographs , and adjustment for age and season , this initial association was believed most probably to be a result of chance alone . The HbOC-DTP vaccine offers the convenience of a single combined vaccine offering protection against diphtheria , pertussis , Hib and tetanus without any substantial or significant change in safety or immunogenicity profile A single centre series of 195 consecutive newly diagnosed untreated myeloma patients under 70 years , seen between September 1986 and March 1994 , were analysed to assess the impact of current intensive treatment methods upon remission rate , response rate and subsequent outcome . They were predominantly an unselected population based group of patients ( other than by age ) that could be used by purchasers of health care as a model for outcome assessment . All patients were scheduled to receive a care plan which included a sequential package of treatment consisting initially of courses of infusional chemotherapy using vincristine , adriamycin and methyl prednisolone ( VAMP ) and 90 of these also received cyclophosphamide ( C-VAMP ) . Thirty-eight patients received verapamil in addition to C-VAMP(V-C-VAMP ) . After VAMP all patients were planned to receive high-dose treatment with melphalan and an autograft ( marrow or blood ) and 112 received this treatment ; a further 29 patients received modified high-dose treatment with melphalan alone ( 23 ) or busulfan ( 6 ) and 54 ( 28 % ) did not proceed to high-dose treatment because of refusal , resistant disease , poor performance or treatment-related death . The patients who received melphalan or busulfan alone instead of high-dose melphalan/autografts did so because of increasing age ( P = 0.001 ) and a raised creatinine ( P = 0.05 ) . The complete remission rate was 53 % for the whole group and 74 % for those receiving high-dose melphalan and an autograft . From July 1988 , the sequential therapy package included continuous three times weekly interferon ( IFN ) after high-dose treatment as maintenance therapy , initially as part of a controlled r and omised trial and then for all suitable patients . Fifty-seven patients received IFN . The median overall survival ( OS ) and progression-free survival ( PFS ) from first treatment for the whole group of 195 patients is 4.5 years and 25 months , respectively . The 112 patients receiving the melphalan autografts fared significantly better than the rest of the patients with OS and PFS ( from high-dose treatment ) of 6.6 years and 27 months , respectively ( P < 0.005 ) , and the 57 patients also receiving ifn have a os yet to reach a median at 8 years and a pfs of 44 months , significantly better than non ifn high-dose patients ( P < 0.0036 ) . however , although we showed benefit for selected patients in studies and trials ( particularly with ifn ) during the 8-year period of the series , this did not translate into overall pfs benefit in our study for unselected cohorts of patients for 1986–1988 ( 64 patients ) 1989–1992 ( 100 patients ) and 1992–1994 ( 31 patients ) in spite of progressive increases in the proportion of patients receiving ifn ( respectively 6 , 35 and 58 % ) . this is likely to be due to the dilution of benefit to specific patients by the overall number of patients involved . outcome data from unselected patients are now expected by purchasers and presented in this way , help qualify the activity impact of advances made from research trials for the treatment of population -based cancer problems The cholecystokinetic effect of ceruletide , a synthetic decapeptide similar in action to cholecystokinin , was examined in both a r and omized and nonr and omized study in 81 patients scheduled for routine oral cholecystograms . Intramuscular injection of ceruletide in a dose of 0.3 microgram/kg result ed in a mean maximum contraction of the gallbladder of 68 % and a mean time until maximum contraction of 28 minutes . Visualization of the cystic duct occurred in 57 patients ( 70 % ) ; the common duct was seen in 67 ( 83 % ) . Ceruletide demonstrated superior gallbladder contraction when compared to fatty meals and demonstrated no interference with a subsequent upper gastrointestinal series One hundred twenty‐three women younger than 70 years of age and at clinical Stages I or II were enrolled in a r and omized clinical trial of radical versus extended radical mastectomy . The 5‐year survival rates in the radical and extended radical groups were 75 ± 6.7 % and 80 ± 6.7 % , respectively . ( Cox P value for comparison of survival curves = 0.32 . ) Of the total series , 112 were treated by the same surgeon and confirmed pathologically as having invasive mammary carcinoma . In this more homogeneous subgroup , the 5‐year survival rates for the radical and extended radical groups were 71 ± 7.6 % and 85 ± 6.2 % , respectively ( P = 0.09 ) . For patients from this subgroup with central or medial tumors , the 5‐year survival rates were 66 ± 10 % and 88 ± 8.2 % , respectively ( P = 0.06 ) . For patients with lateral tumors , the 5‐year survival rates were nearly equal : 79 ± 11 % and 81 ± 9.7 % , respectively . The findings in a nonr and omized series of similar patients were comparable . The results are not definitive , but suggest an advantage of extended radical mastectomy over radical mastectomy for patients with central or medial tumors . Continued follow‐up of the r and omized series may lead to more conclusive results Eleven-year mortality rates were studied in middle aged men who had participated in a r and omised 5-year multifactorial primary prevention trial on cardiovascular diseases during 1974 - 1980 . The men were given health education advice before the study . The 5-year trial markedly improved the risk factor status in the men in the intervention group ( n = 612 ) , but their 5-year incidence of total coronary events tended to be higher than in the r and omised non-treated control group ( n = 610 ) and significantly higher than in an non-r and omised , non-treated low risk group ( n = 593 ) . During the six years following the discontinuation of the trial , 11 deaths from cardiovascular disease occurred both in the intervention and in the control groups and three in the non-r and omised low risk group . Thus , the cumulative eleven-year cardiovascular mortality rates and their 95 % confidence intervals ( Cl95 ) were 2.45 % ( Cl95 : 1.38 , 3.67 ) in the intervention group and 1.97 % ( Cl95 : 1.01 , 3.34 ) in the r and omised high risk control group . In the non-r and omised low risk group the mortality rate was 0.51 ( Cl95 : 0.01 , 1.46 ) . Multiple logistic regression analysis showed that overweight and hypercholesterolaemia , and smoking in the high risk controls , were the initial risk factors associated with the 11-year cardiovascular mortality . The latter was not accumulated in any treatment measure during the prevention period . Furthermore , despite the unfavourable effect of beta-blocking agents on total cardiac events during the intervention , beta-blockers were not associated with cardiac deaths in the 11-year follow up . ( ABSTRACT TRUNCATED AT 250 WORDS In a double blind , prospect i ve , r and omised study of 100 patients undergoing elective cardiac surgery , a significant ( p less than 0.01 ) reduction in wound colonisation , defined as positive culture of any wound discharge irrespective of wound appearance , occurred in those receiving preincisional presternal antibiotic infiltration ( 2 % ) as compared to a control group who received a similar volume of normal saline by the same route ( 24 % ) . Both groups received , in addition , the same conventional intravenous regimen of broad spectrum antibiotic . A comparable concurrent group of patients , not entered into the study , demonstrated a wound colonisation rate similar to the trial control group ( 22 % ) , thus excluding an adverse bias from the control saline infiltration . Analysis of control cases demonstrated a significant ( p less than 0.001 ) discriminant effect in the degree of preoperative haemodilution with haematocrit falling on bypass by a mean of 25 % in those who developed wound colonisation as compared to 13 % in those who did not OBJECTIVE To study the effectiveness and acceptability of day case hysteroscopic surgery . DESIGN Prospect i ve r and omised controlled trial . SETTING Aberdeen Royal Infirmary . SUBJECTS One hundred and ninety four consecutive women who underwent hysteroscopic endometrial ablation . INTERVENTION Seventy three women were allocated to day case surgery and 37 to inpatient admission ; 84 women though otherwise fit for day case surgery were scheduled for in-patient admission as they lived more than 20 miles away . All women completed a question naire 24 h after their operations . Readmission rates were obtained from case notes . Satisfaction rates 12 months after the operation were recorded by means of a follow-up question naire . RESULTS Post-operative pain was absent or slight in 48 ( 75 % ) of the women in the day case group 27 ( 84 % ) of women in the in-patient group , and 55 ( 82 % ) in the non-r and omised in-patient group . Post-operative analgesia was necessary in 34 ( 52 % ) women in the day case group , 24 ( 75 % ) women in the in-patient group and 36 ( 53 % ) women in the non-r and omised in-patient group . Hospital costs were significantly less in the day case group . Satisfaction with stay 92 % in the day case group , and 100 % in the other two groups . CONCLUSION In this setting , day care is a safe acceptable and less expensive alternative to in-patient care for hysteroscopic endometrial ablation The external validity or generalizability of a treatment outcome study may be influenced by the choices patients make ( self- selection ) and by study requirements intended to increase internal validity or protect subject welfare ( e.g. sample selection ) . Although these effects are well-known , they have rarely been studied , and little is known about the impact they may have on generalizability of findings . In this study , subjects accepting r and om assignment to a larger study examining pharmacologic and cognitive-behavioral treatments for social phobia were compared with subjects refusing r and om assignment ( i.e. self-selected ) and excluded subjects ( i.e. " sample -selected " ) . " Acceptors " differed from " refusers " on some measures suggesting that they have a lower annual income and may have fewer social supports . Therefore , they may have fewer available re sources and might be more willing to accept help wherever it is offered . Despite these differences , acceptors differed from refusers on just one pretreatment measure of clinical functioning . Excluded subjects did not differ from refusers or acceptors on demographic or pretreatment clinical measures . Refusers and excluded subjects were treated with the same cognitive-behavioral treatment used in the comparative outcome study , and their posttreatment data were compared with the subgroup of acceptors who were r and omly assigned to that treatment . Again , there were few significant differences . These results suggest that while self- selection and sample selection may have influenced some characteristics of the sample in this comparative outcome study , the three groups of subjects were clinical ly similar and responded similarly to cognitive-behavioral treatment of social phobia A controlled prospect i ve evaluation of pregnancy complicated by chronic hypertension is proposed and preliminary data on population selection and pregnancy outcome are presented . Sixty-three women with evidence of underlying hypertensive disease were followed prospect ively throughout pregnancy . Twenty-three patients were followed in a protocol of intensified prenatal care and r and omized assignment of antihypertensive agents : placebo , hydralazine , or methyldopa . Forty patients were followed in the high-risk pregnancy clinics at Duke University . The incidence of preeclampsia in the r and omized prophylactic antihypertensive group was statistically lower than that in the nonr and omized group ( 8.7 versus 32.5 % ; P<.01 ) . There were no other statistically significant differences between the groups . The 63 hypertensive women had a high incidence of diabetes mellitus diagnosed during pregnancy ( 49.2 % ) as compared to the authors ' general obstetric population ( 8.1 % ) OBJECTIVES The aim of this study was to assess the reliability of patency rates calculated on basis of data from a st and ard vascular registry . DESIGN AND SETTING Since 1989 , all patients undergoing infrainguinal bypass procedures have been offered a st and ard follow-up programme at 3 month intervals and all data have been recorded prospect ively in a vascular registry . As part of a r and omised trial on adjuvant medication in femorocrural bypass surgery , 102 patients , operated on between 1990 and 1992 were independently and simultaneously monitored . This subgroup was examined at 3 and 12 months postoperatively and 100 % follow-up was obtained . After completion of the trial we calculated the patency and survival rates using life-table methods and compared the results based on the vascular registry with those achieved in the clinical trial . RESULTS Comparing the results from the two data bases revealed a marked discrepancy between the calculated figures : primary ( 68 % in the registry and 52 % in the trial ) and secondary patency rates ( 90 % vs. 63 % ) , limb survival ( 97 % vs. 77 % as well as patients survival rates ( 95 % vs. 85 % ) . The differences could be explained by a substantial number of patients being lost to follow-up according to the vascular registry data base and the fact that these patients turned out to have a significantly increased rate of graft thrombosis , limb amputation and death , respectively . CONCLUSIONS Life-table statistics may inadvertently become unreliable if a large proportion of patients is lost to follow-up , since failure to examine the patient for any reason may be related to the patients health . In addition to the number of patients at risk , it is suggested , that life-table plots should be supplemented with information on the number of patients lost to follow-up OBJECTIVES We sought to determine whether the prehospital electrocardiogram ( ECG ) improves the diagnosis of an acute coronary syndrome . BACKGROUND The ECG is the most widely used screening test for evaluating patients with chest pain . METHODS Prehospital and in-hospital ECGs were obtained in 3,027 consecutive patients with symptoms of suspected acute myocardial infa rct ion , 362 of whom were r and omized to prehospital versus hospital thrombolysis and 2,665 of whom did not participate in the r and omized trial . Prehospital and hospital records were abstract ed for clinical characteristics and diagnostic outcome . RESULTS ST segment and T and Q wave abnormalities suggestive of myocardial ischemia or infa rct ion were more common on both the prehospital and hospital ECGs of patients with as compared with those without acute coronary syndromes ( p < or = 0.00001 ) . Those with prehospital thrombolysis were more likely to show resolution of ST segment elevation by the time of hospital admission ( 14 % vs. 5 % in patients treated in the hospital , p = 0.004 ) . In patients not considered for prehospital thrombolysis , both persistent and transient ST segment and T or Q wave abnormalities discriminated those with from those without acute coronary ischemia or infa rct ion . Compared with ST segment elevation on a single ECG , added consideration of dynamic changes in ST segment elevation between serial ECGs improved the sensitivity for an acute coronary syndrome from 34 % to 46 % and reduced specificity from 96 % to 93 % ( both p < 0.00004 ) . Overall , compared with abnormalities observed on a single ECG , consideration of serial evolution in ST segment , T or Q wave or left bundle branch block ( LBBB ) abnormalities between the prehospital and initial hospital ECG improved the diagnostic sensitivity for an acute coronary syndrome from 80 % to 87 % , with a fall in specificity from 60 % to 50 % ( both p < 0.000006 ) . CONCLUSIONS ECG abnormalities are an early manifestation of acute coronary syndromes and can be identified by the prehospital ECG . Compared with a single ECG , the additional effect of evolving ST segment , T or Q waves or LBBB between serially obtained prehospital and hospital ECGs enhanced the diagnosis of acute coronary syndromes , but with a fall in specificity Summary Purpose : Bryostatin-1 is a PKC modulator with direct anti-tumor activity and immunomodulatory properties . We combined different doses of Bryostatin-1 with IL-2 to determine effects on clinical response rate and T cell phenotype in patients with advanced kidney cancer . Experimental Design : IL-2 naïve patients were given 11 × 106 IU subcutaneously of IL-2 on days 1–4 , 8–11 , and 15–18 of every 28-day cycle . Twenty four patients were r and omized to treatment cohorts of 5 , 15 or 25 mcg/m2 of Bryostatin-1 on days 1 , 8 and 15 , starting in the second cycle . An additional nine , non-r and omized patients were given 35 mcg/m2 . Lymphocytes were analyzed for number , activation status , and production of IL-2 , IL-4 and IFN-γ . Response evaluation was performed every 3 cycles . Results : Common grade 3 toxicities included fatigue ( 5 ) , nausea/vomiting ( 5 ) , myopathy ( 3 ) , dyspnea ( 3 ) , and syncope ( 3 ) . Four patients , in the two highest dose cohorts , demonstrated evidence of tumor shrinkage , although there was only 1 objective PR . The median time to progression was 104 days ( 95 % CI 88–120 ) and the median survival was 452 days ( 95 % CI = 424–480 ) . There was no significant boosting effect of Bryostatin-1 on lymphocytes . Conclusions : The addition of Bryostatin-1 to IL-2 was well tolerated , but the overall response rate was low ( 3.2 % ) , indicating that further studies with this combination are not warranted We studied spontaneous resolution of congenital nasolacrimal duct obstruction in the second year of life and compared this with the cure rate after probings undertaken between the ages of 11 and 15 months . Of the 111 eyes of 95 patients studied , 26 eyes were included in a r and omised prospect i ve comparison of probing with spontaneous resolution . A further 63 eyes followed a similar management plan to the r and omised group and are reported as an observational study . Thirty of the 50 eyes followed up without treatment resolved spontaneously before the age of 2 years , of which 24 resolved before 18 months . The overall cure rate for probing was 74 % compared with 60 % for spontaneous resolution . At 15 months of age the r and omised study confirmed that probing at 12 - 14 months is an effective intervention compared with spontaneous resolution ( p = 0.04 ) . At 24 months of age probing was superior in both r and omised and nonr and omised studies , but with increased numbers in the spontaneous resolution groups the difference was no longer statistically significant . Up to 18 months of age the frequency of spontaneous resolution makes delay in probing a viable management option to be discussed with the parents . It will also lead to an overestimate of the cure rate in any study of interventional treatment unless controls are included The Pediatric Oncology Group ( POG ) undertook a prospect i ve r and omized trial using a single chemotherapy regimen with or without trimethoprim/sulfamethoxazole ( TS ) . In a previous acute lymphocytic leukemia ( ALL ) study of initial therapy , investigators were free to use TS prophylaxis or not . Analysis of those data seemed to favor TS for duration of continuous complete remission . In the study reported here , of 126 r and omized patients with ALL , 63 received TS . There was no effect of TS on disease‐free survival after 3 years follow‐up . Overall severe toxicity did not differ . However , granulocytopenia was somewhat more severe in the TS group . Hepatic toxicity , measured by enzyme elevation approached significance in the TS group versus controls . Some institutions declined r and omization and treated with or without TS as a routine . Outcome and toxicities did not differ from r and omized patients . There was no statistically significant effect on severe , life‐threatening or fatal infection between the r and omized TS versus control groups . Children not receiving TS developed varicella more often , a disease for which one would not expect TS to show a preventative effect . Pneumocystis pneumonias were not reported . The authors conclude that TS prophylaxis did not increase the continuous complete remission rate in children with ALL or decrease the incidence of infection . Toxicity is somewhat higher on TS . Cancer 59:19–23 , 1987 The best surgical procedure to treat bleeding bulbar peptic ulcer is unknown . The rates of postoperative bleeding recurrence , duodenal leakage , and mortality were compared in patients undergoing oversewing plus vagotomy ( O+V ) or gastric resection ( GR ) with ulcer excision . Of 202 patients undergoing emergency surgery for massive , persistent , or recurrent bleeding from bulbar peptic ulcer , 120 patients were enrolled in a prospect i ve r and omized trial . Fiftynine were assigned to O+V and 61 to GR . One patient in each group was excluded after r and omization . The two groups were well matched with respect to clinical and prognostic factors . The rate of postoperative bleeding recurrence was 17 % after O+V and 3 % after GR ( p<0.05 ) . The duodenal leak rate was higher after GR than after O+V ( 13 % vs. 3 % ) ( p<0.10 ) but was not different when the morbidity of reoperations for bleeding recurrence after O+V was considered on an “ intention to treat ” basis ( 12 % vs. 13 % ) . Overall postoperative mortality was similar : 22 % ( O+V ) versus 23 % ( GR ) . Sixteen deaths were unrelated to the surgical procedure itself . Of 82 nonr and omized patients , 10 were not analyzed . In the 72 other nonr and omized patients , bleeding recurrence , duodenal leakage , and postoperative mortality rates were consistent with the results of the controlled trial , as they were 29 % ( O+V 32 % ; GR 0.7 % ) , 16 % ( O+V 0.7 % ; GR 26 % ) and 27 % ( O+V 18 % ; GR 33.3 % ) , respectively . We conclude that GR with ulcer excision is the procedure of choice for the emergency surgical treatment of bleeding duodenal ulcer because postoperative bleeding recurrence is lower , and the overall rates of mortality and duodenal leakage are the same as with O+V.RésuméLa meilleure technique chirurgicale pour traiter l'ulcère du bulbe hémorragique n'est pas connue avec certitude . On a comparé les fréquences de récidive hémorragique , de lâchage du moignon duodénal et de mortalité chez des malades ayant une vagotomie avec suture de l'ulcère ( VS ) avec celles des patients ayant eu une gastrectomie avec excision de l'ulcère ( GE ) . Parmi 202 malades ayant eu une chirurgie d'urgence pour ulcère du bulbe do nt l'hémorragie était massive , persistante ou recidivante , 120 ont été tirés au sort dans le cadre d'une étude prospect i ve r and omisée . Cinquante-neuf malades ont eu une VS et 61 , une GE . Les deux groupes étaient similaires en ce qui concerne les facteurs pronostiques et leurs caractéristiques cliniques . La fréquence de récidive hémorragique a été de 17 % après VS et de 3 % après GE ( p<0.05 ) . La fréquence de lâchage du moignon était plus élèvée après VS ( 13 % vs 3 % ) ( p < 0.01 ) mais ne différait plus lorsque ces mêmes fréquences ont été calculées en incluant les malades qui ont eu une gastrectomie secondaire après échec de VS ( 12 % vs 13 % ) . La mortalité postopératoire globale était similaire dans les deux groupes : 22 % ( VS ) vs 23 % ( GE ) . Seize des décès n'étaient pas en rapport avec l'acte chirurugical lui-même . Parmi 82 autres malades non r and omisés , 10 dossiers n'ont pas été analysés . Des 72 malades restants , la fréquence de récidive hémorragique , de lâchage du moignon duodénal et de mortalité postopératoire étaient compatibles avec les résultats de l'étude r and omisée : 29 % ( VS : 32 % ; GE 0.7 % ) , 16 % ( VS : 0.7 % vs GE : 26 % ) et 27 % ( VS : 18 % ; GE : 33.3 % ) , respectivement . Nous concluons que , par rapport à la VS , la GE est le procédé de choix pour traiter l'ulcère duodénal hémorragique car la fréquence de récidive hémorragique est plus basse mais la fréquence globale de mortalité et de lâchage du moignon sont similaires . ResumenNo se sabe cual es el mejor procedimiento quirúrgico en el manejo de una úlcera duodenal bulbar sangrante . Las tasas de resangrado postoperatorio , de fuga de la sutura duodenal y de mortalidad fueron comparadas en pacientes sometidos a sutura + vagotomía ( S+V ) o a resección gástrica ( RG ) con resección de la úlcera . De 202 pacientes sometidos a cirugía de urgencia por hemorragia masiva , persistente o recurrente a partir de una úlcera péptica bulbar , 120 fueron incorporados en un ensayo clínico prospect ivo y r and omizado . Cincuenta y nueve fueron asignados a S+V y 61 a RG . Un paciente de cada grupo fue excluido luego de la r and omización . Los dos grupos eran similares en cuanto a factores clínicos y de pronóstico . La tasa de sangrado recurrente postoperatorio fue 17 % después de S+V y de 3 % después de GR ( p<0.05 ) . La tasa de fuga de la sutura duodenal fue mayor con la RG que con la S+V ( 13 % vs. 3 % ) ( p<0.10 ) , pero no hubo diferencia cu and o la morbilidad de las reoperaciones por recurrencia del sangrado después de S+V fue considerada sobre la base de una “ intención de tratamiento ” ( 12 % vs. 13 % ) . La mortalidad postoperatoria global fue similar : 22 % ( S+V ) vs. 23 % ( RG ) . Dieciseis muertes no estuvieron relacionadas con el procedimiento quirúrgico mismo . De 82 pacientes no r and omizados , 10 no fueron analizados ; en los otros 72 no r and omizados , las tasas de sangrado recurrente , escape duodenal y mortalidad postoperatoria aparecieron consistentes con los result ados observados en el ensayo clínico controlado : 29 % ( S+V : 32 % ; RG : 0.7 % ) , 16 % ( S+V : 0.7 % ; RG : 26 % ) y 27 % ( S+V : 18 % ; RG : 33.3 % ) , respectivamente . Nuestra conclusión es que la RG con resección de la úlcera es el procedimiento de elección en el tratamiento quirúrgico de urgencia de la úlcera duodenal sangrante , en virtud de una menor tasa de recurrencia postoperatoria del sangrado al tiempo que las tasas de mortalidad y de fugas de la sutura duodenal son iguales a las de la OBJECTIVE To examine safety aspects and vocal fold function after vocal fold augmentation with a cross-linked hyaluronan derivative ( hylan B gel ) as compared with bovine collagen . STUDY DESIGN ; A prospect i ve , r and omized trial . METHODS Eighty-three patients with glottal insufficiency were treated with injection augmentation with hylan B gel and bovine collagen and were examined at 1 , 6 , and 12 months after treatment . Seventy patients with unilateral vocal fold paresis ( n = 35 ) or atrophy ( n = 35 ) were r and omly assigned to receive either hylan B gel ( n = 47 ) or collagen ( n = 23 ) injections into one vocal fold . Thirteen patients with glottal insufficiency caused by scar defects or paresis result ing from malignant disease were included in a nonr and omized group and were treated only with hylan B gel . Evaluations were made from patients ' subjective ratings ( visual analogue scales ) , digitized videostroboscopic measurements , phonetograms , maximum phonation time , and phonation quotients . RESULTS Twelve months after injections , the patients ' self-ratings were significantly improved for both the hylan B gel and the collagen groups . In addition , the videostroboscopic measurements showed significantly improved glottal closure for both groups . However , for the hylan B gel group , vibration amplitude and glottal area variations were preserved , and this group showed significantly less resorption at the injected vocal fold edge . Furthermore , maximum phonation time had increased significantly for the hylan B gel patients ( collagen , nonsignificant ) . No serious adverse events were observed ; three patients injected with hylan B gel had temporary inflammation at the injection site , which resolved without sequelae . CONCLUSIONS The results showed that both hylan B gel and collagen can be safely used for injection treatment of glottal insufficiency . Both treatments result ed in significantly improved voice as rated by the patients . However , the patients treated with hylan B gel showed better vocal fold status and longer maximum phonation time at 12 months after treatment as compared with patients treated with collagen To determine whether informed consent in a therapeutic trial modifies the analgesic effect of naproxen and placebo , we conducted a prospect i ve , r and omised , single dose , placebo-controlled trial . Patients were r and omly selected to receive or not information concerning the study . All patients included were then given a single dose of naproxen and placebo according to a crossover , double-blind design . Forty-nine patients with mild or moderate cancer pain which did not need narcotic analgesics entered the study . Twenty-five received both treatments without any information and constituted the uninformed group . Twenty-four had a complete information about the trial ; six refused to participate . The 18 others constituted the informed-consent group . Visual analogue scales of pain before and 30 , 60 , 120 and 180 min after the intake of naproxen and placebo were recorded . As an analgesic , naproxen was more effective than placebo in both groups of patients ( p = 0.001 ) . For naproxen as well as for placebo , the analgesic effect was better in the informed-consent group compared to the uninformed group ( p = 0.012 ) . The difference in therapeutic activity between naproxen and placebo was moderately higher in the uninformed patients ( p = 0.08 ) . We concluded that , in contrast with parallel studies , giving information in a crossover , placebo-controlled trial may increase the apparent efficacy of both the tested agent and the placebo , and decrease the perceived difference the two Objective To compare the characteristics and outcomes of patients with intraabdominal infections enrolled in prospect i ve r and omized trials ( PRTs ) with those of a cohort of patients not enrolled in a trial . Summary Background Data Prospect i ve r and omized trials are the gold st and ard for the evaluation of new treatments . Patients are screened using rigorous eligibility criteria and sometimes are excluded from PRTs because of associated medical conditions or more severe illness . However , the effect that the exclusion of these patients has on the applicability of clinical trial outcomes has not been defined . Methods One hundred sixty-eight adults with intraabdominal infection were treated at a single institution during 7 years . Fifty-three patients were enrolled in four PRTs comparing various antibiotic regimens for treatment ; 115 were not enrolled . Patient characteristics and outcomes of these two groups were compared . Results Patients with infections from appendicitis ( n = 68 ) had a low severity of illness and similar outcomes in both groups . These patients and those for whom a concurrent PRT was unavailable were excluded from subsequent analysis . Eighty-eight patients ( 42 PRT , 46 not enrolled ) with serious infection remained for analysis . Patients enrolled in PRTs were younger , had less severe illness , had a decreased length of stay , a lower incidence of antibiotic resistance , and less frequent extraabdominal infections than those not enrolled in a trial . Patients enrolled in PRTs were more likely to be cured and were less likely to die . Logistic regression analysis demonstrated that cure was associated with a lower initial severity of illness , absence of antibiotic resistance , and participation in a PRT . Conclusions Patients with intraabdominal infection enrolled in PRTs have an increased likelihood of cure and survival . This is due in part to a lower incidence of antibiotic resistance , which may reflect improved drug selection . Patients not enrolled in PRTs are at greater risk for treatment failure and death because of concomitant illness . Outcomes from PRTs may not be applicable to all patients with intraabdominal infections Abstract Objective : To compare outcomes between groups of patients with irreversible chronic airflow limitation given theophylline by n of 1 trials or st and ard practice . Design : R and omised controlled study of n of 1 trials versus st and ard practice . Setting : Tertiary care centre outpatient department . Subjects : 31 patients with irreversible chronic airflow limitation who were unsure that theophylline was helpful after an open trial . Interventions : n Of 1 trials ( single patient r and omised multiple crossover comparisons of theophylline against placebo ) followed published guidelines . For st and ard practice patients theophylline was stopped and resumed if their dyspnoea worsened ; if their dyspnoea then improved theophylline was continued . For both groups a decision to continue or stop the drug was made within three months of r and omisation . Main outcome measures : Exercise capacity as measured by six minute walking distance , quality of life as measured by the chronic respiratory disease question naire at baseline and six months after r and omisation , and proportions of patients taking theophylline at six months . Results : 26 patients completed follow up . 47 % fewer n of 1 trial patients than st and ard practice patients were taking theophylline at six months ( 5/14 versus 10/12 ; 95 % confidence interval of difference 14 % to 80 % ) without differences in exercise capacity or quality of life . Conclusions : n Of 1 trials led to less theophylline use without adverse effects on exercise capacity or quality of life in patients with irreversible chronic airflow limitation . These data directly support the presence of a clinical ly important bias towards unnecessary treatment during open prescription of theophylline for irreversible chronic airflow limitation . Confirmation in a larger study and similar studies for other problems appropriate for n of 1 trials are needed before widespread use of n of 1 trials can be advocated in routine clinical practice . Key messages Several common clinical problems suit n of 1 tri- als , including prescription of theophylline for irre- versible chronic airflow limitation , yet they are rarely used Among patients with chronic airflow limitation r and omised to receive theophylline by an n of 1 trial or st and ard practice 47 % fewer n of 1 trial patients were taking theophylline after six months without difference in exercise capacity or quality of life There seems to be a clinical ly important bias towards unnecessary treatment in st and ard prac- tice in this setting ; n of 1 trials may limit this This trial compared blinded 10 mg aliquots of adrenaline with placebo in 194 cardiac arrest patients treated in hospital using American Heart Association guidelines . In-hospital and out-of-hospital arrests were included . Of the 339 eligible patients a large proportion ( 145 ( 45 % ) ) were not r and omised and received open 1 mg aliquots of adrenaline . This group is also analysed . Supervising physicians gave significant preference for males , patients with no previous cardiac history and without multiple organ disease to be given open 1 mg adrenaline . Patients in asystole at the time of consideration for entry were preferentially placed in the trial group ( 114 ( 69 % ) vs. 170 ( 88 % ) ) and patients in ventricular fibrillation were preferentially given open 1 mg adrenaline ( 31 ( 21 % ) vs. 24 ( 12 % ) P < 0.03 ) . The most beneficial rhythm changes which led to survival were sinus rhythm and ventricular tachycardia . Analysis of rhythm changes result ing from the dosing showed a significant ( P = 0.01 ) change to a beneficial rhythm with 10 mg adrenaline but not for 1 mg adrenaline or placebo . This was not reflected by an improvement in immediate survival . No significant differences in immediate survival ( IS ) or hospital discharge ( HD ) exists between open 1 mg adrenaline ( IS 14 ( 9.7 % ) , HD 3 ( 2 % ) ) or the 10 mg adrenaline ( IS 9 ( 9.6 % ) , HD 0 ) vs. placebo ( IS 7 ( 7 % ) , HD 0 ) trial arms . Patients reaching the point of use of adrenaline have a uniformly poor immediate survival ( 8.8 % ) and hospital discharge rate ( 0.9 % ) . Dosing with 10 mg or 1 mg adrenaline does not influence outcome compared with placebo At the Massachusetts General Hospital , all 190 patients who presented with the clinical and ECG criteria of the national Unstable Angina Pectoris Study ( NUAPS ) for unstable angina pectoris ( UAP ) were prospect ively evaluated from their entrance between 1972 and 1976 ( the entry period for NUAPS ) . Coronary angiography was performed in 166 patients . Of these , 83 patients ( 50 % ) were not eligible for r and omization because of obstruction in the left main coronary artery ( 4 % ) , inoperable diffuse coronary disease ( 11 % ) , failure of initial medical therapy ( 20 % ) , minimal coronary disease ( 13 % ) , or other reasons ( 2 % ) . The other 83 patients ( 50 % ) were eligible for r and omization by NUAPS criteria ; 39 received medical therapy and 44 underwent urgent coronary artery bypass surgery ( CABG ) . The medical and surgical patients were comparable in terms of clinical characteristics and extent of anatomical disease . In-hospital ( 3 % medical and 2 % surgical ) and late ( 5 % medical and 5 % surgical ) mortality were similar over a mean follow-up period of 46 months . Myocardial infa rct ion rate was statistically similar in-hospital ( 5 % medical and 11 % surgical ) and during chronic evaluation ( 5 % medical and 14 % surgical ) . However , late severe angina ( NYHA class III or IV ) occurred in a significantly higher percentage of medical patients ( 28 % medical versus 9 % surgical ; p less than 0.05 ) and nine medical patients ( 23 % ) required late elective CABG for relief of persistent angina . This experience is comparable to NUAPS , and supports the conclusion that acute management of unstable angina pectoris may begin with intensive medical treatment followed later by more elective CABG for those patients with persistent angina despite medical therapy Abstract Objectives : To compare the efficacy of antidepressant drugs and generic counselling for treating mild to moderate depression in general practice . To determine whether the outcomes were similar for patients with r and omly allocated treatment and those expressing a treatment preference . Design : R and omised controlled trial , with patient preference arms . Follow up at 8 weeks and 12 months and abstract ion of GP case notes . Setting : 31 general practice s in Trent region . Participants : Patients aged 18–70 who met research diagnostic criteria for major depression ; 103 patients were r and omised and 220 patients were recruited to the preference arms . Main outcome measures : Difference in mean Beck depression inventory score ; time to remission ; global outcome assessed by a psychiatrist using all data sources ; and research diagnostic criteria . Results : At 12 months there was no difference between the mean Beck scores in the r and omised arms . Combining the r and omised and patient preference groups , the difference in Beck scores was 0.4 ( 95 % confidence interval −2.7 to 3.5 ) . Patients choosing counselling did better than those r and omised to it ( mean difference in Beck score 4.6 , 0.0 to 9.2 ) . There was no difference in the psychiatrist 's overall assessment of outcome between any of the groups . 221/265 ( 83 % ) of participants with a known outcome had a remission . Median time to remission was shorter in the group r and omised to antidepressants than the other three groups ( 2 months v 3 months ) . 33/221 ( 15 % ) patients had a relapse . Conclusions : Generic counselling seems to be as effective as antidepressant treatment for mild to moderate depressive illness , although patients receiving antidepressants may recover more quickly . General practitioners should allow patients to have their preferred treatment . What is already known on this topic Antidepressants and specific psychological interventions are effective in major depression . Generic counselling has not previously been compared with antidepressants in primary care What this study adds 12 months after starting treatment , generic counselling is as effective as antidepressants Patients treated with antidepressants may recover more quickly Given a choice , more patients opt for counselling Patients who choose counselling may benefit more than those with no strong OBJECTIVE There has been continuing concern that clients who accept r and omization into a controlled trial may not be representative of those in noncontrolled trials or ordinary treatment situations . However , it is not possible to test the impact of r and omization through a r and omized trial . Two parallel studies conducted at the same treatment facility provided an opportunity for a quasi-experimental study to evaluate whether participation in a controlled trial itself affects treatment outcome . METHOD Two concomitant sample s of clients were enrolled during overlapping recruitment periods : one ( n = 226 ) into a r and omized clinical trial ( RCT ) and the other ( n = 122 ) offered treatment as usual ( non- RCT ) . Both sample s were given extensive baseline and follow-up assessment . RESULTS Baseline assessment indicated demographic similarity of the two sample s , with somewhat higher problem severity in the non- RCT sample , consistent with the RCT selection criteria . Client retention in treatment was somewhat comparable , and follow-up rates exceeded 90 % in both studies . Overall outcomes did not differ for the RCT and non- RCT sample s. CONCLUSIONS It appeared that clients enrolled into an RCT did not differ from those receiving ordinary treatment . Retention was similarly high in both studies , clients completed a comparable number of outpatient sessions , and the number of informal treatment sessions attended during the 6 months of follow-up was comparable . There are some aspects of this study that limit the ability to draw firmer conclusions but despite some pretreatment differences , participation in the RCT did not itself exert an apparent effect on aggregate treatment outcomes PURPOSE The aim of this study was to match patient information requirements by determining whether giving patients a choice for additional preprocedural audiovisual information modifies the effectiveness of this information on anxiety , worry , knowledge , and patient satisfaction . METHODS Patients scheduled to undergo colonoscopy were approached one week before their procedure . All patients received an information leaflet during their st and ard preanesthetic clinic visit . Patients were r and omly assigned to a choice or no-choice condition . Patients in the choice condition were free to watch or not watch the video , people in the no-choice condition were further r and omized to watch or not watch the video . Measures of anxiety and worry were completed before watching the video . Anxiety , worry , knowledge , and satisfaction were measured one week later just before the colonoscopy . RESULTS One hundred sixty-six patients completed the study . Of those patients r and omized to the choice condition , 69 percent wanted to watch the video . Those who chose not to watch the video were significantly more worried on the day of their procedure . Consistent with current evidence , watching the video was associated with improvements in short-term knowledge ( F ( 1,161 ) = 4.8 , P = 0.03 ) . There was , however , no significant effect of the choice or video conditions on anxiety or patient satisfaction . CONCLUSIONS There appears to be no additional benefits in terms of patient outcomes by allowing patients to choose whether they want additional audiovisual information . We suggest that all patients undergoing colonoscopy would benefit from watching such an educational video in the week before their procedure BACKGROUND Since 1991 , mifepristone in combination with a prostagl and in analogue has been licensed for termination of pregnancy in the UK at up to 9 weeks amenorrhoea , and since 1995 , beyond 13 weeks . Surgical methods are used almost exclusively at 10 - 13 weeks amenorrhoea . METHODS A patient-centred , partially r and omized , controlled trial was carried out . Those who expressed a strong preference for either medical ( n = 15 ) or surgical ( n = 62 ) abortion were allocated to that method . The remainder agreed to be r and omized . The medical method ( n = 188 ) was mifepristone 200 mg followed by misoprostol up to 3 doses , and surgery ( n = 180 ) was by vacuum aspiration under general anaesthesia . Outcome measures included efficacy rates , medical complications within 8 weeks of the procedure , patient preferences and acceptability . RESULTS Among women who underwent medical abortion , 5.4 % required a second procedure compared with 2.1 % who had surgery , although this difference was not statistically significant . Side effects experienced were higher in women who underwent medical abortion compared with those who underwent surgery . There were no significant differences in the rates of major complications up to 8 weeks . Prior to termination , 80 % of women had a preference for a method , with 72 % preferring medical and 28 % preferring surgical abortion . Following abortion , 70 % of those who underwent medical termination and 79 % who underwent surgery would opt for the same method in the future . CONCLUSION Medical abortion is safe and effective at 10 - 13 weeks gestation and should be considered an option for those women who wish to avoid surgery and anaesthesia Summary . During the 3 years 1984–86 , 314 cases of multiple myeloma were diagnosed in the Health Care Region of Western Sweden . 180 of these cases were included in a clinical trial ; 71 were notified to the trial but excluded ; 49 cases were not reported to the trial ; 14 were diagnosed post mortem OBJECTIVE To determine whether postoperative forced-air warming of cardiac bypass patients in the intensive care unit ( ICU ) results in faster rate of warming and improved outcomes compared with more conventional ICU warming methods . DESIGN Prospect i ve r and omized effectiveness study . SETTING Three hundred fifty-bed university-affiliated hospital . PARTICIPANTS Sixty consenting r and omized patients from a consecutive series of 84 patients undergoing routine adult cardiac surgery . INTERVENTIONS One group of patients received usual patient care , which includes warm blankets and overhead heat lamps . Patients in the other group were placed under forced-air warming devices on arrival in the ICU . Sixty consenting patients ( 30 in each group ) were r and omly assigned to one or the other method of warming . The remaining 24 patients refused r and omization and self-selected a treatment group . MEASUREMENTS AND MAIN RESULTS Results are presented for the r and omized groups . Core temperature , measured by pulmonary artery catheter thermistor , increased in both groups at the rate of 0.25 degree C per hour . No statistically or clinical ly significant differences were found between the group for whom the warming device was used and the st and ard care group in the incidence of postoperative cardiac arrhythmia , duration of time in the ICU , or any other clinical variable . CONCLUSIONS There is no evidence from this study to warrant use of forced-air warming devices for the care of postoperative cardiac surgical patients in the ICU To determine whether the natural history of strictures is affected by the type of dilator used to treat newly diagnosed peptic strictures , we design ed a prospect i ve r and omized trial to compare the results after Eder-Puestow or Medi-Tech balloon dilation . We entered 31 patients into the trial . We also prospect ively followed up all 92 nonr and omized patients who underwent their first dilation for a benign stricture during the same period as the prospect i ve r and omized trial . The nonr and omized patients also underwent dilation with either the Eder-Puestow or the balloon technique at the discretion of the gastroenterologist performing the endoscopy . We found no statistically significant differences in the immediate or long-term results of the two methods among the r and omized , nonr and omized , and overall combined groups . All but 1 of the 123 patients had immediate relief of dysphagia . Within each group of patients , the probability of remaining free of dysphagia 1 year after the initial dilation was approximately 20 % , and the probability of not requiring a second dilation was approximately 65 % with either technique . Major ( esophageal rupture ) and minor ( bleeding or chest pain ) complications occurred in 1 % and 5 % of the patients and 0.4 % and 3 % of the total dilation procedures , respectively . The esophageal rupture and four of six minor complications occurred after repeated dilations . Five of the six minor complications occurred with use of the Eder-Puestow dilators . We conclude that Eder-Puestow and balloon dilations of benign esophageal strictures are associated with similar outcomes , but repeated dilations and the Eder-Puestow technique may be associated with an increased risk of complications BACKGROUND Arrhythmias cause much morbidity and mortality after myocardial infa rct ion , but in previous trials , antiarrhythmic drug therapy has not been convincingly effective . Dofetilide , a new class III agent , was investigated for effects on all-cause mortality and morbidity in patients with left-ventricular dysfunction after myocardial infa rct ion . METHODS In 37 Danish coronary-care units , 1510 patients with severe left-ventricular dysfunction ( wall motion index < or = 1.2 , corresponding to ejection fraction < or = 0.35 ) were enrolled in a r and omised , double-blind study comparing dofetilide ( n=749 ) with placebo ( n=761 ) . The primary endpoint was all-cause mortality . Secondary endpoints included cardiac and arrhythmic mortality and total arrhythmic deaths . Analyses were by intention to treat . FINDINGS No significant differences were found between the dofetilide and placebo groups in all-cause mortality ( 230 [ 31 % ] vs 243 [ 32 % ] ) , cardiac mortality ( 191 [ 26 % ] vs 212 [ 28 % ] ) , or total arrhythmic deaths ( 129 [ 17 % ] vs 140 [ 18 % ] ) . Atrial fibrillation or flutter was present in 8 % of the patients at study entry . In these patients , dofetilide was significantly better than placebo at restoring sinus rhythm ( 25 of 59 vs seven of 56 ; p=0.002 ) . There were seven cases of torsade de pointes ventricular tachycardia , all in the dofetilide group . INTERPRETATION In patients with severe left-ventricular dysfunction and recent myocardial infa rct ion , treatment with dofetilide did not affect all-cause mortality , cardiac mortality , or total arrhythmic deaths . Dofetilide was effective in treating atrial fibrillation or flutter in this population Abstract . The long-term effects on bone of estrogen therapy ( HRT ) combined with vitamin D3 supplementation were evaluated and compared with the effects of HRT without vitamin D3 supplementation in a 4-year prospect i ve , partly r and omized study among 60 osteoporotic women ( mean age 55.4 years ; range 49.7–59.4 years ) . The women studied were a subgroup of the population -based Kuopio Osteoporosis Risk Factor and Prevention Study ( OSTPRE ) ( n = 13100 ) . The bone mineral densities ( BMD ) of the lumbar spine and femoral neck were determined by dual-energy X-ray absorptiometry ( DXA ) in 3236 perimenopausal women . Those 106 women with baseline BMD more than 2 SDs less than the mean value in this population , either at the lumbar spine ( BMD < 0.826 g/cm2 ) and /or femoral neck ( BMD < 0.684 g/cm2 ) , were offered treatment for osteoporosis . After exclusions , 60 women were included in the analyses . Group allocation was : HRT ( estradiol valerate ( 2 mg ) plus cyproterone acetate , 1 mg , sequentially : ClimenR ) ( n = 21 ) ; HRT + Vit D : Climen + vitamin D3 ( cholecalciferol , 300 IU/day , no intake during June – August ) ( n = 23 ) ; controls : 16 women who refused all treatment served as a non-r and omized control group . In the HRT group , the highly significant increase in lumbar BMD was 5.4 % , 5.3 % , 4.7 % and 4.0 % after 1 , 2 , 3 and 4 years of treatment , respectively , all compared with the baseline values and with the control group . The increase in femoral neck BMD was statistically insignificant ( 1.4 % , 2.2 % , 1.9 % and 2.1 % , respectively ; p > 0.05 ) . In the HRT + Vit D group , the lumbar BMD increased by 3.7 % , 4.9 % , 4.9 % and 4.9 % ( p < 0.001 ) , whereas the 5.8 % increase in femoral neck BMD reached significance at 4 years ( p < 0.01 ) when compared with the control group as well as with the baseline values . However , there were no statistically significant differences in lumbar or femoral BMD changes between the two HRT groups . In conclusion , estrogen can substantially increase lumbar bone mass in patients with postmenopausal osteoporosis . In addition , the combination of HRT and vitamin D3 may increase femoral neck BMD in osteoporotic women more than estrogen alone The authors studied the effect of nitrous oxide on success rates for in vitro fertilization and pregnancy in women undergoing laparoscopy for oocyte retrieval . Ninety-eight patients in an in vitro fertilization program were r and omly assigned to an anesthetic regimen including either 0.7 % ( end-tidal ) isoflurane with 60 % nitrous oxide in oxygen , or 1.4 % ( end-tidal ) isoflurane in oxygen . Success rates for fertilization and pregnancy in 44 additional patients who declined r and omization were also studied . Among the 51 r and omized patients who did not receive nitrous oxide , 192 oocytes were obtained and 122 fertilized ( 63.5 % ) , result ing in eight pregnancies ( 16.3 % ) . From the 47 r and omized patients given nitrous oxide , 168 oocytes were retrieved and 114 fertilized ( 67.9 % ) , result ing in nine pregnancies ( 19.1 % ) . No significant differences between rates of fertilization or pregnancy emerged between groups . Such differences would have been found with an 80 % probability had nitrous oxide had a 20 % effect on oocyte fertilization There are distinct advantages to the comprehensive cohort design for r and omized clinical trials . The design allows the research er to systematic ally compare the trial participants and the trial results with the characteristics and results in the population of eligible patients who were not r and omly assigned to treatment . There are some problems with this design . The added costs of enrollment and follow-up for the nonr and omized cohort can add substantially to the cost of a trial . As the CASS example illustrates , careful attention must be given to definition of the treatment groups in the nonr and omized cohort . For the r and omized patients , group assignment by " intention to treat " is preferred in most cases . The definition of " intention to treat " in the nonr and omized cohort may be difficult , since the patient may receive recommendations from several sources and , in the case of chronic disease , the decision may be postponed for a long period . This problem is not specific to the comprehensive cohort design , however , and a comparison group of concurrently enrolled and followed patients is almost always preferred over a comparison group found elsewhere The Surgical Treatments Outcomes Project for Dysfunctional Uterine Bleeding ( STOP-DUB ) was a multicenter , r and omized clinical trial that assessed the efficacy and effectiveness of hysterectomy versus endometrial ablation ( EA ) for dysfunctional uterine bleeding ( DUB ) in women for whom medical management has not provided relief . Re source centers included a coordinating center , a chair 's office , the American College of Obstetricians and Gynecologists , the Agency for Healthcare Research and Quality Project Office and 33 clinical centers in the United States and Canada . STOP-DUB enrolled : ( 1 ) eligible patients for whom medical treatment had not been successful and who were r and omized to either hysterectomy or EA and ( 2 ) an observational cohort of patients who were " provisionally ineligible " or who were eligible but did not wish to be r and omized . Enrollment began in October 1997 and ended in June 2001 . The primary outcome addressed by the r and omized trial was the impact of surgery on bleeding , pain , fatigue , and the major problem ( symptom ) that led the woman to seek treatment for her condition , measured 1 year following surgery . Additional outcomes included the impact of surgery at time points after 1 year ; changes in quality of life , activity limitation , sexual functioning , and urinary incontinence ; surgical complications ; additional surgery ; and re source utilization . The costs and the relative cost-effectiveness of the two surgeries were calculated . The main scientific objective for the observational study was to examine changes over time in terms of treatment selected , DUB-related symptoms , and quality of life The relative efficacy of five drugs in the treatment of hypercalcemia of malignancy was assessed in a r and omized study . The drugs were oral phosphate , mithramycin , glucocorticoids , indomethacin , and ethane-1-hydroxy-1 , 1-diphosphonate ( EHDP ) . No single agent was universally effective . Oral phosphate and mithramycin were the most efficacious , each producing a decrease in serum calcium concentrations in four of five patients , although there were serious disadvantages with the use of each . Glucocorticoids were effective in only two of five patients who received r and omized treatment . A further five patients received nonr and omized treatment with glucocorticoids , and only three of these showed response . Indomethacin was effective in only one of five patients to whom it was given , and EHDP was effective also in only one of five patients . The new diphosphonate , 3-amino-1-hydroxypropane-1 , 1-diphosphonate ( APD ) was evaluated in the treatment of hypercalcemia in 13 patients with malignant disease and two with primary hyperparathyroidism . APD caused a significant decrease in serum calcium concentration in nine of 12 patients within 72 hours . These results indicate that there is no currently available pharmacologic agent that is entirely satisfactory in the treatment of hypercalcemia . The most effective agents were mithramycin , oral phosphate , and APD . Glucocorticoids and orally administered EHDP showed limited effectiveness , and indomethacin was ineffective in the majority of patients To evaluate the use of intravenously administered immune globulin ( IVIG ) for prevention of sepsis in preterm infants , we administered IVIG in a protocol design ed to maintain a therapeutic serum " target level " of 700 mg/dl . The 200 patients who were eligible for the study ( 600 to 2000 gm birth weight ) were monitored throughout their initial hospitalization . Of these , 115 patients were r and omly assigned in a double-blind , controlled trial to treatment and placebo groups . The remaining 85 infants were not r and omly assigned to a group , by parental request , but were followed and analyzed separately . In one patient who received IVIG , transient tachycardia and a decrease in blood pressure developed during an infusion ; resolution occurred promptly after the infusion was discontinued . No persistent hepatic or renal abnormalities were noted in either the IVIG- or the placebo-treated group . There were seven episodes of sepsis in the placebo group and nine in the group whose parents refused consent to the study . No infant who received IVIG acquired nosocomial sepsis ( p less than 0.01 ) . All patients in the placebo group in whom sepsis developed had serum IgG levels less than 400 mg/dl at the time sepsis developed . Serum IgG levels were maintained near 700 mg/dl in patients who received IVIG . These data indicate that administration of sufficient IVIG to maintain target serum IgG levels throughout hospitalization may decrease the incidence of nosocomial sepsis in preterm infants BACKGROUND The best treatment ( steroids , irradiation , or both ) for moderately severe Graves ' orbitopathy , a self-limiting disease is not known . We tested the efficacy of external beam irradiation compared with sham-irradiation . METHODS In a double-blind r and omised clinical trial , 30 patients with moderately severe Graves ' orbitopathy had radiotherapy ( 20 Gy in ten fractions ) , and 30 were assigned sham-irradiation ( ten fractions of 0 Gy ) . Treatment outcome was measured qualitatively by changes in major and minor criteria and quantitatively in several ophthalmic and other variables , such as eyelid aperture , proptosis , eye movements , subjective eye score , and clinical -activity score at 24 weeks . FINDINGS The qualitative treatment outcome was successful in 18 of 30 ( 60 % ) irradiated patients versus nine of 29 ( 31 % ) sham-irradiated patients at week 24 ( relative risk [RR]=1.9 [ 95 % CI 1.0 - 3.6 ] , p=0.04 ) . This difference was caused by improvements in diplopia grade , but not by reduction of proptosis , nor of eyelid swelling . Quantitatively , elevation improved significantly in the radiotherapy group , whereas all other variables remained unchanged . The field of binocular single vision was enlarged in 11 of 17 patients after irradiation compared with two of 15 after sham-irradiation . Nevertheless , only 25 % of the irradiated patients were spared from additional strabismus surgery . INTERPRETATION In these patients with moderately severe Graves ' orbitopathy , radiotherapy should be used only to treat motility impairment BACKGROUND In animals , acceleration of neonatal growth is thought to increase the later propensity to insulin resistance and non-insulin-dependent diabetes , whereas slow growth as a consequence of undernutrition is thought to have a beneficial effect . To test this hypothesis in people , we measured fasting concentrations of 32 - 33 split proinsulin , a marker of insulin resistance , in adolescents born preterm who had participated in r and omised intervention trials of neonatal nutrition , and in adolescents born at term . METHODS We determined fasting 32 - 33 split proinsulin concentration in participants aged 13 - 16 years born preterm and r and omised to receive a nutrient-enriched or lower-nutrient diet ( n=216 ) or in a reference group born at term ( n=61 ) . FINDINGS Fasting 32 - 33 split proinsulin concentration was greater in children given a nutrient-enriched diet ( geometric mean 7.2 pmol/L , 95 % CI 6.4 - 8.1 ) than in those given the lower-nutrient diet ( 5.9 pmol/L [ 5.2 - 6.4 ] ; mean difference 20.6 % [ 5.0 - 36.3 ] ; p=0.01 ) . Healthy babies born at term had similar fasting 32 - 33 split proinsulin concentrations ( 6.9 pmol/L ; 6.0 - 8.2 ) to the nutrient-enriched group . In non-r and omised analyses , fasting 32 - 33 split proinsulin concentration was associated with greater weight gain the first 2 weeks of life ( 13.2 % [ 5.4 - 20.9 ] change per 100 g weight increase ; p=0.001 ) independent of birthweight , gestation , neonatal morbidity , and demographic , anthropometric , and socioeconomic factors . INTERPRETATION Our results suggest that relative undernutrition early in life in children born preterm may have beneficial effects on insulin resistance The intergroup study of involved-field ( IF ) radiotherapy , IF radiotherapy plus MOPP chemotherapy , and extended-field ( EF ) radiotherapy for treatment of Hodgkin 's disease in children has assessed 305 patients . Of these , 279 were " not ineligible " ( no mediate cause for disqualification ) . Among 223 r and omized patients , 144 were evaluable , 131 had documentation of complete or partial remission , 20 of the remitters relapsed , and two died . Among 62 nonr and omized patients with favorable presentations ( unilateral upper neck , unilateral inguinal , or massive mediastinal disease ) , 29 had documented remission , two relapsed , and none died . Length of initial disease control ( LIDC ) was used to measure duration of response . LIDC was best in patients given IF plus MOPP , and 95 % are disease free . EF was better than IF radiotherapy ( P = 0.004 ) . Of the disease characteristics prognostic for response ( stage , histologic subtype , and presence of symptoms ) , only the last factor had a statistically significant effect on LIDC ( P = 0.004 ) . Ninety-six percent of the patients survive . Using criteria developed by the committee , 23 % of the staging procedures review ed were nonevaluable and 28 % of the radiotherapy treatments were nonevaluable . The necessity for criteria for evaluation of staging and treatment is certain . Length of followup is too short for correlations of treatment with significant late effects and for relevant therapeutic recommendations Prescription of low osmolar contrast to prevent nephrotoxicity in subjects with pre-existing renal impairment is costly and has not been clearly shown to be effective . We entered 249 subjects with a pre-contrast serum creatinine greater than 120 mumol/liter ( 1.35 mg/dl ) having cardiac catheterization or intravenous contrast into a r and omized controlled trial comparing high and low osmolar contrast . The outcome assessed was a rise in serum creatinine repeated 48 to 72 hours after contrast . A further 117 patients entered the non-r and omized prospect i ve arm of the study . In the r and omized study the serum creatinine rose by at least 25 % after contrast in 8 of 117 ( 6.8 % ) given high and in 5 of 132 ( 3.8 % ) given low osmolar contrast ( P greater than 0.05 , one-tailed 95 % confidence interval for the difference 3 to 7.8 % ) . More severe renal failure ( greater than 50 % increase in serum creatinine ) after contrast was uncommon ( 3.4 % with high and 1.5 % with low osmolar contrast ) . A rise in serum creatinine after contrast was significantly associated with the severity of the pre-contrast renal impairment and the presence of diabetes mellitus , but not with type of contrast . Diabetics with a serum creatinine greater than 200 mumol/liter ( 2.25 mg/dl ) pre-contrast had a highest risk of deterioration in renal function after contrast . We conclude that in patients with pre-existing renal impairment the incidence of contrast nephropathy was not significantly different comparing high osmolar and nonionic contrast . The potential benefit of nonionic contrast in moderate renal impairment is likely to be small , but trials in diabetics with severe renal impairment should be undertaken urgently BACKGROUND AND PURPOSE The applicability of prospect i ve carotid endarterectomy protocol s to the general population has been question ed . Outcomes for asymptomatic patients undergoing carotid endarterectomy were compared with the results of the Asymptomatic Carotid Atherosclerosis Study ( ACAS ) patients treated concurrently at our institution . METHODS Asymptomatic patients undergoing carotid endarterectomies ( n = 277 ) from 1987 to 1993 ( ACAS enrollment period ) were review ed . Primary end points were mortality , myocardial infa rct ion , and stroke . Five subgroups were studied : ( 1 ) ACAS surgical patients ; ( 2 ) ACAS-eligible patients not enrolled and ACAS surgeons ; ( 3 ) ACAS-eligible patients not enrolled and non-ACAS surgeons ; ( 4 ) ACAS-ineligible patients and ACAS surgeons ; and ( 5 ) ACAS-ineligible patients and non-ACAS surgeons . RESULTS ACAS-eligible patients were younger ( P = .014 ) , had more severe carotid stenosis ( P = .001 ) , and had lower incidences of pulmonary ( P = .015 ) and renal ( P = .008 ) diseases compared with ineligible patients . Patient selection ( ACAS eligibility ) significantly improved outcomes for mortality ( P = .014 ) and myocardial infa rct ion ( P = .006 ) . Length of stay favored ACAS-eligible patients ( P = .004 ) . ACAS surgeons operated on more severely stenotic carotid lesions ( P = .005 ) and on patients with a lower incidence of coronary artery disease ( P = .007 ) . There was no difference in outcomes between ACAS and non-ACAS surgeons . CONCLUSIONS Patient selection was a significant factor in determining outcome . With strict adherence to ACAS enrollment guidelines , the conclusions of ACAS appear applicable to patients seen at our institution with asymptomatic carotid stenosis The present study comprises 847 women operated upon for invasive breast carcinoma at 19 surgical departments and enrolled in protocol DBCG-82TM from January 1983 to November 1987 . Among them 662 ( 78 % ) were allocated for breast-preserving therapy or mastectomy by r and omization , while 185 patients ( 22 % ) did not accept r and omization . Within the r and omized group 6 % could not be entered into adjuvant protocol s , i.e. subsequent programmes of postoperative therapy and follow-up . This left 619 evaluable patients . In the non-r and omized series 26 % did not fulfil the dem and s for entrance into the adjuvant protocol s , leaving 136 evaluable patients , 60 of whom had chosen a breast-preserving operation and 76 mastectomy . In the r and omized series the patients in the two treatment arms were comparable in age , menopausal status , site of tumour , pathoanatomical diameter of the tumour , number of removed axillary lymph nodes , number of metastatic axillary lymph nodes , and distribution on adjuvant regimens . Ninety per cent of the patients in the r and omized group accepted the method offered , whereas 10 % declined and wanted the alternate form of operation . The median follow-up period was approximately 1.75 years . The cumulative recurrence rate in the r and omized group was 13 % and in the non-r and omized group 7 % . These results are preliminary . Life-table analyses have not so far demonstrated differences in recurrence-free survival either in the r and omized or the non-r and omized series The SIOP PNET 3 study was design ed to determine whether 10 weeks of moderately intensive chemotherapy given after surgery and before radiotherapy ( RT ) would improve the outcome for patients with primitive neuroectodermal tumours ( PNETs ) compared with RT alone . Patients with a histological diagnosis of supratentorial PNET ( StPNET ) and no radiological evidence of metastatic disease were initially eligible for r and omisation to either chemotherapy followed by craniospinal RT 35 Gy in 21 fractions with a boost of 20 Gy in 12 fractions to the primary site , or RT alone . In respect of the increasing recognition that StPNET were high-risk tumours , r and omisation for this group closed in November 1999 . This analysis includes both r and omised and non-r and omised patients with StPNET entered into the study data base . Sixty-eight patients aged 2.9 - 16.6 years ( median 6.5 years ) were included in the analysis ( chemotherapy+RT : 44 , RT alone : 24 ) . Fifty-four patients ( 79 % ) had a non-pineal and 14 ( 21 % ) a pineal site . At a median follow-up of 7.4 years , for all patients overall survival ( OS ) at 3 and 5 years was 54.4 % and 48.3 % , respectively . Event-free survival ( EFS ) at 3 and 5 years was 50.0 % and 47.0 % , respectively . There was no statistically significant difference in OS or EFS according to treatment received . OS ( P=0.05 ) and EFS ( P=0.03 ) were significantly better for patients with pineal primary sites . EFS for pineal tumours were 92.9 % at 3 years and 71.4 % at 5 years and for non-pineal primaries 40.7 % at 3 years and 40.7 % at 5 years . This study confirmed the relatively good survival for non-metastatic pineal PNETs but poor survival of non-pineal StPNETs . There was no evidence that pre-radiation chemotherapy improved outlook . Future treatment programs should be directed at the particular natural history of these tumours , to further define prognostic factors and to explore further biological characteristics BACKGROUND AND PURPOSE Some stroke patients and their families express reservations about participating in trials of experimental therapies for acute stroke . Among many reasons given for this is the concern that by participating , patients may be deprived of some component of routine care . We sought to determine the effect on outcome of participating in a clinical stroke trial while being treated with placebo . METHODS Prospect i ve clinical information was collected for all patients admitted with acute ischemic stroke between July 1995 and July 1996 . A subgroup of these patients was enrolled in a clinical trial of acute stroke therapy and had been r and omly assigned to the placebo group . The control group was selected from concurrent stroke patients who were not enrolled in any clinical trial . The National Institutes of Health Stroke Scale ( NIHSS ) was performed on admission and on day 7 after admission . The Glasgow Outcome Scale ( GOS ) was also performed at discharge . Stroke severity was classified as " severe " if NIHSS was > /=9 or GOS > /=3 . Group comparisons were performed with chi(2 ) tests . RESULTS One hundred twenty-six patients were evaluated . Forty-seven were placebo patients , and 79 were selected as control subjects . There were no significant differences between the groups with respect to age , sex , hematocrit , blood glucose level , history of hypertension , diabetes , smoking , or initial NIHSS . In addition , there was no difference between groups in terms of the frequency of baseline stroke subtype . Among our controls , 55 patients ( 70 % ) were on antithrombotic treatment during hospitalization , whereas none of our placebo patients were on any antithrombotic treatment . For the GOS at follow-up , a good outcome was attained by 76 % of the control subjects and 72 % of placebo patients ( not significant ) . A severe NIHSS ( > 9 ) at follow-up , however , was documented in 15 % of controls and 59 % of placebo patients ( P<0.001 ) . There was a trend toward a higher ( " worse " ) mean follow-up NIHSS among placebo patients ( mean NIHSS , 11 ) versus controls ( mean NIHSS , 6 ) ( P=0.09 ) . CONCLUSIONS Patients enrolled in the placebo arms of some acute clinical stroke trials have similar functional outcomes but more severe neurological deficits at 1 week than did a control group . These findings might be partially explained by the withholding of antithrombotic medication and the exclusion criteria inherent in most trials . Vigilance is required to ensure that all patients participating in stroke studies be guaranteed optimal known medical therapy A pilot trial was conducted to test adherence to specific lifestyle interventions among Pima Indians of Arizona , and to compare them for changes in risk factors for diabetes mellitus . Ninety-five obese , normoglycaemic men and women , aged 25 - 54 years , were r and omized to treatments named ' Pima Action ' ( Action ) and ' Pima Pride ' ( Pride ) , which were tested for 12 months . Action involved structured activity and nutrition interventions , and Pride included unstructured activities emphasizing Pima history and culture . Adherence to interventions , changes in self-reported activity and diet , and changes in weight , glucose concentrations , and other risk factors were assessed regularly . Thirty-five eligible subjects who had declined r and omization were also followed as an ' observational ' group and 22 members of this group were examined once at a median of 25 months for changes in weight and glucose concentration . After 12 months of intervention , members of both intervention groups reported increased levels of physical activity ( median : Action 7.3 h month(-1 ) , Pride 6.3 h month(-1 ) , p < 0.001 for each ) , and Pride members reported decreased starch intake ( 28 g , p = 0.008 ) . Body mass index , systolic and diastolic blood pressures , weight , 2-h glucose and 2-h insulin had all increased in Action members ( p < 0.003 for each ) , and waist circumference had decreased in Pride members ( p = 0.05 ) . Action members gained more weight than Pride members ( 2.5 kg vs 0.8 kg , p = 0.06 ) , and had a greater increase in 2-h glucose than Pride members ( 1.33 mM vs 0.03 mM , p = 0.007 ) . Members of the observational group gained an average of 1.9 kg year(-1 ) in weight and had an increase of 0.36 mM year(-1 ) in 2-h glucose . Sustaining adherence in behavioural interventions over a long term was challenging . Pimas may find a less direct , less structured , and more participative intervention more acceptable than a direct and highly structured approach OBJECTIVE The Swedish Rectal Cancer Trial ( S RCT ) demonstrated that a short-term regimen of high-dose preoperative radiotherapy ( 5 x 5 Gy ) not only reduced the local recurrence rates but also improved the overall survival rate . This compelling evidence will have a significant impact on the primary treatment of rectal cancer . The authors ' aim was to explore the representativeness of the study . SUMMARY BACKGROUND DATA Until the S RCT was presented in 1997 , no major trial had established that radiotherapy has a positive effect on the overall survival rate . METHODS A review of all rectal cancer cases reported to the Swedish Cancer Registry during the same period that the S RCT accrued patients ( 1987 to 1990 ) was performed at 57 of 68 participating hospitals . At these 57 hospitals , there were 2366 patients with invasive rectal cancer , with 1664 of these patients fulfilling the criteria for inclusion in the S RCT . RESULTS Fifty-two percent ( 866/1664 ) of eligible patients were included in the S RCT . The patients not included , of whom 8 % ( 67/798 ) received adjuvant radiotherapy , had an overall 5-year survival rate of 48 % , which was identical to the overall survival rate in the S RCT surgery-alone group ( 48 % ) but was inferior to the S RCT radiotherapy group ( 58 % ) . The cancer-specific 5-year survival rates were 65 % and 66 % among the patients not included and the surgery-alone group , respectively . The local recurrence rates reached 27 % in both groups . The results were still comparable when stratifying for curative surgery , tumor stage , and surgical procedure . CONCLUSIONS The achieved inclusion level of 52 % in a r and omized multicenter trial is comparatively high . Because the population in the S RCT was representative , it was concluded that the study results are reliable Objectives To examine the generalizability of two large r and omized controlled clinical trials of antiretroviral therapy in HIV‐infected individuals Study Design . A prospect i ve , r and omized , multicenter , FDA -regulated Investigational Device Exemption clinical trial . Objectives . To analyze the incidence of , and reasons for , reoperation in all patients ( treatment and control ) enrolled in the IDE study . Summary of Background Data . This is the first report of the incidence and nature of reoperations following lumbar TDR as part of a controlled , prospect i ve , multicenter trial . Methods . A total of 688 patients meeting the inclusion and exclusion criteria were enrolled in one of three arms of the study at 14 centers across the United States . This cohort includes 71 nonr and omized cases , 205 r and omized cases , and 313 continued access cases , all receiving the CHARITÉ Artificial Disc , as well as 99 r and omized cases in the control group ( ALIF with threaded fusion cages and autograft ) . A detailed analysis was performed of clinical chart notes , operative notes , and adverse event reports for all patients requiring reoperation following their index surgery . Results . Of the 589 patients with TDR , 52 ( 8.8 % ) required reoperation . Of the 99 patients with lumbar fusion , 10 ( 10.1 % ) required reoperation , and an additional 2 required surgery for adjacent level disease ( P = 0.7401 ) . There were 24 TDR patients who underwent a repeated anterior retroperitoneal approach , with 22 ( 91.7 % ) having had a successful removal of the prosthesis . Seven of the 24 TDR prostheses requiring removal were revised to another CHARITÉ Artificial Disc . The mean time to reoperation in all patients was 9.7 months . A total of 29 patients ( 4.9 % ) in the TDR group required posterior instrumentation and fusion as did 10 ( 10.1 % ) in the control group ( P = 0.0562 ) . At 2 years or more follow-up , 93.9%(553/589 = 93.9 % ) of patients receiving TDR with the CHARITÉ Artificial Disc had a successfully functioning prosthesis with a mean of over 7 ° of flexion-extension mobility . Conclusions . Lumbar TDR with the CHARITÉ Artificial Disc did not preclude any further procedures at the index level during primary insertion , with nearly one third being revisable to a new motion-preserving prosthesis and just over two thirds being successfully converted to ALIF and / or posterior pedicle screw arthrodesis , the original alternative procedure The relative effectiveness of an inpatient and an outpatient withdrawal programme for opiate addicts was studied . Forty five men and 15 women ( mean age 26.13 ( SD 5.12 ) years ) took part in the study , all of whom were voluntary patients at the drug dependence clinic of the Maudsley Hospital in London between 1984 and 1985 . Subjects were asked if they were prepared to accept either inpatient or outpatient withdrawal , and those who were willing to do so were assigned r and omly to the r and omised outpatient group or the r and omised inpatient group . Those who expressed a strong preference were assigned , as appropriate , to the preferred outpatient group or the preferred inpatient group . Addicts in the inpatient group were more likely to achieve complete withdrawal ( 25 out of 31 , 81 % ) than those in the outpatient group ( five out of 29 , 17 % ) . This difference could not be attributed to pretreatment factors related to drugs or to social or psychological differences between the groups . These results have clinical and policy implication s for the treatment of opiate addicts Fifty North American centers have combined to evaluate the benefit of carotid endarterectomy in r and omized patients who have experienced symptoms related to arteriosclerotic stenosis of the carotid artery and who have received either best medical therapy alone or best medical therapy plus carotid endarterectomy . The outcome events are nonfatal and fatal stroke or death . A three-tier system identifies and adjudicates the type , severity , and location of each stroke and the cause of any death . Data about patients su bmi tted to carotid endarterectomy outside the trial are compiled at the Nonr and omized Data Center at the Mayo Clinic . Between December 27 , 1987 , and October 1 , 1990 , 1,212 patients were r and omized , 596 to medical therapy , 616 to carotid endarterectomy . Cross-over from the medical to the surgical arm has been low ( 4.2 % ) . Patients eligible for the trial , but not r and omized totaled 1,044 ; their characteristics were similar to those r and omized so that , for the type of symptomatic patient in this study , our conclusions about the benefit of carotid endarterectomy can be generalized . Patients excluded by medical criteria totaled 679 . Another 1,591 had carotid endarterectomy , but either lacked the disease under study , were asymptomatic , or received inadequate investigation to meet entry criteria . We set sample size at 1,900 patients , with continuing enrollment . The Monitoring Committee review s at intervals the confidential analyses performed on the groups with moderate ( 30 - 69 % ) and severe ( 70 - 99 % ) stenosis . Stopping rules will be invoked for one or both groups if unequivocal benefit or harm is identified OBJECTIVE --To investigate pretrial risk factors and long term mortality ( 1964 - 1992 ) in participants and non- participants of a multifactorial primary prevention trial . DESIGN --A prospect i ve study among 3313 initially healthy businessmen . During the 1960s ( 1964 onwards ) , 3490 healthy male business executives born between 1919 and 1934 participated in voluntary health checks at the Institute of Occupational Health in Helsinki . From that period cardiovascular disease ( CVD ) risk factors were available in 3313 men . In the beginning of the 1970s these men were invited to join a multifactorial primary prevention trial of CVD . Six groups were formed : ( I ) healthy participants in a high risk intervention group ( n = 612 ) , and ( II ) their r and omised control group ( n = 610 ) ; ( III ) a non-participant low risk group ( n = 593 ) ; ( IV ) an excluded group with signs of CVD ( n = 563 ) ; ( V ) a refused group ( n = 867 ) ; and ( VI ) dead ( n = 68 ) . Groups I and II participated in the five year prevention trial which started in 1974 . Other groups were followed up through registers , with no personal contact . MEASUREMENTS --Cardiovascular risk factors during the 1960s . Mortality follow up using national registers up to 31 December , 1992 . MAIN RESULTS --Baseline risk factors were lowest in the low risk group , highest in the excluded group , intermediate and comparable in other groups . Eighteen-year ( 1974 - 1992 ) mortality ( per 1000 ) was 79.3 , 106.6 , 155.2 , 179.9 , and 259.3 in the low risk , control , intervention , refused , and excluded groups , respectively ( P < 0.001 ) . In the whole population of 3313 men , the 28-year ( 1964 - 1992 ) total ( n = 577 ) and coronary deaths ( n = 199 ) were significantly predicted by smoking , blood pressure , and cholesterol ; cancer deaths ( n = 163 ) by smoking only ; and violent deaths ( n = 83 ) by none of the risk factors . One-hour postload glucose was significantly associated with total mortality in the intervention group only . When the intervention and control groups were included in the same model , the effect of group on total mortality tended to be dependent on the 1 h blood glucose value ( P = 0.06 for the group by 1 h glucose interaction term ) . CONCLUSION --The traditional risk factors ( smoking , blood pressure , and cholesterol ) are significantly associated with 28-year mortality in this high social class population with previous health education . Conversely , a " clustering " of low risk factors predicted low total , coronary , and cancer mortality . The findings on 1 h blood glucose suggest that factors related to glucose tolerance explain in part the excess mortality in the intervention group compared with the control group The influence of dietary omega-3 fatty acid supply on visual acuity development was evaluated in very low birth weight ( VLBW ) infants using visual-evoked potential ( VEP ) and forced-choice preferential-looking ( FPL ) procedures at 36 and 57 wk postconception . The VLBW infants born at 27 - 33 wk postconception were r and omized to one of three diet groups : corn oil , which provided solely linoleic acid ; soy oil , which provided linoleic and alpha-linolenic acids ; or soy/marine oil ; which was similar to the soy oil formula but also provided preformed long chain omega-3 fatty acids . The VLBW infants in the soy/marine oil group had higher omega-3 levels in erythrocyte membranes and better VEP and FPL acuities at 36 and 57 wk than infants in the corn oil group . The soy oil group had intermediate omega-3 levels in erythrocyte membranes and significantly poorer VEP acuity at 57 wk compared with the soy/marine oil group . Only the soy/marine oil group had acuities comparable to the " gold st and ards " of VLBW infants fed human milk and preterm infants who were born and tested at 35 - 36 wk postconception . In addition , VEP and FPL acuity were poorer in a nonr and omized group of formula-fed full-term infants than in breast-fed full-term infants . The results suggest that dietary omega-3 fatty acid supply may play an important role in early human visual development Both psychosocial and biologic interventions may delay or prevent Alzheimer disease . Staying mentally active may help older people maintain their cognitive abilities . In the Alzheimer Disease Cooperative Study Prevention Instrument Project a book club was introduced as a recruitment and retention device . A 3-arm study was design ed and included : a nonr and omized , self-selected group ( n=211 ) who chose not to participate in the book club , and 2 groups r and omly assigned to receive 2 books per year in individual self-improvement ( n=210 ) or community involvement ( n=207 ) categories . Participants reported their reactions to the selection s and other reading behaviors . Results from the first 2 years revealed that most book club participants agreed with Likert-type statements indicating the readings were enjoyable ( P<0.001 ) , had an impact on their thinking ( P=0.01 ) , and were shared by them with others ( P=0.002 ) . Respondents in the community involvement group agreed more strongly with these statements than those in the self-improvement category . Comments from participants in response to open-ended questions in the reader survey revealed such themes as developing plans for successful aging and reflecting on attitudes and behaviors in their own lives . Further longitudinal analyses are planned to determine whether the book club influenced retention and whether participation was associated with slowing cognitive decline This study investigated the external validity ( or generalizability of results ) of r and omized clinical trials in cancer . Tao ECOG lung cancer chemotherapy protocol s active in the early 1970s were studied using a case-control design . All lung cancer patients of the four specified cell types resident in Monroe County during the ECOG study period were identified from the Rochester Regional Tumor Registry . All of the patients entered into either protocol ( " ECOG cases " ) and a r and om sample of the non protocol cases were examined by medical records review . Thirty-seven percent of the non protocol cases were determined to have been eligible for either of the two ECOG protocol s , but not entered ( " eligible controls " ) . A comparison of the ECOG cases ( n = 65 ) and the eligible controls ( n = 109 ) revealed that ( 1 ) ECOG cases were more likely than eligible controls to have been diagnosed at a hospital which participated in the University of Rochester Cancer Center 's medical oncology program ; ( 2 ) ECOG cases were of higher occupational status than eligible controls ; ( 3 ) duration from diagnosis to protocol entry for ECOG cases was longer than duration from diagnosis to earliest date of eligibility for eligible controls . The implication s of these findings for the conduct of cancer clinical trials are discussed Summary The first objective of this study was to analyze the survival rate in a group of 69 breast cancers detected among nonattenders in a r and omized mammographic screening trial in relation to 142 clinical ly detected cancers in a nonscreened control population . By analyzing the cancers of the nonattenders we identified two subgroups , one ( A ) had actively avoided mammography , had cancers in more advanced stages on diagnosis , and had significantly higher mortality from breast cancer than the control group ( p = 0.003 ) . The second subgroup ( B ) had mammography done outside the screening program . This subgroup had a nonsignificant , slightly better survival ( p = 0.19 ) compared to the control group . Concerning stage the cancers in group B were similar to the cancers by the screening program . The second objective was to analyze women 's reasons for nonattendance in the screening program . We interviewed 200 r and omly selected nonattenders ; 33 % stated that they never could imagine having mammography ( definite nonattenders ) , 29.5 % that they for various reasons had missed the mammography but could imagine having it next time ( possible future attenders ) , and 32 % had been examined outside the program . Reasons for nonattendance included disinterest , medical problems , and fear of X-rays . From this interview investigation we believe that the subgroup of definite nonattenders ( 33 % ) is difficult to influence . The second subgroup classified as possible future attenders ( 29.5 % ) we believe can be influenced by more information and a new opportunity to receive mammography , i.e. , a reminder letter . The third subgroup , those examined outside the screening program ( 32 % ) were aware of the benefit of mammography , taking action on their own . Concerning these women 's health this seems acceptable ; screening outside the program seemed equivalent to that inside the program concerning stage and mortality in breast cancer as shown in the first part of the study In a prospect i ve clinical r and omized investigation 487 women had the condition of the fetus during labour supervised by means of stethoscope ( AUS ) , while 482 women went through labour under surveillance of electronic fetal monitoring , cardiotocography ( EFM ) . 349 women refused to participate in the investigation ( NAI ) and had delivery conducted according to the normal procedures of the department ( 70 % AUS , 30 % EFM ) . Significantly more pathological fetal heart rate patterns ( FHR ) were found in the EFM group compared to the AUS group in both the first and the second stage of labour . As a result significantly more vacuum extraction s were performed in the EFM group than in the AUS group , while no statistical difference was found between the groups in the incidence of acute cesarean sections carried out for asphyxia . One case of intrapartum death occurred in the AUS group . No differences were found in Apgar scores after 1 and 5 min or in neonatal morbidity at examination on the 2nd and 5th days after delivery . A tendency towards more biochemically compromised children was found in the AUS group . The specificity for both methods was found to be acceptably high ( 80 % ) , while the predictive value for both methods was low ( 50 % ) . More research is therefore urgently needed to evaluate supplementary investigations and parameters for the evaluation of the intrapartum fetal condition EDITORIAL COMMENT : This study shows how necessary it is for any research finding relevant to patient care or clinical belief to be verified before enshrinement in the regimens of clinical practice — the more important the finding , the more necessary the verification . This paper will not be the last word on the effect of condom use on prevention of initiation or progression of cervical intraepithelial neoplasia , but it does make one wonder if the role of seminal fluid in the pathogenesis of carcinoma of the cervix should be reexamined — or is the die cast and the role of seminal fluid as carcinogenic factor complete once there is histological evidence of intraepithelial neoplasia Grade 1 OBJECTIVES : Patient-controlled sedation ( PCS ) with propofol , is well tolerated and reduces recovery time and staff required during endoscopic interventions . “ Who ” administers the drug proves economically crucial . With the aim of maintaining safety , medical quality , and patient satisfaction , this study investigates PCS versus nurse-administered propofol sedation ( NAPS ) in a cohort of consecutive patients . METHODS : One hundred and fourteen patients , aged 22–90 yr , undergoing only colonoscopy participated in this prospect i ve r and omized trial . Patients were r and omly assigned to either PCS or NAPS . If patients declined r and omization for different reasons of reluctance to PCS they were assigned to a st and ard nurse-se date d control group . All patients received pethidine presedation for analgesia . Visual analogue scales followed patient anxiety level , tolerability , pain , and satisfaction , and endoscopist 's assessment of the procedure . RESULTS : Given the choice , 35 % of the patients who were rather younger and more anxious declined r and omization to PCS . The mean total dose of propofol needed in this group was higher , but the patients had a tendency to rate the global tolerance and the pain of the examination as less comfortable compared to the two r and omized groups . Self-administration of propofol created a significantly different drug profile and higher medication costs . With regard to the safety parameters there was no difference between PCS and NAPS . In their global assessment s , the patients and endoscopists tended to prefer NAPS . CONCLUSIONS : Individual patient characteristics and attitudes toward self-control are crucial for PCS . While being a viable option for patients who are able and willing to h and le , this technique is not applicable in a considerable portion of everyday patients We report a retrospective analysis of survival , and attrition to a study , of patients with anaplastic glioma seen at a regional cancer center during its participation in a prospect i ve r and omized clinical trial . Median length of survival for all patients was 35 weeks . Median length of survival for study patients was 60 weeks . Study patients were not representative of all patients ; they were younger and less disabled than the non study patients . Survival predictions for patients with anaplastic glioma based on the results of clinical trials may be overly optimistic . Many trials study a nonrepresentative subset of patients with anaplastic glioma , excluding those who do poorly at the outset and those who have poor function This study examines potential improvement in treatment adherence during a study of involuntary outpatient commitment among individuals with severe mental illnesses . Involuntarily hospitalized subjects , awaiting discharge under outpatient commitment , were r and omly assigned to be released or continue under outpatient commitment after hospital discharge . A nonr and omized group with a recent history of serious violence was also studied under outpatient commitment . R and omized control and outpatient commitment groups did not differ significantly in group comparisons of treatment adherence . However , analyses of all subjects , including nonr and omized violent subjects , showed that those who underwent sustained periods of outpatient commitment ( 6 months or more ) were significantly more likely to remain adherent with medication and other treatment , compared with those who underwent only brief outpatient commitment or none . Administration of depot antipsychotics also significantly improved treatment adherence independently of the effect of sustained outpatient commitment . Sustained periods of outpatient commitment may significantly improve adherence with community-based mental health treatment for persons with severe mental illness and thus may help improve other clinical outcomes affected by adherence This prospect i ve study evaluated whether prophylactic saline amnioinfusion among patients with amniotic fluid index ( AFI ) < or = 5.0 cm decreases the incidence of adverse fetal outcomes . R and omization of 53 patients with decreased AFI at term , result ed in 21 patients ' receiving prophylactic saline amnioinfusion early in labor , prior to development of an abnormal fetal heart rate tracing . For the treatment group the mean AFI on admission was 3.0 cm , and the postamnioinfusion AFI was 8.9 cm . For 32 comparison ( noninfusion ) patients , the mean AFI was 2.9 cm ; the group consisted of 17 patients r and omized to receive no amnioinfusion ( control group ) and 15 patients who refused to participate in the study . There was no statistically significant difference between the amnioinfused and nonamnioinfused patients with regard to age , parity , gestational age , AFI at admission or duration of first or second stage of labor . Amnioinfusion result ed in no statistically significant reduction in the incidence of recurrent variable decelerations/bradycardia ( 26.3 % vs. 46.6 % ) , intrapartum resuscitation with terbutaline ( 5.2 % vs. 10.0 % ) , cesarean section for fetal distress ( 9.5 % vs. 9.3 % ) , fetal-acidosis ( 10.5 % vs. 12.0 % ) or Apgar scores < 7 at five minutes ( 5.2 % vs. 0 % ) in patients with oligohydramnios The aim of this study was to establish whether the mobilisation technique selected by the treating physiotherapist is more effective in relieving low back pain than a r and omly selected mobilisation technique . Two manipulative physiotherapists and 140 subjects suffering non-specific low back pain participated . Baseline measurements were taken before treatment allocation ; the therapist then assessed subjects and nominated the preferred treatment grade , spinal level to be treated and mobilisation technique to be used . The subjects were then r and omly allocated to one of two groups . One group received the preferred mobilisation technique as selected by the therapist ; the other group received a r and omly assigned mobilisation technique . All mobilisation treatments were applied to the nominated spinal level using the nominated treatment grade . Follow-up measures were taken immediately after intervention . Two-way ANOVA was used to analyse the data ; the first factor was the treatment group and the second factor was the direction of the patient s most painful movement . The choice of mobilisation treatment had no effect on any outcome measure investigated in this study ; however , post hoc tests revealed that mobilisation treatment applied to the lower lumbar levels had a greater analgesic effect than when applied to upper lumbar levels . The results of this study confirm that lumbar mobilisation treatment has an immediate effect in relieving low back pain , however the specific technique used seems unimportant OBJECTIVE To study , whether and how the results from open and double-blind r and omized trials on antidepressants differ . METHODS Seventy-one patients were included in a study comparing open , non-r and omized , st and ardized treatment with paroxetine ( PAROX ) and amitriptyline ( AMI ) after a minimum of six drug-free days ( OPEN ) . A second group of 56 patients received the same treatment under blind-r and omized conditions ( BLIND-R AND OM ) . The course of psychopathology as assessed by the Hamilton Depression Rating Scale was compared using repeated measurements ANOVA-(rm ) . RESULTS While the rate of adverse events was higher in the BLIND-R AND OM compared to the OPEN condition , completer-analyses revealed no differences in psychopathological outcome . CONCLUSIONS With similar clinical outcome BLIND-R AND OM trials of antidepressants may expose depressed patients to an increased risk of adverse events , when compared to OPEN conditions . However , the clinical outcome in study completers did not differ between the BLIND-R AND OM and the OPEN condition . Thus , the psychiatrist 's choice may have impact on adverse events rather than on clinical outcome of antidepressant treatment The aim of the present trial was to evaluate the effects of chemotherapy on the quality of life and survival of patients with advanced non-small cell lung cancer ( NSCLC ) ( stage IIIB or IV ) . In a controlled multicentre trial , patients were r and omised to receive supportive care only or supportive care plus chemotherapy . Chemotherapy consisted of intravenous ( i.v . ) carboplatin 300 mg/m2 on day 1 and etoposide 120 mg/m2 orally on days 1 - 5 every 4 weeks for a maximum of eight courses . Quality of life was measured at r and omisation and prior to each treatment course and at corresponding 4-week intervals in the control arm , using the EORTC QLQ-C30 + LC13 question naire . 48 patients were r and omised ( supportive care 26 , chemotherapy 22 ) , being eligible for comparative analyses . Another 102 patients , 97 of which received chemotherapy , were subsequently included in the study on an individual treatment preference basis . Data from these patients were used for confirmative purpose s. Patients in the chemotherapy group reported better overall physical functioning and symptom control compared with the supportive care group . Group differences were smaller within the psychosocial domain , although trends were seen in favour of the chemotherapy group . No significant differences were seen in favour of the supportive care group , except for hair loss . Median survival times were 29 weeks in the chemotherapy group versus 11 weeks in the supportive care group , and 1-year survival rates were 28 % versus 8 % . Quality of life and survival outcomes were similar in the r and omised and non-r and omised patients receiving chemotherapy . No treatment-related deaths occurred . In conclusion , treatment with carboplatin and etoposide can improve both the quality of life and the survival of patients with advanced NSCLC AIM To test whether emergency revascularization improves survival in patients with acute myocardial infa rct ion and shock . METHODS AND RESULTS Patients with acute myocardial infa rct ion and early shock were r and omized either to undergo emergency angiography , followed immediately by revascularization when indicated , or to receive initial medical management . In five of the nine participating centres , patients with shock but not r and omized were entered in a registry . Only 55 patients could be r and omized . Of the 32 patients in the invasive group , 30 ( 94 % ) underwent early angiography , 27 ( 84 % ) PTCA , and one ( 4 % ) CABG . Twenty-two ( 69 % ) died within 30 days in the invasive group vs 18/23 ( 78 % ) in the medically managed group ( ns , RR=0.88 , 95 % confidence interval 0.6 - 1.2 ) . Among the registry patients , 24/51 were excluded from r and omization solely because of patient or physician preference for the invasive approach : 23 ( 96 % ) of them underwent emergency angiography , 21 ( 88 % ) PTCA , and 12 ( 50 % ) died within 30 days . Among the remaining registry patients ( n=27 ) only nine ( 33 % ) underwent early angiography , nine ( 33 % ) PTCA and 20 ( 74 % ) died . CONCLUSION We failed to demonstrate that emergency PTCA significantly improves survival in patients with acute myocardial infa rct ion and early cardiogenic shock . Because the study was stopped prematurely , due to an insufficient patient inclusion rate , a clinical ly meaningful benefit of early reperfusion may have been missed Summary : It has been suggested that the polypeptide hormone relaxin is an early pregnancy factor which facilitates implantation and pregnancy maintenance . To test this hypothesis a double blind r and omized placebo controlled trial was conducted where 2 mg purified porcine relaxin or distilled water was given in a vaginal gel on the day of embryo transfer and again 3 days later in a human in vitro fertilization ( IVF ) programme . There were 96 patients in the r and omized trial and 73 patients who were treated concurrently in the same IVF programme acted as a further control group . Of the 51 patients who received relaxin , 10 pregnancies were confirmed and 8 continued successfully . In the 45 patients treated with placebo 10 pregnancies were also confirmed and 6 continued successfully . Amongst the 73 patients concurrently treated outside the trial 14 achieved a pregnancy and 10 continued to term . Thus , porcine relaxin given in these circumstances in a human IVF programme did not appear to improve or interfere with the pregnancy rate . Possible factors that affected the implantation rates in this trial are discussed OBJECTIVE To describe time trends , from 1987 through 1997 , ( 1 ) in size of choroidal melanoma among patients with recent diagnosis confirmed at a clinical center that participated in the Collaborative Ocular Melanoma Study ( COMS ) and ( 2 ) in choice of treatment by patients who did not enroll in one of the COMS r and omized trials . METHODS Investigators at all COMS clinical centers ( 41 in the United States and 2 in Canada ) agreed to report , in a masked fashion that did not include personal identifiers , all patients diagnosed as having choroidal melanoma during the accrual period for COMS r and omized trials of radiotherapy . Information reported for patients who did not enroll in a COMS r and omized trial included tumor dimensions , date of diagnosis , and initial treatment selected . Patients reported by centers that continued to report cases until 1997 and diagnosed as having choroidal melanoma no more than 1 year before evaluation at a participating COMS center contributed the data analyzed . OUTCOME MEASURES Time trends in tumor size among patients reported and in elective treatment of patients not enrolled in COMS r and omized trials . RESULTS Of 8712 patients with choroidal melanoma examined , 6703 met criteria for analysis of time trend in tumor size and 4077 were analyzed for treatment trends over time . The number of cases with longest tumor basal diameter greater than 15.0 mm declined over time from 393 ( 30 % ) of 1330 cases reported in 1987 through 1989 to 345 ( 25 % ) of 1397 cases reported in 1996 or 1997 . The proportion of patients eligible for COMS r and omized trials who did not enroll and who elected enucleation remained stable over time for tumors of all sizes ; the proportion of these patients who elected eye-conserving radiotherapy increased over time . Juxtapapillary tumors accounted for nearly half of the enucleations among ineligible patients who had tumors no larger than 15.0 mm in longest basal diameter . CONCLUSIONS Among patients examined at COMS centers during 1987 through 1997 , the trends observed for patients with recently diagnosed choroidal melanoma included increasing presentation with tumors of smaller size , decreasing use of enucleation for choroidal melanoma 15.0 mm or less in longest basal diameter , and increasing use of such strategies for larger tumors We studied the efficacy of tonsillectomy , or tonsillectomy with adenoidectomy , in 187 children severely affected with recurrent throat infection . Ninety-one of the children were assigned r and omly to either surgical or nonsurgical treatment groups , and 96 were assigned according to parental preference . In both the r and omized and nonr and omized trials , the effects of tonsillectomy and of tonsillectomy with adenoidectomy were similar . By various measures , the incidence of throat infection during the first two years of follow-up was significantly lower ( P less than or equal to 0.05 ) in the surgical groups than in the corresponding nonsurgical groups . Third-year differences , although in most cases not significant , also consistently favored the surgical groups . On the other h and , in each follow-up year many subjects in the nonsurgical groups had fewer than three episodes of infection , and most episodes among subjects in the nonsurgical groups were mild . Of the 95 subjects treated with surgery , 13 ( 14 per cent ) had surgery-related complications , all of which were readily managed or self-limited . These results warrant the election of tonsillectomy for children meeting the trials ' stringent eligibility criteria , but also provide support for nonsurgical management . Treatment for such children must therefore be individualized OBJECTIVE To determine the efficacy of ciprofloxacin therapy in eradicating convalescent fecal excretion of salmonellae after acute salmonellosis . DESIGN R and omized , placebo-controlled , double-blind trial of ciprofloxacin , with prospect i ve follow-up of non participants . SETTING An acute care community hospital experiencing an outbreak of salmonellosis . PATIENTS Twenty-eight health care workers developed acute infection with Salmonella java ; 15 participated in a placebo-controlled trial of ciprofloxacin , beginning on day 9 after infection . INTERVENTIONS Eight patients were r and omly assigned to receive ciprofloxacin , 750 mg , and 7 patients to receive placebo ; both were administered orally twice daily for 14 days . Non participants who received therapy were placed on the same ciprofloxacin regimen . MEASUREMENTS AND MAIN RESULTS Study participants had follow-up stool cultures every 3 days initially and then weekly for 3 weeks ; non participants were followed until three consecutive cultures were negative . All eight ciprofloxacin recipients showed eradication of S. java from stool cultures within 7 days of beginning therapy ( compared with 1 of 7 placebo recipients ) , and their stool cultures remained negative up to 14 days after discontinuing therapy ( P less than 0.01 ) . However , 4 of 8 relapsed ; their stool cultures became positive between 14 and 21 days after therapy . In addition , 3 of 3 hospitalized patients treated with ciprofloxacin who did not participate in the controlled trial also relapsed . Thus , the total relapse rate was 7 of 11 ( 64 % ; 95 % CI , 31 % to 89 % ) . In 4 of these 7 patients , relapse was associated with a longer duration of fecal excretion of salmonellae than that of the placebo group . Relapse could not be explained on the basis of noncompliance , development of resistance , or presence of biliary disease . CONCLUSIONS Despite its excellent antimicrobial activity against salmonellae and its favorable pharmacokinetic profile , ciprofloxacin at a dosage of 750 mg orally twice daily had an unacceptably high failure rate in patients with acute salmonellosis and may have prolonged fecal excretion of salmonellae . The late occurrence of relapses indicates the need to obtain stool cultures up to 21 days after therapy to document fecal eradication in acute salmonellosis OBJECTIVE To assess the effect of medical nutrition therapy ( MNT ) provided by dietitians on medical and clinical outcomes for adults with non-insulin-dependent diabetes mellitus ( NIDDM ) , and to compare MNT administered according to practice guidelines nutrition care ( PGC ) to MNT administered with basic nutrition care ( BC ) . DESIGN A prospect i ve , r and omized , controlled clinical trial of two levels of MNT on metabolic control in persons newly diagnosed with or currently under treatment for NIDDM was conducted at diabetes centers in three states ( Minnesota , Florida , and Colorado ) . BC consisted of a single visit with a dietitian ; PGC involved an initial visit with a dietitian followed by two visits during the first 6 weeks of the study period . Data were collected at entry to the study and at 3 and 6 months . SUBJECTS Results are reported for 179 men and women aged 38 to 76 years : 85 assigned r and omly to BC and 94 to PGC . This represents 72 % of the 247 subjects enrolled . An additional 62 adults with NIDDM at one site who had no contact with a dietitian were identified as a nonr and om comparison group . OUTCOMES Medical outcome measures included fasting plasma glucose ( FPG ) , glycated hemoglobin ( HbA1c ) , and serum lipid levels . Clinical outcomes included weight , body mass index , waist-to-hip ratio , and changes in medical therapy . STATISTICAL ANALYSES Initial analysis of the discrete variables was done using the chi 2 statistic with Yates ' correction . Initial analysis of continuous variables was done by analysis of variance . The changes in variables between time periods were analyzed by paired t test , and comparisons between groups were analyzed using a t test for independent groups . RESULTS At 6 months , PGC result ed in significant improvements in blood glucose control as indicated by FPG and HbA1c levels and BC result ed in significant improvements in HbA1c level . Participants assigned to the PGC group had a mean FPG level at 6 months that was 10.5 % lower than the level at entry , and those in the BC group had a 5.3 % lower value . Among subjects who had diabetes for longer than 6 months , those who received PGC had a significantly better HbA1c level at 3 months compared with those receiving BC . The comparison group showed no improvement in glycemic control over a comparable 6 months . PGC subjects had significant improvements in cholesterol values at 6 months , and subjects in both the PGC and the BC groups had significant weight loss . CONCLUSIONS MNT provided by dietitians result ed in significant improvements in medical and clinical outcomes in both the BC and PGC groups and is beneficial to persons with NIDDM . Persons with a duration of diabetes longer than 6 months tended to do better with PGC than with BC . Because of the upward trend in glucose levels after 3 months , ongoing MNT by dietitians is important for long-term metabolic control BACKGROUND Patients in clinical trials of fibrinolytic agents have been shown to be younger , less often female , and to have lower risk characteristics and a better outcome compared with unselected patients with ST-elevation myocardial infa rct ion . However , a direct comparison of patients treated with fibrinolytic agents and not enrolled versus those enrolled in a trial , including a large number of patients , has not been performed . METHODS Prospect i ve data from the Swedish Register of Cardiac Intensive Care on patients admitted with acute myocardial infa rct ion treated with thrombolytic agents in 60 Swedish hospitals were linked to data on trial participants in the ASsessment of Safety and Efficacy of a New Thrombolytic (ASSENT)-2 trial of fibrinolytic agents . Baseline characteristics , treatments , and long-term outcome were evaluated in 729 trial participants ( A2 ) , 2048 non participants at trial hospitals ( non-A2 ) , and 964 non participants at other hospitals ( non-A2-Hosp ) . RESULTS Nontrial patients compared with A2 patients were older and had higher risk characteristics and more early complications , although the treatments were similar . Patients at highest risk of death were the least likely to be enrolled in the trial . The 1-year mortality rate was 8.8 % versus 20.3 % and 19.0 % ( P < .001 for both ) among A2 compared with non-A2 and non-A2-Hosp patients , respectively . After adjustment for a number of risk factors , the 1-year mortality rate was still twice as high in nontrial compared with A2 patients . CONCLUSIONS The adjusted 1-year mortality rate was twice as high in patients treated with fibrinolytic agents and not enrolled in a clinical trial compared with those enrolled . One major reason for the difference in outcome appeared to be the selection of less critically ill patients to the trial BACKGROUND Patients with multivessel coronary artery disease are c and i date s for either angioplasty and stenting or coronary artery bypass grafting . A prospect i ve r and omized study design ed to compare the both methods included only a minority of the eligible patients . OBJECTIVE To compare coronary artery bypass grafting to angioplasty plus stenting in patients with multivessel disease who declined r and omization to a multicenter study ( the ARTS ) . METHODS During 1997 - 98 we prospect ively followed 96 consecutive patients who were eligible according to the ARTS criteria but refused r and omization . Of these patients , 50 underwent angioplasty + stenting and 46 underwent coronary bypass surgery . We compared the incidence of major adverse cardiac and cerebral events , chest pain recurrence , quality of life and procedural cost during the first 6 months . RESULTS All procedures were completed successfully without mortality or cerebral events . The rate of Q-wave myocardial infa rct ion was 2 % in the AS group vs. 0 % in the CABG group ( not significant ) . Minor complications occurred in 7 patients ( 14 % ) in the AS group and in 21 patients ( 45 % ) in the CABG group ( P < 0.01 ) . At 6 months follow-up the incidence of major cardiac and cerebral events was similar in both groups ( 11 % and 4 % in the AS and CABG groups respectively , P = NS ) . Seventeen patients ( 36 % ) in the AS group required repeat revascularization compared to only 3 ( 7 % ) in the CABG group ( P = 0.002 ) . Nevertheless , quality of life was better , hospitalization was shorter and the cost was lower during the first 6 months after angioplasty . CONCLUSION Angioplasty with stenting compared to coronary bypass surgery in patients with multivessel disease result ed in similar short-term major complications . However , 36 % of patients undergoing angioplasty may need further revascularization procedures during the first 6 months Study Design . A prospect i ve , r and omized , multicenter , Food and Drug Administration regulated Investigational Device Exemption ( IDE ) clinical trial . Objectives . To discern whether there is a correlation between surgical volume and clinical outcomes , as well as the complication rate and perioperative data points , for lumbar total disc replacement . To examine the early experience for lumbar total disc replacement as part of an IDE study . Summary of Background Data . To our knowledge , an analysis of the effect of surgical volume has not been performed for any spine surgical procedure . Prior reports of the early experience with lumbar total disc replacement consist of retrospective review s with nonspecific indications . Methods . An analysis was performed of the Food and Drug Administration IDE Study of the Charité Artificial Disc ( DePuy Spine , Inc. , Raynham , MA ) . Patients enrolled in the control group were omitted from the analysis . Up to 5 nonr and omized cases ( representing the early experience ) were performed at each site before beginning the r and omized arm of the study . There were 3 comparisons performed : nonr and omized cases ( 71 ) versus r and omized cases ( 205 ) ; r and omized cases performed by high-enrolling surgeons versus low-enrolling surgeons ; and r and omized cases at high-volume institutions versus low-volume institutions . Results . The high-enrolling groups had a significantly lower mean hospital stay and operating time compared to the low-enrolling groups ( P < 0.05 ) . High-enrolling surgeons and institutions showed significantly shorter operating times , length of hospital stay , and complication rates . High-enrolling surgeons had significantly fewer device failures and cases of neurologic deterioration . Mean operating time and hospital stay were significantly lower in the r and omized group ( P < 0.05 ) compared to the nonr and omized group . Blood loss and approach-related complications were similar between the 2 groups . Device failure requiring removal was 4.2 % in the nonr and omized group and 1.5 % in the r and omized group . Conclusions . Surgeons and institutions with a high volume of lumbar total disc replacement cases have a reduction in key perioperative and postoperative parameters that provide a clinical and /or economic benefit . Surgeons may expect longer hospital stays , higher blood loss , and a higher rate of certain complications in their early experience with total disc replacement procedures , but there was no effect on clinical outcomes BACKGROUND Exemplified by a r and omised trial on antimanic treatment , this paper addresses the question of whether selection of patients for drug trials may limit the applicability of study results from the r and omised patients to a wider population . METHOD During two-year period , all consecutively admitted patients from a defined catchment area were screened for inclusion criteria concerning age , diagnosis and severity of illness . The subsequently excluded subgroups of patients were compared with the r and omised patients by multivariate data analysis . RESULTS One hundred and sixty-four patients met the inclusion criteria . However , after exclusion for various reasons , only 27 ( 17 % ) patients remained for r and omisation . The r and omised patients and the excluded patients differed substantially . CONCLUSIONS The generalisability of trial results is limited . Reports of r and omised drug trials should carefully describe the screening procedure for inclusion and , when possible , present relevant comparisons-between the r and omised patients and the various subgroups of excluded patients Abstract Objective : To determine which groups of patients may derive particular benefit or experience harm from the use of low dose aspirin for the primary prevention of coronary heart disease . Design : R and omised controlled trial . Setting : 108 group practice s in the Medical Research Council 's general practice research framework who were taking part in the thrombosis prevention trial . Participants : 5499 men aged between 45 and 69 years at entry who were at increased risk of coronary heart disease . Main outcome measures : Myocardial infa rct ion , coronary death , and stroke . Results : Aspirin reduced coronary events by 20 % . This benefit , mainly for non-fatal events , was significantly greater the lower the systolic blood pressure at entry ( interaction P=0.0015 ) , the relative risk at pressures 130 mm Hg being 0.55 compared with 0.94 at pressures > 145 mm Hg . Aspirin also reduced strokes at low but not high pressures , the relative risks being 0.41 and 1.42 ( P=0.006 ) respectively . The relative risk of all major cardiovascular events — that is , the sum of coronary heart disease and stroke — was 0.59 at pressures < 130 mm Hg compared with 1.08 at pressures > 145 mm Hg ( P=0.0001 ) . Conclusion : Even with the limitations of subgroup analyses the evidence suggests that the benefit of low dose aspirin in primary prevention may occur mainly in those with lower systolic blood pressures , although it is not clear even in these men that the benefit outweighs the potential hazards . Men with higher pressures may be exposed to the risks of bleeding while deriving no benefit through reductions in coronary heart disease and stroke 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 STUDY OBJECTIVES To evaluate five different preoperative anxiolytic regimens in cataract surgery performed under regional anesthesia ; to quantify the pain associated with combined peri- and retrobulbar injection ( PRBI ) of local anesthetic drugs ; and to describe a technique of painless eye block . DESIGN R and omized , double blind , placebo-controlled study . SETTING Private clinic . PATIENTS 376 ASA I and II patients presenting for cataract surgery . INTERVENTIONS Patients were extensively briefed by the nursing staff on the various procedures . Of the 376 study patients , 136 preferred to have no anxiolytic drug . The remaining 240 patients were r and omly allocated to one of six groups to receive either 3 mg of bromazepam , 6 mg of bromazepam , 0.5 mg of alprazolam , 1 mg of alprazolam , 5 mg of diazepam , or a placebo on a double-blind protocol . All patients received a st and ard combined peri- and retrobulbar eye block ( PRBB ) before surgery . MEASUREMENTS AND MAIN RESULTS Anxiety at various stages of the procedure and PRBB were measured on visual analog scale ( 0 - 10 ) . PRBB pain was compared with pain of intravenous ( i.v . ) cannula placement . On admission , anxiety of the 136 patients who preferred no anxiolytic premedication was significantly less than that of the 240 patients assigned to one of the six treatment groups ( p < 0.05 ) . There was no difference between the six treatment groups in reported anxiety before surgery ( p > 0.05 ) except for Group 1 ( 3 mg bromazepam ) , where anxiety increased before and during PRBB administration ( p < 0.05 ) . In all six treatment groups , anxiety decreased significantly 30 minutes after medication was administered ( p < 0.05 ) . For the total group , 61.18 % of patients reported more or equal pain associated with the placement of the 20-gauge i.v . cannula than by the PRBB . Of the patients who received medication , 94 % stated that , should they require another eye operation , they would like the same anxiolytic treatment . No patient requested general anesthesia for their next operation or to be rendered unconscious for PRBB . CONCLUSIONS 1 . There was interpersonal variation in the level of preoperative anxiety . 2 . In patients who were anxious , the anxiolytic drugs and placebo decreasedanxiety although the level of anxiety did not differ between the anxiolytic drugs or between placebo and the anxiolytic drugs . The only difference was in Group 1 patients ( 3 mg promazepam ) , who reported slightly increased anxiety before and during PRBB administration ( p < 0.05 ) . 3 . Placement of the PRBB is less painful than the insertion of a 20 g i.v . cannula PURPOSE To examine the prevalence and incidence of second eye nonarteritic anterior ischemic optic neuropathy ( NAION ) and associated patient characteristics in patients enrolled in the Ischemic Optic Neuropathy Decompression Trial ( IONDT ) Follow-up Study . DESIGN R and omized clinical trial with observational cohort . METHODS Patients r and omized to optic nerve sheath decompression surgery or careful follow-up had a diagnosis of acute unilateral NAION , visual acuity between 20/64 and light perception , and were aged 50 years or older . Eligible patients who declined r and omization or whose visual acuity was better than 20/64 were not r and omized but followed as part of an observational cohort . Follow-up examinations took place at 3 , 6 , 12 , 18 , and 24 months and annually thereafter . RESULTS Four hundred eighteen patients were enrolled ; 258 r and omized and 160 observed . Previous NAION or other optic neuropathy was present in the fellow eye of 21.1 % ( 88/418 ) of patients at baseline . Four patients developed optic neuropathy in the fellow eye at follow up that could not be conclusively diagnosed as NAION . New NAION in the fellow eye occurred in 14.7 % ( 48/326 ) of patients at risk during a median follow up of 5.1 years . R and omized patients experienced a higher incidence ( 35/201 ; 17.4 % ) than nonr and omized patients ( 13/125 ; 10.4 % ) . A history of diabetes and baseline visual acuity of 20/200 or worse in the study eye , but not age , sex , aspirin use , or smoking were significantly associated with new NAION in the fellow eye . Final fellow eye visual acuity was significantly worse in those patients with new fellow eye NAION whose baseline study eye visual acuity was 20/200 or worse . CONCLUSIONS Follow-up data from the IONDT cohort provide evidence that the incidence of fellow eye NAION is lower than expected : new NAION was diagnosed in 14.7 % of IONDT patients over approximately 5 years . Increased incidence is associated with poor baseline visual acuity in the study eye and diabetes , but not age , sex , smoking history , or aspirin use A r and omised , prospect i ve study was performed to compare local ( LA ) and general anaesthesia ( GA ) in carotid surgery with special emphasis on complications and the need for intra-operative shunting . Fifty-six patients were r and omised to LA and 55 to GA . Eight patients in the LA group required a GA for various reasons . During the same period 14 patients were not r and omised . Seven perioperative neurological deficits occurred ( 5.6 % ) , four in the LA group , two in the GA group , and one in the non-r and omised group ( NS ) . Selective shunting was used , in the Ga group according to stump pressure or in cases with a previous stroke and in the LA group according to the appearance of neurological symptoms . In the GA group 25 patients were shunted and in the LA group five patients ( P less than 0.001 ) needed a shunt . If strict pressure criteria for shunting had been used in the LA patients , ten would have been shunted and three of the patients who developed symptoms during clamping would not have been shunted . During surgery the highest recorded systolic pressure was significantly higher in the LA group ( 210 mmHg versus 173 mmHg , P less than 0.001 ) . LA for carotid endarterectomy is comparable with general anaesthesia regarding peroperative complications but produces significantly higher blood pressures than general anaesthesia . On the other h and it allows the possibility of neurologic monitoring of the patient and leads to significantly less use of an intra-operative shunt Patients with poorly differentiated prostatic carcinoma and skeletal metastases were r and omized to treatment with 2.6-cis-diphenylhexamethylcyclotetrasiloxane ( 2.6-cis ) and estramustine-17-phosphate ( estramustine ) . Parallel with the clinical study a group of non-r and omized patients were treated with 2.6-cis . Cytological regression of the tumor could be registered in half of the estramustine group but not in the 2.6-cis group . There were no drug-related changes in blood chemistry , kidney function tests , hematology or liver enzymes . There was in increase in acid and alkaline phosphatase in both groups but more pronounced in the 2.6-cis group . In both groups follicle-stimulating and luteinizing hormone values were depressed . Testicular and penis atrophy was observed in the 2.6-cis group . Relief of pain and marked improvement of conditions occurred in the majority of the cases in both groups . In general , no tumor regression was observed during administration of 300 mg . 2.6-cis daily for at least 3 months . Some tumor regression was noted during 600 mg . estramustine therapy daily The recently reported VA Cooperative Study " A R and omized Clinical Trial of Total Parenteral Nutrition ( TPN ) in Malnourished Surgical Patients " r and omized 395 pre-operative patients to TPN treatment or control . The study concluded that the use of perioperative TPN should be limited to the most severely malnourished patients . The study also followed 233 patients eligible for the study who refused to give informed consent for r and omization ( Eligible Refusers ) as well as 1220 patients who were ineligible because they were not sufficiently malnourished ( Index Group ) . Patients in the Index Group were determined to be significantly healthier than those in the two eligible groups of patients . Those in the Eligible Refuser group were shown to be slightly less malnourished than the R and omized Patients . The 395 patients r and omized to the study ( R and omized Patients ) showed the highest rate of septic complications at 30 days and at 90 days ( 10 % and 13 % respectively ) with rates for the Eligible Refusers slightly lower ( 8 % and 9 % ) and Index Group rates still lower ( 4 % and 4 % ) . Nonseptic complication rates showed the same pattern ( 19 % and 22 % for the R and omized group , 12 % and 12 % for Eligible Refusers , and 10 % and 10 % for the Index Group ) . Because ( a ) the beneficial effect of TPN is attained only in severely malnourished patients , ( b ) there is increased risk of septic complications with TPN use in patients not severely malnourished , ( c ) Index Group patients , and presumably the population of patients from which they are drawn , are not severely malnourished , it follows that unless specifically indicated , TPN should not be used in nonseverely malnourished patients BACKGROUND AND OBJECTIVES Patient preferences play an important role when choosing between different treatment options and may have an influence on outcome . We performed a study to investigate ( 1 ) to what extent patients make use of the offer to receive acupuncture as a pretreatment for gastroscopy , ( 2 ) whether this is perceived as being as effective as sedation , and ( 3 ) whether characteristics and outcomes differ between patients giving consent to r and om allocation and patients choosing their pretreatment . DESIGN Partially r and omized patient preference trial . Patients who gave consent to r and omization were allocated r and omly while patients who had a preference received the treatment of their choice . PATIENTS One hundred and six ( 106 ) in patients of a district hospital in southern Germany undergoing gastroscopy for diagnostic purpose s. INTERVENTIONS Pretreatment with a sedative ( midazolam ) or acupuncture . MAIN OUTCOME MEASURE Patient 's overall assessment on a visual analogue scale ( VAS ) . RESULTS Twenty-eight ( 28 ) patients ( 26 % ) agreed to be r and omized , 21 ( 20 % ) chose acupuncture , 51 ( 47 % ) midazolam , and 8 ( 7 % ) did not want pretreatment . Patients receiving midazolam rated the examination as slightly less troublesome than those receiving acupuncture . Oxygen saturation , blood pressure , and heart rate were significantly lower in patients receiving midazolam . Characteristics and outcomes of r and omized and nonr and omized patients did not differ significantly . CONCLUSIONS Because of the low number of patients giving consent to r and om allocation conclusions on effectiveness are difficult to draw . The partially r and omized patient preference design is recommended for use in future trials of acupuncture for gastroscopy . Such trials should be performed in an outpatient setting Fifty-seven patients with cervical bruits and abnormal ocular pneumoplethysmography but without symptoms were followed prospect ively . Mean follow-up was 32 months and all patients were followed for at least 1 year . Twenty-nine patients consented to join a r and omized study comparing treatment with aspirin , close follow-up , and no intervention unless symptoms developed [ ( NI : ASA ] n = 14 ) versus intervention with arteriography and prophylactic surgery [ ( I : A/S ] n = 15 ) . Among patients who refused r and omization , 14 were treated with NI : ASA and 14 with I : A/S. Endpoints for analysis included all unfavorable outcomes related to both management plans and included stroke , death of stroke , major angiographic and perioperative complications , asymptomatic carotid occlusion , and recurrent carotid artery stenosis . In both the r and omized and nonr and omized portions of the study unfavorable outcomes were more frequent in patients treated with I : A/S , and by combining the results of both studies a significant difference was observed ( N : ASA - 3.6 % versus I : A/S - 31 % ; X:2 = 4.78 ; p less than 0.05 ) . Among patients treated with NI : ASA , a single minor stroke occurred without warning . In patients from all groups who underwent arteriography , advanced carotid stenosis was found in 78 % ( mean percent diameter stenosis = 72 % + /- 2 % ; mean residual lumen = 1.3 + /- 0.1 mm ) . We conclude that , despite the probability of underlying severe carotid stenosis , most patients with cervical bruit and abnormal ocular pneumoplethysmography but without symptoms are appropriately managed without intervention unless symptoms develop Background . Trivalent inactivated influenza vaccine ( TIV ) is recommended for all children ages 6 to 23 months . Delivering 2 doses of TIV at least 4 weeks apart to young children receiving this vaccine for the first time is challenging . Methods . We compared the immunogenicity and reactogenicity of the st and ard 2-dose regimen of TIV administered in the fall with an early schedule of a single spring dose followed by a fall dose of the same vaccine in healthy toddlers 6 to 23 months of age . Children were recruited in the spring to be r and omized into either the st and ard or early schedule . An additional group was also enrolled in the fall as part of a nonr and omized st and ard comparison group . The 2002–2003 licensed TIV was administered in the spring ; the fall 2003–2004 vaccine contained the same 3 antigenic components . Reactogenicity was assessed by parental diaries and telephone surveillance . Blood was obtained after the second dose of TIV for all children . The primary outcome measure was antibody response to influenza A/H1N1 , A/H3N2 , and B after 2 doses of vaccine , as determined by hemagglutination-inhibition titers ≥1:32 and geometric mean titer ( GMT ) . Results . Two hundred nineteen children were r and omized to receive either the st and ard or early TIV schedule ; 40 additional children were enrolled in the fall in the nonr and omized st and ard group . Response rates in the combined st and ard versus early groups were similar overall : 78 % ( GMT : 48 ) vs 76 % ( GMT : 57 ) to H1N1 , 89 % ( GMT : 115 ) vs 88 % ( GMT : 129 ) to H3N2 , and 52 % ( GMT : 24 ) vs 60 % ( GMT : 28 ) to B. Reactogenicity after TIV in both groups of children was minimal and did not differ by dose , age , or time between doses . Reaction rates were higher in those receiving TIV and concomitant vaccines compared with those receiving TIV alone . Overall rates of fever > 38 ° C axillary and injection-site pain , redness , or swelling were 5.4 % , 3.1 % , 0.9 % , and 1.1 % , respectively . Conclusions . When the spring and fall influenza vaccines had the same 3 antigenic components , the early vaccine schedule result ed in similar immunogenicity and reactogenicity compared with the st and ard schedule . When the vaccine components do not change between years , initiating influenza vaccine in the spring at the time of routine office visits would facilitate full immunization of children against influenza earlier in the season A r and omised study named SVEA to compare three methods for delayed breast reconstruction was initiated in 1994 . The methods were : the lateral thoracodorsal flap , the latissimus dorsi flap , and the pedicled transverse rectus abdominis muscle flap . In the present paper we describe the study design , primary endpoints , and inclusion and exclusion criteria . Results from preoperative question naires about problems after mastectomy and expectations of the reconstruction are presented . The preoperative question naires , completed before r and omisation , included a health related quality of life question naire , the SF-36 , and a question naire concerning the impact of breast loss and expectations of the reconstruction . A total of 87 patients have been r and omised in SVEA and 30 patients have been followed up outside the r and omised study , comprising a reference group . The results from preoperative question naires , completed by 106 of the total 117 women , showed that they encountered many problems after mastectomy , primarily about feeling mutilated and being bothered socially . They held high expectations on the breast reconstruction in these areas . The women in the present study did not differ from Swedish women in general regarding health related quality of life , with two exceptions : the study sample scored lower on physical functioning and mental health The therapeutic benefit of maintenance chemotherapy beyond three years for children with acute lymphocytic leukemia ( ALL ) in continuous complete remission was evaluated by the investigators of Childrens Cancer Study Group ( CCSG ) . Two hundred and twenty leukemic children in first remission for three years or longer and who had received at least three years of continuous chemotherapy were eligible . One hundred and one patients were r and omized to either continue chemotherapy for an additional three years or to discontinue therapy , and 119 patients nonr and omly continued or discontinued therapy . The patients had received a variety of chemotherapy regimens . The study period extended from April 1970 until December 1977 , with a median follow-up time of 25 months . Relapses occurred in 15 r and omized patients ( 15 % ) . R and omized patients remaining on chemotherapy experienced a statistically significant lower relapse rate than patients r and omized to discontinue therapy . Also among r and omized patients , bone marrow relapse was significantly more frequent in males than in females . Considering the total patient group , age and white blood count at diagnosis had no significance in predicting relapse . Of relapse events in males , 21 % were isolated testicular relapses , identifying the testicles as a major risk site in males completing three years of continuous complete remission . This study demonstrates that continuing chemotherapy beyond three years results in a significant prolongation of remission in males , although the eventual survival outcome for later discontinuance of therapy will require longer follow-up Objective To identify the advantages and disadvantages of using a partially r and omised patient preference design rather than a conventional r and omised controlled design when evaluating alternative managements for heavy menstrual bleeding Aims : To evaluate the effect of the implementation of an asthma clinical pathway on asthma in children in general practice . Methods : A r and omized , controlled trial involving 270 general practitioners . One group of general practitioners implemented the asthma clinical pathway for children ( intervention group ) and the control group continued with their usual asthma medical care management . The main outcome measures were admissions to hospital for asthma and attendance at the Children 's Emergency Department . Compliance with the guidelines was assessed by examining asthma drug prescriptions . Results : Admissions to hospital for asthma dropped 40 % in the intervention group , by 33 % in the control group and by 22 % in general practitioners not participating in the trial . The differences between the intervention and control and between the intervention and non‐participating general practitioners were not statistically significant . The decrease in attendance at the Children 's Emergency Department decreased by 25 % , 30 % and 19 % , respectively , but this was not statistically significant . There was a significant decrease in prescriptions for oral relievers , dry powder relievers in the under 6s , mast cell stabilizers and methylxanthines in both control and intervention groups . However , only for oral relievers was there a significant difference between the intervention group and control , with the decrease larger in the intervention group ( p<0.001 ) Study Design A prospect i ve study was performed . Objectives The goals of the study were to determine the incidence of deep vein thrombosis after major adult spinal surgery and the optimal mode of prophylaxis in this surgical population . Summary of Background Data Few studies have evaluated deep vein thrombosis incidence and prophylaxis after major adult spinal surgery . Incidence rates have ranged from 0.9‐14 % . Methods Three hundred twenty‐nine patients were evaluated . One hundred ten patients were r and omized to 3 different deep vein thrombosis prophylaxis groups . These patients had duplex doppler scans between the fifth and seventh postoperative days . The remaining 219 patients formed a nonr and omized group and received either thrombosis embolic deterrent stockings alone or thrombosis embolic deterrent stockings and pneumatic compression boots for deep vein thrombosis prophylaxis . The type of deep vein thrombosis prophylaxis in this group was based on surgeon preference . All 329 patients were followed for clinical signs and symptoms of thromboembolic disease . Patients were followed clinical ly for a minimum of 1 year . Results All 110 prophylaxis study group patients were clinical ly asymptomatic and 109 duplex scans were normal . One scan was indeterminate and a follow‐up venogram was negative . Two patients in the coumadin group ( 5.7 % ) experienced excessive blood loss . One of the 219 patients from the nonr and omized group developed a clinical ly detectable proximal deep vein thrombosis which was confirmed by duplex ultrasonography . The overall clinical incidence of deep vein thrombosis was 0.3 % ( 1 in 329 patients ) . Conclusions This low 0.3 % rate is in agreement with recent studies that focus on thromboembolic disease . Given the low incidence , routine screening for asymptomatic thrombi appears unwarranted . In addition , mechanical prophylaxis with graduated compression stockings and pneumatic compression boots is preferable to anticoagulation therapy In a recently started clinical trial , the short-term effects of radiotherapy of cervix cancer Stage IIb and III in combination with topical infusion of metronidazole solution were evaluated by determining the local clearance rate and cytologic damage in r and omized and non-r and omized cases . In regard to the short term effects the combined treatment was found to be superior to treatment without metronidazole The objective of this study was to determine whether participation in clinical trials effects long-term outcomes in Alzheimer 's disease ( AD ) . Participation in clinical trials for persons with dementia is often justified on the grounds that patients benefit from the medical oversight typical of trials , even when experimental agents do not demonstrate short-term benefits . This cl aim has not been rigorously assessed . Of 215 community-resident subjects enrolled in a prospect i ve study of outcomes in AD , 101 participated in r and omized clinical trials ( RCTs ) during the first 2 years of follow-up . These subjects were compared with subjects who met eligibility requirements for RCTs but did not participate ( N = 57 ) and with subjects who were ineligible ( N = 57 ) , over a total of 3.5 years of follow-up . Survival analyses assessed risk of death , nursing home placement , and incident functional deficit end points , adjusting for baseline differences . Subjects who participated in RCTs were younger and more highly educated . Mortality , risk of hospitalization , number of medical examinations conducted by study physicians , and onset of severe functional deficit did not differ between the groups , but risk of nursing home admission was significantly lower among RCT participants compared with eligible non participants and ineligible subjects(16.8 % versus 36.8 % and 31.6 % , respectively [ p = 0.01 ] ) . The difference in risk of nursing home placement may represent a long-term , drug-related benefit to patients , a selection effect ( caregivers of patients who participate in RCTs differ from caregivers of patients who do not ) , or a positive effect on caregivers ( greater contact with a medical service may be associated with better care-giving outcomes ) . Further research is required to assess these effects Every adult acute nonlymphocytic leukemia patient in Rochester , New York seen from January 1975 to January 1982 was studied . Fifty percent of the patients did not receive combination chemotherapy . Among those who did , there was a significant selection bias toward placing patients with better prognostic features on protocol . Protocol patients were also treated with higher doses of chemotherapy than non protocol patients . However , these factors did not completely explain the significantly better complete response ( CR ) rate and survival among protocol patients . Eastern Cooperative Oncology Group ( ECOG ) participation remained an independent variable associated with a better outcome . An improvement in CR rate was seen during the 7‐year period studied as compared to that seen between 1965 and 1974 . The study provided evidence that the availability and use of ECOG protocol s was a positive factor in the improvement of leukemia treatment in Rochester Controversy persists as to the optimal means of providing adjuvant nutritional support . The aim of this study was to compare enteral nutrition ( EN ) and parenteral nutrition ( TPN ) in terms of adequacy of nutritional intake , septic and nonseptic morbidity , and mortality . This was a prospect i ve pragmatic study , whereby the route of delivery of nutritional support was determined by the attending clinician 's assessment of gastrointestinal function . Patients considered to have inadequate gastrointestinal function were given TPN ( group 1 ) , while those deemed to have a functioning gastrointestinal tract received EN ( group 2 ) . Patients in whom there was reasonable doubt as to the adequacy of intestinal function were r and omized to receive either TPN ( group 3 ) or EN ( group 4 ) . The trial setting was a large district general hospital with a dedicated nutrition team . A total of 562 patients were included in the study ( 331 males ; median age 67 y ) . Gastrointestinal function on entry into the study was considered inadequate in 267 patients who were given TPN ( group 1 ) and adequate in 231 whom received EN ( group 2 ) . There was clinical uncertainty about the adequacy of gut function in 64 patients ( 11.4 % ) who were r and omized to receive either TPN ( group 3 , 32 patients ) or EN ( group 4 , 32 patients ) . The incidence of inadequate nutritional intake was significantly higher in group 4 compared with group 3 ( 78.1 % versus 25 % , P < 0.001 ) . Complications related to the delivery system and other feed-related morbidity were significantly more frequent in both EN groups compared with the respective TPN groups . EN was associated with a higher overall mortality in both nonr and omized and r and omized patients . There were no significant differences observed in the incidences of septic morbidity between patients receiving TPN and those given EN . EN is associated with a higher incidence of inadequate nutritional intake , complications related to the delivery system , and other feed-related morbidity than TPN . There is no evidence from this study to support a difference between the two modalities in terms of septic morbidity . Patients in whom there is reasonable doubt as to the adequacy of gastrointestinal function should be fed by the parenteral route During a 27-month period , 215 new cases of lung cancer were diagnosed at five McGill University hospitals . Only 44 patients ( 20 % ) so diagnosed were treated on available chemotherapy protocol s. Six categories were used to define reasons for nonparticipation . The most important were medical reasons ( MRs ) , 46 % ; non-medical reasons ( NMRs ) , 20 % ; and physician preference ( PP ) , 16 % . The three remaining categories , representing 18 % of exclusions , were death before diagnosis ( DBD ) , surgical treatment ( S ) , and a miscellaneous group ( M ) . Median survival of patients on and off protocol was 10 and 7 months , respectively . Patients with limited disease treated off protocol for NMR and those treated with surgery did better than patients on protocol . Patients with extensive disease not enrolled because of MR did worse , and those excluded because of PP did better than patients treated on protocol . The implication of these findings for other cancer studies is that analysis of chemotherapy trials often represents treatment results in a small proportion of all patients with a given neoplasm . As such , caution must be exercised when extrapolating results to the group as a whole . We suggest that complete demographic data , including proportion of patients participating and reasons for exclusion , be included in all chemotherapeutic trial reports IN 1976 the National Surgical Adjuvant Project for Breast and Bowel Cancers ( NSABP ) launched a multicenter r and omized clinical trial to compare mastectomy with " lumpectomy , " with and without radiation , in the treatment of breast cancer . Two years later , only a small fraction of the expected number of patients had been enlisted , and the trial was in jeopardy because of this low rate of accrual . What happened ? In this issue of the Journal , Taylor and her colleagues present the results of a question naire study of why participating physicians entered so few of their eligible patients into the trial.1 They found a . . Objective To determine whether choice of colposcopy or six month cytological surveillance would be beneficial to women with mildly abnormal smears when compared with the national policy of six months surveillance in terms of psychological morbidity This study was planned in the context of a regional high blood pressure programme , to compare the efficacy of two educative methods . The group of 722 hypertensive patients ( 58.8 % women ) , mean age 61 years , was r and omly selected from 19 primary care centres . Initial assessment was based on a patient interview including 22 questions on high blood pressure , its consequences and treatment . Patients agreeing to participate in an active education team programme were distributed into three groups : individual education , team education and a control group . Those who declined to participate formed two groups : individual education and controls . Team education consisted of two audiovisual sessions attended by groups of 8 - 12 patients and conducted by treating physicians and nurses . Individual education included comments related to the 22 questions . Follow-up assessment was made after two months . An increase in the level of hypertension control was observed only in the accepting group , in which educative action was followed by increased knowledge . Results were similarly favourable for both the individual and team education groups and suggested the need to consider educational factors together with those influencing patient attitude towards an active educational programme This study examines factors that contribute to the subjective strain experienced by caregivers of persons with severe mental illness and addresses potential improvement in caregiver strain associated with involuntary outpatient commitment . Subjects from a population of involuntarily hospitalized people awaiting discharge under outpatient commitment were r and omly assigned to be released or continue under outpatient commitment after hospital discharge . A nonr and omized group with a recent history of serious violence was also studied under outpatient commitment . R and omized control and outpatient commitment groups did not differ significantly in caregiver strain . However , analyses of all subjects , including the nonr and omized violent group , showed that among subjects who underwent sustained periods of outpatient commitment , caregivers reported significantly decreased subjective strain compared with caregivers of those who underwent only brief outpatient commitment or none . Improved treatment adherence also reduced caregiver strain independently of the effect of sustained outpatient commitment Purpose . The aim of this study was to determine the impact of a vocational training programme on short- and long-term results after psychosomatic rehabilitation . Method . 1,590 in patients were screened for vocational integration . A high-risk group of 266 patients was r and omly assigned to the vocational training programme plus psychosomatic treatment ; treatment- as- usual served as a control condition . An occupational training was conducted at local companies , closely integrated into psychosomatic treatment . Vocational attitudes and adjustment were studied at intake , discharge , three , 12 and 24 month follow-ups . Results . More than half of the study participants were unemployment and /or long-term work-disabled harbouring strong negative attitudes toward return to work . Forty-six percent of the intervention group declined from participation , but complied with follow-up investigation . At discharge , participants of the vocational training programme had become more optimistic regarding resuming work . One year following discharge , participants of the training programme reported less absence from work . After 24 months , vocational adjustment had improved considerably among programme participants , and declined among controls and refusers . Conclusion . An intensive vocational training programme is effective in promoting positive attitudes to work , reducing work disability and promoting return-to-work . However , a r and omized design may be not optimal ; evaluation necessitates long-term follow-up PURPOSE To compare multi-detector row computed tomographic ( CT ) angiography and digital subtraction angiography ( DSA ) prior to revascularization in patients with symptomatic peripheral arterial disease for the purpose of assessing recommendations for additional imaging and physician confidence ratings for chosen therapy . MATERIAL S AND METHODS In a r and omized controlled trial , 73 patients were assigned to CT angiography , and 72 were assigned to DSA . Physician confidence in the treatment decision was measured as a continuous outcome on a scale of 0 - 10 ( uncertain to certain ) and as a dichotomous outcome ( further imaging recommended , yes or no ) . Mean confidence scores and additional imaging recommendations were compared between CT and DSA groups in an intention-to-diagnose- and -treat analysis . To detect trends in confidence , confidence scores were plotted over time , and multiple linear regression analysis was performed . To detect trends in additional imaging recommendations , logistic regression analysis was used . Data from eligible nonr and omized patients were analyzed separately . RESULTS No statistically significant difference in baseline characteristics between r and omized groups was found . CT had a lower confidence score than did DSA ( 7.2 vs 8.2 , P < .001 ) . Further imaging was recommended more often after CT ( 25 of 71 patients , 35 % ) than after DSA ( nine of 66 patients , 14 % ; P = .003 ) . Analysis of trends demonstrated increasing ( but not statistically significant ) confidence in CT and stable confidence in DSA . No significant difference was found in baseline characteristics between r and omized and nonr and omized patients . Among nonr and omized patients , no significant difference in mean confidence score ( 8.2 vs 8.3 , P = .26 ) was found between CT ( n = 24 ) and DSA ( n = 26 ) . CONCLUSION With CT angiography , physician confidence decreases with an associated increase in additional imaging prior to revascularization in patients with symptomatic peripheral arterial disease . Given that CT is less invasive than DSA , results suggest that CT may replace DSA in selected cases PURPOSE We performed a r and omized , placebo controlled double-blind trial to evaluate the effectiveness of Entonox ( BOC Gases , Manchester , United Kingdom ) , that is 50 % nitrous oxide and oxygen , as analgesia during transrectal ultrasound guided prostate biopsy . MATERIAL S AND METHODS Patients referred for transrectal ultrasound guided prostate biopsy for the first time as an outpatient procedure were recruited subject to exclusion criteria and r and omized to breathe Entonox or air via similar breath activated devices . At the end of the procedure patients completed a visual pain analog scale . Patients who refused study participation also completed the visual analog pain scale to assess the placebo effect of receiving gas through a mask . RESULTS A total of 110 patients were studied . Statistical analysis using 1-way analysis of variance showed a highly significant difference in pain perception among the 3 groups ( F [ 2,107 ] = 73.348 , p < 0.001 ) . This significant decrease in pain was noted in the Entonox versus air and Entonox versus placebo groups . There was no significant difference in the air and placebo groups . Seven of the 51 patients receiving Entonox complained of feeling drowsy during the procedure , which resolved at completion of the procedure . In this group 49 patients would undergo this procedure again if needed . In 2 of the 45 patients in the group receiving air the procedure was ab and oned due to pain , while another 19 would prefer more analgesia and 2 would prefer general anesthesia if the procedure was to be repeated . CONCLUSIONS Our study shows that Entonox is a safe , rapidly acting and effective form of analgesia for the pain of prostate biopsy . We believe that it should be the analgesia of choice for this procedure BACKGROUND Intravenous sedation/analgesia for colonoscopy is accompanied with certain risks and postprocedure drowsiness . We sought to determine whether inhaled nitrous oxide ( Entonox : 50 % nitrous oxide , 50 % oxygen ) provides adequate analgesia for colonoscopy and the impact of this agent on recovery . METHODS All patients undergoing outpatient colonoscopy were considered for the study ( n = 248 ) except those with previous colonic resection . Data for patients unsuitable for r and omization ( n = 58 ) and those who declined to participate ( n = 88 ) were also analyzed . RESULTS One hundred two patients were r and omized to receive inhaled Entonox alone ( n = 56 ) or intravenous midazolam and meperidine ( n = 46 ) . Forty-nine ( 88 % ) patients r and omized to Entonox underwent complete colonoscopy without conversion to intravenous medications . Entonox patients reported more pain ( p < 0.0001 ) , tolerated colonoscopy less well ( p < 0.0001 ) , were less satisfied ( p = 0.01 ) , and less willing to undergo colonoscopy again under the same circumstances ( p = 0.04 ) . Of patients receiving intravenous medication , 91 % found colonoscopy less unpleasant and 9 % as unpleasant as anticipated ; this compares with 52 % and 21 % Entonox patients , respectively , and an additional 27 % Entonox patients who found colonoscopy more unpleasant than anticipated . Recovery was faster among Entonox patients ( median 30 versus 60 minutes , p < 0.0001 ) . CONCLUSION Entonox is less effective than midazolam with meperidine for colonoscopy but is acceptable in many patients and allows faster recovery OBJECTIVES The aim of this study was to determine both the clinical and cost-effectiveness of usual general practitioner ( GP ) care compared with two types of brief psychological therapy ( non-directive counselling and cognitive-behaviour therapy ) in the management of depression as well as mixed anxiety and depression in the primary care setting . DESIGN The design was principally a pragmatic r and omised controlled trial , but was accompanied by two additional allocation methods allowing patient preference : the option of a specific choice of treatment ( preference allocation ) and the option to be r and omised between the psychological therapies only . Of the 464 patients allocated to the three treatments , 197 were r and omised between the three treatments , 137 chose a specific treatment , and 130 were r and omised between the psychological therapies only . The patients underwent follow-up assessment s at 4 and 12 months . SETTING The study was conducted in 24 general practice s in Greater Manchester and London . SUBJECTS A total of 464 eligible patients , aged 18 years and over , were referred by 73 GPs and allocated to one of the psychological therapies or usual GP care for depressive symptoms . INTERVENTIONS The interventions consisted of brief psychological therapy ( 12 sessions maximum ) or usual GP care . Non-directive counselling was provided by counsellors who were qualified for accreditation by the British Association for Counselling . Cognitive-behaviour therapy was provided by clinical psychologists who were qualified for accreditation by the British Association for Behavioural and Cognitive Psychotherapies . Usual GP care included discussion s with patients and the prescription of medication , but GPs were asked to refrain from referring patients for psychological intervention for at least 4 months . Most therapy sessions took place on a weekly basis in the general practice s. By the 12-month follow-up , GP care in some cases did include referral to mental healthcare specialists . MAIN OUTCOME MEASURES The clinical outcomes included depressive symptoms , general psychiatric symptoms , social function and patient satisfaction . The economic outcomes included direct and indirect costs and quality of life . Assessment s were carried out at baseline during face-to-face interviews as well as at 4 and 12 months in person or by post . RESULTS At 4 months , both psychological therapies had reduced depressive symptoms to a significantly greater extent than usual GP care . Patients in the psychological therapy groups exhibited mean scores on the Beck Depression Inventory that were 4 - 5 points lower than the mean score of patients in the usual GP care group , a difference that was also clinical ly significant . These differences did not generalize to other measures of outcome . There was no significant difference in outcome between the two psychological therapies when they were compared directly using all 260 patients r and omised to a psychological therapy by either r and omised allocation method . At 12 months , the patients in all three groups had improved to the same extent . The lack of a significant difference between the treatment groups at this point result ed from greater improvement of the patients in the GP care group between the 4- and 12-month follow-ups . At 4 months , patients in both psychological therapy groups were more satisfied with their treatment than those in the usual GP care group . However , by 12 months , patients who had received non-directive counselling were more satisfied than those in either of the other two groups . There were few differences in the baseline characteristics of patients who were r and omised or expressed a treatment preference , and no differences in outcome between these patients . Similar outcomes were found for patients who chose either psychological therapy . Again , there were no significant differences between the two groups at 4 or 12 months . Patients who chose counselling were more satisfied with treatment than those who chose OBJECTIVE To determine whether the initiation of estrogen replacement therapy ( ERT ) in the postoperative period increases the incidence of symptom recurrence following laparoscopic hysterectomy ( LH ) and /without bilateral salpingo-oophorectomy ( BSO ) for the treatment of endometriosis and adenomyosis . DESIGN Prospect i ve partially r and omized patient preference follow up trial ( PRPPT ) . SETTING Department of Gynaecology , Endoscopic Training Centre , Kladno Hospital . METHODS Chart review of 286 consecutive patients who underwent LH and /or without BSO for endometriosis or adenomyosis between April 1994 and June 1999 and who subsequently received ERT . The methods of second phase of trial was prepared . The symptoms of recurrence in patients who started ERT after surgery and in those who did not start ERT ( control group ) will be compared and adjusted . RESULTS Seventy-three percent had preoperative pelvic pain . One hundred thirty two women ( 46.2 % ) had only endometriosis . Of the cases of endometriosis , 35.4 % was stage I and 64.4 % was stage II.-IV . One hundred fifty four women had adenomyosis , 60 with endometriosis . CONCLUSION In the first phase of follow study the collection of clinical data was performed . Preliminary results from the PRPPT demonstrate that laparoscopic approach to surgery for endometriosis increased significantly the number of this disease OBJECTIVES To study the fracture reducing potential of hormonal replacement therapy ( HRT ) in recent postmenopausal women in a primary preventive scenario . METHODS Prospect i ve controlled comprehensive cohort trial : 2016 healthy women aged 45 - 58 years , from three to 24 months past last menstrual bleeding were recruited from a r and om sample of the background population . Mean age was 50 . 8+/-2.8 years , and the number of person years followed was 9335.3 . There were two main study arms : a r and omised arm ( r and omised to HRT ; n=502 , or not ; n=504 ) and a non-r and omised arm ( on HRT ; n=221 , or not ; n=789 by own choice ) . First line HRT was oral sequential oestradiol/norethisterone in women with intact uterus and oral continuous oestradiol in hysterectomised women . RESULTS After five years , a total of 156 fractures were sustained by 140 women . There were 51 forearm fractures in 51 women . By intention-to-treat analysis ( n=2016 ) , overall fracture risk was borderline statistically significantly reduced ( RR=0.73 , 95 % CI : 0.50 - 1.05 ) , and forearm fracture risk was significantly reduced ( RR=0.45 , 95 % CI : 0.22 - 0.90 ) with HRT . Restricting the analysis to women who had adhered to their initial allocation of either HRT ( n=395 ) or no HRT ( n=977 ) showed a significant reduction in both the overall fracture risk ( RR=0.61 , 95 % CI : 0.39 - 0.97 ) and the risk of forearm fractures ( RR=0.24 , 95 % CI : 0.09 - 0.69 ) . Compliance with HRT was 65 % after five years . CONCLUSIONS It is possible to reduce the number of forearm fractures and possibly the total number of fractures in recent postmenopausal women by use of HRT as primary prevention OBJECTIVE To examine the effects of patient choice between two education curriculums that emphasized either the st and ard or nutritional management of type 2 diabetes on class attendance and other outcomes among a mostly Hispanic patient population . RESEARCH DESIGN AND METHODS A total of 596 patients with type 2 diabetes were r and omly assigned to either a choice or no choice condition . Patients in the choice condition were allowed to choose their curriculum , while patients in the no choice condition were r and omly assigned to one of the two curriculums . Outcomes were assessed at baseline and at a 6-month follow-up . RESULTS When given a choice , patients chose the nutrition curriculum almost four times more frequently than the st and ard curriculum . Contrary to our hypothesis , however , patients who had a choice did not significantly increase their attendance rates or demonstrate improvements in other diabetes outcomes compared with patients who were r and omly assigned to the two curriculums . Patients in the nutrition curriculum had significantly lower serum cholesterol at a 6-month follow-up , whereas patients in the st and ard curriculum had significant improvements in glycemic control . Of the r and omized patients , 30 % never attended any classes ; the most frequently cited reasons for nonattendance were socioeconomic . Hispanic patients , however , were just as likely as non-Hispanic patients to attend classes and participate at the follow-up . Patients who attended all five classes of either curriculum significantly increased their diabetes knowledge , gained less weight , and reported improved physical functioning compared with patients who did not attend any classes . CONCLUSIONS Although providing patients with a choice in curriculums at the introductory level did not improve outcomes , differential improvements were noted between patients who attended curriculums with different content emphasis . We suggest that diabetes education programs should provide the opportunity for long-term , repetitive contacts to exp and on the modest gains achieved at the introductory level , as well as provide more options to match individual needs and interests and to address socioeconomic barriers to participation The delivery room management of meconium-stained amniotic fluid remains controversial . We attempted to determine if intubation of the low-risk newborn with thin meconium affects the incidence of respiratory symptoms . Exclusion criterion included moderate or thick meconium , fetal distress , neonatal depression , or prematurity . Eligible infants were r and omized to either an intubation ( group I ) or to a nonintubation group ( group II ) . The outcome was the presence of respiratory symptoms . Patients were studied from May 1994 to June 1997 . There were 8967 births during this period : 7.9 % ( 708/8967 ) were delivered through meconium . Thin meconium was noted in 50.3 % ( 356/708 ) of all births . 24/356 infants with thin meconium were excluded for medical criterion . One hundred sixty-three infants were medically eligible but could not be r and omized due to lack of consent , late arrival of the team , or obstetrician request . These were placed into intubation ( group I B ) and nonintubation ( group II B ) groups . Seventy-seven infants were r and omized into group I and 92 infants into group II . From the intubation groups I and I B , one required supplemental oxygen and was weaned to room air in 7 hr . From the nonintubation groups II and II B , two infants required oxygen , weaning to room air in 11 and 46 hr . Comparing birth weight , gestational age , sex , mode of delivery and 5-min Apgar , there were no significant differences . However , the intubation groups had significantly lower 1-min Apgar scores . There was no airway morbidity reported in the intubation groups . In the infant with thin meconium and an otherwise low-risk pregnancy , we were unable to demonstrate a difference in respiratory symptoms with intubation and intratracheal suctioning The survival of 78 patients with resected non‐small cell lung cancer entered in prospect i ve , r and omized investigational trials is compared to that of a population ‐based group of control patients not included in such trials . The survival of trial patients is significantly better than that of controls ( P < 0.001 ) . This survival advantage for trial participants is most apparent among late Stage I patients , and is observed after matching for known prognostic factors ( i.e. , primary tumor size , nodal status , tumor histology ) and after adjusting in the analysis for age , sex , and the administration of radiation therapy . Several explanations for the improved outcome for trial patients are explored , including differences in preoperative evaluation , staging , surgical technique , placebo effects , and patient motivation . These results suggest the possibility that inclusion in these controlled cancer trials may have had an inherent advantage for all participants . Cancer 56 : 1710‐1718 , 1985 STUDY OBJECTIVE To compare quality of life and exercise capacity ( primary aim ) , and drug usage ( secondary aim ) , between groups of patients with irreversible chronic airflow limitation ( CAL ) who were undergoing theophylline Theo-Dur ; Key Pharmaceuticals ; Kenilworth , NJ ) therapy guided by n of 1 trials or st and ard practice . DESIGN R and omized study of n of 1 trials vs st and ard practice . SETTING Outpatient departments in two tertiary care centers . PATIENTS Sixty-eight patients with irreversible CAL who were symptomatic despite the use of inhaled bronchodilators , and who were unsure whether theophylline was helping them following open treatment , were r and omized into n of 1 trials ( N=34 ) or st and ard practice . INTERVENTIONS The n of 1 trials ( single-patient , r and omized , double-blind , multiple crossover comparisons of the effect on dyspnea of theophylline vs a placebo ) followed published guidelines . St and ard practice patients stopped taking theophylline but resumed it if their dyspnea worsened . If their dyspnea then improved , theophylline was continued . In both groups , a decision about continuing or stopping the use of theophylline was made within 3 months of r and omization . MEASUREMENTS AND RESULTS The primary outcomes ( the chronic respiratory disease question naire [ CRQ ] and 6-min walk ) were measured at baseline , 6 months , and 12 months by personnel blinded to treatment group allocation . No between-group differences ( n of 1 minus st and ard practice ) were seen in within-group changes over time ( 1 year minus baseline ) in the CRQ Physical Function score ( point estimate on the difference , -2.8 ; 95 % confidence limits [ CLs ] , -8.2 , 2.5 ) , CRQ Emotional Function score ( point estimate on the difference , 0.5 ; 95 % CLs , -4.7 , 5.7 ) , or 6-min walk ( point estimate on the difference , 8 m ; 95 % CLs , -26 , 44 m ) . No differences between groups were seen in the secondary outcome of the proportion of patients taking theophylline at 6 and 12 months . In 7 of 34 n of 1 trial patients ( 21 % ) , dyspnea improved during theophylline treatment compared with placebo treatment . CONCLUSIONS Using n of 1 trials to guide theophylline therapy in patients with irreversible CAL did not improve their quality of life or exercise capacity , or reduce drug usa e , over 1 year compared to st and ard practice . Under the objective conditions of an n of 1 trial , 21 % of patients with CAL responded to theophylline . There remains a rationale for considering theophylline in patients with irreversible CAL who remain symptomatic despite the use of inhaled bronchodilators , but the use of n of 1 trials to guide this decision did not yield clinical ly important advantages over st and ard practice As medicine has become increasingly scientific and less accepting of unsupported opinion or proof by anecdote , the r and omized controlled clinical trial has become the st and ard technique for changing diagnostic or therapeutic methods . The use of this technique creates an ethical dilemma.1 , 2 Research ers participating in such studies are required to modify their ethical commitments to individual patients and do serious damage to the concept of the physician as a practicing , empathetic professional who is primarily concerned with each patient as an individual . Research ers using a r and omized clinical trial can be described as physician-scientists , a term that expresses the tension between the . . The Coronary Artery Surgery Study ( CASS ) includes a r and omized trial of coronary artery bypass surgery and medical therapy in the management of patients with mild or moderate stable angina pectoris or free of angina but with a documented history of myocardial infa rct ion . While 780 patients at 11 participating institutions entered the r and omized trial , 1,315 patients at the same institutions met r and omization criteria but declined participation in the r and omized study ; they constitute the " r and omizable " patients . Half the r and omized patients were assigned to surgery and half to the medical group . Of the 1,315 r and omizable patients , 43 % started with surgical therapy and 57 % constitute the medical group . Follow-up periods average 64 months ( range 46 to 92 ) . The only entry characteristic in which the r and omized and r and omizable medical groups differ importantly is the extent of coronary artery disease , which is less extensive in the latter . The two surgical groups also differ in this respect , but with more extensive disease in the r and omizable group . At 5 year follow-up , 24 % of the medically-assigned r and omized patients and 22 % of the medically-started r and omizable patients have had coronary bypass surgery . Survival in the medically-r and omized and r and omizable patient groups is similar in the aggregate ( both 92 % at 5 years ) and also in all subgroups based on clinical classification , the number of diseased vessels , the presence of proximal left anterior descending coronary artery disease and ejection fraction . Survival for the surgically-assigned r and omized patients and the surgically-started r and omizable patients is also similar in the aggregate ( 95 and 94 % , respectively ) and in all subgroups . It is concluded that the r and omized patients in CASS are not a special or atypical subset of those eligible for r and omization . The data from the r and omizable patients thus support and extend the inference of the generally very good survival of both the medically- and surgically-assigned patients of the r and omized trial Abstract : Veno‐occlusive disease ( VOD ) is a major cause of toxic death after autologous bone marrow transplantation ( ABMT ) . We studied the potential role of continuous administration of low‐dose heparin for VOD prevention in 234 consecutive patients who underwent ABMT in our institution . The population consisted of 98 patients autografted before October 1984 who did not receive heparin , and a series of 136 patients autografted from October 1984 to March 1989 containing 98 patients included in a r and omized trial comparing heparin administration ( n = 52 ) vs no heparin ( n = 46 ) , and an additional group of 38 patients who received non‐r and omized heparin in view of high‐risk criteria to develop VOD ( n = 31 ) or other reasons unrelated to VOD ( n = 7 ) . Overall , 90 patients ( 38 % ) received heparin and 144 ( 62 % ) did not . The global incidence of VOD was 13/234 ( 5–5 % ) . Heparin did not reduce the risk of VOD in all subgroups studied . In particular , in the r and omized trial , the incidence of VOD was 2.2 % in the group without heparin vs 7–7 % in the group receiving heparin . We analyzed in depth the 13 patients who developed VOD and we compared them to a control group of 13 patients pair‐matched for age , sex , diagnosis and preparative regimen , who did not develop VOD . We found that abnormal LFT before ABMT predisposed patients to VOD ; refractoriness to platelet transfusion was observed in 85 % of the patients in the VOD group vs 15 % in the control group ( p<0.05 ) . VOD patients had an increased requirement for red cells and platelet transfusions , a lower recovery ( R<25 % ) after the second and third platelet transfusion , and shorter intervals separating the first four platelet transfusions . Further , the platelet reconstitution after ABMT in the VOD group was slower in comparison to the control group ( p<0.01 ) . Again , in this pair‐matched analysis continuous infusion of low‐dose heparin did not prevent VOD We studied the efficacy of adenoidectomy in 213 children who had received tympanostomy-tube placement because of persistent and /or recurrent otitis media and had again developed otitis media after tubal extrusion . Ninety-nine of the children were assigned r and omly to either an adenoidectomy group or a control group ; in a separate trial , 114 children whose parents withheld consent for r and omization were assigned according to parental preference . In both trials , control group outcomes appeared to have been biased favorably by the withdrawal of certain severely affected subjects from control status to receive adenoidectomy . Nonetheless , in both trials , adenoidectomy group outcomes were more favorable than control group outcomes during the first 2 follow-up years . Statistically significant differences were found mainly in the r and omized trial , where during the first and second years , respectively , adenoidectomy subjects had 47 % and 37 % less time with otitis media than control subjects and 28 % and 35 % fewer suppurative ( acute ) episodes than control subjects . We conclude that adenoidectomy is warranted on an individualized basis for children who develop recurrent otitis media after extrusion of tympanostomy tubes We compared the surgical and medical managements of reflux esophagitis in a prospect i ve managements of reflux esophagitis in a prospect i ve clinical trial . Patients wissigned to surgical ( 15 patients ) and medical ( 16 patients ) groups . A non-r and omized medical group ( 20 patients ) was also studied . Seventy three per cent of the surgical and 19 per cent of the medical group had an excellent to good response . A fair to poor response was observed in 81 per cent of medical and 27 per cent of surgical patients . Symptomatic improvement was accompanied by normal findings on acid infusion test and esophagoscopy . The histologic appearance of the squamous mucosa , however , remained abnormal in all but one patient . In patients who did well after operation there was improvement in resting lower-esophageal-sphincter pressures and absence of gastroesophageal reflux . The relative increases in pphincter pressure to grade d increases in gastric pressure , however , remained abnormal in all but one patient This article describes the outcome of a behavioral approach with or without preceding surgical intervention in 48 women with the vulvar vestibulitis syndrome . In the first part of the study , 14 women with the vulvar vestibulitis syndrome were r and omly assigned to one of two treatment programs : either a behavioral approach or a behavioral approach preceded by surgery . In the second part of the study , 34 women and their partners were given a choice of treatment . Follow-up data were gathered a mean of 3 and 2 1/2 years after treatment , respectively . In the r and omized patient population , the intervention had a positive effect on all of them : the complaints disappeared , diminished or did not change but formed less of a problem . The difference in outcome between the two different treatments , a behavioral approach with or without preceding surgery , was not statistically significant . In the second non-r and omized part of the study , 28 out of the 34 women ( 82 % ) chose the behavioral approach without preceding surgery . The difference in outcome between the two treatments was not statistically significant . Two out of the 28 women who chose behavioral treatment without preceding surgery had to be referred for psychiatric consultation because of serious psycho-sexual problems . In one woman , psychiatric treatment was successful . Three other women , whose behavioral treatment failed , underwent additional surgery , which clearly helped them to overcome the deadlock in the behavioral approach . The behavioral approach should be the first choice of treatment for the vulvar vestibulitis syndrome . Surgical intervention should be considered as an additional form of treatment in some cases with the vulvar vestibulitis syndrome to facilitate breaking the vicious circle of irritation , pelvic floor muscle hypertonia and sexual maladaptive behavior The purpose of this study was to compare the baseline patient characteristics , treatments and outcomes of elderly patients with aggressive histology lymphoma who were entered or not entered onto a r and omized phase II trial . We previously conducted a r and omized phase II trial in patients > 65 years of age who had advanced stage intermediate grade lymphoma . A registry of all patients meeting the inclusion criteria for that trial was maintained . Many patients were not entered on to the r and omized trial because of the presence of at least one exclusion criterion , or because of patient or physician choice . We have compared the baseline characteristics , treatment , and survival of the r and omized and non-r and omized patients . Results show that 68 consecutive patients met inclusion criteria for the r and omized trial . Thirty-eight patients satisfied all eligibility criteria , consented , and were r and omized ; 30 patients ( 44 % ) were not entered . In comparison with r and omized patients , non-r and omized patients were older ( mean 75.9 vs. 72.4 years ; P=0.013 ) , had a poorer performance status ( P=0.0006 ) , were less likely to be given treatment with curative intent ( 60 % vs. 100 % ; P<0.001 ) , and were less likely to complete 6 cycles of such treatment ( 27 % vs. 89 % ; P<0.001 ) . With a median follow-up of > 7 years , actuarial 5-year survival is superior in r and omized patients ( 44.3 % vs. 10 % ; P<0.00001 ) . In conclusion , a substantial number of patients did not enter our r and omized trial phase II trial and had different characteristics , received different therapy and had inferior outcomes in comparison with r and omized patients . R and omized trials of therapy for elderly lymphoma patients may include special selection criteria and results may not be generalizable to a substantial proportion of other older patients The effects of different methods of treatment of Graves ' ophthalmopathy were evaluated in a series of 48 patients . Thirty-six patients were given combined treatment with orbital cobalt irradiation and systemic 6 alpha-methylprednisolone ( methylprednisolone ) . Included in this group were 12 of 24 consecutive patients who were r and omly assigned to either combined therapy or systemic methylprednisolone alone . The degree of ocular involvement and responses to treatment were evaluated by numerical scoring ( ophthalmopathy index ) and clinical assessment . Of the 36 patients treated by combined therapy , 12 ( 33 % ) showed excellent responses , 14 ( 39 % ) showed good responses , 9 ( 25 % ) showed slight responses , and 1 ( 3 % ) had no response . Treatment was more effective for soft tissue involvement , newly developed ophthalmoplegia , and optic neuropathy , while proptosis and longst and ing ophthalmoplegia were less responsive . There was an inverse relationship between the duration of ophthalmopathy and the efficacy of treatment , more favorable results being observed when symptoms had been present for less than 2 yr . Treatment with systemic methylprednisolone alone was also effective , but , in general , responses were less satisfactory ; 4 of the 12 patients of this group ( 33 % ) had good responses , 6 ( 50 % ) had slight responses , and 2 ( 17 % ) had no response . The results obtained in the 24 patients r and omly assigned to combined therapy or steroid treatment alone were compared by evaluating changes in the ophthalmopathy index . Mean initial ophthalmopathy indices ( 6.4 vs. 6.2 , respectively ) showed no significant differences between the 2 groups , whereas the mean decrease in the group receiving combined therapy ( 4.8 ) was significantly greater ( P less than 0.05 ) than that in the other group ( 3.2 ) . In conclusion , the present study indicates that both orbital cobalt irradiation combined with systemic methylprednisolone treatment and systemic methylprednisolone therapy alone are valuable methods of treatment for Graves ' ophthalmopathy , but the combined therapy proved to be more effective BACKGROUND We have previously shown that the preemptive use of cytomegalovirus ( CMV ) immunoglobulin ( Ig ) replacement ( CytoGam ) decreases the incidence of opportunistic infections in cardiac transplant recipients with severe hypogammaglobulinemia . However , the impact of Ig replacement in moderately hypogammaglobulinemic patients is unknown . METHODS Periodic monitoring of the IgG levels was done in 300 heart transplant recipients . Moderate hypogammaglobulinemia ( IgG , 350 - 500 mg/dl ) developed in 56 patients ( 18.6 % ) . Thirty-three patients declined r and omization but agreed to have their IgG levels monitored . Twenty-three patients were r and omized to placebo ( n = 10 ) or CytoGam ( n = 13 ) at 105 + /- 63 days after transplantation . RESULTS The baseline characteristics were similar . A significant reduction in CMV infection was noted in the CytoGam Group compared with the Placebo Group ( 15.4 % [ 2/13 ] vs 60 % [ 6/10 ] , p = .039 ) . Among patients who declined r and omization , CMV infection developed in 13 ( 39.4 % ) of 33 , and 6 ( 46.1 % ) of the 13 progressed to severe hypogammaglobulinemia . A trend for reduction in the average episodes of > or = grade 2 rejection during the 6-month period after r and omization was noted in the CytoGam group ( 0.4 + /- 0.6 vs 1.4 + /- 1.3 , p = 0.065 ) . CONCLUSIONS The preemptive use of CytoGam decreases the incidence of CMV infection in patients with moderate hypogammaglobulinemia . A larger r and omized study is needed to substantiate these results BACKGROUND Venom immunotherapy ( VIT ) is a treatment with established efficacy for the prevention of repeated anaphylactic reactions in patients with Hymenoptera allergy , which also allows patients to discontinue carrying an EpiPen . Despite their merits , both treatments can have negative aspects potentially important to patients . OBJECTIVE We examined possible negative aspects of the EpiPen in comparison with VIT as perceived by patients . METHODS Positive and negative aspects of both treatments were measured by using a burden of treatment question naire together with statements about the EpiPen . RESULTS One hundred ninety-three patients were included , of whom 94 consented to r and omization : 47 received VIT , and 47 received the EpiPen . Of the remaining 99 , 75 chose VIT , and 26 chose the EpiPen . Of the patients receiving VIT , 91.5 % were ( extremely ) positive about their treatment , and 85 % would choose VIT again . Of the patients receiving the EpiPen , only 48 % were positive about their treatment , and even of these patients , 68 % preferred to be treated with VIT after 1 year of carrying the EpiPen . Although most patients indicated that it is reassuring to carry an EpiPen and makes them feel safe , many patients also indicated that it is inconvenient and troublesome . Especially patients who were negative about the EpiPen indicated that they would not dare use the EpiPen if necessary and were afraid at possible side effects . CONCLUSION In contrast to VIT , the EpiPen is perceived as burdensome by most patients with venom allergy . For most patients , an EpiPen is an unsuitable definitive treatment . CLINICAL IMPLICATION S As VIT enables patients with venom allergy to get rid of the EpiPen , patients should be offered VIT The Multi-Institutional Osteosarcoma Study ( MIOS ) was design ed to determine whether intensive multiagent adjuvant chemotherapy improves the outcome of patients with nonmetastatic high- grade osteosarcoma of the extremity as compared with concurrent controls . After definitive surgery of the primary tumor , patients were r and omly assigned to immediate adjuvant chemotherapy or to observation without adjuvant treatment . Up date d results of this trial indicate that the projected six-year event-free survival for the control group is 11 % compared to 61 % for the chemotherapy group ( p less than 0.001 ) . Similar results were observed in patients who declined r and omization but who were followed according to the treatment arms of the protocol . When r and omized and nonr and omized patients are pooled according to assigned treatment , a survival advantage favoring those patients treated with immediate adjuvant chemotherapy is apparent . An analysis of prognostic factors among patients receiving immediate adjuvant chemotherapy reveals that elevation of the serum lactic dehydrogenase at diagnosis is the factor most predictive of adverse outcome . Location of the primary site in the tibia confers a favorable prognosis . The authors conclude that the natural history of high- grade osteosarcoma of the extremity has not changed over the past two decades . The administration of immediate adjuvant chemotherapy has a significant favorable impact on event-free survival and should be recommended for all such patients The Danish Ovarian Cancer Study Group registered 722 patients in stages III and IV during the period 1981–1986 . The material included 85 % of all ovarian cancer patients in the catchment area of the group and patients allocated to protocol as well as patients treated outside protocol s. Five and 10-year survival were : stage III 17 % , and 8 % , respectively ; and stage IV 4 % and 2 % . Patients allocated to protocol had a significantly better survival than patients not included in protocol s even when only patients younger than 70 years were compared . All non- protocol patients had a poorer prognosis irrespective of the reason for exclusion . Five-year survival for stage III protocol patients was 25 % vs. 9 % , for non- protocol patients younger than 70 years . The 10-year survival was 11 % and 4 % for stage III protocol and non- protocol patients , respectively . A multivariate analysis showed that residual tumor , age , stage , and performance status had prognostic value . In non protocol patients histologic grade had an additional marginal prognostic impact . In conclusion the study showed that the statement that long-term survival in advanced ovarian cancer has been increased could not be proven by comparison of survival from r and omized studies performed in the early eighties with survival of stage III and IV patients before the introduction of cisplatinum chemotherapy . It is necessary to consider survival of all patients , protocol and non- protocol in a geographically well-defined region for evaluation of survival improvement We conducted a r and omized controlled trial to determine whether intensive multi-agent adjuvant chemotherapy improves the chances of relapse-free survival in patients with nonmetastatic high- grade osteosarcoma of the extremity , as compared with concurrent controls . After undergoing definitive surgery , 36 patients were r and omly assigned to adjuvant chemotherapy or to observation without adjuvant treatment . At two years the actuarial relapse-free survival was 17 percent in the control group , similar to that found in studies before 1970 , and 66 percent in the adjuvant-chemotherapy group ( P less than 0.001 ) . Similar results were observed among 77 additional patients who declined to undergo r and omization but who elected observation or chemotherapy . We conclude that the natural history of osteosarcoma of the extremity has remained stable over the past two decades , that adjuvant chemotherapy increases the chances of relapse-free survival of patients with high- grade osteosarcoma , and that it should be given to all such patients Sotalol is the prototype class III agent that combines beta-blocking properties with the propensity to prolong the effective refractory period by lengthening the action potential duration . Its precise effect on the prevention of ventricular tachycardia-ventricular fibrillation ( VTVF ) compared to class I agents has not been evaluated in a blinded study . In a double-blind parallel- design multicenter study , the electrophysiologic and antiarrhythmic effects of intravenous and oral sotalol ( n = 55 ) and procainamide ( n = 55 ) were therefore compared in patients with VTVF inducible by programmed electric stimulation . Sotalol produced a greater effect on lengthening the ventricular effective refractory period ( VERP ) . It prevented the inducibility of VTVF in 30 % versus 20 % for procainamide , but this was not significantly different . In an alternate therapy group ( n = 41 ) of similar patients previously refractory to or intolerant of procainamide , intravenous sotalol prevented inducibility in 32 % . The pooled overall sotalol efficacy rate was 31 % . There was a significant relation between the increase in the VERP and the prevention of inducibility of VTVF ( n = 56 ; p < 0.02 ) . VERP of > or = 300 msec was critical for the prevention of VTVF inducibility . Thirteen sotalol and 6 procainamide responders from the r and omized group and 30 from the nonr and omized groups completed 1 year of oral sotalol therapy follow-up . Life-table analysis of these patient in each group showed a trend in favor of sotalol ; however , statistical analysis was not possible because of the small numbers of patients . Both sotalol and procainamide were well tolerated . In the r and omized group there was one case of sudden death during treatment with sotalol and two cases of nonfatal torsades de pointes in the procainamide group and two in the sotalol group ; in the nonr and omized alternate therapy group , there were 6 cases of nonfatal torsades de pointes . The data support the emerging role of sotalol in the control of symptomatic ventricular tachycardia and fibrillation UNLABELLED The use of a UV-box disconnect system reduces the incidence of peritonitis as compared with manual exchanges . An integrated disconnect system ( IDS ) also gives good results . See Figure 1 . From 1988 - 1991 , we prospect ively compared two groups of patients using either a UV-box disconnect system ( Baxter , n = 18 , mean age 64 , range 28 - 75 yrs ) or an IDS ( Baxter , n = 25 , mean age 53 , range 30 - 78 ) . The Tenckhoff catheter had been inserted by the same technique in all patients , and the training program and nursing care were also identical . Since many younger patients preferred IDS and refused r and omization , age was significantly lower in the IDS group . All peritonitis episodes ( PER ) were registered . Excluded from calculations of PER were episodes most probably not due to failure in connective device : PER after incidental penetration of the dialysis bags , deep penetrating tunnel infections and in the direct course of abdominal surgery . RESULTS There were significantly fewer months with PER ( one month = 1 PER ; Chi-2 = 6.45 , p < 0.05 ) in patients using the IDS ( 3 PER/269 months ) compared with those using the UV-box system ( 15 PER/355 months ) . The IDS was requested mainly by younger patients , while some older patients found it to be too complicated . CONCLUSION The integrated disconnect system is especially acceptable by younger patients , and patients using the IDS show a low incidence of peritonitis BACKGROUND Selection of patients for a clinical trial is affected by awareness of the existence of the trial , interest in the study question and clinical practice s and views of the clinicians . AIMS To investigate the selectivity that may have occurred at Peter MacCallum Cancer Institute ( PMCI ) during the ANZ Lymphoma Group trial of MACOP-B vs CHOP in non-Hodgkin 's lymphoma ( NHL ) . METHODS NHL patients at PMCI in the study period were assessed against the trial 's eligibility criteria . Comparisons were made between eligible ( except for consent ) non-trial patients and all patients actually r and omised into the trial . RESULTS Of 497 patients presenting during the trial period , 320 ( 64 % ) did not meet the specified eligibility criteria , 102 ( 21 % ) were unsuitable on other grounds ( age and medical ) and 75 ( 15 % ) were eligible . Of those eligible , 43 ( 57 % ) were entered into the trial and 32 ( 43 % ) were not . Four non-trial patients had inappropriate application of eligibility criteria and 13 unknown reason . Eligible non-trial patients were similar to trial patients in most patient and tumour characteristics and overall survival . Significantly more non-trial patients had higher stage disease ( p = 0.02 ) . More non-trial patients had lower grade histology , but this was not significant . CONCLUSIONS Physician selectivity occurred with respect to patient entry , but trial and non-trial patients were similar in most characteristics . Eligibility criteria should specify that patients can withst and all trial drugs and patient availability for treatment and follow-up . PMCI trial accural could have been up to 33 % greater . These results suggest the trial accrual period could have been 25 % shorter . Patient entry into this trial by PMCI clinicians compared favourably with other centres BACKGROUND Patients with treated diabetes in the r and omized-trial segment of the Bypass Angioplasty Revascularization Investigation ( BARI ) who were r and omized to initial revascularization with PTCA had significantly worse 5-year survival than patients assigned to CABG . This treatment difference was not seen among diabetic patients eligible for BARI who opted to select their mode of revascularization . We hypothesized that differences in patient characteristics , assessed and unmeasured , together with the treatment selection in the registry , at least partially account for this discrepancy . METHODS AND RESULTS Among diabetics taking insulin or oral hypoglycemic drugs at entry , angiographic and clinical presentations were comparable between r and omized and registry patients . However , more registry patients were white , and registry diabetics tended to be more educated and more physically active and to report better quality of life . Procedural characteristics and in-hospital complications were comparable . The 5-year all-cause mortality rate was 34.5 % in r and omized diabetic patients assigned to PTCA versus 19.4 % in CABG patients ( P=0.0024 ; relative risk [RR]=1.87 ) ; corresponding cardiac mortality rates were 23.4 % and 8.2 % , respectively ( P=0.0002 ; RR=3.10 ) . The CABG benefit was more apparent among patients requiring insulin . In the registry , all-cause mortality was 14.4 % for PTCA versus 14.9 % for CABG ( P=0.86 , RR=1.10 ) , with corresponding cardiac mortality rates of 7.5 % and 6 . 0 % , respectively ( P=0.73 ; RR=1.07 ) . These RRs in the registry increased to 1.29 and 1.41 , respectively , after adjustment for all known differences between treatment groups . CONCLUSIONS BARI registry results are not inconsistent with the finding in the r and omized trial that initial CABG is associated with better long-term survival than PTCA in treated diabetic patients with multivessel coronary disease suitable for either surgical or catheter-based revascularization Objective To compare laparoscopic with open hernia repair in a r and omized clinical trial at a median follow-up of 5 years . Summary Background Data Follow-up of patients in clinical trials evaluating laparoscopic hernia repair has been short . Methods Of 379 consecutive patients admitted for surgery under the care of one surgeon , 300 were r and omized to totally extraperitoneal hernia repair or open repair , with the open operation individualized to the patient ’s age and hernia type . All patients , both r and omized and nonr and omized , were followed up by clinical examination annually by an independent observer . Results Recurrence rates were similar for both r and omized groups . In 1 of the 79 nonr and omized patients , a recurrent hernia developed . Groin or testicular pain was the most common symptom on follow-up of r and omized patients . The most common reason for reoperation was development of a contralateral hernia , which was noted in 9 % of patients ; 11 % of all patients died on follow-up , mainly as a result of cardiovascular disease or cancer . Conclusions These data show a similar outcome for laparoscopic and open hernia repair , and both procedures have a place in managing this common problem Background . Reduced bone mineral density ( BMD ) is common in long-term renal transplant recipients and results in a high incidence of fractures . The optimal therapy for these patients is not known . Methods . Baseline BMD determinations were obtained in 211 long-term adult renal transplant recipients . One hundred and seventeen patients with a reduced BMD ( T score ≤ −1 ) were r and omly assigned to treatment with alendronate and calcium ( n=60 ) versus calcitriol and calcium ( n=57 ) . Of these , 46 and 51 patients , respectively , completed 1 year of treatment . Forty-nine patients who were not eligible or did not consent to the trial were followed prospect ively . Results . Reduced baseline BMD ( T score ≤ −1 ) was present in 159 ( 78.7 % ) of patients at the lumbar spine or femur . There was no significant loss of BMD in the prospect ively followed patients during 2.7 years . The average lumbar BMD increased from 0.984±0.149 to 1.025±0.143 g/cm2 ( P < 0.001 ) with alendronate and from 1.014±0.15 to 1.034±0.146 g/cm2 ( P = 0.002 ) with calcitriol . BMD at the femur increased from 0.809±0.092 to 0.836±0.107 g/cm2 ( P < 0.001 ) with alendronate and from 0.830±0.144 to 0.857±0.125 g/cm2 ( P = 0.023 ) with calcitriol . Conclusions . One year of treatment with alendronate or calcitriol , both with calcium supplementation , result ed in significant increases in BMD at the lumbar spine and femur , with a trend toward alendronate being more effective at the spine ( P = 0.082 ) . Further studies are needed to determine whether BMDs continue to increase after 1 year and whether there is any additional benefit to combining vitamin D and alendronate . Larger studies are needed to determine whether treatment decreases fracture rates OBJECTIVES To evaluate whether use of beta-adrenergic blocking agents , alone or in combination with specific antiarrhythmic therapy , is associated with improved survival in persons with ventricular fibrillation ( VF ) or symptomatic ventricular tachycardia ( VT ) . BACKGROUND The ability of beta-blockers to alter the mortality of patients with VF or VT receiving contemporary medical management is not well defined . METHODS Survival of 1,016 r and omized and 2,101 eligible , nonr and omized patients with VF or symptomatic VT followed in the Antiarrhythmics Versus Implantable Defibrillators ( AVID ) trial through December 31 , 1996 was assessed using Cox proportional hazards analysis . RESULTS The 817 ( 28 % ) patients discharged from hospital receiving beta-blockers had less ventricular dysfunction , fewer symptoms of heart failure and a different pattern of medication use compared with patients not receiving beta-blockers . Before adjustment for important prognostic variables , beta-blockade was not significantly associated with survival in r and omized or in eligible , nonr and omized patients treated with specific antiarrhythmic therapy . After adjustment , beta-blockade remained unrelated to survival in r and omized or in eligible , nonr and omized patients treated with amiodarone alone ( n = 1142 ; adjusted relative risk [ RR ] = 0.96 ; 95 % confidence interval [ CI ] 0.64 - 1.45 ; p = 0.85 ) or a defibrillator alone ( n = 1347 ; adjusted RR = 0.88 ; 95 % CI 0.55 to 1.40 ; p = 0.58 ) . In contrast , beta-blockade was independently associated with improved survival in eligible , nonr and omized patients who were not treated with specific antiarrhythmic therapy ( n = 412 ; adjusted RR = 0.47 ; 95 % CI 0.25 to 0.88 ; p = 0.018 ) . CONCLUSIONS Beta-blocker use was independently associated with improved survival in patients with VF or symptomatic VT who were not treated with specific antiarrhythmic therapy , but a protective effect was not prominent in patients already receiving amiodarone or a defibrillator BACKGROUND There are few data on the long-term outcome of growth-hormone treatment in short normal children . We assessed the impact of growth-hormone treatment on pubertal development and near-final height in girls . METHODS In a r and omised controlled trial , we studied ten girls , with a mean age of 8.07 years and height 2 SDs or more below the mean for their age , and eight short untreated controls matched for age , and 20 short untreated girls who did not give consent for r and omisation . The girls received either 30 IU/m2 somatropin per week as daily subcutaneous injections or no treatment . We assessed pubertal staging and height gain every 6 months . FINDINGS Eight treated girls completed a mean of 6.2 years ' therapy . By a mean age of 16.4 years , their mean height SD score had changed significantly from -2.42 to -1.14 ( p=0.008 ) and they were , on average , 7.5 cm taller than the girls in the control group ( height SD scores did not change significantly from -2.55 ) and 6.0 cm taller than the non-consent group . The timing of each pubertal stage , and the age and amplitude of peak height velocity were similar for all groups . INTERPRETATION Growth-hormone therapy effectively increased height SD score among short normal girls started on treatment in early to mid childhood , with no untoward effect on pubertal progression We report follow-up findings after two to almost four years on 100 patients who were described in a previously published prospect i ve r and omized series . Horizontally stapled gastric partition ( gastroplasty ) was compared with gastric exclusion ( bypass ) using a Roux-en-Y jejunal loop . An additional 142 patients had the identical operative procedures performed during the same time period , but chose their own operation . Both procedures used a small gastric pouch ( 15 mL ) and calibrated 10-mm opening . Weight loss was better after exclusion and has continued to be better . Patients who lose weight well do not regain . There were complications in 8 % of the exclusion patients and 12 % of the partitioning patients and one death in the exclusion group--0.4 % of the total group . Since gastric exclusion is safe and produces significantly better weight loss , we believe it sets the current st and ard against which all other bariatric surgery must be compared Objective : The purpose of the study was to compare in prospect i ve r and omized fashion a manually sutured esophagogastric anastomosis in the neck and a stapled in the chest after esophageal resection and gastric tube reconstruction . Summary Background Data : Despite the fact that all reconstructions after esophagectomy will result in a cervical or a thoracic anastomosis , controversy still exists as to the optimal site for the anastomosis . In uncontrolled studies , both neck and chest anastomoses have been advocated . The only reported r and omized study is difficult to evaluate because of varying routes of the substitute and different anastomotic techniques within the groups . The reported high failure rate of stapled anastomoses in the neck and the fact that most surgeons prefer to suture cervical anastomoses made us choose this technique for anastomosis in the neck . Our routine and the preference of most surgeons to staple high thoracic anastomoses became decisive for type of thoracic anastomoses . Methods : Between May 9 , 1990 and February 5 , 1996 , 83 patients undergoing esophageal resection were prospect ively r and omized to receive an esophagogastric anastomosis in the neck ( 41 patients ) or an esophagogastric anastomosis in the chest ( 42 patients ) . To evaluate selection bias , patients undergoing esophageal resection during the same period but not r and omized ( n = 29 ) were also followed and compared with those in the study ( n = 83 ) . Objective measurements of anastomotic level and diameter were assessed with an endoscope and balloon catheter 3 , 6 , and 12 months after surgery . The long-term survival rates were compared with the log-rank test . Results : Two patients ( 1.8 % ) died in hospital , and the remaining 110 patients were followed until death or for a minimum of 60 months . The genuine 5-year survival rate was 29 % for chest anastomoses and 30 % for neck anastomoses . The overall leakage rate was 1.8 % ( 2 cases of 112 ) with no relation to mortality or anastomotic method . All patients in the r and omized group had tumor-free proximal and distal resection lines , but 1 patient in the nonr and omized group had tumor infiltrates in the proximal resection margin . At 3 , 6 , and 12 months after operation , there was no difference in anastomotic diameter between the esophagogastric anastomosis in the neck and in the thorax ( P = 0.771 ) , and both increased with time ( P = 0.004 , ANOVA repeated measures ) . Body weight development was the same in the two groups . With similar results in r and omized and nonr and omized patients , study bias was eliminated . Conclusions : When performed in a st and ardized way , neck and chest anastomoses after esophageal resection are equally safe . The additional esophageal resection of 5 cm in the neck group did not increase tumor removal and survival ; on the other h and , it did not adversely influence morbidity , anastomotic diameter , or eating as reflected by body weight development Cholecystectomy is the most common surgical procedure performed in sickle cell anemia ( SCA ) patients . We investigated the effects of transfusion and surgical method on perioperative outcome . A total of 364 patients underwent cholecystectomy : group 1 ( r and omized to aggressive transfusion ) 110 patients ; group 2 ( r and omized to conservative transfusion ) 120 patients ; group 3 ( nonr and omized nontransfusion ) 37 patients ; and group 4 ( nonr and omized transfusion ) 97 patients . Patients were similar except group 3 patients were more likely to be female , over 20 years old , smokers , and more healthy by American Society of Anesthesiologists ( ASA ) physical status score . Total complication rate was 39 % : sickle cell events 19 % ; intraoperative or recovery room events 11 % ; transfusion complications 10 % ; postoperative surgical events 4 % ; and death 1 % . Group 3 patients had the highest incidence of sickle cell events ( 32 % ) . Open cholecystectomies were performed in 58 % and laparoscopic in 42 % . Laparoscopic patients were younger and more healthy by ASA score . Laparoscopic patients had longer anesthesia time ( 3.2 v 2.9 hours ) , but shorter hospitalization time ( 6.4 days v 9.8 ) . Complications were similar between these two groups . We conclude that SCA patients undergoing cholecystectomy have a high perioperative morbidity , and the incidence of sickle cell events may be higher in patients not preoperatively transfused . We recommend a conservative preoperative transfusion regimen , and we encourage the use of the laparoscopic technique for SCA patients undergoing elective cholecystectomy OBJECTIVE Comparison of the results of term breech births in our clinic with the Term Breech Trial ( TBT ) . MATERIAL AND METHODS During the investigation period prospect i ve data were collected on all deliveries of a term baby in breech presentation . Some pregnant women were included in the TBT and r and omized in a planned cesarean section (CS)-group and a planned vaginal birth (VB)-group . The remaining non-r and omized women were divided into a primary CS-group and a started VB-group . Neonatal and maternal mortality and morbidity were analyzed retrospectively , according to the intended mode of delivery . RESULTS Neonatal or maternal mortality occurred in none of the groups . Neither in the r and omized group nor in the non-r and omized group were significant differences in serious neonatal and maternal morbidity observed between the intended cesarean section-group and the group that started vaginal delivery . However , in the non-r and omized group , moderate neonatal morbidity was significantly lower in the primary CS-group than in the started VB-group . CONCLUSION The differences in moderate neonatal morbidity support the conclusion of the TBT , that primary cesarean section may be safer for the term breech baby than a trial of vaginal labor Participants of a r and omised trial may differ from eligible non- participants as a result of selection . We studied the distribution of prognostic factors and survival in eligible patients of a multi-centre trial of long-term oral anticoagulant treatment after myocardial infa rct ion . All hospital survivors of myocardial infa rct ion in one participating clinical centre of a multi-centre , r and omised , double-blind , placebo-controlled trial of long-term anticoagulant treatment after myocardial infa rct ion were screened for entry criteria . Subsequently , prognostic factors and survival of participants were compared with eligible but not r and omised patients . The 350 participants were younger and were more often of male gender and more often smokers compared with 587 non- participants . Non- participants had more frequently suffered a previous myocardial infa rct ion and were treated more often with diuretics and ACE-inhibitors , suggesting a higher proportion of patients with chronic heart failure in this group . Age , previous myocardial infa rct ion and the use of diuretics at discharge were independent predictors of mortality , consent showed no association . Our findings indicate that participants of a clinical trial have a better prognosis during the first years following myocardial infa rct ion compared to eligible non- participants as a result of a higher prevalence of cardiovascular risk factors associated with mortality in the non- participants The authors estimated the incidence rates of cholera and death between 1985 and 1988 for 32,642 age- and sex-eligible persons who did not participate in a r and omized , placebo-controlled field trial of killed oral cholera vaccines in rural Bangladesh . As compared with 20,744 placebo recipients , the relative risk of cholera for all non participants , adjusted for potentially confounding demographic variables , was 1.20 ( 95 % confidence interval ( CI ) 1.03 - 1.41 ) ; this adjusted relative risk reflected elevated adjusted relative risks in non participants who were medically ineligible ( RR = 1.65 ; 95 % CI 1.22 - 2.22 ) or refused to participate ( RR = 1.19 ; 95 % CI 1.01 - 1.41 ) , but not in persons absent at the time of vaccination ( RR = 1.00 ; 95 % CI 0.78 - 1.28 ) . The adjusted relative risk of death was also elevated in non participants as compared with placebo recipients ( RR = 1.28 ; 95 % CI 1.10 - 1.48 ) , with the same pattern of adjusted relative risks for different categories of non participants : for ineligible subjects , 2.64 ( 95 % CI 2.12 - 3.29 ) ; for refusers , 1.20 ( 95 % CI 1.02 - 1.41 ) ; and for absentees , 0.95 ( 95 % CI 0.75 - 1.22 ) . The authors concluded that nonparticipation was associated with clinical ly cogent adverse health outcomes , but that the magnitude of these associations varied according to the reason for nonparticipation . These findings underscore the caution required in assessing vaccine efficacy with controls who are not vaccinated because of choices made by patients or vaccinators BACKGROUND Prior endoscopic studies evaluating conscious sedation have recruited only a small proportion of the patients actually approached . The generalizability of such results to an unselected adult ambulatory care population is thus question able . The objectives of this study were to determine the characteristics of patients who refused inclusion in a r and omized controlled trial of sedation and to compare these characteristics to those of patients who agreed to participate . METHODS Patients who refused participation in a r and omized controlled trial of sedation completed st and ardized question naires addressing demographic data and possible confounding variables , and they also completed a vali date d anxiety question naire . Characteristics associated with refusal to participate in the r and omized controlled trial were assessed by using uni- and multivariate analysis . Exploratory comparisons of outcomes between both groups included self-reported satisfaction with level of comfort and technical adequacy . RESULTS Of 302 patients screened , 203 refused to participate in the r and omized controlled trial . The most common reason for refusal was the request for no sedation ( 135/203 ) . A total of 163 were enrolled in this synchronous study . Patients who refused to participate exhibited 3 distinguishing characteristics : prior treatment for an anxiety disorder ( risk difference 9.4 % : 95 % CI[3 % , 17 % ] ) , use of analgesic medication ( risk difference 10.4 % : 95 % CI[2 % , 19 % ] ) , and prior experience with EGD ( risk difference 17.9 : 95 % CI[5 % , 30 % ] ) . Only upper endoscopy experience was predictive of refusal to participate in the r and omized controlled trial . No differences in outcomes existed between patients r and omized to sedation and those refusing the r and omized controlled trial who chose to receive sedative medication . Patients who refused participation in the r and omized controlled trial and who underwent upper endoscopy without sedation were more satisfied than patients r and omized to placebo ( 1.33 vs. 2.58 ; risk difference -1.25 : 95 % CI[-0.38 , -2.1 ] ) . Moreover , the procedure in these patients was more adequate technically ( 4.86 vs. 4.18 ; risk difference 0.68 : 95 % CI[0.21 , 1.13 ] ) . CONCLUSIONS Characteristics of patients accepting and refusing r and omization were highly similar , differing only with regard to upper endoscopy experience . An exploratory analysis of outcomes suggests that r and omized controlled trial results may be biased in a direction that may underestimate the benefits of not administering sedative medication in a real-life setting OBJECTIVES To test the hypotheses that : ( 1 ) Lumbar spine radiography in primary care patients with low back pain is not associated with improved patient outcomes , including pain , disability , health status , sickness absence , reassurance , and patient satisfaction or belief in the value of radiography . ( 2 ) Lumbar spine radiography in primary care patients with low back pain is not associated with changes in patient management , including medication use , and the use of primary and secondary care services , physical therapies and complementary therapies . ( 3 ) Participants choosing their treatment group ( i.e. radiography or no radiography ) do not have better outcomes than those r and omised to a treatment group . ( 4 ) Lumbar spine radiography is not cost-effective compared with usual care without lumbar spine radiography . DESIGN A r and omised unblinded controlled trial . SETTING Seventy-three general practice s in Nottingham , North Nottinghamshire , Southern Derbyshire , North Lincolnshire and North Leicestershire . Fifty-two practice s recruited participants to the trial . SUBJECTS R and omised arm : 421 participants with low back pain , with median duration of 10 weeks . Patient preference arm : 55 participants with low back pain , with median duration of 11 weeks . INTERVENTION Lumbar spine radiography and usual care versus usual care without radiography . MAIN OUTCOME MEASURES Rol and adaptation of the Sickness Impact Profile , visual analogue pain scale , health status scale , EuroQol , use of primary and secondary care services , and physical and complementary therapies , sickness absence , medication use , patient satisfaction , reassurance and belief in value of radiography at 3 and 9 months post-r and omisation . RESULTS Participants r and omised to receive an X-ray were more likely to report low back pain at 3 months ( odds ratio ( OR ) = 1.56 ; 95 % confidence interval ( CI ) , 1.02 to 2.40 ) and had a lower overall health status score ( p = 0.02 ) . There were no differences in health or functional status at 9 months . A higher proportion of participants consulted the general practitioner ( GP ) in the 3 months following an X-ray ( OR = 2.72 ; 95 % CI , 1.80 to 4.10 ) . There were no differences in use of any other services , medication use or sickness absence at 3 or 9 months . No serious spinal pathology was identified in either group . The commonest X-ray reports were of discovertebral degeneration and normal findings . Many patients did not perceive their information needs were met within the consultation . Satisfaction with care was greater in the group receiving radiography at 9 months . Participants r and omised to receive an X-ray were not less worried , or more reassured about serious disease causing their low back pain . Satisfaction was associated with meeting participants ' information needs and reduced belief in the necessity for investigations for low back pain , including X-rays and blood tests . In both groups , at 3 and 9 months 80 % of participants would choose to have an X-ray if the choice was available . Participants in the patient preference group achieved marginally better outcomes than those r and omised to a treatment group , but the clinical significance of these differences is unclear . Lumbar spine radiography was associated with a net economic loss at 3 and 9 months . CONCLUSIONS Lumbar spine radiography in primary care patients with low back pain of at least 6 weeks duration is not associated with improved functioning , severity of pain or overall health status , and is associated with an increase in GP workload . Participants receiving X-rays are more satisfied with their care , but are not less worried or more reassured about serious disease causing their low back pain . CONCLUSIONS - RECOMMENDATIONS FOR FURTHER RESEARCH : Further work is required to develop and test an educational package that educates patients and GPs about the utility of radiography and provides strategies for identifying and meeting the information needs of patients , and the needs of patients and GPs to be reassured about missing serious disease . Guidelines on the management of low back pain in primary care should be consistent about not recommending lumbar spine radiography in patients with low back pain in the absence of red flags for serious spinal pathology , even if the pain has persisted for at least 6 weeks PURPOSE To investigate the efficacy and toxicity of cisplatin/etoposide ( PE ) chemotherapy ( CHT ) with or without accelerated hyperfractionated radiation therapy ( ACC HFX RT ) and concurrent daily carboplatin/etoposide ( CE ) in patients with extensive-disease small-cell lung cancer . PATIENTS AND METHODS A total of 210 patients were treated with three cycles of st and ard PE . Patients with a complete response ( CR ) at both the local and distant levels ( CR/CR ) or a partial response ( PR ) at the local level and CR at the distant level ( PR/CR ) received either thoracic ACC HFX RT with 54 Gy in 36 fractions over 18 treatment days in combination with CE followed by two cycles of PE ( group 1 , n = 55 ) or an additional four cycles of PE ( group 2 , n = 54 ) . Patients who experienced less response were treated nonr and omly ( groups 3 , 4 , and 5 ) . All patients with a CR at the distant level received prophylactic cranial irradiation . RESULTS For 206 assessable patients , the median survival time ( MST ) was 9 months and the 5-year survival rate was 3.4 % . Patients in group 1 had significantly better survival rates than those in group 2 ( MST , 17 v 11 months ; 5-year survival rate , 9.1 % v 3.7 % , respectively ; P = .041 ) . Local control was also better in group 1 , but the difference was only marginally not significant ( P = .062 ) . There was no difference in distant metastasis-free survival between groups 1 and 2 . Acute high- grade toxicity was higher in group 2 than in group 1 . CONCLUSION The addition of ACC HFX RT to the treatment of the most favorable subset of patients led to improved survival over that obtained with CHT alone OBJECTIVE To determine if the density of diode laser photocoagulation for the treatment of zone 1 or zone 2 threshold retinopathy of prematurity ( ROP ) affects the rate of progression of the disease . DESIGN Retrospective , nonr and omized , comparative trial ( n = 12 ) and prospect i ve , r and omized , clinical trial ( n = 46 ) . PARTICIPANTS Two surgeons treated a total of 107 eyes from 58 patients with zone 1 or zone 2 threshold ROP within 72 hours of diagnosis . The two consecutive groups of patients were treated with two different diode laser photocoagulation patterns between May 1995 and October 1997 and were observed for at least 3 months . INTERVENTION All patients underwent diode laser photocoagulation of the peripheral avascular retina extending from the ridge of extraretinal proliferation to the ora serrata . One cohort received a near confluent laser pattern , whereas the second cohort received a pattern of laser spots placed 1 to 1.5 burn widths apart . MAIN OUTCOME MEASURES Anatomic outcome , rate of progression to stage 4 or 5 retinopathy of prematurity , postoperative complications , and timing and frequency of retreatment . RESULTS For analysis , the retrospective and r and omized outcome data were grouped . The rate of progression in the near confluent laser treatment group was 3.6 % overall , 0 % of zone 1 eyes , and 3.8 % of zone 2 eyes . The rate of progression in the less dense treatment group was 29 % overall , 44 % of zone 1 eyes , and 21 % of zone 2 eyes . Mean time to retreatment was 16 days in cohort 1 and 24 days in cohort 2 . CONCLUSIONS A dense pattern of diode laser treatment for threshold ROP and prompt retreatment for residual plus disease significantly reduce the rate of progression in eyes with zone 2 disease ( P = 0.02 ) and may be beneficial in eyes with zone 1 disease It has been postulated that treatment with nicotinamide may prevent or delay the onset of insulin dependent diabetes mellitus . We report the findings of a population based diabetes prevention trial which tests this hypothesis . 33,658 school children aged 5 - 7.9 years were r and omly selected ( by school ) from a total population of 81,993 of such children in the Auckl and ( New Zeal and ) region . They were offered testing for islet cell antibodies . 20,195 ( 60 % ) consented to testing . Of these 185 had islet cell antibodies and met the criteria for treatment with nicotinamide . 173 received this treatment . The study population has an average follow up time of 7.1 years . The diabetes incidence of the untested controls was : 16.07 ( 12.4 - 20.5 95 % CI ) /100,000 person years at risk ; in the group who were tested and treated when deemed appropriate : 7.14 ( 3.1 - 14.1 95 % CI ) ; and in the group offered testing but who did not consent ( " refusers ' ) : 18.48 ( 10.1 - 31.0 95 % CI ) . The tested group had a rate of diabetes of 41 % ( 20 - 85 95 % CI ) of the other groups combined after an age adjustment , which is significant ( p = 0.008 ) . The tested group combined with the " refuser ' group ( i.e. " intention to treat ' ) also has a lower incidence than the control group ( p = 0.12 ) . Nicotinamide has a protective effect against the development of insulin dependent diabetes in this setting but the size of the effect has a wide confidence interval . Further follow up may define the magnitude of the protective effect within narrower limits The authors tested the hypothesis that patients ( treatment-seeking cocaine-dependent persons ) given the opportunity to choose between treatment approaches would do better than patients r and omly assigned to the same approaches in treatment retention and 9-month outcome . Subjects were 34 patients who voluntarily chose to enter individual therapy 1 hour per week ( IND ) and 33 who chose intensive group therapy for 3 hours , 3 times weekly ( INT ) . There were no significant differences between these two groups on demographic , personality , or addiction severity variables or in treatment retention or 9-month outcome . Comparison with sample s of 30 patients who had been r and omly assigned to IND and 30 to INT did not confirm the hypothesis that patients who chose their treatment would either remain in treatment for longer periods of time or manifest improved 9-month outcomes . The authors raise several motivational issues Background : Little is known about the influence of preference for a given therapy or preference against a modality of treatment on the outcome of that treatment . Results so far have been conflicting . The primary aim of this study was to investigate possible differences in outcome between panic disorder patients treated with preferred cognitive therapy and patients treated by r and omization with the same intervention . Methods : A 12-week study comparing 35 patients treated by allocation with 31 patients treated by preference . Results : There were no differences at pretest between the two conditions on demographic or outcome measures . Outcome was assessed with measurements rating the panic frequency and severity of agoraphobia , general anxiety and depression . Both conditions improved significantly on nearly all ratings . There were no significant differences demonstrable between the two conditions on any of the outcome measures . Conclusion : Preference for a given therapy is not a powerful moderator of effect in the psychological treatment of panic disorder AIM To investigate the efficacy of a single ultrasonic scan at age 65 to identify patients at risk from ruptured abdominal aortic aneurysm ( AAA ) . METHOD A total of 6058 men aged 64 - 81 were recruited to a r and omised trial , and 3000 were invited to attend a single screening test . An additional population of 1011 men was offered screening as they reached age 65 . If a normal aorta was identified in this sub-group , further scans were offered at two-yearly intervals . Follow up and treatment of those identified as having an aortic dilatation of 3 cm or greater was undertaken . All subject groups were monitored for deaths occurring over the study period , and date and cause of death were recorded . RESULTS A total of 2212 men attended screening in the r and omised trial ; the overall compliance was 74 % , and prevalence of AAA was 7.7 % . Compliance decreased , and prevalence increased , with age . Mortality from ruptured AAA was reduced by 68 % at 5 years ( screened group compared to the age-matched control population ) , and by 42 % in the study arm ( screened and refusers ) compared with controls . The benefit persisted at ten years ( 53 % and 21 % respectively ) . Of the uncontrolled sample of 1011 men offered a scan at age 65 , 681 attended and 649 of these were found to have a normal aortic diameter ; re-screening demonstrated new aneurysm development in 4 % over ten years . The aortic diameters of the new AAAs were under 4 cm and would therefore have a low risk of rupture.1 Mortality from rupture in all those with an initially normal aortic diameter was low , at 1 case per 1000 scans over ten years . CONCLUSION Screening once for AAA at age 65 can identify the majority of AAA that are of clinical significance and can identify a large population at low risk from rupture who do not require surveillance . This policy has been effective when combined with selective treatment in reducing the risk of rupture for ten years in those who attend the screening programme BACKGROUND Expectant management , although less effective , is an alternative treatment option for surgical evacuation in women with a miscarriage . We assessed health-related quality of life ( HRQL ) differences over time between expectant and surgical management in women with a miscarriage . METHODS Women with a miscarriage were r and omized to either expectant ( n = 64 ) or surgical ( n = 58 ) management , and 305 eligible women who refused r and omization because of a preference for either treatment option were managed according to their choice following the same clinical protocol ( 126 expectant , 179 surgical ) . The main outcome measures were score differences of HRQL during 12 weeks . Repeated measures analysis was applied . RESULTS Out of a total of 427 women , 198 were excluded in the question naire follow-up , leaving 229 women who participated . Mental health of women allocated to expectant management improved more and earlier ( treatment effect ) than of women allocated to surgical evacuation . Mental health scores were significantly better in women who chose , rather than women who were r and omized , to curettage . The groups managed according to their own preference showed no differences in mental health scores . CONCLUSION Women with a miscarriage who chose their own treatment had the best HRQL over time , supporting the role of free choice from a clinical point of view . Women without a treatment preference should be encouraged to start with expectant management for psychological reasons Between September 1981 and November 1984 the Danish Ovarian Cancer Group ( DACOVA ) performed two r and omised trials . One for adjuvant therapy in stages Ib , Ic and II and one for chemotherapy treatment in stages III and IV . One hundred and twenty patients fulfilled criteria for the early stage protocol but only 60 % was r and omised . Three hundred and sixty-one fulfilled criteria for the advanced stages protocol , 73 % was r and omised . In early stages 11 % were excluded because of unavoidable reasons and 29 % because of avoidable reasons . In contrast , in advanced stages 21 % were excluded because of unavoidable reasons and only 6 % because of avoidable reasons . Allocation to the early stage protocol varied with stage , histologic type , residual tumour , and the presence of ascites . These factors had no influence upon allocation to the advanced stages protocol . The experience from this study is : only essential and simple questions should be examined in multicentre trials . Patient accrual and the difference between r and omisation groups are usually overestimated , large scale trials are often required to get statistically significant differences , and the participation of departments only r and omising a small and selected part of their patients is question able |
1,969 | 25,363,192 | Reported grade 3/4 toxicities were regimen-specific and it includes hepatotoxicity , hypertension , and hematologic toxicities . | This systematic review aims at evaluation of the level of evidence for the use of second-line systemic therapy for patients with hepatocellular carcinoma . | PURPOSE We assessed the safety of the multikinase inhibitor regorafenib in patients with hepatocellular carcinoma ( HCC ) that had progressed following first-line sorafenib . PATIENTS AND METHODS Thirty-six patients with Barcelona Clinic Liver Cancer stage B or C HCC and preserved to mildly impaired liver function ( Child-Pugh class A ) received regorafenib 160 mg once daily in cycles of 3 weeks on/1 week off treatment until disease progression , unacceptable toxicity , death or patient/physician decision to discontinue . The primary end-point was safety ; secondary end-points included efficacy ( including time to progression and overall survival ) . RESULTS The median treatment duration was 19.5 weeks ( range 2 - 103 ) . At data cutoff , three patients remained on treatment . Reasons for discontinuation were adverse events ( n=20 ) , disease progression ( n=10 ) , consent withdrawal ( n=2 ) and death ( n=1 ) . Seventeen patients required dose reductions ( mostly for adverse events [ n=15 ] ) ; 35 patients had treatment interruption ( mostly for adverse events [ n=32 ] or patient error [ n=11 ] ) . The most frequent treatment-related adverse events were h and -foot skin reaction ( any grade n=19 ; grade ≥3 n=5 ) , diarrhoea ( n=19 ; n=2 ) , fatigue ( n=19 ; n=6 ) , hypothyroidism ( n=15 ; n=0 ) , anorexia ( n=13 ; n=0 ) , hypertension ( n=13 ; n=1 ) , nausea ( n=12 ; n=0 ) and voice changes ( n=10 ; n=0 ) . Disease control was achieved in 26 patients ( partial response n=1 ; stable disease n=25 ) . Median time to progression was 4.3 months . Median overall survival was 13.8 months . CONCLUSION Regorafenib had acceptable tolerability and evidence of antitumour activity in patients with intermediate or advanced HCC that progressed following first-line sorafenib Summary Background The combination of bevacizumab ( B ) and erlotinib ( E ) has shown promising clinical outcomes as the first-line treatment of advanced HCC patients . We aim ed to evaluate the efficacy and safety of using combination of B + E in treating advanced HCC patients who had failed prior sorafenib treatment . Methods Eligible advanced HCC patients with documented radiological evidence of disease progression with sorafenib treatment were recruited . All patients received bevacizumab(B ) at 10 mg/kg every 2 weeks with erlotinib(E ) at 150 mg daily for a maximum of 6 cycles . Response assessment s using both RECIST and modified RECIST criteria were performed after every 6 weeks . The primary endpoint was clinical benefit ( CB ) rate and a Simon two-stage design was employed . Results The trial was halted in the first stage according to the pre-set statistical criteria with 10 patients recruited . The median age was 47 years ( range , 28–61 ) and all patients were in ECOG performance status 1 . Eighty percent of patients were chronic hepatitis B carriers and all patients had Child A cirrhosis . Among these 10 patients , none of the enrolled patients achieved response or stable disease . The median time-to-progression was 1.81 months ( 95 % confidence interval [ C.I. ] , 1.08–1.74 months ) and overall survival was 4.37 months ( 95 % C.I. , 1.08–11.66 months ) . Rash ( 70 % ) , diarrhea ( 50 % ) and malaise ( 40 % ) were the most commonly encountered toxicities . Conclusion The combination of B + E was well tolerated but had no activity in an unselected sorafenib-refractory advanced HCC population . Condensed abstract The combination of bevacizumab and erlotinib had no clinical activity in sorafenib-refractory HCC population Background : A phase I dose-escalating study of pazopanib was conducted to determine the maximum tolerated dose ( MTD ) , pharmacokinetic/pharmacodynamic relationships , and clinical activity in patients with advanced hepatocellular carcinoma ( HCC ) . Experimental Design : Asian patients ( N = 28 ) were dose escalated on pazopanib ( 200–800 mg ) once daily ( QD ) on 21-day cycles , with MTD as the primary endpoint using a modified 3 + 3 design . Changes in tumor vasculature were evaluated by dynamic contrast-enhanced MRI ( DCE — MRI ) . Results : Two of five patients at the 800-mg dose level experienced dose-limiting toxicities [ grade 3 aspartate aminotransferase (AST)/alanine aminotransferase ( ALT ) elevations and grade 3 malaise ] . The MTD in patients with HCC ( Child – Pugh class A ) was 600 mg QD . Diarrhea , skin hypopigmentation , and AST elevation were the most commonly reported adverse events at the MTD . Mean Cmax and area under the concentration-time curve ( AUC0–6 ) of pazopanib and its metabolites did not increase dose proportionally across the 200 to 800 mg range . Reductions in IAUGC and Ktrans were shown at all pazopanib doses evaluated , with the greatest reductions at 600 and 800 mg . Although larger DCE-MRI parameter decreases were associated with larger C24 and Cmax values , there was no constant relationship between tumor perfusion decreases measured by DCE-MRI and plasma pazopanib pharmacokinetic parameters . Overall , 19 patients ( 73 % ) had either partial response or stable disease . Conclusion : Pazopanib has a manageable safety profile in patients with advanced HCC , and 600 mg was chosen for further development of pazopanib in advanced HCCs . Moreover , pazopanib reduced tumor vessel leakage , as shown by DCE-MRI , indicating a direct effect on HCC vasculature that might be associated with its antitumor activity . Clin Cancer Res ; 17(21 ) ; 6914–23 . © 2011 AACR BACKGROUND Sorafenib has proven survival benefits in patients with advanced hepatocellular carcinoma ( HCC ) . The viability of continuing sorafenib at a higher dosage in patients who experienced radiologic disease progression was investigated . METHODS Patients who experienced disease progression while on sorafenib 400 mg twice daily were r and omized to sorafenib 600 mg twice daily ( n = 49 ) or best supportive care ( n = 52 ) . The primary end point was progression-free survival ( PFS ) . Time to progression , overall survival , and safety were also evaluated . RESULTS The study did not meet its primary end point . The difference in PFS between the sorafenib arm ( 3.91 months ) and the best supportive care arm ( 2.69 months ) did not reach statistical significance ( p = 0.086 ) . Adverse events were mainly grade 1 - 2 and similar across both groups . In the sorafenib arm , the most frequent events were diarrhea ( 80 % ) , weight loss ( 75 % ) , fatigue ( 67 % ) , h and -foot-skin reaction ( 49 % ) , abdominal pain ( 37 % ) , and stomatitis ( 26 % ) . CONCLUSIONS Escalated-dose sorafenib in patients with advanced HCC who progressed while on sorafenib , failed to provide any clinical benefit . Second-line treatment still remains an open issue to be explored in appropriate clinical trials Background : Hepatocellular carcinoma ( HCC ) is a highly vascularised and poor-prognosis tumour . NGR-hTNF is a vascular-targeting agent consisting of human tumour necrosis factor-alpha fused to the tumour-homing peptide NGR , which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels . Methods : Twenty-seven patients with advanced-stage disease resistant to either locoregional ( 59 % ; range , 1–3 ) , systemic treatments ( 52 % ; range , 1–3 ) or both ( 33 % ) received NGR-hTNF 0.8 μg m−2 once every 3 weeks . The primary aim of the study was progression-free survival ( PFS ) . Results : No grade 3–4 treatment-related toxicities were noted . Common toxicity included mild-to-moderate , short-lived chills ( 63 % ) . Median PFS was 2.3 months ( 95 % CI : 1.7–2.9 ) . A complete response ongoing after 20 months was observed in a sorafenib-refractory patient and a partial response in a Child-Pugh class-B patient , yielding a response rate of 7 % . Six patients ( 22 % ) experienced stable disease . The disease control rate ( DCR ) was 30 % and was maintained for a median PFS time of 4.3 months . Median survival was 8.9 months ( 95 % CI : 7.5–10.2 ) . In a subset of 12 sorafenib-resistant patients , the response rate was 8 % and the median survival was 9.5 months . Conclusion : NGR-hTNF was well tolerated and showed single-agent activity in HCC . Further investigation in HCC is of interest Summary Background Sorafenib is the only systemic treatment that has shown a significant benefit in overall survival ( OS ) and in progression-free survival ( PFS ) in advanced hepatocellular carcinoma ( HCC ) patients . No st and ard of care currently exists for second-line treatment . The association of Gemcitabine-Oxaliplatine ( GEMOX ) has shown efficacy in the first-line setting . The aim of this study was to evaluate the efficacy of GEMOX after failure of at least one line of anti-angiogenic ( AA ) therapy . Patient and methods We performed a multicenter retrospective analysis of advanced HCC patients that received GEMOX chemotherapy after progression on at least one line of AA therapy . Results We analyzed a total of 40 patients that received a median of 7 cycles of GEMOX over a 6-year period . Grade 3/4 toxicity was observed in 25 % of patients , mainly neurotoxicity , thrombocytopenia and neutropenia in 12.5 % , 5 % and 5 % of patients respectively . Grade <3 toxicity was mainly hematological and neurotoxicity . In the sub-cohort of 35 patients evaluable for response , partial response was observed in 20 % of patients , while 46 % had stable disease . Median OS was 8.3 months , with a 6-month OS rate of 59 % . Median PFS was 3.1 months . Prognostic factors for OS in univariable analysis were the performance status and AFP levels at GEMOX start , and the BCLC score at diagnosis . None of these factors were prognostic for PFS or tumor response . Conclusion The GEMOX schedule seems to show clinical activity and an acceptable toxicity profile in advanced HCC patients who progressed after anti-angiogenic treatment . The observed median OS of over 8 months is encouraging in this population of heavily pretreated patients . These results would merit confirmation in a prospect i ve r and omized study The classifications of hepatocellular carcinoma ( HCC ) currently used are based on prognostic factors obtained from studies performed years ago when most tumors were diagnosed at advanced stages and the survival rates were substantially poor . Recent investigations have review ed the survival of early tumors properly selected to receive radical therapies and the natural outcome of nonsurgical HCC patients . These data enable a new staging system to be proposed , the Barcelona Clinic Liver Cancer ( BCLC ) staging classification , that comprises four stages that select the best c and i date s for the best therapies currently available . Early stage ( A ) includes patients with asymptomatic early tumors suitable for radical therapies -- resection , transplantation or percutaneous treatments . Intermediate stage ( B ) comprises patients with asymptomatic multinodular HCC . Advanced stage ( C ) includes patients with symptomatic tumors and /or an invasive tumoral pattern ( vascular invasion/extrahepatic spread ) . Stage B and C patients may receive palliative treatments/new agents in the setting of phase II investigations or r and omized controlled trials . End-stage disease ( D ) contain patients with extremely grim prognosis ( Okuda stage III or PST 3 - 4 ) that should merely receive symptomatic treatment Objectives : Hepatocellular carcinoma ( HCC ) is the fifth most common cancer worldwide . Sorafenib is considered the st and ard of care for patients with advanced HCC . Methods : We conducted a retrospective analysis of our cancer center ’s experience with sorafenib in patients with advanced HCC . Eligible patients were required to have measurable disease and were allowed to have been refractory ( with documented progression ) to prior systemic therapies before starting on sorafenib . Results : Twenty-six patients ( median age = 56 years ) who were treated at the Ohio State University with sorafenib were included in this study . Thirty-eight percent had exposure to prior systemic therapy . The median time to tumor progression was 5.4 months and the median overall survival 7 months . For the patients with exposure to prior systemic therapy , the median time to tumor progression was 9.1 months and is the median overall survival 9.83 months . There were no unexpected toxicities . Conclusion : Sorafenib has interesting activity and acceptable tolerability in patients with advanced HCC , including those who failed prior therapies Second‐line treatment options in advanced hepatocellular carcinoma ( HCC ) are limited . Axitinib , a selective potent tyrosine kinase inhibitor ( TKI ) of vascular endothelial growth factor VEGF ) receptors 1 , 2 , and 3 , merits exploration in HCC PURPOSE Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma ( HCC ) . An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who can not tolerate it . This multicenter , double-blind , r and omized , placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib . PATIENTS AND METHODS In all , 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were r and omly assigned ( 2:1 ) to receive brivanib 800 mg orally once per day plus best supportive care ( BSC ) or placebo plus BSC . The primary end point was overall survival ( OS ) . Secondary end points included time to progression ( TTP ) , objective response rate ( ORR ) , and disease control rate based on modified Response Evaluation Criteria in Solid Tumors ( mRECIST ) and safety . RESULTS Median OS was 9.4 months for brivanib and 8.2 months for placebo ( hazard ratio [ HR ] , 0.89 ; 95.8 % CI , 0.69 to 1.15 ; P = .3307 ) . Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 ( 95 % CI , 0.63 to 1.04 ; P = .1044 ) . Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo ( HR , 0.56 ; 95 % CI , 0.42 to 0.76 ; P < .001 ) , and an mRECIST ORR of 10 % for brivanib and 2 % for placebo ( odds ratio , 5.72 ) . Study discontinuation due to treatment-related adverse events ( AEs ) occurred in 61 brivanib patients ( 23 % ) and nine placebo patients ( 7 % ) . The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension ( 17 % ) , fatigue ( 13 % ) , hyponatremia ( 11 % ) , and decreased appetite ( 10 % ) . CONCLUSION In patients with HCC who had been treated with sorafenib , brivanib did not significantly improve OS . The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation Purpose : Brivanib , a selective dual inhibitor of fibroblast growth factor and VEGF signaling , has recently been shown to have activity as first-line treatment for patients with advanced hepatocellular carcinoma ( HCC ) . This phase II open-label study assessed brivanib as second-line therapy in patients with advanced HCC who had failed prior antiangiogenic treatment . Experimental Design : Brivanib was administered orally at a dose of 800 mg once daily . The primary objectives were tumor response rate , time to response , duration of response , progression-free survival , overall survival ( OS ) , disease control rate , time to progression ( TTP ) , and safety and tolerability . Results : Forty-six patients were treated . Best responses to treatment with brivanib ( N = 46 patients ) using modified World Health Organization criteria were partial responses for two patients ( 4.3 % ) , stable disease for 19 patients ( 41.3 % ) , and progressive disease for 19 patients ( 41.3 % ) . The tumor response rate was 4.3 % ; the disease control rate was 45.7 % . Median OS was 9.79 months . Median TTP as assessed by study investigators following second-line treatment with brivanib was 2.7 months . The most common adverse events were fatigue , decreased appetite , nausea , diarrhea , and hypertension . Conclusion : Brivanib had a manageable safety profile and is one of the first agents to show promising antitumor activity in advanced HCC patients treated with prior sorafenib . Clin Cancer Res ; 18(7 ) ; 2090–8 . © 2012 AACR The oncologic community is faced with a steady increase in the incidence of hepatocellular carcinoma ( HCC ) [ 1 ] . Liver cancer represents the sixth most common cancer in the world ( 749 000 new cases ) and the third cause of cancer-related death ( 692 000 cases ) . The incidence varies from 3 out of 100 000 in Western countries , to more than 15 out of 100 000 in certain areas of the world , mapping the geographical distribution of viral hepatitis B ( HBV ) and hepatitis C ( HCV ) , the most important causes of chronic liver disease and HCC [ 2 ] . Most cases arise in those regions with limited re sources . The incidence of HCC increases progressively with advancing age in all population s , with a strong male preponderance . The association of chronic liver disease and HCC represents the basis for preventive strategies , including universal vaccination at birth against hepatitis B , programs to stop transmission and early antiviral eradication of viral hepatitis B and C [ III , A ] . It is unclear whether HBV vaccination will result in a decline in HCC as was seen in Taiwan , given the importance of other risk factors in Europe , such as alcoholic and non-alcoholic fatty liver disease . The control of other risk factors for chronic liver disease and cancer is more difficult to implement , such as cutting down on the consumption of alcohol and programs aim ing at a healthier lifestyle in the light of the obesity p and emic [ 3 , 4 ] . In Africa , reduction of exposure to aflatoxin B1 , especially in HBV-infected individuals , may lower the risk of HCC . HCC may evolve from subclasses of adenomas , and in < 10 % of cases HCC occurs in a normal liver . Surveillance of HCC involves the repeated application of screening tools in patients at risk for HCC and aims for the reduction in mortality of this patient population . The success of surveillance is influenced by the incidence of HCC in the target population , the availability and acceptance of efficient diagnostic tests and the availability of effective treatment . Costeffectiveness studies suggest surveillance of HCC is warranted in cirrhotic patients irrespective of its etiology [ 5 ] . Surveillance of non-cirrhotic patients is also advocated , especially in HBV carriers with serum viral load > 10 000 copies/ml [ 6 ] or HCVinfected patients with bridging fibrosis ( F3 ) [ III , A ] . Patients with HCV infection and advanced fibrosis remain at risk for HCC even after achieving sustained virological response following antiviral treatment [ III , A ] . Japanese cohort studies have shown that surveillance by abdominal ultrasound result ed in an average size of the detected tumors of 1.6 ± 0.6 cm , with < 2 % of the cases exceeding 3 cm [ 7 ] . In the Western world and in less experienced centers , sensitivity of finding early-stage HCC by ultrasound is considerably less effective [ 8 ] . There are no data to support the use of contrast-enhanced computed tomography ( CT ) or magnetic resonance imaging ( MRI ) for surveillance . In many centers , ultrasound surveillance is complemented with the determination of serum alphafetoprotein ( AFP ) , which can lead to a 6%–8 % gain in the tumor detection rate but at the price of false-positive results . A r and omized , controlled trial ( RCT ) of Chinese patients with chronic hepatitis B infection compared surveillance ( ultrasound and serum AFP measurements every 6 months ) versus no surveillance [ 9 ] . Despite low compliance with the surveillance program ( 55 % ) , HCC-related mortality was reduced by 37 % in the surveillance arm . Considering the most appropriate surveillance interval , a r and omized study comparing a 3versus 6-month based schedule failed to detect any differences [ 10 ] . Therefore , surveillance of patients at risk for HCC should be carried out by abdominal ultrasound every 6 months [ I , A ] BACKGROUND Most cases of hepatocellular carcinoma occur in the Asia-Pacific region , where chronic hepatitis B infection is an important aetiological factor . Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important . We did a multinational phase III , r and omised , double-blind , placebo-controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced ( unresectable or metastatic ) hepatocellular carcinoma . METHODS Between Sept 20 , 2005 , and Jan 31 , 2007 , patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A , were r and omly assigned to receive either oral sorafenib ( 400 mg ) or placebo twice daily in 6-week cycles , with efficacy measured at the end of each 6-week period . Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread ( or both ) , Eastern Cooperative Oncology Group performance status , and geographical region . R and omisation was done central ly and in a 2:1 ratio by means of an interactive voice-response system . There was no predefined primary endpoint ; overall survival , time to progression ( TTP ) , time to symptomatic progression ( TTSP ) , disease control rate ( DCR ) , and safety were assessed . Efficacy analyses were done by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00492752 . FINDINGS 271 patients from 23 centres in China , South Korea , and Taiwan were enrolled in the study . Of these , 226 patients were r and omly assigned to the experimental group ( n=150 ) or to the placebo group ( n=76 ) . Median overall survival was 6.5 months ( 95 % CI 5.56 - 7.56 ) in patients treated with sorafenib , compared with 4.2 months ( 3.75 - 5.46 ) in those who received placebo ( hazard ratio [ HR ] 0.68 [ 95 % CI 0.50 - 0.93 ] ; p=0.014 ) . Median TTP was 2.8 months ( 2.63 - 3.58 ) in the sorafenib group compared with 1.4 months ( 1.35 - 1.55 ) in the placebo group ( HR 0.57 [ 0.42 - 0.79 ] ; p=0.0005 ) . The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were h and -foot skin reaction ( HFSR ; 16 patients [ 10.7 % ] ) , diarrhoea ( nine patients [ 6.0 % ] ) , and fatigue ( five patients [ 3.4 % ] ) . The most common adverse events result ing in dose reductions were HFSR ( 17 patients [ 11.4 % ] ) and diarrhoea ( 11 patients [ 7.4 % ] ) ; these adverse events rarely led to discontinuation . INTERPRETATION Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region , and is well tolerated . Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment R and omised Protocol ( SHARP ) trial , sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma BACKGROUND Tivantinib ( ARQ 197 ) , a selective oral inhibitor of MET , has shown promising antitumour activity in hepatocellular carcinoma as monotherapy and in combination with sorafenib . We aim ed to assess efficacy and safety of tivantinib for second-line treatment of advanced hepatocellular carcinoma . METHODS In this completed , multicentre , r and omised , placebo-controlled , double-blind , phase 2 study , we enrolled patients with advanced hepatocellular carcinoma and Child-Pugh A cirrhosis who had progressed on or were unable to tolerate first-line systemic therapy . We r and omly allocated patients 2:1 to receive tivantinib ( 360 mg twice-daily ) or placebo until disease progression . The tivantinib dose was amended to 240 mg twice-daily because of high incidence of treatment-emergent grade 3 or worse neutropenia . R and omisation was done central ly by an interactive voice-response system , stratified by Eastern Cooperative Oncology Group performance status and vascular invasion . The primary endpoint was time to progression , according to independent radiological review in the intention-to-treat population . We assessed tumour sample s for MET expression with immunohistochemistry ( high expression was regarded as ≥2 + in ≥50 % of tumour cells ) . This study is registered with Clinical Trials.gov , number NCT00988741 . FINDINGS 71 patients were r and omly assigned to receive tivantinib ( 38 at 360 mg twice-daily and 33 at 240 mg twice-daily ) ; 36 patients were r and omly assigned to receive placebo . At the time of analysis , 46 ( 65 % ) patients in the tivantinib group and 26 ( 72 % ) of those in the placebo group had progressive disease . Time to progression was longer for patients treated with tivantinib ( 1·6 months [ 95 % CI 1·4 - 2·8 ] ) than placebo ( 1·4 months [ 1·4 - 1·5 ] ; hazard ratio [ HR ] 0·64 , 90 % CI 0·43 - 0·94 ; p=0·04 ) . For patients with MET-high tumours , median time to progression was longer with tivantinib than for those on placebo ( 2·7 months [ 95 % CI 1·4 - 8·5 ] for 22 MET-high patients on tivantinib vs 1·4 months [ 1·4 - 1·6 ] for 15 MET-high patients on placebo ; HR 0·43 , 95 % CI 0·19 - 0·97 ; p=0·03 ) . The most common grade 3 or worse adverse events in the tivantinib group were neutropenia ( ten patients [ 14 % ] vs none in the placebo group ) and anaemia ( eight [ 11 % ] vs none in the placebo group ) . Eight patients ( 21 % ) in the tivantinib 360 mg group had grade 3 or worse neutropenia compared with two ( 6 % ) patients in the 240 mg group . Four deaths related to tivantinib occurred from severe neutropenia . 24 ( 34 % ) patients in the tivantinib group and 14 ( 39 % ) patients in the placebo group had serious adverse events . INTERPRETATION Tivantinib could provide an option for second-line treatment of patients with advanced hepatocellular carcinoma and well-compensated liver cirrhosis , particularly for patients with MET-high tumours . Confirmation in a phase 3 trial is needed , with a starting dose of tivantinib 240 mg twice-daily . FUNDING ArQule , Daiichi Sankyo ( Daiichi Sankyo Group ) Purpose : To assess the activity and toxicity of lenalidomide for patients with advanced hepatocellular cancer ( HCC ) previously treated with sorafenib . Material s and Methods : Patients with advanced HCC who progressed on or were intolerant to sorafenib were eligible . Patients received lenalidomide 25 mg orally for 1 to 21 days in a 28-day cycle until disease progression or unacceptable toxicities . Results : Forty patients were enrolled and were classified according to the Child-Pugh score : 19 were Child-Pugh A , 16 patients were Child-Pugh B , and 5 were Child-Pugh C. Seventeen patients had extrahepatic disease . Grade 4 neutropenia occurred in 1 of 40 patients ( 2.5 % ) . Grade 3 fatigue ( n=3 ) and rash ( n=4 ) were the most common nonhematologic toxicities attributable to lenalidomide . Six of 40 patients ( 15 % ) had a partial response . Two patients ( 5 % ) have not progressed at 36 and 32 months . The median progression-free survival was 3.6 months and the median overall survival was 7.6 months . Conclusions : Lenalidomide can be administered to patients with advanced HCC and hepatic dysfunction . Promising , and in a small percentage of patients , durable activity has been demonstrated . Investigations are needed to explore the mechanism of action of lenalidomide in HCC IMPORTANCE Aside from the multikinase inhibitor sorafenib , there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma . OBJECTIVE To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed . DESIGN , SETTING , AND PARTICIPANTS EVOLVE-1 was a r and omized , double-blind , phase 3 study conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were intolerant of sorafenib . Patients were enrolled from 17 countries between May 2010 and March 2012 . R and omization was stratified by region ( Asia vs rest of world ) and macrovascular invasion ( present vs absent ) . INTERVENTIONS Everolimus , 7.5 mg/d , or matching placebo , both given in combination with best supportive care and continued until disease progression or intolerable toxicity . Per the 2:1 r and omization scheme , 362 patients were r and omized to the everolimus group and 184 patients to the placebo group . MAIN OUTCOMES AND MEASURES The primary end point was overall survival . Secondary end points included time to progression and the disease control rate ( the percentage of patients with a best overall response of complete or partial response or stable disease ) . RESULTS No significant difference in overall survival was seen between treatment groups , with 303 deaths ( 83.7 % ) in the everolimus group and 151 deaths ( 82.1 % ) in the placebo group ( hazard ratio [ HR ] , 1.05 ; 95 % CI , 0.86 - 1.27 ; P = .68 ; median overall survival , 7.6 months with everolimus , 7.3 months with placebo ) . Median time to progression with everolimus and placebo was 3.0 months and 2.6 months , respectively ( HR , 0.93 ; 95 % CI , 0.75 - 1.15 ) , and disease control rate was 56.1 % and 45.1 % , respectively ( P = .01 ) . The most common grade 3/4 adverse events for everolimus vs placebo were anemia ( 7.8 % vs 3.3 % , respectively ) , asthenia ( 7.8 % vs 5.5 % , respectively ) , and decreased appetite ( 6.1 % vs 0.5 % , respectively ) . No patients experienced hepatitis C viral flare . Based on central laboratory results , hepatitis B viral reactivation was experienced by 39 patients ( 29 everolimus , 10 placebo ) ; all cases were asymptomatic , but 3 everolimus recipients discontinued therapy . CONCLUSIONS AND RELEVANCE Everolimus did not improve overall survival in patients with advanced hepatocellular carcinoma whose disease progressed during or after receiving sorafenib or who were intolerant of sorafenib . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01035229 UNLABELLED Sorafenib improves overall survival ( OS ) of patients with hepatocellular carcinoma ( HCC ) in the absence of objective response . Thus , time to tumor progression ( TTP ) is used to capture benefits of novel molecular agents , but proof of its surrogacy with survival is lacking . Furthermore , survival predictors upon progression are not established and there is a need to characterize postprogression survival ( PPS ) and assess with time-dependent covariates analysis if it is influenced by progression pattern , and not solely by simultaneous impairment of liver function and performance status . We prospect ively followed HCC patients treated with sorafenib . Clinical and biochemical evaluation were done every 4 weeks . Radiologic assessment of progression was done at week 4 and then every 8 weeks using RECIST 1.1 . The progression pattern was divided into : intrahepatic/extrahepatic increase in tumor size , new intrahepatic lesion , and new extrahepatic lesion ( NEH ) . We included 147 patients ( hepatitis C virus [ HCV ] 57.1 % , performance status [ PS ] 0 83.6 % , Child-Pugh A 82.3 % , and BCLC-C 47.3 % ) . The median OS was 12.7 months and its independent predictors ( hazard ratio [ HR ] , 95 % confidence interval [ CI ] ) were : baseline BCLC 2.49 [ 1.66 - 3.73 ] , PS 1.86 [ 1.12 - 3.10 ] , registration during follow-up of Child-Pugh B or Child-Pugh C scores ( 2.36 [ 1.51 - 3.69 ] and 2.89 [ 1.62 - 5.15 ] , respectively ) , definitive sorafenib interruption 2.48 [ 1.54 - 4.01 ] , and TTP 3.39 [ 1.89 - 6.1 ] . The presence of NEH 2.42 [ 1.32 - 4.44 ] is also an independent predictor of OS and PPS in patients with radiologic progression . CONCLUSION Tumor progression is a surrogate of survival but its impact varies according to progression pattern . Thus , PPS is influenced by progression pattern and this is key in prognostic prediction and second-line trial design and analysis BACKGROUND & AIMS The Sorafenib Hepatocellular Carcinoma ( HCC ) Assessment R and omized Protocol ( SHARP ) trial demonstrated that sorafenib improves overall survival and is safe for patients with advanced HCC . In this trial , 602 patients with well-preserved liver function ( > 95 % Child-Pugh A ) were r and omized to receive either sorafenib 400 mg or matching placebo orally b.i.d . on a continuous basis . Because HCC is a heterogeneous disease , baseline patient characteristics may affect individual responses to treatment . In a comprehensive series of exploratory subgroup analyses , data from the SHARP trial were analyzed to discern if baseline patient characteristics influenced the efficacy and safety of sorafenib . METHODS Five subgroup domains were assessed : disease etiology , tumor burden , performance status , tumor stage , and prior therapy . Overall survival ( OS ) , time to progression ( TTP ) , disease control rate ( DCR ) , and safety were assessed for subgroups within each domain . RESULTS Subgroup analyses showed that sorafenib consistently improved median OS compared with placebo , as reflected by hazard ratios ( HRs ) of 0.50 - 0.85 , similar to the complete cohort ( HR=0.69 ) . Sorafenib also consistently improved median TTP ( HR , 0.40 - 0.64 ) , except in HBV-positive patients ( HR , 1.03 ) , and DCR . Results are limited by small patient numbers in some subsets . The most common grade 3/4 adverse events included diarrhea , h and -foot skin reaction , and fatigue ; the incidence of which did not differ appreciably among subgroups . CONCLUSIONS These exploratory subgroup analyses showed that sorafenib consistently improved median OS and DCR compared with placebo in patients with advanced HCC , irrespective of disease etiology , baseline tumor burden , performance status , tumor stage , and prior therapy BACKGROUND & AIMS No approved therapy is available for patients with advanced hepatocellular carcinoma ( HCC ) who fail first-line therapy . The prognosis of these patients , especially those eligible for clinical trials of second-line therapy , is unclear . METHODS All patients who participated in clinical trials of first-line systemic therapy for metastatic or locally advanced HCC in a referral center of Taiwan between 2005 and 2011 were included . Their clinicopathologic characteristics , when the first-line treatment failed , were analyzed and correlated with the overall survival ( OS ) from the date of first-line treatment failure . RESULTS A total of 192 patients were included . Before the start of the first-line therapy , all patients had Child-Pugh class A liver reserves and Cancer of the Liver Italian Program ( CLIP ) scores ≤4 . After the failure of the first-line therapy , the median OS of the entire group was 4.0 months . Patients with Child-Pugh class A liver reserves , when the first-line treatment failed , had significantly better OS than patients with Child-Pugh class B or C liver reserves ( median , A vs. B vs. C=7.5 vs. 1.3 vs. 1.0 month , p<0.001 ) . According to the key eligibility criteria of 3 published clinical trials for second-line therapy , 41%-56 % of patients were potentially eligible . Compared to patients who were ineligible for clinical trials , potentially eligible patients had longer OS with a median of 7.8 - 8.6 months . CONCLUSIONS Patients with advanced HCC who failed first-line therapy could have substantially improved prognosis if they had Child-Pugh A liver reserves or were potentially eligible for clinical trials |
1,970 | 31,369,575 | Conclusions Despite an increase in cholesterol levels , TCZ has safe cardiovascular outcomes compared to other bDMARD | Objectives Our objective was to compare the cardiovascular safety of tocilizumab and other biological disease-modifying antirheumatic drugs ( bDMARD ) in rheumatoid arthritis using a network meta- analysis ( NMA ) . | Introduction The objective of this study was to directly compare the safety of tocilizumab ( TCZ ) and TNF inhibitors ( TNFIs ) in rheumatoid arthritis ( RA ) patients in clinical practice . Methods This prospect i ve cohort study included RA patients starting TCZ [ TCZ group , n = 302 , 224.68 patient-years ( PY ) ] or TNFIs [ TNFI group , n = 304 , 231.01 PY ] from 2008 to 2011 in the registry of Japanese RA patients on biologics for long-term safety registry . We assessed types and incidence rates ( IRs ) of serious adverse events ( SAEs ) and serious infections ( SIs ) during the first year of treatment . Risks of the biologics for SAEs or SIs were calculated using the Cox regression hazard analysis . Results Patients in the TCZ group had longer disease duration ( P < 0.001 ) , higher disease activity ( P = 0.019 ) and more frequently used concomitant corticosteroids ( P < 0.001 ) than those in the TNFI group . The crude IR ( /100 PY ) of SIs [ TCZ 10.68 vs. TNFI 3.03 ; IR ratio ( 95 % confidence interval [ CI ] ) , 3.53 ( 1.52 to 8.18 ) ] , but not SAEs [ 21.36 vs. 14.72 ; 1.45 ( 0.94 to 2.25 ) ] , was significantly higher in the TCZ group compared with the TNFI group . However , after adjusting for covariates using the Cox regression hazard analysis , treatment with TCZ was not associated with higher risk for SAEs [ hazard ratio ( HR ) 1.28 , 95 % CI 0.75 to 2.19 ] or SIs ( HR 2.23 , 95 % CI 0.93 to 5.37 ) . Conclusions The adjusted risks for SAEs and SIs were not significantly different between TCZ and TNFIs , indicating an influence of clinical characteristics of the patients on the safety profile of the biologics in clinical practice CONTEXT High levels of lipoprotein(a ) are associated with increased risk of myocardial infa rct ion ( MI ) . OBJECTIVE To assess whether genetic data are consistent with this association being causal . DESIGN , SETTING , AND PARTICIPANTS Three studies of white individuals from Copenhagen , Denmark , were used : the Copenhagen City Heart Study ( CCHS ) , a prospect i ve general population study with 16 years of follow-up ( 1991 - 2007 , n = 8637 , 599 MI events ) ; the Copenhagen General Population Study ( CGPS ) , a cross-sectional general population study ( 2003 - 2006 , n = 29 388 , 994 MI events ) ; and the Copenhagen Ischemic Heart Disease Study ( CIHDS ) , a case-control study ( 1991 - 2004 , n = 2461 , 1231 MI events ) . MAIN OUTCOME MEASURES Plasma lipoprotein(a ) levels , lipoprotein(a ) kringle IV type 2 ( KIV-2 ) size polymorphism genotype , and MIs recorded from 1976 through July 2007 for all participants . RESULTS In the CCHS , multivariable-adjusted hazard ratios ( HRs ) for MI for elevated lipoprotein(a ) levels were 1.2 ( 95 % confidence interval [ CI ] , 0.9 - 1.6 ; events/10,000 person-years , 59 ) for levels between the 22nd and 66th percentile , 1.6 ( 95 % CI , 1.1 - 2.2 ; events/10,000 person-years , 75 ) for the 67th to 89th percentile , 1.9 ( 95 % CI , 1.2 - 3.0 ; events/10,000 person-years , 84 ) for the 90th to 95th percentile , and 2.6 ( 95 % CI , 1.6 - 4.1 ; events/10,000 person-years , 108 ) for levels greater than the 95th percentile , respectively , vs levels less than the 22nd percentile ( events/10,000 person-years , 55 ) ( trend P < .001 ) . Numbers of KIV-2 repeats ( sum of repeats on both alleles ) ranged from 6 to 99 and on analysis of variance explained 21 % and 27 % of all variation in plasma lipoprotein(a ) levels in the CCHS and CGPS , respectively . Mean lipoprotein(a ) levels were 56 , 31 , 20 , and 15 mg/dL for the first , second , third , and fourth quartiles of KIV-2 repeats in the CCHS , respectively ( trend P < .001 ) ; corresponding values in the CGPS were 60 , 34 , 22 , and 19 mg/dL ( trend P < .001 ) . In the CCHS , multivariable-adjusted HRs for MI were 1.5 ( 95 % CI , 1.2 - 1.9 ; events/10,000 person-years , 75 ) , 1.3 ( 95 % CI , 1.0 - 1.6 ; events/10,000 person-years , 66 ) , and 1.1 ( 95 % CI , 0.9 - 1.4 ; events/10,000 person-years , 57 ) for individuals in the first , second , and third quartiles , respectively , as compared with individuals in the fourth quartile of KIV-2 repeats ( events/10,000 person-years , 51 ) ( trend P < .001 ) . Corresponding odds ratios were 1.3 ( 95 % CI , 1.1 - 1.5 ) , 1.1 ( 95 % CI , 0.9 - 1.3 ) , and 0.9 ( 95 % CI , 0.8 - 1.1 ) in the CGPS ( trend P = .005 ) , and 1.4 ( 95 % CI , 1.1 - 1.7 ) , 1.2 ( 95 % CI , 1.0 - 1.6 ) , and 1.3 ( 95 % CI , 1.0 - 1.6 ) in the CIHDS ( trend P = .01 ) . Genetically elevated lipoprotein(a ) was associated with an HR of 1.22 ( 95 % CI , 1.09 - 1.37 ) per doubling of lipoprotein(a ) level on instrumental variable analysis , while the corresponding value for plasma lipoprotein(a ) levels on Cox regression was 1.08 ( 95 % CI , 1.03 - 1.12 ) . CONCLUSION These data are consistent with a causal association between elevated lipoprotein(a ) levels and increased risk of MI BACKGROUND To date , head-to-head trials comparing the efficacy and safety of biological disease-modifying antirheumatic drugs within the same class , including TNF inhibitors , in patients with active rheumatoid arthritis despite methotrexate therapy are lacking . We aim ed to compare the efficacy and safety of two different TNF inhibitors and to assess the efficacy and safety of switching to the other TNF inhibitor without a washout period after insufficient primary response to the first TNF inhibitor at week 12 . METHODS In this 104-week , r and omised , single-blind ( double-blind until week 12 and investigator blind thereafter ) , parallel-group , head-to-head superiority study ( EXXELERATE ) , eligible patients from 151 centres worldwide were aged 18 years or older with a diagnosis of rheumatoid arthritis at screening , as defined by the 2010 ACR/EULAR criteria , and had prognostic factors for severe disease progression , including a positive rheumatoid factor , or anti-cyclic citrullinated peptide antibody result , or both . Participants were r and omly assigned ( 1:1 ) via an interactive voice and web response system with no stratification to receive certolizumab pegol plus methotrexate or adalimumab plus methotrexate . All study staff were kept masked throughout the study and participants were masked until week 12 . At week 12 , patients were classified as responders ( by either achieving low disease activity [ LDA ] according to Disease Activity Score 28-erythrocyte sedimentation rate [ DAS28-ESR ] ≤3·2 or DAS28-ESR reduction ≥1·2 from baseline ) or as non-responders . Non-responders to the first TNF inhibitor to which they were r and omised were switched to the other TNF inhibitor with no washout period . Primary endpoints were the percentage of patients achieving a 20 % improvement according to the American College of Rheumatology criteria ( ACR20 ) at week 12 and LDA at week 104 ( week 12 non-responders were considered LDA non-responders ) . This study is registered with Clinical Trials.gov , number NCT01500278 . FINDINGS Between Dec 14 , 2011 , and Nov 11 , 2013 , 1488 patients were screened of whom 915 were r and omly assigned ; 457 to certolizumab pegol plus methotrexate and 458 to adalimumab plus methotrexate . No statistically significant difference was observed in ACR20 response at week 12 ( 314 [ 69 % ] of 454 patients and 324 [ 71 % ] of 454 patients ; odds ratio [ OR ] 0·90 [ 95 % CI 0·67 - 1·20 ] ; p=0·467 ) or DAS28-ESR LDA at week 104 ( 161 [ 35 % ] of 454 patients and 152 [ 33 % ] of 454 patients ; OR 1·09 [ 0·82 - 1·45 ] ; p=0·532 ) between certolizumab pegol plus methotrexate and adalimumab plus methotrexate , respectively . At week 12 , 65 non-responders to certolizumab pegol were switched to adalimumab and 57 non-responders to adalimumab were switched to certolizumab pegol ; 33 ( 58 % ) of 57 patients switching to certolizumab pegol and 40 ( 62 % ) of 65 patients switching to adalimumab responded 12 weeks later by achieving LDA or a DAS28-ESR reduction 1·2 or greater . 389 [ 75 % ] of 516 patients who received certolizumab pegol plus methotrexate and 386 [ 74 % ] of 523 patients who received adalimumab plus methotrexate reported treatment-emergent adverse events . Three deaths ( 1 % ) occurred in each group . No serious infection events were reported in the 70-day period after treatment switch . INTERPRETATION These results show that certolizumab pegol plus methotrexate is not superior to adalimumab plus methotrexate . The data also show the clinical benefit and safety of switching to a second TNF inhibitor without a washout period after primary failure to a first TNF inhibitor . FUNDING UCB Pharma Objectives The interleukin-6 receptor ( IL-6R ) blocker tocilizumab ( TCZ ) reduces inflammatory disease activity in rheumatoid arthritis ( RA ) but elevates lipid concentrations in some patients . We aim ed to characterise the impact of IL-6R inhibition on established and novel risk factors in active RA . Methods R and omised , multicentre , two-part , phase III trial ( 24-week double-blind , 80-week open-label ) , MEASURE , evaluated lipid and lipoprotein levels , high-density lipoprotein ( HDL ) particle composition , markers of coagulation , thrombosis and vascular function by pulse wave velocity ( PWV ) in 132 patients with RA who received TCZ or placebo . Results Median total-cholesterol , low-density lipoprotein-cholesterol ( LDL-C ) and triglyceride levels increased in TCZ versus placebo recipients by week 12 ( 12.6 % vs 1.7 % , 28.1 % vs 2.2 % , 10.6 % vs −1.9 % , respectively ; all p<0.01 ) . There were no significant differences in mean small LDL , mean oxidised LDL or total HDL-C concentrations . However , HDL-associated serum amyloid A content decreased in TCZ recipients . TCZ also induced reductions ( > 30 % ) in secretory phospholipase A2-IIA , lipoprotein(a ) , fibrinogen and D-dimers and elevation of paraoxonase ( all p<0.0001 vs placebo ) . The ApoB/ApoA1 ratio remained stable over time in both groups . PWV decreases were greater with placebo than TCZ at 12 weeks ( adjusted mean difference 0.79 m/s ( 95 % CI 0.22 to 1.35 ; p=0.0067 ) ) . Conclusions These data provide the first detailed evidence for the modulation of lipoprotein particles and other surrogates of vascular risk with IL-6R inhibition . When compared with placebo , TCZ induced elevations in LDL-C but altered HDL particles towards an anti-inflammatory composition and favourably modified most , but not all , measured vascular risk surrogates . The net effect of such changes for cardiovascular risk requires determination BACKGROUND Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses . Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis . METHODS In this double-blind , r and omised , placebo-controlled , parallel group phase III study , 623 patients with moderate to severe active rheumatoid arthritis were r and omly assigned with an interactive voice response system , stratified by site with a r and omisation list provided by the study sponsor , to receive tocilizumab 8 mg/kg ( n=205 ) , tocilizumab 4 mg/kg ( 214 ) , or placebo ( 204 ) intravenously every 4 weeks , with methotrexate at stable pre- study doses ( 10 - 25 mg/week ) . Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20 % improvement in both swollen and tender joint counts . The primary endpoint was the proportion of patients with 20 % improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria ( ACR20 response ) at week 24 . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00106548 . FINDINGS The intention-to-treat analysis population consisted of 622 patients : one patient in the 4 mg/kg group did not receive study treatment and was thus excluded . At 24 weeks , ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo ( 120 [ 59 % ] patients in the 8 mg/kg group , 102 [ 48 % ] in the 4 mg/kg group , 54 [ 26 % ] in the placebo group ; odds ratio 4.0 [ 95 % CI 2.6 - 6.1 ] , p<0.0001 for 8 mg/kg vs placebo ; and 2.6 [ 1.7 - 3.9 ] , p<0.0001 for 4 mg/kg vs placebo ) . More people receiving tocilizumab than those receiving placebo had at least one adverse event ( 143 [ 69 % ] in the 8 mg/kg group ; 151 [ 71 % ] in the 4 mg/kg group ; 129 [ 63 % ] in the placebo group ) . The most common serious adverse events were serious infections or infestations , reported by six patients in the 8 mg/kg group , three in the 4 mg/kg group , and two in the placebo group . INTERPRETATION Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis . FUNDING F Hoffmann-La Roche , Chugai Pharmaceutical Objective Investigate whether the efficacy and safety of intravenous tocilizumab ( TCZ ) demonstrated at week 52 in patients with early rheumatoid arthritis ( RA ) are maintained to week 104 . Methods Methotrexate (MTX)-naive patients with early progressive RA were r and omly assigned to double-blind 4 mg/kg TCZ+MTX , 8 mg/kg TCZ+MTX , 8 mg/kg TCZ+placebo or placebo+MTX for 104 weeks . Patients not receiving 8 mg/kg TCZ and not achieving Disease Activity Score-28 joints ( DAS28-erythrocyte sedimentation rate ( ESR ) ) ≤3.2 at week 52 switched to escape therapy ( 8 mg/kg TCZ+MTX ) . Analyses were exploratory . Results Intent-to-treat and safety population s included 1157 and 1153 patients , respectively . DAS28-ESR remission ( < 2.6 ) rates were maintained from weeks 52 to 104 ( eg , 8 mg/kg TCZ+MTX , 49.3 % to 47.6 % ) . Placebo+MTX and 4 mg/kg TCZ+MTX escape patients ' week 104 response rates were 51.4 % and 30.5 % , respectively . Inhibition of radiographic progression was maintained with 8 mg/kg TCZ ( eg , 8 mg/kg TCZ+MTX mean ( SD ) change from baseline in modified total Sharp score : 0.13 ( 1.28 ) , week 52 ; 0.19 ( 2.08 ) , week 104 ) . The safety profile of TCZ was consistent with that of previous reports . Conclusions Patients with early RA treated with TCZ monotherapy or TCZ+MTX maintained clinical benefits during their second year of treatment with no new safety signals . Trial registration number : NCT01007435 ; Results Background Atherosclerosis is a chronic inflammatory disease , with interleukin 6 ( IL‐6 ) as a major player in inflammation cascade . IL‐6 blockade may reduce cardiovascular risk , but current treatments to block IL‐6 also induce dyslipidemia , a finding with an uncertain prognosis . Methods and Results We aim ed to determine the endothelial function responses to the IL‐6–blocking agent tocilizumab , anti – tumor necrosis factor α , and synthetic disease‐modifying antirheumatic drug therapies in patients with rheumatoid arthritis in a 16‐week prospect i ve study . Sixty consecutive patients with rheumatoid arthritis were enrolled . Tocilizumab and anti – tumor necrosis factor α therapy were started in 18 patients each while 24 patients were treated with synthetic disease‐modifying antirheumatic drugs . Forty patients completed the 16‐week follow‐up period . The main outcome was flow‐mediated dilation percentage variation before and after therapy . In the tocilizumab group , flow‐mediated dilation percentage variation increased statistically significantly from a pre‐treatment mean of ( 3.43 % [ 95 % CI , 1.28–5.58 ] to 5.96 % [ 95 % CI , 3.95–7.97 ] ; P=0.03 ) . Corresponding changes were 4.78 % ( 95 % CI , 2.13–7.42 ) to 6.75 % ( 95 % CI , 4.10–9.39 ) ( P=0.09 ) and 2.87 % ( 95 % CI , −2.17 to 7.91 ) to 4.84 % ( 95 % CI , 2.61–7.07 ) ( P=0.21 ) in the anti – tumor necrosis factor α and the synthetic disease‐modifying antirheumatic drug groups , respectively ( both not statistically significant ) . Total cholesterol increased significantly in the tocilizumab group from 197.5 ( 95 % CI , 177.59–217.36 ) to 232.3 ( 201.62–263.09 ) ( P=0.003 ) and in the synthetic disease‐modifying antirheumatic drug group from 185.8 ( 95 % CI , 169.76–201.81 ) to 202.8 ( 95 % CI , 176.81–228.76 ) ( P=0.04 ) , but not in the anti – tumor necrosis factor α group . High‐density lipoprotein did not change significantly in any group . Conclusions Endothelial function is improved by tocilizumab in a high‐risk population , even as it increases total cholesterol and low‐density lipoprotein levels Objective Compare changes in lipids and lipid-associated cardiovascular ( CV ) risk markers in patients with rheumatoid arthritis ( RA ) treated with tocilizumab or adalimumab . Methods Post-hoc analysis was performed in patients with RA who received tocilizumab intravenously every 4 weeks or adalimumab subcutaneously every 2 weeks for 24 weeks in the ADACTA trial . Lipid and lipid-associated CV risk biomarkers , including high-density lipoprotein-associated serum amyloid-A ( HDL-SAA ) , secretory phospholipase A2 IIA ( sPLA2 IIA ) and lipoprotein(a ) ( Lp(a ) ) , were measured at baseline and at week 8 . Results The study included 162 patients treated with tocilizumab and 162 patients treated with adalimumab ; HDL-SAA and sPLA2 IIA were measured in a sub population of 87 and 97 patients , respectively . Greater increases in mean low-density lipoprotein cholesterol ( LDL-C ) ( 0.46 mmol/L ( 95 % CI 0.30 to 0.62 ) ) , high-density lipoprotein cholesterol ( HDL-C ) ( 0.07 mmol/L ( 0.001 to 0.14 ) ) , total cholesterol ( TC ) ( 0.67 mmol/L ( 0.47 to 0.86 ) ) , triglycerides ( 0.24 mmol/L ( 0.10 to 0.38 ) ) and TC : HDL ratio ( 0.27 ( 0.12 to 0.42 ) ) occurred with tocilizumab from baseline to 8 weeks . HDL-SAA , sPLA2 IIA and Lp(a ) decreased more with tocilizumab than adalimumab . Median changes from baseline to week 8 were –3.2 and –1.1 mg/L ( p=0.0077 ) for HDL-SAA and –4.1 and –1.3 ng/mL ( p<0.0001 ) for sPLA2 IIA ; difference in adjusted means was –7.12 mg/dL ( p<0.0001 ) for Lp(a ) . Similar results were observed in efficacy responders and non-responders per American College of Rheumatology and European League against Rheumatism criteria . Conclusion LDL-C and HDL-C increased more with tocilizumab than adalimumab . HDL-SAA , sPLA2 IIA and Lp(a ) decreased more with tocilizumab . Lipid change effects of interleukin-6 and tumour necrosis factor ( TNF ) inhibition , manifest by their net impact on lipids and lipoproteins , are not synonymous ; the clinical significance is unclear and requires further study . Trial registration number NCT01119859 . ; post- Objectives To assess the efficacy and safety of certolizumab pegol (CZP)+dose-optimised methotrexate ( MTX ) versus placebo (PBO)+dose-optimised MTX in inducing and sustaining clinical remission in DMARD-naïve patients with moderate-to-severe , active , progressive rheumatoid arthritis ( RA ) , with poor prognostic factors over 52 weeks . Methods DMARD-naïve patients with ≤1 year of active RA were r and omised ( 3:1 ) in a double-blind manner to CZP ( 400 mg Weeks 0 , 2 , 4 , then 200 mg Q2W to Week 52)+MTX or PBO+MTX ( the mean optimised-MTX dose=21 and 22 mg/week , respectively ) . Sustained remission ( sREM ) and sustained low disease activity ( sLDA ; DAS28(ESR)<2.6 and DAS28(ESR)≤3.2 , respectively , at both Weeks 40 and 52 ) were the primary and secondary endpoints . Results Patients were r and omised to CZP+MTX ( n=660 ) and PBO+MTX ( n=219 ) . At Week 52 , significantly more patients assigned to CZP+MTX compared with PBO+MTX achieved sREM ( 28.9 % vs 15.0 % , p<0.001 ) and sLDA ( 43.8 % vs 28.6 % , p<0.001 ) . Inhibition of radiographic progression and improvements in physical functioning were significantly greater for CZP+MTX versus PBO+MTX ( van der Heijde modified total Sharp score ( mTSS ) mean absolute change from baseline ( CFB ) : 0.2 vs 1.8 , p<0.001 , rate of mTSS non-progressors : 70.3 % vs 49.7 % , p<0.001 ; least squares ( LS ) mean CFB in Health Assessment Question naire-Disability Index ( HAQ-DI ) : −1.00 vs −0.82 , p<0.001 ) . Incidence of adverse events ( AEs ) and serious AEs was similar between treatment groups . Infection was the most frequent AE , with higher incidence for CZP+MTX ( 71.8/100 patient-years ( PY ) ) versus PBO+MTX ( 52.7/100 PY ) ; the rate of serious infection was similar between CZP+MTX ( 3.3/100 PY ) and PBO+MTX ( 3.7/100 PY ) . Conclusions CZP+dose-optimised MTX treatment of DMARD-naïve early RA result ed in significantly more patients achieving sREM and sLDA , improved physical function and inhibited structural damage compared with PBO+dose-optimised MTX . Trial registration number NCT01519791 BACKGROUND Conventional factors do not fully explain the distribution of cardiovascular outcomes . Biomarkers are known to participate in well-established pathways associated with cardiovascular disease , and may therefore provide further information over and above conventional risk factors . This study sought to determine whether individual and /or combined assessment of 9 biomarkers improved discrimination , calibration and reclassification of cardiovascular mortality . METHODS 3267 patients ( 2283 men ) , aged 18 - 95 years , at intermediate-to-high-risk of cardiovascular disease were followed in this prospect i ve cohort study . Conventional risk factors and biomarkers were included based on forward and backward Cox proportional stepwise selection models . RESULTS During 10-years of follow-up , 546 fatal cardiovascular events occurred . Four biomarkers ( interleukin-6 , neutrophils , von Willebr and factor , and 25-hydroxyvitamin D ) were retained during stepwise selection procedures for subsequent analyses . Simultaneous inclusion of these biomarkers significantly improved discrimination as measured by the C-index ( 0.78 , P = 0.0001 ) , and integrated discrimination improvement ( 0.0219 , P<0.0001 ) . Collectively , these biomarkers improved net reclassification for cardiovascular death by 10.6 % ( P<0.0001 ) when added to the conventional risk model . CONCLUSIONS In terms of adverse cardiovascular prognosis , a biomarker panel consisting of interleukin-6 , neutrophils , von Willebr and factor , and 25-hydroxyvitamin D offered significant incremental value beyond that conveyed by simple conventional risk factors Objective To compare adalimumab versus etanercept in patients with active rheumatoid arthritis ( RA ) to test the hypothesis that adalimumab was not inferior to etanercept in terms of drug continuation by a margin of 15 % after 52 weeks of treatment . Design Pragmatic , r and omised , parallel group , multicentre , unblinded and non-inferiority trial . R and omisation stratified by baseline use of methotrexate . Participants 125 adults with active RA despite treatment with two disease-modifying drugs ( DMARDs ) , including methotrexate r and omised ( 1 : 1 ) to adalimumab 40 mg alternate weeks or etanercept 50 mg weekly , added to existing medication . Measurements The primary outcome was proportion of patients continuing treatment after 52 weeks . Secondary outcomes included : disease activity score using 28 joints ( DAS28 ) , treatment satisfaction ( TSQM V.2 ) , health status ( Euroqol-5D ) , drug toxicity and persistence with therapy after 2 years . Results Persistence with therapy was 65 % for adalimumab versus 56.7 % for etanercept ( one-sided 95 % CI for proportion still taking adalimumab minus proportion on etanercept ≥−7.9 % ) ; demonstrating non-inferiority at the 15 % margin . After 2 years these figures were : adalimumab 58.3 % and etanecept 43.3 % ( CI ≥−1.7 % ) . The proportion of good , moderate and non-responders based on DAS28-C reactive protein , after 52 weeks , were 26.3 % , 33.3 % and 40.4 % , respectively , for adalimumab versus 16.7 % , 31.7 % and 51.7 % , respectively , for etanercept ( p=0.158 ) . Baseline median EQ-5D scores improved from 0.52 to 0.69 for adalimumab and from 0.52 to 0.64 for etanercept ( p=0.046 ) after 52 weeks . Global satisfaction , effectiveness , side effects and convenience scores based on the TSQM were similar for both drugs . Fourteen serious adverse events occurred including two deaths from myocardial infa rct ion , one patient with ovarian cancer and one with acute myeloid leukaemia . Conclusions Clinicians choosing a first tumour necrosis factor inhibitor for active RA , despite trying two DMARDs including methotrexate , may choose either adalimumab or etanercept in the knowledge that these drugs are similarly effective . Clinical trial registration number EU Clinical Trials Register 2006 - 006275 - 21/GB Objectives This 52-week , r and omised , double-blind phase IIIb study assessed efficacy and safety of certolizumab pegol ( CZP ) as add-on therapy to non-biologic disease-modifying antirheumatic drugs ( DMARDs ) in rheumatoid arthritis ( RA ) patients with low to moderate disease activity , and stopping therapy in patients in sustained remission . Methods Patients were r and omised 1:1 to CZP ( 400 mg at weeks 0 , 2 and 4 , then 200 mg every 2 weeks ) or placebo ( every 2 weeks ) plus current non-biologic DMARDs . At week 24 , patients who achieved the primary endpoint of Clinical Disease Activity Index ( CDAI ) remission at both weeks 20 and 24 stopped study treatment and continued in the study until week 52 . Results Of 194 patients ( CZP=96 ; placebo=98 ) , > 90 % had moderate disease activity at baseline . Significantly more CZP patients met the primary endpoint than placebo patients ( week 20 and 24 CDAI remission rates : 18.8 % vs 6.1 % ; p≤0.05 ) . At week 24 , 63.0 % vs 29.7 % of CZP versus placebo patients ( p<0.001 ) achieved LDA . Disease activity score ( ESR ) based on 28-joint count and Simplified Disease Activity Index remission rates were also significantly higher with CZP versus placebo ( 19.8 % vs 3.1 % ; p≤0.01 and 14.6 % vs 4.1 % ; p≤0.05 ) . CZP patients reported improvements in physical function versus placebo ( mean Health Assessment Question naire-Disability-Index change from baseline : CZP , −0.25 vs placebo , −0.03 ; p≤0.01 ) . During the period following withdrawal of CZP or placebo , only 3/17 prior CZP patients and 2/6 prior placebo patients maintained CDAI remission until week 52 , but CZP reinstitution allowed renewed improvement . Adverse and serious adverse event rates were comparable between CZP and placebo groups . Conclusions Addition of CZP to non-biologic DMARDs is an effective treatment in RA patients with predominantly moderate disease activity , allowing low-disease activity or remission to be reached in a majority of the patients . However , the data suggest that CZP can not be withdrawn in patients achieving remission . Trial registration number NCT00674362 Background : Prevalence estimates of rheumatoid arthritis ( RA ) vary across Europe . Recent estimates in southern European countries showed a lower prevalence than in northern countries . Objectives : To estimate the prevalence of RA in France in a multiregional representative sample in the year 2001 . Methods : A two stage r and om sample was constituted in seven areas ( 20 counties ) from the national telephone directory of households and by the next birthday method in each household . Patient-interviewers , member of self help groups , were trained to administer telephone surveys using a vali date d question naire for case detection of inflammatory rheumatism , and conducted the survey under quality control . All suspected cases of RA were confirmed by their rheumatologist or by clinical examination . Prevalence estimates after probability sampling correction were st and ardised for age and sex ( national census 1999 ) . Results : An average response rate of 64.7 % ( two stages combined ) led to a total of 9395 respondents . St and ardised prevalence was 0.31 % ( 95 % confidence interval 0.18 to 0.48 ) for RA , 0.51 % in women and 0.09 % in men , with a higher age-specific prevalence in the 65–74 year age b and . A geographical analysis of county clustering showed significant variation across the country . Conclusion : This national multiregional cooperative study demonstrates the usefulness of working in association with patients of self help groups . It showed a similar prevalence of RA to that of the spondyloarthropathies estimated concomitantly during the survey . It provides a reliable basis for definition of population targets for healthcare delivery and drug treatments Non-r and omised studies of the effects of interventions are critical to many areas of healthcare evaluation , but their results may be biased . It is therefore important to underst and and appraise their strengths and weaknesses . We developed ROBINS-I ( “ Risk Of Bias In Non-r and omised Studies - of Interventions ” ) , a new tool for evaluating risk of bias in estimates of the comparative effectiveness ( harm or benefit ) of interventions from studies that did not use r and omisation to allocate units ( individuals or clusters of individuals ) to comparison groups . The tool will be particularly useful to those undertaking systematic review s that include non-r and omised studies A previous investigation by Lambert et al. , which used computer simulation to examine the influence of choice of prior distribution on inferences from Bayesian r and om effects meta- analysis , is critically examined from a number of viewpoints . The practical example used is shown to be problematic . The various prior distributions are shown to be unreasonable in terms of what they imply about the joint distribution of the overall treatment effect and the r and om effects variance . An alternative form of prior distribution is tentatively proposed . Finally , some practical recommendations are made that stress the value both of fixed effect analyses and of frequentist approaches as well as various diagnostic investigations BACKGROUND Roughly a third of patients with rheumatoid arthritis treated with biological treatments receive them as monotherapy . Tocilizumab -- an inhibitor of interleukin 6 receptor signalling -- has been studied as monotherapy in several clinical trials . We assessed the efficacy and safety of tocilizumab monotherapy compared with adalimumab monotherapy for patients with rheumatoid arthritis . METHODS We did this r and omised , double-blind , parallel-group , phase 4 superiority study in 76 centres in 15 countries in North and South America , Australasia , and Europe . We enrolled patients who were aged at least 18 years , had severe rheumatoid arthritis for 6 months or more , and were intolerant to methotrexate or were inappropriate for continued methotrexate treatment . Patients were r and omly assigned ( 1:1 ; block size of four ) to receive tocilizumab 8 mg per kg bodyweight intravenously every 4 weeks plus placebo subcutaneously every 2 weeks or adalimumab 40 mg subcutaneously every 2 weeks plus placebo intravenously every 4 weeks for 24 weeks . Investigators , patients , and sponsor personnel were masked to assignment . The primary endpoint was change in disease activity score using 28 joints ( DAS28 ) from baseline to week 24 . This trial is registered with Clinical Trials.gov , number NCT01119859 . FINDINGS We screened 452 patients and enrolled 326 patients . The intention-to-treat population contained 325 patients ( 163 assigned to tocilizumab , 162 assigned to adalimumab ) . Week 24 mean change from baseline in DAS28 was significantly greater in the tocilizumab group ( -3·3 ) than in the adalimumab group ( -1·8 ) patients ( difference -1·5 , 95 % CI -1·8 to -1·1 ; p<0·0001 ) . 16 of 162 ( 10 % ) patients in the adalimumab group versus 19 of 162 ( 12 % ) in the tocilizumab group had serious adverse events . More patients in the tocilizumab group than in the adalimumab group had increased LDL-cholesterol , increased alanine aminotransferase concentrations , and reduced platelet and neutrophil counts . INTERPRETATION Tocilizumab monotherapy was superior to adalimumab monotherapy for reduction of signs and symptoms of rheumatoid arthritis in patients for whom methotrexate was deemed inappropriate . The adverse event profiles of tocilizumab and adalimumab were consistent with previous findings . FUNDING F Hoffmann-La Roche Objective . To evaluate the safety and efficacy of golimumab ( GOL ) , a human antitumor necrosis factor antibody , in patients with active rheumatoid arthritis ( RA ) despite methotrexate ( MTX ) therapy through 5 years in the GO-FORWARD trial . Methods . Patients with active RA despite MTX therapy were r and omly assigned to receive placebo + MTX ( Group 1 ) , GOL 100 mg + placebo ( Group 2 ) , GOL 50 mg + MTX ( Group 3 ) , or GOL 100 mg + MTX ( Group 4 ) . Patients in groups 1 , 2 , and 3 with inadequate response could enter early escape at Week 16 to GOL 50 mg + MTX or GOL 100 mg + MTX , and all remaining Group 1 patients crossed over to GOL 50 mg + MTX at Week 24 . The blind was maintained through the 52-week data base lock , after which treatment adjustments were permitted . Adverse events ( AE ) were monitored through Week 268 . Efficacy was evaluated using the American College of Rheumatology ( ACR ) 20/50/70 responses and a 28-joint Disease Activity Score using C-reactive protein ( DAS28-CRP ) . Response rates at Week 256 were analyzed by an intent-to-treat analysis . Results . A total of 444 patients were r and omized , and 313 received GOL through Week 252 ; 301 patients completed the safety followup through Week 268 . Infections were the most common type of AE ; 172 patients ( 39.6 % ) had ≥ 1 serious AE . No unexpected safety signals were observed . At Week 256 , ACR20/50/70 responses were achieved by 63.1 % , 40.8 % , and 24.1 % , respectively , of all r and omized patients . About 78 % of all patients achieved a good or moderate DAS28-CRP response . Conclusion . Improvements in the signs and symptoms of RA were maintained through 5 years . AE through 5 years were consistent with earlier reports of the GO-FORWARD trial ; no apparent increased risk was observed over time Abstract Objectives . This 24-week , multicenter , double-blind , r and omized , placebo-controlled study ( NCT00791999 ) compared efficacy and safety of certolizumab pegol ( CZP ) in combination with methotrexate ( MTX ) vs placebo plus MTX in Japanese rheumatoid arthritis ( RA ) patients with inadequate response to MTX . Methods . In total , 316 patients were r and omized 1:1:1:1 to subcutaneous CZP 100 , 200 , or 400 mg ( induction dose : 200 mg or 400 mg CZP at Weeks 0 , 2 , and 4 ) plus MTX or placebo plus MTX every 2 weeks . Primary endpoint was ACR20 response at Week 12 . Results . ACR20 response rates were 62.5 % , 76.8 % , 77.6 % , and 28.6 % at Week 12 , and 61.1 % , 73.2 % , 71.8 % , and 24.7 % at Week 24 for CZP 100 , 200 , and 400 mg , and placebo groups , respectively , with statistical significance between each CZP group and placebo . Change in Total Sharp Score over 24 weeks was significantly smaller in CZP 200 and 400 mg groups vs placebo . Improvements in health-related quality of life ( HRQoL ) were observed in all three CZP groups vs placebo . Incidence of adverse events was similar between CZP groups . Conclusions . CZP plus MTX result ed in rapid , sustained reductions in RA signs and symptoms in Japanese patients with inadequate response to MTX , with significant inhibition of radiographic progression and improved OBJECTIVE To assess the risk of serious infections following 22 weeks of infliximab therapy , and to further characterize the safety profile of infliximab in combination with background treatments during 1 year in patients with rheumatoid arthritis ( RA ) with various comorbidities . METHODS Patients with active RA despite receiving methotrexate ( MTX ) were r and omly assigned to receive infusions of placebo ( group 1 , n=363 ) , 3 mg/kg infliximab ( group 2 , n=360 ) , or 10 mg/kg infliximab ( group 3 , n=361 ) at weeks 0 , 2 , 6 , and 14 . At week 22 , patients in placebo group 1 began receiving 3 mg/kg infliximab , and patients in group 3 continued to receive an infliximab dose of 10 mg/kg . Patients in group 2 who failed to meet predefined response criteria received increasing doses of infliximab in increments of 1.5 mg/kg . RESULTS At week 22 , the relative risk of developing serious infections in groups 2 and 3 , compared with group 1 , was 1.0 ( 95 % confidence interval [ 95 % CI ] 0.3 - 3.1 , P=0.995 ) and 3.1 ( 95 % CI 1.2 - 7.9 , P=0.013 ) , respectively . The incidence of serious adverse events was 7.8 % in groups 2 and 3 compared with 7.5 % in group 1 . From week 22 to week 54 , 11.8 % , 9.9 % , and 10.3 % of patients in groups 1 , 2 , and 3 , respectively , reported occurrences of serious adverse events . Through week 54 , 1 patient in group 1 , 2 patients in group 2 , and 4 patients in group 3 developed active tuberculosis . CONCLUSION The risk of serious infections in patients receiving the approved infliximab dose of 3 mg/kg plus MTX was similar to that in patients receiving MTX alone . Patients receiving the unapproved induction regimen of 10 mg/kg infliximab plus MTX followed by a 10 mg/kg maintenance regimen had an increased risk of serious infections through week 22 Objective : To explore the feasibility of prospect ively monitoring treatment efficacy and tolerability of infliximab , etanercept , and leflunomide over a two year period in patients with established rheumatoid arthritis ( RA ) in clinical practice using a structured protocol . Methods : All patients with RA at seven centres in southern Sweden , for whom at least two disease modifying antirheumatic drugs , including methotrexate , had failed or not been tolerated , who started treatment with either infliximab , etanercept , or leflunomide were included . They were evaluated at predefined times using a st and ardised protocol including items required for evaluating response to the American College of Rheumatology ( ACR ) or EULAR criteria . All adverse events were recorded using World Health Organisation terminology . Concomitant treatment and survival while receiving a drug were recorded . Results : During the study 166 patients were treated with etanercept , 135 with infliximab , and 103 with leflunomide . Treatment response as determined by the ACR and EULAR response criteria was similar for the tumour necrosis factor ( TNF ) blockers . The TNF blockers performed significantly better than leflunomide both as determined by the response criteria and by survival on drug analysis . Thus 79 % and 75 % continued to receive etanercept or infliximab compared with 22 % of patients who started leflunomide after 20 months . The spectrum of side effects did not differ from those previously reported in the clinical trials . The initial two year experience of a protocol for postmarketing surveillance of etanercept , infliximab , and leflunomide shows that a structured protocol with central data h and ling can be used in clinical practice for documenting the performance of newly introduced drugs . Conclusions : Efficacy data for the TNF blockers comply with results in clinical trials , whereas leflunomide appeared to perform worse than in clinical trials . Prolonged monitoring is required to identify possible rare side effects OBJECTIVE To evaluate the safety of etanercept in patients with rheumatoid arthritis ( RA ) and concomitant comorbidities . METHODS The safety of etanercept ( 25 mg twice weekly ) in RA patients with at least one comorbidity ( i.e. diabetes mellitus , chronic pulmonary disease , recent pneumonia , recurrent infections ) was evaluated in a 16-week placebo-controlled , r and omized , double-blinded study . The primary endpoint was the incidence of medically important infections ( MIIs ; defined as those result ing in hospitalization or treatment with intravenous antibiotics ) . RESULTS Data from 535 patients were analysed ; the study was terminated early because of slow enrolment and lower than predicted incidence of infections . Serious adverse events ( 5.9 % placebo , 8.6 % etanercept ) were most commonly observed in the cardiovascular system . Six patients ( 1 placebo ; 5 etanercept ) died during the study ; four deaths were attributed to cardiovascular events . The numerically higher mortality in the etanercept group was not statistically significant [ relative risk ( 95 % CI ) = 5.06 ( 0.59 , 42.99 ) ] but remains unexplained . No etanercept-related increase in the incidence of MIIs ( 3.7 % placebo , 3.0 % etanercept ) or overall infections was observed in the total study population or in subgroups of patients who were > or = 65 yrs of age , had diabetes or had chronic pulmonary disease . CONCLUSIONS Etanercept was generally well tolerated by RA patients with comorbidities . Serious adverse events and deaths occurred more frequently in the etanercept group but event numbers were small and CIs were broad , preventing reliable conclusions from being drawn . Although the study had limited statistical power , the incidence of MIIs in these patients was not increased by etanercept treatment OBJECTIVE To assess the efficacy , safety , and pharmacology of subcutaneous administration of golimumab in patients with active rheumatoid arthritis ( RA ) despite treatment with methotrexate ( MTX ) . METHODS Patients were r and omly assigned in a double-blinded manner to receive injections of placebo plus MTX or 50 mg or 100 mg golimumab every 2 or 4 weeks plus MTX through week 48 . Patients originally assigned to receive injections every 2 weeks had the interval increased to every 4 weeks starting at week 20 . The primary end point was the proportion of patients meeting the American College of Rheumatology 20 % improvement criteria ( achieving an ACR20 response ) at week 16 . The study was powered to detect a difference in the primary end point when the combined golimumab groups and at least 1 of the individual dose groups were compared with placebo . RESULTS The primary end point was attained . Sixty-one percent of patients in the combined golimumab plus MTX dose groups achieved an ACR20 response at week 16 compared with 37 % of patients in the placebo plus MTX group ( P=0.010 ) . In addition , 79 % of patients in the group receiving 100 mg golimumab every 2 weeks achieved an ACR20 response ( P<0.001 versus placebo ) . Through week 20 ( after which patients receiving placebo were switched to active infliximab therapy ) , serious adverse events were reported in 9 % of patients in the combined golimumab groups and in 6 % of patients in the placebo group . CONCLUSION Golimumab plus MTX effectively reduces the signs and symptoms of RA and is generally well tolerated in patients with an inadequate response to MTX BACKGROUND Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease . Yet , the inflammatory hypothesis of atherothrombosis has remained unproved . METHODS We conducted a r and omized , double‐blind trial of canakinumab , a therapeutic monoclonal antibody targeting interleukin‐1β , involving 10,061 patients with previous myocardial infa rct ion and a high‐sensitivity C‐reactive protein level of 2 mg or more per liter . The trial compared three doses of canakinumab ( 50 mg , 150 mg , and 300 mg , administered subcutaneously every 3 months ) with placebo . The primary efficacy end point was nonfatal myocardial infa rct ion , nonfatal stroke , or cardiovascular death . RESULTS At 48 months , the median reduction from baseline in the high‐sensitivity C‐reactive protein level was 26 percentage points greater in the group that received the 50‐mg dose of canakinumab , 37 percentage points greater in the 150‐mg group , and 41 percentage points greater in the 300‐mg group than in the placebo group . Canakinumab did not reduce lipid levels from baseline . At a median follow‐up of 3.7 years , the incidence rate for the primary end point was 4.50 events per 100 person‐years in the placebo group , 4.11 events per 100 person‐years in the 50‐mg group , 3.86 events per 100 person‐years in the 150‐mg group , and 3.90 events per 100 person‐years in the 300‐mg group . The hazard ratios as compared with placebo were as follows : in the 50‐mg group , 0.93 ( 95 % confidence interval [ CI ] , 0.80 to 1.07 ; P=0.30 ) ; in the 150‐mg group , 0.85 ( 95 % CI , 0.74 to 0.98 ; P=0.021 ) ; and in the 300‐mg group , 0.86 ( 95 % CI , 0.75 to 0.99 ; P=0.031 ) . The 150‐mg dose , but not the other doses , met the prespecified multiplicity‐adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization ( hazard ratio vs. placebo , 0.83 ; 95 % CI , 0.73 to 0.95 ; P=0.005 ) . Canakinumab was associated with a higher incidence of fatal infection than was placebo . There was no significant difference in all‐cause mortality ( hazard ratio for all canakinumab doses vs. placebo , 0.94 ; 95 % CI , 0.83 to 1.06 ; P=0.31 ) . CONCLUSIONS Antiinflammatory therapy targeting the interleukin‐1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo , independent of lipid‐level lowering . ( Funded by Novartis ; CANTOS Clinical Trials.gov number , NCT01327846 . Objective . The aim of our pilot study was to prospect ively evaluate the effect of inhibiting interleukin 6 on the left ventricular ( LV ) structure and function in patients with rheumatoid arthritis ( RA ) without cardiac symptoms , using cardiac magnetic resonance ( CMR ) . Methods . Female patients with RA with active disease and healthy controls were enrolled . Cardiac symptoms were absent in all subjects . Tocilizumab ( TCZ ; 8 mg/kg IV every 4 weeks ) was prescribed for patients with RA with an inadequate clinical response to methotrexate . All subjects underwent baseline evaluation of LV function and structure measured by CMR . We compared measures of LV geometry and function between patients with RA and patients without RA controls at baseline , and changes in the same variables between baseline and after 52 weeks of treatment among the group with RA . Results . Twenty women with RA were compared with 20 women without RA of similar mean age . In patients with RA at baseline , ejection fraction ( EF ) was significantly lower ( −3.7 % ) and LV mass index ( LVMI ) significantly higher ( + 9.2 % ) compared with controls . TCZ treatment result ed in a significant decrease in the Simplified Disease Activity Index ( SDAI ) after 52 weeks of treatment , paralleling a significant increase in EF ( + 8.2 % ) and a significant decrease in LVMI ( −24.4 % ) over the same period . The percentage change in LVMI correlated strongly with the percentage change in SDAI ( r = −0.63 , p = 0.0028 ) . LV geometry in the group with RA at baseline showed eccentric hyper-trophy compared with the group without RA , a condition that normalized after TCZ treatment . Conclusion . TCZ treatment significantly increased EF and decreased LVMI associated with disease activity Introduction For patients with rheumatoid arthritis ( RA ) whose treatment with a tumour necrosis factor inhibitor ( TNFi ) is failing , several biological treatment options are available . Often , another TNFi or a biological with another mode of action is prescribed . The objective of this study was to compare the effectiveness and cost-effectiveness of three biologic treatments with different modes of action in patients with RA whose TNFi therapy is failing . Methods We conducted a pragmatic , 1-year r and omised trial in a multicentre setting . Patients with active RA despite previous TNFi treatment were r and omised to receive abatacept , rituximab or a different TNFi . The primary outcome ( Disease Activity Score in 28 joints ) and the secondary outcomes ( Health Assessment Question naire Disability Index and 36-item Short Form Health Survey scores ) were analysed using linear mixed models . Cost-effectiveness was analysed on the basis of incremental net monetary benefit , which was based on quality -adjusted life-years ( calculated using EQ-5D scores ) , and all medication expenditures consumed in 1 year . All analyses were also corrected for possible confounders . Results Of 144 r and omised patients , 5 were excluded and 139 started taking abatacept ( 43 patients ) , rituximab ( 46 patients ) or a different TNFi ( 50 patients ) . There were no significant differences between the three groups with respect to multiple measures of RA outcomes . However , our analysis revealed that rituximab therapy is significantly more cost-effective than both abatacept and TNFi over a willingness-to-pay range of 0 to 80,000 euros . Conclusions All three treatment options were similarly effective ; however , when costs were factored into the treatment decision , rituximab was the best option available to patients whose first TNFi treatment failed . However , generalization of these costs to other countries should be undertaken carefully . Trial registration Netherl and s Trial Register number NTR1605 . Registered 24 December 2008 |
1,971 | 18,268,497 | The results provide no evidence to suggest that parenteral oestrogen , in doses sufficient to produce castrate levels of testosterone , is less effective than luteinising hormone-releasing hormone ( LHRH ) or orchidectomy in controlling prostate cancer , or that it is consistently associated with an increase in cardiovascular mortality . | The objectives of this study were to assess the effectiveness and safety of parenteral oestrogen in the treatment of prostate cancer , and to examine any dose relationship . | Forty-two patients with previously untreated T3/4 N1 - 4 MO/1 prostatic adenocarcinoma were treated with either cyproterone acetate ( n = 21 ; 300 mg intramuscularly per week ) or oestradiol undecylate ( n = 21 ; 100 mg intramuscularly per month ) after extensive staging which included open skeletal biopsy and pelvic lymphadenectomy in some cases . Subjective and objective parameters as well as signs of drug toxicity were recorded regularly . Evaluation after 6 months showed cyproterone acetate to be more effective in the following respects : ( 1 ) the significantly different castration effect as judged by plasma testosterone , ( 2 ) the objective voiding pattern and tumour response , with regression of palpable and histologically evaluable local tumour in 16 of 21 patients , and ( 3 ) side effects and untoward reactions . Thus cyproterone acetate is suggested as a valuable alternative in the treatment of advanced prostatic cancer 151 patients with locally advanced prostatic cancer ( T3 - 4 M0 ) , representing 38 % of the 404 cancer patients in a Finnish multicenter study , were r and omly assigned to one of three treatment arms : orchiectomy , estrogens or radiotherapy . During the 4-year follow-up period there were no significant differences in the progression rates ( appearance of metastases in bone scan ) between the therapy groups . The frequency of thromboembolic and other cardiovascular complications was highest in the estrogen group ( 13/50 patients ) . In the radiotherapy group , 19 of 45 patients had bowel or bladder complications . On the other h and , orchiectomy has few , if any , complications . The high risk of complications associated with estrogens and radiotherapy has to be taken into consideration in the selection of treatment Thirty previously untreated patients with carcinoma of the prostate were prospect ively r and omised to one of the following treatments : ethinyl oestradiol ( Etivex ) combined with polyoestradiol phosphate ( Estradurin ) ; estramustine phosphate ( Estracyt ) ; bilateral orchiectomy . Oestrogenic effects were measured by blood levels of pregnancy zone protein , sex hormone binding globulin , LH , FSH and prolactin . During a follow-up period of 6 months , estramustine phosphate and ethinyl oestradiol/polyoestradiol phosphate induced comparable changes in these proteins , suggesting comparable oestrogenic effects of these two forms of treatment in patients with prostatic carcinoma The authors made a r and omized prospect i ve study of estrogen therapy versus orchidectomy in patients with prostatic cancer ( n = 100 , Huddinge Hospital , Sweden ) to investigate the possibility of predicting cardiovascular events during hormonal treatment . Patients with preexisting cardiovascular morbidity were excluded ( 16 % ) . Prior to the allocation of therapy , the following were performed : exercise stress test ; physiologic evaluation of the peripheral circulation ; blood volume estimation ; chest x-ray ; blood tests , including hormones , lipoproteins , and antithrombin III ; and a physical examination and history by a cardiologist . Thirteen ( 25 % ) of the patients given estrogen therapy ( n = 53 ) had cardiovascular complications during the first year of treatment compared with none in the orchidectomy group . The authors made a multivariate discriminant analysis of the pretreatment examinations of the estrogen-treated patients ; this result ed in a discriminant function including S-T segment depression in lead CH2 during the exercise stress test and blood tests for cholesterol , follicle-stimulating hormone , and luteinizing hormone . This function correctly classified 84 % of the estrogen-treated patients as patients with or without risk of a cardiovascular complication . Briefly stated , if patients with prostatic cancer are examined by means of exercise stress tests and blood tests for luteinizing hormone , cholesterol , and follicle-stimulating hormone prior to treatment , the discriminant function enables the authors to identify an extremely high-risk group for cardiovascular complications if estrogen therapy is commenced . The strong association of an increased luteinizing hormone with cardiovascular complications during estrogen treatment makes it m and atory to investigate its role in the pathogenesis of atherosclerosis and cardiovascular events BACKGROUND Mortality increases after hip fractures in women and more so in men . Little is known , however , about mortality after other fractures . We investigated the mortality associated with all fracture types in elderly women and men . METHODS We did a 5-year prospect i ve cohort study in the semi-urban city of Dubbo , Australia , of all residents aged 60 years and older ( 2413 women and 1898 men ) . Low-trauma osteoporotic fractures that occurred between 1989 and 1994 , confirmed by radiography and personal interview , were classified as proximal femur , vertebral , and groupings of other major and minor fractures . We calculated st and ardised mortality rates from death certificates for people with fractures compared with the Dubbo population . FINDINGS 356 women and 137 men had low-trauma fractures . In women and men , mortality was increased in the first year after all major fractures . In women , age-st and ardised mortality ratios were 2.18 ( 95 % CI 2.03 - 2.32 ) for proximal femur , 1.66 ( 1.51 - 1.80 ) for vertebral , 1.92 ( 1.70 - 2.14 ) for other major , and 0.75 ( 0.66 - 0.84 ) for minor fractures . In men , these ratios were 3.17 ( 2.90 - 3.44 ) for proximal femur , 2.38 ( 2.17 - 2.59 ) for vertebral , 2.22 ( 1.91 - 2.52 ) for other major , and 1.45 ( 1.25 - 1.65 ) for minor fractures . There were excess deaths ( excluding minor fractures in women ) in all age-groups . INTERPRETATION All major fractures were associated with increased mortality , especially in men . The loss of potential years of life in the younger age-group shows that preventative strategies for fracture should not focus on older patients at the expense of younger women and of men BACKGROUND The present pilot study tested the clinical performance of a new pharmacokinetically guided dosing regimen of parenteral estrogen in patients with advanced prostatic carcinoma . The aim was to accelerate endocrine effects and to avoid cardiovascular side effects . METHODS Seventeen patients were r and omized to intramuscular injections of 240 mg polyestradiol phosphate ( PEP ) every second week for the first 8 weeks ( five doses ) , followed by a maintenance dose of 240 mg every month ; and 16 patients were r and omized to bilateral orchidectomy . The estrogen dosing was calculated by pharmacokinetic modelling to achieve a rapid increase in serum estradiol and thereby a fast decrease in testosterone . RESULTS The predicted increment in serum estrogen was achieved , together with a subsequent decrease in testosterone in the PEP group . In addition , there were no signs of an increased cardiovascular morbidity . This was probably due to a minimal estrogenic influence on the liver and was reflected by unchanged levels of coagulation factor VII . Clinical effects , during the first 2 years of treatment , were similar in the two treatment arms , with 12 patients in the orchidectomy group and 14 patients in the PEP group responding to treatment . CONCLUSIONS The present parenteral regimen is an efficient and time-saving estrogen regimen with a favorable side-effect profile . PEP seems to offer a potential for revival of the most cost-effective endocrine treatment of cancer of the prostate , i.e. , estrogen OBJECTIVE To evaluate the clinical efficacy and cardiovascular complications of orchidectomy or polyoestradiol phosphate ( PEP ) in the treatment of advanced prostatic cancer . PATIENTS AND METHODS In a prospect i ve , r and omized study 444 patients ( mean age 73 years , range 45 - 91 ) with T3 - 4 M0 or T1 - 4 M1 prostatic cancer were treated either by orchidectomy ( group 1 , n = 217 ) or parenteral PEP ( group 2 , n = 227 ; 240 mg/month ) . The patients were examined at 3 and 6 months after start of the therapy and thereafter every 6 months ; they were also assessed whenever they had symptoms indicating progression . Possible cardiovascular complications included myocardial infa rct ion , cerebrovascular accident , pulmonary embolism and deep vein thrombosis . RESULTS After a follow-up of 2 years there was no statistically significant difference between the groups in progression-free time ; 65 of 217 ( 30 % ) patients in group 1 showed evidence of progression , including seven ( 3 % ) who died from prostate cancer . In group 2 , 64 of 227 ( 28 % ) patients showed progression and eight ( 3.5 % ) died from prostatic cancer . There were 10 ( 5 % ) cardiovascular complications in patients in group 1 , including five ( 2 % ) cardiovascular deaths ; in group 2 there were 24 ( 11 % ) and 14 ( 6 % ) , respectively . During the first year of treatment there were three ( 1.4 % ) cardiovascular complications in group 1 and 14 ( 6 % ) in group 2 ( P < 0.05 ) , and during the second year , seven ( 4 % ) and 10 ( 6 % ) , respectively . CONCLUSION Parenteral PEP ( 240 mg/month ) seems to be as efficient as orchidectomy in inhibiting disease in patients with advanced prostatic cancer ( T3 - 4 M0 and T1 - 4 M1 ) . There were more cardiovascular complications in patients treated with PEP than after orchidectomy ; the difference was statistically significant during the first year of treatment BACKGROUND The aim of the study was to evaluate overall and prostate cancer ( PCa ) specific survival with special attention to cardiovascular ( CV ) mortality in patients primarily treated by parenteral polyestradiol phosphate ( PEP ) 240 mg/month or with orchiectomy ( OE ) , taking into account the effect of pretreatment diseases and medication , and later PCa therapies . METHODS The present Finnprostate 6 study ( 10-year follow-up ) consisted of 244 patients with locally advanced PCa ( T3 - 4 M0 ) and 200 patients with metastatic PCa ( T1 - 4 M1 ) . Patients were r and omized to OE or PEP therapy . The T3 - 4 M0 and T1 - 4 M1 patients were analyzed separately . RESULTS There was no difference in overall or PCa specific survival between the primary therapy groups in T3 - 4 M0 or T1 - 4 M1 patients . In the T3 - 4 M0 patients the primary treatment ( PEP vs. OE ) was statistically significantly associated with a risk of CV deaths ( P = 0.001 ) . Such an association was not found in the T1 - 4 M1 patients . CONCLUSIONS The primary PEP and OE therapies are equal in terms of overall and PCa specific survival in patients with T3 - 4 M0 or T1 - 4 M1 disease . In T3 - 4 M0 patients PEP increases the risk of CV deaths compared to OE but not in T1 - 4 M1 patients Thirty-eight patients with cancer of the prostate were treated with strict parenteral estrogen in the form of monthly polyestradiol phosphate injections--160 mg , 240 mg , and 320 mg -- in this nonr and omized study . In contrast to studies with oral estrogens , there have been no cardiovascular complications at a mean follow-up of 12.9 + /- 0.7 months ( SEM ) . Twenty-nine of the 38 patients ( 76 % ) have responded to therapy Objective To evaluate the cardiovascular ( CV ) complications associated with orchiectomy ( OE ) and parenteral polyestradiol phosphate ( PEP ) therapy ( 240 mg/month ) , taking into account the effect of pretreatment diseases and pretreatment medication . Material and methods A total of 244 T3–4 M0 patients and 200 T1–4 M1 patients were r and omized to either OE or PEP therapy . The two groups of patients were analyzed separately . The follow-up period was 36 months . The effect of pretreatment vascular and other diseases and pretreatment medication which may be associated with a risk of CV complications was evaluated . Results In the T3–4 M0 patients , the treatment ( PEP versus OE ) and the presence of pretreatment vascular diseases were statistically significantly associated with a risk of CV complications ( p=0.01 and 0.003 , respectively ) . In the T1–4 M1 patients , such an association was not found . No association was observed between pretreatment medication and CV complications . There was no difference in progression-free time between the therapy groups in either the T3–4 M0 or T1–4 M1 patients . Conclusion In patients with locally advanced prostatic cancer , PEP therapy is associated with a statistically significantly higher risk of CV complications compared to OE In a population -based r and omized study comparing 150 patients with advanced prostatic cancer treated with orchiectomy or estrogen , some possible prognostic factors were analyzed . The observation period was 78 to 114 months . M category , T category , tumor grade , performance status , pain , prostatic acid phosphatase , sedimentation rate , hemoglobin and serum creatinine level were all statistically significantly related to the interval to progression and to disease-specific death on univariate analyses . Variables that were statistically significant on multivariate analyses were M category , T category , sedimentation rate and patient age . The sedimentation rate predicted the intervals to progression and to disease-specific death , with the relative hazard and 95 % confidence interval for the latter end point being 1.018 ( range 1.010 to 1.027 ) for each millimeter increase in sedimentation rate per hour . An analysis that was stratified according to the extent of the disease as measured on a bone scan showed that the sedimentation rate was the only prognostic factor of statistical significance with an estimate of relative hazard of 1.52 if the sedimentation rate was elevated 20 mm . per hour . Progression-free survival but not disease-specific survival was statistically significantly better in the estrogen group ( relative hazard 0.47 ) , as assessed by multivariate analysis in which all variables were taken into account Four hundred and seventy-seven prospect ively r and omized patients with prostatic carcinoma were treated with a combination of intramuscular polyestradiol phosphate ( PEP ) and oral ethinyl estradiol , with intramuscular PEP alone , or with orchiectomy . The cardiovascular and all-cause mortality of the two estrogen therapy modalities and orchiectomy were compared with those of the Finnish male population in general . The age-st and ardized rate ratios ( approximately relative risk ) for cardiovascular mortality and for all-cause mortality were 1.51 and 2.31 in the combination estrogen therapy group , 0.17 and 1.50 in the PEP monotherapy group , and 0.78 and 1.78 in the orchiectomy group , respectively . Further mortality rates by cause for all three treatment groups were st and ardized for age using the age-specific person-years at risk as st and ard . Age-st and ardized mortality from cardiovascular diseases was very low in the PEP group , as compared to other treatment modalities , and the mortality rates for prostatic cancer were about equal in all three treatment groups . It is concluded that intramuscular PEP monotherapy is associated with low cardiovascular mortality and with an all-cause and prostatic cancer mortality equal to orchiectomy CONTEXT Observational studies have found lower rates of coronary heart disease ( CHD ) in postmenopausal women who take estrogen than in women who do not , but this potential benefit has not been confirmed in clinical trials . OBJECTIVE To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease . DESIGN R and omized , blinded , placebo-controlled secondary prevention trial . SETTING Outpatient and community setting s at 20 US clinical centers . PARTICIPANTS A total of 2763 women with coronary disease , younger than 80 years , and postmenopausal with an intact uterus . Mean age was 66.7 years . INTERVENTION Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily ( n = 1380 ) or a placebo of identical appearance ( n = 1383 ) . Follow-up averaged 4.1 years ; 82 % of those assigned to hormone treatment were taking it at the end of 1 year , and 75 % at the end of 3 years . MAIN OUTCOME MEASURES The primary outcome was the occurrence of nonfatal myocardial infa rct ion ( MI ) or CHD death . Secondary cardiovascular outcomes included coronary revascularization , unstable angina , congestive heart failure , resuscitated cardiac arrest , stroke or transient ischemic attack , and peripheral arterial disease . All-cause mortality was also considered . RESULTS Overall , there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes : 172 women in the hormone group and 176 women in the placebo group had MI or CHD death ( relative hazard [ RH ] , 0.99 ; 95 % confidence interval [ CI ] , 0.80 - 1.22 ) . The lack of an overall effect occurred despite a net 11 % lower low-density lipoprotein cholesterol level and 10 % higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group ( each P<.001 ) . Within the overall null effect , there was a statistically significant time trend , with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5 . More women in the hormone group than in the placebo group experienced venous thromboembolic events ( 34 vs 12 ; RH , 2.89 ; 95 % CI , 1.50 - 5.58 ) and gallbladder disease ( 84 vs 62 ; RH , 1.38 ; 95 % CI , 1.00 - 1.92 ) . There were no significant differences in several other end points for which power was limited , including fracture , cancer , and total mortality ( 131 vs 123 deaths ; RH , 1.08 ; 95 % CI , 0.84 - 1.38 ) . CONCLUSIONS During an average follow-up of 4.1 years , treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease . The treatment did increase the rate of thromboembolic events and gallbladder disease . Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events , we do not recommend starting this treatment for the purpose of secondary prevention of CHD . However , given the favorable pattern of CHD events after several years of therapy , it could be appropriate for women already receiving this treatment to continue The primary clinical efficacy of orchiectomy and polyoestradiol phosphate ( PEP ) 160 mg/month i.m . was evaluated by progression and cancer mortality rates in a Finnish multicentre study comprising 200 prostatic cancer patients . After the minimum follow-up time of 2 years there was a significant difference between the groups -- orchiectomy delayed progression of the disease more effectively . The follow-up time is rather short for prostatic cancer , but on the basis of this preliminary study the dose of PEP seems to be insufficient in the treatment of advanced prostatic cancer Of 163 new consecutively diagnosed cases of advanced ( T3 - 4 M0 or T04M1 ) prostatic cancer 13 had contraindications for estrogen treatment , and the remainder were r and omized to orchiectomy ( 76 ) or to estrogen treatment ( 74 ) , consisting of 150 micrograms ethinyl estradiol daily and 80 mg . polyestradiol monthly . During the followup period of 7 to 10 years disease progression was noted in 27 patients ( 36 % ) treated with estrogen and 39 ( 51 % ) orchiectomized patients . The free of progression survival rate was significantly better ( less than 0.05 ) among the estrogen treated patients but the over-all survival rates after orchiectomy and estrogen treatment were almost identical . A significantly higher frequency of cardiovascular side effects was noted in the estrogen group ( 23 cases ) compared to the orchiectomy group ( 4 cases ) . Therefore , estrogen treatment in this form can not be recommended for the palliative treatment of prostate cancer The Heart and Estrogen/progestin Replacement Study ( HERS ) was a r and omized clinical trial of postmenopausal hormone use in 2763 women ( 1 ) . Unlike previous observational studies , it included only women with previous coronary heart disease , and hormone therapy was exclusively oral conjugated estrogen plus progestin . In HERS , overall rates of recurrent coronary heart disease did not differ between the treated and nontreated groups . However , in additional , unplanned analyses , the results of HERS were not uniformly null . A marked and statistically significant trend toward decreasing risk was observed with increasing duration of hormone use ( 1 ) ; in the first year , the rate of major coronary events was 52 % higher in the treatment group . In the second year , rates were equal , but during the final fourth and fifth years , women assigned to hormone therapy had a 33 % lower risk for coronary events . The overall results of HERS and the apparent changes in risk over time were both unexpected . Since no previous investigations have examined the relation between duration of hormone use or combined hormone treatment to secondary prevention of coronary heart disease events , it remains unclear whether the time trend was authentic and whether the observations in HERS are limited to that hormone regimen ( 2 ) . In addition , we were interested in underst and ing how women 's use of hormone therapy before their initial coronary disease event might affect the outcome of their hormone use after that event . In HERS , duration of hormone therapy before trial entry was necessarily disregarded ( although 23 % of participants had previously taken hormones ) ; thus , it remains unknown how , or whether , to account for hormone use or duration of use before a patient 's initial coronary event . To further examine the effects of duration of hormone therapy and to explore the effect of different hormone regimens , we investigated the relation between postmenopausal hormone use and secondary prevention of major coronary events in 2489 women with established coronary disease in the Nurses ' Health Study , a large observational cohort . Methods The Nurses ' Health Study Cohort The Nurses ' Health Study began in 1976 , when 121 700 female nurses 30 to 55 years of age completed a mailed question naire about postmenopausal hormone use and medical history , including cardiovascular disease and its risk factors . Every 2 years , we mail follow-up question naires to the original participants to up date information on risk factors and to identify newly diagnosed cases of major illnesses . The total follow-up for the cohort to date exceeds 92 % . Sample for Analysis For this analysis , we limited the cohort to postmenopausal women who reported a previous myocardial infa rct ion or documented coronary atherosclerosis ( coronary artery bypass graft surgery , percutaneous coronary revascularization , or angiographic evidence of 70 % occlusion of one or more major coronary arteries ) . Such women were identified on the baseline question naire in 1976 ; postmenopausal women who reported one of these conditions on a subsequent follow-up question naire were added to the sample at that time . Women ranged in age from 34 to 73 years at entry into the sample for analysis ; 60 % of women had a natural menopause . These criteria closely parallel those used in HERS ( 1 ) ; however , in HERS , women with hysterectomy were excluded , occlusion was defined as at least 50 % , and participants ranged in age from 44 to 79 years . We classified women as postmenopausal from the time of natural menopause or hysterectomy with bilateral oophorectomy . Women who underwent hysterectomy without bilateral oophorectomy were considered postmenopausal when they reached the age at which natural menopause had occurred in 90 % of the cohort ( 54 years for smokers and 56 years for nonsmokers ) ( 3 ) . The women 's reports of age at menopause and type of menopause were highly accurate ( 4 ) . In HERS , women with a history of breast or endometrial cancers were excluded . In the current study , we excluded women who reported stroke or cancer ( except nonmelanoma skin cancer ) on the 1976 baseline question naire at the outset and excluded women from further follow-up if they reported these diseases on a subsequent biennial question naire . This was done to avoid potential bias , in which major diseases such as stroke or cancer may have caused women to alter their hormone use and may be related to risk for coronary heart disease . This type of bias could not have occurred in a r and omized trial , such as HERS . Two hundred forty-eight postmenopausal women with coronary disease entered the analysis in 1976 , and 2241 postmenopausal women were added during follow-up as they reported heart disease ; thus , 17 239 person-years accrued during up to 20 years of follow-up from 1976 to 1996 . Ascertainment of Hormone Use In 1976 , women were asked about current and past use and duration of hormone therapy ; this information was up date d on each biennial question naire . Beginning in 1978 and on each subsequent question naire , we collected information on type of hormone used . For the period 19761978 , we assigned women to the type of hormone reported on the 1978 question naire . If no data were available on hormone therapy for a given 2-year period , those women were assigned to a missing category for that period . In the HERS trial , women who had taken hormones in the 3 months before their screening visit were excluded ( although 23 % to 24 % of the enrolled participants had previously used hormones ) . Because this study is observational , we could not impose a 3-month washout period ; thus , we could not duplicate that aspect of the HERS protocol . We analyzed duration of hormone use in two different ways . In the main analysis , we performed a HERS replication and used a method similar to that in HERS to calculate duration of use . In HERS , duration of hormone therapy began to accrue at r and omization ( regardless of previous hormone use ) ; r and omization occurred sometime after the participant 's initial coronary disease event . Therefore , in our main analysis , we began accruing duration of hormone use for each participant immediately after her initial coronary disease event ( regardless of hormone use before this event ) . For example , if a woman began hormone therapy in 1984 and had a revascularization procedure in 1986 , her duration of use in 1990 would be 4 years . In an alternative analysis , we considered the women 's full experience with hormone therapy ( both before and after the initial coronary disease event ) . Thus , duration of hormone use accumulated continuously from start to termination of therapy . For example , if a woman began hormone therapy in 1984 and had a revascularization procedure in 1986 , her duration of use in 1990 would be 6 years . Similar to HERS participants , 29 % of the nurses had taken hormones before their first coronary disease event . Identification of Second Coronary Disease Events Similar to HERS , in our study the category of recurrent major coronary heart disease included nonfatal myocardial infa rct ion and fatal coronary disease that occurred between the return of the 1976 question naire and 1 June 1996 . Nurses who reported a nonfatal infa rct ion were asked for permission to review their medical records . Nonfatal myocardial infa rct ions were confirmed by hospital records if they met the World Health Organization criteria ( 5 ) ( symptoms , plus either elevated cardiac enzyme levels or diagnostic electrocardiograms ) . Infa rct ions requiring hospitalization and corroborated by interview or letter , but for which medical records were unobtainable , were included as probable . Most deaths were reported by the participants ' families . Every 2 years , we search the National Death Index ( 6 ) to identify deaths among nonrespondents ; follow-up for death remains more than 98 % complete to date . For all deaths possibly attributable to cardiovascular causes , we requested permission from relatives ( subject to state regulations ) to review the medical records . Deaths were considered due to coronary disease if medical records or autopsy findings confirmed a fatal myocardial infa rct ion . Cases in which coronary disease was listed on the death certificate as the underlying cause of death and another , more plausible cause could not be discerned were included as probable cases , since the nurse was known to have had coronary disease before death . The investigators conducted all interviews and medical record review s without knowledge of participants ' hormone use status . In separate analyses , results for probable cases of coronary disease ( 20 % ) were almost identical to those for confirmed cases ( 80 % ) ; thus , we present data from analyses in which confirmed and probable cases are combined . Statistical Analysis For each participant , person-months were allocated to hormone categories according to the baseline data and were up date d every 2 years according to information received on follow-up question naires . Examination of type of hormone therapy was limited to users of oral conjugated estrogen with or without oral medroxyprogesterone acetate , as this was the most common hormone regimen . If information on hormone use was missing during a follow-up period , then person-time was assigned to a missing category for that time period . So that the study would be prospect i ve , we established hormone status during each 2-year follow-up period from women 's reports at the start of the time period ; thus , we probably underestimate duration of use by an average of 1 year in both the main analysis and the alternate analysis . Follow-up for a participant ended with diagnosis of myocardial infa rct ion , death , or 1 June 1996 , whichever came first . The analysis is based on incidence rates , using person-months of follow-up as the denominator . We used relative risk as the measure of association , defined as the incidence of second major coronary events among women in various categories of hormone use divided by the rate among women who never used hormones We present the results of a prospect i ve r and omised trial of Estradurin , a long-acting oestrogen preparation ( polyoestradiol phosphate ) , 160 mg per month , compared with bilateral orchiectomy in patients with advanced prostatic carcinoma ( T3M1 ; T4MO/M1 ) . The dose was lower than that usually recommended to induce a consistent fall in serial plasma testosterone levels to within the castrate range . Most patients treated with oestrogen showed an initial clinical and biochemical response equal to that obtained for patients undergoing orchiectomy . The inevitable relapse in hormone sensitivity sometimes occurred very soon after the start of oestrogen treatment . Many patients had poorly suppressed plasma testosterone expressed as a mean of monthly serial measurements , but then responded to secondary orchiectomy . These data only suggest that , in the treatment of hormone-sensitive prostatic carcinoma , it may be necessary to reduce plasma testosterone to midway between castrate and normal ranges . The data support the theory that response to and rogen withdrawal is qualitative rather than quantative . The effective dose of oestrogen may therefore be reduced and the risk of thrombo-embolic complications minimised The clinical efficacy of high dose ( 160 mg ) polyoestradiol phosphate ( PEP ) was compared with that of orchiectomy in a prospect i ve r and omised multicentre study including 200 prostatic cancer patients . The effect of daily low dose ( 75 mg ) acetosalicylic acid ( ASA ) on possible cardiovascular complications during the first 6 months of therapy was also evaluated . Oestrogen-treated patients had more progressions , but follow-up was too short to draw any definite conclusions on the efficacy of treatment . There was no cardiovascular mortality and there were no thromboembolic complications in any treatment group . It was concluded that parenteral high dose PEP is not associated with an increased risk of cardiovascular complications and there is no need for daily low dose ASA In a prospect i ve , r and omized open study , a long-acting LHRH agonist ( Zoladex ) was compared with polyoestradiol phosphate ( Estradurin ) , both widely used in Finl and for palliative treatment of prostatic carcinoma , as regards efficacy and side effects . Of the 236 enrolled patients , 129 were r and omized to receive LHRH agonist and 107 to oestrogen treatment . The median follow-up was 25 months . Reduction of prostatic volume was quicker and more effective in the LHRH than in the oestrogen group , and serum testosterone concentrations fell to castration level after 1 month and 1 year , respectively . In locally advanced ( M0 ) and histologically well or moderately differentiated tumours , LHRH agonist therapy was considerably more effective than oestrogen as regards time to progression of the carcinoma , but in metastatic ( M1 ) and histologically poorly differentiated tumours both methods gave similar results . Cardiovascular complications showed equal incidence in both groups . LHRH agonist therapy thus seemed to be more effective than polyoestradiol phosphate against locally advanced prostatic cancer in the doses used One hundred consecutive patients aged up to 75 with newly diagnosed cancer of the prostate suitable for hormonal treatment were included in a controlled study of the cardiovascular effects of oestrogen versus orchidectomy . In all cases pre-existing cardiovascular morbidity was excluded . Of the 100 patients , 91 were strictly r and omised to receive either oestrogen ( n = 47 ) or orchidectomy ( n = 44 ) and 9 ( 6 given oestrogen , 3 orchidectomy ) either chose their own treatment ( five cases ) or had it selected for them by the urologist ( four ) . Oestrogen was given in the lowest recommended dosage in Sweden -- namely , as 160 mg polyestradiol phosphate intramuscularly every month for the first three months , then 80 mg monthly , plus ethinyloestradiol 1 mg by mouth daily for the first two weeks , then 150 micrograms daily . At entry to the study the two treatment groups showed no difference in demographic characteristics or conventional risk factors for cardiovascular disease . During the first year , however , 13 ( 25 % ) of the patients given oestrogen suffered major cardiovascular events as compared with none of the patients after orchidectomy . Patients in the oestrogen treatment group who did not have minor signs of atherosclerosis at entry to the study suffered a similar incidence of cardiovascular complications to those who did have these signs at entry . The substantially increased risk of cardiovascular complications in patients given oestrogen for prostatic cancer warrants careful consideration when choosing treatment for this disorder In a prospect i ve r and omized multicenter trial patients with highly or moderately differentiated prostatic carcinoma , previously untreated , were allotted either to oral Estramustine phosphate or to intramuscular polyestradiol phosphate plus oral ethinyl estradiol . As regards frequency and duration of tumour remission there was no statistical difference between the two groups . Nor did they differ significantly with respect to adverse reactions . This is an interim report and will be followed later on by a final evaluation PURPOSE We evaluated whether the timing of fatal myocardial infa rct ion ( MI ) was influenced by the administration of and rogen suppression therapy ( AST ) . PATIENTS AND METHODS The study cohort comprised 1,372 men who were enrolled onto three r and omized trials between February 1995 and June 2001 . In the three trials , the men were r and omly assigned to receive radiation therapy with 0 versus 3 versus 6 , 3 versus 8 , or 0 versus 6 months of AST . Fine and Gray 's regression was used to determine the clinical factors associated with the time to fatal MI , and estimates of time to fatal MI were calculated using a cumulative incidence method . When comparing the cumulative incidence estimates using Gray 's k- sample P values , increased weight was ascribed to the earlier data because recovery of testosterone is expected for most men within 2 years after short-course AST . RESULTS Men age 65 years or older who received 6 months of AST experienced shorter times to fatal MIs compared with men in this age group who did not receive AST ( P = .017 ) and men younger than 65 years ( P = .016 ) . No significant difference ( P = .97 ) was observed in the time to fatal MIs in men age 65 years or older who received 6 to 8 months of AST compared with 3 months of AST . CONCLUSION The use of AST is associated with earlier onset of fatal MIs in men age 65 years or older who are treated for 6 months compared with men who are not treated with AST |
1,972 | 25,193,246 | Results showed compromised control of overt and covert eye movements , dynamic postural control , manual control for tasks that vary in complexity , and for motor imagery of manual and whole-body postures .
Importantly , this review shows support for general hypothesis that deficits of predictive control manifest in DCD across effector systems | A viable hypothesis to explain the compromised motor ability of children with Developmental Coordination Disorder ( DCD ) suggests a fundamental deficit in their ability to utilize internal models for motor control .
Dysfunction in this mode of control is thought to compromise their motor learning capabilities .
The aim of this systematic review is to examine the available evidence for the internal modeling deficit ( IMD ) hypothesis . | In a recent study , children with movement clumsiness ( or Developmental Coordination Disorder-DCD ) were shown to have difficulties making rapid online corrections when reaching , demonstrated by slower and less accurate movements to double-step targets ( Hyde & Wilson , 2011 ) . These results suggest that children with DCD have difficulty using predictive estimates of limb position when making rapid adjustments to movement , in-flight . However , chronometric data alone does not provide strong evidence for this hypothesis : it remains unclear whether early ( and rapid ) control parameters or post-correction stages of the movement trajectory are affected . Thus , the overarching aim of this study was to conduct a kinematic analysis of double-step reaching in order to isolate the different control parameters that might explain the slower and less accurate double-step reaching performance of children with DCD . Participants were a new sample of 13 children with DCD aged between 8 - 12 years and 13 age-matched controls . Children were required to reach and touch one of three possible targets presented at the coordinates -20 ° , 0 ° and 20 ° on a 17 in . LCD touch-screen . For most trials ( 80 % ) the target remained stationary for the duration of movement ( non-jump trials ) , while for the remainder ( 20 % ) , the target jumped r and omly to one of two peripheral locations at movement onset ( jump trials ) . Consistent with earlier work , children with DCD were slower to initiate reaching compared to controls and showed longer MT and more errors on jump trials . Kinematic data showed that while the two groups did not differ on time to peak velocity or acceleration , children with DCD were slower to correct reach trajectory on jump trials . No group differences were observed on late kinematic markers , e.g. , post-correction time . The pattern of results support and extend earlier work showing deficits in ROC in DCD . From a computational perspective , delayed corrections to the reach trajectory suggests some difficulty integrating information about the target perturbation with a predictive ( or forward ) estimate of limb position relative to the initial target . These conclusions are discussed , along with directions for future research Children with developmental coordination disorder ( DCD ) have been demonstrated to show a deficit of inhibitory control in volitional shifts of attention . The aim of this study was to use ecological intervention to investigate the efficacy of table-tennis training on treating both problems with attentional networks and motor disorder in children with DCD . Forty-three children aged 9 - 10 years old were screened using the Movement Assessment Battery for Children and divided into DCD ( n=27 ) and typically developing ( TD , n=16 ) groups . Children with DCD were then quasi-r and omly assigned to either a DCD-training group who underwent a ten-week table-tennis training program with a frequency of 3 times a week or a DCD non-training group . Before and after training , the capacity of inhibitory control was examined with the endogenous Posner paradigm task for DCD and TD groups . Table-tennis training result ed in significant improvement of cognitive and motor functions for the children with DCD . The study demonstrated that exercise intervention employed within the school setting can benefit the inhibitory control and motor performance in children with DCD . However , future research efforts should continue to clarify whether the performance gains could be maintained over time Theoretical motor control predicts that because of delays in sensorimotor pathways , a neural system should exist in the brain that uses efferent copy of comm and s to the arm , sensory feedback , and an internal model of the dynamics of the arm to predict the future state of the h and ( i.e. , a forward model ) . We tested this theory under the hypothesis that saccadic eye movements , tracking an unseen reaching movement , would reflect the output of this state predictor . We found that in unperturbed reaching movements , saccade occurrence at any timet consistently provided an unbiased estimate of h and position at t + 196 msec . To investigate the behavior of this predictor during feedback error control , we applied 50 msec r and om-force perturbations to the moving h and . Saccades showed a sharp inhibition at 100 msec after perturbation . At ∼170 msec , there was a sharp increase in saccade probabilities . These postperturbation saccades were an unbiased estimator of h and position at saccade timet + 150 msec . The ability of the brain to guide saccades to the future position of the h and failed when a force field unexpectedly changed the dynamics of the h and immediately after perturbation . The behavior of the eyes suggested that during reaching movements , the brain computes an estimate of future h and position based on an internal model that relies on real-time proprioceptive feedback . When an error occurs in reaching movements , the estimate of future h and position is recomputed . The saccade inhibition period that follows the h and perturbation may indicate the length of time it takes for this computation to take place Children with impaired motor coordination ( or developmental coordination disorder ) have difficulty representing internally the visuospatial coordinates of intended movements . We have proposed that this deficit reflects impairment in the generation of forward models of the efference copy of intended movements―the efference-copy-deficit hypothesis . In this study , we challenged this hypothesis by examining the efficacy of an imagery intervention design ed specifically to train the forward modeling of purposive actions . A pre-post design was adopted . Fifty-four children referred with motor coordination problems were assigned r and omly to one of three groups : imagery training , traditional perceptual-motor training , and wait-list control . The imagery protocol ―delivered by an interactive CD―ROM―was shown to be equally effective to perceptual-motor training in facilitating the development of motor skill in the referred children . These results support the efference-copy-deficit hypothesis in explaining the cause of motor clumsiness in most children . Directions for future intervention studies and remediation in the field of developmental clumsiness are discussed . ( J Child Neurol 2002;17:491 - 498 ) The study investigated whether 10-week soccer training can benefit the inhibitory control and neuroelectric indices in children with developmental coordination disorder ( DCD ) . Fifty-one children were divided into groups of typically developing ( TD , n=21 ) , DCD-training ( n=16 ) , and DCD non-training ( n=14 ) individuals using the for Children test , and , before and after training , were assessed with the visuospatial attention orienting task with their lower extremities , while brain event-related potentials ( ERPs ) were concurrently recorded . The results indicated that , when compared to TD children , children with DCD responded significantly more slowly across conditions of the visuospatial attention orienting task and showed a deficit of inhibitory control capacity in their lower extremities , whereas no group differences were observed for the accuracy rate . Neuroelectric data indicated that , before training , P3 amplitude was smaller and P3 latency was slower for both DCD groups compared to TD children across conditions of the visuospatial attention orienting task ; after training , the beneficial effects were seen in the strength of inhibitory control and P3 latency in the DCD-training group . The data suggest that soccer training result ed in significant improvements in ERP and task performance indices for the children with DCD Abstract The motor control of a sequence of two motor acts forming an action was studied in the present experiment . The two analysed motor acts were reaching-grasping an object ( first target ) and placing it on a second target of the same shape and size ( experiment 1 ) . The aim was to determine whether extrinsic properties of the second target ( i.e. target distance ) could selectively influence the kinematics of reaching and grasping . Distance , position and size of both targets were r and omly varied across the experimental session . The kinematics of the initial phase of the first motor act , that is , velocity of reaching and h and shaping of grasping , were influenced by distance of the second target . No kinematic difference was found between movements executed with and without visual control of both h and and targets . These results could be due to computation of the general program of an action that takes into account extrinsic properties of the final target . Conversely , they could depend on a visual interference effect produced by the near second target on the control of the first motor act . In order to dissociate the effects due to second target distance from those due to visual interference , two control experiments were carried out . In the first control experiment ( experiment 2 ) subjects executed movements directed towards spatial locations at different distances from the first target , as in experiment 1 . However , the near second target was not presented and subjects were required to place the object on an arbitrary near position . Distance of the second ( either real or arbitrary ) target affected the reaching component of the first motor act , as in experiment 1 , but not the grasp component . In the second control experiment ( experiment 3 ) , the pure visual interference effect was tested . Subjects were required to reach and grasp the object and to lift it in either presence or absence of a second near stimulus . No effect on the initial phase of the first motor act was observed . The results of the this study suggest a dissociation in the control of reaching and grasping , concerning not only visual analysis of extrinsic properties of the immediate target but also visual analysis of the final target of the action . In other words , the notion of modularity for the motor control can be extended to the construction of an entire action & NA ; The chronometry of imagined and actual movements was investigated in a patient with a unilateral lesion of the motor cortex . Motor imagery generated highly accurate estimates of motor performance in a variety of situations , reflecting the hypokinesia of the contralesional h and . There were parallel increases in mental and actual movement times from proximal to distal limb segments . Bimanual movements adopted the slower speed of the impaired h and in both conditions . Imagined motor sequences to the beat of a metronome predicted the maximum speed reached in actual performance . Finally , visually guided pointing showed the same target‐size effects in the imagery and movement conditions . The results are in agreement with the hypothesis that common cerebral motor representations are activated when imaging and planning voluntary movements The aims of this study were to determine the motor outcome of extremely‐low‐birthweight ( ELBW ; < 1000 g ) or very preterm ( < 28wks ) children compared with normal birthweight ( NBW ) children , to establish the perinatal associations of developmental coordination disorder ( DCD ) and its cognitive and behavioural consequences . Participants were consecutive surviving ELBW or very preterm children and r and omly selected NBW(>2499 g ) children born in the state of Victoria , Australia , in 1991 or 1992 . Main outcomes were : ( 1 ) results of the Movement Assessment Battery for Children ( MABC ) at 8 years of age ; ( 2 ) cognitive function ; ( 3 ) academic progress ; and ( 4 ) behaviour . Of 298 consecutive ELBW/very preterm survivors , 255 ( 85.6 % ; 117 males , 138 females ) had the MABC at a mean age of 8 years 8 months . More ELBW/very preterm children ( 9.5 % ) had DCD than the NBW group ( 2 % , p=0.001 ) . Only male sex increased the likelihood of DCD in ELBW/very preterm children ( p=0.017 ) . ELBW/very preterm children with DCD had worse cognitive function and academic test scores ( up to 1SD below those without DCD ) ; they also had more adaptive behaviour and externalizing problems , but not internalizing problems . DCD is more common in ELBW/very preterm children , has few perinatal correlates , and is associated with poor cognitive and academic performance as well as increased behaviour problems The purpose of the study was to examine the relationship between the extremities in different aspects of motor performance , including simple reaction time , choice reaction time , speed of movement , tapping speed , and coordination , i.e. , speed of movement/accuracy . 186 healthy r and omly selected right-h and ed subjects ( 93 men , 93 women ; aged 21–70 years ) were measured on a test battery of five tests for both h and s and feet . Correlations between the extremities in motor performance were highest between h and s ( r = .71–.80 , p<.001 ) or between feet ( r = .57–.88 , p<.001 ) depending on the complexity of response for all subjects . These relations remained at almost the same magnitude even when age was eliminated . Correlations between the upper and lower extremities were lower ( r = .40–.62 ) . Correlations between extremities were lower for one age group ( 21–30 years ) than for all subjects ( 21–70 years ) . These results showed that the motor performance for the h and s is not a very good indicator of the motor performance of the lower extremities , especially in a homogeneous age group , and it seems that the lower extremities should be studied with specific motor performance tests Consistent preferences for particular types of movement suggest criteria for movement selection . These can be important when , as is usually the case , infinitely many movements allow a task to be achieved . The experiments reported here were design ed to identify the source of a strong preference observed in earlier object-manipulation studies . In those earlier studies , subjects usually grabbed objects to be moved from one location to another in a way that afforded a comfortable final posture rather than a comfortable initial posture ( the end-state comfort effect ) . The comfortable final state usually allowed the forearm to be at or near the middle of its range of motion on the pronation-supination dimension . The hypothesis tested here was that the end-state comfort effect stemmed from an expectation that movements can be made more quickly in the middle of the pronation-supination range than at either extreme . To test this hypothesis , we asked subjects , in the first experiment , to perform a h and le rotation task that dem and ed little or no precision and so no need to make rapid to- and -fro homing-in movements near the end of the rotation . Half the subjects did not show the end-state comfort effect , in contrast to all previous studies , where all subjects showed the effect . An incidental finding of the first experiment was that h and le rotations that ended at or near the end of the range of motion took longer than h and le rotations that ended at or near the middle of the range of motion . To test the latter result more carefully , we asked subjects , in Experiments 2 and 3 , to oscillate the forearm as quickly as possible , either in the supination part of the forearm rotation range , in the middle part of the range , or in the pronation part of the range . As predicted , oscillation frequencies were highest in midrange , and this was true for both h and s. The results as a whole have implication s for the relation between cognitive psychology and biomechanics , and for human factors |
1,973 | 20,613,475 | Treatment of preoperative anemia with iron , with or without erythropoietin , and perioperative cell salvage decreased the need for blood transfusion and may contribute to improved patient outcomes . | null | null |
1,974 | 15,684,151 | No differences in rates of hospital admissions for threatened preterm labor or perinatal mortality were noted for subjects receiving progestational agents in general or for those receiving only 17α-hydroxyprogesterone caproate specifically .
: The use of progestational agents and 17α-hydroxyprogesterone caproate reduced the incidence of preterm birth and low birth weight newborns | OBJECTIVE : To perform an up date d systematic review with meta- analysis to further eluci date the efficacy of progestational agents for the prevention of preterm births in patients at elevated risk . | BACKGROUND Midtrimester amniocentesis to investigate fetal karyotype carries a small risk of fetal loss . AIM To test the hypothesis that progesterone prophylaxis may reduce this . STUDY DESIGN A r and omised controlled trial comparing a short prophylactic treatment with progesterone after amniocentesis with untreated controls . RESULTS There were no differences in frequency of miscarriage , preterm delivery or neonatal outcome . CONCLUSION Prophylactic progesterone treatment after amniocentesis does not improve obstetric outcome A prior report suggested that active-duty pregnant women are at increased risk for low-birth weight infants and a higher perinatal mortality rate . The present double-blind investigation was design ed to prospect ively evaluate that risk and to test the efficacy of 17 alpha-hydroxyprogesterone caproate to prevent reported complications . Three groups of active-duty women were studied , beginning between 16 and 20 weeks ' gestation . They were similar for parity , previous abortion , race , cigarette smoking , and marital status . Of these , 80 were given 17 alpha-hydroxyprogesterone caproate , 88 received placebo , and 78 declined to participate in the protocol . There was no significant differences in the three groups when comparisons were made for low-birth weight infants and for perinatal mortality . However , when comparison was made to a military dependent population , they had a significantly worse outcome with regard to both perinatal mortality ( p = 0.001 ) and infants with a birth weight less than 2,500 gm ( p = 0.01 ) . We concluded that pregnant military personnel were at increased risk for adverse pregnancy outcome , but that this risk was not altered by therapy with 17 alpha-hydroxyprogesterone caproate OBJECTIVE The purpose of this study was to evaluate the effect of prophylactic vaginal progesterone in decreasing preterm birth rate in a high-risk population . STUDY DESIGN A r and omized , double-blind , placebo-controlled study included 142 high-risk singleton pregnancies . Progesterone ( 100 mg ) or placebo was administered daily by vaginal suppository and all patients underwent uterine contraction monitoring with an external tocodynamometer once a week for 60 minutes , between 24 and 34 weeks of gestation . Progesterone ( n = 72 ) and placebo ( n = 70 ) groups were compared for epidemiologic characteristics , uterine contraction frequency , and incidence of preterm birth . Data were compared by chi(2 ) analysis and Fisher exact test . RESULTS The preterm birth rate was 21.1 % ( 30/142 ) . Differences in uterine activity were found between the progesterone and placebo groups ( 23.6 % vs 54.3 % , respectively ; P < .05 ) and in preterm birth between progesterone and placebo ( 13.8 % vs 28.5 % , respectively ; P < .05 ) . More women were delivered before 34 weeks in the placebo group ( 18.5 % ) than in the progesterone group ( 2.7 % ) ( P < .05 ) . CONCLUSION Prophylactic vaginal progesterone reduced the frequency of uterine contractions and the rate of preterm delivery in women at high risk for prematurity Patients with multiple gestations or recalcitrant preterm labor are at very high risk for preterm birth in spite of adequate tocolysis . Subcutaneous infusion of tocolytic medications on an ambulatory basis has been used in several small series and has effectively prolonged gestation . This retrospective analysis presents data from 992 patients at very high risk for preterm delivery who were prescribed this therapy . The amount of tocolytic medication was individualized by utilizing the patient 's volume of distribution and clearance . Pharmacists adjusted the dosage based on uterine activity strips received by nursing personnel . The average basal rate was .073 + /- .020 mg/h . Patients received an average of seven scheduled boluses per day and 1.54 + /- .93 unscheduled boluses per week ( .25 + /- .03 mg each ) . The therapy extended the gestation a mean of 38 + /- 23 days and average gestational age at delivery was 36.3 + /- 2.6 weeks with a mean birthweight of 2759 + /- 681 g. This study , utilizing a large number of patients , confirms earlier reports that for women at very high risk for preterm delivery subcutaneous tocolytic infusion therapy is beneficial . Prospect i ve studies evaluating such treatment on a r and omized basis are indicated The potential tocolytic effect of natural progesterone administration on premature labor was investigated in a double-blind study . An oral progesterone formulation was used because its ability to increase both plasma and myometrial concentration of progesterone in pregnant women had been previously demonstrated . Furthermore , no commercial intravenous or intramuscular natural progesterone formulation is currently available in France . Fifty-seven patients in two obstetric clinics , admitted because of the risk of premature delivery , were included in the study , and uterine contractility and fetal cardiac rhythm were monitored in all of them . At r and om and after 30 minutes ' rest , 29 women absorbed four capsules of 100 mg of progesterone each and 28 women absorbed four capsules of a placebo . Plasma progesterone levels were evaluated in all cases after 30 minutes ' rest and 1 hour after absorption of the capsules . The results showed that bed rest and placebo administration decrease uterine activity in 42 % of the cases and oral progesterone decreases activity in 75 % to 88 % of cases , depending on the initial severity of the menace of premature delivery . The difference between the effects of progesterone and of placebo is significant . The tocolytic effect of oral progesterone is not as intense or as rapid as the effect of intravenous beta-mimetics but is sufficient in 80 % of cases , on the average , to stop the premature labor without any detectable side effects . This tocolytic effect of oral progesterone is related not just to an increase in plasma progesterone levels but probably to an increase in myometrial progesterone concentration There are indications that prophylactic administration of 17α-hydroxyprogesterone caproate ( 17α-OHP-C ) could be beneficial in the treatment of women at risk for preterm delivery . Since twin pregnancy is commonly associated with prematurity , 77 women with twin pregnancy were treated during the last trimester until the 37th gestational week with weekly injections of either 17α-OHP-C or a placebo , following double-blind principles . The gestational length and birth weight and the outcome of the neonates were similar in both groups . The administration of 17α-OHP-C thus seems ineffective in the prevention of prematurity risks associated with twin pregnancy . ( Obstet Gynecol 56:692 , 1980 The results of a study concerning the treatment of acute menace of preterm labor are given : beta-mimetics were administered intravenously in all cases ( 44 ) and micronized progesterone or placebo was administered orally after classical double-blind r and omization ( 22 cases in each group ) . The mean index of pregnancy prolongation was the same in both groups . However the mean duration of the intravenous perfusion and the mean quantity of beta-mimetics administered intravenously were significantly reduced in the progesterone group ( P less than 0.01 ) . The mean duration of hospital stay was also significantly reduced ( P less than 0.05 ) . Cost and risks are finally significantly lessened |
1,975 | 23,870,277 | Stigma and fear of status disclosure to partners , family or community members ( community-level factors ) were the most frequently cited barriers overall and across time .
The extent of partner/community support was another major factor impeding or facilitating the uptake of PMTCT ARVs , while cultural traditions including preferences for traditional healers and birth attendants were also common .
Key health-systems issues included poor staff-client interactions , staff shortages , service accessibility and non-facility deliveries . | OBJECTIVES To investigate and synthesize reasons for low access , initiation and adherence to antiretroviral drugs by mothers and exposed babies for prevention of mother-to-child transmission ( PMTCT ) of HIV in sub-Saharan Africa .
CONCLUSIONS Long-st and ing health-systems issues ( such as staffing and service accessibility ) and community-level factors ( particularly stigma , fear of disclosure and lack of partner support ) have not changed over time and continue to plague PMTCT programmes more than 10 years after their introduction .
The potential of PMTCT programmes to virtually eliminate vertical transmission of HIV will remain elusive unless these barriers are tackled . | Background Human re source limitations are a challenge to the delivery of antiretroviral therapy ( ART ) in low-re source setting s. We conducted a cluster r and omized trial to assess the effect of community-based peer health workers ( PHW ) on AIDS care of adults in Rakai , Ug and a. Methodology /Principal Findings 15 AIDS clinics were r and omized 2∶1 to receive the PHW intervention ( n = 10 ) or control ( n = 5 ) . PHW tasks included clinic and home-based provision of counseling , clinical , adherence to ART , and social support . Primary outcomes were adherence and cumulative risk of virologic failure ( > 400 copies/mL ) . Secondary outcomes were virologic failure at each 24 week time point up to 192 weeks of ART . Analysis was by intention to treat . From May 2006 to July 2008 , 1336 patients were followed . 444 ( 33 % ) of these patients were already on ART at the start of the study . No significant differences were found in lack of adherence ( < 95 % pill count adherence risk ratio [ RR ] 0.55 , 95 % confidence interval [ CI ] 0.23–1.35 ; < 100 % adherence RR 1.10 , 95 % CI 0.94–1.30 ) , cumulative risk of virologic failure ( RR 0.81 , 95 % CI 0.61–1.08 ) or in shorter-term virologic outcomes ( 24 week virologic failure RR 0.93 , 95 % CI 0.65–1.32 ; 48 week , RR 0.83 , 95 % CI 0.47–1.48 ; 72 week , RR 0.81 , 95 % CI 0.44–1.49 ) . However , virologic failure rates ≥96 weeks into ART were significantly decreased in the intervention arm compared to the control arm ( 96 week failure RR 0.50 , 95 % CI 0.31–0.81 ; 120 week , RR 0.59 , 95 % CI 0.22–1.60 ; 144 week , RR 0.39 , 95 % CI 0.16–0.95 ; 168 week , RR 0.30 , 95 % CI 0.097–0.92 ; 192 week , RR 0.067 , 95 % CI 0.0065–0.71 ) . Conclusions / Significance A PHW intervention was associated with decreased virologic failure rates occurring 96 weeks and longer into ART , but did not affect cumulative risk of virologic failure , adherence measures , or shorter-term virologic outcomes . PHWs may be an effective intervention to sustain long-term ART in low-re source setting s. Trial Registration Clinical Trials.gov Background Prevention of mother to child HIV transmission ( PMTCT ) programmes have great potential to achieve virtual elimination of perinatal HIV transmission provided that PMTCT recommendations are properly followed . This study assessed mothers and infants adherence to medication regimen for PMTCT and the proportions of exposed infants who were followed up in the PMTCT programme . Methods A prospect i ve cohort study was conducted among 282 HIV-positive mothers attending 15 health facilities in Addis Ababa , Ethiopia . Descriptive statistics , bivariate and mulitivariate logistic regression analyses were done . Results Of 282 mothers enrolled in the cohort , 232 ( 82 % , 95 % CI 77 - 86 % ) initiated medication during pregnancy , 154 ( 64 % ) initiated combined zidovudine ( ZDV ) prophylaxis regimen while 78 ( 33 % ) were initiated lifelong antiretroviral treatment ( ART ) . In total , 171 ( 60 % , 95 % CI 55 - 66 % ) mothers ingested medication during labour . Of the 221 live born infants ( including two sets of twins ) , 191 ( 87 % , 95 % CI 81 - 90 % ) ingested ZDV and single-dose nevirapine ( sdNVP ) at birth . Of the 219 live births ( twin births were counted once ) , 148 ( 68 % , 95 % CI 61 - 73 % ) mother-infant pairs ingested their medication at birth . Medication ingested by mother-infant pairs at birth was significantly and independently associated with place of delivery . Mother-infant pairs attended in health facilities at birth were more likely ( OR 6.7 95 % CI 2.90 - 21.65 ) to ingest their medication than those who were attended at home . Overall , 189 ( 86 % , 95 % CI 80 - 90 % ) infants were brought for first pentavalent vaccine and 115 ( 52 % , 95 % CI 45 - 58 % ) for early infant diagnosis at six-weeks postpartum . Among the infants brought for early diagnosis , 71 ( 32 % , 95 % CI 26 - 39 % ) had documented HIV test results and six ( 8.4 % ) were HIV positive . Conclusions We found a progressive decline in medication adherence across the perinatal period . There is a big gap between mediation initiated during pregnancy and actually ingested by the mother-infant pairs at birth . Follow up for HIV-exposed infants seem not to be organized and is inconsistent . In order to maximize effectiveness of the PMTCT programme , the rate of institutional delivery should be increased , the quality of obstetric services should be improved and missed opportunities to exposed infant follow up should be minimized Background The aim of this study was to describe barriers to accessing and accepting highly active antiretroviral therapy ( HAART ) by HIV-positive mothers in the Ug and an Kabarole District 's Programme for the Prevention of Mother to Child Transmission-Plus ( PMTCT-Plus ) . Methods Our study was a qualitative descriptive exploratory study using thematic analysis . Individual in-depth interviews ( n = 45 ) were conducted with r and omly selected HIV-positive mothers who attended this programme , and who : ( a ) never enrolled in HAART ( n = 17 ) ; ( b ) enrolled but did not come back to receive HAART ( n = 2 ) ; ( c ) defaulted/interrupted HAART ( n = 14 ) ; and ( d ) are currently adhering to HAART ( n = 12 ) . A focus group was also conducted to verify the results from the interviews . Results Results indicated that economic concerns , particularly transport costs from residences to the clinics , represented the greatest barrier to accessing treatment . In addition , HIV-related stigma and non-disclosure of HIV status to clients ' sexual partners , long waiting times at the clinic and suboptimal provider-patient interactions at the hospital emerged as significant barriers . Conclusions These barriers to antiretroviral treatment of pregnant and post-natal women need to be addressed in order to improve HAART uptake and adherence for this group of the population . This would improve their survival and , at the same time , drastically reduce HIV transmission from mother to child Background Global coverage of prevention of mother-to-child ( PMTCT ) services reached 53 % in 2009 . However the number of pregnant women who test positive for HIV in antenatal clinics and who link into long-term HIV care is not known in many re source -poor countries . We measured the proportion of HIV-positive pregnant women in Mwanza city , Tanzania , who completed the cascade of care from antenatal HIV diagnosis to assessment and engagement in care in adult HIV clinics . Methods Thirty antenatal and maternity ward health workers were interviewed about PMTCT activities . Nine antenatal HIV education sessions were observed . A prospect i ve cohort of 403 HIV-positive women was enrolled by specially-trained clinicians and nurses on admission to delivery and followed for four months post-partum . Information was collected on referral and attendance at adult HIV clinics , eligibility for highly active antiretroviral therapy ( HAART ) and reasons for lack of attendance . Results Overall , 70 % of PMTCT health workers referred HIV-positive pregnant women to the HIV clinic for assessment and care . Antenatal HIV education sessions did not cover on-going care for HIV-infected women . Of 310 cohort participants tested in pregnancy , 51 % had received an HIV clinic referral pre-delivery . Only 32 % of 244 women followed to four months post-partum had attended an HIV clinic and been assessed for HAART eligibility . Non-attendance for HIV care was independently associated with fewer antenatal visits , poor PMTCT prophylaxis compliance , non-disclosure of HIV status , and non-Sukuma ethnicity . Conclusion Most women identified as HIV-positive during pregnancy were not assessed for HAART eligibility during pregnancy or in the first four months post-partum . Initiating HAART at the antenatal clinic , improved counselling and linkages to care between PMTCT and adult HIV treatment services and reducing stigma surrounding disclosure of HIV results would benefit on-going care of HIV-positive pregnant women Objective : There is limited evidence on whether growing mobile phone availability in sub-Saharan Africa can be used to promote high adherence to antiretroviral therapy ( ART ) . This study tested the efficacy of short message service ( SMS ) reminders on adherence to ART among patients attending a rural clinic in Kenya . Design : A r and omized controlled trial of four SMS reminder interventions with 48 weeks of follow-up . Methods : Four hundred and thirty-one adult patients who had initiated ART within 3 months were enrolled and r and omly assigned to a control group or one of the four intervention groups . Participants in the intervention groups received SMS reminders that were either short or long and sent at a daily or weekly frequency . Adherence was measured using the medication event monitoring system . The primary outcome was whether adherence exceeded 90 % during each 12-week period of analysis and the 48-week study period . The secondary outcome was whether there were treatment interruptions lasting at least 48 h. Results : In intention-to-treat analysis , 53 % of participants receiving weekly SMS reminders achieved adherence of at least 90 % during the 48 weeks of the study , compared with 40 % of participants in the control group ( P = 0.03 ) . Participants in groups receiving weekly reminders were also significantly less likely to experience treatment interruptions exceeding 48 h during the 48-week follow-up period than participants in the control group ( 81 vs. 90 % , P = 0.03 ) . Conclusion : These results suggest that SMS reminders may be an important tool to achieve optimal treatment response in re source -limited setting Objective : To compare compliance and infant HIV-1 infection risk at 6 weeks with the Thai-CDC and HIVNET-012 antiretroviral regimens in a field setting . Design : R and omized clinical trial . Setting : Tertiary hospital antenatal clinic in Nairobi , Kenya . Participants : HIV-1 infected women referred from primary care clinics . Interventions : Thai-CDC zidovudine regimen or HIVNET-012 nevirapine regimen . Main outcome measures : Women were considered compliant if they used ⩾ 80 % of the doses . Infants were tested for HIV-1 at 6 weeks . Results : Seventy women were r and omized to Thai-CDC and 69 to HIVNET-012 regimens . More women were compliant with the antenatal ( 86 % ) than the intrapartum ( 44 % ) Thai-CDC regimen doses ( P = 0.001 ) . Ninety-seven per cent took the maternal and 91 % gave the infant dose of the HIVNET-012 regimen ( P = 0.2 ) . Overall , 41 % were compliant with the Thai-CDC regimen and 87 % with the HIVNET-012 regimen ( P < 0.001 ) . Compliance with the Thai-CDC regimen was associated with partner support of antiretroviral use [ odds ratio ( OR ) , 3.0 ; , 95 % confidence interval ( CI ) , 1.0–9.1 ] and knowledge at recruitment that antiretroviral drugs could prevent infant HIV-1 ( OR , 2.9 ; 95 % CI , 1.0–8.1 ) . Compliance with the HIVNET-012 regimen was associated with partner notification ( OR , 8.0 ; 95 % CI , 1.5–50 ) and partner willingness to have HIV-1 testing ( OR , 7.5 ; 95 % CI , 1.4–40 ) . There was a trend for a higher risk of transmission with the HIVNET-012 regimen than with the Thai-CDC regimen ( 22 % versus 9 % ; P = 0.07 ) . Conclusion : Compliance with the Thai-CDC and HIVNET-012 regimens was comparable to that in efficacy trials . Partner involvement , support and education on perinatal HIV-1 prevention may improve compliance and increase the number of infants protected from HIV-1 infection Universal nevirapine ( NVP ) therapy ( provision of the drug without HIV testing ) has been suggested as potentially superior to targeted NVP therapy ( provision of the drug to seropositive patients identified through voluntary HIV counseling and testing [ VCT ] ) for perinatal HIV prevention in low-re source , high-prevalence setting s. The authors postulated that uptake ( the proportion of women who accept the strategy when offered ) may be higher for universal therapy , since it does not require a woman to learn her serostatus ; they further postulated that adherence ( the proportion of women who actually ingest the NVP tablet at labor onset ) may be higher for targeted therapy , since knowledge of serostatus could motivate better adherence . Two clinics in Lusaka , Zambia were assigned to provide either the targeted or universal strategy . Halfway through the study period , the approach offered at each clinic was crossed over . Adherence was assessed by liquid chromatographic assay for NVP of cord blood . Regarding uptake , 1524 pregnant women were offered participation , and 1025 ( 67 % ) accepted . Of 694 women offered enrollment in the universal strategy , 496 ( 71 % ) accepted ; of 830 women offered enrollment in the targeted strategy , 529 ( 64 % ) accepted ( p < .01 ) . Uptake was similar at both clinics for the universal strategy : 250 of 339 ( 74 % ) at clinic A and 246 of 355 ( 69 % ) at clinic B ( p = .2 ) , but differed significantly between clinics for the targeted strategy : 229 of 316 ( 72 % ) at clinic A and 300 of 514 ( 58 % ) at clinic B ( RR , 1.51 ; 95 % CI , 1.23 , 1.86 ) . Increased uptake correlated with having been offered the universal rather than the targeted strategy ( AOR , 1.5 ; 95 % CI , 1.1 , 2.1 ) , attendance at clinic A ( AOR , 1.4 ; 95 % CI , 1.01 , 2.0 ) , and maternal report of a prior fetal or infant death ( AOR , 1.6 ; 95 % CI , 1.1 , 2.5 ) . Regarding adherence , in the universal strategy , 40 of 103 women ( 39 % ) were nonadherent compared with 25 of 98 women ( 26 % ) in the targeted strategy ( RR , 1.5 ; 95 % CI , 1.004 , 2.3 ) . Failure to adhere correlated with participation in the universal strategy ( AOR , 2.0 ; 95 % CI , 1.04 , 4.2 ) and illiteracy ( AOR , 2.6 ; 95 % CI , 1.2 , 5.3 ) . In high-prevalence setting s with adequate VCT services , uptake of NVP using the universal or targeted approach appears comparable . However , the universal strategy may result in better uptake in clinics with less well-functioning VCT services ( as with clinic B ) . Adherence to the single-dose NVP intervention was lower among women who did not learn their HIV status . Programs that seek to save the greatest possible number of infants from perinatal HIV acquisition should consider a combination approach , in which women who desire HIV testing can access NVP through a targeted strategy , and women who do not desire testing can access NVP through a universal strategy Background : Provision of HIV testing in labor provides an opportunity to reach susceptible women and infants . Methods : As part of a cluster r and omized trial of labor ward-based prevention of mother-to-child transmission services in Lusaka , Zambia , we determined predictors of testing acceptance and nevirapine ( NVP ) administration in labor . HIV counseling and testing were offered to women unaware of their HIV status . NVP was administered to women who tested positive , and an inert ( calcium ) tablet was provided to women who tested negative , to avoid stigmatization . Results : Among the 2435 women who presented in labor , 393 ( 16 % ) were unaware of their HIV status , of whom 278 ( 71 % ) met eligibility criteria . We offered counseling to 217 ( 78 % ) of eligible women : 146 ( 67 % ) agreed , 82 ( 56 % ) of those counseled were tested for HIV , and 23 ( 28 % ) were seropositive . Testing rates were higher among primigravida women [ adjusted odds ratio ( AOR ) 1.5 ; 95 % confidence interval ( CI ) : 1.1 to 2.1 ] and among those not offered HIV testing during their pregnancy ( AOR 3.7 ; 95 % CI : 2.8 to 5.1 ) . Cervical dilation ≤3 cm at the time of admission was associated strongly with NVP ingestion > 1 hour ( AOR 11.5 ; 95 % CI : 4.5 to 29.2 ) and > 2 hours ( AOR 11.4 ; 95 % CI : 4.7 to 27.5 ) before delivery . Conclusion : Labor ward HIV testing is feasible in this re source -limited setting CONTEXT Few studies have objective ly evaluated the coverage of services to prevent transmission of human immunodeficiency virus ( HIV ) from mother to child . OBJECTIVE To measure the coverage of services to prevent mother-to-child HIV transmission in 4 African countries . DESIGN , SETTING , AND PATIENTS Cross-sectional surveillance study of mother-infant pairs using umbilical cord blood sample s collected between June 10 , 2007 , and October 30 , 2008 , from 43 r and omly selected facilities ( grouped as 25 service clusters ) providing delivery services in Cameroon , Côte d'Ivoire , South Africa , and Zambia . All sites used at least single-dose nevirapine to prevent mother-to-child HIV transmission and some sites used additional prophylaxis drugs . MAIN OUTCOME MEASURE Population nevirapine coverage , defined as the proportion of HIV-exposed infants in the sample with both maternal nevirapine ingestion ( confirmed by cord blood chromatography ) and infant nevirapine ingestion ( confirmed by direct observation ) . RESULTS A total of 27,893 cord blood specimens were tested , of which 3324 were HIV seropositive ( 12 % ) . Complete data for cord blood nevirapine results were available on 3196 HIV-seropositive mother-infant pairs . Nevirapine coverage varied significantly by site ( range : 0%-82 % ) . Adjusted for country , the overall coverage estimate was 51 % ( 95 % confidence interval [ CI ] , 49%-53 % ) . In multivariable analysis , failed coverage of nevirapine-based services was significantly associated with maternal age younger than 20 years ( adjusted odds ratio [ AOR ] , 1.44 ; 95 % CI , 1.18 - 1.76 ) and maternal age between 20 and 25 years ( AOR , 1.28 ; 95 % CI , 1.07 - 1.54 ) vs maternal age of older than 30 years ; 1 or fewer antenatal care visits ( AOR , 2.91 ; 95 % CI , 2.40 - 3.54 ) , 2 or 3 antenatal care visits ( AOR , 1.93 ; 95 % CI , 1.60 - 2.33 ) , and 4 or 5 antenatal care visits ( AOR , 1.56 ; 95 % CI , 1.34 - 1.80 ) vs 6 or more antenatal care visits ; vaginal delivery ( AOR , 1.22 ; 95 % CI , 1.03 - 1.44 ) vs cesarean delivery ; and infant birth weight of less than 2500 g ( AOR , 1.34 ; 95 % CI , 1.11 - 1.62 ) vs birth weight of 3500 g or greater . CONCLUSION In this r and om sampling of sites with services to prevent mother-to-child HIV transmission , only 51 % of HIV-exposed infants received the minimal regimen of single-dose nevirapine |
1,976 | 22,832,857 | A complex pattern of systemic immune activation , endothelial dysfunction and HPA axis hyperactivity is suggestive of the biological relationship between CVD and depression subtypes . | A compelling association has been observed between cardiovascular disease ( CVD ) and depression , suggesting individuals with depression to be at significantly higher risk for CVD and CVD-related mortality .
Systemic immune activation , hypothalamic – pituitary – adrenal ( HPA ) axis hyperactivity , arterial stiffness and endothelial dysfunction have been frequently implicated in this relationship .
Although a differential epidemiological association between CVD and depression subtypes is evident , it has not been determined if this indicates subtype specific biological mechanisms . | BACKGROUND Whether there is an association between depression at the time of acute myocardial infa rct ion and subsequent risk of cardiac complications and death remains controversial . Most studies of this risk factor have been limited to patients of single institutions , and this might account for the varying results . We prospect ively evaluated patients admitted to 5 tertiary care and 5 community hospitals and followed them for 1 year to measure the prevalence and prognostic impact of depressive symptoms after acute myocardial infa rct ion . METHODS Patients were recruited for the study by trained nurse interviewers who had documented acute myocardial infa rct ion within 2 - 3 days of admission . The nurses collected information from the medical records and asked study subjects to complete the Beck Depression Inventory question naire during their stay in hospital and using a mailed question naire 30 days , 6 months and 1 year later . We obtained information on vital status for patients lost to follow-up from a central death registry . RESULTS Of the 587 study subjects , 550 ( 94 % ) completed the Beck Depression Inventory at baseline and 191 ( 35 % ) had a score of 10 or more , indicating at least mild depression . Rates of depression did not vary over the follow-up period and were similar among patients admitted to tertiary care or community hospitals . Depressed patients were more likely to undergo catheterization ( 57 % v. 47 % , 95 % confidence interval [ CI ] around the difference 0.1%-19.6 % ) and were more likely to undergo percutaneous coronary intervention ( 32 % v. 24 % , 95 % CI around the difference 0.1%-16.2 % ) within 30 days of first admission to hospital . Patients with depression on admission had higher rates of a composite of cardiac complications , including recurrent ischemia , infa rct ion or congestive heart failure during their first stay in hospital or readmission for angina , recurrent acute myocardial infa rct ion , congestive heart failure or arrhythmia ( adjusted hazard ratio 1.4 , 95 % CI 1.05 - 1.86 ) , compared with patients who were not depressed on admission . After 1 year , death rates were higher among patients who were depressed at admission ( 30 patients , 16 % ) compared with nondepressed patients ( 28 patients , 8 % ) , although the difference was not statistically significant ( hazard ratio 1.3 , 95 % CI 0.59 - 3.05 ) . INTERPRETATION Depressive symptoms are common after acute myocardial infa rct ion and are associated with a slight increase in risk of in-hospital catheterization and angiography and readmission because of cardiac complications . Death was infrequent , with no statistically significant difference between the 2 groups Plasma cortisol and platelet serotonin ( 5-hydroxytryptamine , 5-HT ) concentrations were determined in 39 male psychotic and 39 male non-psychotic depressed in patients , and in 69 male healthy control subjects . Psychotic or non-psychotic depressed patients had higher predexamethasone plasma cortisol levels than found in the control group . After the dexamethasone suppression test ( DST ) , psychotic and non-psychotic depressed patients were subdivided into suppressors and non-suppressors . Psychotic and non-psychotic patients had significantly different platelet 5-HT concentrations among themselves and compared with the control group . However , there was no significant correlation between plasma cortisol levels and platelet 5-HT concentrations . Dexamethasone administration did not affect platelet 5-HT concentrations within subtypes of depressed patients . Abnormal cortisol suppression after the DST occurred more frequently in psychotic than in non-psychotic patients . Platelet 5-HT and plasma cortisol concentrations were decreased in patients with pronounced suicidal behaviour . Our results suggest that plasma cortisol and platelet 5-HT concentrations might serve as independent biological markers for different subtypes of depression Background and Purpose — Depression may be a risk factor for cardiovascular disease ( CVD ) mortality . We evaluated long-term mortality risk associated with depressive symptoms measured at middle age among men at high risk for coronary heart disease ( CHD ) . Methods — 12 866 men without definite evidence of CHD at study entry but who had above average risk of CHD based on blood pressure , blood cholesterol levels , and /or cigarette smoking were recruited into the Multiple Risk Factor Intervention Trial ( MRFIT ) . Survivors at the end of the trial were followed-up for mortality for an additional 18 years . Men who had completed the Center for Epidemiologic Studies Depression ( CES-D ) scale near the end of the trial ( n=11 216 ) were used in a prospect i ve analysis of post-trial all-cause and cause-specific mortality during 18-year follow-up after CES-D assessment . Results — Greater depressive symptoms measured at the end of the trial were associated with significantly higher risk of all-cause mortality and for cause-specific death , a higher risk of CVD , and , more specifically , stroke mortality ( all P values < 0.02 ) but not CHD mortality ( P=0.48 ) in linear trend analyses . The significant associations were strongest for those reporting the greatest depression : hazard ratio (HR)=1.15 ( 95 % CI , 1.03 to 1.28 ; P<0.01 ) for all-cause mortality for those in the highest depressive symptom quintile , HR=1.21 for CVD mortality ( 95 % CI , 1.03 to 1.41 ; P<0.05 ) , and HR=2.03 for stroke mortality ( 95 % CI , 1.20 to 3.44 ; P<0.01 ) compared with those in the lowest quintile . These associations were adjusted for age , intervention group , race , educational attainment , smoking at baseline and visit 6 , trial averaged systolic blood pressure , alcohol consumption , and fasting cholesterol , as well as the occurrence of nonfatal cardiovascular events during the trial . Conclusions — Greater depressive symptoms are associated with an increase in the risk of all-cause and , more specifically , CVD mortality in men . Stroke but not CHD was the form of CVD with which depressive symptoms were associated Background and Purpose — This study examined depressive disorder as a risk factor for incident stroke in a prospect i ve , population -based design . Methods — The Baltimore Epidemiologic Catchment Area Study is a prospect i ve 13-year follow-up of a probability sample of household residents from Baltimore , Md. Depressive disorder was measured with the diagnostic interview schedule , and stroke was assessed by questions from the health interview survey or by documentation on a death certificate . Results — During the 13-year follow-up of 1703 individuals , 66 strokes were reported and 29 strokes were identified by death certificate search . Individuals with a history of depressive disorder were 2.6 times more likely to report stroke than those without this disorder after controlling for heart disease , hypertension , diabetes , and current and previous use of tobacco . Medications used in the treatment of depressive disorder at baseline did not alter this finding . A history of dysthymia demonstrated a similar relationship to stroke , although the estimate was not statistically significant . Conclusions — Depressive disorder is a risk factor for stroke that appears to be independent of traditional cardiovascular risk factors . Further research on mechanisms for the association and the impact of treatment for depressive disorder on subsequent stroke is needed 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 Aortic pulse wave velocity ( PWV ) is a significant and independent predictor of cardiovascular mortality in subjects with essential hypertension and in patients with end-stage renal disease . Its contribution to cardiovascular risk in subjects 70 to 100 years old has never been tested . A cohort of 141 subjects ( mean±SD age , 87.1±6.6 years ) was studied in 3 geriatrics departments in a Paris suburb . Together with sphygmomanometric blood pressure measurements , aortic PWV was measured with a vali date d automatic device . During the 30-month follow-up , 56 patients died ( 27 from cardiovascular events ) . Logistic regressions indicated that age ( P = 0.005 ) and a loss of autonomy ( P = 0.01 ) were the best predictors of overall mortality . For cardiovascular mortality , aortic PWV was the major risk predictor ( P = 0.016 ) . The odds ratio was 1.19 ( 95 % confidence interval , 1.03 to 1.37 ) . Antihypertensive drug treatment and blood pressure , including systolic and pulse pressure , had no additive role . In subjects 70 to 100 years old , aortic PWV is a strong , independent predictor of cardiovascular death , whereas systolic or pulse pressure was not . This prospect i ve result will need to be confirmed in an intervention trial BACKGROUND AND PURPOSE Evidence is mounting linking cerebrovascular disease with depressive symptoms in the elderly . Lesions in both white and gray matter have been associated with depressive symptoms and major depression . We sought to investigate the relationship between depressive symptoms and white and gray matter lesions in subjects participating in the Cardiovascular Health Study . METHODS In a sample of 3660 men and women who underwent a st and ardized interview , physical examination , and MRI scan , we examined the association between number of white and gray matter lesions and white matter grade ( a measure of severity ) and reported depressive symptoms using a modified version of the Centers for Epidemiologic Studies Depression ( CES-D ) scale . We controlled for a variety of demographic and medical variables as well as functional status and Modified Mini-Mental State Examination score . RESULTS The number of small ( <3 mm ) basal ganglia lesions was significantly associated with reported depressive symptoms , but white matter grade was not . In subsequent logistic regression models , number of basal ganglia lesions remained a significant predictor after controlling for non-MRI variables and severity of white matter lesions . CONCLUSIONS Our findings extend previous reports that linked cerebrovascular changes to depressive symptoms in clinical population s to a large community-based population . This report provides further evidence of the importance of basal ganglia lesions in geriatric depression Background Availability of a range of techniques and devices allow measurement of many variables related to the stiffness of large or medium sized arteries . There is good evidence that , pulse wave velocity is a relatively simple measurement and is a good indicator of changes in arterial properties . The pulse wave velocity calculated from pulse wave recording by other methods like doppler or tonometry is tedious , time-consuming and above all their reproducibility depends on the operator skills . It requires intensive re source involvement . For epidemiological studies these methods are not suitable . The aim of our study was to clinical ly evaluate the validity and reproducibility of a new automatic device for measurement of pulse wave velocity that can be used in such studies . Methods In 44 subjects including normal healthy control and patients with coronary artery disease , heart brachial , heart ankle , brachial ankle and carotid femoral pulse wave velocities were recorded by using a new oscillometric device . Lead I and II electrocardiogram and pressure curves were simultaneously recorded . Two observers recorded the pulse wave velocity for validation and one observer recorded the velocity on two occasions for reproducibility . Results and Discussion Pulse wave velocity and arterial stiffness index were recorded in 24 control and 20 coronary artery disease patients . All the velocities were significantly high in coronary artery disease patients . There was highly significant correlation between the values noted by the two observers with low st and ard deviation . The Pearson 's correlation coefficient for various velocities ranged from ( r = 0.88–0.90 ) with ( p < 0.0001 ) . The reproducibility was also very good as shown by Bl and -Altman plot ; most of the values were lying within 2 SD . The interperiod measurements of pulse wave velocity were also significantly correlated ( r = 0.71 – 0.98 ) ( P < 0.0001 ) . Carotid-femoral pulse wave velocity was found to correlate significantly with heart brachial , heart ankle , brachial ankle pulse wave velocity and arterial stiffness index values . Reproducibility of our method was good with very low variability in both interobserver and interperiod analysis . Conclusion The new device " PeriScope " based on oscillometric technique has been found to be a simple , non-invasive and reproducible device for the assessment of pulse wave velocity and can be used to determine arterial stiffness in large population based studies OBJECTIVE To determine if the diagnosis of major depression in patients hospitalized following myocardial infa rct ion ( MI ) would have an independent impact on cardiac mortality over the first 6 months after discharge . DESIGN Prospect i ve evaluation of the impact of depression assessed using a modified version of the National Institute of Mental Health Diagnostic Interview Schedule for major depressive episode . Cox proportional hazards regression was used to evaluate the independent impact of depression after control for significant clinical predictors in the data set . SETTING A large , university-affiliated hospital specializing in cardiac care , located in Montreal , Quebec . PATIENTS All consenting patients ( N = 222 ) who met established criteria for MI between August 1991 and July 1992 and who survived to be discharged from the hospital . Patients were interviewed between 5 and 15 days following the MI and were followed up for 6 months . There were no age limits ( range , 24 to 88 years ; mean , 60 years ) . The sample was 78 % male . PRIMARY OUTCOME MEASURE Survival status at 6 months . RESULTS By 6 months , 12 patients had died . All deaths were due to cardiac causes . Depression was a significant predictor of mortality ( hazard ratio , 5.74 ; 95 % confidence interval , 4.61 to 6.87 ; P = .0006 ) . The impact of depression remained after control for left ventricular dysfunction ( Killip class ) and previous MI , the multivariate significant predictors of mortality in the data set ( adjusted hazard ratio , 4.29 ; 95 % confidence interval , 3.14 to 5.44 ; P = .013 ) . CONCLUSION Major depression in patients hospitalized following an MI is an independent risk factor for mortality at 6 months . Its impact is at least equivalent to that of left ventricular dysfunction ( Killip class ) and history of previous MI . Additional study is needed to determine whether treatment of depression can influence post-MI survival and to assess possible underlying mechanisms BACKGROUND Increased arterial stiffness ( AS ) might be one significant acute mediator of the well-attested association between female depression and cardiovascular disease . METHODS We tested this hypothesis in an inpatient sample of 20 drug-free women undergoing a new clinical ly severe major depressive episode of recent onset with an adequately matched mentally healthy control group . Patients ' clinical ( Hamilton Depression Rating Scale ) and vascular ( Pulse-Wave-Velocity , PWV ) assessment s were performed both before the initiation and after the completion of their six-week antidepressant treatment . RESULTS Although initially patients exhibited significantly higher PWV values than controls , this was decreased and reached comparable levels to controls after treatment completion . Moreover , full-responders exhibited significantly greater vascular improvement than their partial-responders counterparts and the magnitude of their amelioration was strongly associated with the magnitude of their clinical improvement . LIMITATIONS Our sample -size was small and patients ' follow-up short . CONCLUSIONS Our findings provide support to the hypothesis that current severe major depressive episode in women leads acutely to aggravation of arterial stiffness , reversible however upon timely and effective antidepressant treatment OBJECTIVE The authors investigated the association between major depressive disorder , including its clinical course , and mortality from ischemic heart disease . METHOD This was a prospect i ve cohort study of 8,261 men and 11,388 women 41 - 80 years of age who were free of clinical manifestations of heart disease and participated in the Norfolk , U.K. , cohort of the European Prospect i ve Investigation Into Cancer . The authors conducted a cross-sectional assessment of major depressive disorder during the period 1996 - 2000 and ascertained subsequent deaths from ischemic heart disease through linkage with data from the U.K. Office for National Statistics . RESULTS As of July 31 , 2006 , 274 deaths from ischemic heart disease were recorded over a total follow-up of 162,974 person-years ( the median follow-up period was 8.5 years ) . Participants who had major depression during the year preceding baseline assessment were 2.7 times more likely to die from ischemic heart disease over the follow-up period than those who did not , independently of age , sex , smoking , systolic blood pressure , cholesterol , physical activity , body mass index , diabetes , social class , heavy alcohol use , and antidepressant medication use . This association remained after exclusion of the first 6 years of follow-up data . Consideration of measures of major depression history ( including recency of onset , recurrence , chronicity , and age at first onset ) revealed recency of onset to be associated most strongly with ischemic heart disease mortality . CONCLUSIONS Major depression was associated with an increased risk of ischemic heart disease mortality . The association was independent of established risk factors for ischemic heart disease and remained undiminished several years after the original assessment Objective : We examined the association between depressive symptoms and all-cause mortality in a population sample . Published findings on the relation between depressive symptoms and mortality risk point to an inconsistent association and one that is likely influenced by health status . Few studies have assessed this relation in r and omly selected population sample s. Methods : Participants were 3617 noninstitutionalized adults , age 25 years or older , from the Americans ’ Changing Lives Study , an ongoing longitudinal study of a nationally representative sample . Depressive symptoms were measured by the 11-item version of the Center for Epidemiological Studies Depression Scale ( CES-D ) . Cox proportional hazards models estimated the relative risk of mortality as a function of the CES-D scores at baseline . Results : In 7.5 years of follow-up , 542 deaths occurred . Each 1-st and ard unit increase on the CES-D predicted a 21 % increased risk of all-cause mortality , adjusting for age , gender , and race ( hazard ratio = 1.21 , 95 % confidence interval = 1.08 to 1.36 , p = .001 ) . This association was weakened somewhat following adjustment for education , income , body mass index , smoking and alcohol consumption ( hazard ratio = 1.13 , 95 % confidence interval = 0.99 to 1.28 , p = .06 ) . However , control for self-reported functional limitations or chronic health conditions at baseline effectively eliminated the relationship . Analyses limited to participants with good to excellent health or no functional impairments at baseline showed no association between depressive symptoms and subsequent mortality risk . Secondary analyses showed no association between depressive symptoms and cardiovascular mortality . Conclusions : These findings from a r and omly selected , nationally representative sample do not support the hypothesis that depressive symptoms are independently related to mortality in the general population , after adequate adjustment for the confounding effects of physical health status . ACL = Americans ’ Changing Lives Study ; CES-D = Center for Epidemiological Studies Depression Scale ; CHD = coronary heart disease ; CI = confidence interval ; HR = hazard ratio BACKGROUND Several lines of evidence indicate that depression is importantly associated with cardiovascular disease end points . However , little is known about the role of depression in stroke mortality . METHODS This study examined the association between depressive symptoms and stroke mortality in a prospect i ve study of behavioral , social , and psychological factors related to health and mortality in a community sample of 6676 initially stroke-free adults ( 45.8 % male ; 79.1 % white ; mean age at baseline , 43.4 years ) from Alameda County , California . Depressive symptoms were assessed by the 18-item Human Population Laboratory Depression Scale . Cox proportional hazards regression models were used to evaluate the impact of depressive symptoms after controlling for age , sex , race , and other confounders . RESULTS A total of 169 stroke deaths occurred during 29 years of follow-up . Reporting 5 or more depressive symptoms at baseline was associated with increased risk of stroke mortality , after adjusting for age , sex , and race ( hazard ratio , 1.66 ; 95 % confidence interval , 1.16 - 2.39 ; P<.006 ) . This association remained significant after additional adjustments for education , alcohol consumption , smoking , body mass index , hypertension , and diabetes ( hazard ratio , 1.54 ; 95 % confidence interval , 1.06 - 2.22 ; P<.02 ) . Time-dependent covariate models , which allowed changes in reported depressive symptoms and risk factor levels during follow-up , revealed the same pattern of associations . CONCLUSIONS This population -based study provides the strongest epidemiological evidence to date for a significant relationship between depressive symptoms and stroke mortality . These results contribute to the growing literature on the adverse health effects of depression OBJECTIVE To determine the relationship between increasing depressive symptoms and cardiovascular events or mortality . DESIGN Cohort analytic study of data from r and omized placebo-controlled double-blind clinical trial of antihypertensive therapy . Depressive symptoms were assessed semi-annually with the Center for Epidemiological Studies -Depression ( CES-D ) scale during an average follow-up of 4.5 years . SETTING Ambulatory patients in 16 clinical centers of the Systolic Hypertension in the Elderly Program . PATIENTS Generally healthy men and women aged 60 years or older r and omized to active antihypertensive drug therapy or placebo who were 70 % white and 53 % women and had follow-up CES-D scores and no outcome events during the first 6 months ( N=4367 ) . MAIN OUTCOME MEASURES All-cause mortality , fatal or nonfatal stroke , or myocardial infa rct ion . RESULTS Baseline depressive symptoms were not related to subsequent events ; however , an increase in depression was prognostic . Cox proportional hazards regression analyses with the CES-D scale as a time-dependent variable , controlling for multiple covariates , indicated a 25 % increased risk of death per 5-unit increase in the CES-D score ( relative risk [ RR ] , 1.25;95 % confidence interval [ CI ] , 1.15 to 1.36 ) . The RR for stroke or myocardial infa rct ion was 1.18(95%CI,1.08 to 1.30 ) . Increase in CES-D score was an independent predictor in both placebo and active drug groups , and it was strongest as a risk factor for stroke among women ( RR,1.29;95%CI,1.07 to 1.34 ) . CONCLUSIONS Among elderly persons , a significant and substantial excess risk of death and stroke or myocardial infa rct ion was associated with an increase in depressive symptoms over time , which may be a marker for subsequent major disease events and warrants the attention of physicians to such mood changes . However , further studies of casual pathways are needed before wide-spread screening for depression in clinical practice is to be recommended Since the mid-1980s , an impressive body of epidemiological research has examined links between depression and coronary heart disease ( CHD ) . Depression is more common in patients with CHD than in those without heart disease , with ≥20 % of hospitalised patients after a myocardial infa rct ion ( MI ) meeting modified psychiatric criteria for major depressive disorder (MDD).1 While available data suggest that depression rates are lower in patients with stable CHD than in hospitalised patients , depression is still more common than in the general community . Depression is associated with increased chances of developing CHD in apparently healthy subjects . In patients with CHD depression predicts cardiac admissions and death , increased healthcare costs and utilisation of services.2 3 There is evidence of an increased cardiac risk associated with measures of depression symptoms as well as with diagnosed MDD , and of a dose – response relationship between depression severity and prognosis in patients with CHD . Many plausible biological explanations have been suggested . The quantity and strength of the epidemiological data is comparable to that leading to the general acceptance of several other cardiac risk factors . Why , then , is depression not considered a major risk factor ? Should it be ? Updating our previous systematic review s3 4 to include publications through 15 September 2009 , we found reports based on prospect i ve studies , using established measures of depression published from at least 28 distinct cohorts each made up of more than 500 people who were apparently CHD-free at baseline , and at least 59 separate studies that examined depression as a predictor of risk for poor prognosis in sample s of at least 100 patients with known CHD . The great majority of the 130 articles based on these studies document statistically significant relationships between depression and cardiac outcomes , and most , but not all , demonstrate that these relationships remain significant after statistical adjustment for a BACKGROUND Depressive illness may be associated with immune and cytokine alterations . However , data are unavailable concerning functional immune changes associated with chronic , low- grade depression ( dysthymia ) . Moreover , the contribution of the neurovegetative features of depression ( e.g. , altered sleep , eating ) to the immune alterations remains to be determined . METHODS Mitogen-stimulated cell proliferation was assessed in major depressive and dysthymic patients exhibiting either typical or atypical features . In a subset of patients , lymphocyte proliferation was also assessed before and after pharmacotherapy to determine whether alleviation of symptoms would be accompanied by normalization of immune functioning . RESULTS Lymphocyte proliferation was reduced to a greater extent among dysthymic than among major depressive patients . Among dysthymic patients reduced cell proliferation was evident irrespective of symptom typicality ; however , among major depressive patients the contribution of neurovegetative features varied with the specific mitogen used . Symptom alleviation following antidepressant treatment was not accompanied by normalization of cell proliferation . LIMITATIONS Patients received 12 weeks of antidepressant treatment , and more sustained therapy may be required for normalization of immune activity . As well , conclusions concerning normalization of immune functioning in drug-treated major depressive patients requires that a greater number of patients be assessed . CONCLUSIONS As the immune variations were more pronounced in dysthymia than in major depression , chronicity of illness may be a pertinent factor in promoting immune disturbances . This does not exclude the possibility that depression is associated with immune activation , which then provokes suppression of other aspects of immunity . As well , it is conceivable that immune alterations indirectly contribute to the symptoms accompanying depressive state , although it does not appear that variations of lymphocyte proliferation are associated with neurovegetative status |
1,977 | 22,374,464 | The systematic review suggested that monetary incentives and paper ( vs web or email ) surveys increase response rates .
We conclude that in addition to monetary incentives and paper surveys , physician-to-physician follow-up telephone calls are an effective method to increase response rates in oncology-focused physician surveys | Although the physician survey has become an important tool for oncology-focused health services research , such surveys often achieve low response rates .
This mini- review reports the results of a structured review of the literature relating to increasing response rates for physician surveys , as well as our own experience from a survey of physicians as to their referral practice s for suspected haematologic malignancy in the United States . | OBJECTIVE Primary care physicians are increasingly being asked to participate in postal surveys . Difficulties in achieving adequate response rates among physicians have been reported . We investigated the effect of two low-cost interventions on response to a primary care physician postal question naire . STUDY DESIGN AND SETTING A 2x2 factorial trial was developed within the context of a national survey assessing views and practice s of physicians regarding prostate-specific antigen testing . We evaluated question naire order ( version 1 : demographics first , version 2 : topic-specific questions first ) and written precontact . A national data base of primary care physicians was compiled . One thous and five hundred ninety-nine physicians were r and omly selected , stratified by health board , and r and omized . RESULTS 47.9 % of eligible physicians completed a question naire . There was a statistically significant 5.1 % higher response rate among physicians receiving version 1 of the question naire than those receiving version 2 ( 50.6 % vs. 45.4 % , P=0.05 ) ; the adjusted odds of response were significantly raised ( odds ratio=1.24 ; 95 % confidence interval=1.01 - 1.54 ) . Precontact result ed in a nonsignificant 3.6 % increase in response ( 49.8 % vs. 46.2 % ; P=0.16 ) . The interventions did not interact . CONCLUSION Ordering question naires with general questions first can significantly increase response rates , whereas precontact can achieve a modest increase . These strategies may enhance response while adding little to the cost of a physician survey PURPOSE This study compared the response time , response rate , and cost of two types of survey administration techniques : e-mail/web-based versus conventional postal mail . The main aim of the survey was to collect descriptive information on the existence of Acute Care for Elders units and their characteristics by surveying geriatric division chiefs . DESIGN AND METHODS Two r and omized cohorts of geriatric division chiefs were formed to receive a survey either by electronic mail ( n = 57 ) or by conventional postal mail ( n = 57 ) . If there was no response to the initial mailing , two follow-up mailings were sent to both groups using the original modality ; a third follow-up was performed using the alternative modality . For each group , response rate and response time were calculated . The average total cost was computed and compared across two groups . RESULTS The aggregate response rate was 58 % ( n = 31 ) for the e-mail group versus 77 % ( n = 44 ) for the postal mail group . The overall average response time was shorter in the e-mail group , 18 days compared with 33 days for the conventional postal mailing group . The cost comparison showed that average cost was $ 7.70 for the e-mail group , compared to $ 10.50 per response for the conventional mail group . IMPLICATION S It appears that although the web-based technology is gaining popularity and leads to lower cost per response , the conventional postal method of surveying continues to deliver a better response rate among the geriatric medicine division chiefs . The web-based approach holds promise given its lower costs and acceptable response rate combined with the shorter response time Background Low response rates among surgeons can threaten the validity of surveys . Internet technologies may reduce the time , effort , and financial re sources needed to conduct surveys . Objective We investigated whether using Web-based technology could increase the response rates to an international survey . Methods We solicited opinions from the 442 surgeon – members of the Orthopaedic Trauma Association regarding the treatment of femoral neck fractures . We developed a self-administered question naire after conducting a literature review , focus groups , and key informant interviews , for which we used sampling to redundancy techniques . We administered an Internet version of the question naire on a Web site , as well as a paper version , which looked similar to the Internet version and which had identical content . Only those in our sample could access the Web site . We alternately assigned the participants to receive the survey by mail ( n=221 ) or an email invitation to participate on the Internet ( n=221 ) . Non-respondents in the mail arm received up to three additional copies of the survey , while non-respondents in the Internet arm received up to three additional requests , including a final mailed copy . All participants in the Internet arm had an opportunity to request an emailed Portable Document Format ( PDF ) version . Results The Internet arm demonstrated a lower response rate ( 99/221 , 45 % ) than the mail question naire arm ( 129/221 , 58 % ) ( absolute difference 13 % , 95 % confidence interval 4%-22 % , P<0.01 ) . Conclusions Our Internet-based survey to surgeons result ed in a significantly lower response rate than a traditional mailed survey . Research ers should not assume that the widespread availability and potential ease of Internet-based surveys will translate into higher response rates BACKGROUND Historically , achieving a high response rate on physician surveys has been a challenging task . Given such concerns , underst and ing research strategies that facilitate adequate response rates is important . Primary care physician responses to a mail survey on smoking cessation are summarized by physician specialty and timing of incentive . METHODS A stratified r and om- sample design , stratified by patient population s-adults , adolescents , and pregnant women-was used . The sampling frame included New Jersey internists , general practitioners , family physicians , pediatricians , and obstetrician-gynecologists . A total of 2100 physicians , 700 physicians from each patient strata , were sample d and mailed a smoking-cessation survey in summer 2002 . The sample was r and omized by incentive timing : Half received the incentive ( i.e. , 25 dollars gift card ) with the first survey mailing , and half received the incentive on receipt of their completed survey . RESULTS The promised-incentive group achieved a significantly lower response rate ( 56 % ) compared with the up-front-incentive group ( 71.5 % ) . Response rates by medical specialty varied overall and within incentive groups . The difference between the incentive groups was greatest among obstetrician-gynecologists ( i.e. , 20.2 percentage points ) and was least among pediatricians ( i.e. , 5.8 percentage points ) . CONCLUSIONS Physician response rates to mail surveys are greatly improved , especially among certain medical specialties , by using up-front incentives Background The use of Internet-based question naires for collection of data to evaluate patient education and other interventions has increased in recent years . Many self-report instruments have been vali date d using paper- and -pencil versions , but we can not assume that the psychometric properties of an Internet-based version will be identical . Objectives To look at similarities and differences between the Internet versions and the paper- and -pencil versions of 16 existing self-report instruments useful in evaluation of patient interventions . Methods Participants were recruited via the Internet and volunteered to participate ( N=397 ) , after which they were r and omly assigned to fill out question naires online or via mailed paper- and -pencil versions . The self-report instruments measured were overall health , health distress , practice mental stress management , Health Assessment Question naire ( HAQ ) disability , illness intrusiveness , activity limitations , visual numeric for pain , visual numeric for shortness of breath , visual numeric for fatigue , self-efficacy for managing disease , aerobic exercise , stretching and strengthening exercise , visits to MD , hospitalizations , hospital days , and emergency room visits . Means , ranges , and confidence intervals are given for each instrument within each type of question naire . The results from the two question naires were compared using both parametric and non-parametric tests . Reliability tests were given for multi-item instruments . A separate sample ( N=30 ) filled out identical question naires over the Internet within a few days and correlations were used to assess test-retest reliability . Results Out of 16 instruments , none showed significant differences when the appropriate tests were used . Construct reliability was similar within each type of question naire , and Internet test-retest reliability was high . Internet question naires required less follow-up to achieve a slightly ( non-significant ) higher completion rate compared to mailed question naires . Conclusions Among a convenience sample recruited via the Internet , results from those r and omly assigned to Internet participation were at least as good as , if not better than , among those assigned mailed question naires , with less recruitment effort required . The instruments administered via the Internet appear to be reliable , and to be answered similarly to the way they are answered when they are administered via traditional mailed paper question naires Background Postal surveys are a frequently used method of data collection in health services research . Low response rates increase the potential for bias and threaten study validity . The objectives of this study were to estimate current response rates , to assess whether response rates are falling , to explore factors that might enhance response rates and to examine the potential for non-response bias in surveys mailed to healthcare professionals . Methods A r and om sample of postal or electronic surveys of healthcare workers ( 1996 - 2005 ) was identified from Medline , Embase or Psycinfo data bases or Biomed Central . Outcome measures were survey response rate and non response analysis . Multilevel , multivariable logistic regression examined the relationship between response rate and publication type , healthcare profession , country and number of survey participants , question naire length and use of reminders . Results The analysis included 350 studies . Average response rate in doctors was 57.5 % ( 95%CI : 55.2 % to 59.8 % ) and significantly lower than the estimate for the prior 10 year period . Response rates were higher when reminders were sent ( adjusted OR 1.3 ; 95%CI 1.1 - 1.6 ) but only half the studies did this . Response rates were also higher in studies with fewer than 1000 participants and in countries other than US , Canada , Australia and New Zeal and . They were not significantly affected by publication type or healthcare profession ( p > 0.05 ) . Only 17 % of studies attempted assessment of possible non-response bias . Conclusion Response rates to postal surveys of healthcare professionals are low and probably declining , almost certainly leading to unknown levels of bias . To improve the informativeness of postal survey findings , research ers should routinely consider the use of reminders and assess potential for non-response bias OBJECTIVES To compare 3 communication modes ( postal , fax , and e-mail ) in a rotavirus vaccine physician survey . METHODS We used 3 communication modes to distribute a survey to physicians listed in the membership directory of the Georgia Chapter of the American Academy of Pediatrics . The directory listed 1391 members ; however , 404 were deemed ineligible on the basis of their listing as a specialist , retiree , resident in training , or government public health employee . Of the 987 members expected to administer vaccines , 150 were selected r and omly to receive the postal survey ( postal group ) . Of the remaining listings , 488 ( 58 % ) of 837 listed a fax number ; 150 members were selected r and omly and faxed a survey ( fax group ) . Of the remaining members , 266 ( 39 % ) of 687 had e-mail addresses listed ; 150 members were selected r and omly for the e-mail survey ( e-mail group ) . A follow-up survey was sent by the same mode at 2 weeks . A final survey was sent via another mode ( mixed mode ) at 1 month : by fax to e-mail and postal nonresponders and by post to fax nonresponders and those without fax . RESULTS Eligible respondents in the 3 survey groups were similar in their practice setting and location . Although the e-mail group had fewer median years ( 8 years ) since medical school graduation than the fax group ( 19 years ) and postal group ( 17 years ) , a similar percentage of responders in all groups had computers ( > 85 % ) and Internet access ( > or = 70 % ) at work . However , only 39 % of members listed an e-mail address in the directory . In the 2 weeks after the first mailing , 39 surveys were completed via postal mail , 50 via fax , and 16 via e-mail . In the 2 weeks after the second contact ( sent at 2 weeks ) , 20 surveys were completed via postal mail , 15 via fax , and 17 via e-mail . The response rate after the first 2 mailings was 41 % ( 59 of 143 ) for postal , 47 % ( 65 of 137 ) for fax , and 26 % ( 33 of 125 ) for e-mail surveys . The third and final survey ( sent 1 month after the first mailing ) was sent by a different ( ie , mixed ) mode and elicited an additional 73 responses : 19 responses ( 15 postal , 4 fax ) from the postal group , 19 responses ( 18 postal , 1 fax ) from the fax group , and 35 responses ( 15 postal , 13 fax , 7 e-mail ) from the e-mail group . Twenty-three percent ( 9 of 40 ) of the e-mail and 18 % ( 15 of 83 ) of the fax surveys completed were returned on the same or subsequent day they were sent , compared with none of the postal surveys . There were significant differences among the 3 groups for invalid addresses/numbers ( 4 % postal , 8 % fax , and 16 % e-mail ) listed in the directory . Using mixed modes as the third contact , the overall response rate increased from 39 % before mixed mode to a final of 53 % . On the basis of the 3 initial groups , responses to 1 of 12 rotavirus questions differed significantly . CONCLUSIONS Future use of e-mail surveys in selected circumstances is promising , because the majority of providers have Internet access and acknowledged interest in participating in e-mail surveys . E-mail surveys could be especially useful if rapid response time is necessary . There were fewer incomplete questions by participants who completed the e-mail survey compared with postal or fax participants . Updating membership e-mail addresses and routinely using e-mail as a communication tool should improve the ability to use e-mail surveys . There may need to be ongoing evaluations that critically evaluate providers ' responses to e-mail surveys compared with other survey modes before e-mail surveys can become a st and ard survey tool . In the meantime , mixed-mode surveys may be an option BACKGROUND Opinion leaders have been shown to have significant influence on the practice of health professionals and patient outcomes . METHODS Using focus groups , key informants , and sampling to redundancy techniques , we developed a question naire of surgeons ' preferences in the treatment of tibial shaft fractures . Twenty-two well-respected and widely known orthopaedic traumatologists endorsed the question naire . We r and omized 395 surgeon members of the Orthopaedic Trauma Association to receive either a question naire that included a letter informing them of the opinion leaders ' endorsement , or a question naire without the endorsement . RESULTS Surgeons who received the letter of endorsement had a significantly lower response rate at 2 , 4 , and 8 weeks . The absolute difference in response rates was 7.8 % ( 4.6 % versus 12.4 % , P < 0.05 ) at 2 weeks , 13.1 % at 4 weeks ( 28.6 % versus 41.7 % P < 0.02 ) , and 12.3 % at 8 weeks ( 47.5 % versus 59.8 % P = 0.02 ) . CONCLUSIONS The addition of a letter listing expert surgeons who endorse the survey lead to significantly lower primary response rates . Those interested in influencing physician responses can not always assume a positive effect from endorsement by opinion PURPOSE To test the effect of a AU dollars 2 scratch lottery ticket on response rates to a national mailed question naire of Australian general practitioners ( GPs ) and medical specialists . METHODS A r and omized controlled trial was conducted and the incentive sent to half of the participants with the first mailing . A single follow-up mailing without incentive was sent to all non-respondents . Survey respondents were then informed of the research question regarding incentives and allowed to withdraw their study data . Differences in response rates between doctors receiving and not receiving the incentive , and between respondents and non-respondents , were examined . RESULTS The overall response rate was 47 % ( 443 respondents ) . Twenty-two respondents ( 5 % ) withdrew their data after being informed of the research question . Of the remaining 421 respondents , 233 had received the incentive ( response rate 49.7 % ) and 188 had not ( 40.1 % , p=0.0032 ) . The absolute increase in response rate with the incentive ( 9.6 % , 95%CI 3.2 , 15.9 ) was quantitatively similar in effect to the reminder mailing ( 11.8 % ) . The incentive had a larger effect among the GP sample compared with specialists ( 13.4 vs. 5.9 % ) , although the difference was not statistically significant ( p=0.20 ) . There were no systematic differences in demographic characteristics between respondents and non-respondents . CONCLUSIONS Increased response rates associated with a small incentive may reduce the need for a second mailed reminder , but strong views about the use of incentives may negatively influence the participation of some practitioners . While the overall response rate was low , there was no evidence of bias in our sample Purpose A r and omized unblinded controlled trial was used to assess the utility of electronic question naires in a survey of Canadian anesthesiologists . Methods Postal or electronic question naires were sent between November 2001 and March 2002 to 1,333 anesthesiologists registered with the Canadian Anesthesiologists ’ Society . The primary outcome measure was the difference in response rates between electronic and postal question naires . Secondary outcome measures included a comparison of demographic characteristics , cost , and knowledge and practice regarding prophylactic perioperative beta blockade . Results The overall response rate was 52 % . E-mail participants were half as likely as postal participants to respond to the question naire ( 35 % vs 69 % , relative risk = 0.51 , 95 % confidence interval 0.45–0.58 ) . Respondents who provided an e-mail address were younger and more likely to be affiliated with an academic institution . There were no significant differences in responses to knowledge and practice questions . The electronic arm was faster than the postal arm and the cost per reply was one-third the cost of the postal arm ( $ 2.50 vs $ 8.02 ) . Conclusions Electronic surveys are a means of acquiring information from a large number of individuals in a rapid , efficient and cost-effective manner . This methodology may be particularly valid and useful in surveys of participants with similar background s and internet access . However the lower response rates achieved as compared with postal surveys indicates a need to use vigilance when generalizing results to a broader population .RésuméObjectifNous avons utilisé une épreuve r and omisée , contrôlée et ouverte pour évaluer l’utilité de question naires électroniques lors d’une enquête auprès des anesthésiologistes canadiens . MéthodeDes question naires postaux et électroniques ont été envoyés entre novembre 2001 et mars 2002 à 1 333 anesthésiologistes membres de la Société canadienne des anesthésiologistes . La principale mesure a été la différence du taux de réponses aux envois postaux et électroniques . La seconde comprenait une comparaison des caractéristiques individuelles , du coût , et des connaissances et de la pratique en regard du bêta blocage périopératoire préventif . RésultatsLe taux de réponse général a été de 52 % . Les participants par courriel ont été deux fois moins nombreux que par la poste à répondre au question naire ( 35 % vs 69 % , le risque relatif a été de 0,51 , l’intervalle de confiance de 95 % 0,45–0,58 ) . Les répondants par courriel étaient plus jeunes et plus souvent affiliés à une institution universitaire . Il n’y a pas eu de différence significative de réponses sur les connaissances et la pratique . Le groupe du courriel a répondu plus rapidement que le groupe de la poste et le coût par réponse a été le tiers du coût postal ( 2,50 $ vs 8,02 $ ) . Conclusion Les enquêtes électroniques permettent d’obtenir de l’information d’un gr and nombre de personnes d’une manière rapide , efficace et économique . Cette méthodologie peut être particulièrement valide et utile auprès de participants do nt les connaissances sont comparables et qui ont accès à Internet . Cependant , les taux de réponses plus bas obtenus en comparaison avec les enquêtes postales indiquent la nécessité d’être vigilant au moment de généraliser les résultats pour une importante population Low response rates , especially among physicians , are a common problem in mailed survey research . We conducted a r and omized trial to examine the effects of cash and lottery incentives on response rates . A total of 4,850 subjects were r and omized to one of three interventions accompanying a mailed survey-no incentive ( n = 1,700 ) , cash payment [ three levels of Hong Kong dollars ( HKD ) $ 10 , $ 20 , and $ 40 ; N = 50 in each subgroup ] , or entry into a lottery ( three levels of HKD$1,000 , $ 2,000 , and $ 4,000 ; N = 1,000 in each subgroup ) on receipt of the completed question naire . The response rates were higher among those offered incentives than those without ( 19.8 % vs. 16.8 % , P = .012 ) . Cash was the more effective incentive compared to lottery ( 27.3 % vs. 19.4 % , P = .017 ) . Response also increased substantially between the first and second mailings ( 14.2 % vs. 18.8 % , P > .001 ) . In addition , those with specialist qualifications were more willing to participate in mailed surveys . We found no significant differences in response outcomes among the various incentive arms . Cash reward at the $ 20 level was the most cost-effective intervention , in terms of cost per responder . Further systematic examination of the effects of different incentive strategies in epidemiologic studies should be encouraged Background Response rates to surveys are declining and this threatens the validity and generalisability of their findings . We wanted to determine whether paper quality influences the response rate to postal surveys Methods A postal question naire was sent to all members of the British Society of Gynaecological Endoscopy ( BSGE ) . Recipients were r and omised to receiving the question naire printed on st and ard quality paper or high quality paper . Results The response rate for the recipients of high quality paper was 43/195 ( 22 % ) and 57/194 ( 29 % ) for st and ard quality paper ( relative rate of response 0.75 , 95 % CI 0.33–1.05 , p = 0.1 Conclusion The use of high quality paper did not increase response rates to a question naire survey of gynaecologists affiliated to an endoscopic society BACKGROUND Non-response is an important potential source of bias in survey research . With evidence of falling response rates from GPs , it is of increasing importance when undertaking postal question naire surveys of GPs to seek to maximize response rates and evaluate the potential for non-response bias . OBJECTIVES Our aim was to investigate the effectiveness of follow-up procedures when undertaking a postal question naire study of GPs , the use of publicly available data in assessing non-response bias and the development of regression models predicting responder behaviour . METHOD A postal question naire study was carried out of a r and om sample of 600 GPs in Wales concerning their training and knowledge in palliative care . RESULTS A cumulative response rate graph permitted optimal timing of follow-up mailings : a final response rate of 67.6 % was achieved . Differences were found between responders and non-responders on several parameters and between sample and population on some parameters : some of these may bias the sample data . Logistic regression analysis indicated medical school of qualification and current membership of the Royal College of General Practitioners to be the only significant predictors of responders . Late responders were significantly more likely to have been qualified for longer . CONCLUSIONS This study has several implication s for future postal question naire studies of GPs . The optimal timing of reminders may be judged from plotting the cumulative response rate : it is worth sending at least three reminders . There are few parameters that significantly predict GPs who are unlikely to respond ; more of these may be included in the sample , or they may be targeted for special attention . Publicly available data may be used readily in the analysis of non-response bias and generalizability Background Response rates to postal question naires are falling and this threatens the external validity of survey findings . We wanted to establish whether the incentive of being entered into a prize draw to win a personal digital assistant ( PDA ) would increase the response rate for a national survey of consultant obstetricians and gynaecologists . Methods A r and omised controlled trial was conducted . This involved sending a postal question naire to all Consultant Obstetricians and Gynaecologists in the United Kingdom . Recipients were r and omised to receiving a question naire offering a prize draw incentive ( on response ) or no such incentive . Results The response rate for recipients offered the prize incentive was 64 % ( 461/716 ) and 62 % ( 429/694 ) in the no incentive group ( relative rate of response 1.04 , 95 % CI 0.96 – 1.13 ) Conclusion The offer of a prize draw incentive to win a PDA did not significantly increase response rates to a national question naire survey of consultant obstetricians and gynaecologists OBJECTIVE Improving response rates , particularly among physicians , is important to minimize nonresponder bias and increase the effective sample size in epidemiologic research . We conducted a r and omized trial to examine the impact of prepayment vs. postpayment incentives on response rates . STUDY DESIGN AND SETTING Self-completion postal question naires were mailed to 949 physicians who were respondents to an earlier survey and representative of the general physician population in Hong Kong . These physicians were r and omly allocated to receive a HK dollar 20 cash prepayment incentive that accompanied the survey ( n=474 ) or a postpayment reward of the same amount on receipt of the completed question naire ( n=475 ) . RESULTS The final prepayment response rate was 82.9 % , compared with 72.5 % in the postpayment arm ( P < .001 ) . Of the eight alternative incentive and follow-up strategies evaluated , three lie on the efficiency frontier ( i.e. , not dominated ) , including postpayment with three mailings at HK dollar 42.7 , prepayment with three mailings at HK dollar 66.5 and prepayment with three mailings and telephone follow-up at HK dollar 112.1 per responder recruited ( US dollar 1=HK dollar 7.8 ) . CONCLUSION The findings demonstrate that prepayment cash incentives are superior to postpayment of the equivalent amount in improving response rates among a representative sample of Hong Kong physicians . Further research should concentrate on confirming the generalizability of these findings in other health care occupation groups and setting PURPOSE Oncologists in the United States and Canada work in different health care systems , but physicians in both countries face challenges posed by the rising costs of cancer drugs . We compared their attitudes regarding the costs and cost-effectiveness of medications and related health policy . METHODS Survey responses of a r and om sample of 1,355 United States and 238 Canadian medical oncologists ( all outside of Québec ) were compared . RESULTS Response rate was 59 % . More US oncologists ( 67 % v 52 % ; P < .001 ) favor access to effective treatments regardless of cost , while more Canadians favor access to effective treatments only if they are cost-effective ( 75 % v 58 % ; P < .001 ) . Most ( 84 % US , 80 % Canadian ) oncologists state that patient out-of-pocket costs influence their treatment recommendations , but less than half the respondents always or frequently discuss the costs of treatments with their patients . The majority of oncologists favor more use of cost-effectiveness data in coverage decisions ( 80 % US , 69 % Canadian ; P = .004 ) , but fewer than half the oncologists in both countries feel well equipped to use cost-effectiveness information . Majorities of oncologists favor government price controls ( 57 % US , 68 % Canadian ; P = .01 ) , but less than half favor more cost-sharing by patients ( 29 % US , 41 % Canadian ; P = .004 ) . Oncologists in both countries prefer to have physicians and nonprofit agencies determine whether drugs provide good value . CONCLUSION Oncologists in the United States and Canada generally have similar attitudes regarding cancer drug costs , cost-effectiveness , and associated policies , despite practicing in different health care systems . The results support providing education to help oncologists in both countries use cost-effectiveness information and discuss drug costs with their patients OBJECTIVE To examine response rate information from mailed physician question naires reported in published articles . DATA SOURCES / STUDY SETTING Citations for articles published between 1985 and 1995 were obtained using a key word search of the Medline , PsychLit , and Sociofile data bases . STUDY DESIGN A 5 percent r and om sample of relevant citations was selected from each year . DATA COLLECTION / EXTRACTION METHODS Citations found to be other than physician surveys were discarded and replaced with the next r and omly assigned article . Selected articles were abstract ed using a st and ardized variable list . PRINCIPAL FINDINGS The average response rate for mailed physician question naires was 61 percent . The average response rate for large sample surveys ( > 1,000 observations ) was 52 percent . In addition , only 44 percent of the abstract ed articles reported a discussion of response bias , and only 54 percent reported any type of follow-up . CONCLUSIONS ( 1 ) Response rates have remained somewhat constant over time , and ( 2 ) research ers need to document the efforts used to increase response rates to mailed physician question naires BACKGROUND The validity of the results of mailed surveys is often threatened by nonresponse bias , which is made more likely when response rates are low . However , the effectiveness and cost-effectiveness of several strategies to increase response rates are uncertain . OBJECTIVES To assess three strategies to increase response rates to mailed physician surveys : including a 10 dollars versus a 5 dollars cash incentive in the initial mailing , including a mint c and y or not , and using a large versus small outgoing envelope . RESEARCH DESIGN AND SUBJECTS Using a 2 x 2 x 2 factorial design , a r and omized trial of these strategies was conducted in a survey of 1200 physicians r and omly selected from the American Medical Association 's Master File . RESULTS Including a 10 dollars incentive yielded a significantly higher response rate ( 60.5 % vs. 52.8 % ) ( P = 0.009 ) . The mailing and incentive costs per completed response were 12.24 dollars ( 95 % CI , 11.75 dollars , 13.64 dollars ) in the 5 dollars group and 18.48 dollars ( 95 % CI , 17.77 dollars , 20.69 dollars ) in the 10 dollars group . Each additional response obtained in the 10 dollars group came at an incremental cost of 61.26 dollars ( 95 % CI , 36.98 dollars , 200.80 dollars ) . Neither inclusion of a mint nor use of a large envelope influenced the response rate . CONCLUSIONS Investigators may increase response rates by including more money in the initial question naire packet , but there may be diminishing returns to serial increments in incentives greater than 5 dollars . Including smaller incentives in more question naires may maximize total responses BACKGROUND AND OBJECTIVES To compare general practitioner ( GP ) response to a telephone interview with response to a postal survey with three reminders in a r and omized controlled trial . METHODS GPs were r and omly assigned to either a telephone interview or a postal survey . GPs in the telephone group were mailed a letter of invitation and asked to undertake a telephone interview . GPs in the postal group were mailed a letter of invitation and question naire . Non-responders were sent up to three reminders , the final by registered post . Response rates were calculated for each group . RESULTS 416 GPs were r and omized to the telephone interview and 451 to the postal survey . Eighty-six in the telephone group and 30 in the postal were ineligible . One hundred thirty-four GPs completed the telephone interview with a response rate of 40.6 % ( 95 % confidence interval [ CI ] : 35.3 % , 46.1 % ) . Two hundred fifty-two GPs completed the postal survey with a response rate of 59.9 % ( 95%CI : 55.0 % , 64.6 % ) . The difference in response was 19.3 % ( 95%CI : 12.2 % , 26.3 % ) . CONCLUSIONS These results show that postal surveys with three reminders can have superior response rates compared with a telephone interview Mailed surveys are a popular means of obtaining data on large population s. In July 1999 a mail survey was conducted among 3000 r and omly selected members of the American Society of Hematology to assess their approach to diagnosis and treatment of polycythemia vera . Because the research ers and the study population are members of the same professional organization with a vested interest in the results , we anticipated that the advantages of return stamped postage seen in previous studies would be less significant . The response rate for stamped return envelopes was 38 % versus 32 % for business reply envelopes . This statistically significant difference ( P = .0005 ) of six percentage points is comparable to previous research . Excluding labor , the total cost per returned survey was $ 2.62 for business reply envelopes versus $ 1.82 for stamped return envelopes . We conclude that stamped return envelopes are a more effective and cost-efficient means of procuring data from physician specialists OBJECTIVE To compare e-mail with regular mail for conducting surveys of physicians . DESIGN R and omized controlled trial . SETTING Ontario , Canada . PARTICIPANTS A r and om sample of physicians listed in the College of Family Physicians of Canada 's membership data base . INTERVENTIONS Survey delivered by e-mail and by post . MAIN OUTCOME MEASURES Response rates and times , and completeness and characteristics of responses to the survey . RESULTS Overall response rate was 44.7 % ( 33.6 % of e-mail recipients , 52.7 % of post recipients who have e-mail , and 47.8 % of post recipients without e-mail ) . While the e-mail rate was significantly lower than for both post groups , e-mail responses were received much faster . There was no significant difference among groups as to completeness of responses , but e-mail responses had more frequent and longer comments . CONCLUSION E-mail provides faster but fewer responses to surveys . Content of structured-response questions was similar in all groups , but e-mail provided more and longer responses to open-ended questions . Where a quick response to a survey is required , e-mail is superior Background It is important that response rates to postal surveys are as high as possible to ensure that the results are representative and to maximise statistical power . Previous research has suggested that any personalisation of approach helps to improve the response rate . This experiment tested whether personalising question naires by h and signing the covering letter improved the response rate compared with a non-personalised group where the investigator 's signature on the covering letter was scanned into the document and printed . Methods R and omised controlled trial . Question naires about surgical techniques of caesarean section were mailed to 3,799 Members and Fellows of the Royal College of Obstetricians and Gynaecologists resident in the UK . Individuals were r and omly allocated to receive a covering letter with either a computer printed signature or a h and written signature . Two reminders were sent to non-respondents . The outcome measures were the proportion of question naires returned and their time to return . Results The response rate was 79.1 % ( 1506/1905 ) in the h and -signed group and 78.4 % ( 1484/1894 ) in the scanned and printed signature group . There was no detectable difference between the groups in response rate or time taken to respond . Conclusion No advantage was detected to h and signing the covering letter accompanying a postal question naire to health professionals OBJECTIVE To examine the association between question naire length and response rate in a mailed survey of generalist physicians r and omly selected from the American Medical Association master file . STUDY DESIGN AND SETTING In a pilot study , otherwise similar question naires of 30 different lengths ( 849 to 1,867 words ) were mailed to 192 physicians in April 1999 . In the main study , question naires of 16 different lengths ( 564 to 988 words ) were mailed to 1,700 physicians between June 1999 and January 2000 . RESULTS In the pilot study , response rate decreased from 60 % for question naires 849 words in length to 16.7 % for question naires over 1,800 words in length . Logistic regression revealed an odds ratio of 0.887 ( 95%CI 0.813 , 0.968 ; p=0.006 ) for word count , expressed in units of 100 words . In the main study , response rate varied between 51.5 % and 71.4 % . Logistic regression showed no association between response and word count ( OR 0.988 ; 95%CI 0.896 , 1.090 ; p=0.81 ) . CONCLUSION There appears to have been a threshold in these studies of approximately 1,000 words . Question naires above the threshold had lower response rates than those below it ( 38.0 % vs. 59.4 % ) Background : Recent experiences of survey research ers suggest that physicians are becoming less willing to complete surveys . Objective : To compare response rates to a mailed physician survey with a prepaid check incentive of $ 20 versus $ 50 . Research Design : R and omized controlled trial . Subjects : Five hundred seventy-eight physicians caring for patients with lung or colorectal cancer in northern California . Measures : Proportion of physicians responding to the survey . Results : Overall , 60.0 % of physicians responded to the survey . The response rate was 52.1 % for physicians who received a $ 20 check versus 67.8 % for physicians who received a $ 50 check ( P < 0.001 ) . Similar differences in response rates were seen in strata by physician sex , year graduated from medical school , and survey version ( all P < 0.001 ) . More than 42 % of physicians who received a $ 50 check responded to the first mailing , compared with only 30.8 % of those who received a $ 20 check ( P < 0.001 ) . Conclusions : Among physicians caring for patients with lung cancer or colorectal cancer in northern California , a $ 50 check incentive was much more effective than a $ 20 check incentive at increasing response rates to a mailed survey . As physicians become increasingly burdened with surveys , larger incentives may be necessary to engage potential respondents and thus maximize response rates BACKGROUND Low response rates to surveys are a problem in general practice . There is evidence that offering GPs incentives improves response rates to postal question naires . However , there is less evidence about the most effective form of incentive . OBJECTIVE Our trial aim ed to maximize response to a postal question naire and to test the most effective form of incentive . METHODS The study involved a r and omized controlled trial of a postal survey RESULTS The incentive of a lottery for six bottles of champagne generated a response rate of 79 % . Furthermore , one chance of six bottles generated 9 % more responses than six chances of one bottle . CONCLUSIONS This study has established that , among incentives for postal question naires , one big prize improves the yield more than many small prizes despite the lower odds of winning . It has also confirmed that offering a modest incentive to GPs generates good response rates for postal question naires Abstract This study investigated whether the opportunity to obtain Continuing Medical Education ( CME ) credit together with a five-dollar bill increased response rates and question naire completion rates in a physician survey involving mailed question naires . One thous and , three hundred and fourteen cardiologists , family practitioners , general internists ( non-surgeons ) and 264 vascular surgeons r and omly identified from the American Medical Association data base participated . After two , of up to four , question naire mailings , the opportunity to obtain CME credit and a five-dollar bill were included with question naire mailings . Among non-surgeons , 26.5 % responded to pre-incentive mailings and 30.2 % of those initially unresponsive replied after the interventions . Among surgeons , 39 % responded to pre-incentive mailings and 32.7 % of those initially unresponsive replied after the interventions . In conclusion , the opportunity to receive CME credit combined with a small monetary incentive is an effective motivation for physicians participating in a study involving mailed question naires Postal surveys are a cost effective method of obtaining information from large numbers of geographically disparate medical professionals about their attributes , behaviours , attitudes and beliefs . The validity of the findings of such surveys is primarily dependent upon an adequate response rate and it is of concern that the rates are declining.1 Inclusion of a pen along with the question naire is often used to counter this trend . In theory , the availability of a pen would enable immediate completion of the question naire . The gift of a pen may also predispose the recipient to look upon the question naire more favourably increasing the likelihood of a response . However , the effectiveness of this strategy has not been established . Therefore as part of a national survey of consultant gynaecologists , we conducted a r and omised controlled trial , to determine if Background .Mail surveys of physicians have been characterized by lower response rates than general population surveys , raising concerns about nonresponse bias . Although monetary incentives have routinely been used to improve survey response among physicians , questions remain regarding how much of an incentive is most cost-effective . The present study seeks to further examine the effects of incentive size on response rates to a national mail survey of physicians . Methods .This study used a r and om sample of 873 physicians practicing in the United States ; the response rate was 65 % ( n = 563 ) . Respondents were r and omly assigned to receive a $ 5 , $ 10 , or $ 20 cash incentive in the initial mailing . Except for the magnitude of the incentive , the procedures for each condition were identical , with each respondent receiving up to 3 follow-up mailings and 2 telephone calls . Results .Overall response rates ranged from 60.3 % for the $ 5 incentive category to 68.0 % for the $ 10 incentive category . Differences in overall response rates across the incentive categories , however , were not significant . Higher levels of incentives also did not significantly reduce the number of mail and /or telephone interventions required to reach the target response rate of 60.0 % . As expected , aggregate costs ( excluding labor ) were lowest for the $ 5 incentive group . Conclusions .Our findings suggest that changes in the magnitude of incentive do not automatically result in increases in survey response among physicians . Possible reasons for this lack of effect as well as alternatives to monetary incentives are addressed Effective strategies to maximize response rates to self-administered surveys of clinicians are crucial to minimize response bias . Offers of charitable donations have been assessed for their potential to promote participation of community sample s but not in the context of medical specialist sample s. We r and omized all Australian colorectal surgeons ( n = 219 ) to whom we mailed a survey about clinical practice guidelines to receive either a st and ard covering letter or one promising a donation to their peak professional organization upon our receipt of their completed survey . Contrary to expectations , surgeons advised that their participation would secure a donation to their college were significantly less likely to return their question naire ( 84.3 % , 95 % CI 76.0 - 90.5 % ) than those receiving a st and ard letter ( 93.7 % , 95 % CI 87.4 - 97.4 % ) . They also were more tardy in their response ( Hazard Ratio = 0.75 , 95 % CI 0.57 - 1.00 ) ( P = 0.047 ) . In this context , offering donations to surgeons was counterproductive in enhancing response rates OBJECTIVES To evaluate whether small monetary incentives improve physicians ' responses to surveys . To the best of the authors ' knowledge , no one has evaluated emergency physicians ' response rate and cost per participant of a small monetary incentive relative to a chance to win a more substantial sum . The authors compared emergency physicians ' responses and per-participant costs between a US 2 dollar bill and a 250 US dollars lottery . METHODS Two groups of 288 emergency physicians were r and omly selected and mailed a survey . Within each group of 288 , half received a US 2 dollar bill and the other half received an offer that respondents would be entered into a drawing to win 250 US dollars . Nonresponders received a reminder postcard one week later , and persistent nonresponders received a second mailing of the survey three weeks after the initial mailing . RESULTS Of the 576 surveys that were mailed , nine ( 2 % ) subjects were ineligible or undeliverable , leaving 567 eligible subjects , of whom 301 ( 53 % ) participated in the survey . The US 2 dollar bill had a substantially higher response rate : 170 ( 56 % ) of those receiving a US 2 dollar bill participated versus 131 ( 44 % ) of those receiving a chance to win 250 US dollars ( 95 % confidence interval = 5 % to 22 % ; p < 0.001 ) . The US 2 dollar bill offer was less expensive per participant than the 250 US dollars offer . The cost of postage and incentives was 997.33 US dollars for 170 participants , or 5.87 US dollars per participant , for the US 2 dollar bill and 979.29 US dollars for 131 participants , or 7.48 US dollars per participant , for the chance to win 250 US dollars . CONCLUSIONS Mailing a US 2 dollar bill incentive produces a better response rate with lower cost per participant than offering a chance to win 250 US dollars OBJECTIVE To assess the effects of two different mixed-mode ( mail and web survey ) combinations on response rates , response times , and nonresponse bias in a sample of primary care and specialty internal medicine physicians . DATA SOURCES / STUDY SETTING Primary data were collected from 500 physicians with an appointment in the Mayo Clinic Department of Medicine ( DOM ) between February and March 2005 . STUDY DESIGN Physicians were r and omly assigned to receive either an initial mailed survey evaluating the Electronic Medical Record ( EMR ) with a web survey follow-up to nonrespondents or its converse-an initial web survey followed by a mailed survey to nonrespondents . Response rates for each condition were calculated using st and ard formula . Response times were determined as well . Nonresponse bias was measured by comparing selected characteristics of survey respondents to similar characteristics in the full sample frame . In addition , the distributions of results on key outcome variables were compared overall and by data collection condition and phase . PRINCIPAL FINDINGS Overall response rates were somewhat higher in the mail/web condition ( 70.5 percent ) than in the web/mail condition ( 62.9 percent ) ; differences were more pronounced before the mode switch prior to the mailing to nonrespondents . Median response time was 2 days faster in the web/mail condition than in the mail/web ( median=5 and 7 days , respectively ) but there was evidence of under-representation of specialist physicians and those who used the EMR a half a day or less each day in the web/mail condition before introduction of the mailed component . This did not translate into significant inconsistencies or differences in the distributions of key outcome variables , however . CONCLUSIONS A methodology that uses an initial mailing of a self-administered form followed by a web survey to nonrespondents provides slightly higher response rates and a more representative sample than one that starts with web and ends with a mailed survey . However , if the length of the data collection period is limited and rapid response is important , perhaps the web survey followed by a mailed question naire is to be preferred . Key outcome variables appear to be unaffected by the data collection method To evaluate the cost-effectiveness of a lottery on physicians ’ responses to a mail survey , a r and omized controlled trial was conducted with a r and om sample of 1,000 members of the Quebec Federation of General Practitioners in 1997 . For the first mailing of this survey , each respondent was r and omly assigned to the control or experimental group , which was offered participation in a lottery upon return of the question naire . Response rate was 41.2 % in the experimental group and 34.8 % in the control group , a 6.4 % difference ( CI95 % : 0.6 % – 12.6 % ) . The additional cost of the lottery was about Can$500 , giving an incremental cost of Can$16 per question naire returned . In conclusion , a lottery result ed in a small but statistically significant increase in the response rate of physicians to a mail survey . This method may be a cost-effective option when applied to large surveys PURPOSE Routine follow-up of adult cancer survivors is an important clinical and health service issue . Because of a lack of evidence supporting advantages of long-term follow-up care in oncology clinics , there is increasing interest for the locus of this care to be provided by primary care physicians ( PCPs ) . However , current Canadian PCP views on this issue have been largely unknown . METHODS A mail survey of a r and om sample of PCPs across Canada , stratified by region and proximity to urban centers , was conducted . Views on routine follow-up of adult cancer survivors and modalities to facilitate PCPs in providing this care were determined . RESULTS A total of 330 PCPs responded ( adjusted response rate , 51.7 % ) . After completion of active treatment , PCPs were willing to assume exclusive responsibility for routine follow-up care after 2.4 + /- 2.3 years had elapsed for prostate cancer , 2.6 + /- 2.6 years for colorectal cancer , 2.8 + /- 2.5 years for breast cancer , and 3.2 + /- 2.7 years for lymphoma . PCPs already providing this care were willing to provide exclusive care sooner . The most useful modalities PCPs felt would assist them in assuming exclusive responsibility for follow-up cancer care were ( 1 ) a patient-specific letter from the specialist , ( 2 ) printed guidelines , ( 3 ) expedited routes of rereferral , and ( 4 ) expedited access to investigations for suspected recurrence . CONCLUSION With appropriate information and support in place , PCPs reported being willing to assume exclusive responsibility for the follow-up care of adult cancer survivors . Insights gained from this survey may ultimately help guide strategies in providing optimal care to these patients |
1,978 | 24,812,148 | Social support was positive and consistently associated with the physical activity level of adolescents in cross-sectional and longitudinal studies .
Those who received more overall social support as well as support from both parents , friends and family showed higher levels of physical activity . | The objective of this review was to systematic ally synthesize the results of original studies on the association between physical activity and social support in adolescents , published until April 2011 . | Background This study aim ed to evaluate the associations of selected demographic , individual , social , and environmental factors with moderate-to-vigorous physical activity ( MVPA ) in a sample of children and adolescents . Methods MVPA was assessed among youth ( n = 294 ) 10 - 17-years-old using the ActiGraph accelerometer . Youth completed measures of demographic and individual variables related to physical activity ( PA ) , perceived social support by parents and peers , and perceived neighborhood characteristics . Parents completed the long-form of the International Physical Activity Question naire . The Physical Activity and Media Inventory was used to measure the home environment and Geographical Information Systems software was used to measure the physical neighborhood environment . Bivariate correlations and hierarchical multiple regression were conducted stratified by gender . Results Boys participated in significantly more MVPA than girls . In hierarchical analyses , peer support , home PA equipment , and temperature were significantly associated with MVPA among boys whereas distance to the school they attended was associated with MVPA among girls . The final models accounted for 25 % and 15 % of the variance in MVPA among boys and girls , respectively . Conclusions Important differences exist among the individual , social , and environmental factors related to MVPA between boys and girls . Boys ' levels of activity appear to be influenced by factors closely linked to unstructured and social types of activities whereas girls ' activities relate to internal and external barriers as well as their proximity to their schools . The prospect i ve contribution of these important individual , social , and environmental factors to changes in MVPA among children and adolescents remains to be determined BACKGROUND Underst and ing the determinants of physical activity in children is critical for the treatment and prevention of childhood obesity . Social-cognitive theory has been used to underst and behavioral patterns in children . OBJECTIVES To explore the relationship between health beliefs , self-efficacy , social support , and sedentary activities and physical activity levels in children and to examine the relationship between physical activity and children 's self-esteem . METHODS Ninety-two children aged 10 to 16 years completed the study . Physical activity was monitored for 1 week with a motion detector ( Actitrac ; IM Systems , Baltimore , Md ) . Moderate-level activity and high-level activity were defined based on the results of treadmill testing . Health beliefs , self-efficacy , social influences , and time spent in sedentary behaviors were determined through question naires . Self-esteem was measured using the Piers-Harris Children 's Self-Concept Scale . Chronic anxiety was measured with the Revised Children 's Manifest Anxiety Scale . RESULTS There was a significant decline in physical activity levels between ages 10 and 16 years , particularly in girls . Preteen girls spent approximately 35 % more time in low- and high-level activity than did teenage girls ( P<.001 ) . Overall , children spent 75.5 % of the day inactive , with a mean + /- SD of 5.2 + /- 1.8 hours watching television , sitting at the computer , and doing homework . In contrast , only 1.4 % of the day ( 12.6 + /- 12.2 minutes ) was spent in vigorous activity . Time spent in sedentary behaviors was inversely correlated with the amount of moderate-level activity ( P<.001 ) but not high-level activity . In contrast , time spent in high-level activity correlated with self-efficacy scores ( P<.001 ) and social influences scores ( P<.005 ) . High-level physical activity was also associated with improved self-esteem ( P<.05 ) . Higher health beliefs scores were not correlated with physical activity levels . CONCLUSIONS Children and adolescents are largely sedentary . Correlates of high- and low-level physical activity are different . Time spent on sedentary activities is inversely correlated with moderate-level activity , while self-efficacy and social influences are positively correlated with more intense physical activity . In addition , increased high-level physical activity is an important component in the development of self-esteem in children OBJECTIVE To test whether self-efficacy for overcoming barriers to physical activity has direct , indirect ( i.e. , mediated ) , or moderating relations with naturally occurring change in perceived social support and declines in physical activity during high school . METHODS Latent growth modeling was used with measures completed in the 8th , 9th , and 12th grade s by a cohort of 195 Black and White girls . RESULTS Self-efficacy was stable and moderated the relation between changes in physical activity and perceived social support . Girls who maintained a perception of strong social support had less of a decline in physical activity if they also had high self-efficacy . However , girls having high self-efficacy had a greater decline in physical activity if they perceived declines in social support . CONCLUSIONS R and omized controlled trials of physical activity interventions based on social cognitive theory should consider that the influence of girls ' perceptions of social support on their physical activity may differ according to their efficacy beliefs about barriers to physical activity OBJECTIVE To identify factors associated with changes in physical activity in adolescent girls at risk for sedentary lifestyles and obesity . DESIGN A cohort study was performed with 201 high school girls recruited to participate in an evaluation study of a school-based obesity prevention physical education program . Three assessment s were performed during an 8-month period . MAIN OUTCOME MEASURES Associations between physical activity and a range of personal factors ( self-acceptance , self-worth , athletic competence , body image , depressive mood , perceived benefits , enjoyment of physical activity , self-efficacy , and body mass index ) , behavioral factors ( watching television and time constraints ) , and socioenvironmental factors ( social support and costs/re sources ) were assessed . RESULTS The 2 strongest and most consistent factors associated with change in physical activity were time constraints and support for physical activity from peers , parents , and teachers . Measures assessing self-perceptions , global ( ie , self-worth ) and specific to physical activity ( ie , self-efficacy to be physically active ) , were also associated with change in physical activity . For example , a decrease of 2.0 U for an adolescent 's perceived time constraints ( possible range , 3.0 - 12.0 U ) would be expected to lead to an increase of 53 minutes of moderate to vigorous physical activity per week ( 95 % confidence interval , 33 - 72 minutes ) . An increase of 2.0 U in perceived support for physical activity ( possible range , 3.0 - 12.0 U ) would be expected to lead to an increase of 35 minutes of moderate to vigorous physical activity per week ( 95 % confidence interval , 13 - 56 minutes ) . An increase of 3.0 U on the self-worth scale ( possible range , 5.0 - 20.0 U ) might be expected to lead to an increase of 19 minutes of moderate to vigorous physical activity per week ( 95 % confidence interval , 0 - 40 minutes ) . CONCLUSION The effectiveness of interventions aim ed at increasing physical activity among adolescent girls might be enhanced by engaging support from friends , family , and caring adults ; addressing real and perceived time constraints ; and helping adolescent girls feel more confident about themselves and their ability to engage in physical activity 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 The aim of this study was to examine modifiable biological , psychological , behavioral and social-environmental correlates of physical activity among 1129 Norwegian 11-year-old children within a cross-sectional sample from the HEalth In Adolescents study . Physical activity was assessed by accelerometer , and weight and height were measured objective ly . Age- and gender-specific cut-off points proposed by the International Obesity Task Force were used to define body mass index . Social-environmental variables were self-reported by question naire . Hierarchical regression ( linear mixed models ) revealed that normal weight children scored higher on percentage daily moderate-to-vigorous physical activity [ % daily moderate to vigorous physical activity ( MVPA ) ] than overweight/obese children ( P<0.001 ) . Self-efficacy ( P<0.01 ) and perceived social support from friends ( P<0.01 ) were positively associated with children 's % daily MVPA , and a negative association was found for computer/game-use on weekends ( P<0.01 ) . A moderator effect of weight category ( normal vs overweight/obese ) in the relationship between computer/game-use on weekends and % daily MVPA was detected ( P<0.05 ) , reflecting that higher computer/game-use on weekends was associated with lower % MVPA among the overweight/obese , but not among the normal weight . Modifiable correlates from multiple domains accounted for 14 % of the variance in % daily MVPA . Prospect i ve and intervention studies are needed to examine whether these factors act as mediators for physical activity change in pre-adolescent children OBJECTIVE This study examined differences in ( 1 ) psychosocial correlates of physical activity and in ( 2 ) physical activity within different context s and sedentary behaviors between normal weight and overweight adolescents . It further explored whether the prediction of physical activity by the psychosocial correlates is different in normal weight and overweight adolescents . RESEARCH METHODS AND PROCEDURE A community sample of 6078 11 to 19 year olds from 38 secondary schools , which were r and omly selected throughout the country , completed a vali date d computerized question naire about physical activity , sedentary behaviors , and psychosocial correlates . Differences in mean scores on the psychosocial correlates and on the self-rated physical activity were analyzed between the normal weight ( n=5563 ) and the overweight ( n=515 , 8.5 % ) group . RESULTS This study showed that overweight adolescents do less intense physical activities ( p<0.001 ) and have less favorable psychosocial correlates related to physical activity ( p<0.001 ) than their normal weight counterparts . However , the strength of the associations between psychosocial variables and total physical activity were comparable in overweight and normal weight adolescents . More support from family and friends , more fun in physical activity , higher self-efficacy , the perception of more competition benefits , and the perception of less lack of interest were all associated with higher total levels of physical activity . The results suggest that no specific tailoring on psychosocial correlates of physical activity is necessary for overweight adolescents compared with normal weight ones . DISCUSSION Both overweight and normal weight adolescents can be approached by interventions focusing on the same psychosocial variables to increase physical activity The present study examined whether self-efficacy mediates the relationship between family social influence and physical activity among youth who have experienced a recent lapse in their physical activity participation . Using a prospect i ve , longitudinal design , participants completed measures of social influence , self-regulatory efficacy and physical activity . Only those participants whose physical activity declined were retained for further analysis . Self-regulatory efficacy partially mediated the relationship between family social influence and physical activity , with self-efficacy mediating 36 percent of the total effect . The results provide support for self-regulatory efficacy as a mediator and provide preliminary insight into the potential mechanisms for preventing lapses in activity from developing into prolonged periods of inactivity within this population OBJECTIVE To determine if perceptions of the social and physical environment are associated with active transport and leisure-time sports among Belgian youth and to investigate if this relationship is moderated by self-efficacy . METHODS In February-May 2008 , 1445 adolescents ( 17.4+/-0.6 yrs ) were recruited in 20 r and omly selected Belgian schools . Physical activity , psychosocial , and environmental factors were assessed using vali date d question naires . Moderated multilevel regression analysis was used to examine the association between physical activity and possible correlates . RESULTS Social environmental variables ( modeling and social support ) were positively associated with active transportation and leisure-time sports ( p<0.05 ) . Higher l and use mix diversity , higher street connectivity , more attractive environments , better access to recreational facilities , and higher emotional satisfaction with the neighborhood were associated with more active transportation ( p<0.05 ) . Higher perceived safety from traffic , better access to recreational facilities , more physical activity equipment at home , and fewer electronic devices in the bedroom were associated with more leisure-time sports ( p<0.05 ) . Lower perceived safety and poorer access to ( recreational ) facilities were only associated with lower active transport among youth with lower self-efficacy ( p<0.05 ) . CONCLUSION Creating more supportive environments could have the potential to affect the physical activity levels of Belgian adolescents with both high and low self-efficacy |
1,979 | 23,076,932 | Adding technology-mediated psychoeducation on top of st and ard care did not clearly improve either general mental state , negative or positive symptoms , global state , level of knowledge or quality of life .
However , the results were not consistent regarding level of knowledge and satisfaction with treatment .
Using ICT to deliver psychoeducational interventions has no clear effects compared with st and ard care , other methods of delivering psychoeducation and support , or both . | BACKGROUND Poor compliance with treatment often means that many people with schizophrenia or other severe mental illness relapse and may need frequent and repeated hospitalisation .
Information and communication technology ( ICT ) is increasingly being used to deliver information , treatment or both for people with severe mental disorders .
OBJECTIVES To evaluate the effects of psychoeducational interventions using ICT as a means of educating and supporting people with schizophrenia or related psychosis . | OBJECTIVES The study aim ed to test two hypotheses . Firstly , that participants who relapsed during the 12-month follow-up period of our r and omized controlled trial , would show increased negative beliefs about their illness and reduced self-esteem , in comparison to the non-relapsed participants . Secondly , that cognitive behavioural therapy ( CBT ) for early signs of relapse would result in a reduction in negative beliefs about psychosis and an improvement in self-esteem at 12 months . DESIGN AND METHODS A total of 144 participants with schizophrenia or a related disorder were r and omized to receive either treatment as usual ( TAU ; N=72 ) or CBT ( N=72 ) . Participants completed the Personal Beliefs about Illness Question naire ( PBIQ ; Birchwood , Mason , MacMillan , & Healy , 1993 ) and the Rosenberg Self-Esteem Scale ( RSES ; Rosenberg , 1965 ) at entry , 3 months , 6 months , and 12 months . RESULTS At 12 months , relapsers showed greater increase in scores for PBIQ entrapment compared with non-relapsers . In addition , after controlling for baseline covariates ( treatment group and PBIQ self versus illness ) , relapsers also showed greater increase in scores for PBIQ self versus illness at 12 months . Furthermore , in comparison to treatment as usual , participants who received CBT showed greater improvement in PBIQ loss and in Rosenberg self-esteem . CONCLUSIONS The study provides evidence that relapse is associated with the development of negative appraisal s of entrapment and self-blame ( self vs. illness ) . In addition , this is the first study to show that CBT reduces negative appraisal s of loss arising from psychosis and improvements in self-esteem . Implication s for future research and treatment are discussed Background The approximately 1100 medical journals now active in China are publishing a rapidly increasing number of research reports , including many studies identified by their authors as r and omized controlled trials . It has been noticed that these reports mostly present positive results , and their quality and authenticity have consequently been called into question . We investigated the adequacy of r and omization of clinical trials published in recent years in China to determine how many of them met acceptable st and ards for allocating participants to treatment groups . Methods The China National Knowledge Infrastructure electronic data base was search ed for reports of r and omized controlled trials on 20 common diseases published from January 1994 to June 2005 . From this sample , a subset of trials that appeared to have used r and omization methods was selected . Twenty-one investigators trained in the relevant knowledge , communication skills and quality control issues interviewed the original authors of these trials about the participant r and omization methods and related quality -control features of their trials . Results From an initial sample of 37,313 articles identified in the China National Knowledge Infrastructure data base , we found 3137 apparent r and omized controlled trials . Of these , 1452 were studies of conventional medicine ( published in 411 journals ) and 1685 were studies of traditional Chinese medicine ( published in 352 journals ) . Interviews with the authors of 2235 of these reports revealed that only 207 studies adhered to accepted methodology for r and omization and could on those grounds be deemed authentic r and omized controlled trials ( 6.8 % , 95 % confidence interval 5.9–7.7 ) . There was no statistically significant difference in the rate of authenticity between r and omized controlled trials of traditional interventions and those of conventional interventions . R and omized controlled trials conducted at hospitals affiliated to medical universities were more likely to be authentic than trials conducted at level 3 and level 2 hospitals ( relative risk 1.58 , 95 % confidence interval 1.18–2.13 , and relative risk 14.42 , 95 % confidence interval 9.40–22.10 , respectively ) . The likelihood of authenticity was higher in level 3 hospitals than in level 2 hospitals ( relative risk 9.32 , 95 % confidence interval 5.83–14.89 ) . All r and omized controlled trials of pre-market drug clinical trial were authentic by our criteria . Of the trials conducted at university-affiliated hospitals , 56.3 % were authentic ( 95 % confidence interval 32.0–81.0 ) . Conclusion Most reports of r and omized controlled trials published in some Chinese journals lacked an adequate description of r and omization . Similarly , most so called ' r and omized controlled trials ' were not real r and omized controlled trials owing toa lack of adequate underst and ing on the part of the authors of rigorous clinical trial design . All r and omized controlled trials of pre-market drug clinical trial included in this research were authentic . R and omized controlled trials conducted by authors in high level hospitals , especially in hospitals affiliated to medical universities had a higher rate of authenticity . That so many non-r and omized controlled trials were published as r and omized controlled trials reflected the fact that peer review needs to be improved and a good practice guide for peer review including how to identify the authenticity of the study urgently needs to be developed BACKGROUND Patient-rated unmet need is cross-sectionally associated with quality of life . Its longitudinal relationship has not been established . AIMS To test the hypotheses that : ( a ) higher patient-rated unmet need is associated with lower individual quality of life assessment s by a patient over time ; and ( b ) reduction in patient-rated unmet need precedes improvement in quality of life . METHOD One hundred and one individuals using adult mental health services were asked to complete 6-monthly question naires , comprising quality of life ( Manchester Short Assessment of Quality of Life , MANSA ) and unmet need ( Camberwell Assessment of Need Short Appraisal Schedule , CANSAS ) assessment s. RESULTS Seventy-three participants provided 240 separate pairs of consecutive assessment s. R and om effects regression models indicated an impact on current quality of life for both average level of unmet need ( B= -0.23 , 95 % CI -0.29 to -0.17 ) and change in unmet need over the past month ( B= -0.04 , 95 % CI -0.02 ) . CONCLUSIONS Changes in patient-rated unmet needs may cause changes in quality of life BACKGROUND Patient-clinician communication is central to mental healthcare but neglected in research . AIMS To test a new computer-mediated intervention structuring patient-clinician dialogue ( DIALOG ) focusing on patients ' quality of life and needs for care . METHOD In a cluster r and omised controlled trial , 134 keyworkers in six countries were allocated to DIALOG or treatment as usual ; 507 people with schizophrenia or related disorders were included . Every 2 months for 1 year , clinicians asked patients to rate satisfaction with quality of life and treatment , and request additional or different support . Responses were fed back immediately in screen displays , compared with previous ratings and discussed . Primary outcome was subjective quality of life , and secondary outcomes were unmet needs and treatment satisfaction . RESULTS Of 507 patients , 56 were lost to follow-up and 451 were included in intention-to-treat analyses . Patients receiving the DIALOG intervention had better subjective quality of life , fewer unmet needs and higher treatment satisfaction after 12 months . CONCLUSIONS Structuring patient-clinician dialogue to focus on patients ' views positively influenced quality of life , needs for care and treatment satisfaction Nonadherence to medication is a widespread problem in schizophrenia and is associated with poor clinical outcomes and inappropriate management and utilization of re sources . The aim of the current investigation was to assess the impact of telemonitoring of medication adherence on symptomatology and service use in patients with schizophrenia . A total of 108 schizophrenia patients were r and omized into three equal groups according to the approaches used to assess medication adherence ; self-report , pill counting , and telemonitoring . Telementoring was achieved through an innovative new platform called @HOME . This platform offers clinicians early warnings about impeding nonadherence as well as information about the pattern of medication taking . Patient 's adherence was observed over an 8-week period , during which patient 's clinical status and service use were recorded . In comparison to the other two groups , patients using @HOME showed improvement in the Global Clinical Impression Scale and a significant reduction in emergency visits and medical appointments . The @HOME platform was highly acceptable by patients , caregivers , and professionals , and required minimal training for implementation . The results of the study suggest that the use of telemonitoring in psychiatric setting s was both feasible and acceptable and may be associated with significant clinical and service related benefits BACKGROUND : Interactive Health Communication Applications ( IHCAs ) are computer-based , usually web-based health information packages for patients that combine information with at least one of social support , decision support , or behaviour change support . These are innovations in health care and their effects on health are uncertain . OBJECTIVES : To assess the effects of IHCAs for people with chronic disease . SEARCH STRATEGY : We design ed a four-part search strategy . First , we search ed electronic bibliographic data bases for published work ; second , we search ed the grey literature and third , we search ed for ongoing and recently completed clinical trials in the appropriate data bases . Finally , research ers of included studies were contacted , and reference lists from relevant primary and review articles were followed up . As IHCAs require relatively new technology , the search commenced at 1990 where possible . SELECTION CRITERIA : R and omised controlled trials ( RCTs ) of Interactive Health Communication Applications for adults and children with chronic disease . DATA COLLECTION AND ANALYSIS : One review er screened abstract s. Two review ers screened all c and i date studies to determine eligibility , apply quality criteria , and extract data from included studies . Authors of included RCTs were contacted for missing data . Results of RCTs were pooled using a r and om effects model and st and ardised mean differences ( SMDs ) were calculated to provide net effect sizes . MAIN RESULTS : We screened 24,757 unique citations and retrieved 958 papers for further assessment , yielding 28 RCTs involving 4042 participants . One of these had an inadequate method of concealment of allocation , and sensitivity analyses were performed to determine the effects of including or excluding these data in the meta-analyses . Results in the abstract are from the meta-analyses excluding data from this study .IHCAs were found to have a positive effect on knowledge ( SMD 0.49 ; 95 % confidence interval ( CI ) 0.14 to 0.84 ) and on social support ( SMD 0.47 ; 95 % CI 0.28 to 0.66 ) . IHCAs were found to have no effect on self-efficacy ( SMD 0.15 ; 95 % CI -0.13 to 0.43 ) or behavioural outcomes ( SMD -0.09 ; 95 % CI -0.49 to 0.32 ) . IHCAs had a negative effect on clinical outcomes ( SMD -0.32 ; 95 % CI -0.63 to -0.02 ) . REVIEW ERS ' CONCLUSIONS : The number and range of IHCAs is increasing rapidly ; however there is a shortage of high quality evaluative data . Consumers who wish to increase their knowledge or social support amongst people with a similar problem may find an IHCA helpful . However , consumers whose primary aim is to achieve optimal clinical outcomes should not use an IHCA at present . Further research is needed to determine the reason for this negative effect on clinical outcomes , whether an optimal IHCA can achieve behaviour change and improved health outcomes , and if so , what are the essential features of such an IHCA , and the extent to which they differ according to patient group or condition BACKGROUND Preliminary results have demonstrated the clinical efficacy of computerised cognitive-behavioural therapy ( CBT ) in the treatment of anxiety and depression in primary care . AIMS To determine , in an exp and ed sample , the dependence of the efficacy of this therapy upon clinical and demographic variables . METHOD A sample of 274 patients with anxiety and /or depression were r and omly allocated to receive , with or without medication , computerised CBT or treatment as usual , with follow-up assessment at 6 months . RESULTS The computerised therapy improved depression , negative attributional style , work and social adjustment , without interaction with drug treatment , duration of preexisting illness or severity of existing illness . For anxiety and positive attributional style , treatment interacted with severity such that computerised therapy did better than usual treatment for more disturbed patients . Computerised therapy also led to greater satisfaction with treatment . CONCLUSIONS Computer-delivered CBT is a widely applicable treatment for anxiety and /or depression in general practice The authors estimated components of variance and intraclass correlation coefficients ( ICCs ) to aid in the design of complex surveys and community intervention studies by analyzing data from the Health Survey for Engl and 1994 . This cross-sectional survey of English adults included data on a range of lifestyle risk factors and health outcomes . For the survey , households were sample d in 720 postal code sectors nested within 177 district health authorities and 14 regional health authorities . Study subjects were adults aged 16 years or more . ICCs and components of variance were estimated from a nested r and om-effects analysis of variance . Results are presented at the district health authority , postal code sector , and household levels . Between-cluster variation was evident at each level of clustering . In these data , ICCs were inversely related to cluster size , but design effects could be substantial when the cluster size was large . Most ICCs were below 0.01 at the district health authority level , and they were mostly below 0.05 at the postal code sector level . At the household level , many ICCs were in the range of 0.0 - 0.3 . These data may provide useful information for the design of epidemiologic studies in which the units sample d or allocated range in size from households to large administrative areas An effective rehabilitation program was developed for psychiatric patients ' self-management of medication and symptoms . The rehabilitation program was design ed to allow the patients to underst and their illness , cope with their medical regimen , and prevent a relapse by recognizing any of the symptoms when they recur . This study consisted of three phases . The first phase was to explore the extent and the specific mental health needs of psychiatric patients . Data was obtained from 82 subjects who had symptoms of a mental illness including schizophrenia , bipolar disorders , and delusional disorder . They had received medication instruction during their hospitalization . The subjects were at the time out patients in a psychiatric hospital . In the second phase , the research ers developed an educational program focused on coping with the residual and relapse warning signs , managing the drug side effects , medication compliance , and daily routines , according to the information acquired in the first step . The developed program includes the self-efficacy method reported by B and ura , including manuals and videotapes focusing on real life situations , small group discussion s , and telephone coaching . Finally , the research ers investigated the effects of this program . Thirty-eight patients were selected for this study , 18 in the experimental program and 20 as controls . The diagnoses were same as those with the first step . The results showed that the subjects who attended this educational program reported significantly more improvement in self-efficacy ( p=0.014 ) and medication compliance ( p= 0.005 ) , and significantly less relapse warning symptom scores ( p=0.000 ) than the controls . In conclusion , these instructional material s will be beneficial for medication and symptom management in rehabilitating psychiatric patients in Korea . In addition , the material s may be a useful psychoeducational re source for professionals in the field of clinical psychiatry OBJECTIVE To evaluate the feasibility of a telehealth psychoeducation intervention for persons with schizophrenia and their family members . STUDY DESIGN R and omized controlled trial . PARTICIPANTS 30 persons with schizophrenia and 21 family members or other informal support persons . INTERVENTIONS Web-based psychoeducation program that provided online group therapy and education . MAIN OUTCOME MEASURES Measures for persons with schizophrenia included perceived stress and perceived social support ; for family members , they included disease-related distress and perceived social support . RESULTS At 3 months , participants with schizophrenia in the intervention group reported lower perceived stress ( p = .04 ) and showed a trend for a higher perceived level of social support ( p = .06 ) . CONCLUSIONS The findings demonstrate the feasibility and impact of providing telehealth-based psychosocial treatments , including online therapy groups , to persons with schizophrenia and their families Abstract Objective : To determine the efficacy of teaching patients with bipolar disorder ( manic-depressive psychosis ) to identify early symptoms of relapse and seek prompt treatment from health services . Design : Single blind r and omised controlled trial with matching on four baseline variables using a minimisation algorithm . Setting : Mental health services in four NHS trusts ( one teaching , three non-teaching ) . Subjects : 69 patients with bipolar disorder who had had a relapse in the previous 12 months . Interventions : Seven to 12individual treatment sessions from a research psychologist plus routine care or routine care alone . Main outcome measures : Time to first manic or depressive relapse , number of manic or depressive relapses , and social functioning examined by st and ardised interviews every six months for 18 months . Results : 25th centile time to first manic relapse in experimental group was 65weeks compared with 17weeks in the control group . Event curves of time to first manic relapse significantly differed between experimental and control groups ( log rank 7.04 , df=1 , P=0.008 ) , with significant reductions in the number of manic relapses over 18months ( median difference 30 % ( 95 % confidence interval 8 % to 52 % ) , P=0.013 ) . The experimental treatment had no effect on time to first relapse or number of relapses with depression , but it significantly improved overall social functioning ( mean difference 2.0(0.7to 3.2 ) , P=0.003 ) and employment ( mean difference 0.7(0.1to 1.3 ) , P=0.030 ) by 18months . Conclusion : Teaching patients to recognise early symptoms of manic relapse and seek early treatment is associated with important clinical improvements in time to first manic relapse , social functioning , and employment Background Cognitive behavior therapy is well recognized as an effective treatment and prevention for depression when delivered face-to-face , via self-help books ( bibliotherapy ) , and through computer administration . The public health impact of cognitive behavior therapy has been limited by cost and the lack of trained practitioners . We have developed a free Internet-based cognitive behavior therapy intervention ( MoodGYM , http://moodgym.anu.edu.au ) design ed to treat and prevent depression in young people , available to all Internet users , and targeted to those who may have no formal contact with professional help services . Objective To document site usage , visitor characteristics , and changes in depression and anxiety symptoms among users of MoodGYM , a Web site delivering a cognitive-behavioral-based preventive intervention to the general public . Methods All visitors to the MoodGYM site over about 6 months were investigated , including 2909 registrants of whom 1503 had completed at least one online assessment . Outcomes for 71 university students enrolled in an Abnormal Psychology course who visited the site for educational training were included and examined separately . The main outcome measures were ( 1 ) site-usage measures including number of sessions , hits and average time on the server , and number of page views ; ( 2 ) visitor characteristics including age , gender , and initial Goldberg self-report anxiety and depression scores ; and ( 3 ) symptom change measures based on Goldberg anxiety and depression scores recorded on up to 5 separate occasions . Results Over the first almost-6-month period of operation , the server recorded 817284 hits and 17646 separate sessions . Approximately 20 % of sessions lasted more than 16 minutes . Registrants who completed at least one assessment reported initial symptoms of depression and anxiety that exceeded those found in population -based surveys and those characterizing a sample of University students . For the Web-based population , both anxiety and depression scores decreased significantly as individuals progressed through the modules . Conclusions Web sites are a practical and promising means of delivering cognitive behavioral interventions for preventing depression and anxiety to the general public . However , r and omized controlled trials are required to establish the effectiveness of these interventions Deprivation of liberty ( DL ) in psychiatric inpatient care is common worldwide . As liberty is a central element of patients ’ rights , there is a need to develop most effective methods supporting patients ’ personal liberty . The article presents initial results from a study to determine the effectiveness of an information technology (IT)-based patient education programme on patients ’ experiences of being deprived of their liberty during their in-hospital stay . An overall sample of 311 patients with schizophrenia spectrum psychosis was r and omized into three groups : an intervention group with needs-based computerized patient education , a patient education group with conventional education and a control group with st and ard care . Data on the general experience of DL were collected at baseline and during the patient discharge process . In general , all patients experienced less DL at the time of their discharge . The change in patients ’ experiences of their DL did not differ statistically between the three groups . Male patients in the st and ard care group were significantly more likely to drop out of the study than female patients . Although technology-based patient education was not found to be superior to other approaches , we did not find any reason to inhibit its utilization in patient care among persons with severe mental health problems . From the healthcare organizations ’ perspective , a cost-effectiveness analysis is needed , as the IT education was slightly more time-consuming BACKGROUND AND AIMS Many people with schizophrenia have severe cognitive impairments that hamper their activities . The effect of pharmacological and behavioural interventions on cognitive functioning has been demonstrated , but even after successful intervention considerable impairments can remain . Therefore , we sought for alternative ways to help patients cope with the effects of their cognitive impairments . In the present study , we have evaluated the efficacy of short message service ( SMS ) text messages to compensate for the effects of cognitive impairments in schizophrenia in daily life . DESIGN A waiting list controlled trial was conducted : patients were quasi-r and omly assigned to an A-B-A ( baseline-intervention-follow-up ) condition or an A-A-B-A condition that included an additional 7-week waiting list . The waiting list was included to control for the effect of time on relevant outcome . METHOD Sixty-two people with schizophrenia or related psychotic disorders were included in the study . All patients showed impaired goal -directed behaviour in daily life-situations . Patients were prompted with SMS text messages to improve their everyday functioning . The primary outcome measure was the percentage of goals achieved . RESULTS The overall percentage of goals achieved increased with prompting , while performance dropped to baseline level after withdrawing the prompts . Keeping appointments with mental health workers and carrying out leisure activities increased with prompting , while medication adherence and attendance at training sessions remained unchanged . A majority of the patients enjoyed receiving the SMS text messages . DISCUSSION Prompting can significantly improve achievement of a number of relevant goals . For other goals , combining prompting with interventions that enhance motivation seems indicated The present study attempted to reduce the missed initial appointment rate of an urban CMHC through the use of several intervention strategies . Individuals who called for an intake appointment were r and omly assigned to either a control group or one of the following treatment conditions : orientation statement at the time the appointment was made , orientation statement plus phone prompt , or phone prompt only . The orientation statement only group had significantly fewer missed initial appointments than the control group ( 28 % vs. 56 % ) . A client reachability factor also played a role in predicting missed initial appointmnts OBJECTIVE The objective of this study was to explore the possibility of the use of Virtual Reality Functional Skills Assessment ( VRFSA ) in a future regular clinical trial , as well as to report a preliminary result about effectiveness of atypical antipsychotics to social competence in schizophrenia . METHODS We developed the VRFSA that measured subjects ' performances automatically and used analogue scale rather than Likert scale . Twenty-four female patients with paranoid schizophrenia and 15 healthy females were recruited . This was a 6-week , r and omized , open-label , and flexible dose study , and 2 treatments ( baseline versus post-treatment ) x 2 skills phases ( receptive versus expressive ) x 2 patient groups ( aripiprazole versus risperidone ) analysis of variance was used in the final analysis . RESULTS There was a significant difference in the VRFAS between the patients and the healthy subjects ( p < 0.05 ) . Eighteen patients were included in the final analysis . We found larger treatment effect than those found in previous studies , and significant treatment x skills phase x group interaction effect on the VRFAS . CONCLUSIONS Our results suggest that the VRFAS is strongly sensitive to changes in social competence and thus especially beneficial in short-term clinical trials . In addition , atypical antipsychotics can improve social competence and differentially improve receptive skills and expressive skills in schizophrenia Remission and relapse are clinical outcomes of increasing interest in schizophrenia . We analyzed remission and relapse , and the sociodemographic and clinical factors associated with these outcomes , in the usual care of schizophrenia using the 3-year , follow-up data from a large cohort of out patients with schizophrenia taking part in the prospect i ve , observational , European Schizophrenia Outpatient Health Outcomes study . Of the 6516 patients analyzed for remission , 4206 ( 64.6 % ) achieved remission during the 3-year , follow-up period . Logistic regression analysis revealed that being female , having a good level of social functioning at study entry , and a shorter duration of illness were factors significantly associated with achieving remission . Treatment with olanzapine was also associated with a higher frequency of remission compared with other antipsychotic agents . A Kaplan-Meier survival curve estimated that relapse occurred in approximately 25 % of the patients who achieved remission , with the risk of relapse remaining constant during the follow-up period . Shorter duration of illness , having hostile behaviors , and substance abuse were factors associated with a higher risk of relapse , whereas good level of social functioning and the use of olanzapine and clozapine were associated with a lower risk of relapse . In conclusion , the 3-year results of the Schizophrenia Outpatient Health Outcomes study indicate that the likelihood of remission decreases over the longitudinal course of schizophrenia , but risk of relapse is maintained even after 3 years of achieving remission severity levels . Results suggest that treatment with olanzapine is associated with a better chance of achieving remission than other antipsychotics . Moreover , the use of olanzapine and clozapine is associated with a lower risk of relapse compared with risperidone , quetiapine , and typical antipsychotics . The results should be interpreted conservatively because of the observational , nonr and omized study design Contacting patients by telephone before their appointment has been shown to increase clinic attendance in various setting s. However , no such studies have been conducted in New Zeal and , which has a unique mix of publicly funded secondary care and largely privately funded primary care . A controlled prospect i ve study of telephone prompting was carried out in a New Zeal and publicly funded community mental health center . One group of 190 patients was phoned the day before their initial appointment , and their attendance rate was compared with that of 496 patients not phoned . Ninety-six percent of the patients who were successfully contacted kept their appointment , compared with 76 percent of those not contacted BACKGROUND A recent review suggested an association between using unpublished scales in clinical trials and finding significant results . AIMS To determine whether such an association existed in schizophrenia trials . METHOD Three hundred trials were r and omly selected from the Cochrane Schizophrenia Group 's Register . All comparisons between treatment groups and control groups using rating scales were identified . The publication status of each scale was determined and cl aims of a significant treatment effect were recorded . RESULTS Trials were more likely to report that a treatment was superior to control when an unpublished scale was used to make the comparison ( relative risk 1.37 ( 95 % CI 1.12 - 1.68 ) ) . This effect increased when a ' gold-st and ard ' definition of treatment superiority was applied ( RR 1.94 ( 95 % CI 1.35 - 2.79 ) ) . In non-pharmacological trials , one-third of ' gold-st and ard ' cl aims of treatment superiority would not have been made if published scales had been used . CONCLUSIONS Unpublished scales are a source of bias in schizophrenia trials BACKGROUND Little evidence exists to indicate whether community psychiatric nurses can achieve the results reported by expert cognitive-behavioural therapists in patients with schizophrenia . AIMS To assess the effectiveness and safety of a brief cognitive-behavioural therapy ( CBT ) intervention in a representative community sample of patients with schizophrenia in secondary care setting s. METHOD A pragmatic r and omised trial was performed involving 422 patients and carers to compare a brief CBT intervention against treatment as usual . RESULTS Patients who received CBT ( n=257 ) improved in overall symptomatology ( P=0.015 ; number needed to treat [NNT]=13 ) , insight ( P<0.001 ; NNT=10 ) and depression ( P=0.003 ; NNT=9 ) compared with the control group ( n=165 ) . Insight was clinical ly significantly improved ( risk ratio=1.15 , 95 % CI 1.01 - 1.31 ) . There was no increase in suicidal ideation . CONCLUSIONS Community psychiatric nurses can safely and effectively deliver a brief CBT intervention to patients with schizophrenia and their carers Abstract Objectives : To compare use , effect , and cost of personalised computer education with community psychiatric nurse education for patients with schizophrenia . Design : R and omised trial of three interventions . Modelling of costs of alternatives . Participants : 112 patients with schizophrenia in contact with community services ; 67 completed the intervention . Interventions : Three interventions of five educational sessions : ( a ) computer intervention combining information from patient 's medical record with general information about schizophrenia ; ( b ) sessions with a community psychiatric nurse ; ( c ) “ combination ” ( first and last sessions with nurse and remainder with computer ) . Main outcome measures : Patients ' attendance , opinions , change in knowledge , and psychological state ; costs of interventions and patients ' use of NHS community services ; modelling of costs for these three , and alternative , interventions . Results : Rates of completion of intervention did not differ significantly ( 71 % for combination intervention , 61 % for computer only , 46 % for nurse only ) . Computer sessions were shorter than sessions with nurse ( 14 minutes v 60 minutes ) . More patients given nurse based education thought the information relevant . Of 20 patients in combination group , 13 preferred the sessions with the nurse and seven preferred the computer . There were no significant differences between groups in psychological outcomes . Because of the need to transport patients to the computer for their sessions , there was no difference between interventions in costs , but computer sessions combined with other patient contacts would be substantially cheaper . Conclusions : The computer based patient education offered no advantage over sessions with a community psychiatric nurse . Investigation of computer use combined with other health service contacts would be worth while . What is already known on this topic Education of patients with schizophrenia has limited but positive outcomes Computer based approaches have not been thoroughly evaluated What this study adds A computer based method of education for patients with schizophrenia , which personalised the information with details from each patient 's medical record , was acceptable and as effective as educational sessions given by a community psychiatric nurse However , because of the need to provide transport for patients to attend their sessions , the computer based intervention was as costly as the nurse based one Investigating the addition of computer based education to other routine patient contacts would be 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 Objective : An intervention to structure patient – key worker communication has been tested in a r and omized controlled trial . The aim of this paper was to investigate effectiveness of the intervention in terms of moderators of effectiveness |
1,980 | 28,430,363 | The findings of this Cochrane Review do not demonstrate clinical benefits of cerebrolysin for treating acute ischaemic stroke .
We found moderate- quality evidence of an increase in non-fatal SAEs with cerebrolysin use but not in total SAEs | BACKGROUND Cerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from pigs ' brain tissue , which has potential neuroprotective and neurotrophic properties .
It is widely used in the treatment of acute ischaemic stroke in Russia , Eastern Europe , China , and other Asian and post-Soviet countries .
OBJECTIVES To assess the benefits and risks of cerebrolysin for treating acute ischaemic stroke . | The purpose of the study was to investigate the efficacy and safety of Cerebrolysin in patients with hemorrhagic stroke . The primary objective of this trial was to assess the clinical efficacy and safety of a 10–days course of therapy with a daily administration of Cerebrolysin ( 50 mL Ⅳ per day ) . The trial had to demonstrate that Cerebrolysin treatment is safe in hemorrhagic stroke . Methods : The study was performed as a prospect i ve , r and omized , double blind , placebo – controlled , parallel group study with 2 treatment groups . Efficacy measures were the Unified Neurological Stroke Scale , Barthel Index , and Syndrome Short Test . The duration of the trial was of 21 days for each patient . Out of 100 r and omized patients , a total of 96 ( 96 % ) completed the study . Results : Overall , no statistically significant group effects were observed based on single average comparisons at the individual visits . It could be shown that the treatment of hemorrhagic stroke with Cerebrolysin is safe and well tolerated . Conclusion : In the changes of UNSS , BI and SST from baseline to day 21 , the group differences are not statistically significant ; however , the use of Cerebrolysin in hemorrhagic stroke is safe and well tolerated and studies with a larger sample size may provide statistical evidence of Cerebrolysin 's efficacy in patients with hemorrhagic stroke Summary . Background and purpose . Cerebrolysin is a compound with neurotrophic and neuroprotective activity . It is produced by enzymatic breakdown of purified brain proteins and consists of low molecular weight peptides and amino acids . Cellular and animal models of cerebral ischaemia have shown that it is a potent neuroprotective agent . We explored the safety and preliminary outcome of Cerebrolysin treatment in patients with acute stroke . Methods . R and omised , placebo-controlled , parallel group trial . Patients with acute stroke were r and omised within 24 h of stroke onset to IV therapy with placebo or Cerebrolysin 50 mL/day for 21 days . Both groups received concomitant treatment with ASA 250 mg/day PO and pentoxifylline 300 mg/day IV . Clinical examinations were performed on days 1 , 3 , 7 , 21 and 90 post baseline . Outcome measures were the Canadian Neurological Scale , the Barthel Index , the Clinical Global Impressions , the Mini-Mental State Examination , and the Syndrome Short Test . Treatment emergent adverse events , lab tests , and vital signs were recorded to assess the safety of Cerebrolysin . Results . 146 patients were enrolled in two groups : 78 Cerebrolysin and 68 placebo . At baseline , no significant group differences were observed . Patients in the Cerebrolysin group had no significant improvement in the CNS score , the Barthel Index and the Clinical Global Impressions when compared to the placebo group . A significant improvement of cognitive function of the patients on Cerebrolysin was observed in the Syndrome Short Test when compared to the placebo group . Cerebrolysin was well tolerated and safe . Adverse events occurred with a similar frequency in both groups . Conclusion . The results demonstrate that neurotrophic treatment with Cerebrolysin is safe and well tolerated by patients with acute stroke . The findings , despite the small sample size , also indicate a potential treatment effect of Cerebrolysin in acute stroke . Larger studies , however , are needed to confirm and extend these findings Background and Purpose — The aim of this trial was to investigate whether stroke patients who receive Cerebrolysin show improved motor function in the upper extremities at day 90 compared with patients who receive a placebo . Methods — This study was a prospect i ve , r and omized , double-blind , placebo-controlled , multicenter , parallel-group study . Patients were treated with Cerebrolysin ( 30 mL/d ) or a placebo ( saline ) once daily for 21 days , beginning at 24 to 72 hours after stroke onset . The patients also participated in a st and ardized rehabilitation program for 21 days that was initiated within 72 hours after stroke onset . The primary end point was the Action Research Arm Test score on day 90 . Results — The nonparametric effect size on the Action Research Arm Test score on day 90 indicated a large superiority of Cerebrolysin compared with the placebo ( Mann – Whitney estimator , 0.71 ; 95 % confidence interval , 0.63–0.79 ; P<0.0001 ) . The multivariate effect size on global status , as assessed using 12 different outcome scales , indicated a small-to-medium superiority of Cerebrolysin ( Mann – Whitney estimator , 0.62 ; 95 % confidence interval , 0.58–0.65 ; P<0.0001 ) . The rate of premature discontinuation was < 5 % ( 3.8 % ) . Cerebrolysin was safe and well tolerated . Conclusions — Cerebrolysin had a beneficial effect on function and global outcome in early rehabilitation patients after stroke . Its safety was comparable with that of the placebo , suggesting a favorable benefit/risk ratio . Because this study was exploratory and had a relatively small sample size , the results should be confirmed in a large-scale , r and omized clinical trial . Clinical Trial Registration — URL : http://www . clinical trialsregister.eu . Unique identifier : 2007 - 000870 - 21 Background The neurotrophic drug Cerebrolysin accelerated recovery and prevented acute neuronal damage in pre clinical models of ischaemia . Previous clinical trials support therapeutic effects in stroke patients . The study investigated whether the combination with alteplase and Cerebrolysin is safe and can further reduce disability after acute ischaemic stroke . Methods This placebo-controlled , double-blind trial involved 119 patients with acute ischaemic hemispheric stroke , r and omly assigned to a combined treatment with alteplase plus Cerebrolysin or placebo ( administered 1 h after thrombolytic treatment ) starting within three-hours after onset of symptoms . A daily i.v . infusion of 30 ml Cerebrolysin or placebo was given for 10 consecutive days . Primary outcome was the modified Rankin Scale at day 90 . A sequential design with interim analyses was applied . Results The third interim analysis did not show a benefit in the modified Rankin Scale for Cerebrolysin on day 90 compared to placebo and the study was stopped . The National Institutes of Health Stroke Scale responder analysis ( secondary outcome measure ) showed significantly more patients with an improvement of 6 or more points ( or a total score of 0 or 1 ) after two- , five- , 10 , and 30 days in the Cerebrolysin group . Similar trends were observed for the modified Rankin Scale responder analysis without achieving statistical significance . There was no difference between treatment groups regarding adverse events . Conclusions The combination of Cerebrolysin with recombinant tissue-Plasminogen Activator is safe for treatment of acute ischaemic stroke but did not improve outcome at day 90 . During the treatment period with Cerebrolysin ( 10 days ) , significantly more patients had a favourable response in neurological outcome measures ( National Institutes of Health Stroke Scale ) as compared to the placebo group Background Cerebrolysin , a brain-derived neuropeptide , has been shown to improve the neurological outcomes of stroke , but no study has demonstrated its effect on cerebral blood flow . This study aim ed to determine the cerebrolysin impact on the neurological outcomes and cerebral blood flow . Methods In a r and omized , double-blinded , placebo-controlled trial , 46 patients who had acute focal ischemic stroke were r and omly assigned into two groups to receive intravenously either 30 mL of cerebrolysin diluted in normal saline daily for 10 days ( n=23 ) or normal saline alone ( n=23 ) adjunct to 100 mg of aspirin daily . All patients were examined using the National Institutes of Health Stroke Scale and transcranial Doppler to measure the mean flow velocity and pulsatility index ( PI ) of their cerebral arteries at baseline as well as on days 30 , 60 , and 90 . Results The patients ’ mean age was 60±9.7 years , and 51.2 % of patients were male . The National Institutes of Health Stroke Scale was significantly lower in the cerebrolysin group compared with the placebo group on day 60 ( median 10 , interquartile range 9–11 , P=0.008 ) and day 90 ( median 11 , interquartile range 10–13.5 , P=0.001 ) . The median of PI in the right middle cerebral artery was significantly lower in the cerebrolysin group compared with the placebo group on days 30 , 60 , and 90 ( P<0.05 ) . One patient in the cerebrolysin group and two patients in the placebo group died before day 30 ( 4.3 % versus 8.7 % ) . Conclusion Cerebrolysin can be useful to improve the neurological outcomes and the PI of middle cerebral artery in patients with acute focal ischemic stroke Cerebrolysin has exhibited neuroprotective as well as neurotrophic properties in various animal models of cerebral ischaemia and has shown clinical efficacy and good safety in several small controlled clinical studies in ischaemic stroke . Therefore , a large double-blind placebo-controlled r and omized clinical trial was launched in Asia to prove the validity of this treatment strategy . In the more than 50 participating centres patients with acute ischemic hemispheric stroke are r and omized within 12 hours of symptoms onset to treatment ( 30 ml Cerebrolysin diluted in physiologic saline ) or placebo ( saline ) given as intravenous infusion once daily added to st and ard care for 10 days . The patients are followed with regular visits for 90 days . Efficacy is evaluated on day 90 by three outcome scales – modified Rankin Scale , Barthel Index and NIH Stroke Scale – combined to single global directional test . Additionally , adverse events are documented to prove safety . In this study a total of 1060 patients will be included and analysis of data will be completed in 2010 . If positive , this trial will add an effective strategy to the treatment of acute ischaemic stroke Background and Purpose Approved use of intravenous alteplase for ischemic stroke offers net benefit . Pooled r and omized controlled trial analysis suggests additional patients could benefit but others be harmed with treatment initiated beyond 4·5 h after stroke onset . We proposed prognostic scoring methods to identify a strategy for patient selection . Methods We selected 500 patients treated by intravenous alteplase and 500 controls from Virtual International Stroke Trials Archive , matching modified Rankin score outcomes to those from pooled r and omized controlled trial 4·5–6 h data . We ranked patients by prognostic score . We chose limits to optimize our sample for a net treatment benefit significant at P = 0·01 by Cochran – Mantel – Haenszel test and by ordinal regression . For validation , we had these applied to the pooled r and omized controlled trial data for 4·5–6 h , testing for net benefit by Cochran – Mantel – Haenszel test , ordinal regression , and also by dichotomized outcomes : modified Rankin score 0–1 , mortality and parenchymal hemorrhage type 2 bleeds . All analyses were adjusted for age and National Institutes of Health Stroke Scale . Results In the training data set , limits of 56–95 on a prognostic score retained 714 patients in whom there was net benefit significant at P = 0·01 . When applied to the 1120 patients in the pooled r and omized controlled trial 4·5–6 h data set , score limits of 56–95 retained 711 patients and gave odds ratio for improved modified Rankin score distribution of 1·13 , 95 % confidence interval 0·87–1·47 , Cochran – Mantel – Haenszel P = 0·89 . More patients achieved modified Rankin score 0–1 ( odds ratio 1·44 , 1·02–2·05 , P = 0·04 ) but mortality and parenchymal hemorrhage type 2 bleeds were increased : odds ratio 1·56 , 1·01–2·40 , P = 0·04 ; odds ratio 15·6 , 3·7–65·8 , P = 0·0002 , respectively . Conclusion Selection of patients between 4·5 and 6 h based on simple clinical measures failed to deliver a population in whom the alteplase effect would be safe and effective Background and Purpose — Cerebrolysin showed neuroprotective and neurotrophic properties in various pre clinical models of ischemia and small clinical trials . The aim of this large double-blind , placebo-controlled r and omized clinical trial was to test its efficacy and safety in patients with acute ischemic stroke . Methods — Patients with acute ischemic hemispheric stroke were r and omized within 12 hours of symptoms onset to active treatment ( 30 mL Cerebrolysin daily ) or placebo ( saline solution ) given as intravenous infusion for 10 days in addition to aspirin ( 100 mg daily ) . The patients were followed up to 90 days . The primary end point was the result of a combined global directional test of modified Rankin Scale , Barthel Index , and National Institutes of Health Stroke Scale . Adverse events were documented to assess safety . Results — A total of 1070 patients were enrolled in this study . Five hundred twenty-nine patients were assigned to Cerebrolysin and 541 to placebo . The confirmatory end point showed no significant difference between the treatment groups . When stratified by severity however , a post hoc analysis of National Institutes of Health Stroke Scale and modified Rankin Scale showed a trend in favor of Cerebrolysin in patients with National Institutes of Health Stroke Scale > 12 ( National Institutes of Health Stroke Scale : OR , 1.27 ; CI lower bound , 0.97 ; modified Rankin Scale : OR , 1.27 ; CI lower bound , 0.90 ) . In this subgroup , the cumulative mortality by 90 days was 20.2 % in the placebo and 10.5 % in the Cerebrolysin group ( hazard ratio , 1.9661 ; CI lower bound , 1.0013 ) . Conclusions — In this study , the confirmatory end point showed neutral results between the treatment groups . However , a favorable outcome trend was seen in the severely affected patients with ischemic stroke treated with Cerebrolysin . This observation should be confirmed by a further clinical trial . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00868283 Abstract s Background Cerebrolysin is a neuropeptide preparation with neuroprotective and neurorestorative effects . Combining Cerebrolysin treatment with a st and ardized rehabilitation program may have a potential synergistic effect in the subacute stage of stroke . This study aims to evaluate whether Cerebrolysin provides additional motor recovery on top of rehabilitation therapy in the subacute stroke patients with moderate to severe motor impairment . Methods This phase IV trial was design ed as a prospect i ve , multicenter , r and omized , double-blind , placebo-controlled , parallel-group study . A total of 70 patients ( Cerebrolysin n = 35 , placebo n = 35 ) with moderate to severe motor function impairment were included within 7 days after stroke onset and were r and omized to receive a 21-day treatment course of either Cerebrolysin or placebo , given in addition to st and ardized rehabilitation therapy . Assessment s were performed at baseline , immediately after treatment as well as 2 and 3 months after stroke onset . The plasticity of motor system was assessed by diffusion tensor imaging and with resting state functional magnetic resonance imaging . Results Both groups demonstrated significant improvement in motor function ( p < 0.05 ) ; however , no significant difference was found between the two groups . In the stroke patients with severe motor impairment , the Cerebrolysin group exhibited significantly more improvement in motor function compared with the placebo group ( p < 0.05 ) . Effects of Cerebrolysin were demonstrated as restricted increments of corticospinal diffusivity and as recovery of the sensorimotor connectivity . Conclusion The combination of st and ard rehabilitation therapy with Cerebrolysin treatment in the subacute stroke has shown additional benefit on motor recovery and plastic changes of the corticospinal tract in patients with severe motor impairment . Trial registration NCT01996761 ( November 5 , 2013 The aim of the study was to assess safety and efficacy of the neuroprotective drug Cerebrolysin in acute ischemic stroke . Thirty-six patients with ischemic stroke in carotid artery territory aged 45 - 85 years , were eligible for inclusion in the trial if they were admitted to the hospital within the first 12h after stroke onset . Patients were r and omly and blindly assigned to placebo ( n = 12 ) or 1 or 2 dosages of Cerebrolysin : 10 ml/d ( n = 12 ) and 50 ml/d ( n = 12 ) for 10 days with concomitant st and ard basic treatment in each group . A quantitative time-related analysis of the dynamics of neurological deficit revealed the tendency towards acceleration of improvement assessed by the Clinical Global Impression Scale and NIHSS in both Cerebrolysin groups by 30 day of the treatment . The significant reduction in the volume of MRI ischemic focus was shown in both Cerebrolysin groups ( p < 0.05 vs Placebo ) on day 3 . Acute pharmacological test revealed a decrease ( p < 0.05 vs Placebo ) of the size and spread of delta and theta foci in 72.7 % patients , receiving 50 ml/d of Cerebrolysin . In none of the cases , Cerebrolysin treatment provoked any paroxysmal activity on EEG . The trial demonstrated safety , efficacy and good tolerability of hige-dose Cerebrolysin in the treatment of ischemic stroke Cerebrolysin and DL-3-n-butylphthalide ( NBP ) have each shown neuroprotective efficacy in pre clinical models of acute ischemic stroke ( AIS ) and passed clinical trials as therapeutic drugs for AIS . The present study was a clinical trial to assess and compare the efficacy and safety of NBP and Cerebrolysin in the reduction of neurological and behavioral disability following AIS . A r and omized , double-blind trial was conducted with enrolment of 60 patients within 12 h of AIS . In addition to routine treatment , patients were r and omly assigned to receive a 10-day intravenous administration of NBP , Cerebrolysin or placebo . National Institutes of Health Stroke Scale ( NIHSS ) and Barthel Index ( BI ) scores were used to evaluate the efficacy of the treatment in the patients with AIS at 11 and 21 days after the initiation of therapy . Adverse events were also analyzed among the three groups . After 10 days of treatment with NBP or Cerebrolysin , the NIHSS and BI scores at day 21 showed statistical differences compared with those in the placebo group ( P<0.05 ) . The improvements of NIHSS and BI scores in the NBP and Cerebrolysin groups were higher than those in the placebo group at days 11 and 21 ( P<0.05 ) . A statistically significant difference in the improvement of 21-day NIHSS scores was observed between the two treatment groups ( P<0.05 ) . No significant difference was found among the three groups with regard to the rate of adverse events . Favorable outcomes and good safety were observed in the patients with moderate AIS treated with NBP or Cerebrolysin . The results indicate that NBP may be more effective than Cerebrolysin in improving short-term outcomes following AIS . This trial is registered at Clinical Trials.gov with clinical trial identifier number NCT02149875 BACKGROUND The free-radical-trapping agent NXY-059 showed promise as a neuroprotectant in the Stroke-Acute Ischemic NXY Treatment I ( SAINT I ) trial , reducing disability when given to patients who had acute ischemic stroke . We sought confirmation of efficacy in a second , larger trial . METHODS We enrolled 3306 patients with acute ischemic stroke in a r and omized , double-blind trial to receive a 72-hour infusion of intravenous NXY-059 or placebo within 6 hours after the onset of stroke symptoms . Our primary end point was the distribution of disability scores on the modified Rankin scale at 90 days . We examined scores on neurologic and activities-of-daily-living scales as secondary end points . We also tested the hypothesis that NXY-059 would reduce alteplase-related intracranial hemorrhages . RESULTS The efficacy analysis was based on 3195 patients . Prognostic factors were well balanced between the treatment groups . Mortality was equal in the two groups , and adverse-event rates were similar . The distribution of scores on the modified Rankin scale did not differ between the group treated with NXY-059 ( 1588 patients ) and the placebo group ( 1607 patients ; P=0.33 by the Cochran-Mantel-Haenszel test ; odds ratio for limiting disability , 0.94 ; 95 % confidence interval [ CI ] , 0.83 to 1.06 ) . Analysis of categorized scores on the modified Rankin scale confirmed the lack of benefit : the odds ratio for trichotomization into modified Rankin scale scores of 0 to 1 versus 2 to 3 versus 4 to 6 was 0.92 ( 95 % CI , 0.80 to 1.06 ) . There was no evidence of efficacy for any of the secondary end points . Among patients treated with alteplase , there was no difference between the NXY-059 group and the placebo group in the frequency of symptomatic or asymptomatic hemorrhage . CONCLUSIONS NXY-059 is ineffective for the treatment of acute ischemic stroke within 6 hours after the onset of symptoms . ( Clinical Trials.gov number , NCT00061022 [ Clinical Trials.gov ] . Cerebrolysin is used as a neurotrophic agent for the treatment of ischemic stroke and Alzheimer 's Disease . Exploratory studies in patients with post-acute traumatic brain injury have shown that this treatment might help improve recovery . Aim of this study was to investigate whether addition of Cerebrolysin to the initial treatment regimen of moderate and severe head injury patients would improve their outcome . At 6 months , 67 % of the patients ( Cerebrolysin group ) attained good outcome ( GOS 3 - 5 ) . The study group was compared with the historical cohort of patients from the hospital trauma data bank , with age , sex and admitting GCS matching . More patients tended to a good outcome in the Cerebrolysin group ( P = 0.065 ) . No significant side-effect requiring cessation of Cerebrolysin was noted . It can be concluded that the use of Cerebrolysin as part of the initial management of moderate and severe head injury is safe and well tolerated . The results suggest that Cerebrolysin is beneficial in regard to the outcome in these patients , especially in elderly patients 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 |
1,981 | 30,116,295 | We found most of the published data that we analyzed to be inconsistent , and very little data was obtained on the correlation between LLD severity and changes in body posture stability during st and ing and walking .
However , the results of the present review study are in line with previous observational studies , which describe asymmetry in the lower limbs corresponding to biomechanical parameters such as gait kinematics , kinetics , and other parameters described during static ( st and ing ) postural balance . | Various studies have examined body posture stability , including postural sway and associated biomechanical parameters , to assess the severity effects of leg length discrepancy ( LLD ) .
However , various viewpoints have been articulated on the results of these studies because of certain drawbacks in the comprehensive analysis of the effect of variations in LLD magnitude .
Therefore , this systematic review was performed to help focus on the current findings to help identify which biomechanical parameters are most relevant , commonly used , and able to distinguish and /or have specific clinical relevance to the effect of variations in LLD magnitude during static ( st and ing ) and dynamic ( walking ) conditions . | We hypothesized that leg-length discrepancies of as little as 1 cm would induce a significant postural shift and increase the extent of postural sway . We had 14 normal volunteers st and on a force platform with their feet in a st and ard position . Center-of-pressure data were recorded at 100Hz for 20 seconds while the subjects stood barefoot with no lifts or ( in r and om order ) with lifts of 1 , 2 , 3 , and 4 cm under their left and right feet . From these data we derived the mean center-of-pressure position and the extent of postural sway . Lifts of as little as 1 cm shifted the mean center-of-pressure toward the longer leg to a statistically significant extent ( p less than 0.001 ) , the mean difference compared with the barefoot condition being 6.1 % of the distance between the feet ; increasing the discrepancy did not proportionately increase the effect . The postural sway ( total travel of the center-of-pressure ) in a mediolateral direction increased significantly with a 1 cm discrepancy ( p less than 0.01 ) , and continued to increase in proportion to the magnitude of the discrepancy . There were no effects on anteroposterior position or sway and no influence of left-right dominance . These results support our hypothesis that a leg-length discrepancy of as little as 1 cm may be biomechanically important Current surgery outcome evaluations in patients with Legg-Calvé-Perthes disease ( LCPD ) are usually based on static radiological changes . The aim of the present study was to assess the development of characteristic gait parameters and passive hip range of motion ( ROM ) measurements during the postoperative period up to healed stage of the femoral head represented by Stulberg classification . Twelve children ( 10 male , 2 female ) with unilateral diagnosis of LCPD and 19 healthy control subjects at the same age participated in this prospect i ve longitudinal study . Instrumented gait analysis was performed preoperatively , 13.4 ( ±1.7 ) , and 28.0 ( ±4.4 ) months postoperatively . At final follow-up , the mean leg length of the involved side was reduced by 1.10 (±0.53)cm compared to the non-involved side . In addition , a significant reduction in maximum knee flexion ( -26 % , p=0.037 ) and knee flexion/extension ROM ( -26 % , p=0.017 ) in stance was still present in the patient group compared to controls indicating a " stiff knee gait pattern " . In contrast , the sagittal plane hip parameters , the ipsilateral trunk lean toward the involved stance limb , and the knee and hip joint loading during gait normalized during the postoperative period . The results of the present study should motivate further exploration if patients with LCPD stiffen their knees to compensate for leg length discrepancy . Besides the st and ard radiological evaluation of the surgery outcome , instrumented gait analysis is a valuable method of recording functional deficits and early recognition of the need for physiotherapeutic treatment or insole supply in patients with LCPD Abstract The purpose of this study was to quantitatively evaluate the effects of experimental leg length discrepancies on body posture and dental occlusion . Thirty asymptomatic subjects ( 15 males and 15 females , ages 19 - 33 , mean age 25.6 years ) were included in this study and r and omly assigned to one of two groups based on a table of r and om numbers . The only difference between group A and group B was the sequence of testing . Experimental leg length discrepancies were provided by using ten types of insoles with heights ranging from one to ten mm at one mm intervals , placed under both feet . The MatScan ( Nitta Corp. , Osaka , Japan ) system was used to measure changes in body posture ( center of foot pressure : COP ) while subjects maintained the following three postural positions : 1 . natural st and ing posture ( control ) ; 2 . control with a heel lift under the right foot ; or 3 . control with a heel lift under the left foot . The T-Scan II system ( Nitta Corp. , Osaka , Japan ) was used to analyze the results of changes in dental occlusion ( center of occlusal force : COF ) in the above-mentioned three postural positions . When subjects used a heel lift of six mm or more under the right foot , lateral weight distribution ( LWD ) shifted to the right side compared to the control ( p<0.05 ) . When a heel lift of four mm or more was used under the left foot , LWD shifted to the left side compared to the control ( p<0.05 ) . When subjects used a heel lift of eight mm or more under the right foot , occlusal force shifted to the right side compared to the control ( p<0.05 ) . When subjects used a heel lift of seven mm or more under the left foot , occlusal force shifted to the left side compared to the control ( p<0.05 ) . Based on these findings , it was concluded that leg length discrepancy affected body posture and dental occlusion Acromegaly is a chronic debilitating disease that presents with multiple systemic manifestations , including changes in body composition , joint abnormalities , muscular impairment and visual disturbances . This study aim ed to assess posture and body balance in acromegalic patients and to establish the correlation between these measures . Twenty-eight acromegalic patients and a similar number of control subjects matched for sex , age , weight , height and body mass index underwent postural evaluation using the photogrammetry and measurement of balance using the stabilometry in two tasks : feet apart , eyes open and feet together , eyes closed . In comparison with the control group , the acromegalic group presented postural deviations in lateral views in the vertical alignment of the trunk ( P=0.001 for the right side and P=0.021 for the left ) , the hip angle ( P=0001 for the right side and P=0.016 for the left side ) and horizontal alignment of the pelvis ( P=0.017 for the right and P<0.001 for the left side ) . Compared with healthy subjects , the acromegalic patients presented displacement of the centre of pressure in both the anterior-posterior direction and the medial-lateral direction in both evaluated tasks . We observed significant correlations between balance measures and the following posture evaluation variables : distance between the lower limbs , horizontal alignment of the head and vertical alignment of the head . Our results suggest that posture and balance need to be evaluated for acromegalic patients in clinical practice , as there are significant postural imbalances and deviations in these patients We aim ed to investigate the relationship between postoperative leg length/offset ( LL/OS ) reconstruction and gait performance after total hip arthroplasty ( THA ) . In the course of a prospect i ve r and omized controlled trial , 60 patients with unilateral hip arthrosis received cementless THA through a minimally-invasive anterolateral surgical approach . One year post-operatively , LL and global OS restoration were analyzed and compared to the contralateral hip on AP pelvic radiographs . The combined postoperative limb length/OS reconstruction of the operated hip was categorized as restored ( within 5 mm ) or non-restored ( more than 5 mm reduction or more than 5 mm increment ) . The acetabular component inclination , anteversion and femoral component anteversion were evaluated using CT scans of the pelvis and the femur . 3D gait analysis of the lower extremity and patient related outcome measures ( HHS , HOOS , EQ-5D ) were obtained pre-operatively , six months and twelve months post-operatively by an observer blinded to radiographic results . Component position of cup and stem was comparable between the restored and non-restored group . Combined LL and OS restoration within 5 mm result ed in higher Froude number ( p<0.001 ) , normalized walking speed ( p<0.001 ) and hip range-of-motion ( ROM ) ( p=0.004 ) during gait twelve months postoperatively , whereas gait symmetry was comparable regardless of LL and OS reconstruction at both examinations . Clinical scores did not show any relevant association between the accuracy of LL or OS reconstruction and gait six/twelve months after THA . In summary , postoperative LL/OS discrepancies larger than 5 mm relate to unphysiological gait kinematics within the first year after THA . DRKS00000739 , German Clinical Trials Register |
1,982 | 31,694,299 | Patient perspectives were categorized into four key themes : ( 1 ) Support system ; ( 2 ) Patient self-management ; ( 3 ) Capacities of HCPs ; ( 4 ) Barriers in healthcare systems . "
The perspectives of patients with LHL provided valuable input for a comprehensive and person-centred educational framework that can enhance the relevance and quality of education for ( future ) HCPs , and contribute to better person-centred care for patients with LHL | Patient-centred care is tailored to the needs of patients and is necessary for better health outcomes , especially for individuals with limited health literacy ( LHL ) .
However , its implementation remains challenging .
The key to effectively address patient-centred care is to include perspectives of patients with LHL within the curricula of ( future ) healthcare providers ( HCP ) .
This systematic review aim ed to explore and synthesize evidence on the needs , experiences and preferences of patients with LHL and to inform an existing educational framework .
Patients with LHL and chronic diseases encounter multiple problems in the care process , which are often related to a lack of person-centeredness . | Objective : Most electronic health record ( EHR ) systems have the capability of generating a printed after-visit summary ( AVS ) , but there has been little research on optimal content . We conducted a qualitative study and a r and omized trial to underst and the effect of AVS content on patient recall and satisfaction . Methods : Adult primary care patients ( n = 272 ) with at least 1 chronic condition were r and omly assigned to 4 AVS content conditions : minimum , intermediate , maximum , or st and ard AVS . Demographics and health literacy were measured at an index clinic visit . Recall and satisfaction were measured by telephone 2 days and 2 to 3 weeks after the clinic visit . Results : Average age was 52 years ; 75 % of patients were female , 61 % were Hispanic , and 21 % were African American , and 64 % had adequate health literacy . Average medication recall accuracy was 53 % at 2 days and 52 % at 3 weeks , with no significant difference among groups at either time . Satisfaction with AVS content was high and did not differ among groups . Recall of specific content categories was low and unrelated to group assignment . Health literacy was unrelated to recall and satisfaction . Conclusion : Primary care patients like to receive an AVS , but the amount of information included does not affect content recall or satisfaction with the information OBJECTIVES Diabetes self-management is a key element in the overall management of diabetes . Identifying barriers to disease self-management is a critical step in achieving optimal health outcomes . Our goal was to explore patients ' perceptions about barriers to self-management of diabetes that could possibly help explain poor health outcomes among minority patients . STUDY DESIGN Four focus groups were conducted among 31 predominately African American patients with diabetes who were enrolled in the Baltimore Cardiovascular Partnership Study , a NIH-funded multiyear prospect i ve partnership study . The topic guide consisted of a series of open-ended questions about knowledge of current health status , medication use , continuity of care , blood glucose level and nutrition . RESULTS The focus groups confirmed that previously reported barriers to self-management persisted and identified new concerns that could be associated with poor health outcomes among minority patients with diabetes . Attitudes , perceptions and behaviors surrounding diabetes and self-management of the condition did vary across individuals , however , the variation appeared to reflect the individual 's knowledge and opinions rather than patient 's age , sex , or culture . The primary barrier to diabetes self-management result ed from lack of knowledge of target blood glucose and blood pressure . Several participants found some of the health information to be quite confusing . CONCLUSIONS Diabetes is a major public health concern and the lack of awareness of target blood glucose and blood pressure further complicates the problem . The limited health literacy seen in this study could help explain several of the barriers to self-management . The barriers to self-management identified in this qualitative study are amenable to intervention that could improve health outcomes Introduction Older , chronically ill patients with limited health literacy are often under-engaged in managing their health and turn to the emergency department ( ED ) for healthcare needs . We tested the impact of an ED-initiated coaching intervention on patient engagement and follow-up doctor visits in this high-risk population . We also explored patients ’ care-seeking decisions . Methods We conducted a mixed- methods study including a r and omized controlled trial and in-depth interviews in two EDs in northern Florida . Participants were chronically ill older ED patients with limited health literacy and Medicare as a payer source . Patients were assigned to an evidence -based coaching intervention ( n= 35 ) or usual post-ED care ( n= 34 ) . Qualitative interviews ( n=9 ) explored patients ’ reasons for ED use . We assessed average between-group differences in patient engagement over time with the Patient Activation Measure ( PAM ) tool , using logistic regression and a difference-in-difference approach . Between-group differences in follow-up doctor visits were determined . We analyzed qualitative data using open coding and thematic analysis . Results PAM scores fell in both groups after the ED visit but fell significantly more in “ usual care ” ( average decline −4.64 ) than “ intervention ” participants ( average decline −2.77 ) ( β=1.87 , p=0.043 ) . There were no between-group differences in doctor visits . Patients described well-informed reasons for ED visits including onset and severity of symptoms , lack of timely provider access , and immediate and comprehensive ED care . Conclusion The coaching intervention significantly reduced declines in patient engagement observed after usual post-ED care . Patients reported well-informed reasons for ED use and will likely continue to make ED visits unless strategies , such as ED-initiated coaching , are implemented to help vulnerable patients better manage their health and healthcare Knowledge of nutrition among breast cancer patients is insufficient , despite their motivation to seek valid information about healthy food choices . This study examines the feasibility of nutrition education workshops for cancer survivors , to inform the design of a multi-center intervention . Fifty-nine female English-speaking breast cancer patients , who had completed treatment , were enrolled . Participants were r and omized to the intervention or control group . The intervention group attended six nutrition education sessions , and the control group received brochures . Measurements were done at baseline and 3-month follow-up and included the Assessment Instrument for Breast Cancer ( NLit-BCa ) , fruit/vegetable and general health literacy screeners . Height and weight were measured . Changes in nutrition literacy , health literacy , and food intake from baseline to follow-up ( within-group change ) were calculated for both groups ( effect sizes were reported as Cohen ’s d ) . Participants were mostly white , with a mean age of 58 years , BMI of 31.6 kg/m2 , and had college degrees . Follow-up rates were high ( 89 % = control and 77 % = intervention group ) . At baseline , participants scored high for most NLit-BCa assessment components except food portions in both groups . At the 3-month follow-up , effect sizes ( d ) on the NLit-BCa ranged from −0.5 to 0.16 . The study met its recruitment goals within 6 months . Focus groups indicated that ( a ) attending six sessions was acceptable , ( b ) patients found social/emotional support , ( c ) improvements should include information for special diets and booster sessions . This pilot study suggests that the intervention was acceptable and that scaling up of this intervention is feasible and could provide benefit to breast cancer survivors BACKGROUND Chronic obstructive pulmonary disease ( COPD ) is an illness that affects patients on multiple levels , both physically and psychologically . While there is a growing body of evidence for the efficacy of self-management among patients with COPD , little evidence is available on the optimal content and methods for delivering self-management support . AIMS The purpose of this study was to address gaps in the literature on self-management support by examining patients ' responses to questions about goals , needs , and expectations regarding self-management using qualitative methods in a broadly representative sample of patients with moderate to severe COPD . By focusing on patients ' perceptions of their needs , we hoped to guide development of cognitive-behavioural interventions for self-management support . METHODS Patients > 45 years of age with a physician diagnosis of COPD were recruited as part of a larger r and omised controlled trial design ed to determine the effectiveness of a lifestyle behavioural intervention to increase physical activity . In-depth interviews were conducted at baseline data collection using 10 st and ardised open-ended questions tailored to examine factors relevant to self-management support including concerns , fears , learning needs , barriers , facilitators , and goals . All interviews were audio recorded and analysed using qualitative methods . Responses were coded by three raters into thematic categories . RESULTS A sample of 47 interviews with patients of mean age 68.4 years , 53 % male , 87 % white were used in the analysis . The distribution of spirometric impairment based on percent predicted forced expiratory volume in 1 second ( FEV1 ) was moderate ( 57.5 % ) , severe ( 31.9 % ) , and very severe ( 10.6 % ) . In response to questions targeting needs and goals for care , three main themes ( loss , fear , and desire for improved care ) and seven associated sub-themes were identified . Because of breathlessness and fatigue as well as symptoms from conditions other than COPD , patients reported the loss of ability to participate in pleasurable and necessary activities of daily living and the desire to recover at least some of their functioning . They expressed problems with social isolation and uncertainty about their prognosis , as well as the hope to improve . In addition , fearful experiences associated with uncontrolled breathlessness and a wish for greater underst and ing and knowledge about treatment were major concerns . CONCLUSIONS These qualitative results suggest that the content of self-management support for patients with COPD should focus on addressing patients ' fears associated with the uncertainty , progression , and suffering of their disease , their expectations about overcoming or replacing losses , their needs for improved health literacy and their desire for improved care . These responses indicate areas where cognitive-behavioural intervention should focus in order to enhance patient self-efficacy , motivation , and behavioural change for improved self-management Background : Stroke patients ’ involvement in the rehabilitation process including decision making has made significant advances clinical ly over the past two decades . However , development of patient-focused interventions in stroke rehabilitation is a relatively under developed area of research . The aim of this study was to interpret the explanations that patients gave of their experience after stroke and how these may vali date an already established patient-focused intervention framework – the Quest for quality and improved performance ( QQUIP ) ( 2006 ) that includes seven quality improvement goals . Methods : A r and om purposive sample of eight stroke patients was interviewed between 3 and 6 months following discharge . Patients ’ reports of their experience after stroke were obtained using in-dept semi-structured interviews and analysed using Qualitative Content Analysis . Results : Explanations given by patients included both positive and negative reports of the stroke experience . Regardless of consequences as a result of physical , psychological and social impairments , there were other life style disruptions that were reported by all patients such as taking new medication and adverse effects of these , experiencing increasing fatigue , difficulties with social activities and situations and having to make changes in health behaviours and lifestyle . Some of the core themes that emerged reflected the aims of QQUIP improvement goals that include improving health literacy , clinical decision-making , self-care , patient safety , access to health advice , care experience and service development . Discussion : Further recommendations based on the findings from this study would be to consider using the QQUIP framework for developing intervention studies in stroke rehabilitation care that are person-centred . This framework provides a template that is equipped to address some of the main concerns that people have following the experience of stroke and also focuses on improving quality of care . Implication s for Rehabilitation Consideration for the use of established patient focused frameworks for improving the design and development of rehabilitation stroke interventions . Identify patients ’ main concerns following the experience of stroke and its result ing consequences in developing stroke rehabilitation interventions Greater need to move from a provider-led model of care towards a more favourably balanced view that includes patient participation and involvement in their self management of the rehabilitation programme |
1,983 | 23,637,579 | Cinacalcet reduces the need for parathyroidectomy in patients with CKD stage 5D , but does not appear to improve all-cause or cardiovascular mortality .
Additional trials in CKD stage 5D are unlikely to change our confidence in the treatment effects of cinacalcet in this population | BACKGROUND Calcimimetic agents lower serum parathyroid hormone levels in people with chronic kidney disease ( CKD ) , but treatment effects on patient-relevant outcomes are uncertain .
We conducted a systematic review and meta- analysis to summarize the benefits and harms of calcimimetic therapy in adults with CKD and used cumulative meta- analysis to identify how evidence for calcimimetic treatment has developed in this clinical setting . | BACKGROUND Treatment of secondary hyperparathyroidism ( SHPT ) with activated vitamin D analogues is associated with better survival in patients receiving dialysis . It is unclear whether such a benefit is present in patients with predialysis chronic kidney disease ( CKD ) . METHODS We examined the association of oral calcitriol treatment with mortality and the incidence of dialysis in 520 male US veterans ( mean [ SD ] age , 69.8 [ 10.3 ] years ; 23.5 % black ) with CKD stages 3 to 5 and not yet receiving dialysis ( mean [ SD ] estimated glomerular filtration rate , 30.8 [ 11.3 ] ) . Associations were examined by the Kaplan-Meier method and in Poisson regression models with adjustment for age , race , comorbidities , smoking , blood pressure , body mass index , use of phosphate binders , estimated glomerular filtration rate , proteinuria , white blood cell count , percentage of lymphocytes , and levels of parathyroid hormone , calcium , phosphorus , albumin , bicarbonate , and hemoglobin . RESULTS Two hundred fifty-eight of 520 subjects received treatment with calcitriol , 0.25 to 0.5 microg/d , for a median duration of 2.1 years ( range , 0.06 - 6.0 years ) . The incidence rate ratios for mortality and combined death and dialysis initiation were significantly lower in treated vs untreated patients ( P < .001 for both in the fully adjusted models ) . Treatment with calcitriol was associated with a trend toward a lower incidence of dialysis . These results were consistent across different subgroups . CONCLUSIONS Treatment with the activated vitamin D analogue calcitriol appears to be associated with significantly greater survival in patients with CKD not yet receiving dialysis . R and omized clinical trials are required to verify the causality of these associations and to examine whether similar associations are seen with different activated vitamin D analogues BACKGROUND A need exists for a therapy that lowers parathyroid hormone ( PTH ) without increasing calcium x phosphorus in patients with secondary hyperparathyroidism . The calcimimetic AMG 073 increases the sensitivity of the parathyroid calcium-sensing receptor to extracellular calcium , thereby reducing PTH secretion . Consequently , AMG 073 may provide a novel therapy for secondary hyperparathyroidism . METHODS Seventy-eight hemodialysis patients with secondary hyperparathyroidism were enrolled into this 18-week , double-blind , r and omized , placebo-controlled , dose titration study . Daily oral AMG 073 doses were administered to determine the effect on PTH , serum calcium , phosphorus , and calcium x phosphorus . RESULTS The mean baseline PTH was similar in patients administered AMG 073 or placebo ( 632 + /- 280.1 pg/mL vs. 637 + /- 455.9 pg/mL , respectively ) . PTH decreased by 26.0 % in the AMG 073-treated group , compared with an increase of 22.0 % in the placebo group ( P < 0.001 ) . A greater proportion in the AMG 073 group ( 38 % ) had a decrease in PTH > or=30 % , compared with the placebo group ( 8 % ) ( P = 0.001 ) . Decreases in PTH were independent of baseline vitamin D usage . Patients receiving AMG 073 had an 11.9 % decrease in calcium x phosphorus compared with a 10.9 % increase in the placebo group ( P < 0.001 ) . Use of vitamin D sterols , as well as both calcium and noncalcium-containing phosphate binders . were similar between treatment groups . Administration of AMG 073 was safe and well tolerated in this 18-week study . CONCLUSIONS The calcimimetic AMG 073 decreases both PTH and calcium x phosphorus levels in hemodialysis patients with secondary hyperparathyroidism Management of secondary hyperparathyroidism is challenging with traditional therapy . The calcimimetic cinacalcet HCl acts on the calcium-sensing receptor to increase its sensitivity to calcium , thereby reducing parathyroid hormone ( PTH ) secretion . This phase 3 , multicenter , r and omized , placebo-controlled , double-blind study evaluated the efficacy and safety of cinacalcet in hemodialysis ( HD ) and peritoneal dialysis ( PD ) patients with PTH > or = 300 pg/ml despite traditional therapy . A total of 395 patients received once-daily oral cinacalcet ( 260 HD , 34 PD ) or placebo ( 89 HD , 12 PD ) titrated from 30 to 180 mg to achieve a target intact PTH ( iPTH ) level of < or = 250 pg/ml . During a 10-wk efficacy assessment phase , cinacalcet was more effective than control for PTH reduction outcomes , including proportion of patients with mean iPTH levels < or = 300 pg/ml ( 46 versus 9 % ) , proportion of patients with > or = 30 % reduction in iPTH from baseline ( 65 versus 13 % ) , and proportion of patients with > or = 20 , > or = 40 , or > or = 50 % reduction from baseline . Cinacalcet had comparable efficacy in HD and PD patients ; 50 % of PD patients achieved a mean iPTH < or = 300 pg/ml . Cinacalcet also significantly reduced serum calcium , phosphorus , and Ca x P levels compared with control treatment . The most common side effects , nausea and vomiting , were usually mild to moderate in severity and transient . Once-daily oral cinacalcet was effective in rapidly and safely reducing PTH , Ca x P , calcium , and phosphorus levels in patients who received HD or PD . Cinacalcet offers a new therapeutic option for controlling secondary hyperparathyroidism in patients with chronic kidney disease on dialysis BACKGROUND The calcimimetic agent R-568 lowers plasma parathyroid hormone ( PTH ) levels in hemodialysis patients with mild secondary hyperparathyroidism , but its efficacy in those with more severe secondary hyperparathyroidism has not been studied . METHODS Twenty-one patients undergoing hemodialysis three times per week with plasma PTH levels between 300 and 1200 pg/mL were r and omly assigned to 15 days of treatment with either 100 mg of R-568 ( N = 16 ) or placebo ( N = 5 ) . Plasma PTH and blood ionized calcium levels were measured at intervals of up to 24 hours after oral doses on days 1 , 2 , 3 , 5 , 8 , 11 , 12 , and 15 . RESULTS Pretreatment PTH levels were 599 + /- 105 ( mean + /- SE ) and 600 + /- 90 pg/mL in subjects given R-568 or placebo , respectively , and values on the first day of treatment did not change in those given placebo . In contrast , PTH levels fell by 66 + /- 5 % , 78 + /- 3 % , and 70 + /- 3 % at one , two , and four hours , respectively , after initial doses of R-568 , remaining below pretreatment values for 24 hours . Blood ionized calcium levels also decreased after the first dose of R-568 but did not change in patients given placebo . Despite lower ionized calcium concentrations on both the second and third days of treatment , predose PTH levels were 422 + /- 70 and 443 + /- 105 pg/mL , respectively , in patients given R-568 , and values fell each day by more than 50 % two hours after drug administration . Predose PTH levels declined progressively over the first nine days of treatment with R-568 and remained below pretreatment levels for the duration of study . Serum total and blood ionized calcium concentrations decreased from pretreatment levels in patients given R-568 , whereas values were unchanged in those given placebo . Blood ionized calcium levels fell below 1.0 mmol/L in 7 of 16 patients receiving R-568 ; five patients withdrew from study after developing symptoms of hypocalcemia , whereas three completed treatment after the dose of R-568 was reduced . CONCLUSIONS The calcimimetic R-568 rapidly and markedly lowers plasma PTH levels in patients with secondary hyperparathyroidism caused by end-stage renal disease BACKGROUND This prospect i ve , r and omized , controlled trial compared the progression of vascular and cardiac valve calcification in 360 prevalent adult hemodialysis patients with secondary hyperparathyroidism treated with either cinacalcet plus low-dose vitamin D sterols or flexible doses of vitamin D sterols alone . METHODS Eligible subjects were on hemodialysis for ≥ 3 months with parathyroid hormone ( PTH ) > 300 pg/mL or PTH 150 - 300 pg/mL with calcium-phosphorus product > 50 mg(2)/dL(2 ) while receiving vitamin D. All subjects received calcium-based phosphate binders . Coronary artery calcification ( CAC ) and aorta and cardiac valve calcium scores were determined both by Agatston and volume scoring using multi-detector computed tomography . Subjects with Agatston CAC scores ≥ 30 were r and omized to cinacalcet ( 30- 180 mg/day ) plus low-dose calcitriol or vitamin D analog ( ≤ 2 μg paricalcitol equivalent/dialysis ) , or flexible vitamin D therapy . The primary end point was percentage change in Agatston CAC score from baseline to Week 52 . RESULTS Median ( P10 , P90 ) Agatston CAC scores increased 24 % ( -22 % , 119 % ) in the cinacalcet group and 31 % ( -9 % , 179 % ) in the flexible vitamin D group ( P = 0.073 ) . Corresponding changes in volume CAC scores were 22 % ( -12 % , 105 % ) and 30 % ( -6 % , 133 % ; P = 0.009 ) . Increases in calcification scores were consistently less in the aorta , aortic valve and mitral valve among subjects treated with cinacalcet plus low-dose vitamin D sterols , and the differences between groups were significant at the aortic valve . CONCLUSIONS In hemodialysis patients with moderate to severe secondary hyperparathyroidism , cinacalcet plus low-dose vitamin D sterols may attenuate vascular and cardiac valve calcification BACKGROUND AND OBJECTIVES Patients with chronic kidney disease ( CKD ) receiving dialysis often develop secondary hyperparathyroidism with disturbed calcium and phosphorus metabolism . The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative ( KDOQI ) was established to guide treatment practice s for these disorders . The ACHIEVE study was design ed to test two treatment strategies for achieving KDOQI goals . DESIGN , SETTING , PARTICIPANTS , MEASUREMENTS Individuals on hemodialysis treated with vitamin D sterols were enrolled in this 33-week study . Subjects were r and omly assigned to treatment with either cinacalcet and low-dose vitamin D ( Cinacalcet-D ) or flexible vitamin D alone ( Flex-D ) to achieve KDOQI-recommended bone mineral targets . ACHIEVE included a 6-week screening phase , including vitamin D washout , a 16-week dose-titration phase , and an 11-week assessment phase . RESULTS Of 173 subjects enrolled , 83 % of Cinacalcet-D and 67 % of Flex-D subjects completed the study . A greater proportion of Cinacalcet-D versus Flex-D subjects had a > 30 % reduction in parathyroid hormone ( PTH ) ( 68 % versus 36 % , P < 0.001 ) as well as PTH < 300 pg/ml ( 44 % versus 23 % , P = 0.006 ) . The proportion of subjects simultaneously achieving targets for intact PTH ( 150 - 300 pg/ml ) and calcium-phosphorus product ( Ca x P ) ( < 55 mg2/dl2 ) was also greater ( 21 % versus 14 % ) , but this was not statistically significant . This was attributable to 19 % of Cinacalcet-D subjects with a PTH value below the KDOQI target range . CONCLUSIONS Achievement of KDOQI targets was difficult , especially with Flex-D. Maintaining calcium and phosphorus target values precluded the use of vitamin D doses necessary to lower PTH to within the narrow target range and highlighted limitations inherent to the KDOQI treatment algorithm BACKGROUND Secondary hyperparathyroidism is observed in patients with early chronic kidney disease ( CKD ) . This study investigated the safety and efficacy of cinacalcet for secondary hyperparathyroidism in participants with CKD not receiving dialysis . STUDY DESIGN Double-blind , r and omized , 32-week , phase 3 study . SETTING & PARTICIPANTS 404 participants with stage 3 or 4 CKD from 73 centers in 9 countries . INTERVENTIONS Cinacalcet : placebo ( 3:1 ratio ) . OUTCOMES & MEASUREMENTS Proportion of participants with a mean decrease of 30 % or greater in intact parathyroid hormone ( iPTH ) level , proportion with iPTH level of 70 or less or 110 or less pg/mL ( stage 3 and 4 CKD , respectively ) , and mean percentage of iPTH change from baseline , all during the efficacy- assessment phase . RESULTS A greater proportion of cinacalcet than placebo participants achieved a 30 % or greater decrease in iPTH level ( 74 % versus 28 % ; P < 0.001 ) , corresponding to a 43.1 % decrease in iPTH level from baseline ( cinacalcet ) compared with a 1.1 % increase ( placebo ) . At week 32 , serum calcium levels were 8.9 + /- 0.8 mg/dL ( -8.9 % ; cinacalcet ) and 9.9 + /- 0.6 mg/dL ( + 0.8 % ; placebo ) , phosphorus levels were 4.5 + /- 1.0 mg/dL ( + 21.4 % ) and 4.0 + /- 0.7 mg/dL ( + 6.8 % ) , and calcium-phosphorus product values were 40.1 + /- 8.3 mg(2)/dL(2 ) ( + 18.9 % ) and 38.9 + /- 6.9 mg(2)/dL(2 ) ( + 17.1 % ) , respectively . During the study course , 62 % ( cinacalcet ) and 1 % ( placebo ) of participants experienced 2 consecutive serum calcium concentrations less than 8.4 mg/dL. They generally were asymptomatic and without significant clinical consequences . Treatment generally was well tolerated , and most adverse events were mild to moderate in severity . LIMITATIONS The study was not design ed to assess the effects of cinacalcet on vascular calcification , bone histomorphometric parameters , or other clinical outcomes . It is not known whether the observed differences in changes in iPTH levels are clinical ly more important than observed differences in changes in serum calcium or phosphorus levels or dosages of vitamin D sterols and phosphate binders . CONCLUSIONS These data show that cinacalcet treatment in patients with CKD not receiving dialysis can decrease plasma iPTH levels , but with frequent ( albeit generally asymptomatic ) serum calcium levels less than 8.4 mg/dL and increases in serum phosphorus levels Treatment with vitamin D sterols can lower plasma parathyroid hormone ( PTH ) in many patients with secondary hyperparathyroidism due to end-stage renal disease , but hypercalcemia , hyperphosphatemia , or both often develop during treatment . As such , alternative therapeutic approaches to managing excess PTH secretion are needed . Calcimimetic agents directly inhibit PTH secretion by activating the calcium-sensing receptor in the parathyroid gl and s , but clinical experience with them is limited . Fifty-two hemodialysis patients with secondary hyperparathyroidism were given single orally administered doses of the calcimimetic agent AMG 073 ranging from 5 to 100 mg , or placebo . Plasma PTH levels decreased 2 h after 25- , 50- , 75- , or 100-mg doses , falling by a maximum of 43 + /- 29 % , 40 + /- 36 % , 54 + /- 28 % , or 55 + /- 39 % , respectively . Plasma PTH levels decreased in all patients given doses of > or = 25 mg but did not change in those who received placebo . In patients treated with daily doses of 25 or 50 mg of AMG 073 for 8 d , plasma PTH levels declined for the first 3 to 4 d and remained below baseline values after 8 d of treatment . Serum calcium concentrations also decreased by 5 to 10 % from pretreatment levels in patients given 50 mg of AMG 073 for 8 d , but values were unchanged in those who received lower doses . Serum phosphorus levels and values for the calcium-phosphorus ion product both decreased after treatment with AMG 073 . Thus , 8 d of treatment with AMG 073 effectively lowers plasma PTH levels and improves several disturbances in mineral metabolism that have been associated with soft tissue and vascular calcification and with adverse cardiovascular outcomes in patients with end-stage renal disease Background Optimal treatment for secondary hyperparathyroidism ( SHPT ) has not been defined . The IMPACT SHPT ( Clinical Trials.gov identifier : NCT00977080 ) study assessed whether dose-titrated paricalcitol plus supplemental cinacalcet only for hypercalcaemia is superior to cinacalcet plus low-dose vitamin D in controlling intact parathyroid hormone ( iPTH ) levels in patients with SHPT on haemodialysis . Methods In this 28-week , multicentre , open-label Phase 4 study , participants were r and omly selected to receive paricalcitol or cinacalcet plus low-dose vitamin D. R and omization and analyses were stratified by mode of paricalcitol administration [ intravenous ( IV ) or oral ] . The primary efficacy end point was the proportion of subjects who achieved a mean iPTH value of 150–300 pg/mL during Weeks 21–28 . Results Of 272 subjects r and omized , 268 received one or more dose of study drug ; 101 in the IV and 110 in the oral stratum with two or more values during Weeks 21–28 were included in the primary analysis . In the IV stratum , 57.7 % of subjects in the paricalcitol versus 32.7 % in the cinacalcet group ( P = 0.016 ) achieved the primary end point . In the oral stratum , the corresponding proportions of subjects were 54.4 % for paricalcitol and 43.4 % for cinacalcet ( P = 0.260 ) . Cochran – Mantel – Haenszel analysis , controlling for stratum , revealed overall superiority of paricalcitol ( 56.0 % ) over cinacalcet ( 38.2 % ; P = 0.010 ) in achieving iPTH 150–300 pg/mL during Weeks 21–28 . Hypercalcaemia occurred in 4 ( 7.7 % ) and 0 ( 0 % ) of paricalcitol-treated subjects in the IV and oral strata , respectively . Hypocalcaemia occurred in 46.9 % and 54.7 % of cinacalcet-treated subjects in the IV and oral strata , respectively . Conclusion Paricalcitol versus cinacalcet plus low-dose vitamin D provided superior control of iPTH , with low incidence of hypercalcaemia This study compared the efficacy of a cinacalcet-based regimen with unrestricted conventional therapy ( vitamin D and phosphate binders ) for achieving Kidney Disease Outcome Quality Initiative ( K/DOQI ) targets for dialysis patients . In this multicenter , prospect i ve study , hemodialysis patients with poorly controlled secondary hyperparathyroidism ( SHPT ) were r and omized to receive a cinacalcet-based regimen ( n=55 ) or a conventional therapy ( n=27 ) . Doses of cinacalcet , vitamin D sterols , and phosphate binders were adjusted during a 12-week dose-titration phase to achieve intact parathyroid hormone ( iPTH ) levels ≤ 31.8 pmol/L. The primary end point was the percentage of patients with values in this range during a 24-week efficacy- assessment phase . The clinical response to 36-week cinacalcet treatment was evaluated . A dual energy X-ray absorptiometry was performed before and after 36 weeks of cinacalcet therapy . Fifty-eight percent of the cinacalcet group reached the primary end point , as compared with 19 % of the conventional therapy group ( P=0.001 ) . A higher percentage of patients receiving the cinacalcet-based regimen versus conventional therapy achieved the targets for calcium , phosphorus and Ca × P. Achievement of targets was greatest in patients with less severe disease ( intact PTH range , 31.8 to 53 pmol/L ) . Cinacalcet therapy increased proximal femur bone mineral density ( BMD ) , but did not affect the lumbar spine . Itching intensity decreased significantly . Cinacalcet based treatment facilitates achievement of the K/DOQI targets for iPTH and bone mineral metabolism compared with conventional therapy in hemodialysis patients . Suppression of iPTH with cinacalcet reverses bone loss in the proximal femur . Cinacalcet alleviated itching AIMS Cinacalcet lowers plasma parathyroid hormone ( PTH ) levels in patients with secondary hyperparathyroidism ( sHPT ) , but the bone histologic response has not been described . This prospect i ve , double-blind , placebo-controlled trial assessed the effects of cinacalcet on bone histology and serum markers of bone metabolism in dialysis patients with sHPT . METHODS Patients with intact PTH ( iPTH ) > or = 300 pg/ml were r and omly assigned 2:1 to receive cinacalcet or placebo with concurrent vitamin D and /or phosphate binder therapy . Cinacalcet ( 30 - 180 mg/day ) was used to achieve iPTH levels < or = 200 pg/ml . Bone biopsies were performed before and after one year of treatment . RESULTS Baseline and end-of- study data were available from 32 patients ( 19 cinacalcet , 13 placebo ) . Baseline bone turnover was elevated in 27 , reduced in 3 and normal in 2 patients . Serum bone-specific alkaline phosphatase ( BSAP ) and N-telopeptide ( NTx ) were elevated . Cinacalcet treatment decreased PTH and diminished activation frequency , bone formation rate/bone surface , and fibrosis surface/bone surface . Adynamic bone was observed in three patients receiving cinacalcet ; in two of these , PTH levels were persistently low ( < 100 pg/ml ) . The histomorphometric parameter changes in bone corresponded to PTH , BSAP and NTx reductions . Bone mineralization parameters remained normal . CONCLUSIONS Treatment with cinacalcet lowered PTH and reduced bone turnover and tissue fibrosis among most dialysis patients with biochemical evidence of sHPT BACKGROUND Statins reduce the incidence of cardiovascular events in persons with type 2 diabetes mellitus . However , the benefit of statins in such patients receiving hemodialysis , who are at high risk for cardiovascular disease and death , has not been examined . METHODS We conducted a multicenter , r and omized , double-blind , prospect i ve study of 1255 subjects with type 2 diabetes mellitus receiving maintenance hemodialysis who were r and omly assigned to receive 20 mg of atorvastatin per day or matching placebo . The primary end point was a composite of death from cardiac causes , nonfatal myocardial infa rct ion , and stroke . Secondary end points included death from all causes and all cardiac and cerebrovascular events combined . RESULTS After four weeks of treatment , the median level of low-density lipoprotein cholesterol was reduced by 42 percent among patients receiving atorvastatin , and among those receiving placebo it was reduced by 1.3 percent . During a median follow-up period of four years , 469 patients ( 37 percent ) reached the primary end point , of whom 226 were assigned to atorvastatin and 243 to placebo ( relative risk , 0.92 ; 95 percent confidence interval , 0.77 to 1.10 ; P=0.37 ) . Atorvastatin had no significant effect on the individual components of the primary end point , except that the relative risk of fatal stroke among those receiving the drug was 2.03 ( 95 percent confidence interval , 1.05 to 3.93 ; P=0.04 ) . Atorvastatin reduced the rate of all cardiac events combined ( relative risk , 0.82 ; 95 percent confidence interval , 0.68 to 0.99 ; P=0.03 , nominally significant ) but not all cerebrovascular events combined ( relative risk , 1.12 ; 95 percent confidence interval , 0.81 to 1.55 ; P=0.49 ) or total mortality ( relative risk , 0.93 ; 95 percent confidence interval , 0.79 to 1.08 ; P=0.33 ) . CONCLUSIONS Atorvastatin had no statistically significant effect on the composite primary end point of cardiovascular death , nonfatal myocardial infa rct ion , and stroke in patients with diabetes receiving hemodialysis Secondary hyperparathyroidism ( SHPT ) affects a significant number of hemodialysis patients , and metabolic disturbances associated with it may contribute to their high mortality rate . As patients with lower serum calcium , phosphorus , and parathyroid hormone are reported to have improved survival , we tested whether prescription of the calcimimetic cinacalcet to hemodialysis patients with SHPT improved their survival . We prospect ively collected data on hemodialysis patients from a large provider beginning in 2004 , a time coincident with the commercial availability of cinacalcet hydrochloride . This information was merged with data in the United States Renal Data System to determine all-cause and cardiovascular mortality . Patients included in the study received intravenous ( i.v . ) vitamin D therapy ( a surrogate for the diagnosis of SHPT ) . Of 19,186 patients , 5976 received cinacalcet and all were followed from November 2004 for up to 26 months . Unadjusted and adjusted time-dependent Cox proportional hazards modeling found that all-cause and cardiovascular mortality rates were significantly lower for those treated with cinacalcet than for those without calcimimetic . Hence , this observational study found a significant survival benefit associated with cinacalcet prescription in patients receiving i.v . vitamin D. Definitive proof , however , of a survival advantage awaits the performance of r and omized clinical trials BACKGROUND Cinacalcet hydrochloride ( HCl ) can be used to manage the secondary hyperparathyroidism of patients with chronic kidney disease . This study investigated the pharmacokinetics , pharmacodynamics , safety , and tolerability of cinacalcet HCl over a dose range of 25 to 300 mg/d in patients receiving dialysis . METHODS Hemodialysis patients were r and omly assigned 4:1 to receive cinacalcet HCl or placebo in this double-blind study . Cinacalcet HCl doses were escalated weekly in 25-mg increments from 25 to 300 mg/d . Noncompartmental methods were used to analyze the pharmacokinetic parameters of cinacalcet ( the free-base ) . The effects of cinacalcet concentration on plasma parathyroid hormone ( PTH ) and serum calcium levels were evaluated . RESULTS Of 23 patients enrolled ( 17 patients , cinacalcet HCl ; 6 patients , placebo ) , 10 patients ( 8 patients , cinacalcet HCl ; 2 patients , placebo ) completed the study . Plasma concentration , median area under the plasma concentration-time curve from time 0 to 24 hours after dosing , and maximal plasma concentration ( Cmax ) of cinacalcet increased with doses up to 200 mg once daily . Median oral clearance ranged from 222 to 599 L/h , and median time after dosing when C max occurred ranged from 2 to 3 hours across all doses . The pharmacokinetics were linear over the 25- to 200-mg once-daily dose range , with no substantial increase in exposure at greater than 200 mg . Changes in plasma PTH concentrations correlated inversely with cinacalcet concentration . The concentration-effect relationship was well described by an inhibitory maximal effect model . Cinacalcet HCl was reasonably tolerated , and the incidence of adverse events was similar between groups ( 76 % , cinacalcet ; 80 % , placebo ) . Gastrointestinal events were noted at greater doses and may be dose related . CONCLUSION Cinacalcet HCl shows a dose-proportional increase in exposure over the range of 25 to 200 mg once daily in patients on hemodialysis therapy , and kinetics were linear up to 200 mg once daily . The incidence of adverse events was similar between groups BACKGROUND AND OBJECTIVES Cinacalcet , a novel calcimimetic , targets the calcium-sensing receptor to lower parathyroid hormone ( PTH ) , calcium , and phosphorus levels in dialysis patients with secondary hyperparathyroidism ( SHPT ) . This study compared the efficacy of a cinacalcet-based regimen with unrestricted conventional care ( vitamin D and phosphate binders ) for achieving the stringent National Kidney Foundation Kidney Disease Outcomes Quality Initiative ( KDOQI ) targets for dialysis patients . STUDY DESIGN In this multicenter , open-label study , hemodialysis patients with poorly controlled SHPT were r and omized to receive conventional care ( n = 184 ) or a cinacalcet-based regimen ( n = 368 ) . Doses of cinacalcet , vitamin D sterols , and phosphate binders were adjusted during a 16-wk dose-optimization phase with the use of algorithms that allowed cinacalcet to be used with adjusted doses of vitamin D. The primary end point was the proportion of patients with mean intact PTH < or = 300 pg/ml during a 7-wk efficacy assessment phase . RESULTS A higher proportion of patients receiving the cinacalcet-based regimen versus conventional care achieved the targets for PTH ( 71 % versus 22 % , respectively ; P < 0.001 ) , Ca x P ( 77 % versus 58 % , respectively ; P < 0.001 ) , calcium ( 76 % versus 33 % , respectively ; P < 0.001 ) , phosphorus ( 63 % versus 50 % , respectively ; P = 0.002 ) , and PTH and Ca x P ( 59 % versus 16 % , respectively , P < 0.001 ) , and allowed a 22 % reduction in vitamin D dosage in patients receiving vitamin D at baseline . Achievement of targets was greatest in patients with less severe disease ( intact PTH range , 300 to 500 pg/ml ) and the cinacalcet dose required was lower in these patients ( median = 30 mg/d ) . CONCLUSIONS Compared with conventional therapy , a cinacalcet-based treatment algorithm increased achievement of KDOQI treatment targets in dialysis patients in whom conventional therapy was no longer effective in controlling this disease BACKGROUND Statins reduce the incidence of cardiovascular events in patients at high cardiovascular risk . However , a benefit of statins in such patients who are undergoing hemodialysis has not been proved . METHODS We conducted an international , multicenter , r and omized , double-blind , prospect i ve trial involving 2776 patients , 50 to 80 years of age , who were undergoing maintenance hemodialysis . We r and omly assigned patients to receive rosuvastatin , 10 mg daily , or placebo . The combined primary end point was death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke . Secondary end points included death from all causes and individual cardiac and vascular events . RESULTS After 3 months , the mean reduction in low-density lipoprotein ( LDL ) cholesterol levels was 43 % in patients receiving rosuvastatin , from a mean baseline level of 100 mg per deciliter ( 2.6 mmol per liter ) . During a median follow-up period of 3.8 years , 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary end point ( 9.2 and 9.5 events per 100 patient-years , respectively ; hazard ratio for the combined end point in the rosuvastatin group vs. the placebo group , 0.96 ; 95 % confidence interval [ CI ] , 0.84 to 1.11 ; P=0.59 ) . Rosuvastatin had no effect on individual components of the primary end point . There was also no significant effect on all-cause mortality ( 13.5 vs. 14.0 events per 100 patient-years ; hazard ratio , 0.96 ; 95 % CI , 0.86 to 1.07 ; P=0.51 ) . CONCLUSIONS In patients undergoing hemodialysis , the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke . ( Clinical Trials.gov number , NCT00240331 . Current treatment of secondary hyperparathyroidism in chronic kidney failure with calcium and active vitamin D is potentially limited by hypercalcemia and hyperphosphatemia . AMG 073 represents a new class of compounds for the treatment of hyperparathyroidism known as calcimimetics , which reduce parathyroid hormone ( PTH ) synthesis and secretion by increasing the sensitivity of the parathyroid calcium-sensing receptor ( CaR ) to extracellular calcium . The current study evaluates the efficacy and safety of AMG 073 when added to conventional treatment of secondary hyperparathyroidism in end-stage renal disease ( ESRD ) . Seventy-one hemodialysis patients with uncontrolled secondary hyperparathyroidism , despite st and ard therapy with calcium , phosphate binders , and active vitamin D sterols , were treated in this 18-wk , dose-titration study with single daily oral doses of AMG 073/placebo up to 100 mg . Changes in plasma PTH , serum calcium , serum phosphorus , and calcium x phosphorus levels were compared between AMG 073 and placebo groups . Mean PTH decreased by 33 % in the AMG 073 patients compared with an increase of 3 % in placebo patients ( P = 0.001 ) . A significantly greater proportion of AMG 073 patients ( 44 % ) had a mean PTH < or = 250 pg/ml compared with placebo patients ( 20 % ; P = 0.029 ) . Also , a significantly greater proportion of AMG 073 patients ( 53 % ) had a decrease in PTH > or = 30 % compared with placebo patients ( 23 % ; P = 0.009 ) . Calcium x phosphorus levels decreased by 7.9 % in AMG 073 patients compared with an increase of 11.3 % in placebo patients ( P = 0.013 ) . Adverse event rates were low and mostly mild to moderate in severity ; however , the incidence of vomiting was higher in AMG 073 patients . In this study , the calcimimetic AMG 073 at doses up to 100 mg for 18 wk provided a safe and effective means to attain significant reductions in PTH and calcium x phosphorus levels in ESRD patients . AMG 073 represents a novel and promising therapy to improve the management of secondary hyperparathyroidism BACKGROUND Secondary hyperparathyroidism develops early in patients with chronic kidney disease ( CKD ) . Clinical guidelines from the National Kidney Foundation-Kidney/Disease Outcomes Quality Initiative emphasize the need to control parathyroid hormone ( PTH ) , calcium , and phosphorus levels in patients with CKD not receiving dialysis to reduce poor outcomes . This phase 2 study evaluated the effects of the oral calcimimetic cinacalcet hydrochloride in patients with CKD not on dialysis therapy . METHODS A r and omized , double-blind , placebo-controlled , 18-week study enrolled adults with an estimated glomerular filtration rate of 15 to 50 mL/min/1.73 m2 ( 0.25 to 0.83 mL/s/1.73 m2 ) and an intact PTH ( iPTH ) level greater than 130 pg/mL ( ng/L ) . Cinacalcet ( or placebo ) was titrated from 30 to 180 mg once daily to obtain a 30 % or greater reduction in iPTH levels from baseline . RESULTS Baseline mean iPTH levels were 243 pg/mL ( ng/L ) in the cinacalcet group ( n = 27 ) and 236 pg/mL ( ng/L ) in the control group ( n = 27 ) . At baseline , 28 % of subjects were being administered vitamin D sterols and 43 % were being administered phosphate binders or calcium supplements . The addition of cinacalcet significantly decreased iPTH concentrations compared with controls during the efficacy- assessment phase : 56 % versus 19 % of subjects achieved a 30 % or greater reduction in iPTH levels ( P = 0.006 ) , and mean iPTH levels decreased by 32 % in the cinacalcet group , but increased by 6 % in the control group ( P < 0.001 ) . Mean serum calcium and phosphorus levels remained within normal range throughout the study . Cinacalcet generally was well tolerated ; the most frequent adverse events were gastrointestinal . CONCLUSION This preliminary study provides evidence that cinacalcet is efficacious for the treatment of secondary hyperparathyroidism in subjects with CKD not receiving dialysis BACKGROUND Cinacalcet hydrochloride ( KRN1493 ) acts on the parathyroid calcium receptors to suppress parathyroid hormone ( PTH ) secretion , and is already in wide use in the United States and the European countries . In this study , we examined the efficacy and safety of cinacalcet in Japanese patients on maintenance haemodialysis . METHODS One hundred forty-four patients with serum intact PTH ( iPTH ) levels > or=300 pg/ml were enrolled and r and omly allocated to two groups assigned to receive either cinacalcet or placebo for 14 weeks . Cinacalcet was started at the dose of 25 mg/day and titrated up to 100 mg/day to achieve the target iPTH level of < 250 pg/ml . RESULTS Cinacalcet significantly decreased the median iPTH level from 606.5 pg/ml to 241.0 pg/ml , despite the mean dialysis vintage being 2.4 times longer ( 14.3+/-7.1 years ) and the proportion of patients receiving vitamin D sterols being higher , than in the phase 3 studies conducted in the US/EU . The target iPTH level was achieved in 51.4 % of the patients in the cinacalcet group , in sharp contrast to only 2.8 % in the placebo group . Furthermore , the percentage of patients with both the serum calcium and phosphorus levels within the target range in the K/DOQI guidelines increased from 4.2 % to 26.4 % by cinacalcet . CONCLUSIONS These results suggest that lower dose levels of cinacalcet , as compared to those in US/EU studies , may be sufficient effectively suppress the serum iPTH levels and allow favourable management of the serum calcium and phosphorus levels in Japanese patients , having a longer average dialysis vintage BACKGROUND Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia , which may contribute to cardiovascular disease and adverse clinical outcomes . Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels . We report the results of two identical r and omized , double-blind , placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride . METHODS Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite st and ard treatment were r and omly assigned to receive cinacalcet ( 371 patients ) or placebo ( 370 patients ) for 26 weeks . Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less . The primary end point was the percentage of patients with values in this range during a 14-week efficacy- assessment phase . RESULTS Forty-three percent of the cinacalcet group reached the primary end point , as compared with 5 percent of the placebo group ( P<0.001 ) . Overall , mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group ( P<0.001 ) . The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group ( P<0.001 ) . Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose . CONCLUSIONS Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism BACKGROUND Disorders of mineral metabolism , including secondary hyperparathyroidism , are thought to contribute to extraskeletal ( including vascular ) calcification among patients with chronic kidney disease . It has been hypothesized that treatment with the calcimimetic agent cinacalcet might reduce the risk of death or nonfatal cardiovascular events in such patients . METHODS In this clinical trial , we r and omly assigned 3883 patients with moderate-to-severe secondary hyperparathyroidism ( median level of intact parathyroid hormone , 693 pg per milliliter [ 10th to 90th percentile , 363 to 1694 ] ) who were undergoing hemodialysis to receive either cinacalcet or placebo . All patients were eligible to receive conventional therapy , including phosphate binders , vitamin D sterols , or both . The patients were followed for up to 64 months . The primary composite end point was the time until death , myocardial infa rct ion , hospitalization for unstable angina , heart failure , or a peripheral vascular event . The primary analysis was performed on the basis of the intention-to-treat principle . RESULTS The median duration of study -drug exposure was 21.2 months in the cinacalcet group , versus 17.5 months in the placebo group . The primary composite end point was reached in 938 of 1948 patients ( 48.2 % ) in the cinacalcet group and 952 of 1935 patients ( 49.2 % ) in the placebo group ( relative hazard in the cinacalcet group vs. the placebo group , 0.93 ; 95 % confidence interval , 0.85 to 1.02 ; P=0.11 ) . Hypocalcemia and gastrointestinal adverse events were significantly more frequent in patients receiving cinacalcet . CONCLUSIONS In an unadjusted intention-to-treat analysis , cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-to-severe secondary hyperparathyroidism who were undergoing dialysis . ( Funded by Amgen ; EVOLVE Clinical Trials.gov number , NCT00345839 . ) Cinacalcet hydrochloride is a calcimimetic agent that activates the calcium-sensing receptor on the surface of parathyroid cells and inhibits parathyroid hormone ( PTH ) secretion . To manage secondary hyperparathyroidism , cinacalcet , which lowers PTH levels without increasing serum calcium , phosphorus and calcium-phosphorus product ( Ca x P ) levels , may provide a new potential therapy . To identify the optimal starting dose of cinacalcet for Japanese hemodialysis patients with secondary hyperparathyroidism , this double-blind , placebo-controlled , parallel , dose-finding study was conducted . One hundred and twenty Japanese hemodialysis patients with intact PTH levels greater than or equal to 300 pg/mL were r and omized into four groups : placebo , and 12.5 , 25 and 50 mg of cinacalcet . The treatment period was three weeks followed by a two-week follow-up observation period . Cinacalcet decreased serum intact PTH levels in a dose-dependent manner , and also decreased serum calcium , phosphorus , Ca x P , tartrate-resistant acid phosphatase and osteocalcin levels . The treatment with cinacalcet was generally well tolerated in this study . However , the incidence of treatment-related adverse events , such as gastrointestinal disorders and hypocalcemia , and the rate of withdrawal from the study due to treatment-related adverse events were higher in the 50 mg dose group than in the other groups . On the basis of both efficacy and safety results , 25 mg has been identified as the optimal starting dose of cinacalcet for Japanese hemodialysis patients with secondary hyperparathyroidism |
1,984 | 24,595,213 | Implementation of healthy food procurement policies in schools , worksites , hospitals , care homes , correctional facilities , government institutions , and remote communities increase markers of healthy eating . | Unhealthy eating is the leading risk for death and disability globally .
As a result , the World Health Organization ( WHO ) has called for population health interventions .
One of the proposed interventions is to ensure healthy foods are available by implementing healthy food procurement policies .
The objective of this systematic review was to evaluate the evidence base assessing the impact of such policies . | OBJECTIVE Owing to modern lifestyles , individuals are dependent on out-of-home eating . The catering sector can have a pivotal role in influencing our food choices . The objective of the present study was to examine the impact of a structured catering initiative on food choices in a public sector workplace setting . DESIGN A cross-sectional comparison study in two hospitals , one of which had implemented a catering initiative design ed to provide nutritious food while reducing sugar , fat and salt intakes . SETTING Two public sector hospitals in Cork , Irel and . SUBJECTS A total of 100 r and om participants aged 18 - 64 years ( fifty intervention , fifty non-intervention ) who consumed at least one main meal in the hospital staff canteen daily . Each respondent was asked to complete one anonymous 24 h dietary recall and question naire . Food and nutrient analysis was conducted using WISP ( Weighed Intake Software Program ) . RESULTS Reported mean intakes of total sugars ( P < 0·001 ) , total fat ( P < 0·000 ) , saturated fat ( P < 0·000 ) and salt ( P < 0·046 ) were significantly lower in the intervention hospital when adjusted for age and gender . In the intervention hospital , 72 % of respondents , compared with 42 % in the non-intervention hospital , complied with the recommended under-3 daily servings of food high in fat and sugar ( P < 0·005 ) . In the intervention hospital , 43 % of respondents exceeded the recommended salt intake of 4 - 6 g/d , compared with 57 % in the non-intervention hospital . CONCLUSIONS Structured catering initiatives in the workplace are a potentially important option in the promotion of healthy food choices . Targeted public health programmes and health policy changes are needed to motivate caterers in the public sector and other industries to develop interventions that promote a healthy diet OBJECTIVE To assess the impact of a school-based nutrition education intervention aim ed at increasing the consumption of fruits and vegetables . DESIGN The intervention programme increased the provision of fruits and vegetables in schools and provided a range of point-of-purchase marketing material s , newsletters for children and parents , and teacher information . Curriculum material s at age 6 - 7 and 10 - 11 years were also developed and utilised . Evaluation was undertaken with groups of younger ( aged 6 - 7 years ) and older ( aged 10 - 11 years ) children . Methods included 3-day dietary records with interview and cognitive and attitudinal measures at baseline , with follow-up at 9 months , in intervention and control schools . SETTING The work was undertaken in primary schools in Dundee , Scotl and . SUBJECTS Subjects comprised 511 children in two intervention schools with a further 464 children from two schools acting as controls . RESULTS Children ( n=64 ) in the intervention schools had an average increase in fruit intake ( 133+/-1.9 to 183+/-17.0 g day(-1 ) ) that was significantly ( P<0.05 ) greater than the increase ( 100+/-11.7 to 107+/-14.2 g day(-1 ) ) estimated in children ( n=65 ) in control schools . No other changes in food or nutrient intake were detected . Increases in scores for variables relating to knowledge about fruits and vegetables and subjective norms were also greater in the intervention than in the control group , although taste preferences for fruits and vegetables were unchanged . CONCLUSIONS It is concluded that a whole school approach to increasing intakes of fruits and vegetables has a modest but significant effect on cognitive and attitudinal variables and on fruit intake The S and y Lake school-based diabetes prevention program is a culturally appropriate intervention for Ojibway-Cree students in the 3rd , 4th , and 5th grade s. This paper reports the results of the program in changing dietary intake behaviors and related psychosocial factors . Physical activity results are not included . The study was a pretest/post-test , single- sample design conducted during the 1998 - 1999 school year . A total of 122 students completed all 4 measurements ( anthropometry , 24-h dietary recall , and 2 question naires ) , at baseline and follow-up . There were significant increases ( P < 0.0001 ) in dietary intention , dietary preference , knowledge , and dietary self-efficacy , and in the curriculum knowledge scale between baseline and follow-up . Intervention exposure was significantly associated with being in the highest category for knowledge about foods that were low in dietary fat [ Medium Exposure odds ratio ( OR ) : 3.4 ; P < 0.05 ; High Exposure OR : 6.4 ; P < 0.05 ] , being in the highest category for dietary self-efficacy ( Medium Exposure OR : 3.7 ; P < 0.05 ; High Exposure OR : 3.9 ; P < 0.1 ) , being in the highest category for knowledge about curriculum concepts ( Medium Exposure OR : 3.4 ; P < 0.05 ; High Exposure OR : 9.4 : P < 0.01 ) , and for having met the age + 5 g dietary fiber intake/d ( Medium Exposure OR : 2.9 ; P < 0.1 ; High Exposure OR : 11.0 ; P < 0.01 ) . Exposure to the intervention was not associated with dietary intent or the percentage of energy from dietary fat . This program was associated with improved knowledge and the psychosocial factors related to healthy eating and dietary fiber intake of students in a remote First Nations community BACKGROUND This study evaluated the effects of a school-based dietary intervention program to increase fruit and vegetable consumption among fourth- grade rs . METHODS Twenty-eight elementary schools were r and omized to an immediate intervention condition or to a delayed intervention control condition . Measures of diet and psychosocial variables were collected at base line and 1 and 2 years post-baseline . The intervention included classroom , parent , and cafeteria components . RESULTS Mean daily consumption of fruit and vegetables was higher for the intervention children compared with controls at Follow-up 1 ( X(t ) = 3.96 , X(c ) = 2.28 ) and at Follow-up 2 ( X(t ) = 3.20 , X(c ) = 2.21 ) . Macro- and micronutrient changes favoring the intervention children were also observed at both Follow-up 1 and Follow-up 2 . Mean daily consumption of fruit and vegetables was higher for intervention parents compared with controls at Follow-up 1 ( X(t ) = 4.23,X(c ) = 3.94 ) but not at Follow-up 2 . CONCLUSIONS Strong effects were found for the High 5 intervention on fruit and vegetable consumption , on macro- and micro-nutrients , and on psychosocial variables . Future work is needed to enhance the intervention effects on parents ' consumption and to test the effectiveness of the intervention when delivered by classroom teachers OBJECTIVES This study examined the effects of pricing and promotion strategies on purchases of low-fat snacks from vending machines . METHODS Low-fat snacks were added to 55 vending machines in a convenience sample of 12 secondary schools and 12 worksites . Four pricing levels ( equal price , 10 % reduction , 25 % reduction , 50 % reduction ) and 3 promotional conditions ( none , low-fat label , low-fat label plus promotional sign ) were crossed in a Latin square design . Sales of low-fat vending snacks were measured continuously for the 12-month intervention . RESULTS Price reductions of 10 % , 25 % , and 50 % on low-fat snacks were associated with significant increases in low-fat snack sales ; percentages of low-fat snack sales increased by 9 % , 39 % , and 93 % , respectively . Promotional signage was independently but weakly associated with increases in low-fat snack sales . Average profits per machine were not affected by the vending interventions . CONCLUSIONS Reducing relative prices on low-fat snacks was effective in promoting lower-fat snack purchases from vending machines in both adult and adolescent population OBJECTIVES A r and omized school based trial sought to increase fruit and vegetable consumption among children using a multicomponent approach . METHODS The intervention , conducted in 20 elementary schools in St. Paul , targeted a multiethnic group of children who were in the fourth grade in spring 1995 and the fifth grade in fall 1995 . The intervention consisted of behavioral curricula in classrooms , parental involvement , school food service changes , and industry support and involvement . Lunchroom observations and 24-hour food recalls measured food consumption . Parent telephone surveys and a health behavior question naire measured psychosocial factors . RESULTS The intervention increased lunchtime fruit consumption and combined fruit and vegetable consumption , lunchtime vegetable consumption among girls , and daily fruit consumption as well as the proportion of total daily calories attributable to fruits and vegetables . CONCLUSIONS Multicomponent school-based programs can increase fruit and vegetable consumption among children . Greater involvement of parents and more attention to increasing vegetable consumption , especially among boys , remain challenges in future intervention research OBJECTIVES We evaluated an environmental intervention intended to increase sales of lower-fat foods in secondary school cafeterias . METHODS Twenty secondary schools were r and omly assigned to either an environmental intervention or a control group for a 2-year period . The intervention increased the availability of lower-fat foods and implemented student-based promotions . RESULTS A steeper rate of increase in sales of lower-fat foods in year 1 ( 10 % intervention vs -2.8 % control , P = .002 ) and a higher percentage of sales of lower-fat foods in year 2 ( 33.6 % intervention vs 22.1 % control , P = .04 ) were observed . There were no significant changes in student self-reported food choices . CONCLUSIONS School-based environmental interventions to increase availability and promotion of lower-fat foods can increase purchase of these foods among adolescents BACKGROUND 5 a Day for Better Health is a simple message encouraging people to eat more fruits and vegetables . The Seattle 5 a Day worksite investigators design ed and evaluated an intervention , organized on stages of behavioral change , to increase worksitewide fruit and vegetable consumption . METHODS We recruited 28 worksites with cafeterias and r and omized 14 to intervention and 14 to control . The intervention addressed both changes in the work environment and individual level behavior change . In each worksite , an employee advisory board , with study interventionist assistance , implemented the program . By surveying cross-sectional sample s of 125 employees per worksite , we compared worksite mean fruit and vegetable consumption at 2-year follow-up with that at baseline . Unobtrusive site-level indicators including plate observation and cafeteria checklist were also used . RESULTS The difference at 2 years was 0.5 for the intervention worksites and 0.2 for the control worksites , with an intervention effect of 0.3 daily serving ( P < 0.05 ) . Other measures of fruit and vegetable consumption , including unobtrusive indicators , supported the effectiveness of the intervention . CONCLUSIONS This simple 5 a Day intervention is feasible and acceptable for use in worksites with cafeterias . There was a significant differential increase in fruit and vegetable consumption in the intervention worksites . This kind of worksite intervention can achieve important health benefits on a population basis , because of its potential to reach large numbers of people The Cafeteria Power Plus project examined whether a cafeteria-based intervention would increase the fruit and vegetable ( FV ) consumption of children . Twenty-six schools were r and omly assigned to either an intervention or control condition . Baseline lunch observations of a sample ( N = 1668 ) of first- and third- grade students occurred in the spring of 2000 ; follow-up was in the spring of 2002 . The intervention took place during two consecutive school years beginning in the fall of 2000 and consisted of daily activities ( increasing the availability , attractiveness , and encouragement for FV ) and special events ( kick-offs , samplings , challenge weeks , theater production , and finale meal ) . Training of food-service staff and cook managers was ongoing throughout the intervention phase . Students in the intervention schools significantly increased their total fruit intake . Process measures indicated that verbal encouragement by food-service staff was associated with outcomes . The outcomes suggest that multicomponent interventions are more powerful than cafeteria programs alone with this age group OBJECTIVE A two-phase study was conducted to determine the effect of an environmental intervention aim ed to increase the selection of low- and moderate-fat entrees at school . DESIGN An evaluation of a school-wide intervention followed for two semesters . SUBJECTS Two schools of similar size and demographic data were r and omly assigned to either intervention or control . Participants were the children in these schools . INTERVENTION In Phase 1 , the rotation of existing entrees was modified such that one of three entree choices was low or moderate in fat . In Phase 2 , the number of competing high-fat entrees was reduced from two choices to one . MAIN OUTCOME MEASURES Data were : ( a ) entree fat content ( determined by a registered dietitian ) and ( b ) the aggregate entree selection s compiled from daily selection reports . STATISTICAL ANALYSES PERFORMED Frequency distributions were used to describe entree availability . Two-way analysis of variance indicated differences in the mean daily selection of low- , moderate- , and high-fat entrees . RESULTS In Phase 1 in the intervention school , the number of days that a low-fat entree was offered increased by 70 % , with no increase in the rate of selection of the low- or moderate-fat entrees . In Phase 2 , both low- and moderate-fat entrees were selected at a higher rate in the intervention school ( 32.1 % and 26.4 % , respectively ) than the control school ( 13.8 % and 7.5 % , respectively ) , P<0.01 . CONCLUSIONS Increasing the availability of low- and moderate-fat entrees is not sufficient to increase their rate of selection . However , their rate of selection is increased as the availability of high-fat entree choices is reduced Cardiovascular disease ( CVD ) , including stroke , heart attack and heart failure , is the leading cause of death and disability worldwide . Raised blood pressure ( BP ) is a major cause of CVD , responsible for 62 % of stroke and 49 % of coronary heart disease cases . There is much evidence for a causal relationship between salt intake and BP . The current salt intake in many countries around the world is between 9 g ⁄d and 12 g ⁄d ( ie , 3.6–4.8 g of sodium ) . R and omized trials have demonstrated that a modest reduction in salt intake lowers BP in individuals with raised BP and also in those with ‘ ‘ normal ’ ’ BP . Furthermore , there is a dose-response relationship . Within the range of 12 g ⁄d to 3 g ⁄d , the lower the salt intake , the lower the BP . Because raised BP throughout its range is a major cause of CVD , salt reduction would reduce cardiovascular risk . It was estimated that a reduction of 6 g ⁄d in salt intake would reduce stroke by 24 % and coronary heart disease by 18 % . This would prevent approximately 35,000 stroke and coronary heart disease deaths a year in the United Kingdom and approximately 2.5 million deaths worldwide . Both prospect i ve studies and outcome trials have demonstrated that a lower salt intake is related to a reduced risk of CVD . Salt reduction is one of the most cost-effective interventions to reduce CVD in both developed and developing countries . For example , the UK salt reduction campaign , which result ed in a fall in salt intake by approximately 10 % ( ie , from 9.5 g ⁄d in 2003 to 8.6 g ⁄d by May 2008 ) , cost just £ 15 million and led to approximately 6000 fewer CVD deaths per year , saving the UK economy approximately £ 1.5 billion per annum according to the recent report by the UK government ’s health advisory agency , the National Institute for Health and Clinical Excellence . In most developed countries , approximately 80 % of salt consumed is added to foods at the stage of manufacturing , and the consumers have no say over how much salt is added . Therefore , to achieve a reduction in population salt intake , it is imperative that the food industry make a gradual and sustained reduction in the amount of salt that is added to all foods . This approach has been successful in the United Kingdom and is now being exp and ed worldwide . World Salt Awareness Week was introduced by the salt reduction action group World Action on Salt and Health ( WASH ) in 2008 . The event serves as a platform for international experts in the fields of hypertension and nephrology to raise the profile of the importance of salt reduction to both the public and health professionals worldwide To increase opportunities for healthy eating and physical activity , US school districts participating in the National School Lunch Program were required to create a Local Wellness Policy ( LWP ) by June 2006 . The What 's Working project described the initial influence of this m and ate on nutrition environments and policies . In 2005 and 2007 ( before and after the m and ate went into effect ) , a survey about school features related to nutrition and physical activity was sent to a r and om sample of 45 low-income , rural elementary foodservice managers and principals . Schools averaged 204 students , 27 % Hispanic . Districts ' LWPs were coded for strength and comprehensiveness . In addition , key informant interviews were conducted with foodservice managers almost 2 years after the LWP went into effect . Three improvements were observed : increases in the percent of schools with policies stipulating predominantly healthy items be offered in classroom parties ( 21.4 % in 2005 vs 48.7 % in 2007 ) , daily fresh fruit offerings in the lunchroom ( 0.80 choices in 2005 vs 1.15 choices in 2007 ) , and the percent of schools using skinless poultry ( 27 % in 2005 vs 59 % in 2007 ) . LWPs were weakly worded and rarely addressed energy content . Nutrition guideline elements most commonly addressed included vending machines , school stores , and à la carte food offerings . Seveny-three percent of foodservice managers were familiar with their district 's LWP but did not perceive it changed lunchroom practice s. Although LWPs offer a framework to support opportunities for healthy eating , few evidence -based practice s were implemented as a direct result of the m and ate . Schools need more information about evidence -based practice s , as well as technical and financial assistance for implementation BACKGROUND The Child and Adolescent Trial for Cardiovascular Health ( CATCH ) tested the effectiveness of a multilevel intervention aim ed at promoting a healthful school environment and positive eating and physical activity behaviors in children . The CATCH Eat Smart Program targeted the school food service staff and aim ed to lower the total fat , saturated fat , and sodium content of school meals . METHODS The Eat Smart intervention was conducted in 56 intervention schools over a 2(1/2)-year period.+Five consecutive days of school menu , recipe , and vendor product information were collected from intervention and control schools at three intervals , Fall 1991 , Spring 1993 , and Spring 1994 , to assess the nutrient content of school menus as offered . RESULTS There was a significantly greater mean reduction in the percentage of calories from total fat ( adjusted mean difference -4.1 % ; P < 0.0001 ) and saturated fat ( adjusted mean difference -1.3 % ; P = 0.003 ) in intervention compared with control schools from baseline to follow-up . Although the sodium content of school lunches increased in both conditions , the mean increase was significantly lower in intervention schools ( adjusted mean difference -89 mg ; P = 0.034 ) . There were no statistically significant differences for total amounts of cholesterol , carbohydrate , protein , dietary fiber , total sugars , calcium , iron , vitamin A value , and vitamin C. Average total calories decreased significantly ; however , the mean total calories ( 683 kcal ) for intervention schools remained above one-third of the Recommended Dietary Allowances for this age group . CONCLUSIONS The CATCH Eat Smart intervention successfully lowered the total fat and saturated fat content of school lunches as offered , while maintaining recommended amounts of calories and essential nutrients OBJECTIVES This study assessed the effects of a 2-year integrated health promotion-health protection work-site intervention on changes in dietary habits and cigarette smoking . METHODS A r and omized , controlled intervention study used the work site as the unit of intervention and analysis ; it included 24 predominantly manufacturing work sites in Massachusetts ( 250 - 2500 workers per site ) . Behaviors were assessed in self-administered surveys ( n = 2386 ; completion rates = 61 % at baseline , 62 % at final ) . Three key intervention elements targeted health behavior change : ( 1 ) joint worker-management participation in program planning and implementation , ( 2 ) consultation with management on work-site environmental changes , and ( 3 ) health education programs . RESULTS Significant differences between intervention and control work sites included reductions in the percentage of calories consumed as fat ( 2.3 % vs 1.5 % kcal ) and increases in servings of fruit and vegetables ( 10 % vs 4 % increase ) . The intervention had a significant effect on fiber consumption among skilled and unskilled laborers . No significant effects were observed for smoking cessation . CONCLUSIONS Although the size of the effects of this intervention are modest , on a population wide basis effects of this size could have a large impact on cancer-related and coronary heart disease end points OBJECTIVES We report on the results of the Treatwell 5-a-Day study , a worksite intervention aim ed at increasing consumption of fruits and vegetables . METHODS Twenty-two worksites were r and omly assigned to 3 groups : ( 1 ) a minimal intervention control group , ( 2 ) a worksite intervention , and ( 3 ) a worksite-plus-family intervention . The interventions used community-organizing strategies and were structured to target multiple levels of influence , following a socioecological model . Data were collected by self-administered employee surveys before and after the intervention ; the response rate was 87 % ( n = 1359 ) at baseline and 76 % ( n = 1306 ) at follow-up . A process tracking system was used to document intervention delivery . RESULTS After control for worksite , gender , education , occupation , race/ethnicity , and living situation , total fruit and vegetable intake increased by 19 % in the worksite-plus-family group , 7 % in the worksite intervention group and 0 % in the control group ( P = .05 ) . These changes reflect a one half serving increase among workers in the worksite-plus-family group compared with the control group ( P = .018 ) . CONCLUSIONS The worksite-plus-family intervention was more successful in increasing fruit and vegetable consumption than was the worksite intervention . Worksite interventions involving family members appear to be a promising strategy for influencing workers ' dietary habits |
1,985 | 28,129,649 | RESULTS The initial search yielded 575 results , but only 32 manuscripts met all eligibility requirements : in terms of radiation-induced side effects , such as gastrointestinal and genitourinary acute and late toxicity , hypofractionated 3DCRT seemed to be more advantageous than 3DCRT with conventional fractionation as well as IMRT with conventional fractionation compared to 3DCRT with conventional fractionation ; furthermore , IMRT hypofractionated technique appeared more advantageous than IMRT with conventional fractionation in late toxicities .
R and omized trials meta- analysis disclosed an advantage in terms of acute gastrointestinal and late genitourinary toxicity for Hypofractionated schemes . | PURPOSE The aim of this review was to compare radiation toxicity in Localized Prostate Cancer ( LPC ) patients who underwent conventional fractionation ( CV ) , hypofractionated ( HYPO ) or extreme hypofractionated ( eHYPO ) radiotherapy .
We analyzed the impact of technological innovation on the management of prostate cancer , attempting to make a meta- analysis of r and omized trials . | PURPOSE To assess in a prospect i ve trial the feasibility and late toxicity of hypofractionated radiotherapy ( RT ) for prostate cancer . METHODS AND MATERIAL S Eligible patients had clinical stage T1c-2cNXM0 disease . They received 60 Gy in 20 fractions over 4 weeks with intensity-modulated radiotherapy including daily on-line image guidance with intraprostatic fiducial markers . RESULTS Between June 2001 and March 2004 , 92 patients were treated with hypofractionated RT . The cohort had a median prostate-specific antigen value of 7.06 ng/mL. The majority had Gleason grade 5 - 6 ( 38 % ) or 7 ( 59 % ) disease , and 82 patients had T1c-T2a clinical staging . Overall , 29 patients had low-risk , 56 intermediate-risk , and 7 high-risk disease . Severe acute toxicity ( Grade 3 - 4 ) was rare , occurring in only 1 patient . Median follow-up was 38 months . According to the Phoenix definition for biochemical failure , the rate of biochemical control at 14 months was 97 % . According to the previous American Society for Therapeutic Radiology and Oncology definition , biochemical control at 3 years was 76 % . The incidence of late toxicity was low , with no severe ( Grade > or =3 ) toxicity at the most recent assessment . CONCLUSIONS Hypofractionated RT using 60 Gy in 20 fractions over 4 weeks with image guidance is feasible and is associated with low rates of late bladder and rectal toxicity . At early follow-up , biochemical outcome is comparable to that reported for conventionally fractionated controls . The findings are being tested in an ongoing , multicenter , Phase III trial 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 BACKGROUND / AIM Based on a radiobiological assumption of a low alpha/beta ( α/β ) ratio for prostate cancer , hypofractionated radiotherapy has increasingly gained traction in the clinical practice and recent guidelines have confirmed the non-inferiority of this approach . Nevertheless , the largest studies that have used hypofractionation so far , employed image-guided radiation therapy/intensity modulated radiation therapy ( IGRT/IMRT ) facilities that might have overcome the radiobiological advantages , which remain to be fully confirmed . The aim of this trial was to evaluate the feasibility of a hypofractionated schedule delivered with 3D-Conformal Radiotherapy to prostate and seminal vesicles in combination with hormonal therapy . PATIENTS AND METHODS The study included 97 consecutive patients with localized prostate cancer ( PCa ) , irrespective of risk class , treated with a schedule of 62 Gy in 20 fractions over 5 weeks ( 4 fractions of 3.1 Gy each per week ) . According to National Comprehensive Cancer Network ( NCCN ) prognostic classification , patients were divided into a favourable group ( 19 % ) , intermediate group ( 41 % ) and unfavourable group ( 40 % ) . Early and late toxicities were scored using the radiation toxicity grading/European Organisation for Research and Treatment of Cancer ( RTOG/EORTC ) criteria . Additionally , the international prostate symptom index ( IPSS ) for benign prostate hypertrophy was used to evaluate obstructive urinary symptoms . Biochemical outcome was reported according to the Phoenix definition for biochemical failure . Hormonal therapy ( HT ) was administrated in 92 % of patients . RESULTS After a median follow-up of 39 months ( range=25 - 52 ) , maximum ≥G2 late genitourinary ( GU ) and gastrointestinal ( GI ) toxicities occurred in 8 % and 11 % patients , respectively . The corresponding figures for acute toxicities were 24 % and 15 % . Patients with higher IPSS score before enrolment had significantly worse urinary function after treatment . Only 2 % of patients died from PCa . Biochemical non- evidence of disease ( bNED ) was 83 % for all patients . CONCLUSION Our study confirms that 3D conformal radiotherapy ( 3DCRT ) remains a safe and effective method to deliver a dose-escalated hypofractionated regimen for PCa patients in all risk classes with acceptable toxicity rates and optimal biochemical control Background Quality of life ( QoL ) is one of the most significant issues in prostate cancer treatment decisions . This study aim ed to investigate the toxicity of hypofractionated stereotactic radiotherapy ( SBRT ) and QoL after treatment in localized prostate cancer patients . Material s and methods A prospect i ve single-center clinical study was performed in low- and intermediate-risk prostate cancer patients . Patients received 33.5 Gy in 5 fractions ( SHARP regimen ) . Acute and late toxicity was assessed according to RTOG/EORTC score . Patients filled out EORTC QLQ-C30 and prostate cancer-specific QLQ-PR25 question naires . Results The analysis included 68 prostate cancer patients ( 55–83 years , median 73 ) with clinical stage T1c-T2cN0M0 , median combined Gleason score of 6 ( 3–8 ) , and median prostate-specific antigen ( PSA ) level of 10 ng/mL ( 4–20 ng/mL ) . Neoadjuvant and rogen deprivation therapy was given to 52 patients ( 76.5 % ) , and stopped in 31 patients ( 45.5 % ) after 6 months ; in 21 patients ( 31 % ) after 2–3 years . Average and median follow-up was 24 months ( 18–45 ) . Median nadir PSA level was 0.03 ng/mL for all patients and 0.6 ng/mL for patients without hormone treatment . No patients had PSA failure . There were no acute grade IV toxicities . One patient ( 1.5 % ) developed grade III and 24 patients ( 35.3 % ) grade II acute bladder toxicity . No one developed grade III and 7 patients ( 10.3 % ) grade II acute rectal toxicity . No grade III or IV late gastrointestinal or genitourinary toxicities were reported . Grade II late urinary symptoms were observed in 8 patients ( 11.8 % ) and gastrointestinal symptoms in 3 patients ( 4.4 % ) . Global health status/QoL was good and improved during the observational period . ConclusionS BRT for prostate cancer patients is a well-tolerated treatment in terms of toxicity and QoL , has no negative impact on functioning and everyday life , with the important benefit of a short treatment period . However , long-term follow-up data are needed . ZusammenfassungHintergrundDie Lebensqualität ( QoL ) ist zu einem der wichtigsten Schwerpunkte bei der Wahl der Prostatakarzinombeh and lung geworden . Das Thema dieser Studie war die Untersuchung der Toxizität der hypofraktionierten stereotaktischen Radiotherapie ( SBRT ) und der QoL nach Beh and lung des lokal begrenzten Prostatakarzinoms . Material ien und Method enDie prospektive , monozentrische , klinische Studie wurde bei Prostatakarzinompatienten mit niedrigem bis mittlerem Risiko durchgeführt . Die Patienten erhielten 33,5 Gy in 5 Fraktionen ( SHARP-Beh and lungsschema ) . Akute und späte Toxizität wurden nach den Kriterien des RTOG/EORTC-Scores klassifiziert . Die Patienten füllten das EORTC-QLQ-C30- und das prostatakarzinomspezifische QLQ-PR25-Formular aus . ErgebnisseDie Analyse umfasste 68 Prostatakarzinompatienten ( medianes Alter 73 , Spanne 55–83 Jahre ) i m klinischen Staging T1c – T2cN0M0 , mit einem medianen Gleason-Score von 6 ( Spanne 3–8 ) und einem medianen PSA-Wert ( prostataspezifisches Antigen ) von 10 ng/ml ( Spanne 4–20 ng/ml ) . Eine neoadjuvante And rogendeprivationstherapie erhielten 52 Patienten ( 76,5 % ) ; die Hormontherapie beendet 31 Patienten ( 45,5 % ) nach 6 Monaten und 21 Patienten ( 31 % ) nach 2–3 Jahren . Das durchschnittliche und mediane Follow-up dauerte 24 Monate ( Spanne 18–45 ) . Der mediane PSA-Nadir betrug 0,03 ng/ml für alle Patienten und 0,6 ng/ml für Patienten ohne Hormontherapie . PSA-Versagen und akute Grad-IV-Toxizitäten traten nicht auf . Ein Patient ( 1,5 % ) hatte eine Grad-III- und 24 Patienten ( 35,3 % ) eine Grad-II-Harnblasentoxizität , kein Patient eine Grad-III- und 7 Patienten ( 10,3 % ) eine akute Grad-II-Rektumtoxizität . Späte gastrointestinale oder urogenitale Toxizitäten III . oder IV . Grade s wurden nicht berichtet . Bei 8 Patienten ( 11,8 % ) traten späte Miktionsbeschwerden II . Grade s und bei 3 Patienten ( 4,4 % ) gastrointestinale Symptome auf . Globaler Gesundheitsstatus/QoL war gut und besserte sich in der untersuchten Zeit . SchlussfolgerungSBRT ist beim Prostatakarzinom eine gut tolerierte Beh and lung hinsichtlich Toxizität und QoL , ohne negativen Einfluss auf das Alltagsleben und dem wichtigen Vorteil einer kurzen Beh and lungszeit . Langfristige Follow-up-Untersuchungen müssen noch folgen Summary Background Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment . We present a pre-planned analysis of the efficacy and side-effects of a r and omised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up . Methods CHHiP is a r and omised , phase 3 , non-inferiority trial that recruited men with localised prostate cancer ( pT1b – T3aN0M0 ) . Patients were r and omly assigned ( 1:1:1 ) to conventional ( 74 Gy delivered in 37 fractions over 7·4 weeks ) or one of two hypofractionated schedules ( 60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks ) all delivered with intensity-modulated techniques . Most patients were given radiotherapy with 3–6 months of neoadjuvant and concurrent and rogen suppression . R and omisation was by computer-generated r and om permuted blocks , stratified by National Comprehensive Cancer Network ( NCCN ) risk group and radiotherapy treatment centre , and treatment allocation was not masked . The primary endpoint was time to biochemical or clinical failure ; the critical hazard ratio ( HR ) for non-inferiority was 1·208 . Analysis was by intention to treat . Long-term follow-up continues . The CHHiP trial is registered as an International St and ard R and omised Controlled Trial , number IS RCT N97182923 . Findings Between Oct 18 , 2002 , and June 17 , 2011 , 3216 men were enrolled from 71 centres and r and omly assigned ( 74 Gy group , 1065 patients ; 60 Gy group , 1074 patients ; 57 Gy group , 1077 patients ) . Median follow-up was 62·4 months ( IQR 53·9–77·0 ) . The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3 % ( 95 % CI 86·0–90·2 ) in the 74 Gy group , 90·6 % ( 88·5–92·3 ) in the 60 Gy group , and 85·9 % ( 83·4–88·0 ) in the 57 Gy group . 60 Gy was non-inferior to 74 Gy ( HR 0·84 [ 90 % CI 0·68–1·03 ] , pNI=0·0018 ) but non-inferiority could not be cl aim ed for 57 Gy compared with 74 Gy ( HR 1·20 [ 0·99–1·46 ] , pNI=0·48 ) . Long-term side-effects were similar in the hypofractionated groups compared with the conventional group . There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures . The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group ( RTOG ) grade 2 or worse bowel and bladder adverse events was 13·7 % ( 111 events ) and 9·1 % ( 66 events ) in the 74 Gy group , 11·9 % ( 105 events ) and 11·7 % ( 88 events ) in the 60 Gy group , 11·3 % ( 95 events ) and 6·6 % ( 57 events ) in the 57 Gy group , respectively . No treatment-related deaths were reported . Interpretation Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new st and ard of care for external-beam radiotherapy of localised prostate cancer . Funding Cancer Research UK , Department of Health , and the National Institute for Health Research Cancer Research Network Hypofractionated radiation therapy for prostate cancer has become of increasing interest with the recognition of a potential improvement in therapeutic ratio with treatments delivered in larger-sized fractions . In addition , the associated reduction in fraction number produces attractive cost and patient convenience advantages as well . A still limited but growing number of hypofractionation trials have reported acceptable short-term levels of toxicity and biochemical control , but most have insufficient follow-up to ensure the long-term safety and efficacy of this approach . This situation will improve as many currently active trials mature , particularly several high-value r and omized trials . In contrast , extreme hypofractionation , with schedules delivering only on the order of 5 fractions , is truly in its infancy for prostate cancer , with extremely limited tolerance and efficacy information currently available . Several uncertainties in the radiobiology of hypofractionation mitigate for an organized , cautious investigational approach . The fractionation response ( alpha/beta ratio ) of prostate cancers and , for that matter , late-responding normal tissues , has yet to be rigorously defined . Additionally , the linear-quadratic ( LQ ) model used in the design of hypofractionation schedules is subject to its own uncertainties , particularly with respect to the upper limit of fraction sizes for which it remains valid . Contemporary dose-escalated radiation therapy is already highly effective , making it imperative that ongoing and future studies of hypofractionation be performed in carefully design ed , r and omized clinical trials . Clinical validation permitting , the adaptation of hypofractionation as a st and ard of care could profoundly influence future management of localized prostate cancer PURPOSE To determine if escalated radiation dose using hypofractionation significantly reduces biochemical and /or clinical disease failure ( BCDF ) in men treated primarily for prostate cancer . PATIENTS AND METHODS Between June 2002 and May 2006 , men with favorable- to high-risk prostate cancer were r and omly allocated to receive 76 Gy in 38 fractions at 2.0 Gy per fraction ( conventional fractionation intensity-modulated radiation therapy [ CIMRT ] ) versus 70.2 Gy in 26 fractions at 2.7 Gy per fraction ( hypofractionated IMRT [ HIMRT ] ) ; the latter was estimated to be equivalent to 84.4 Gy in 2.0 Gy fractions . High-risk patients received long-term and rogen deprivation therapy ( ADT ) , and some intermediate-risk patients received short-term ADT . The primary end point was the cumulative incidence of BCDF . Secondarily , toxicity was assessed . RESULTS There were 303 assessable patients with a median follow-up of 68.4 months . No significant differences were seen between the treatment arms in terms of the distribution of patients by clinicopathologic or treatment-related ( ADT use and length ) factors . The 5-year rates of BCDF were 21.4 % ( 95 % CI , 14.8 % to 28.7 % ) for CIMRT and 23.3 % ( 95 % CI , 16.4 % to 31.0 % ) for HIMRT ( P = .745 ) . There were no statistically significant differences in late toxicity between the arms ; however , in subgroup analysis , patients with compromised urinary function before enrollment had significantly worse urinary function after HIMRT . CONCLUSION The hypofractionation regimen did not result in a significant reduction in BCDF ; however , it is delivered in 2.5 fewer weeks . Men with compromised urinary function before treatment may not be ideal c and i date s for this approach PURPOSE Hypofractionated radiotherapy has an intrinsically different normal tissue and tumor radiobiology . The results of a prospect i ve trial of stereotactic body radiotherapy ( SBRT ) for prostate cancer with long-term patient-reported toxicity and tumor control rates are presented . METHODS AND MATERIAL S From 2003 through 2009 , 67 patients with clinical ly localized low-risk prostate cancer were enrolled . Treatment consisted of 36.25 Gy in 5 fractions using SBRT with the CyberKnife as the delivery technology . No patient received hormone therapy . Patient self-reported bladder and rectal toxicities were grade d on the Radiation Therapy Oncology Group scale ( RTOG ) . RESULTS Median follow-up was 2.7 years . There were no grade 4 toxicities . Radiation Therapy Oncology Group Grade 3 , 2 , and 1 bladder toxicities were seen in 3 % ( 2 patients ) , 5 % ( 3 patients ) , and 23 % ( 13 patients ) respectively . Dysuria exacerbated by urologic instrumentation accounted for both patients with Grade 3 toxicity . Urinary incontinence , complete obstruction , or persistent hematuria was not observed . Rectal Grade 3 , 2 , and 1 toxicities were seen in 0 , 2 % ( 1 patient ) , and 12.5 % ( 7 patients ) , respectively . Persistent rectal bleeding was not observed . Low- grade toxicities were substantially less frequent with QOD vs. QD dose regimen ( p = 0.001 for gastrointestinal and p = 0.007 for genitourinary ) . There were two prostate-specific antigen ( PSA ) , biopsy-proven failures with negative metastatic workup . Median PSA at follow-up was 0.5 ± 0.72 ng/mL. The 4-year Kaplan-Meier PSA relapse-free survival was 94 % ( 95 % confidence interval , 85%-102 % ) . CONCLUSION Significant late bladder and rectal toxicities from SBRT for prostate cancer are infrequent . PSA relapse-free survival compares favorably with other definitive treatments . The current evidence supports consideration of stereotactic body radiotherapy among the therapeutic options for localized prostate cancer PURPOSE To identify dosimetric parameters derived from anorectal , rectal , and anal wall dose distributions that correlate with different late gastrointestinal ( GI ) complications after three-dimensional conformal radiotherapy for prostate cancer . METHODS AND MATERIAL S In this analysis , 641 patients from a r and omized trial ( 68 Gy vs. 78 Gy ) were included . Toxicity was scored with adapted Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer ( RTOG/EORTC ) criteria and five specific complications . The variables derived from dose-volume histogram of anorectal , rectal , and anal wall were as follows : % receiving > or = 5 - 70 Gy ( V5-V70 ) , maximum dose ( Dmax ) , and mean dose ( D(mean ) ) . The anus was defined as the most caudal 3 cm of the anorectum . Statistics were done with multivariate Cox regression models . Median follow-up was 44 months . RESULTS Anal dosimetric variables were associated with RTOG/EORTC Grade > or = 2 ( V5-V40 , D(mean ) ) and incontinence ( V5-V70 , D(mean ) ) . Bleeding correlated most strongly with anorectal V55-V65 , and stool frequency with anorectal V40 and D(mean ) . Use of steroids was weakly related to anal variables . No volume effect was seen for RTOG/EORTC Grade > or =3 and pain/cramps/tenesmus . CONCLUSION Different volume effects were found for various late GI complications . Therefore , to evaluate the risk of late GI toxicity , not only intermediate and high doses to the anorectal wall volume should be taken into account , but also the dose to the anal wall PURPOSE In general late side-effects after prostate cancer radiotherapy are presented by the use of actuarial incidence rates . The aim of this analysis was to describe additional relevant aspects of late side effects after prostate cancer radiotherapy . MATERIAL S AND METHODS All 178 primary prostate-cancer patients were treated within the Austrian-German multicenter trial by three-dimensional radiotherapy up to a local dose of 70 Gy ( low/intermediate-risk ) or 74 Gy ( high-risk ) , respectively . Late gastrointestinal/urogenital ( GI/GU ) side-effects were prospect ively assessed by the use of EORTC/RTOG score . Maximum side-effects , actuarial incidence rate and prevalence rates , initial appearance and duration of ≥ grade 2 toxicity were evaluated . RESULTS Median follow-up was 74 months . Late GI/GU side-effects ≥ grade 2 were detected in 15 % ( 27/178 ) and 22 % ( 40/178 ) . The corresponding 5-year actuarial incidence rates for GI/GU side-effects were 19 % and 23 % , whereas the prevalence was 1 - 2 % and 2 - 7 % after 5 years , respectively . Late side effects ≥ grade 2 appeared within 5 years after radiotherapy in all patients with GI side-effects ( 27/27 ) and in 85 % ( 34/40 ) of the patients with GU side-effects , respectively and lasted for less than 3 years in 90 % ( GI ) and 98 % ( GU ) . CONCLUSIONS This study demonstrates that the majority of late GI and GU side effects after primary external beam radiotherapy for prostate cancer are transient . Using only actuarial incidence rates for reporting side effects may lead to misinterpretation or overestimation . The combination of incidence and prevalence rates provides a more comprehensive view on the complex issue of late side effects Background To investigate the feasibility of dose escalation ( 86 Gy at 2 Gy/fraction ) with intensity modulated radiation therapy ( IMRT ) in intermediate-risk prostate cancer without and rogen deprivation therapy . Methods Patients with histologically proven adenocarcinoma of the prostate , intermediate prognostic category , were enrolled in this study . Early and late toxicity were scored according to the Cancer Therapy Evaluation Program , Common Terminology Criteria for Adverse Events , Version 3.0 . Treatment outcome was stated in terms of biochemical failure , biopsy result and clinical failure . Results 39 patients with a median follow-up of 71 months were analyzed . No patient experienced G3 or G4 acute gastrointestinal ( GI ) or genitourinary ( GU ) toxicity . G2 acute GI and GU toxicity were observed in 17 ( 44 % ) and 20 ( 51 % ) patients , respectively . Fourteen patients ( 36 % ) did not experience acute GI toxicity and 4 patients ( 10 % ) did not experience acute GU toxicity . G2 late GI bleeding occurred in 7 of 39 patients ( 18 % ) . Both G3 and G4 late GI toxicity were seen only in one patient ( 2.5 % ) . Two patients ( 5 % ) experienced G2 late GU toxicity , while G3 late GU toxicity occurred in 3 patients ( 8 % ) . The 5-year actuarial freedom from biochemical failure ( FFBF ) was 87 % . Thirty-four patients ( 87 % ) did not show biochemical relapse . Seventeen patients ( 44 % ) underwent biopsy two year after radiotherapy ; of these only two were non-negative and both did not show evidence of biochemical disease . Conclusions IMRT treatment of patients with localized intermediate-risk prostate cancer at high dose levels without using and rogen deprivation therapy ( ADT ) seems to give good disease control . Nevertheless , future trials should aim at further decreasing toxicity by exploiting image guidance techniques and by reducing the dose delivered at the interface between organs at risk and prostate PURPOSE Several r and omized trials have shown a benefit of dose escalation to 78 to 79 Gy for men treated with external radiation for localized prostate cancer . Single-institution data suggest a benefit with even higher doses . American College of Radiology 03 - 12 is a Phase II trial testing the safety and efficacy of 82 GyE ( Gray equivalent ) delivered with conformal proton radiation . METHODS AND MATERIAL S From 2003 - 2006 , 85 men with localized prostate cancer were accrued to American College of Radiology 03 - 12 . Eighty-four were eligible for analysis . They were treated with conformal proton radiation alone to a total dose of 82 GyE. The study was design ed to test whether the rate of 18-month Grade 3 + late toxicity was greater than 10 % . RESULTS The median follow-up was 31.6 months . Regarding treatment-related acute toxicity , there were 39 Grade 1 cases ( 46 % ) , 19 Grade 2 cases ( 23 % ) and 2 Grade 3 cases ( 2 % ) . Regarding genitourinary/gastrointestinal toxicity , there were 42 Grade 1 cases ( 50 % ) , 12 Grade 2 cases ( 14 % ) and 1 Grade 3 case ( 1 % ) . Regarding late toxicity , there were 28 Grade 1 cases ( 33 % ) , 22 Grade 2 cases ( 26 % ) , 6 Grade 3 cases ( 7 % ) , and 1 Grade 4 case ( 1 % ) . The late genitourinary/gastrointestinal rates were the same . The estimated rate of Grade 3 + late toxicity at 18 months was 6.08 % . CONCLUSIONS Although not free of late toxicity , 82 GyE at 2 GyE per fraction delivered with conformal proton radiation did not exceed the late morbidity target tested in this trial . There was sufficient morbidity , however , that this may be the maximal dose that can be delivered safely with this technique and fractionation BACKGROUND AND PURPOSE Biological dose escalation through stereotactic ablative radiotherapy ( SABR ) holds promise of improved patient convenience , system capacity and tumor control with decreased cost and side effects . The objectives are to report the toxicities , biochemical and pathologic outcomes of this prospect i ve study . MATERIAL S AND METHODS A phase I/II study was performed where low risk localized prostate cancer received SABR 35 Gy in 5 fractions , once weekly on st and ard linear accelerators . Common Terminology Criteria for Adverse Events v3.0 and Radiation Therapy Oncology Group late morbidity scores were used to assess acute and late toxicities , respectively . Biochemical control ( BC ) was defined by the Phoenix definition . RESULTS As of May 2012 , 84 patients have completed treatment with a median follow-up of 55 months ( range 13 - 68 months ) . Median age was 67 years and median PSA was 5.3 ng/ml . The following toxicities were observed : acute grade 3 + : 0 % gastrointestinal ( GI ) , 1 % genitourinary ( GU ) , 0 % fatigue ; late grade 3 + : 1 % GI , 1 % GU . Ninety-six percent were biopsy negative post-treatment . The 5-year BC was 98 % . CONCLUSIONS This novel technique employing st and ard linear accelerators to deliver an extreme hypofractionated schedule of radiotherapy is feasible , well tolerated and shows excellent pathologic and biochemical control PURPOSE Nowadays , advanced irradiation techniques make it possible to escalate safely the dose in prostate cancer . We studied the effect of a higher dose on tumor control in a r and omized trial with a median follow-up of 110 months . PATIENTS AND METHODS Patients with T1b-T4N0 prostate cancer ( n=664 ) were r and omized between 78 Gy and 68 Gy . Primary endpoint was biochemical and /or clinical failure ( BCF ) according to the American Society for Therapeutic Radiology and Oncology ( ASTRO ) guidelines ( 3 consecutive rises ) , and to Phoenix ( nadir plus 2 μg/L ) . Secondary endpoints were clinical failure ( CF ) , local failure ( LF ) , prostate cancer death ( PCD ) , and overall survival ( OS ) . Explorative subgroup analyses were performed . RESULTS BCF rate ( HR=0.8 ; 20 % less events ) and LF rate ( HR=0.5 ; 50 % less events ) were significantly lower in the 78 Gy arm ( p<0.05 ) . CF , PCD and OS were similar in both arms . A significant heterogeneity of treatment effect was found for PSA cutoffs between 7 and 10 μg/L. CONCLUSION We observed significantly less BCF and LF in the high-dose arm . This suggests improvement of the therapeutic ratio . However , we observed similar rates of CF and PCD at the current up date . More follow-up is needed to investigate which patients benefit in terms of prolonged OS Background Radiotherapy is an increasingly preferred treatment option for localized prostate cancer , and stereotactic body radiation therapy ( SBRT ) a relatively established modality of therapeutic irradiation . The present study analyzes the toxicity and biochemical efficacy of SBRT in 100 consecutive prostate cancer patients treated with CyberKnife Robotic Radiosurgery System . Methods One hundred patients were treated with SBRT at the Radiation Oncology department of San Bortolo Hospital , Vicenza , Italy . All patients included in this IRB-approved protocol -driven prospect i ve study had biopsy-proven prostate cancer . Risk category was low in 41 , intermediate in 42 , and high in 17 patients . The patients were treated with CyberKnife-SBRT ( CK-SBRT ) , the prescription dose was 35 Gy in five fractions , corresponding to 92 Gy in 2-Gy fractions ( α/β = 1.5 Gy ) ; 29 patients also received and rogen deprivation therapy ( ADT ) . Results Median follow-up was 36 months ( range , 6–76 months ) . Acute Grade 2 genitourinary and gastrointestinal toxicity occurred in respectively 12 % and 18 % of the patients ; there were no Grade 3 or higher acute toxicities . Late Grade 1 , 2 , and 3 genitourinary toxicities occurred in 4 % , 3 % , and 1 % of the patients , respectively ; late Grade 1 gastrointestinal toxicity occurred in two patients and Grade 2 toxicity in one patient ; no late gastrointestinal toxicities of grade 3 or 4 were observed . Median PSA nadir was 0.45 ng/ml at 36 months for all patients . In the SBRT-monotherapy group , the median PSA nadir at 36 months was 0.62 ng/ml ; in the ADT-SBRT group , it was 0.18 ng/ml . Four patients had clinical recurrence : one local , two lymph nodes , and one to the bone . Ninety-six patients had no evidence of biochemical or clinical recurrence . A benign PSA bounce of median 1.08 ng/ml occurred in 12 % of the 71 SBRT monotherapy patients at a mean 23 months ( range , 18–30 months ) . Conclusions In this study CK-SBRT has provided promising outcomes in localized prostate cancer with good PSA response , minimal toxicity and patient inconvenience Objective To determine late toxicity and quality of life ( QoL ) in patients with localized prostate cancer after high-dose intensity-modulated radiotherapy (IMRT).Patient and methods This was a prospect i ve study in patients with localized prostate adenocarcinoma who had been treated by IMRT ( 76 Gy ) between February and November 2006 . Physicians scored acute and late toxicity using the Common Terminology Criteria for Adverse Events ( version 3.0 ) . Patients completed cancer and prostate-specific QoL question naires ( EORTC QLQ-C30 and QLQ-PR25 ) before IMRT ( baseline ) and at 2 , 6 , 18 and 54 months . Result Data were available for 38 patients ( median age , 73 years ) ( 18 % low risk ; 60 % intermediate risk ; 32 % high risk ) . The incidence of urinary and gastrointestinal toxicity was respectively : immediately post IMRT : 36.8 % and 23.7 % ( grade 1 ) , 5.3 % and 5.3 % ( grade 2 ) , 2.6 % and 0 % ( grade 3 ) ; at 18 months : 23.7 % and 10.3 % ( grade 1 ) , 26.3 % and 13.2 % ( grade 2 ) , 0 % and 2.6 % ( grade 3 ) ; at 54 months : 34.2 % and 23.7 % ( grade 1 ) , 5.3 % and 15.8 % ( grade 2 ) , 5.3 % and 0 % ( grade 3 ) . At 54 months , significant worsening was reported by patients for 11/19 QoL items but the worsening was clinical ly relevant ( > 10 points ) for 7 items only : physical , role as well as social functioning , fatigue , pain , dyspnoea and constipation . There was no significant difference between 54-month and baseline QoL scores for global health , gastrointestinal symptoms , treatment-related symptoms and sexual function . However , there was significant - but clinical ly non-relevant ( < 10 points ) - worsening of urinary symptom . Conclusion High-dose IMRT to the prostate with accurate patient positioning did not induce any clinical ly relevant worsening in late urinary and gastrointestinal QoL at 54 months . Impaired physical and role functioning may be related to age and comorbidities PURPOSE To evaluate the tolerability of escalating doses of stereotactic body radiation therapy in the treatment of localized prostate cancer . PATIENTS AND METHODS Eligible patients included those with Gleason score 2 to 6 with prostate-specific antigen ( PSA ) ≤ 20 , Gleason score 7 with PSA ≤ 15 , ≤ T2b , prostate size ≤ 60 cm(3 ) , and American Urological Association ( AUA ) score ≤ 15 . Pretreatment preparation required an enema and placement of a rectal balloon . Dose-limiting toxicity ( DLT ) was defined as grade 3 or worse GI/genitourinary ( GU ) toxicity by Common Terminology Criteria of Adverse Events ( version 3 ) . Patients completed quality -of-life question naires at defined intervals . RESULTS Groups of 15 patients received 45 Gy , 47.5 Gy , and 50 Gy in five fractions ( 45 total patients ) . The median follow-up is 30 months ( range , 3 to 36 months ) , 18 months ( range , 0 to 30 months ) , and 12 months ( range , 3 to 18 months ) for the 45 Gy , 47.5 Gy , and 50 Gy groups , respectively . For all patients , GI grade ≥ 2 and grade ≥ 3 toxicity occurred in 18 % and 2 % , respectively , and GU grade ≥ 2 and grade ≥ 3 toxicity occurred in 31 % and 4 % , respectively . Mean AUA scores increased significantly from baseline in the 47.5-Gy dose level ( P = .002 ) as compared with the other dose levels , where mean values returned to baseline . Rectal quality -of-life scores ( Exp and ed Prostate Cancer Index Composite ) fell from baseline up to 12 months but trended back at 18 months . In all patients , PSA control is 100 % by the nadir + 2 ng/mL failure definition . CONCLUSION Dose escalation to 50 Gy has been completed without DLT . A multicenter phase II trial is underway treating patients to 50 Gy in five fractions to further evaluate this experimental therapy BACKGROUND The aim of this trial was to compare dose-escalated conformal radiotherapy with control-dose conformal radiotherapy in patients with localised prostate cancer . Preliminary findings reported after 5 years of follow-up showed that escalated-dose conformal radiotherapy improved biochemical progression-free survival . Based on the sample size calculation , we planned to analyse overall survival when 190 deaths occurred ; this target has now been reached , after a median 10 years of follow-up . METHODS RT01 was a phase 3 , open-label , international , r and omised controlled trial enrolling men with histologically confirmed T1b-T3a , N0 , M0 prostate cancer with prostate specific antigen of less than 50 ng/mL. Patients were r and omly assigned central ly in a 1:1 ratio , using a computer-based minimisation algorithm stratifying by risk of seminal vesicle invasion and centre to either the control group ( 64 Gy in 32 fractions , the st and ard dose at the time the trial was design ed ) or the escalated-dose group ( 74 Gy in 37 fractions ) . Neither patients nor investigators were masked to assignment . All patients received neoadjuvant and rogen deprivation therapy for 3 - 6 months before the start of conformal radiotherapy , which continued until the end of conformal radiotherapy . The co primary outcome measures were biochemical progression-free survival and overall survival . All analyses were done on an intention-to-treat basis . Treatment-related side-effects have been reported previously . This trial is registered , number IS RCT N47772397 . FINDINGS Between Jan 7 , 1998 , and Dec 20 , 2001 , 862 men were registered and 843 subsequently r and omly assigned : 422 to the escalated-dose group and 421 to the control group . As of Aug 2 , 2011 , 236 deaths had occurred : 118 in each group . Median follow-up was 10·0 years ( IQR 9·1 - 10·8 ) . Overall survival at 10 years was 71 % ( 95 % CI 66 - 75 ) in each group ( hazard ratio [ HR ] 0·99 , 95 % CI 0·77 - 1·28 ; p=0·96 ) . Biochemical progression or progressive disease occurred in 391 patients ( 221 [ 57 % ] in the control group and 170 [ 43 % ] in the escalated-dose group ) . At 10 years , biochemical progression-free survival was 43 % ( 95 % CI 38 - 48 ) in the control group and 55 % ( 50 - 61 ) in the escalated-dose group ( HR 0·69 , 95 % CI 0·56 - 0·84 ; p=0·0003 ) . INTERPRETATION At a median follow-up of 10 years , escalated-dose conformal radiotherapy with neoadjuvant and rogen deprivation therapy showed an advantage in biochemical progression-free survival , but this advantage did not translate into an improvement in overall survival . These efficacy data for escalated-dose treatment must be weighed against the increase in acute and late toxicities associated with the escalated dose and emphasise the importance of use of appropriate modern radiotherapy methods to reduce side-effects . FUNDING UK Medical Research Council BACKGROUND Hypofractionated radiotherapy in the radical treatment of localized prostate cancer has potential biological advantages relative to conventional fractionation . We report prospect ively collected toxicity data from a cohort of patients treated with a 3D conformal technique ( 3DCRT ) . MATERIAL S AND METHODS 90 patients receiving curative intent hypofractionated radiotherapy with 57Gy in 19 daily fractions over 3.8 weeks were evaluated prospect ively for the development of radiation related toxicity over a 3 year period . RESULTS All patients completed treatment . Maximal acute toxicity experienced was 58.6 , 10 and 1.1 % for grade 1 , 2 and 3 genitourinary ( GU ) toxicity respectively and 75.6 , 9 and 0 % for gastrointestinal ( GI ) toxicity . For late toxicity the three year actuarial rates of grade 1 , 2 and 3 GU and GI toxicity respectively were 47.3 , 2.4 and 0 % ; and 40 , 9.3 and 4.7 % . There were no grade 4 or worse acute or late toxicities . 97.6 % of evaluable patients remained free of biochemical failure 36 months post radiotherapy . CONCLUSIONS A 57Gy in 19 daily fraction radiotherapy schedule using 3D conformal radiotherapy for the definitive treatment of localized prostate cancer has acceptable early and late toxicity PURPOSE We prospect ively analyzed quality of life in a cohort of patients with prostate cancer undergoing a course of hypofractionated image guided radiotherapy . MATERIAL S AND METHODS Between August 2006 and January 2011 , 337 patients with a median age of 73 years who had cT1-T2N0M0 prostate cancer were eligible for this prospect i ve , longitudinal study of hypofractionated image guided radiotherapy ( 70.2 Gy/26 fractions ) using 1 of 3 image guided radiotherapy modalities ( transabdominal ultrasound , x-ray or cone beam computerized tomography ) available in our radiation oncology department . Patients completed 4 question naires before treatment , and 6 , 12 and 24 months later , including the International Index of Erectile Function-5 , International Prostate Symptom Score , and EORTC ( European Organization for Research and Treatment of Cancer ) prostate cancer specific QLQ-PR25 and QLQ-C30 . RESULTS Patient followup was up date d to at least the last question naire time point . Median followup was 19 months . Significant deterioration in erectile function on the International Index of Erectile Function-5 was documented with time only in patients without and rogen deprivation ( p = 0.0002 ) . No change with time was observed in urinary symptom related quality of life on the QLQ-PR25 or International Prostate Symptom Score . Slight deterioration in QLQ-PR25 bowel symptom related quality of life was observed ( p = 0.02 ) . Overall QLQ-C30 Global Health Status improved with time ( p = 0.03 ) . On univariate analysis it significantly correlated with the maximum RTOG ( Radiation Therapy Oncology Group)/EORTC urinary and bowel late toxicity scores after radiotherapy . CONCLUSIONS The regimen of hypofractionated image guided radiotherapy with multiple imaging modalities adopted in our radiation oncology department for localized prostate cancer might be a successful strategy for dose escalation with a limited impact on different aspects of quality of life with time PURPOSE The optimal radiation dose fractionation schedule for localized prostate cancer is unclear . This study was design ed to compare two dose fractionation schemes ( a shorter 4-week radiation schedule v a longer 6.5-week schedule ) . PATIENTS AND METHODS Patients with early-stage ( T1 or T2 ) prostate cancer were r and omly assigned to 66 Gy in 33 fractions over 45 days ( long arm ) or 52.5 Gy in 20 fractions over 28 days ( short arm ) . The study was design ed as a noninferiority investigation with a predefined tolerance of -7.5 % . The primary outcome was a composite of biochemical or clinical failure ( BCF ) . Secondary outcomes included presence of tumor on prostate biopsy at 2 years , survival , and toxicity . RESULTS From March 1995 to December 1998 , 936 men were r and omly assigned to treatment ; 470 were assigned to the long arm , and 466 were assigned to the short arm . The median follow-up time was 5.7 years . At 5 years , the BCF probability was 52.95 % in the long arm and 59.95 % in the short arm ( difference = -7.0 % ; 90 % CI , -12.6 % to -1.4 % ) , favoring the long arm . No difference in 2-year postradiotherapy biopsy or in overall survival was detected between the arms . Acute toxicity was found to be slightly higher in the short arm ( 11.4 % ) compared with the long arm ( 7 % ; difference = -4.4 % ; 95 % CI , -8.1 % to -0.6 % ) ; however , late toxicity was similarly low in both arms ( 3.2 % ) . CONCLUSION Given the results , we can not exclude the possibility that the chosen hypofractionated radiation regimen may be inferior to the st and ard regimen . Further evaluation involving higher dose hypofractionated radiation regimens in contemporary radiation setting s is necessary PURPOSE To estimate the late morbidity of a novel , hypofractionated external beam radiotherapy schedule of 55 Gy in 16 fractions ( 4 fractions/week , 3.4 Gy per fraction ) for localized prostate cancer . METHODS AND MATERIAL S A multi-center phase 2 study enrolled seventy-three patients between September 2004 and June 2006 . After insertion of fiducial gold markers , they were treated with image-guidance ( IGRT ) using conformal techniques with intensity-modulation , if necessary , and then followed every 6 months for toxicity rating and PSA . Patient reported outcomes were collected yearly . Median follow up was 4.6 years . RESULTS At 4 years post-radiotherapy , the cumulative incidence of combined urinary and bowel grade 3 toxicity was 7 % ( 95 % CI 3 - 16 % ) and grade 2 + was 33 % ( 95 % CI 24 - 46 % ) . All except two patients recovered from their grade 3 events . Patient-reported reduction of function was most pronounced at year two for urinary function ( mean -7 , SD 16 ) , and at year one for bowel function ( mean -7 , SD 21 ) . The cumulative incidence of biochemical ( PSA nadir+2 ) or biopsy-proven relapse at 4 years was 9 % ( 95 % CI 4 - 18 % ) . CONCLUSIONS Hypofractionated radiotherapy is clinical ly feasible and more convenient than conventional schedules for patients with localized prostate cancer . Phase 3 multicenter studies are on-going ( NCT00126165 ) PURPOSE To evaluate the feasibility and toxicity of stereotactic hypofractionated accurate radiotherapy ( SHARP ) for localized prostate cancer . METHODS AND MATERIAL S A Phase I/II trial of SHARP performed for localized prostate cancer using 33.5 Gy in 5 fractions , calculated to be biologically equivalent to 78 Gy in 2 Gy fractions ( alpha/beta ratio of 1.5 Gy ) . Noncoplanar conformal fields and daily stereotactic localization of implanted fiducials were used for treatment . Genitourinary ( GU ) and gastrointestinal ( GI ) toxicity were evaluated by American Urologic Association ( AUA ) score and Common Toxicity Criteria ( CTC ) . Prostate-specific antigen ( PSA ) values and self-reported sexual function were recorded at specified follow-up intervals . RESULTS The study includes 40 patients . The median follow-up is 41 months ( range , 21 - 60 months ) . Acute toxicity Grade 1 - 2 was 48.5 % ( GU ) and 39 % ( GI ) ; 1 acute Grade 3 GU toxicity . Late Grade 1 - 2 toxicity was 45 % ( GU ) and 37 % ( GI ) . No late Grade 3 or higher toxicity was reported . Twenty-six patients reported potency before therapy ; 6 ( 23 % ) have developed impotence . Median time to PSA nadir was 18 months with the majority of nadirs less than 1.0 ng/mL. The actuarial 48-month biochemical freedom from relapse is 70 % for the American Society for Therapeutic Radiology and Oncology definition and 90 % by the alternative nadir + 2 ng/mL failure definition . CONCLUSIONS SHARP for localized prostate cancer is feasible with minimal acute or late toxicity . Dose escalation should be possible PURPOSE To test the hypothesis that increasing radiation dose delivered to men with early-stage prostate cancer improves clinical outcomes . PATIENTS AND METHODS Men with T1b-T2b prostate cancer and prostate-specific antigen < /= 15 ng/mL were r and omly assigned to a total dose of either 70.2 Gray equivalents ( GyE ; conventional ) or 79.2 GyE ( high ) . No patient received and rogen suppression therapy with radiation . Local failure ( LF ) , biochemical failure ( BF ) , and overall survival ( OS ) were outcomes . Results A total of 393 men were r and omly assigned , and median follow-up was 8.9 years . Men receiving high-dose radiation therapy were significantly less likely to have LF , with a hazard ratio of 0.57 . The 10-year American Society for Therapeutic Radiology and Oncology BF rates were 32.4 % for conventional-dose and 16.7 % for high-dose radiation therapy ( P < .0001 ) . This difference held when only those with low-risk disease ( n = 227 ; 58 % of total ) were examined : 28.2 % for conventional and 7.1 % for high dose ( P < .0001 ) . There was a strong trend in the same direction for the intermediate-risk patients ( n = 144 ; 37 % of total ; 42.1 % v 30.4 % , P = .06 ) . Eleven percent of patients subsequently required and rogen deprivation for recurrence after conventional dose compared with 6 % after high dose ( P = .047 ) . There remains no difference in OS rates between the treatment arms ( 78.4 % v 83.4 % ; P = .41 ) . Two percent of patients in both arms experienced late grade > /= 3 genitourinary toxicity , and 1 % of patients in the high-dose arm experienced late grade > /= 3 GI toxicity . CONCLUSION This r and omized controlled trial shows superior long-term cancer control for men with localized prostate cancer receiving high-dose versus conventional-dose radiation . This was achieved without an increase in grade > /= 3 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 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 The alpha/beta ratio for prostate cancer is postulated to be between 1 and 3 , giving rise to the hypothesis that there may be a therapeutic advantage to hypofractionation . The dosimetry and acute toxicity are described in the first 100 men enrolled in a r and omized trial . PATIENTS AND METHODS The trial compares 76 Gy in 38 fractions ( Arm I ) to 70.2 Gy in 26 fractions ( Arm II ) using intensity modulated radiotherapy . The planning target volume ( PTV ) margins in Arms I and II were 5 mm and 3 mm posteriorly and 8 mm and 7 mm in all other dimensions . The PTV D95 % was at least the prescription dose . RESULTS The mean PTV doses for Arms I and II were 81.1 and 73.8 Gy . There were no differences in overall maximum acute gastrointestinal ( GI ) or genitourinary ( GU ) toxicity acutely . However , there was a slight but significant increase in Arm II GI toxicity during Weeks 2 , 3 , and 4 . In multivariate analyses , only the combined rectal DVH parameter of V65 Gy/V50 Gy was significant for GI toxicity and the bladder volume for GU toxicity . CONCLUSION Hypofractionation at 2.7 Gy per fraction to 70.2 Gy was well tolerated acutely using the planning conditions described PURPOSE To determine prospect ively intermediate-term toxicity and quality of life ( QoL ) of prostate cancer patients after intensity-modulated radiotherapy ( IMRT ) . PATIENTS AND METHODS Fifty-five patients with localized prostate adenocarcinoma were treated by IMRT ( 76 Gy ) . Physicians scored acute and late toxicity using the Common Terminology Criteria for Adverse Events version 3.0 . Patients assessed general and prostate-specific QoL before IMRT ( baseline ) and at 2 , 6 , and 18 months using European Organization for Research and Treatment of Cancer question naires QLQ-C30(+3 ) and QLQ-PR25 . RESULTS Median age was 73 years ( range , 54 - 80 years ) . Risk categories were 18 % low risk , 60 % intermediate risk , and 22 % high risk ; 45 % of patients received hormonal therapy ( median duration , 6 months ) . The incidence of urinary and bowel toxicity immediately after IMRT was , respectively , 38 % and 13 % ( Grade 2 ) and 2 % and none ( Grade 3 ) ; at 18 months it was 15 % and 11 % ( Grade 2 ) and none ( Grade 3 ) . Significant worsening of QoL was reported at 2 months with regard to fatigue ( + 11.31 , p = 1.10(-7 ) ) , urinary symptoms ( + 9.07 , p = 3.10(-11 ) ) , dyspnea ( + 7.27 , p = 0.008 ) , and emotional ( -7.02 , p = 0.002 ) , social ( -6.36 , p = 0.003 ) , cognitive ( -4.85 , p = 0.004 ) , and physical ( -3.39 , p = 0.007 ) functioning . Only fatigue ( + 5.86 , p = 0.003 ) and urinary symptoms ( + 5.86 , p = 0.0004 ) had not improved by 6 months . By 18 months all QoL scores except those for dyspnea ( + 8.02 , p = 0.01 ) and treatment-related symptoms ( + 4.24 , p = 0.01 ) had returned to baseline . These adverse effects were exacerbated by hormonal therapy . CONCLUSION High-dose IMRT with accurate positioning induces only a temporary worsening of PURPOSE To evaluate the toxicity and preliminary outcome of patients with localized prostate cancer treated with twice-weekly hypofractionated intensity-modulated radiotherapy ( IMRT ) . METHODS AND MATERIAL S Between 2003 and 2006 , 82 prostate cancer patients with a nodal involvement risk ≤20 % ( Roach index ) have been treated to the prostate with or without seminal vesicles with 56 Gy ( 4 Gy/fraction twice weekly ) and an overall treatment time of 6.5 weeks . Acute and late genitourinary ( GU ) and gastrointestinal ( GI ) toxicities were scored according to the Radiation Therapy Oncology Group ( RTOG ) grading system . Median follow-up was 48 months ( range , 9 - 67 months ) . RESULTS All patients completed the treatment without interruptions . No patient presented with Grade ≥3 acute GU or GI toxicity . Of the patients , 4 % presented with Grade 2 GU or GI persistent acute toxicity 6 weeks after treatment completion . The estimated 4-year probability of Grade ≥2 late GU and GI toxicity-free survival were 94.2 % ± 2.9 % and 96.1 % ± 2.2 % , respectively . One patient presented with Grade 3 GI and another patient with Grade 4 GU late toxicity , which were transitory in both cases . The 4-year actuarial biochemical relapse-free survival was 91.3 % ± 5.9 % , 76.4 % ± 8.8 % , and 77.5 % ± 8.9 % for low- , intermediate- , and high-risk groups , respectively . CONCLUSIONS In patients with localized prostate cancer , acute and late toxicity were minimal after dose-escalation administering twice-weekly 4 Gy to a total dose of 56 Gy , with IMRT . Further prospect i ve trials are warranted to further assess the best fractionation schemes for these patients PURPOSE To investigate the relationship between late urinary obstruction and the details of the dose distribution of irradiated prostate cancer patients , taking into account their baseline symptoms and acute complaints . PATIENTS AND METHODS We selected patients from the Dutch multicenter trial r and omized between 68 Gy and 78 Gy , for whom toxicity data and dose data were available ( n = 557 ) . The absolute dose surface parameters of the delineated bladder were calculated . Next , we constructed three-dimensional dose maps of the area around the prostate , providing an approximate identification of the corresponding anatomic locations . The dose difference maps were constructed by subtracting the mean dose maps of the patients with and without late urinary obstruction . Selected local dose points were analyzed using Cox regression analysis . RESULTS Urinary obstruction was scored for 40 patients , including 19 of 296 patients who received 68 - 72 Gy and 21 of 261 patients who received 76 - 78 Gy . A total of 19 events occurred within 2 years after irradiation and 21 events after 2 years . The bladder surface receiving > or=80 Gy predicted ( p < .01 ) the occurrence of obstruction within 2 years . The dose difference map indicated highly significant differences in the bladder neck situated in the trigonal region ( p < .001 ) that were especially predictive of obstruction after 2 years and of the diagnosis of bladder neck obstruction . Baseline complaints and transurethral resection of the prostate and acute complaints were mainly predictive for obstruction within 2 years . CONCLUSION Relatively early events of urinary obstruction were associated with urinary problems existing before RT , acute toxicity , previous transurethral resection of the prostate , and hotspots in the bladder . Events after 2 years were associated with the local dose in the trigonal area PURPOSE To determine the effect of radiotherapy dose on prostate cancer patient outcome and biopsy positivity in a phase III trial . PATIENTS AND METHODS A total of 305 stage T1 through T3 patients were r and omized to receive 70 Gy or 78 Gy of external-beam radiotherapy between 1993 and 1998 . Of these , 301 were assessable ; stratification was based on pretreatment prostate-specific antigen level ( PSA ) . Dose was prescribed to the isocenter at 2 Gy per fraction . All patients underwent planning pelvic computed tomography scan to confirm prostate position . Treatment failure was defined as an increasing PSA on three consecutive follow-up visits or the initiation of salvage treatment . Median follow-up was 40 months . RESULTS One hundred fifty patients were r and omized to the 70-Gy arm and 151 to the 78-Gy arm . The difference in freedom from biochemical and /or disease failure ( FFF ) rates of 69 % and 79 % for the 70-Gy and 78-Gy groups , respectively , at 5 years was marginally significant ( log-rank P : = .058 ) . Multiple-covariate Cox proportional hazards regression showed that the study r and omization was an independent correlate of FFF , along with pretreatment PSA , Gleason score , and stage . The patients who benefited most from the 8-Gy dose escalation were those with a pretreatment PSA of more than 10 ng/mL ; 5-year FFF rates were 48 % and 75 % ( P : = .011 ) for the 70-Gy and 78-Gy arms , respectively . There was no difference between the arms ( approximately 80 % 5-year FFF ) when the pretreatment PSA was < or = 10 ng/mL. CONCLUSION A modest dose increase of 8 Gy using conformal radiotherapy result ed in a substantial improvement in prostate cancer FFF rates for patients with a pretreatment PSA of more than 10 ng/mL. These findings document that local persistence of prostate cancer in intermediate- to high-risk patients is a major problem when doses of 70 Gy or less are used PURPOSE Proton beam therapy ( PBT ) is theoretically an excellent modality for external beam radiotherapy , providing an ideal dose distribution . However , it is not clear whether PBT for prostate cancer can clinical ly control toxicities . The purpose of the present study was to estimate prospect ively the incidence of late rectal toxicities after PBT for organ-confined prostate cancer . METHODS AND MATERIAL S The major eligibility criteria included clinical Stage T1-T2N0M0 ; initial prostate-specific antigen level of ≤20 ng/mL and Gleason score ≤7 ; no hormonal therapy or hormonal therapy within 12 months before registration ; and written informed consent . The primary endpoint was the incidence of late Grade 2 or greater rectal toxicity at 2 years . Three institutions in Japan participated in the present study after institutional review board approval from each . PBT was delivered to a total dose of 74 GyE in 37 fractions . The patients were prospect ively followed up to collect the data on toxicities using the National Cancer Institute-Common Toxicity Criteria , version 2.0 . RESULTS Between 2004 and 2007 , 151 patients were enrolled in the present study . Of the 151 patients , 75 , 49 , 9 , 17 , and 1 had Stage T1c , T2a , T2b , T2c , and T3a , respectively . The Gleason score was 4 , 5 , 6 , and 7 in 5 , 15 , 80 and 51 patients , respectively . The initial prostate-specific antigen level was < 10 or 10 - 20 ng/mL in 102 and 49 patients , respectively , and 42 patients had received hormonal therapy and 109 had not . The median follow-up period was 43.4 months . Acute Grade 2 rectal and bladder toxicity temporarily developed in 0.7 % and 12 % , respectively . Of the 147 patients who had been followed up for > 2 years , the incidence of late Grade 2 or greater rectal and bladder toxicity was 2.0 % ( 95 % confidence interval , 0 - 4.3 % ) and 4.1 % ( 95 % confidence interval , 0.9 - 7.3 % ) at 2 years , respectively . CONCLUSION The results of the present prospect i ve study have revealed a valuable piece of evidence that PBT for localized prostate cancer can achieve a low incidence of late Grade 2 or greater rectal toxicities 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 is the first report of toxicity outcomes at dose Level V ( 78 Gy ) on Radiation Therapy Oncology Group 9406 for Stages T1-T2 adenocarcinoma of the prostate . METHODS AND MATERIAL S A total of 225 patients were entered in this cooperative group , Phase I-II dose-escalation trial of three-dimensional conformal radiotherapy for localized carcinoma of the prostate treated to a dose of 78 Gy ( Level V ) . Of these patients , 219 were analyzed for acute and 218 for late toxicity . A minimum of 2 Gy/fraction was prescribed to the planning target volume ( PTV ) . Patients were stratified according to the risk of seminal vesicle invasion as determined by Gleason score and presenting prostate-specific antigen level . Group 1 patients had clinical Stages T1-T2 tumors with a seminal vesicle invasion risk of < 15 % . Group 2 patients had clinical Stages T1-T2 tumors with a seminal vesicle invasion risk of > /=15 % . Patients in Group 1 were prescribed 78 Gy to a prostate PTV . Patients in Group 2 were prescribed 54 Gy to the prostate and seminal vesicles ( PTV1 ) followed by a boost to the prostate only ( PTV2 ) to 78 Gy . PTV margins of between 5 and 10 mm were required . The average time at risk for late Grade 3 + toxicity after therapy completion was 23.2 and 23.1 months for Groups 1 and 2 , respectively . The frequency of Grade 3 or worse late effects was compared with a similar group of patients treated in Radiation Therapy Oncology Group ( RTOG ) studies 7506 and 7706 , with length of follow-up adjustments made for the interval from therapy completion . A second comparison was made with 170 patients treated to dose Level III ( 79.2 Gy in 1.8 Gy/fraction ) to see whether the fraction size affected toxicity . Unlike other dose levels , patients treated at dose Level III had treatment prescribed as a minimum to the gross tumor volume . This effectively lowered the volume of the rectum treated to the study dose . RESULTS Acute toxicity at dose Level V ( 78 Gy ) was remarkably low , with Grade 3 acute effects reported in only 4 % of Group 1 and 2 % of Group 2 patients . No Grade 4 or 5 acute toxicity was reported . There was no statistically significant difference in rates of acute toxicities in patients who were treated to 79.2 Gy at 1.8 Gy/fraction or 78 Gy at 2.0 Gy/fraction . Late toxicity continues to be low compared with RTOG historical controls . The observed rate of Grade 3 or worse late effects for Group 1 ( 6 cases ) was significantly lower ( p = 0.0042 ) than the 18.2 cases that would have been expected from the historical control . The observed rate for Group 2 ( 8 cases ) was lower than the 15.5 cases expected , but this difference was not statistically significant ( p = 0.06 ) . A trend was noted that Group 2 patients treated on dose Level V had more late Grade 3 or worse toxicity than patients treated to a similar dose on Level III ( 7 % vs. 1 % , p = 0.06 ) . A significantly ( p < 0.0001 ) greater incidence of late Grade 2 or greater toxicity occurred in patients treated at dose Level V ( 30 % and 33 % for Groups 1 and 2 , respectively ) than at dose Level III ( 13 % and 9 % for Groups 1 and 2 , respectively ) . The longer follow-up at dose Level III suggests these differences may increase with additional follow-up . CONCLUSION Tolerance to three-dimensional conformal radiotherapy with 78 Gy in 2-Gy fractions remains better than expected compared with historical controls . The magnitude of any effect from fraction size and treatment volume requires additional follow-up PURPOSE To evaluate acute and late genitourinary ( GU ) and gastrointestinal ( GI ) toxicity and biochemical control of hypofractionated , image-guided ( fiducial markers or ultrasound guidance ) , simplified intensity-modulated arc therapy for localized prostate cancer . METHODS AND MATERIAL S This Phase II prospect i ve clinical trial for T1a-2cNXM0 prostate cancer enrolled 66 patients who received 63.2 Gy in 20 fractions over 4 weeks . Fiducial markers were used for image guidance in 30 patients and daily ultrasound for the remainder . Toxicity was scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 . RESULTS Median follow-up was 36 months . Acute Phase Grade 2 and 3 toxicity was 34 % and 9 % for GU vs. 25 % and 10 % for GI symptoms . One Grade 4 acute GI toxicity occurred in a patient with unrecognized Crohn 's disease . Late Grade 2 and 3 toxicity for GU was 14 % and 5 % , and GI toxicity was 25 % and 3 % . One late GI Grade 4 toxicity was observed in a patient with significant comorbidities ( anticoagulation , vascular disease ) . Acute GI toxicity ≥ Grade 2 was shown to be a predictor for late toxicity Grade ≥ 2 ( p < 0.001 ) . The biochemical disease-free survival at 3 years was 95 % . CONCLUSIONS Hypofractionated simplified intensity-modulated arc therapy radiotherapy given as 63.2 Gy in 20 fractions demonstrated promising biochemical control rates ; however , higher rates of acute Grade 3 GU and GI toxicity and higher late Grade 2 GU and GI toxicity were noted . Ongoing r and omized controlled trials should ultimately clarify issues regarding patient selection and the true rate of severe toxicity that can be directly attributed to hypofractionated radiotherapy |
1,986 | 20,031,903 | Left-sided CE is consistently associated with higher postoperative adverse event rates . | BACKGROUND Studies suggest that the side of carotid endarterectomy ( CE ) may influence the rate of postoperative complications .
We sought to clarify this by ( 1 ) analysis of individual-level data from 3 large studies and ( 2 ) systematic review and meta- analysis of additional published descriptions of outcomes by side . | Although the incidence of carotid atheromatous disease is presumably equal between the right and left carotid arteries , right and left carotid endarterectomies ( CEs ) may not be performed with equal frequency on the two sides . This study sought to examine whether right and left CEs are performed with equal frequency and whether there are any differences in outcome between these groups . Detailed chart review was performed on all CEs performed from 1979 through 1998 at our institution , and those lacking side data were excluded . Data were collected on the side of the procedure , demographics , comorbid conditions , details of the procedure , hospital stay , and major complications . The surgeons performing CE were surveyed about their practice of considering side factors . CE was performed on the left in 1190 ( 52 % ) of 2305 procedures ; 1115 ( 48 % ) of the procedures were right CEs . This difference is statistically significant ( P = 0.014 ) . No significant differences in demographics , comorbidity , presence of symptoms before surgery , length of stay , or postoperative morbidity or mortality between the left and right groups were found . A majority of the surgeons surveyed indicated they do consider the relationship of side of the carotid disease to the patient 's dominant side . The significant difference in the performance of left CE more often than right has not been previously reported . This may reflect willingness by surgeons to intervene more frequently in carotid disease on the side supplying the dominant hemisphere . A prospect i ve CE outcome study that identifies the side of CE and the patient 's dominant side is needed for further exploration of this issue BACKGROUND The objective of this study was to assess whether carotid endarterectomy is an appropriate treatment for patients with recent cerebrovascular events in the territory supplied by a moderately stenosed ( 30 - 69 % ) internal carotid artery . Results have previously been reported for severe ( 70 - 99 % ) and mild ( 0 - 29 % ) stenosis . METHODS A multicentre r and omised controlled trial recruited 1599 patients with moderate stenosis treated in 97 hospitals from 15 countries . 60 % of patients were allocated to receive and 40 % to avoid carotid endarterectomy . The analysis was by intention to treat . FINDINGS Nine patients were omitted from the analysis because no follow-up data were received . Stroke-free life expectancy ( curtailed at 8 years ) was shorter in the surgery patients than in the non-surgery control groups ( patients with 30 - 49 % stenosis , life expectancy = 6.16 years [ controls : 6.63 years ] ; patients with 50 - 69 % stenosis , life expectancy = 5.93 [ 6.14 ] years ) . It remains possible that patients might derive some benefit from surgery in the very long term ; however , our data show that no benefit would be gained over a period of < 4 - 5 years in patients with 50 - 69 % stenosis and < 6 - 7 years in patients with 30 - 49 % stenosis . INTERPRETATION Previous interim results from this study showed that surgery is beneficial in patients with severe stenosis but harmful in those with mild stenosis . With more r and omised patients and longer follow-up , the study now shows that endarterectomy is not indicated for most , possibly all , patients with moderate symptomatic carotid stenosis BACKGROUND AND PURPOSE This study reports the surgical results in those patients who underwent carotid endarterectomy in the North American Symptomatic Carotid Endarterectomy Trial ( NASCET ) . METHODS The rates of perioperative stroke and death at 30 days and the final assessment of stroke severity at 90 days were calculated . Regression modeling was used to identify variables that increased or decreased perioperative risk . Non outcome surgical complications were summarized . The durability of carotid endarterectomy was examined . RESULTS In 1415 patients there were 92 perioperative outcome events , for an overall rate of 6.5 % . At 30 days the results were as follows : death , 1.1 % ; disabling stroke , 1.8 % ; and nondisabling stroke , 3.7 % . At 90 days , because of improvement in the neurological status of patients judged to have been disabled at 30 days , the results were as follows : death , 1.1 % ; disabling stroke , 0.9 % ; and nondisabling stroke , 4.5 % . Thirty events occurred intraoperatively ; 62 were delayed . Most strokes result ed from thromboembolism . Five baseline variables were predictive of increased surgical risk : hemispheric versus retinal transient ischemic attack as the qualifying event , left-sided procedure , contralateral carotid occlusion , ipsilateral ischemic lesion on CT scan , and irregular or ulcerated ipsilateral plaque . History of coronary artery disease with prior cardiac procedure was associated with reduced risk . The risk of perioperative wound complications was 9.3 % , and that of cranial nerve injuries was 8.6 % ; most were of mild severity . At 8 years , the risk of disabling ipsilateral stroke was 5.7 % , and that of any ipsilateral stroke was 17.1 % . CONCLUSIONS The overall rate of perioperative stroke and death was 6.5 % , but the rate of permanently disabling stroke and death was only 2.0 % . Other surgical complications were rarely clinical ly important . Carotid endarterectomy is a durable procedure The Feasibility And Safety Trial for its embolic protection device during transluminal intervention in coronary vessels : a European Registry ( FASTER ) was design ed to demonstrate that ( 1 ) the Proxis embolic protection system can control antero grade flow and reverse blood flow in native coronary arteries and saphenous vein grafts ; and ( 2 ) this system can capture embolic debris . Percutaneous coronary intervention on stenotic coronary lesions revolutionized treatment of coronary disease , but is associated with the risk of major adverse cardiac events . This prospect i ve , nonr and omized , multicenter clinical feasibility and safety study enrolled 40 patients with 51 lesions at 4 centers who underwent treatment of stenotic lesions with proximal emboli protection ( Proxis system ) . Proxis was successfully used 95 % of the time , and embolic debris was qualitatively identified in all cases . Major adverse cardiac events occurred in 2 patients ( 5.0 % ) : 1 late in-stent thrombosis result ing in death and 1 non-Q-wave infa rct ion when a lesion was crossed before deployment of the Proxis system . Mean vessel occlusion time was 4.3 + /- 2.4 minutes . Native flow reversal was sufficient in 31 patients , with a mean aspirate volume of 11.8 + /- 6.5 ml . When the infusion catheter was used to augment reflow , mean occlusion time was 4.6 minutes . In conclusion , this trial is the first to demonstrate that retro grade blood flow can be achieved during proximal occlusion and that the Proxis system can be used safely during intervention of saphenous vein grafts and native coronary arterial lesions to capture embolic material BACKGROUND The efficacy of carotid endarterectomy for selected patients has been evaluated with r and omized controlled clinical trials . The generalizability of these studies to average surgical practice remains an important public health concern . OBJECTIVE The objective of the study was to determine the predictors of outcome after carotid endarterectomy on a regional basis . PATIENTS AND METHODS The study was design ed as a retrospective cohort study and included all consecutive patients presented for carotid endarterectomy at the 8 University of Toronto-affiliated hospitals in the period from January 1 , 1994 , to December 31 , 1996 . The main outcome measure was 30-day postoperative stroke or death rate . RESULTS During the study interval , 1280 primary carotid endarterectomies were performed . The overall combined stroke and death rate was 6.3 % for all patients who underwent endarterectomy ( 4.0 % for patients who were asymptomatic ) . The significant predictors of poor outcome were the following : presenting symptoms ( odds ratio , 1.74 ; 95 % confidence interval [ CI ] , 0.96 , 3.12 ) , low surgeon volume ( < 6 cases per year ; odds ratio , 3.98 ; 95 % CI , 1.65 , 9.58 ) , and left-sided surgery ( odds ratio , 1.72 ; 95 % CI , 1.07 , 2.76 ) . CONCLUSION These data suggest that adoption of the recommendations of the symptomatic carotid endarterectomy trials is appropriate . However , endarterectomy for asymptomatic lesions remains of uncertain benefit on a regional basis and must be individualized to the experience of the specific surgeon . The surgeon volume/ outcome relationship that is identified in this study suggests a need for a minimum volume threshold for this procedure BACKGROUND Without strong evidence of benefit , the use of carotid endarterectomy for prophylaxis against stroke rose dramatically until the mid-1980s , then declined . Our investigation sought to determine whether carotid endarterectomy reduces the risk of stroke among patients with a recent adverse cerebrovascular event and ipsilateral carotid stenosis . METHODS We conducted a r and omized trial at 50 clinical centers throughout the United States and Canada , in patients in two predetermined strata based on the severity of carotid stenosis--30 to 69 percent and 70 to 99 percent . We report here the results in the 659 patients in the latter stratum , who had had a hemispheric or retinal transient ischemic attack or a nondisabling stroke within the 120 days before entry and had stenosis of 70 to 99 percent in the symptomatic carotid artery . All patients received optimal medical care , including antiplatelet therapy . Those assigned to surgical treatment underwent carotid endarterectomy performed by neurosurgeons or vascular surgeons . All patients were examined by neurologists 1 , 3 , 6 , 9 , and 12 months after entry and then every 4 months . End points were assessed by blinded , independent case review . No patient was lost to follow-up . RESULTS Life-table estimates of the cumulative risk of any ipsilateral stroke at two years were 26 percent in the 331 medical patients and 9 percent in the 328 surgical patients --an absolute risk reduction ( + /- SE ) 17 + /- 3.5 percent ( P less than 0.001 ) . For a major or fatal ipsilateral stroke , the corresponding estimates were 13.1 percent and 2.5 percent -- an absolute risk reduction of 10.6 + /- 2.6 percent ( P less than 0.001 ) . Carotid endarterectomy was still found to be beneficial when all strokes and deaths were included in the analysis ( P less than 0.001 ) . CONCLUSIONS Carotid endarterectomy is highly beneficial to patients with recent hemispheric and retinal transient ischemic attacks or nondisabling strokes and ipsilateral high- grade stenosis ( 70 to 99 percent ) of the internal carotid artery BACKGROUND Our objective was to assess the risks and benefits of carotid endarterectomy , primarily in terms of stroke prevention , in patients with recently symptomatic carotid stenosis . METHODS This multicentre , r and omised controlled trial enrolled 3024 patients . We enrolled men and women of any age , with some degree of carotid stenosis , who within the previous 6 months had had at least one transient or mild symptomatic ischaemic vascular event in the distribution of one or both carotid arteries . Between 1981 and 1994 , we allocated 1811 ( 60 % ) patients to surgery and 1213 ( 40 % ) to control ( surgery to be avoided for as long as possible ) . Follow-up was until the end of 1995 ( mean 6.1 years ) , and the main analyses were by intention to treat . FINDINGS The overall outcome ( major stroke or death ) occurred in 669 ( 37.0 % ) surgery-group patients and 442 ( 36.5 % ) control-group patients . The risk of major stroke or death complicating surgery ( 7.0 % ) did not vary substantially with severity of stenosis . On the other h and , the risk of major ischaemic stroke ipsilateral to the unoperated symptomatic carotid artery increased with severity of stenosis , particularly above about 70 - 80 % of the original luminal diameter , but only for 2 - 3 years after r and omisation . On average , the immediate risk of surgery was worth trading off against the long-term risk of stroke without surgery when the stenosis was greater than about 80 % diameter ; the Kaplan-Meier estimate of the frequency of a major stroke or death at 3 years was 26.5 % for the control group and 14.9 % for the surgery group , an absolute benefit from surgery of 11.6 % . However , consideration of variations in risk with age and sex modified this simple rule based on stenosis severity . We present a graphical procedure that should improve the selection of patients for surgery . INTERPRETATION Carotid endarterectomy is indicated for most patients with a recent non-disabling carotid-territory ischaemic event when the symptomatic stenosis is greater than about 80 % . Age and sex should also be taken into account in decisions on whether to operate OBJECTIVES Neurologic complications during carotid artery stenting ( CAS ) are most clearly associated with embolization of visible debris . Distal filter devices may provide cerebral protection by capturing clinical ly significant debris . However , they increase procedural time and expense and have their own set of complications . The current study was undertaken to identify the clinical factors predictive for the presence or absence of visible debris captured by distal filter devices during CAS . METHODS Patients undergoing CAS with use of a distal filter device ( n = 279 ) were prospect ively entered into an investigational carotid registry . Recorded variables were classified as patient- , lesion- , or procedure-related . The filter was assessed for visible debris in each case . The odds ratio ( OR ) and 95 % confidence interval ( CI ) were determined for each variable to predict visible debris . The ability of each variable to predict the absence of visible debris was assessed by calculating the individual negative predictive value ( NPV ) . RESULTS Visible debris was present in 169 filters ( 60.3 % ) . There was an increased risk of visible debris found with several variables ( OR , 95 % CI ) : hypertension ( 2.9 , 1.7 to 5.2 ) , hypercholesterolemia ( 2.3 , 1.4 to 3.9 ) , stent diameter > 9 mm ( 16.6 , 9.0 to 30.0 ) , and any neurologic event ( 4.2 , 1.5 to 9.9 ) . The NPV failed to exceed 0.80 ( 80 % ) for any variable . The NPV of the variables with a significantly elevated OR was as follows : hypertension ( 0.60 ) , hypercholesterolemia ( 0.52 ) , stent diameter > 9 mm ( 0.75 ) , and any neurologic event ( 0.38 ) . CONCLUSIONS Several clinical variables are associated with the presence of visible debris captured by distal filter devices . The current study failed to identify any variables capable of consistently predicting the absence of visible debris . These findings support the routine rather than the selective use of cerebral protection during CAS BACKGROUND Endarterectomy benefits certain patients with carotid stenosis , but benefits are lessened by perioperative surgical risk . Acetylsalicylic acid lowers the risk of stroke in patients who have experienced transient ischaemic attack and stroke . We investigated appropriate doses and the role of acetylsalicylic acid in patients undergoing carotid endarterectomy . METHODS In a r and omised , double-blind , controlled trial , 2849 patients scheduled for endarterectomy were r and omly assigned 81 mg ( n=709 ) , 325 mg ( n=708 ) , 650 mg ( n=715 ) , or 1300 mg ( n=717 ) acetylsalicylic acid daily , started before surgery and continued for 3 months . We recorded occurrences of stroke , myocardial infa rct ion , and death . We compared patients on the two higher doses of acetylsalicylic acid with patients on the two lower doses . FINDINGS Surgery was cancelled in 45 patients , none were lost to follow-up by 30 days , and two were lost by 3 months . The combined rate of stroke , myocardial infa rct ion , and death was lower in the low-dose groups than in the high-dose groups at 30 days ( 5.4 vs 7.0 % , p=0.07 ) and at 3 months ( 6.2 vs 8.4 % , p=0.03 ) . In an efficacy analysis , which excluded patients taking 650 mg or more acetylsalicylic acid before r and omisation , and patients r and omised within 1 day of surgery , combined rates were 3.7 % and 8.2 % , respectively , at 30 days ( p=0.002 ) and 4.2 % and 10.0 % at 3 months ( p=0.0002 ) . INTERPRETATION The risk of stroke , myocardial infa rct ion , and death within 30 days and 3 months of endarterectomy is lower for patients taking 81 mg or 325 mg acetylsalicylic acid daily than for those taking 650 mg or 1300 mg A r and omised controlled trial of endarterectomy in patients with carotid artery disease showed that operation significantly reduced the frequency of transient ischaemic attacks ( TIA ) in the relevant vascular territory . Because of the high post-operative morbidity in the surgical group , the trial was ab and oned before conclusions could be drawn as to the influence of endarterectomy on long-term survival or on the incidence of subsequent strokes The European Carotid Surgery Trial is a multicentre trial of carotid endarterectomy for patients who , after a carotid territory non-disabling ischaemic stroke , transient ischaemic attack , or retinal infa rct , are found to have a stenotic lesion in the relevant ( ipsilateral ) carotid artery . Over the past 10 years 2518 patients have been r and omised , and the mean follow-up is now almost 3 years among the 2200 thus far available for analysis of the incidence of strokes that lasted more than 7 days . For the patients with " moderate " ( 30 - 69 % ) stenosis on their prer and omisation angiogram the balance of surgical risk and eventual benefit remains uncertain , and full recruitment continues . For 374 patients with only " mild " ( 0 - 29 % ) stenosis there was little 3-year risk of ipsilateral ischaemic stroke , even in the absence of surgery , so any 3-year benefits of surgery were small , and were outweighed by its early risks . For 778 patients with " severe " ( 70 - 99 % ) stenosis , however , the risks of surgery were significantly outweighed by the later benefits : although 7.5 % had a stroke ( or died ) within 30 days of surgery , during the next 3 years the risks of ipsilateral ischaemic stroke were ( by life-table analysis ) an extra 2.8 % for surgery-allocated and 16.8 % for control patients ( a sixfold reduction , p less than 0.0001 ) . There was also a small reduction in other strokes , and at 3 years the total risk of surgical death , surgical stroke , ipsilateral ischaemic stroke , or any other stroke was 12.3 % for surgery and 21.9 % for control ( difference 9.6 % SD 3.3 , 2p less than 0.01 ) . The main concern was to avoid disabling or fatal events , and , among severe stenosis patients , 3.7 % had a disabling stroke ( or died ) within 30 days of surgery , an extra 1.1 % surgery versus 8.4 % control ( p less than 0.0001 ) had a disabling or fatal ipsilateral ischaemic stroke by 3 years , and the total 3-year risk of any disabling or fatal stroke ( or surgical death ) was 6.0 % surgery versus 11.0 % control ( overall difference 5.0 % SD 2.3 , 2p less than 0.05 ) ; but , for disabling or fatal stroke the control risks seemed to diminish after the first year , so delay of surgery by just a few months after clinical presentation might make this overall difference non-significant |
1,987 | 27,055,486 | Advantageous dosimetric and outcome patterns using ART was documented by the studies of this review .
Despite this , clinical implementations were scarce due to challenges in target/organ re-contouring and suboptimal patient selection in the ART workflows | UNLABELLED Introdution : Variation in shape , position and treatment response of both tumor and organs at risk are major challenges for accurate dose delivery in radiotherapy .
Adaptive radiotherapy ( ART ) has been proposed to customize the treatment to these motion/response patterns of the individual patients , but increases workload and thereby challenges clinical implementation .
This paper review s strategies and workflows for clinical and in silico implemented ART for prostate , bladder , gynecological ( gyne ) and ano-rectal cancers . | 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 Abstract The urinary bladder shows considerable individual variation in shape and position during a course of radiotherapy ( RT ) . In this study we have developed and compared three different adaptive RT ( ART ) strategies for bladder cancer involving daily cone beam CT ( CBCT ) imaging and plan selection . Material and methods . Ten patients treated for bladder cancer had daily CBCTs acquired that were registered online using bony anatomy registration . Seven patients received intensity modulated RT ( IMRT ) with a simultaneous integrated boost ( SIB ) technique to the bladder and pelvic lymph nodes . Three patients received treatment to the bladder only . Retrospectively , we compared three ART strategies that were all based on daily selection of the most suitable plan from a library consisting of three IMRT-plans corresponding to a small , medium and large target volume . ART method A utilised population -based margins while methods B and C used the bladder as seen on CBCT-scans from the first week of treatment ; method B without delineation of the bladder on CBCT and method C with delineation of the bladder . Total dose distributions were calculated using the planning CT . For each patient , we calculated ratios of the dose volume histograms ( DVHs ) for the three ART strategies relative to non-adaptive therapy . Results . The inter-patient variation was large for all three ART strategies . The mean ratios of the volumes receiving 57 Gy or more ( corresponding to 95 % of prescribed dose ) for methods A , B and C were 0.66 ( SD : 0.11 ) , 0.67 ( SD : 0.13 ) and 0.67 ( SD : 0.16 ) respectively when compared to the non-adaptive plan . Conclusion . When using any of the ART strategies , it is possible to reduce significantly the volumes receiving high doses compared to the use of a st and ard non-adaptive plan . The differences in dose volume parameters between the three methods were small compared with the differences from the st and ard plan Background To analyse the overall clinical outcome and benefits by applying protocol based image guided adaptive brachytherapy combined with 3D conformal external beam radiotherapy ( EBRT ) ± chemotherapy ( ChT ) . Methods Treatment schedule was EBRT with 45–50.4 Gy ± concomitant cisplatin chemotherapy plus 4 × 7 Gy High Dose Rate ( HDR ) brachytherapy . Patients were treated in the “ protocol period ” ( 2001–2008 ) with the prospect i ve application of the High Risk CTV concept ( D90 ) and dose volume constraints for organs at risk including biological modelling . Dose volume adaptation was performed with the aim of dose escalation in large tumours ( prescribed D90 > 85 Gy ) , often with inserting additional interstitial needles . Dose volume constraints ( D2cc ) were 70–75 Gy for rectum and sigmoid and 90 Gy for bladder . Late morbidity was prospect ively scored , using LENT/SOMA Score . Disease outcome and treatment related late morbidity were evaluated and compared using actuarial analysis . Findings One hundred and fifty-six consecutive patients ( median age 58 years ) with cervix cancer FIGO stages IB – IVA were treated with definitive radiotherapy in curative intent . Histology was squamous cell cancer in 134 patients ( 86 % ) , tumour size was > 5 cm in 103 patients ( 66 % ) , lymph node involvement in 75 patients ( 48 % ) . Median follow-up was 42 months for all patients . Interstitial techniques were used in addition to intracavitary brachytherapy in 69/156 ( 44 % ) patients . Total prescribed mean dose ( D90 ) was 93 ± 13 Gy , D2cc 86 ± 17 Gy for bladder , 65 ± 9 Gy for rectum and 64 ± 9 Gy for sigmoid . Complete remission was achieved in 151/156 patients ( 97 % ) . Overall local control at 3 years was 95 % ; 98 % for tumours 2–5 cm , and 92 % for tumours > 5 cm ( p = 0.04 ) , 100 % for IB , 96 % for IIB , 86 % for IIIB . Cancer specific survival at 3 years was overall 74 % , 83 % for tumours 2–5 cm , 70 % for tumours > 5 cm , 83 % for IB , 84 % for IIB , 52 % for IIIB . Overall survival at 3 years was in total 68 % , 72 % for tumours 2–5 cm , 65 % for tumours > 5 cm , 74 % for IB , 78 % for IIB , 45 % for IIIB . In regard to late morbidity in total 188 grade 1 + 2 and 11 grade 3 + 4 late events were observed in 143 patients . G1 + 2/G3 + 4 events for bladder were n = 32/3 , for rectum n = 14/5 , for bowel ( including sigmoid ) n = 3/0 , for vagina n = 128/2 , respectively . Interpretation 3D conformal radiotherapy ± chemotherapy plus image ( MRI ) guided adaptive intracavitary brachytherapy including needle insertion in advanced disease results in local control rates of 95–100 % at 3 years in limited/favourable ( IB/IIB ) and 85–90 % in large/poor response ( IIB/III/IV ) cervix cancer patients associated with a moderate rate of treatment related morbidity . Compared to the historical Vienna series there is relative reduction in pelvic recurrence by 65–70 % and reduction in major morbidity . The local control improvement seems to have impact on CSS and OS . Prospect i ve clinical multi-centre studies are m and atory to evaluate these challenging mono-institutional findings Abstract Background . The first Nordic protocol for three-dimensional ( 3D ) planned radiotherapy in locally advanced cervical cancer was the prospect i ve NOCECA study ( 1994–2000 ) . NOCECA consisted of computed tomography (CT)-based 3D conformal external beam radiotherapy ( EBRT ) with a simultaneous integrated boost ( SIB ) to the primary tumour combined with brachytherapy ( BT ) based on x-ray imaging . In NOCECA the planning aim was to achieve 80 Gy at point A from EBRT and BT combined . However , the balance of dose between EBRT and BT was determined by tumour size at diagnosis with more EBRT dose given to point A and less by BT in more advanced stages . In 2005 image-guided adaptive brachytherapy ( IGABT ) based on magnetic resonance imaging ( MRI ) and optimisation of the BT dose distribution to the remaining tumour and cervix at time of BT ( HR CTV ) was introduced in Aarhus . EBRT remained like in NOCECA until 2008 when the SIB to the primary tumour was ab and oned and IMRT was introduced as routine technique . In this study , we report outcome of our first five-year experience with IGABT using our NOCECA cohort as reference . Material and methods . The NOCECA cohort comprising 99 patients was compared with 140 consecutive patients treated by IGABT . Patients with para-aortic nodes were excluded in NOCECA but were present in 9 % of the patients treated with IGABT . No patient in NOCECA received chemotherapy whereas concomitant cisplatin was given to 79 % of the IGABT patients . Results . With IGABT actuarial local control was 91 % at three years . When comparing NOCECA with IGABT overall survival was significantly improved from 63 % to 79 % ( p = 0.005 ) . In parallel , both moderate and severe late morbidity were reduced by about 50 % ( p = 0.02 ) . Conclusion . Introduction of IGABT reduced morbidity and generated a very high rate of local control , which likely has improved survival by at least as much as concomitant chemotherapy PURPOSE Report of clinical cancer control outcomes on Radiation Therapy Oncology Group ( RTOG ) 9406 , a three-dimensional conformal radiation therapy ( 3D-CRT ) dose escalation trial for localized adenocarcinoma of the prostate . METHODS AND MATERIAL S RTOG 9406 is a Phase I/II multi-institutional dose escalation study of 3D-CRT for men with localized prostate cancer . Patients were registered on five sequential dose levels : 68.4 Gy , 73.8 Gy , 79.2 Gy , 74 Gy , and 78 Gy with 1.8 Gy/day ( levels I-III ) or 2.0 Gy/day ( levels IV and V ) . Neoadjuvant hormone therapy ( NHT ) from 2 to 6 months was allowed . Protocol -specific , American Society for Therapeutic Radiation Oncology ( ASTRO ) , and Phoenix biochemical failure definitions are reported . RESULTS Thirty-four institutions enrolled 1,084 patients and 1,051 patients are analyzable . Median follow-up for levels I , II , III , IV , and V was 11.7 , 10.4 , 11.8 , 10.4 , and 9.2 years , respectively . Thirty-six percent of patients received NHT . The 5-year overall survival was 90 % , 87 % , 88 % , 89 % , and 88 % for dose levels I-V , respectively . The 5-year clinical disease-free survival ( excluding protocol prostate-specific antigen definition ) for levels I-V is 84 % , 78 % , 81 % , 82 % , and 82 % , respectively . By ASTRO definition , the 5-year disease-free survivals were 57 % , 59 % , 52 % , 64 % and 75 % ( low risk ) ; 46 % , 52 % , 54 % , 56 % , and 63 % ( intermediate risk ) ; and 50 % , 34 % , 46 % , 34 % , and 61 % ( high risk ) for levels I-V , respectively . By the Phoenix definition , the 5-year disease-free survivals were 68 % , 73 % , 67 % , 84 % , and 80 % ( low risk ) ; 70 % , 62 % , 70 % , 74 % , and 69 % ( intermediate risk ) ; and 42 % , 62 % , 68 % , 54 % , and 67 % ( high risk ) for levels I-V , respectively . CONCLUSION Dose-escalated 3D-CRT yields favorable outcomes for localized prostate cancer . This multi-institutional experience allows comparison to other experiences with modern radiation therapy This study compares three online image guidance techniques ( IGRT ) for prostate IMRT treatment : bony-anatomy matching , soft-tissue matching , and online replanning . Six prostate IMRT patients were studied . Five daily CBCT scans from the first week were acquired for each patient to provide representative " snapshots " of anatomical variations during the course of treatment . Initial IMRT plans were design ed for each patient with seven coplanar 15 MV beams on a Eclipse treatment planning system . Two plans were created , one with a PTV margin of 10 mm and another with a 5 mm PTV margin . Based on these plans , the delivered dose distributions to each CBCT anatomy was evaluated to compare bony-anatomy matching , soft-tissue matching , and online replanning . Matching based on bony anatomy was evaluated using the 10 mm PTV margin ( " bone10 " ) . Soft-tissue matching was evaluated using both the 10 mm ( " soft10 " ) and 5 mm ( " soft5 " ) PTV margins . Online reoptimization was evaluated using the 5 mm PTV margin ( " adapt " ) . The replanning process utilized the original dose distribution as the basis and linear goal programming techniques for reoptimization . The reoptimized plans were finished in less than 2 min for all cases . Using each IGRT technique , the delivered dose distribution was evaluated on all 30 CBCT scans ( 6 patients x 5 CBCT/patient ) . The mean minimum dose ( in percentage of prescription dose ) to the CTV over five treatment fractions were in the ranges of 99%-100 % ( SD = 0.1%-0.8 % ) , 65%-98 % ( SD = 0.4%-19.5 % ) , 87%-99 % ( SD = 0.7%-23.3 % ) , and 95%-99 % ( SD = 0.4%-10.4 % ) for the adapt , bone10 , soft5 , and soft10 techniques , respectively . Compared to patient position correction techniques , the online reoptimization technique also showed improvement in OAR sparing when organ motion/deformations were large . For bladder , the adapt technique had the best ( minimum ) D90 , D50 , and D30 values for 24 , 17 , and 15 fractions out of 30 total fractions , while it also had the best D90 , D50 , and D30 values for the rectum for 25 , 16 , and 19 fractions , respectively . For cases where the adapt plans did not score the best for OAR sparing , the gains of the OAR sparing in the repositioning-based plans were accompanied by an underdosage in the target volume . To further evaluate the fast online replanning technique , a gold-st and ard plan ( " new " plan ) was generated for each CBCT anatomy on the Eclipse treatment planning system . The OAR sparing from the online replanning technique was compared to the new plan . The differences in D90 , D50 , and D30 of the OARs between the adapt and the new plans were less than 5 % in 3 patients and were between 5 % and 10 % for the remaining three . In summary , all IGRT techniques could be sufficient to correct simple geometrical variations . However , when a high degree of deformation or differential organ position displacement occurs , the online reoptimization technique is feasible with less than 2 min optimization time and provides improvements in both CTV coverage and OAR sparing over the position correction techniques . For these cases , the reoptimization technique can be a highly valuable online IGRT tool to correct daily treatment uncertainties , especially when hypofractionation scheme is applied and daily correction , rather than averaging over many fractions , is required to match the original plan PURPOSE In 2005 a French multicentric non r and omized prospect i ve study was initiated to compare two groups of patients treated for cervix carcinoma according to brachytherapy ( BT ) method : 2D vs 3D dosimetry . The BT dosimetric planning method was chosen for each patient in each center according to the availability of the technique . This study describes the results for 705 out of 801 patients available for analysis . PATIENTS AND METHODS For the 2D arm , dosimetry was planned on orthogonal X-Rays using low dose rate ( LDR ) or pulsed dose rate ( PDR ) BT . For the 3D arm , dosimetry was planned on 3D imaging ( mainly CT ) and performed with PDR BT . Each center could follow the dosimetric method they were used to , according to the chosen radioelement and applicator . Manual or graphical optimization was allowed . PATIENTS AND METHODS Three treatment regimens were defined : Group 1 : BT followed by surgery ; 165 patients ( 2D arm : 76 ; 3D arm : 89 ) ; Group 2 : EBRT ( + chemotherapy ) , BT , then surgery ; 305 patients ( 2D arm : 142 ; 3D arm : 163 ) ; Group 3 : EBRT ( + chemotherapy ) , then BT ; 235 patients , ( 2D arm : 118 ; 3D arm : 117 ) . PATIENTS AND METHODS The DVH parameters for CTVs ( High Risk CTV and Intermediate Risk CTV ) and organs at risk ( OARs ) were computed as recommended by GYN GEC ESTRO guidelines . Total doses were converted to equivalent doses in 2Gy fractions ( EQD2 ) . Side effects were prospect ively assessed using the CTCAEv3.0 . RESULTS The 2D and 3D arms were well balanced with regard to age , FIGO stage , histology , EBRT dose and chemotherapy . For each treatment regimen , BT doses and volumes were comparable between the 2D and 3D arms in terms of dose to point A , isodose 60 Gy volume , dose to ICRU rectal points , and TRAK . RESULTS Dosimetric data in the 3D arm showed that the dose delivered to 90 % of the High Risk CTV ( HR CTV D90 ) was respectively , 81.2Gy(α/β10 ) , 63.2Gy(α/β10 ) and 73.1Gy(α/β10 ) for groups 1 , 2 and 3 . The Intermediate Risk ( IR ) CTV D90 was respectively , 58.5Gy(α/β10 ) , 57.3Gy(α/β10 ) and 61.7Gy(α/β10 ) for groups 1 , 2 and 3 . For the OARs , doses delivered to D2cc ranged 60 - 70Gy(α/β3 ) for the bladder , 33 - 61Gy(α/β3 ) for the rectum , and 44 - 58Gy(α/β3 ) for the sigmoid according to the regimen . RESULTS At 24 months , local relapse-free survival was 91.9 % and 100 % in group 1 , 84.7 % and 93 % in group 2 , 73.9 % and 78.5 % in group 3 ; grade 3 - 4 toxicity rate was 14.6 % and 8.9 % in group 1 , 12.5 % and 8.8 % in group 2 , and 22.7 % and 2.6 % in group 3 for 2D and 3D arm . CONCLUSION This multicentric study has shown that 3D BT is feasible and safe in routine practice . It has improved local control with half the toxicity observed with 2D dosimetry . The combined treatment with radiotherapy and surgery was more toxic than definitive radiotherapy . For patients with advanced tumors , it is necessary to improve coverage of target volumes without raising toxicity PURPOSE To evaluate the validity of the chosen adaptive radiotherapy ( ART ) dose-volume constraints while testing the hypothesis that toxicity would not be greater at higher tumor dose levels . MATERIAL S AND METHODS In the ART dose escalation/ selection trial , treatment was initiated with a generic planning target volume ( PTV ) formed as a 1-cm expansion of the clinical target volume ( CTV ) . After the first week of therapy , the patient was replanned with a patient-specific PTV , constructed with CT and electronic portal images obtained in the first 4 days of treatment . A new multileaf collimator beam aperture was used . A minimum dose prescribed to the patient-specific PTV , ranging 70.2 - 79.2 Gy , was determined on the basis of the following rectal and bladder constraints : < 5 % of the rectal wall has a dose > 82 Gy , < 30 % of the rectal wall has a dose > 75.6 Gy , < 50 % of the bladder volume has a dose > 75.6 Gy , and the maximum bladder dose is 85 Gy . A conformal four-field and /or intensity-modulated radiotherapy ( IMRT ) technique was used . Independent review ers scored toxicities . The worst toxicity score seen was used as per the Common Toxicity Criteria grade scale ( version 2 ) . We divided the patients into three separate groups : 70.2 - 72 Gy , > 72 - 75.6 Gy , and > 75.6 - 79.2 Gy . Toxicities in each group were quantified and compared by the Pearson chi-squared test to vali date our dose escalation/ selection model . Grade s 0 , 1 , 2 , and 3 were censored as none vs. each category and none vs. any . RESULTS We analyzed patients with follow-up greater than 1 year . The mean duration of follow-up was 29 months ( range , 12 - 46 months ) . We report on 280 patients , mean age 72 years ( range , 51 - 87 years ) . Only 60 patients received adjuvant hormones . Mean pretreatment prostate-specific antigen level was 9.3 ng/mL ( range , 0.6 - 120 ng/mL ) . Mean Gleason score was 6 ( range , 3 - 9 ) . The lowest dose level was given to 49 patients , the intermediate dose to 131 patients , and 100 patients received the highest dose escalation . One hundred eighty-one patients ( 65 % ) were treated to a prostate field only and 99 patients ( 35 % ) to prostate and seminal vesicles . Chronic genitourinary and /or gastrointestinal categories were incontinence , persistent urinary retention , increased urinary frequency/urgency , urethral stricture , hematuria , diarrhea , rectal pain , bleeding , ulcer , fistula , incontinence , and proctitis . Toxicity at the high dose level was not different from toxicity at the intermediate or lower dose levels . No significant difference was observed in any of the individual toxicity categories . CONCLUSIONS By applying the ART process -- namely , developing a patient-specific PTV -- to prostate cancer patients , significant dose escalation can be achieved without increases in genitourinary or gastrointestinal toxicity . Our data vali date the rectal and bladder dose-volume constraints chosen for our three-dimensional conformal and IMRT prostrate radiotherapy planning In this paper , an adaptive radiation therapy algorithm is derived and evaluated using numerical simulations . Patient setup errors are considered and an off-line adaptive method to compensate for the effect of these is provided . The method consists of two parts , one for correction of patient position to account for the systematic error , and one for modulation of the fluence profiles to account for the r and om errors . The method is based on st and ard control theory for linear systems . It is investigated if this adaptive method can replace the use of a planning target volume ( PTV ) and therefore increase the possibilities to escalate the dose . Numerical simulations of treatments of a prostate patient indicate that this is the case . The simulations show that better organ-at-risk protection can be achieved when using the adaptation algorithm to correct for the geometrical uncertainties than when using a PTV We investigated if an adaptive radiotherapy approach based on cone beam CT ( CBCT ) acquired during radical treatment was feasible and result ed in improved dosimetric outcomes for bladder cancer patients compared to conventional planning and treatment protocol . A secondary aim was to compare a conventional plan with a theoretical online process where positioning is based on soft tissue position on a daily basis and treatment plan choice is based on bladder size . A conventional treatment plan was derived from a planning CT scan in the radical radiotherapy of five patients with muscle invasive bladder cancer . In this offline adaptive protocol using CBCT , the patients had 10 CBCT : daily CBCT for the first five fractions and then CBCT scan on a weekly basis . The first five daily CBCT in each patient were used to create a single adaptive plan for treatment from fraction eight onwards . A different process using the planning CT and the first five daily CBCT was used to create small , average and large bladder volumes , giving rise to small , average and large adaptive bladder treatment plans , respectively . In a retrospective analysis using the CBCT scans , we compared the clinical target volume ( CTV ) coverage using three protocol s : ( i ) conventional ; ( ii ) offline adaptive ; and ( iii ) online adaptive with choice of ' plan of the day ' . Daily CBCT prolonged treatment time by an average of 7 min . Two of the five patients demonstrated such variation in CTV that an offline adaptive plan was used for treatment after the first five CBCT . Comparing the offline adaptive plan with the conventional plan , the CTV coverage improved from a minimum of 60.1 to 94.7 % in subsequent weekly CBCT . Using the CBCT data , modelling an online adaptive protocol showed that coverage of the CTV by the 95 % prescribed dose line by small , medium and large adaptive plans were 34.9 , 67.4 and 90.7 % of occasions , respectively . More normal tissue was irradiated using a conventional CTV to planning target volume margin ( 1.5 cm ) compared to an online adaptive process ( 0.5 cm ) . An offline adaptive strategy improves dose coverage in certain patients to the CTV and results in a higher conformity index compared to conventional planning . Further research in online adaptive radiation therapy for bladder cancer is indicated PURPOSE Using daily setup variation measured from an electronic portal imaging device ( EPID ) , radiation treatment of the individual patient can be adaptively reoptimized during the course of therapy . In this study , daily portal images were retrospectively examined to : ( a ) determine the number of initial days of portal imaging required to give adequate prediction of the systematic and r and om setup errors ; and ( b ) explore the potential of using the prediction as feedback to reoptimize the individual treatment part-way through the treatment course . METHODS AND MATERIAL S Daily portal images of 64 cancer patients , whose treatment position was not adjusted during the course of treatment , were obtained from two independent clinics with similar setup procedures . Systematic and r and om setup errors for each patient were predicted using different numbers of initial portal measurements . The statistical confidence of the predictions was tested to determine the number of daily portal measurements needed to give reasonable predictions . Two treatment processes were simulated to examine the potential opportunity for setup margin reduction and dose escalation . The first process mimicked a conventional treatment . A constant margin was assigned to each treatment field to compensate for the average setup error of the patient population . A treatment dose was then prescribed with reference to a fixed normal tissue tolerance , and then fixed in the entire course of treatment . In the second process , the same treatment fields and prescribed dose were used only for the initial plan and treatment . After several initial days of treatments , the treatment field shape and position were assumed to be adaptively modified using a computer-controlled multileaf collimator ( MLC ) in light of the predicted systematic and r and om setup errors . The prescribed dose was then escalated until the same normal tissue tolerance , as determined in the first treatment process , was reached . RESULTS The systematic setup error and the r and om setup error were predicted to be within + /-1 mm for the former and + /-0.5 mm for the latter at a > or = 95 % confidence level using < or = 9 initial daily portal measurements . In the study , a large number of patients could be treated using a smaller field margin if the adaptive modification process were used . Simulation of the adaptive modification process for prostate treatment demonstrates that additional treatment dose could be safely applied to 64 % of patients . CONCLUSION The adaptive modification process represents a different approach for use of on-line portal images . The portal imaging information from the initial treatments is used as feedback for reoptimization of the treatment plan , rather than adjustment of the treatment setup . Results from the retrospective study show that the treatment of individual patient can be improved with the adaptive modification process PURPOSE To investigate the clinical feasibility of magnetic resonance image-guided adaptive brachytherapy ( IGABT ) for patients with locally advanced vaginal cancer and to report treatment outcomes . METHODS AND MATERIAL S Thirteen patients with vaginal cancer were treated with external beam radiotherapy ( 45 - 50.4 Gy ) plus IGABT with or without chemotherapy . Distribution of International Federation of Gynecology and Obstetrics stages among patients were as follows : 4 patients had Stage II cancer , 5 patients had Stage III cancer , and 4 patients had Stage IV cancer . The concept of IGABT as developed for cervix cancer was transferred and adapted for vaginal cancer , with corresponding treatment planning and reporting . Doses were converted to the equivalent dose in 2 Gy , applying the linear quadratic model ( α/β = 10 Gy for tumor ; α/β = 3 for organs at risk ) . Endpoints studied were gross tumor volume ( GTV ) , dose-volume parameters for high-risk clinical target volume ( H RCT V ) , and organs at risk , local control ( LC ) , adverse side effects , and survival . RESULTS The mean GTV ( ± 1 st and ard deviation ) at diagnosis was 45.3 ( ±30 ) cm(3 ) , and the mean GTV at brachytherapy was 10 ( ±14 ) cm(3 ) . The mean D90 for the H RCT V was 86 ( ±13 ) Gy . The mean D2cc for bladder , urethra , rectum , and sigmoid colon were 80 ( ±20 ) Gy , 76 ( ±16 ) Gy , 70 ( ±9 ) Gy , and 60 ( ±9 ) Gy , respectively . After a median follow-up of 43 months ( range , 19 - 87 months ) , one local recurrence and two distant metastases cases were observed . Actuarial LC and overall survival rates at 3 years were 92 % and 85 % . One patient with Stage IVA and 1 patient with Stage III disease experienced fistulas ( one vesicovaginal , one rectovaginal ) , and 1 patient developed periurethral necrosis . CONCLUSIONS The concept of IGABT , originally developed for treating cervix cancer , appears to be applicable to vaginal cancer treatment with only minor adaptations . Dose-volume parameters for H RCT V and organs at risk are in a comparable range . First clinical results indicate excellent LC . Further prospect i ve multicenter studies are needed to establish this method and to confirm these results PURPOSE To evaluate the first clinical results of an off-line adaptive radiotherapy ( ART ) protocol for prostate cancer using kilovoltage cone-beam computed tomography ( CBCT ) in combination with a diet and mild laxatives . METHODS AND MATERIAL S Twenty-three patients began treatment with a planning target volume ( PTV ) margin of 10 mm . The CBCT scans acquired during the first six fractions were used to generate an average prostate clinical target volume ( AV-CTV ) , and average rectum ( AV-Rect ) . Using these structures , a new treatment plan was generated with a 7-mm PTV margin . Weekly CBCT scans were used to monitor the CTV coverage . A diet and mild laxatives were introduced to improve image quality and reduce prostate motion . RESULTS Twenty patients were treated with conform ART protocol . For these patients , 91 % of the CBCT scans could be used to calculate the AV-CTV and AV-Rect . In 96 % of the follow-up CBCT scans , the CTV was located within the average PTV . In the remaining 4 % , the prostate extended the PTV by a maximum of 1 mm . Systematic and r and om errors for organ motion were reduced by a factor of two compared with historical data without diet and laxatives . An average PTV reduction of 29 % was achieved . The volume of the AV-Rect that received > 65 Gy was reduced by 19 % . The mean dose to the anal wall was reduced on average by 4.8 Gy . CONCLUSIONS We safely reduced the high-dose region by 29 % . The reduction in irradiated volume led to a significant reduction in the dose to the rectum . The diet and laxatives improved the image quality and tended to reduce prostate motion PURPOSE To improve the efficacy of dose delivery and dose escalation for external beam radiotherapy of prostate cancer , an off-line strategy for constructing a patient-specific planning target volume is developed in the adaptive radiotherapy process using image feedback of target location and patient setup position . MATERIAL S AND METHODS We hypothesize that a patient-specific confidence-limited planning target volume ( cl-PTV ) , constructed using an initial sequence of daily measurements of internal target motion and patient setup error , exists and ensures that the clinical target volume ( CTV ) in the prostate cancer patient receives the prescribed dose within a predefined dose tolerance . A patient-specific bounding volume to correct for target location and compensate for target r and om motion was first constructed using the convex hull of the first k days of CT measurements . The bounding volume and the initial days of CT measurements were minimized based on a predefined dosimetric criterion . The hypothesis was tested using multiple daily CT images by mimicking the actual treatment of both conventional 4-field-box and intensity-modulated radiotherapy ( IMRT ) on each of 30 patients with prostate cancer . For each patient , a patient-specific setup margin was also applied to the bounding volume to form the final cl-PTV . This margin was determined using the r and om setup error predicted from the initial days of portal imaging measurements and the residuals after correcting for the systematic setup error . RESULTS The bounding volume constructed using daily CT measurements in the first week of treatment are adequate for the conventional beam delivery to achieve maximum dose reduction in the CTV of 2 % or less of the prescription dose , for at least 80 % of patients ( p = 0.08 ) , and 4.5 % or less for 95 % of patients ( p = 0.1 ) . However , for IMRT delivery , 2 weeks of daily CT measurements are required to achieve a similar level of the dosimetric criterion , otherwise the maximum dose reduction of 7 % , on average , in the CTV is expected . Furthermore , the patient-specific setup margin required for the IMRT treatment is at least twice larger than that for the conventional treatment , to maintain the same dosimetric criterion . As compared to the conventional PTV , the volume of cl-PTV is significantly reduced , while maintaining the same dosimetric criterion . CONCLUSION The cl-PTV for prostate treatment can be constructed within the first week of treatment using the feedback of imaging measurements . The cl-PTV has the capability to exclude the systematic variation and compensate for the patient-specific r and om variation on target location and patient setup position . This implies that in the current off-line image feedback adaptive treatment process , a single plan modification can be performed within the second week of treatment to improve the efficacy of dose delivery and dose escalation for external beam therapy of prostate cancer 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 Substantial organ motion and tumor shrinkage occur during radiotherapy for cervix cancer . IMRT planning studies have shown that the quality of radiation delivery is influenced by these anatomical changes , therefore the adaptation of treatment plans may be warranted . Image guidance with off-line replanning , i.e. hybrid-adaptation , is recognized as one of the most practical adaptation strategies . In this study , we investigated the effects of soft tissue image guidance using on-line MR while varying the frequency of off-line replanning on the adaptation of cervix IMRT . MATERIAL S AND METHOD 33 cervical cancer patients underwent planning and weekly pelvic MRI scans during radiotherapy . 5 patients of 33 were identified in a previous retrospective adaptive planning study , in which the coverage of gross tumor volume/ clinical target volume ( GTV/CTV ) was not acceptable given single off-line IMRT replan using a 3 mm PTV margin with bone matching . These 5 patients and a r and omly selected 10 patients from the remaining 28 patients , a total of 15 patients of 33 , were considered in this study . Two matching methods for image guidance ( bone to bone and soft tissue to dose matrix ) and three frequencies of off-line replanning ( none , single , and weekly ) were simulated and compared with respect to target coverage ( cervix , GTV , lower uterus , parametrium , upper vagina , tumor related CTV and elective lymph node CTV ) and OAR sparing ( bladder , bowel , rectum , and sigmoid ) . Cost ( total process time ) and benefit ( target coverage ) were analyzed for comparison . RESULTS Hybrid adaptation ( image guidance with off-line replanning ) significantly enhanced target coverage for both 5 difficult and 10 st and ard cases . Concerning image guidance , bone matching was short of delivering enough doses for 5 difficult cases even with a weekly off-line replan . Soft tissue image guidance proved successful for all cases except one when single or more frequent replans were utilized in the difficult cases . Cost and benefit analysis preferred ( soft tissue ) image guidance over ( frequent ) off-line replanning . CONCLUSIONS On-line MRI based image guidance ( with combination of dose distribution ) is a crucial element for a successful hybrid adaptive radiotherapy . Frequent off-line replanning adjuvantly enhances adaptation quality PURPOSE To quantify the potential margin reduction with adaptive radiotherapy ( ART ) during neo-adjuvant treatment of locally-advanced rectal cancer . METHODS AND MATERIAL S Repeat CT scans were acquired for 28 patients treated with 25 × 2 Gy , daily during the first week , and followed by weekly scans . The CTV was delineated on all scans , and shape variation was estimated . Five ART strategies were tested , consisting of an average CTV over the planning CT and one to five repeat CTs . Required PTV margins were calculated for adapted and non-adapted treatment . The strategy with the least PTV volume over the whole treatment was selected and bowel area dose reduction was estimated . RESULTS Substantial systematic and r and om shape variation dem and ed for a PTV margin up to 2.4 cm at the upper-anterior part of the CTV . Plan adaptation after fraction 4 result ed in a maximum 0.7 cm margin reduction and a significant PTV reduction from 1185 to 1023 cc ( p<0.0001 ) . The bowel area volume receiving 15 , 45 , and 50 Gy was reduced from 436 to 402 cc , 111 to 81 cc , and 49 to 29 cc , respectively ( p<0.0001 ) . CONCLUSIONS With adaptive radiotherapy , maximum required PTV margins can be reduced from 2.4 to 1.7 cm , result ing in significantly less dose to the bowel area The second part of the GYN GEC ESTRO working group recommendations is focused on 3D dose-volume parameters for brachytherapy of cervical carcinoma . Methods and parameters have been developed and vali date d from dosimetric , imaging and clinical experience from different institutions ( University of Vienna , IGR Paris , University of Leuven ) . Cumulative dose volume histograms ( DVH ) are recommended for evaluation of the complex dose heterogeneity . DVH parameters for GTV , HR CTV and IR CTV are the minimum dose delivered to 90 and 100 % of the respective volume : D90 , D100 . The volume , which is enclosed by 150 or 200 % of the prescribed dose ( V150 , V200 ) , is recommended for overall assessment of high dose volumes . V100 is recommended for quality assessment only within a given treatment schedule . For Organs at Risk ( OAR ) the minimum dose in the most irradiated tissue volume is recommended for reporting : 0.1 , 1 , and 2 cm3 ; optional 5 and 10 cm3 . Underlying assumptions are : full dose of external beam therapy in the volume of interest , identical location during fractionated brachytherapy , contiguous volumes and contouring of organ walls for > 2 cm3 . Dose values are reported as absorbed dose and also taking into account different dose rates . The linear-quadratic radiobiological model-equivalent dose (EQD2)-is applied for brachytherapy and is also used for calculating dose from external beam therapy . This formalism allows systematic assessment within one patient , one centre and comparison between different centres with analysis of dose volume relations for GTV , CTV , and OAR . Recommendations for the transition period from traditional to 3D image-based cervix cancer brachytherapy are formulated . Supplementary data ( available in the electronic version of this paper ) deals with aspects of 3D imaging , radiation physics , radiation biology , dose at reference points and dimensions and volumes for the GTV and CTV ( adding to [ Haie-Meder C , Pötter R , Van Limbergen E et al. Recommendations from Gynaecological ( GYN ) GEC ESTRO Working Group ( I ) : concepts and terms in 3D image-based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV . Radiother Oncol 2005;74:235 - 245 ] ) . It is expected that the therapeutic ratio including target coverage and sparing of organs at risk can be significantly improved , if radiation dose is prescribed to a 3D image-based CTV taking into account dose volume constraints for OAR . However , prospect i ve use of these recommendations in the clinical context is warranted , to further explore and develop the potential of 3D image-based cervix cancer brachytherapy PURPOSE The purpose of this comparative prospect i ve study was to assess the effect of CT and MR based individualisation and adaptation on the dose distribution in the target volume and organs at risk compared to a radiography based procedure . MATERIAL AND METHODS In 15 patients MR scans , in 10 patients additional axial CT-scans with compatible tube-ring applicator in situ were performed and digitally transferred to the PLATO(R ) planning system . Considering clinical examination and MR-scan before radiotherapy individual 3-D dose distribution was calculated and adapted based on ( 1 ) two orthogonal radiographs ; ( 2 ) isodoses superimposed on the CT images ; and ( 3 ) isodoses superimposed on the MR images . Adaptation was strictly limited by the dose level at 2 cm(3 ) bladder or rectum volume ( D(2 ) ) to allow comparison of CT and MR plans . All three individualised dose distributions were superimposed on the MR images and cumulative dose-volume histograms were calculated for comparison . RESULTS 3-D individualisation based on sectional imaging enabled higher dose to the target volume ( isodose enclosing 95 % of the CTV = CTV(95 ) ) compared to individualised treatment plans based on orthogonal radiographs by a mean factor of 1.2 ( 1 - 1.7 ) . The dose to bladder and /or rectum wall was at the same time not increased beyond the prescribed tolerance level ( 71 % of the prescribed target dose ) . In a subgroup of 10 patients MRI based treatment plans were superior to CT based treatment plans allowing for a higher dose ( 138 % vs. 124 % ) . CONCLUSION Sectional imaging based treatment planning , in particular using MR , was superior to radiography allowing for a clinical meaningful dose escalation without increasing the dose to bladder and rectum beyond the tolerance level PURPOSE The widespread use of intensity modulated radiation therapy ( IMRT ) for cervical cancer has been limited by internal target and normal tissue motion . Such motion increases the risk of underdosing the target , especially as planning margins are reduced in an effort to reduce toxicity . This study explored 2 adaptive strategies to mitigate this risk and proposes a new , automated method that minimizes replanning workload . METHODS AND MATERIAL S Thirty patients with cervical cancer participated in a prospect i ve clinical study and underwent pretreatment and weekly magnetic resonance ( MR ) scans over a 5-week course of daily external beam radiation therapy . Target volumes and organs at risk ( OARs ) were contoured on each of the scans . Deformable image registration was used to model the accumulated dose ( the real dose delivered to the target and OARs ) for 2 adaptive replanning scenarios that assumed a very small PTV margin of only 3 mm to account for setup and internal interfractional motion : ( 1 ) a preprogrammed , anatomy-driven midtreatment replan ( A-IMRT ) ; and ( 2 ) a dosimetry-triggered replan driven by target dose accumulation over time ( D-IMRT ) . RESULTS Across all 30 patients , clinical ly relevant target dose thresholds failed for 8 patients ( 27 % ) if 3-mm margins were used without replanning . A-IMRT failed in only 3 patients and also yielded an additional small reduction in OAR doses at the cost of 30 replans . D-IMRT assured adequate target coverage in all patients , with only 23 replans in 16 patients . CONCLUSIONS A novel , dosimetry-triggered adaptive IMRT strategy for patients with cervical cancer can minimize the risk of target underdosing in the setting of very small margins and substantial interfractional motion while minimizing programmatic workload and cost PURPOSE Adaptive Radiation Therapy ( ART ) is a feedback treatment process that optimizes a patient 's treatment according to the patient specific information measured during the course of treatment . Utilizing an electronic portal imaging device ( EPID ) and a computer-controlled multileaf collimator ( MLC ) , the ART process is currently being implemented in our clinic to improve the treatment accuracy by compensating for the treatment setup error . A prospect i ve study was conducted to evaluate the feasibility and efficacy of the ART process for clinical use . METHODS AND MATERIAL S The prospect i ve study included 20 patients who underwent conventional radiotherapy on a linear accelerator equipped with an EPID and a MLC . No specific changes were made in the routine clinical procedures except daily portal images were obtained for each treatment field . Two-dimensional setup error for each treatment field was then measured offline using a software tool . The measured setup errors from initial treatment days were used to predict the systematic and r and om setup errors for each treatment field . An adjustment decision was made if the predicted systematic error was larger than or equal to 2 mm . Furthermore , the treatment field was extended if the predicted r and om setup error could not be effectively compensated by the predefined treatment setup margin . Instead of the conventional approach of patient repositioning , setup adjustment was implemented by reshaping the MLC field . The entire process from measuring setup error to reshaping the MLC field was performed offline through a computer network . After completion of a patient 's treatment , the systematic and r and om setup errors after adjustment were compared with those predicted prior to the adjustment . The accuracy of the adjustment , and the reliability and stability of the process were analyzed . RESULTS Treatment fields of 13 patients were modified to correct for systematic errors . The mean systematic error was 4 mm with a range of 2 to 7 mm before adjustment . It was reduced to 0.5 mm with a range of 0.2 to 1.4 mm after adjustment . There was no significant difference in r and om setup errors before and after adjustment . The ART process was found to be stable , as more than 95 % of patient specific setup margins were predictable within 1 mm using the first four to nine fractions of treatment , confirming the feasibility of treatment plan reoptimization with the ART process . CONCLUSIONS The prospect i ve study demonstrates that the ART process can be effectively implemented in routine clinical practice to improve treatment accuracy . This process is also ready to be further extended to reoptimize the treatment plan by incorporating the predicted patient specific setup variation PURPOSE Advances in technology allow the creation of complex treatment plans with tightly conforming doses . However , variations in positioning of the organ/patient with respect to treatment beams necessitate the use of an appreciable margin , potentially limiting dose escalation in many patients . To ( 1 ) reduce this margin and ( 2 ) test the hypothesis that the achievable level of dose escalation is patient dependent , a patient-specific , confidence-limited planning target volume ( cl-PTV ) was constructed using an adaptive radiotherapy ( ART ) process for prostate cancer treatment developed in-house . The potential dose escalation achievable with this ART process is quantified for both conformal radiotherapy ( CRT ) delivery and intensity-modulated radiotherapy ( IMRT ) delivery . MATERIAL AND METHODS Patients with organ confined prostate cancer were entered prospect ively into an ART process developed in-house . This ART process has been design ed to improve accuracy and precision of dose delivery , consequently enhancing dose escalation . In this process , a cl-PTV is constructed for each patient in the second week of treatment based upon on-line portal and CT images acquired during the first week of treatment . The treatment prescription dose , defined as the minimum dose to the cl-PTV , is selected based on predefined dose-volume constraints for rectum/bladder and derived from the pretreatment planning CT image . In addition , the treatment modality ( CRT or IMRT ) is determined based on the level of dose escalation achievable and the risk of inaccurate targeting . The potential for both dose escalation and the application of IMRT was evaluated by comparing the prescription doses delivered using the ART process , with the cl-PTV , to those in the traditional treatment process , with a conventional generic PTV . In addition , the distributions of potential geometric target underdosing and normal tissue overdosing were also calculated to evaluate the quality of the conventional treatment plans . RESULTS One hundred and fifty patients have been treated with the ART process . When compared to the treatment dose delivered with the conventional treatment process ( generic PTV ) , an average 5 % ( 2.5 - -10 % ) more dose could be delivered using the ART process with CRT , and 7.5 % ( 2.5 - -15 % ) more dose could be delivered with IMRT . Of the 150 patients , 70 % were treated to a minimum cl-PTV dose > or = 77.4 Gy ( 81.3 Gy ICRU isocenter dose ) . Dosimetric analysis revealed that 81 Gy to the cl-PTV ( or 86.7 Gy ICRU ) could be prescribed to at least 50 % of patients if IMRT was applied using the ART process . In contrast , IMRT did not yield an obvious dose escalation gain if patients were treated using the generic PTV . Our results also demonstrate that the cl-PTV is significantly smaller than the conventional generic PTV for most patients , with a mean volume reduction of 24 % ( range , 5 - -43 % ) . CONCLUSION These results support our hypothesis that the achievable level of dose escalation using ART is patient dependent . By using the ART process to develop a cl-PTV , one can ( 1 ) optimize the dose level , ( 2 ) increase the applicability of IMRT , and ( 3 ) improve the quality of dose delivery . The ART process provides the foundation to identify a suitable option ( CRT or IMRT ) for the delivery of a safe treatment and dose escalation . It is now our st and ard of practice for prostate cancer treatment Abstract Background . Patients with urinary bladder cancer often display large changes in the shape and size of their bladder target during a course of radiotherapy ( RT ) , making adaptive RT ( ART ) appealing for this tumour site . We are conducting a clinical phase II trial of daily plan selection -based ART for bladder cancer and here report dose-volume data from the first 20 patients treated in the trial . Material and methods . All patients received 60 Gy in 30 fractions to the bladder ; in 13 of the patients the pelvic lymph nodes were simultaneously treated to 48 Gy . Daily patient set-up was by use of cone beam computed tomography ( CBCT ) guidance . The first 5 fractions were delivered with large , population -based ( non-adaptive ) margins . The bladder contours from the CBCTs acquired in the first 4 fractions were used to create a patient-specific library of three plans , corresponding to a small , medium and large size bladder . From fraction 6 , daily online plan selection was performed , where the smallest plan covering the bladder was selected prior to each treatment delivery . A total of 600 treatment fractions in the 20 patients were evaluated . Results . Small , medium and large size plans were used almost equally often , with an average of 10 , 9 and 11 fractions , respectively . The median volume ratio of the course-averaged PTV ( PTV-ART ) relative to the non-adaptive PTV was 0.70 ( range : 0.46–0.89 ) . A linear regression analysis showed a 183 cm3 ( CI 143–223 cm3 ) reduction in PTV-ART compared to the non-adaptive PTV ( R2 = 0.94 ) . Conclusion . Daily adaptive plan selection in RT of bladder cancer results in a considerable normal tissue sparing , of a magnitude that we expect will translate into a clinical ly significant reduction of the treatment-related morbidity PURPOSE To describe and quantify bladder movement during radical radiation therapy ( RT ) . To attempt to identify factors that predict for excessive alterations in bladder position . To use the above information to assist in defining the " adequate " planning target volume margin . METHODS AND MATERIAL S Thirty patients with bladder cancer suitable for radical courses of RT were followed prospect ively . Patients had an initial planning computerized tomography ( CT ) scan of the pelvis and three subsequent scans performed weekly during the treatment period . The following measurements were made on each scan in the midbladder slice : maximum anteroposterior ( AP ) and lateral bladder dimensions , AP rectal diameter , and the distance ( margin ) between the bladder walls ( anterior , posterior , right , and left lateral ) and the 95 % isodose line . Various patient and tumor data , including bladder and bowel symptoms , were recorded to attempt correlation with bladder movement . RESULTS Bladder size : the median bladder size ( area ) over all scans in all patients was 36.9 cm2 ( range : 16.2 to 80.9 cm2 ) . The change in bladder area across each sequence varied from 3.3 to 29.1 cm2 ( 7 - 55 % change in area between scans ) . Patients with bladders of larger than the median size on the planning scan ( despite emptying ) were more likely to have alteration in size than those with small bladders , and this change was in the direction of contraction ( p = 0.01 ) . Bladder displacement : bladder wall movement of > 1.5 cm was defined as " significant . " Eighteen of 30 patients ( 60 % ) demonstrated " significant " movement of at least one bladder wall relative to the original isodose plot . Movement result ing in margin reduction occurred in 10 patients ( 33 % ) . Two patients required treatment replanning due to consistently altered bladder position . There was no pattern to displacement through RT , and all walls were at approximately equal risk of movement . Factors influencing bladder movement : posterior bladder wall movement appeared to relate to " marked " ( > 2 cm ) rectal diameter change . There was a trend for patients with larger amounts of residual bladder tumor ( greater than the median ) to exhibit more bladder movement ; 11 of 14 " moved " compared with 7 of 16 patients with less residual tumor . Other clinical factors including age , sex , body size , acute RT reaction , and tumor stage did not appear to relate to bladder movement . CONCLUSION Bladder movement during RT is clinical ly relevant and is r and om with respect to both time and direction . We recommend , at least with respect to tumor-bearing regions of the bladder , that no less than a 2.0 cm margin should be allowed PURPOSE In our Phase II prostate cancer Adaptive Radiation Therapy ( ART ) study , the highest possible dose was selected on the basis of normal tissue tolerance constraints . We analyzed rectal toxicity rates in different dose levels and treatment groups to determine whether equivalent toxicity rates were achieved as hypothesized when the protocol was started . METHODS AND MATERIAL S From 1999 to 2002 , 331 patients with clinical stage T1 to T3 , node-negative prostate cancer were prospect ively treated with three-dimensional conformal adaptive RT . A patient-specific confidence-limited planning target volume was constructed on the basis of 5 CT scans and 4 sets of electronic portal images after the first 4 days of treatment . For each case , the rectum ( rectal solid ) was contoured in its entirety . The rectal wall was defined by use of a 3-mm wall thickness ( median volume : 29.8 cc ) . The prescribed dose level was chosen using the following rectal wall dose constraints : ( 1 ) Less than 30 % of the rectal wall volume can receive more than 75.6 Gy . ( 2 ) Less than 5 % of the rectal wall can receive more than 82 Gy . Low-risk patients ( PSA < 10 , Stage < or = T2a , Gleason score < 7 ) were treated to the prostate alone ( Group 1 ) . All other patients , intermediate and high risk , where treated to the prostate and seminal vesicles ( Group 2 ) . The risk of chronic toxicity ( NCI Common Toxicity Criteria 2.0 ) was assessed for the different dose levels prescribed . HIC approval was acquired for all patients . Median follow-up was 1.6 years . RESULTS Grade 2 chronic rectal toxicity was experienced by 34 patients ( 10 % ) ( 9 % experienced rectal bleeding , 6 % experienced proctitis , 3 % experienced diarrhea , and 1 % experienced rectal pain ) at a median interval of 1.1 year . Nine patients ( 3 % ) experienced grade 3 or higher chronic rectal toxicity ( 1 Grade 4 ) at a median interval of 1.2 years . The 2-year rates of Grade 2 or higher and Grade 3 or higher chronic rectal toxicity were 17 % and 3 % , respectively . No significant difference by dose level was seen in the 2-year rate of Grade 2 or higher chronic rectal toxicity . These rates were 27 % , 15 % , 14 % , 17 % , and 24 % for dose levels equal to or less than 72 , 73.8 , 75.6 , 77.4 , and 79.2 Gy , respectively ( p = 0.3 ) . Grade 2 or higher chronic rectal bleeding was significantly greater for Group 2 than for Group 1 , 17 % vs. 8 % ( p = 0.035 ) . CONCLUSIONS High doses ( 79.2 Gy ) were safely delivered in selected patients by our adaptive radiotherapy process . Under the rectal dose-volume histogram constraints for the dose level selection , the risk of chronic rectal toxicity is similar among patients treated to different dose levels . Therefore , rectal chronic toxicity rates reflect the dose-volume cutoff used and are independent of the actual dose levels . On the other h and , a larger PTV will increase the rectal wall dose and chronic rectal toxicity rates . PTV volume and dose constraints should be defined , considering their potential benefit PURPOSE This study was design ed to vali date a fully automated adaptive planning ( AAP ) method which integrates automated recontouring and automated replanning to account for interfractional anatomical changes in prostate cancer patients receiving adaptive intensity modulated radiation therapy ( IMRT ) based on daily repeated computed tomography (CT)-on-rails images . METHODS AND MATERIAL S Nine prostate cancer patients treated at our institution were r and omly selected . For the AAP method , contours on each repeat CT image were automatically generated by mapping the contours from the simulation CT image using deformable image registration . An in-house automated planning tool incorporated into the Pinnacle treatment planning system was used to generate the original and the adapted IMRT plans . The cumulative dose-volume histograms ( DVHs ) of the target and critical structures were calculated based on the manual contours for all plans and compared with those of plans generated by the conventional method , that is , shifting the isocenters by aligning the images based on the center of the volume ( COV ) of prostate ( prostate COV-aligned ) . RESULTS The target coverage from our AAP method for every patient was acceptable , while 1 of the 9 patients showed target underdosing from prostate COV-aligned plans . The normalized volume receiving at least 70 Gy ( V70 ) , and the mean dose of the rectum and bladder were reduced by 8.9 % , 6.4 Gy and 4.3 % , 5.3 Gy , respectively , for the AAP method compared with the values obtained from prostate COV-aligned plans . CONCLUSIONS The AAP method , which is fully automated , is effective for online replanning to compensate for target dose deficits and critical organ overdosing caused by interfractional anatomical changes in prostate cancer |
1,988 | 24,274,224 | Improvement was described by all studies in symptoms , clinical outcomes , and /or immune parameters after LTA treatment , with greater improvements in a subset of symptoms beyond that observed with INCSs .
Concomitant asthma , aspirin-exacerbated respiratory disease , and atopy did not significantly or consistently affect these results .
Conclusion LTAs are an effective tool for treating CRSwNP , with limited benefit as an adjunctive therapy . | Background Leukotriene antagonists ( LTAs ) provide a potential strategy for the management of chronic rhinosinusitis with nasal polyposis ( CRSwNP ) , which is often refractory to medical and surgical treatment .
The purpose of this study is to determine the impact of LTA treatment alone and in conjunction with intranasal corticosteroids ( INCSs ) on nasal symptoms , objective clinical outcomes , and immune parameters in CRSwNP . | This was a prospect i ve double blind comparative study on 40 patients . It compared the effects of the leukotriene receptor antagonist montelukast and beclomethasone nasal spray on the post-operative course of patients with sinonasal polyps . All patients underwent endoscopic sphenoethmoidectomy and were r and omized post-operatively into two groups . Group I : 20 patients ( 9 females and 11 males ) age 17 to 67 ( 32.4 ± 9.5 years ) , receiving 10 mg montelukast orally daily and Group II : 20 patients ( 6 females and 14 males ) age 17 years to 57 years ( 33.5 ± 11.9 years ) , receiving 400 ug beclomethasone local sprays daily . All patients were followed up for 1 year and a symptom score was recorded throughout this period . There was a significant reduction in symptom scores in both groups throughout the study period . In the montelukast group improvement was more marked in itching , post-nasal discharge and headache . The control of sneezing and rhinorrhea was comparable in both groups with a marginal advantage of montelukast . Steroids had a more marked effect on smell disturbances and obstruction . There was no difference in the recurrence rate or in the need for rescue medications between both groups . Both drugs seem to have a complementary action and further studies are needed to determine which patients should receive which treatment BACKGROUND Leukotrienes , especially LTC4 , are important inflammatory mediators in allergic and nonallergic inflammation of the entire airways . Of particular interest are numerous theories regarding the pathogenesis of aspirin intolerance with subsequent hyperproduction of leukotrienes and inhibition of cyclooxygenase . OBJECTIVE To examine the influence of the cysteinyl-leukotriene receptor antagonist montelukast on clinical symptoms and inflammatory markers in nasal lavage fluid in patients with bronchial asthma and nasal polyps , and determine its dependency on aspirin sensitization . METHODS Twenty-four patients ( 7 women , 17 men ; median age , 55.5 years ) with nasal polyps and controlled asthma ( n=12 with aspirin intolerance ) were treated with 10 mg montelukast once daily for 6 weeks in a blinded , placebo-controlled fashion . The placebo phase was r and omly assigned 4 weeks before ( n=12 ) or after treatment ( n=12 ) . Symptom score , rhinoendoscopy , rhinomanometry , smears for eosinophils , and nasal lavages for the determination of different mediators were performed . RESULTS Compared to placebo , there were significant improvements in the nasal symptom score and airflow limitation as well as a reduction in the inflammatory mediators in nasal lavage fluid after treatment . Furthermore , reduced eosinophils in nasal smears and peripheral blood were observed 2 and 6 weeks after treatment . CONCLUSION Leukotriene 1 receptor blockade led to a significant decrease in eosinophil inflammation accompanied by a reduction in other mediators such as neurokinin A and substance P in the nasal lavage fluid of patients with nasal polyps and asthma , with or without aspirin intolerance Objective To examine the potential of montelukast , a leukotriene receptor antagonist , as an adjunct to oral and inhaled steroid in subjects with chronic nasal polyps . Study Design Prospect i ve , r and omized controlled trial . Subjects and Methods Thirty-eight consecutive adult patients with bilateral nasal polyps were r and omized into two groups . Eighteen subjects were treated with oral prednisolone for 14 days and budenoside nasal spray for 8 weeks . Twenty subjects received similar treatment with additional oral montelukast for 8 weeks . Subjects completed a modified nasal ICSD symptom score at 8 and 12 weeks after beginning treatment and the SF-36 quality of life question naire at 12 weeks . Results Symptom scores improved in both groups after treatment . Subjects treated with montelukast reported significantly less headache ( P = 0.013 ) , facial pain ( P = 0.048 ) and sneezing ( P = 0.03 ) than controls . Four weeks after completing treatment , no significant differences were recorded . Conclusion Montelukast therapy may have clinical benefit as an adjunct to oral and inhaled steroid in chronic nasal polyposis , but effects are not maintained after cessation of treatment The leukotrienes are known to be important mediators of bronchial asthma . The ability of montelukast , a potent and selective CysLT1 leukotriene receptor antagonist , to cause a dose-related improvement in chronic asthma was investigated in a placebo-controlled , multicentre , parallel-group study . After a two week placebo run-in period , chronic asthmatic patients with a forced expiratory volume in one second ( FEV1 ) 40 - 80 % predicted with > or = 15 % increase ( absolute value ) after beta2-agonist were r and omly assigned to one of four treatment groups ( placebo or montelukast 2 , 10 , or 50 mg once daily in the evening ) for a three week , double-blind treatment period . For patient-reported end-points ( daytime symptom score , use of as needed inhaled beta2 agonist , asthma-specific quality of life ) and frequency of asthma exacerbations , montelukast 10 and 50 mg caused similar responses , superior to 2 mg and significantly ( p<0.05 ; linear trend test ) different from placebo . All three doses caused improvements in FEV1 and morning and evening peak expiratory flow rate ( PEFR ) that were significantly ( p<0.05 ) different from placebo . Differences ( least square mean ) between the pooled 10 and 50 mg montelukast treatment groups and placebo were : 7.1 % change from baseline in FEV1 , 19.23 L x min(-1 ) in morning PEFR , -0.29 in daytime asthma symptom score ( absolute value ) , and -0.82 in beta2-agonist use ( puff x day(-1 ) ) . The incidence of adverse experiences was neither dose-related nor different between montelukast and placebo treatments . We conclude that montelukast causes a dose-related improvement in patient-reported asthma end-points over the range 2 - 50 mg . Montelukast causes benefit to chronic asthmatic patients by improving asthma control end-points Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more OBJECTIVE : To investigate the hypothesis that eosinophil major basic protein is released in high concentrations in the nasal mucus of patients with polypoid chronic rhinosinusitis . STUDY DESIGN : Single center , open , prospect i ve trial . SETTING : Medical University of Graz , Austria . SUBJECTS AND METHODS : Patients with polypoid chronic rhinosinusitis ( n = 23 ) were compared to three different control groups : patients with chronic rhinosinusitis-like symptoms but without general mucosal thickening , patients who underwent functional endoscopic sinus surgery for reasons other than chronic rhinosinusitis , and patients without sinus disease ( total n = 21 ) . Mucus was harvested from each patient using a st and ardized technique and analyzed for eosinophil major basic protein with an enzyme-linked immunosorbent assay . RESULTS : In the patient group with polypoid chronic rhinosinusitis , 20 of 23 ( 87 % ) were positive for eosinophil major basic protein . In contrast , only one control patient was positive , whereas the remainder had no detectable amount of eosinophil major basic protein in the mucus ( P = 0.001 vs chronic rhinosinusitis ) . CONCLUSION : Toxic eosinophil major basic protein levels are elevated in polypoid chronic rhinosinusitis patients compared to control groups that have similar clinical presentations but upon closer examination turn out not to have chronic rhinosinusitis . In the future , the detection of eosinophil major basic protein in nasal mucus may become a sensitive and specific marker for chronic rhinosinusitis and a helpful diagnostic tool . © 2010 American Academy of Otolaryngology-Head and Neck Surgery Foundation . All rights reserved Eosinophils are the principal effector cells involved in the pathogenesis of allergic inflammation . We conducted a study to investigate the validity of the nasal smear examination for detecting eosinophilia in patients with allergic rhinitis . Our study group was made up of 50 patients with allergic rhinitis and 50 age- and sex-matched controls without allergic rhinitis . Smears were obtained from nasal secretions in both groups and then fixed , stained , and studied under light microscopy . Statistical analysis revealed that the odds ratio for eosinophilia positivity in nasal smears in the rhinitis group was 25.61 with a 95 % confidence interval of 8 to 78 . The sensitivity , specificity , positive predictive value , and negative predictive value of this test were 74 , 90 , 88 , and 77 % , respectively . We conclude that the nasal eosinophilia test is highly specific and moderately sensitive in diagnosing allergic rhinitis , and that it therefore can be used as an easy , noninvasive , and inexpensive procedure for screening patients and for conducting epidemiologic studies of this disorder Background We assessed the course of treatment in patients with persistent allergic rhinitis ( AR ) treated with montelukast , levocetirizine , or desloratadine alone or combinations of antihistamine and montelukast . Methods A 32-week r and omized , double-blind , placebo-controlled , crossover , double-armed study in 40 adult patients with history of persistent AR , clinical allergy to house-dust mites , and a total nasal symptom score of at least 5 ( congestion of at least 2 ) has been performed . Patients with asthma , chronic obstructive pulmonary disease , nonallergic rhinitis with clinical allergy associated with seasonal allergens , and other serious diseases were excluded . There were four 6-week treatment periods separated by 2-week washout periods . Twenty patients received either montelukast or antihistamine , a combination of montelukast and antihistamine , or placebo . The sequence of treatment was r and omly assigned . Nasal symptoms were assessed using a 4-point scale at baseline , daily during the 1st week and on days 14 , 21 , 28 , 35 , and 42 of treatment . Results Montelukast alone , levocetirizine alone , desloratadine alone , and the montelukast/antihistamine combinations significantly improved nasal symptoms during the first 24 hours . Improvement gradually increased during the 6 weeks of treatment , especially in patients receiving montelukast alone or in combination therapy with the antihistamine in both arms . Improvement at 42 days of treatment was significantly greater than that achieved on the 1st day of therapy in patients treated with the combination of montelukast and levocetirizine . Conclusion Montelukast alone or in combination with antihistamines gave a gradual increase in nasal symptom improvement within 6 weeks of treatment in patients with persistent AR OBJECTIVES In this study we investigated the effect of adding montelukast to the treatment of nasal polyposis patients with bronchial asthma on quality of life . PATIENTS AND METHODS Thirty consecutive subjects with nasal polyposis accompanying bronchial asthma treated in our clinic were prospect ively evaluated . Subjects with aspirin hypersensitivity and seasonal allergic rhinitis were excluded . Patients were evaluated using the Turkish version of rhinosinusitis disability index ( RSDI ) and visual analog scores before the montelukast therapy , one and three months after the therapy started . It must be noted that in addition to being treated with anti-leukotriene therapy , all of these subjects continued to receive routine nasal steroid treatment . In all subjects paranasal sinus tomography scans were obtained during the study . Lund-Mackay staging system , which is a radiological scoring system , was used in the staging of the disease severity . RESULTS Rhinosinusitis disability index scores improved during the study period . Functional , emotional and physical sub-scales of RSDI were compared separately . But 1st and 3rd month scores are not statistically significant when compared with scores previous to montelukast therapy ( p>0.05 ) . Visual analog scale also showed a statistically significant decrease during the study period ( p<0.01 ) . Lund-Mackay staging did not show a statistically significant difference during the study period ( p>0.05 ) . CONCLUSION This study showed that montelukast therapy might have a clinical benefit as an adjunct to nasal steroids in subjects with nasal polyposis accompanying bronchial asthma We have studied the immunohistology of the nasal mucosa in allergen-induced rhinitis . Sixteen grass pollen-sensitive patients were challenged twice by r and omly allocated allergen or control solutions applied on filter paper disks to the inferior turbinate . All had immediate nasal responses , but late-phase responses were equivocal and only evident as nostril blockage . When cell counts in the nasal submucosa were compared with control values 24 h after allergen , there were no changes in CD45 + ( total leukocytes ) , CD3 + , or CD8 + cells . Significant increases were found in the numbers of CD4 + T-helper cells ( p less than 0.05 ) and CD25 + [ interleukin-2 receptor ( IL-2R+ ) ] cells ( p less than 0.02 ) . Increases in eosinophils ( anti-major basic protein , p less than 0.01 ) and neutrophils ( antineutrophil elastase , p less than 0.01 ) were also observed . There were increases in tissue macrophages and HLA-DR-positive immunostaining and a reduction in mast cells ( tryptase positive ) , but none of these changes was statistically significant . No significant changes in epithelial thickness , cross-sectional area , or integrity were observed . There was a significant correlation between CD4 + and CD25 + cells ( r = 0.61 , p less than 0.01 ) but not between macrophages and CD25 + cells ( r = 0.18 ) . The changes in the nasal submucosa were not merely a reflection of alterations in circulating cell population s since it was shown that a significant increase in the lymphocyte CD4/CD8 ratio ( p less than 0.05 ) was observed in nasal biopsies but not in peripheral blood after allergen challenge . ( ABSTRACT TRUNCATED AT 250 WORDS OBJECTIVES Chronic rhinosinusitis associated with asthma is often difficult to treat effectively with intranasal corticosteroids alone . Thus , the aim of this study was to evaluate the effectiveness of combination treatment with an intranasal corticosteroid and a leukotriene-receptor antagonist ( montelukast ) in reducing the size of nasal polyps . METHODS The subjects of this study were 20 patients with chronic rhinosinusitis associated with adult-onset asthma , which was being treated with inhaled corticosteroids . All patients were treated with intranasal fluticasone propionate , 200 microg/day , and montelukast , 10 mg/day , for 1 year . The size of nasal polyps and the score of sinus shadows were assessed with nasal endoscopy and computed tomography ( CT ) , respectively , before and after treatment . The peripheral blood eosinophil counts were also evaluated before and after treatment . RESULTS Nasal polyps were significantly smaller after both 6 months ( p<0.01 ) and 12 months of treatment ( p<0.01 ) than before treatment . The decrease in the shadow score was statistically significant after both 6 months ( p<0.01 ) and 12 months of treatment ( p<0.01 ) . Significant reductions in peripheral blood eosinophil counts were also seen after both 6 months ( p<0.05 ) and 12 months of treatment ( p<0.01 ) . A significant correlation was found between the rate of change in the peripheral blood eosinophil count and that in the CT score after both 6 months ( r=0.578 , p=0.012 ) and 12 months ( r=0.625 , p=0.007 ) . CONCLUSION Combined treatment with intranasal fluticasone propionate and montelukast , for at least 1 year , is effective for chronic rhinosinusitis associated with adult-onset asthma BACKGROUND The cysteinyl leukotrienes are important mediators of bronchial asthma . The clinical effect of montelukast , a potent cysteinyl leukotriene-receptor antagonist , was investigated in a r and omized , placebo-controlled , multicenter , parallel-group , dose-ranging study . METHODS After a 3-week , single-blind , placebo run-in period , 343 asthmatic patients ( FEV1 40 % to 80 % of the predicted value with an improvement in FEV1 of at least 15 % [ absolute value ] after receiving inhaled beta-agonists on at least two occasions ) were r and omly assigned to one of six treatment groups : placebo ; 10 , 100 , or 200 mg once daily montelukast in the evening ; or 10 or 50 mg twice daily montelukast for a 6-week , double-blind treatment period followed by a 1-week placebo washout period . All patients used inhaled , short-acting beta-agonists as needed . RESULTS All montelukast doses caused similar and significant differences compared with placebo in asthma control endpoints . The least-square mean difference between pooled montelukast groups and placebo in the percentage change from baseline in morning FEV1 ( 10.30 % ; 95 % CI : 5.56 to 15.04 ) , as-needed beta-agonist use ( -0.98 puffs ; 95 % CI : -1.53 to -0.44 ) , morning peak expiratory flow rate ( 18.80 L/min ; 95 % CI : 8.62 to 28.98 ) , physicians ' and patients ' global evaluations , and asthma-specific quality -of-life scores were all significant ( p < or = 0.050 ) . The incidence of adverse experiences was not dose related and was similar between placebo and montelukast treatment . CONCLUSION Montelukast caused a significant improvement in chronic asthma at an oral , once daily evening dose as low as 10 mg Objectives : Twenty-four consecutive patients with symptomatic nasal polyposis and nonallergic or perennial rhinitis who were undergoing chronic nasal steroid therapy were prospect ively evaluated for response to adjunctive oral montelukast sodium therapy . Methods : The patients were undergoing daily intranasal steroid sprays for a minimum of 6 months before being started on montelukast sodium 10 mg by mouth per day for 3 months while intranasal steroids were continued . The patients were given a vali date d symptom score survey at the start and end of therapy , with a lower score indicating fewer symptoms . The nasal polyps were su bmi tted to biopsy before and after treatment to determine their degree of eosinophilia . Eosinophilia was grade d in a blinded fashion by an independent pathologist on a scale of 0 to 3 , with 3 being severe . Patients with seasonal allergies were excluded , and the studied patients were treated during the winter season to avoid confounding by potential seasonal allergic responses . Results : The patients tended to improve on montelukast therapy in terms of their symptom scores and polyp eosinophil counts . The symptoms improved in 17 patients ( 71 % ) and remained the same or worsened in 7 patients ( 29 % ) . The symptom score for the group improved from a pretreatment value of 33.4 ( SD , 7.73 ) to a posttreatment value of 23.3 ( SD , 13.73 ; p < .001 ) . In addition , the eosinophilia score improved from 2.3 ( SD , 0.68 ) to 1.5 ( SD , 0.82 ; p < .01 ) . The improvement was most noticeable in the patients with perennial allergies . Conclusions : These results suggest that montelukast appears to be beneficial for some patients with nasal polyposis . Patients with perennial allergies and nasal polyposis seem more likely to respond to the treatment than those with nonallergic nasal polyposis Objective : To determine the effects of montelukast monotherapy on health-related quality of life ( HRQL ) in patients with persistent allergic rhinitis . Study Design : The study was placebo-controlled , r and omized , and double blinded . Setting : Tertiary university hospital . Subjects and Methods : There were 46 patients in the study group and 24 patients in the control group , all of whom had a diagnosis of persistent allergic rhinitis of at least two years . The patients were evaluated at two control visits after the diagnosis . The study group was given 10-mg montelukast oral tablets , while the control group was given a placebo , and these were taken daily for one month . For evaluation of HRQL in both groups , the Rhinoconjunctivitis Quality of Life Question naire ( RQLQ ) was used . Results : There was a larger decrease in the overall RQLQ score for the group using montelukast compared with the placebo group ( P < 0.001 ) . The difference between scores at baseline versus the end of the first month for all domains was statically significant in both the placebo group and study group ( P < 0.001 ) . The difference in change from baseline to the end of the first month ( treatment difference ) between the placebo group and the study group was statically significant , in favor of the study group , for sleep , practical problems , nasal problems , and activities that have been limited by nose or eye symptoms , and for overall score ( P < 0.001 , P < 0.001 , P = 0.003 , P < 0.001 , and P < 0.001 , respectively ) . Conclusion : Montelukast is a drug that improves the disease-specific quality of life in patients being treated for persistent allergic rhinitis better than placebo OBJECTIVES To determine the clinical effect of oral montelukast sodium , a leukotriene receptor antagonist , in asthmatic patients aged 15 years or more . DESIGN R and omized , multicenter , double-blind , placebo-controlled , parallel-group study . A 2-week , single-blind , placebo run-in period was followed by a 12-week , double-blind treatment period ( montelukast sodium , 10 mg , or matching placebo , once daily at bedtime ) and a 3-week , double-blind , washout period . SETTING / PATIENTS Fifty clinical centers r and omly allocated 681 patients with chronic , stable asthma to receive placebo or montelukast after demonstrating a forced expiratory volume in 1 second 50 % to 85 % of the predicted value , at least a 15 % improvement in forced expiratory volume in 1 second ( absolute value ) after inhaled beta-agonist administration , a minimal predefined level of daytime asthma symptoms , and inhaled beta-agonist use . Twenty-three percent of the patients used concomitant inhaled corticosteroids . PRIMARY END POINTS : Forced expiratory volume in 1 second and daytime asthma symptoms . RESULTS Montelukast improved airway obstruction ( forced expiratory volume in 1 second , morning and evening peak expiratory flow rate ) and patient-reported end points ( daytime asthma symptoms , " as-needed " beta-agonist use , nocturnal awakenings ) ( P<.001 compared with placebo ) . Montelukast provided near-maximal effect in these end points within the first day of treatment . Tolerance and rebound worsening of asthma did not occur . Montelukast improved outcome end points , including asthma exacerbations , asthma control days ( P<.001 compared with placebo ) , and decreased peripheral blood eosinophil counts ( P<.001 compared with placebo ) . The incidence of adverse events and discontinuations from therapy were similar in the montelukast and placebo groups . CONCLUSIONS Montelukast , compared with placebo , significantly improved asthma control during a 12-week treatment period . Montelukast was generally well tolerated , with an adverse event profile comparable with that of placebo BACKGROUND Sulfido-Leukotrienes are important inflammatory mediators of bronchial asthma , intolerance of acetylsalicylic acid ( ASA ) , polyposis nasi and allergic rhinitis . Receptorantagonists like Montelukast constitute a well-established asthma- and ASA intolerance-therapy . The aim of our study was to evaluate changes in patients Health-Related- Quality -of-Life ( HRQL ) during Montelukast-monotherapy of nasal polyposis . METHODS The study was performed in a prospect i ve , double blind and placebo-controlled matter . The study included 30 patients of our ENT outpatient 's dept . ( 77 % male , mean age 49 yrs ) , suffering from nasal polyposis grade II to IV . Polyps were endoscopically grade d , nasal Eosinophilic Cationic Protein ( ECP ) was measured , and HRQL-score was taken prior to and four weeks after Montelukast-(0 - 0 - 10 mg ) compared to placebo . An established HRQL- question naire - including 25 items , summarized in 6 symptom-groups - was used . Given was a symptom-score of 1 ( not troubled ) to 4 ( extremely troubled ) . RESULTS Patients treated with Montelukast improved their nasal symptoms ( Delta HRQL-score 0.58 + /- 0.94 , P < 0.01 ) , practical problems ( Delta HRQL-score 0.42 + /- 0.71 , P < 0.05 ) , headaches ( Delta HRQL-score 0.38 + /- 0.56 , P < 0.05 ) , non-nasal symptoms ( Delta HRQL-score 0.35 + /- 0.92 , P < 0.05 ) , sleep ( Delta HRQL-score 0.26 + /- 0.71 ) and emotional problems ( Delta HRQL-score 0.18 + /- 0.75 ) . Intranasal ECP ( Delta 210.67 ng/ml + /- 332.68 ) and polyp grading ( Delta 0.72 + /- 1.77 ) tended to improve as well , but did not reach statistical significance . Patients treated with placebo revealed no significant changes neither in HRQL-score , ECP , nor polyp grading . CONCLUSIONS Montelukast-therapy of nasal polyposis significantly improved patient 's HRQL in 4 out of 6 symptom-groups . Measuring HRQL proofed to constitute a more sensitive tool than looking at eosinophilic parameters of inflammation or polyp size |
1,989 | 17,115,429 | Findings revealed areas of weakness in analytic aspects of the behavioral health RCTs reported in both sets of journals .
Weaknesses were more pronounced in behavioral journals . | Adoption of evidence -based practice ( EBP ) policy has implication s for clinicians and research ers alike .
In fields that have already adopted EBP , evidence -based practice guidelines derive from systematic review s of research evidence .
Ultimately , such guidelines serve as tools used by practitioners .
Systematic review s of treatment efficacy and effectiveness reserve their strongest endorsements for treatments that are supported by high- quality r and omized clinical trials ( RCTs ) .
It is unknown how well RCTs reported in behavioral science journals fare compared to quality st and ards set forth in fields that pioneered the evidence -based movement . | BACKGROUND The effects of a carbohydrate-restricted diet on weight loss and risk factors for atherosclerosis have been incompletely assessed . METHODS We r and omly assigned 132 severely obese subjects ( including 77 blacks and 23 women ) with a mean body-mass index of 43 and a high prevalence of diabetes ( 39 percent ) or the metabolic syndrome ( 43 percent ) to a carbohydrate-restricted ( low-carbohydrate ) diet or a calorie- and fat-restricted ( low-fat ) diet . RESULTS Seventy-nine subjects completed the six-month study . An analysis including all subjects , with the last observation carried forward for those who dropped out , showed that subjects on the low-carbohydrate diet lost more weight than those on the low-fat diet ( mean [ + /-SD ] , -5.8+/-8.6 kg vs. -1.9+/-4.2 kg ; P=0.002 ) and had greater decreases in triglyceride levels ( mean , -20+/-43 percent vs. -4+/-31 percent ; P=0.001 ) , irrespective of the use or nonuse of hypoglycemic or lipid-lowering medications . Insulin sensitivity , measured only in subjects without diabetes , also improved more among subjects on the low-carbohydrate diet ( 6+/-9 percent vs. -3+/-8 percent , P=0.01 ) . The amount of weight lost ( P<0.001 ) and assignment to the low-carbohydrate diet ( P=0.01 ) were independent predictors of improvement in triglyceride levels and insulin sensitivity . CONCLUSIONS Severely obese subjects with a high prevalence of diabetes or the metabolic syndrome lost more weight during six months on a carbohydrate-restricted diet than on a calorie- and fat-restricted diet , with a relative improvement in insulin sensitivity and triglyceride levels , even after adjustment for the amount of weight lost . This finding should be interpreted with caution , given the small magnitude of overall and between-group differences in weight loss in these markedly obese subjects and the short duration of the study . Future studies evaluating long-term cardiovascular outcomes are needed before a carbohydrate-restricted diet can be endorsed This study examined the effects of dietary weight loss and exercise on the health-related quality of life ( HRQL ) of overweight and obese , older adults with knee osteoarthritis . A total of 316 older men and women with documented evidence of knee osteoarthritis were r and omly assigned to 1 of 4 18-month interventions : dietary weight loss , exercise , dietary weight loss and exercise , or healthy lifestyle control . Measures included the SF-36 Health Survey and satisfaction with body function and appearance . Results revealed that the combined diet and exercise intervention had the most consistent , positive effect on HRQL compared with the control group ; however , findings were restricted to measures of physical health or psychological outcomes that are related to the physical self Sedentary adults ( N = 379 ) were r and omly assigned in a 2 x 2 design to walk 30 min per day at a frequency of either 3 - 4 or 5 - 7 days per week , at an intensity of either 45%-55 % or 65%-75 % of maximum heart rate reserve . Analyses of exercise accumulated over 6 months showed greater amounts completed in the higher frequency ( p = .0001 ) and moderate intensity ( p = .021 ) conditions . Analyses of percentage of prescribed exercise completed showed greater adherence in the moderate intensity(p = .02 ) condition . Prescribing a higher frequency increased the accumulation of exercise without a decline in adherence , whereas prescribing a higher intensity decreased adherence and result ed in the completion of less exercise CONTEXT Rapid increases in access to the Internet have made it a viable mode for public health intervention . No controlled studies have evaluated this re source for weight loss . OBJECTIVE To determine whether a structured Internet behavioral weight loss program produces greater initial weight loss and changes in waist circumference than a weight loss education Web site . DESIGN R and omized , controlled trial conducted from April to December 1999 . SETTING AND PARTICIPANTS Ninety-one healthy , overweight adult hospital employees aged 18 to 60 years with a body mass index of 25 to 36 kg/m(2 ) . Analyses were performed for the 65 who had complete follow-up data . INTERVENTIONS Participants were r and omly assigned to a 6-month weight loss program of either Internet education ( education ; n = 32 with complete data ) or Internet behavior therapy ( behavior therapy ; n = 33 with complete data ) . All participants were given 1 face-to-face group weight loss session and access to a Web site with organized links to Internet weight loss re sources . Participants in the behavior therapy group received additional behavioral procedures , including a sequence of 24 weekly behavioral lessons via e-mail , weekly online su bmi ssion of self-monitoring diaries with individualized therapist feedback via e-mail , and an online bulletin board . MAIN OUTCOME MEASURES Body weight and waist circumference , measured at 0 , 3 , and 6 months , compared the 2 intervention groups . RESULTS Repeated- measures analyses showed that the behavior therapy group lost more weight than the education group ( P = .005 ) . The behavior therapy group lost a mean ( SD ) of 4.0 ( 2.8 ) kg by 3 months and 4.1 ( 4.5 ) kg by 6 months . Weight loss in the education group was 1.7 ( 2.7 ) kg at 3 months and 1.6 ( 3.3 ) kg by 6 months . More participants in the behavior therapy than education group achieved the 5 % weight loss goal ( 45 % vs 22 % ; P = .05 ) by 6 months . Changes in waist circumference were also greater in the behavior therapy group than in the education group at both 3 months ( P = .001 ) and 6 months ( P = .005 ) . CONCLUSIONS Participants who were given a structured behavioral treatment program with weekly contact and individualized feedback had better weight loss compared with those given links to educational Web sites . Thus , the Internet and e-mail appear to be viable methods for delivery of structured behavioral weight loss programs CONTEXT Although the use of electron beam tomography ( EBT ) as a motivational tool to change behavior is practice d , its efficacy has not been studied . OBJECTIVE To assess the effects of incorporating EBT as a motivational factor into a cardiovascular screening program in the context of either intensive case management ( ICM ) or usual care by assessing its impact over 1 year on a composite measure of projected risk . DESIGN R and omized controlled trial with a 2 x 2 factorial design and 1 year of follow-up . SETTING AND PARTICIPANTS A consecutive sample of 450 asymptomatic active-duty US Army personnel aged 39 to 45 years stationed within the Washington , DC , area and scheduled to undergo a periodic Army-m and ated physical examination were enrolled between January 1999 and March 2001 ( mean age , 42 years ; 79 % male ; 66 [ 15 % ] had coronary calcification ; mean [ SD ] predicted 10-year coronary risk , 5.85 % [ 3.85 % ] ) . INTERVENTIONS Patients were r and omly assigned to 1 of 4 intervention arms : EBT results provided in the setting of either ICM ( n = 111 ) or usual care ( n = 119 ) or EBT results withheld in the setting of either ICM ( n = 124 ) or usual care ( n = 96 ) . MAIN OUTCOME MEASURE The primary outcome measure was change in a composite measure of risk , the 10-year Framingham Risk Score ( FRS ) . RESULTS Comparing the groups who received EBT results with those who did not , the mean absolute risk change in 10-year FRS was + 0.30 vs + 0.36 ( P = .81 ) . Comparing the groups who received ICM with those who received usual care , the mean absolute risk change in 10-year FRS was -0.06 vs + 0.74 ( P = .003 ) . Improvement or stabilization of cardiovascular risk was noted in 157 patients ( 40.2 % ) . In multivariable analyses predicting change in FRS , after controlling for knowledge of coronary calcification , motivation for change , and multiple psychological variables , only the number of risk factors ( odds ratio , 1.42 ; 95 % confidence interval , 1.16 - 1.75 for each additional risk factor ) and receipt of ICM ( odds ratio , 1.62 ; 95 % confidence interval , 1.04 - 2.52 ) were associated with improved or stabilized projected risk . CONCLUSIONS Using coronary calcification screening to motivate patients to make evidence -based changes in risk factors was not associated with improvement in modifiable cardiovascular risk at 1 year . Case management was superior to usual care in the management of risk factors BACKGROUND We tested the hypothesis that dietary intervention can inhibit the development of recurrent colorectal adenomas , which are precursors of most large-bowel cancers . METHODS We r and omly assigned 2079 men and women who were 35 years of age or older and who had had one or more histologically confirmed colorectal adenomas removed within six months before r and omization to one of two groups : an intervention group given intensive counseling and assigned to follow a diet that was low in fat ( 20 percent of total calories ) and high in fiber ( 18 g of dietary fiber per 1000 kcal ) and fruits and vegetables ( 3.5 servings per 1000 kcal ) , and a control group given a st and ard brochure on healthy eating and assigned to follow their usual diet . Subjects entered the study after undergoing complete colonoscopy and removal of adenomatous polyps ; they remained in the study for approximately four years , undergoing colonoscopy one and four years after r and omization . RESULTS A total of 1905 of the r and omized subjects ( 91.6 percent ) completed the study . Of the 958 subjects in the intervention group and the 947 in the control group who completed the study , 39.7 percent and 39.5 percent , respectively , had at least one recurrent adenoma ; the unadjusted risk ratio was 1.00 ( 95 percent confidence interval , 0.90 to 1.12 ) . Among subjects with recurrent adenomas , the mean ( + /-SE ) number of such lesions was 1.85+/-0.08 in the intervention group and 1.84+/-0.07 in the control group . The rate of recurrence of large adenomas ( with a maximal diameter of at least 1 cm ) and advanced adenomas ( defined as lesions that had a maximal diameter of at least 1 cm or at least 25 percent villous elements or evidence of high- grade dysplasia , including carcinoma ) did not differ significantly between the two groups . CONCLUSIONS Adopting a diet that is low in fat and high in fiber , fruits , and vegetables does not influence the risk of recurrence of colorectal adenomas Infertile women express higher levels of distress than fertile women , with distress peaking between the 2nd and 3rd year . The purpose of this study was to determine whether group psychological interventions could prevent this surge . One hundred eighty-four women who had been trying to conceive between 1 and 2 years were r and omized into either a cognitive-behavioral group , a support group , or a control group . All experimental participants attended a 10-session group program . Participants completed psychological question naires at intake and again at 6 and 12 months . Substantial attrition occurred , particularly in the control group . The cognitive-behavioral and support participants experienced significant psychological improvement at 6 and 12 months compared with the control participants , with the cognitive-behavioral participants experiencing the greatest positive change This study compared the effectiveness of 4 videotaped educational programs design ed to motivate HIV testing among low-income , ethnic minority women . Four hundred eighty women were assigned r and omly to watch one of 2 gain-framed or 2 loss-framed videos . Consistent with prospect theory , participants ' perceptions of the certainty of the outcome of an HIV test moderated the effects of framing on self-reported testing behavior 6 months after video exposure . Among participants who reported being certain of the test 's outcome , those who saw a gain-framed video reported a higher rate of testing than those who saw a loss-framed message . Among women who perceived the outcome of HIV testing as relatively uncertain , gain- and loss-framed videos led to similar rates of self-reported testing , with some advantage for the loss-framed message CONTEXT Depression and low perceived social support ( LPSS ) after myocardial infa rct ion ( MI ) are associated with higher morbidity and mortality , but little is known about whether this excess risk can be reduced through treatment . OBJECTIVE To determine whether mortality and recurrent infa rct ion are reduced by treatment of depression and LPSS with cognitive behavior therapy ( CBT ) , supplemented with a selective serotonin reuptake inhibitor ( SSRI ) antidepressant when indicated , in patients enrolled within 28 days after MI . DESIGN , SETTING , AND PATIENTS R and omized clinical trial conducted from October 1996 to April 2001 in 2481 MI patients ( 1084 women , 1397 men ) enrolled from 8 clinical centers . Major or minor depression was diagnosed by modified Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition criteria and severity by the 17-item Hamilton Rating Scale for Depression ( HRSD ) ; LPSS was determined by the Enhancing Recovery in Coronary Heart Disease Patients ( ENRICHD ) Social Support Instrument ( ESSI ) . R and om allocation was to usual medical care or CBT-based psychosocial intervention . INTERVENTION Cognitive behavior therapy was initiated at a median of 17 days after the index MI for a median of 11 individual sessions throughout 6 months , plus group therapy when feasible , with SSRIs for patients scoring higher than 24 on the HRSD or having a less than 50 % reduction in Beck Depression Inventory scores after 5 weeks . MAIN OUTCOME MEASURES Composite primary end point of death or recurrent MI ; secondary outcomes included change in HRSD ( for depression ) or ESSI scores ( for LPSS ) at 6 months . RESULTS Improvement in psychosocial outcomes at 6 months favored treatment : mean ( SD ) change in HRSD score , -10.1 ( 7.8 ) in the depression and psychosocial intervention group vs -8.4 ( 7.7 ) in the depression and usual care group ( P<.001 ) ; mean ( SD ) change in ESSI score , 5.1 ( 5.9 ) in the LPSS and psychosocial intervention group vs 3.4 ( 6.0 ) in the LPSS and usual care group ( P<.001 ) . After an average follow-up of 29 months , there was no significant difference in event-free survival between usual care ( 75.9 % ) and psychosocial intervention ( 75.8 % ) . There were also no differences in survival between the psychosocial intervention and usual care arms in any of the 3 psychosocial risk groups ( depression , LPSS , and depression and LPSS patients ) . CONCLUSIONS The intervention did not increase event-free survival . The intervention improved depression and social isolation , although the relative improvement in the psychosocial intervention group compared with the usual care group was less than expected due to substantial improvement in usual care patients CONTEXT The Consoli date d St and ards for Reporting of Trials ( CONSORT ) statement was developed to help improve the quality of reports of r and omized controlled trials ( RCTs ) . To date , a paucity of data exists regarding whether it has achieved this goal . OBJECTIVE To determine whether use of the CONSORT statement is associated with improvement in the quality of reports of RCTs . DESIGN AND SETTING Comparative before- and -after evaluation in which reports of RCTs published in 1994 ( pre-CONSORT ) were compared with RCT reports from the same journals published in 1998 ( post-CONSORT ) . We included 211 reports from BMJ , JAMA , and The Lancet ( journals that adopted CONSORT ) as well as The New Engl and Journal of Medicine ( a journal that did not adopt CONSORT and was used as a comparator ) . MAIN OUTCOME MEASURES Number of CONSORT items included in a report , frequency of unclear reporting of allocation concealment , and overall trial quality score based on the Jadad scale , a 5-point quality assessment instrument . RESULTS Compared with 1994 , the number of CONSORT checklist items in reports of RCTs increased in all 4 journals in 1998 , and this increase was statistically significant for the 3 adopter journals ( pre-CONSORT , 23.4 ; mean change , 3.7 ; 95 % confidence interval [ CI ] , 2.1 - 5.3 ) . The frequency of unclear reporting of allocation concealment decreased for each of the 4 journals , and this change was statistically significant for adopters ( pre-CONSORT , 61 % ; mean change , -22 % ; 95 % CI , -38 % to -6 % ) . Similarly , 3 of the 4 journals showed an improvement in the quality score for reports of RCTs , and this increase was statistically significant for adopter journals overall ( pre-CONSORT , 2.7 ; mean change , 0.4 ; 95 % CI , 0.1 - 0.8 ) . CONCLUSION Use of the CONSORT statement is associated with improvements in the quality of reports of RCTs We tested the comparative efficacy of 4 interventions to increase the physical activity behavior of college personnel r and omly assigned to one condition ( N = 196 , 74 % female , M age = 43.4 years ) for 16 weeks . Stage-matched and mismatched interventions were developed based on the stages of change from the Transtheoretical Model and were contrasted with st and ard care ( action-oriented ) and control interventions to test the requirements of a true stage behavior . Repeated measures of multi-variate analyses of covariance indicated that the stage-matched and st and ard care interventions result ed in greater levels of both total and lifestyle physical activity compared with the mismatched and control interventions . The results supported the requirements of a stage behavior as defined by Weinstein , Rothman , and Sutton ( 1 ) and the superiority of the stage-matched intervention versus the mismatched intervention . However , the st and ard care intervention performed as well as the matched intervention , suggesting the need for further investigation . The results are discussed with respect to the high proportion of individuals in the action-oriented stages and previous research findings in the smoking literature This study was design ed to determine whether a 6-month Tai Chi exercise program can improve self-reported physical functioning limitations among healthy , physically inactive older individuals . Ninety-four community residents ages 65 to 96 ( M age = 72.8 years , SD = 5.1 ) volunteered to participate in the study . Participants were r and omly assigned to either a 6-month experimental ( Tai Chi ) group ( n = 49 ) , which exercised twice per week for 60 min , or a wait-list control group ( n = 45 ) . A 6-item self-report physical functioning scale , assessing the extent of behavioral dysfunction caused by health problems , was used to evaluate change in physical functioning limitations as a result of Tai Chi intervention . Results indicated that compared to the control group , participants in the Tai Chi group experienced significant improvements in all aspects of physical functioning over the course of the 6-month intervention . Overall , the experimental group had 65 % improvement across all 6 functional status measures ranging from daily activities such as walking and lifting to moderate-vigorous activities such as running . It was concluded that the 6-month Tai Chi exercise program was effective for improving functional status in healthy , physically inactive older adults . A self-paced and self-controlled activity such as Tai Chi has the potential to be an effective , low-cost means of improving functional status in older persons Optimists ( people who have positive expectations about the future ) have been shown to perform more health-promoting behaviors than pessimists . This study attempts to alter individuals ’ levels of optimism , and thereby their health behaviors , by having them write about a positive future . HIV-infected women ( N = 40 ) on combination therapies were r and omly assigned to write about a positive future or assigned to a no-writing control group . Among participants who were low in optimism , the writing intervention led to increased optimism , a trend toward increased self-reported adherence to medications , and decreased distress from medication side effects , compared to controls who did not write . Participants who were high in optimism showed the opposite effects after writing about the future . Results suggest that a future-oriented writing intervention may be a promising technique to increase medication adherence and decrease symptom , distress in pessimistic individuals This study examined the direct and mediated impact of a self-administered , computer-based intervention on nutrition behavior , self-efficacy , and outcome expectations among supermarket food shoppers . The intervention , housed in kiosks in supermarkets and based on social cognitive theory , used tailored information and self-regulation strategies delivered in 15 brief weekly segments . The study sample ( N = 277 ) , stratified and r and omly assigned to treatment or control , was 96 % female , was 92 % White , had a median annual income of about $ 35,000 , and had a mean education of 14.78 ±2.11 years . About 12 % of the sample reported incomes of $ 20,000 or less , and about 20 % reported 12 years or fewer of education . Analysis of covariance immediately after intervention and at a 4- to 6-month follow-up found that treatment led to improved levels of fat , fiber , and fruits and vegetables . Treatment also led to higher levels of nutrition-related self-efficacy , physical outcome expectations , and social outcome expectations . Logistic regression analysis determined that the treatment group was more likely than the control group to attain goals for fat , fiber , and fruits and vegetables at posttest and to attain goals for fat at follow-up . Latent variable structural equation analysis revealed self-efficacy and physical outcome expectations mediated treatment effects on nutrition . In addition , physical outcome expectations mediated the effect of self-efficacy on nutrition outcomes . Implication s for future computer-based health promotion interventions are discussed The recent decrease in breast cancer mortality has been linked in part to increased breast cancer screening . Although the percentage of women screened once is rising , rate of continued adherence is poor . The purpose of this article is to assess the effects of tailored mammography interventions implemented prospect ively in a factorial design contrasting groups receiving either ( a ) usual care ( no intervention ) , ( b ) tailored telephone counseling for mammography , ( c ) tailored mailed material s promoting mammography , or ( d ) a combination of tailored mail and telephone counseling . This prospect i ve , r and omized study with a 2 x 2 factorial design included women 51 years and older ( N = 1,367 ) who were not adherent with mammography at baseline . The intervention is based on integration of the Transtheoretical and Health Belief Models . Participants were enrolled in one of two health maintenance organizations or seen in a university-related primary care clinic . Baseline data were collected on mammography history and beliefs and knowledge related to mammography . Data were collected via telephone interviews using previously developed scales . The follow-up interviewers were conducted with 976 women . The sample was 41 % White , 56 % African American , and 3 % other . Mean age at baseline was 66.5 . Logistic regression indicates that postintervention mammography status in all three intervention groups was significantly better than usual care , with odds ratios ranging from 1.66 ( telephone only ) to 2.16 ( telephone plus mail ) A r and omized controlled trial examined the growth and form of multidimensional self-esteem over a 12-month period ( 6-month exercise intervention and 6-month follow-up ) in 174 older adults engaged in either a walking or stretching/toning program . The extent to which changes in physical fitness parameters and physical self-efficacy were related to changes in perceptions of attractive body , strength , physical conditioning , and physical self-worth was also determined . Latent growth curve analyses showed a curvilinear pattern of growth in esteem with significant increases at all levels of self-esteem upon completion of the intervention followed by significant declines at 6 months poistintervention in both groups . Frequency of activity and changes in physical fitness , body fat , and self-efficacy were related to improvements in esteem perceptions relative to attractive body , strength , and physical condition . Model fitting procedures suggested that the best fit of the data was to a model in which the influence of changes in efficacy and physical parameters on physical self-worth were mediated by perceptions of attractive body and physical conditions Cognitive behavioral stress management ( CBSM ) has previously been found to reduce fatigue , depression , and cortisol response to heavy exercise training among competitive collegiate athletes and to speed physical and psychological recovery from surgery ( 1,2 ) . Our study assessed the efficacy of a CBSM program to reduce the frequency of injury and illness among collegiate athletes in a r and omized , single-blind , controlled clinical trial . Following assessment of baseline medical history , mood state , stress , cortisol , sleep , alcohol use , and exercise training , collegiate rowers were stratified by gender and competitive level and r and omly assigned to either a control group or a CBSM group . Exercise training information and psychosocial assessment s were repeated immediately following the intervention period , and health care providers who were blinded to participant assignment recorded the frequency of medical visits and the number of days injured or ill until the end of the season . Athletes r and omly assigned to a CBSM group experienced significant reductions in the number of illness and injury days as compared to control group athletes . CBSM participants also had half the number of health service visits as did controls . The data suggest that a time-limited CBSM intervention design ed specifically for an athlete population may be an effective prophylactic treatment to reduce the incidence of injury and illness among competitive collegiate athletes Background : Intervention trials with self-selected participants have shown that mailed stage-targeted print material s can increase participation in physical activity in the short term . We examined the effects of a mailed stage-targeted print intervention design ed to promote physical activity , in a r and om sample of adults living in a regional city . Method : Participants ( n = 462 , 40–60 years of age ) were r and omly allocated to an intervention in - 227 ) or control group ( n - 235 ) . Measures included vali date d 2-week physical activity recall and stage of motivational readiness for physical activity . The intervention consisted of a single mailing of a letter and full-color stage-targeted booklets ( specific to precontemplation , contemplation , preparation , and action/maintenance ) 1 week postbaseline . Follow-up interviews were conducted at 2 and 6 months postbaseline . Results : After 2 months , participants in the intervention group were significantly More likely to meet the current American College of Sports Medicine/Centers for Disease Control and Prevention recommendation for sufficient physical activity than those in the control group ( adjusted odds ratio [ OR ] - 2.40 ; 95 % confidence interval [ CI ] = 1.44–3.99 ) . After 6 months , intervention participants who reported receiving and reading the intervention material s were significantly more likely to be meeting the sufficient physical activity criterion compared with the control group ( adjusted OR = 2.03 ; 95 % Cl = 1.16–3.56 ) . Conclusions : The stage-targeted print intervention was effective in promoting short-term increases in physical activity and was most effective for participants who recognized and used the material s. This low-cost , generalizable intervention has demonstrated potential as a practical population -based physical activity promotion strategy . Further research is required before widespread dissemination would be justified , as additional strategies may be required to ensure sustained change The Women ’s Lifestyle Heart Trial was a small ( N=28 ) r and omized controlled trial to evaluate the effects of a comprehensive lifestyle self-management program ( very low-fat vegetarian diet , stress-management training , exercise , group support , and smoking cessation ) on reduction of cardiovascular risk factors in postmenopausal women with coronary heart disease ( CHD ) . Women assigned to the treatment condition ( Prime Time ) participated in a week-long retreat followed by twice-weekly 4-hour meetings . Endpoints were program adherence ; changes in lipid profiles , body mass , blood pressure , hypolipidemic and antihypertensive medications ; and quality of life . Risk factor and psychosocial evaluations were conducted at baseline and at 4 , 12 , and 24 months . Repeated measures analyses of covariance revealed that the dietary , stress management , and physical activity changes made by intervention women were dramatic and lasting . There were significantly greater improvements in the Prime Time condition compared to the usual care control group on body mass , angina symptoms , and quality of life , and a tendency for a greater reduction in blood pressure-lowering medications . Similar patterns were seen in lipids , blood pressure , and lipid-lowering medications , but did not reach significance . These results demonstrate that postmenopausal CHD women can make lasting lifestyle changes , and that these changes may reduce the need for cardiac medications and improve CHD risk factors and quality of life Objective : To evaluate the effect of Brief Supportive-Expressive Group Psychotherapy as an adjunct to st and ard medical care in reducing psychological distress , medical symptoms , and health care costs and improving quality of life in women with systemic lupus erythematosus ( SLE ) . Methods : A r and omized clinical trial was conducted with 133 SLE female patients from 9 clinics across Canada . Clinical and psychosocial measures were taken at baseline , posttreatment , and 6 and 12 months posttreatment . Outcomes assessed were psychological distress , quality of life , disease activity , health service utilization , and diminished productivity . Results : Intention-to-treat analyses revealed that there were no clinical ly important group differences on any of the outcome measures . Conclusion : Although both groups improved over time on several measures ( e.g. , decreases in psychological distress , stress , and emotion-oriented coping ) , these changes could not be attributed to the psychotherapeutic intervention . Thus , evidence does not support the referral of these patients to this type of intervention This study examined predictors of exercise maintenance following completion of a physical activity intervention . Sedentary adults recruited through newspaper advertisements were r and omly assigned to receive either ( a ) a motivation-matched intervention with feedback reports that were individually tailored ( IT ) to psychological variables from social cognitive theory and the Transtheoretical Model via computer expert system , or ( b ) a st and ard , print-based intervention ( ST ) . The intervention phase of the study included mailed assessment s and intervention material s at baseline , 1 , 3 , and 6 months . An assessment -only follow-up was conducted 6 months after the end of the intervention ( Month 12 ) . Participants were assessed for current physical activity participation , motivational readiness for physical activity , a number of psychological constructs posited to influence participation in physical activity ( e.g. , self-efficacy ) , and current affect . Significantly more participants in the IT condition met or exceeded exercise participation goals at the end of the intervention period and maintained , this level of physical activity through the Month 12 follow-up compared to ST participants . Prospect i ve analyses revealed significant differences in several psychological constructs both at program entry ( baseline ) and the end of the intervention period between individuals who maintained their physical activity participation through Month 12 and those who did not . Results suggest that the maintenance of physical activity following the end of an active intervention program , may be influenced by attitudes and behaviors acquired along with increased participation in physical activity , as well as by preexisting characteristics that individuals bring into treatment Strategic self-presentation ( motivational intervention [ MI ] ) is a theoretical approach that is distinct from social cognitive theory ( SCT ) . Specifically , strategic self-presentation involves increasing motivation by creating cognitive dissonance and inducing shifts in self-concept by generating positive coping strategies during a videotaped session . Fifty-three healthy African American adolescents were r and omized to a SCT + MI , SCT-only , or an education-only group for increasing fruit and vegetable ( F&V ) intake and physical activity . The SCT + MI and SCT-only groups received a 12-week SCT program . Students in the SCT+ MI group also participated in a strategic self-presentation videotape session . Participants completed3-dayfoodrecords , completed measures of self-concept and self-efficacy , and wore an activity monitor for 4 days atpre- and posttreatment . Both the SCT+MI ( 2.6 ± 1.4vs . 5.7 ± 2.2 , p<. 05 ) and the SCT-only ( 2.5 ± 1.2 vs. 4.8 ± 2.4 , p < . 05 ) groups showed greater increases in F&V intake from pre-to posttreatment as compared with the education-only group ( 2.3 ± 1.0 , vs. 3.3 ± 2.1 , p > .05 ) . There were no significant time or group effects for any of the physical activity measures . Correlation analyses revealed that only the SCT + MI group showed that dietary self-concept ( r = .58,r = .67,p<.05 ) and dietary self-efficacy ( r = .65 , r = .85 , p < .05 ) were significantly correlated with posttreatment F&V intake and change in F&V intake , respectively . These findings suggest that the change in F&V intake in the SCT + MI group result ed from strategic self-presentation , which induced positive shifts in self-concept and self-efficacy The Internet has the potential for delivering innovative , interactive physical activity ( PA ) interventions to large numbers of people . This study was design ed to test the efficacy of an Internet intervention that consisted of a Web site plus 12 weekly e-mail tip sheets , compared with a waiting list control group . The Internet intervention was theory based and emphasized clear , graphical presentation of PA information . Sixty-five ( 30 intervention and 35 control ) sedentary adult employees of several large hospitals ( 9 men and 56 women ) were r and omly assigned to 1 of the 2 study arms . Of the 65 participants , 57 completed the 1-month follow-up , and 52 completed the 3-month follow-up . At both 1 and 3 months , those in the intervention group were significantly more likely to have progressed in stage of motivational readiness for PA than participants in the control group : 1 month , χ2(1 , N=52 ) = 4.05 , p > .05 ; 3 months , χ2(1 , N = 52 ) = 6.45 , p > .01 . We hypothesized that at 1 and 3 months , the intervention group would exhibit significant increases relative to the control group on the number of minutes of moderate activity . At the 1-month assessment , the intervention group did exhibit significant increases , relative to the control group in moderate minutes , F(1 , 54 ) = 5.79 , p > .05 ; however , at the 3-month assessment this difference was no longer significant . In addition , secondary analyses were conducted to examine total number of minutes of walking reported . At 1 month , the intervention group did exhibit significant increases , relative to the control group , in walking minutes , F(1 , 54 ) = 12.1 , p > .001 . At the 3-month assessment , amount of time spent in walking activity continued to be significantly higher for the intervention group compared with the control group , F(1 , 48 ) = 5.2 , p > .05 . These findings show that a theoretically based PA Web site and weekly e-mail tip sheets can have a short-term impact on PA motivation and behavior both at 1 and 3 months . As Internet access increases , and as b and with and other technical attributes of this medium improve , Web site delivered health behavior interventions will become increasingly useful in public health promotion Testing behavioral interventions to increase safer sex practice s of HIV+ individuals has the potential to significantly reduce the number of new infections . This study evaluated a behavioral intervention design ed to reduce the sexual risk behaviors of HIV+ individuals . HIV+ individuals ( N = 387 ) who reported engaging in unprotected sex with HIV- or partners of unknown serostatus were r and omly assigned to ( a ) a single counseling session targeting problem areas identified by the participant in 3 possible intervention domains ( i.e. , condom use , negotiation , disclosure ) ; ( b ) a single-session comprehensive intervention that covered all 3 intervention domains ; ( c ) the same comprehensive intervention , plus 2 monthly booster sessions ; or ( d ) a 3-session diet and exercise attention-control condition . The median number of unprotectedsex acts decreasedfrom 14 at baseline to6 , 6 , and 4 at 4- , 8- , and 12-month follow-ups , respectively . A repeated measures analysis of variance revealed a significant decrease in unprotected sex acts across all groups across time . A significant Group x Time interaction revealed that the comprehensive-with-boosters group had the most unprotected sex at 8-month follow-up as compared to the other 3 groups . These findings suggest that a brief intervention can result in large reductions in HIV transmission risks among HIV+ individuals , but the relative benefit of one intervention approach over another remains unclear CONTEXT Gulf War veterans ' illnesses ( GWVI ) , multisymptom illnesses characterized by persistent pain , fatigue , and cognitive symptoms , have been reported by many Gulf War veterans . There are currently no effective therapies available to treat GWVI . OBJECTIVE To compare the effectiveness of cognitive behavioral therapy ( CBT ) , exercise , and the combination of both for improving physical functioning and reducing the symptoms of GWVI . DESIGN , SETTING , AND PATIENTS R and omized controlled 2 x 2 factorial trial conducted from April 1999 to September 2001 among 1092 Gulf War veterans who reported at least 2 of 3 symptom types ( fatigue , pain , and cognitive ) for more than 6 months and at the time of screening . Treatment assignment was unmasked except for a masked assessor of study outcomes at each clinical site ( 18 Department of Veterans Affairs [ VA ] and 2 Department of Defense [ DOD ] medical centers ) . INTERVENTIONS Veterans were r and omly assigned to receive usual care ( n = 271 ) , consisting of any and all care received from inside or outside the VA or DOD health care systems ; CBT plus usual care ( n = 286 ) ; exercise plus usual care ( n = 269 ) ; or CBT plus exercise plus usual care ( n = 266 ) . Exercise sessions were 60 minutes and CBT sessions were 60 to 90 minutes ; both met weekly for 12 weeks . MAIN OUTCOME MEASURES The primary end point was a 7-point or greater increase ( improvement ) on the Physical Component Summary scale of the Veterans Short Form 36-Item Health Survey at 12 months . Secondary outcomes were st and ardized measures of pain , fatigue , cognitive symptoms , distress , and mental health functioning . Participants were evaluated at baseline and at 3 , 6 , and 12 months . RESULTS The percentage of veterans with improvement in physical function at 1 year was 11.5 % for usual care , 11.7 % for exercise alone , 18.4 % for CBT plus exercise , and 18.5 % for CBT alone . The adjusted odds ratios ( OR ) for improvement in exercise , CBT , and exercise plus CBT vs usual care were 1.07 ( 95 % confidence interval [ CI ] , 0.63 - 1.82 ) , 1.72 ( 95 % CI , 0.91 - 3.23 ) , and 1.84 ( 95 % CI , 0.95 - 3.55 ) , respectively . The OR for the overall ( marginal ) effect of receiving CBT ( n = 552 ) vs no CBT ( n = 535 ) was 1.71 ( 95 % CI , 1.15 - 2.53 ) and for exercise ( n = 531 ) vs no exercise ( n = 556 ) was 1.07 ( 95 % CI , 0.76 - 1.50 ) . For secondary outcomes , exercise alone or in combination with CBT significantly improved fatigue , distress , cognitive symptoms , and mental health functioning , while CBT alone significantly improved cognitive symptoms and mental health functioning . Neither treatment had a significant impact on pain . CONCLUSION Our results suggest that CBT and /or exercise can provide modest relief for some of the symptoms of chronic multisymptom illnesses such as GWVI OBJECTIVE We investigated the frequency of quality assessment of r and omized controlled trials within systematic review s and the incorporation of the quality assessment in the analysis . STUDY DESIGN AND SETTING We included new systematic review s of at least five trials of therapeutic or preventive interventions that appeared in issue 2 , 2003 , of the Cochrane Data base of Systematic Review s. All systematic review s in the 2002 issues of the Annals of Internal Medicine , BMJ , JAMA , and Lancet were identified in Pubmed . All review s were assessed under unblinded conditions using preprinted extraction forms . RESULTS Trial quality was assessed in all Cochrane review s and most ( 74 % ) of the paper review s. When we excluded 11 paper review s that were also published as Cochrane review , the percentage remained similar ( 67 % ) . Fifty percent of all Cochrane review s and 61 % of all paper review s incorporated the results of the quality assessment in the analysis . CONCLUSION Half of the review s did not incorporate the results of the quality assessment in the analysis . Authors , peer- review ers , and editors should no longer focus exclusively on whether quality assessment has been performed but should also concentrate on incorporation of quality assessment s in the analysis of the systematic review Statistical procedures for missing data have vastly improved , yet misconception and unsound practice still abound . The authors frame the missing- data problem , review methods , offer advice , and raise issues that remain unresolved . They clear up common misunderst and ings regarding the missing at r and om ( MAR ) concept . They summarize the evidence against older procedures and , with few exceptions , discourage their use . They present , in both technical and practical language , 2 general approaches that come highly recommended : maximum likelihood ( ML ) and Bayesian multiple imputation ( MI ) . Newer developments are discussed , including some for dealing with missing data that are not MAR . Although not yet in the mainstream , these procedures may eventually extend the ML and MI methods that currently represent the state of the art BACKGROUND Telephone services that offer smoking-cessation counseling ( quitlines ) have proliferated in recent years , encouraged by positive results of clinical trials . The question remains , however , whether those results can be translated into real-world effectiveness . METHODS We embedded a r and omized , controlled trial into the ongoing service of the California Smokers ' Helpline . Callers were r and omly assigned to a treatment group ( 1973 callers ) or a control group ( 1309 callers ) . All participants received self-help material s. Those in the treatment group were assigned to receive up to seven counseling sessions ; those in the control group could also receive counseling if they called back for it after r and omization . RESULTS Counseling was provided to 72.1 percent of those in the treatment group and 31.6 percent of those in the control group ( mean , 3.0 sessions ) . The rates of abstinence for 1 , 3 , 6 , and 12 months , according to an intention-to-treat analysis , were 23.7 percent , 17.9 percent , 12.8 percent , and 9.1 percent , respectively , for those in the treatment group and 16.5 percent , 12.1 percent , 8.6 percent , and 6.9 percent , respectively , for those in the control group ( P<0.001 ) . Analyses factoring out both the subgroup of control subjects who received counseling and the corresponding treatment subgroup indicate that counseling approximately doubled abstinence rates : rates of abstinence for 1 , 3 , 6 , and 12 months were 20.7 percent , 15.9 percent , 11.7 percent , and 7.5 percent , respectively , in the remaining subjects in the treatment group and 9.6 percent , 6.7 percent , 5.2 percent , and 4.1 percent , respectively , in the remaining subjects in the control group ( P<0.001 ) . Therefore , the absolute difference in the rate of abstinence for 12 months between the remaining subjects in the treatment and control groups was 3.4 percent . The 12-month abstinence rates for those who made at least one attempt to quit were 23.3 percent in the treatment group and 18.4 percent in the control group ( P<0.001 ) . CONCLUSIONS A telephone counseling protocol for smoking cessation , previously proven efficacious , was effective when translated to a real-world setting . Its success supports Public Health Service guidelines calling for greater availability of quitlines Smoking treatment for newly recovering drug and alcohol-dependent smokers in a residential rehabilitation program was examined . The r and omly assigned conditions ( n = 50 each ) were multicomponent smoking treatment ( MST ) , MST plus generalization training of smoking cessation to drug and alcohol cessation ( MST+G ) , or usual care ( UC ) . Fifty participants who declined smoking treatment ( treatment refusers ) also were studied . Both treatment conditions achieved continuous smoking abstinence rates ( MST : 12 % , MST+G : 10 % , at 12-month follow-up ) that were significantly higher than in the UC condition ( 0 % ) . The MST condition had a continuous drug and alcohol abstinence rate that was significantly higher than that of the MST+G condition ( 40 % vs. 20 % at 12-month follow-up ) although neither differed significantly from that of the UC condition ( 33 % ) . These results support the feasibility of smoking treatment for this population and provide information regarding appropriate treatment components CONTEXT Early childhood introduction of nutritional habits aim ed at atherosclerosis prevention is compatible with normal growth , but its effect on neurological development is unknown . OBJECTIVE To analyze how parental counseling aim ed at keeping children 's diets low in saturated fat and cholesterol influences neurodevelopment during the first 5 years of life . DESIGN R and omized controlled trial conducted between February 1990 and November 1996 . SETTING Outpatient clinic of a university department in Turku , Finl and . PARTICIPANTS A total of 1062 seven-month-old infants and their parents , recruited at well-baby clinics between 1990 and 1992 . At age 5 years , 496 children still living in the city of Turku were available to participate in neurodevelopmental testing . INTERVENTION Participants were r and omly assigned to receive individualized counseling aim ed at limiting the child 's fat intake to 30 % to 35 % of daily energy , with a saturated : monounsaturated : polyunsaturated fatty acid ratio of 1:1:1 and a cholesterol intake of less than 200 mg/d ( n = 540 ) or usual health education ( control group , n = 522 ) . MAIN OUTCOME MEASURES Nutrient intake , serum lipid concentrations , and neurological development at 5 years , among children in the intervention vs control groups . RESULTS Absolute and relative intakes of fat , saturated fatty acids , and cholesterol among children in the intervention group were markedly less than the respective values of control children . Mean ( SD ) percentages of daily energy at age 5 years for the intervention vs control groups were as follows : for total fat , 30.6 % ( 4.5 % ) vs 33.4 % ( 4.4 % ) ( P<. 001 ) ; and for saturated fat , 11.7 % ( 2.3 % ) vs 14.5 % ( 2.4 % ) ( P<.001 ) . Mean intakes of cholesterol were 164.2 mg ( 60.1 mg ) and 192.5 mg ( 71 . 9 mg ) ( P<.001 ) for the intervention and control groups , respectively . Serum cholesterol concentrations were continuously 3 % to 5 % lower in children in the intervention group than in children in the control group . At age 5 years , mean ( SD ) serum cholesterol concentration of the intervention group was 4.27 ( 0.63 ) mmol/L ( 165 [ 24 ] mg/dL ) and of the control group , 4.41 ( 0.74 ) mmol/L ( 170 [ 29 ] mg/dL ) ( P = .04 ) . Neurological development of children in the intervention group was at least as good as that of children in the control group . Relative risks for children in the intervention group to fail tests of speech and language skills , gross motor functioning plus perception , and visual motor skills were 0.95 ( 90 % confidence interval [ CI ] , 0.60 - 1.49 ) , 0.95 ( 90 % CI , 0.58 - 1.55 ) , and 0.65 ( 90 % CI , 0.39 - 1.08 ) , respectively ( P = .85,.86 , and .16 , respectively , vs control children ) . CONCLUSION Our data indicate that repeated child-targeted dietary counseling of parents during the first 5 years of a child 's life lessens age-associated increases in children 's serum cholesterol and is compatible with normal neurological development . JAMA . 2000;284:993 - CONTEXT Although commercial weight loss programs provide treatment to millions of clients , their efficacy has not been evaluated in rigorous long-term trials . OBJECTIVE To compare weight loss and health benefits achieved and maintained through self-help weight loss vs with a structured commercial program . DESIGN AND SETTING A 2-year , multicenter r and omized clinical trial with clinic visits at 12 , 26 , 52 , 78 , and 104 weeks conducted at 6 academic research centers in the United States between January 1998 and January 2001 . PARTICIPANTS Overweight and obese men ( n = 65 ) and women ( n = 358 ) ( body mass index , 27 - 40 ) aged 18 to 65 years . INTERVENTION R and om assignment to either a self-help program ( n = 212 ) consisting of two 20-minute counseling sessions with a nutritionist and provision of self-help re sources or to a commercial weight loss program ( n = 211 ) consisting of a food plan , an activity plan , and a cognitive restructuring behavior modification plan , delivered at weekly meetings . MAIN OUTCOME MEASURES Weight change was the primary outcome measure . Secondary outcomes included waist circumference , body mass index , blood pressure , serum lipids , glucose , and insulin levels . RESULTS At 2 years , 150 participants ( 71 % ) in the commercial group and 159 ( 75 % ) in the self-help group completed the study . In the intent-to-treat analysis , mean ( SD ) weight loss of participants in the commercial group was greater than in the self-help group at 1 year ( -4.3 [ 6.1 ] kg vs -1.3 [ 6.1 ] kg , respectively ; P<.001 ) and at 2 years ( -2.9 [ 6.5 ] kg vs -0.2 [ 6.5 ] kg , respectively ; P<.001 ) . Waist circumference ( P = .003 ) and body mass index ( P<.001 ) decreased more in the commercial group . Changes in blood pressure , lipids , glucose , and insulin levels were related to changes in weight in both groups , but between-group differences in biological parameters were mainly nonsignificant by year 2 . CONCLUSION The structured commercial weight loss program provided modest weight loss but more than self-help over a 2-year period This experiment tested the transtheoretical model ( J.O. Prochaska & C.C. DiClemente , 1983 ) of smoking cessation by matching or mismatching interventions to smokers in a particular stage . The interventions were tested against a no-intervention condition with 92 college-aged daily smokers in the precontemplation stage of change . The stage-matched intervention asked smokers to think more about quitting smoking ; the stage-mismatched intervention provided action-oriented activities typically used for those ready to quit smoking . The results failed to support the value of matching interventions to a smoker 's stage of change . Instead , more smokers who received the action intervention tried to quit smoking . Matching interventions to an individual 's current stage may be less important than the transtheoretical model suggests BACKGROUND Despite the popularity of the low-carbohydrate , high-protein , high-fat ( Atkins ) diet , no r and omized , controlled trials have evaluated its efficacy . METHODS We conducted a one-year , multicenter , controlled trial involving 63 obese men and women who were r and omly assigned to either a low-carbohydrate , high-protein , high-fat diet or a low-calorie , high-carbohydrate , low-fat ( conventional ) diet . Professional contact was minimal to replicate the approach used by most dieters . RESULTS Subjects on the low-carbohydrate diet had lost more weight than subjects on the conventional diet at 3 months ( mean [ + /-SD ] , -6.8+/-5.0 vs. -2.7+/-3.7 percent of body weight ; P=0.001 ) and 6 months ( -7.0+/-6.5 vs. -3.2+/-5.6 percent of body weight , P=0.02 ) , but the difference at 12 months was not significant ( -4.4+/-6.7 vs. -2.5+/-6.3 percent of body weight , P=0.26 ) . After three months , no significant differences were found between the groups in total or low-density lipoprotein cholesterol concentrations . The increase in high-density lipoprotein cholesterol concentrations and the decrease in triglyceride concentrations were greater among subjects on the low-carbohydrate diet than among those on the conventional diet throughout most of the study . Both diets significantly decreased diastolic blood pressure and the insulin response to an oral glucose load . CONCLUSIONS The low-carbohydrate diet produced a greater weight loss ( absolute difference , approximately 4 percent ) than did the conventional diet for the first six months , but the differences were not significant at one year . The low-carbohydrate diet was associated with a greater improvement in some risk factors for coronary heart disease . Adherence was poor and attrition was high in both groups . Longer and larger studies are required to determine the long-term safety and efficacy of low-carbohydrate , high-protein , high-fat diets This article describes a trial of a psychoeducational intervention design ed to modify negative attitudes toward flexible sigmoidoscopy screening and thereby increase screening attendance . The intervention material s addressed the multiple barriers shown to be associated with participation in earlier studies . Adults ages 55 - 64 ( N = 2,966 ) , in a " harder-to-reach " group were r and omized either to receive an intervention brochure or to a st and ard invitation group . Attitudes and expectations were assessed by question naire , and attendance at the clinic was recorded . Compared with controls , the intervention group had less negative attitudes , anticipated a more positive experience , and had a 3.6 % higher level of attendance . These results indicate that psychoeducational interventions can provide an effective means of modifying attitudes and increasing rates of screening attendance CONTEXT Previous research on urge urinary incontinence has demonstrated that multicomponent behavioral training with biofeedback is safe and effective , yet it has not been established whether biofeedback is an essential component that heightens therapeutic efficacy . OBJECTIVE To examine the role of biofeedback in a multicomponent behavioral training program for urge incontinence in community-dwelling older women . DESIGN Prospect i ve , r and omized controlled trial conducted from April 1 , 1995 , to March 30 , 2001 . SETTING University-based outpatient continence clinic in the United States . PATIENTS A volunteer sample of 222 ambulatory , nondemented , community-dwelling women aged 55 to 92 years with urge incontinence or mixed incontinence with urge as the predominant pattern . Patients were stratified by race , type of incontinence ( urge only vs mixed ) , and severity ( frequency of accidents ) . INTERVENTIONS Patients were r and omly assigned to receive 8 weeks ( 4 visits ) of biofeedback-assisted behavioral training ( n = 73 ) , 8 weeks ( 4 visits ) of behavioral training without biofeedback ( verbal feedback based on vaginal palpation ; n = 74 ) , or 8 weeks of self-administered behavioral treatment using a self-help booklet ( control condition ; n = 75 ) . MAIN OUTCOME MEASURES Reduction in the number of incontinence episodes as documented in bladder diaries , patients ' perceptions and satisfaction , and changes in quality of life . RESULTS Intention-to-treat analysis showed that behavioral training with biofeedback yielded a mean 63.1 % reduction ( SD , 42.7 % ) in incontinence , verbal feedback a mean 69.4 % reduction ( SD , 32.7 % ) , and the self-help booklet a mean 58.6 % reduction ( SD , 38.8 % ) . The 3 groups were not significantly different from each other ( P = .23 ) . The groups differed significantly regarding patient satisfaction : 75.0 % of the biofeedback group , 85.5 % of the verbal feedback group , and 55.7 % of the self-help booklet group reported being completely satisfied with treatment ( P = .001 ) . Significant improvements were seen across all 3 groups on 3 quality -of-life instruments , with no significant between-group differences . CONCLUSIONS Biofeedback to teach pelvic floor muscle control , verbal feedback based on vaginal palpation , and a self-help booklet in a first-line behavioral training program all achieved comparable improvements in urge incontinence in community-dwelling older women . Patients ' perceptions of treatment were significantly better for the 2 behavioral training interventions Women smokers concerned about weight gain ( N = 219 ) were r and omly assigned to 1 of 3 adjunct treatments accompanying group smoking cessation counseling : ( a ) behavioral weight control to prevent weight gain ( weight control ) ; ( b ) cognitive-behavioral therapy ( CBT ) to directly reduce weight concern , in which dieting was discouraged ; and ( c ) st and ard counseling alone ( st and ard ) , in which weight gain was not explicitly addressed . Ten sessions were conducted over 7 weeks , and no medication was provided . Continuous abstinence was significantly higher at posttreatment and at 6 and 12 months of follow-up for CBT ( 56 % , 28 % , and 21 % , respectively ) , but not for weight control ( 44 % , 18 % , and 13 % , respectively ) , relative to st and ard ( 31 % , 12 % , and 9 % , respectively ) . However , weight control , and to a lesser extent CBT , was associated with attenuation of negative mood after quitting . Prequit body mass index , but not change in weight or in weight concerns postquit , predicted cessation outcome at 1 year . In sum , CBT to reduce weight concerns , but not behavioral weight control counseling to prevent weight gain , improves smoking cessation outcome in weight-concerned women CONTEXT Weight loss programs on the Internet appear promising for short-term weight loss but have not been studied for weight loss in individuals at risk of type 2 diabetes ; thus , the longer-term efficacy is unknown . OBJECTIVE To compare the effects of an Internet weight loss program alone vs with the addition of behavioral counseling via e-mail provided for 1 year to individuals at risk of type 2 diabetes . DESIGN , SETTING , AND PARTICIPANTS A single-center r and omized controlled trial conducted from September 2001 to September 2002 in Providence , RI , of 92 overweight adults whose mean ( SD ) age was 48.5 ( 9.4 ) years and body mass index , 33.1 ( 3.8 ) . INTERVENTIONS Participants were r and omized to a basic Internet ( n = 46 ) or to an Internet plus behavioral e-counseling program ( n = 46 ) . Both groups received 1 face-to-face counseling session and the same core Internet programs and were instructed to su bmi t weekly weights . Participants in e-counseling su bmi tted calorie and exercise information and received weekly e-mail behavioral counseling and feedback from a counselor . MAIN OUTCOME MEASURES Measured weight and waist circumference at 0 and 12 months . RESULTS Intent-to-treat analyses showed the behavioral e-counseling group lost more mean ( SD ) weight at 12 months than the basic Internet group ( -4.4 [ 6.2 ] vs -2.0 [ 5.7 ] kg ; P = .04 ) , and had greater decreases in percentage of initial body weight ( 4.8 % vs 2.2 % ; P = .03 ) , body mass index ( -1.6 [ 2.2 ] vs -0.8 [ 2.1 ] ; P = .03 ) , and waist circumference ( -7.2 [ 7.5 ] vs -4.4 [ 5.7 ] cm ; P = .05 ) . CONCLUSION Adding e-mail counseling to a basic Internet weight loss intervention program significantly improved weight loss in adults at risk of diabetes 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 Purpose . To measure the impact of a resident focused evidence -based medicine ( EBM ) educational intervention on EBM knowledge of residents and students , to assess its feasibility , and to evaluate residents ’ attitudes regarding this rotation . Method . In 2002 , based on the EBM user and EBM practitioner model , the authors design ed the EBM elective rotation and conducted a controlled trial of its implementation in the internal medicine residency program in three teaching hospitals affiliated with the University at Buffalo , New York . The intervention group ( one hospital , 17 medical students and residents ) received a multifaceted intervention . In the control group ( two hospitals , 23 medical students and residents ) , there was no curriculum change . The effectiveness in a pre- and posttest was assessed using the English version of the Berlin Question naire . A survey of all internal medicine residents ( n = 119 ) was conducted to evaluate their attitudes toward the EBM elective rotation . Results . In the intervention group , knowledge improved slightly , but not significantly ( .71 on a scale ranging from 0–15 on the Berlin question naire , p = .3 ) . The mean score in the control group decreased significantly ( 1.65 , p = .005 ) . The difference in change scores between the two groups was significant even after adjustment for covariates ( 2.52 , p = .006 ) . Residents ( response rate 83 % ) had positive attitudes regarding the rotation . Conclusion . An EBM elective rotation was successfully integrated into a residency program . This multifaceted educational approach with an “ on-the-ward ” EBM resident , may improve the EBM knowledge and skills of targeted students and residents CONTEXT The evaluation of the method ologic quality of r and omized controlled trials ( RCTs ) is central to evidence -based health care . Important method ologic detail may , however , be omitted from published reports , and the quality of reporting is therefore often used as a proxy measure for method ologic quality . We examined the relationship between reporting quality and method ologic quality of published RCTs . METHODS Study of 60 reports of placebo-controlled trials published in English- language journals from 1985 to 1997 . Reporting quality was measured using a 25-item scale based on the 1996 issue of the Consoli date d St and ards of Reporting Trials ( CONSORT ) . Concealment of allocation , appropriate blinding , and analysis according to the intention-to-treat principle were indicators of method ologic quality . Method ologic quality was compared between groups of trials defined by reporting quality scores of low , intermediate , and high . Reporting quality scores were compared between groups defined by high and low method ologic quality . RESULTS Among 23 trials of low reporting quality ( median score , 9 [ range , 3.5 - 10.5 ] ) , allocation concealment was unclear for all but 1 trial , but there were 16 trials ( 70 % ) with adequate blinding and 9 trials ( 39 % ) that had been analyzed according to the intention-to-treat principle . Among 18 trials of high reporting quality ( median score , 18 [ range 16.5 - 22.0 ] ) , there were 8 trials ( 44 % ) with adequate allocation concealment , 16 trials ( 89 % ) with adequate blinding , and 13 trials ( 72 % ) analyzed according to the intention-to-treat principle . The median reporting score was 15.0 for the 33 trials that were analyzed according to intention-to-treat principle and 14.5 for the 14 trials with on-treatment analyses ( P = .67 ) . CONCLUSIONS Similar quality of reporting may hide important differences in method ologic quality , and well-conducted trials may be reported badly . A clear distinction should be made between these 2 dimensions of the quality of RCTs 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 This study examined the efficacy of an 8-week telephone-administered cognitive-behavioral therapy ( CBT ) for the treatment of depressive symptomatology in multiple sclerosis ( MS ) patients . The treatment , Coping with MS ( CMS ) , included a patient workbook design ed to structure the treatment , provide visual aids , and help with homework assignments . Thirty-two patients with MS , who scored at least 15 on the Profile of Mood States Depression-Dejection scale , were r and omly assigned to either the telephone CMS or to a usual-care control ( UCC ) condition . Depressive symptomatology decreased significantly in the CMS condition compared with the UCC condition . Furthermore , adherence to interferon beta-1a , a disease-modifying medication for the treatment of MS , was significantly better at the 4-month follow-up among patients who received CMS as compared with those in the UCC condition This study investigated the effects of nondirective counseling on health screening decisions . Ninety women ( mean age = 51 years ) received information about bone density screening and osteoporosis . They were then r and omly allocated to 1 of 4 groups and were encouraged to focus on positive issues about bone density screening ( positive group ) , on negative issues ( negative group ) , on both positive and negative issues ( all-focusing group ) , or on issues relating to the common cold ( control group ) . Women were asked to rate how likely they would be to opt for bone density screening if they saw it available . After being informed that they could have bone density screening , actual uptake was assessed . It was found that the issues on which individuals focused significantly influenced their rate likelihood of opting for the scan . Rated likelihood of testing was significantly associated with whether individuals actually did opt for testing when it was subsequently offered to them This field experiment examined effects of a support intervention on the physical and mental health of coronary artery bypass graft ( CABG ) surgery patients . Control participants ( N = 90 ) received usual hospital care ; experimental participants ( N = 100 ) also received visits from a " similar other " while in the hospital . Similar others were Veterans Administration veterans who had CABG surgery previously and were trained in simple supportive techniques . Outcomes were assessed prior to surgery and at 1 , 6 , and 12 months afterwards . Unexpectedly , the intervention generally had no effects on participants ' well-being . Further analysis showed that participants who talked often with fellow cardiac patients in the hospital ( " de facto similar others " ) experienced improvements in their physical and emotional well-being over time The authors report the short-term effects of a clinical trial testing 2 telephone therapies for breast cancer patients . Women ( N = 222 ) with breast cancer were recruited and r and omly assigned to cancer education , emotional expression , or st and ard care . Oncology nurses conducted 6 individual 30-min-therapy phone sessions . Women in the cancer education condition reported greater perceived control than women in the st and ard care condition . No treatment effects were obtained for mood or quality of life . These are the 1st data from a large-scale study testing telephone therapy , and they suggest that such therapies may be ineffective . Explanations for the results include therapy type and delivery , participant characteristics , short- versus long-term results , therapy conent , and whether therapy is necessary for breast cancer patients 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 A r and omized controlled trial assessed 3 interventions design ed to increase safer sex behaviors of substance-dependent adolescents . Participants ( N = 161 ) received 12 sessions of either a health information intervention ( I only ) , information plus skills-based safer sex training ( I + B ) , or the same experimental condition plus a risk-sensitization manipulation ( I + M + B ) . The I + B and I + M + B conditions , as compared with the I only condition , ( a ) produced more favorable attitudes toward condoms ; ( b ) reduced the frequency of unprotected vaginal sex ; and ( c ) increased behavioral skill performance , frequency of condom-protected sex , percentage of intercourse occasions that were condom protected , and number of adolescents who abstained from sex . The intervention that included the risk-sensitization procedure was more resistant to decay . An unexpected finding was that the I + B and I + M + B conditions produced substantial increases in sexual abstinence The effects of a 10-week group-based cognitive-behavioral stress management ( CBSM ) intervention on psychological distress and plasma free testosterone in symptomatic , HIV-seropositive men were examined . Participants were r and omized to either CBSM ( n = 42 ) or a wait-list control group ( n = 23 ) . Men in the CBSM intervention showed significant increases in testosterone , whereas control participants showed significant decreases . Those participating in CBSM had significant distress reductions , whereas controls showed no such change . Alterations in free testosterone were inversely related to changes in distress states over time , independent of any changes in cortisol . These findings demonstrate that a short-term CBSM intervention increases free testosterone levels among symptomatic , HIV-seropositive men , and alterations in free testosterone are associated with changes in psychological distress observed during CBSM The Internet can reach a large number of people at a low cost and offers the opportunity for 2-way communication . The present study was design ed to evaluate the effects of applied relaxation and problem solving in the treatment of recurrent headache when implemented via the Internet and E-mail . A group of 102 headache sufferers were r and omized to 2 conditions : a 6-week treatment condition or a waiting-list control . The dropout was proportionately large ( 56 % ) , and at the end of the study there were 20 participants in the treatment condition and 25 participants in the control condition . Results showed statistically significant reductions in headache for the treated participants . In 50 % of these , the reduction was clinical ly significant . The Internet has the potential to serve as a complement in the treatment of recurrent headache and deserves further study Assessing the quality of r and omized controlled trials ( RCTs ) is important and relatively new . Quality gives us an estimate of the likelihood that the results are a valid estimate of the truth . We present an annotated bibliography of scales and checklists developed to assess quality . Twenty-five scales and nine checklists have been developed to assess quality . The checklists are most useful in providing investigators with guidelines as to what information should be included in reporting RCTs . The scales give readers a quantitative index of the likelihood that the reported methodology and results are free of bias . There are several shortcomings with these scales . Future scale development is likely to be most beneficial if questions common to all trials are assessed , if the scale is easy to use , and if it is developed with sufficient rigor This study evaluated a distraction intervention design ed to reduce the distress of preschool children undergoing repeated chemotherapy injections . Twenty-nine children aged 2 - 5 years were r and omly assigned either to distraction by a developmentally appropriate electronic toy or to a wait-list control . Children who received the distraction intervention demonstrated lower overt behavioral distress and were rated by parents and nurses as less anxious than children in the control condition . The improvements were maintained over the 8-week intervention . The results suggest that a developmentally appropriate , multisensory , variable-distracting activity that requires active cognitive processing and active motor responses may be a viable cost-effective alternative to more time-intensive parent-training programs for preschool-age children Smokers ( N = 224 ) were r and omized to 1 of 3 groups : ( a ) transdermal system ( TNS ) + placebo ; ( b ) TNS + paroxetine ( 20 mg ) ; ( c ) TNS + paroxetine ( 40 mg ) . Assignment to treatment was double-blind . Nicotine patch ( TNS ) treatment was provided for 8 weeks ; paroxetine or placebo was provided for 9 weeks . Abstinence rates at Weeks 4 , 10 , and 26 were as follows : ( a ) TNS + placebo : 45 % , 36 % , and 25 % ; ( b ) TNS + paroxetine ( 20 mg ) : 48 % , 33 % , and 21 % ; ( c ) TNS + paroxetine ( 40 mg ) : 57 % , 39 % , and 27 % . The differences were not statistically significant . The combined treatment was more effective in reducing both craving and depression symptoms associated with smoking cessation . A subgroup analysis comparing compliant participants was also conducted . Abstinence rates at Weeks 4 , 10 , and 26 were as follows : ( a ) TNS + placebo : 46 % , 35 % , and 24 % ; ( b ) TNS + paroxetine ( 20 mg ) : 64 % , 43 % , and 33 % ; ( c ) TNS + paroxetine ( 40 mg ) : 74 % , 51 % , and 38 % . The differences between paroxetine groups and placebo at Week 4 were statistically significant . Although paroxetine may add value to the current st and ard of care in excess of potential risk , more conclusive evidence is needed CONTEXT Current evidence that breastfeeding is beneficial for infant and child health is based exclusively on observational studies . Potential sources of bias in such studies have led to doubts about the magnitude of these health benefits in industrialized countries . OBJECTIVE To assess the effects of breastfeeding promotion on breastfeeding duration and exclusivity and gastrointestinal and respiratory infection and atopic eczema among infants . DESIGN The Promotion of Breastfeeding Intervention Trial ( PROBIT ) , a cluster-r and omized trial conducted June 1996-December 1997 with a 1-year follow-up . SETTING Thirty-one maternity hospitals and polyclinics in the Republic of Belarus . PARTICIPANTS A total of 17 046 mother-infant pairs consisting of full-term singleton infants weighing at least 2500 g and their healthy mothers who intended to breastfeed , 16491 ( 96.7 % ) of which completed the entire 12 months of follow-up . INTERVENTIONS Sites were r and omly assigned to receive an experimental intervention ( n = 16 ) modeled on the Baby-Friendly Hospital Initiative of the World Health Organization and United Nations Children 's Fund , which emphasizes health care worker assistance with initiating and maintaining breastfeeding and lactation and postnatal breastfeeding support , or a control intervention ( n = 15 ) of continuing usual infant feeding practice s and policies . MAIN OUTCOME MEASURES Duration of any breastfeeding , prevalence of predominant and exclusive breastfeeding at 3 and 6 months of life and occurrence of 1 or more episodes of gastrointestinal tract infection , 2 or more episodes of respiratory tract infection , and atopic eczema during the first 12 months of life , compared between the intervention and control groups . RESULTS Infants from the intervention sites were significantly more likely than control infants to be breastfed to any degree at 12 months ( 19.7 % vs 11.4 % ; adjusted odds ratio [ OR ] , 0.47 ; 95 % confidence interval [ CI ] , 0.32 - 0.69 ) , were more likely to be exclusively breastfed at 3 months ( 43.3 % vs 6.4 % ; P<.001 ) and at 6 months ( 7.9 % vs 0.6 % ; P = .01 ) , and had a significant reduction in the risk of 1 or more gastrointestinal tract infections ( 9.1 % vs 13.2 % ; adjusted OR , 0.60 ; 95 % CI , 0.40 - 0.91 ) and of atopic eczema ( 3.3 % vs 6.3 % ; adjusted OR , 0.54 ; 95 % CI , 0.31 - 0.95 ) , but no significant reduction in respiratory tract infection ( intervention group , 39.2 % ; control group , 39.4 % ; adjusted OR , 0.87 ; 95 % CI , 0.59 - 1.28 ) . CONCLUSIONS Our experimental intervention increased the duration and degree ( exclusivity ) of breastfeeding and decreased the risk of gastrointestinal tract infection and atopic eczema in the first year of life . These results provide a solid scientific underpinning for future interventions to promote breastfeeding This study r and omized obese children from 67 families to groups that received a 6-month family-based behavioral weight-control program plus parent and child problem solving , child problem solving , or st and ard treatment with no additional problem solving . The st and ard group showed larger body mass index ( BMI ) decreases than the parent + child group through 2 years , with significant differences in the percentage of children who showed large BMI changes . Significant statistical and clinical improvements were observed over time in child behavior problems and parental distress . Parent problem solving increased in the parent + child condition relative to the other conditions , whereas child problem solving increased equally in all conditions . The bulk of evidence suggests that problem solving did not add to treatment effectiveness beyond the st and ard family-based treatment The efficacies of 2 group counseling step-up treatments for smoking cessation , cognitive-behavioral/skill training therapy ( CBT ) and motivational interviewing/supportive ( MIS ) therapy , were compared with brief intervention ( BI ) treatment in a sample of 677 smokers . Differential efficacy of the 2 step-up treatments was also tested in smokers at low and high risk for relapse ( no smoking vs. any smoking during the first postquit week . respectively ) . All participants received 8 weeks of nicotine patch therapy . BI consisted of 3 brief individual cessation counseling sessions ; CBT and MIS participants received BI treatment and 6 group counseling sessions . Neither CBT nor MIS treatment improved long-term abstinence rates relative to BI . Limited support was found for the hypothesis that high-risk smokers would benefit more from MIS than CBT . Other hypotheses were not supported Sixty participants with insomnia secondary to chronic pain were assigned r and omly to either a cognitive-behavioral therapy ( CBT ) or a self-monitoring/waiting-list control condition . The therapy consisted of a multicomponent 7-week group intervention aim ed at promoting good sleep habits , teaching relaxation skills , and changing negative thoughts about sleep . Treated participants were significantly more improved than control participants on self-report measures of sleep onset latency , wake time after sleep onset , sleep efficiency , and sleep quality , and they showed less motor activity in ambulatory recordings of nocturnal movement . At a 3-month follow-up assessment , treated participants showed good maintenance of most therapeutic gains . These results provide the 1st evidence from a r and omized controlled trial that CBT is an effective treatment for insomnia that is secondary to chronically painful medical conditions Cigarette smokers with past major depressive disorder ( MDD ) received 8 group sessions of st and ard , cognitive-behavioral smoking cessation treatment ( ST ; n = 93 ) or st and ard , cognitive-behavioral smokiig cessation treatment plus cognitive-behavioral treatment for depression ( CBT-D ; n = 86 ) . Although abstinence rates were high in both conditions ( ST , 24.7 % ; CBT-D , 32.5 % , at 1 year ) for these nonpharmacological treatments , no main effect of treatment was found . However , secondary analyses revealed significant interactions between treatment condition and both recurrent depression history and heavy smoking ( > or = 25 cigarettes a day ) at baseline . Smokers with recurrent MDD and heavy smokers who received CBT-D were significantly more likely to be abstinent than those receiving ST ( odds ratios = 2.3 and 2.6 , respectively ) . Results suggest that CBT-D provides specific benefits for some , but not all , smokers with a history of MDD CONTEXT Weight loss , sodium reduction , increased physical activity , and limited alcohol intake are established recommendations that reduce blood pressure ( BP ) . The Dietary Approaches to Stop Hypertension ( DASH ) diet also lowers BP . To date , no trial has evaluated the effects of simultaneously implementing these lifestyle recommendations . OBJECTIVE To determine the effect on BP of 2 multicomponent , behavioral interventions . DESIGN , SETTING , AND PARTICIPANTS R and omized trial with enrollment at 4 clinical centers ( January 2000-June 2001 ) among 810 adults ( mean [ SD ] age , 50 [ 8.9 ] years ; 62 % women ; 34 % African American ) with above-optimal BP , including stage 1 hypertension ( 120 - 159 mm Hg systolic and 80 - 95 mm Hg diastolic ) , and who were not taking antihypertensive medications . INTERVENTION Participants were r and omized to one of 3 intervention groups : ( 1 ) " established , " a behavioral intervention that implemented established recommendations ( n = 268 ) ; ( 2 ) " established plus DASH,"which also implemented the DASH diet ( n = 269 ) ; and ( 3 ) an " advice only " comparison group ( n = 273 ) . MAIN OUTCOME MEASURES Blood pressure measurement and hypertension status at 6 months . RESULTS Both behavioral interventions significantly reduced weight , improved fitness , and lowered sodium intake . The established plus DASH intervention also increased fruit , vegetable , and dairy intake . Across the groups , gradients in BP and hypertensive status were evident . After subtracting change in advice only , the mean net reduction in systolic BP was 3.7 mm Hg ( P<.001 ) in the established group and 4.3 mm Hg ( P<.001 ) in the established plus DASH group ; the systolic BP difference between the established and established plus DASH groups was 0.6 mm Hg ( P = .43 ) . Compared with the baseline hypertension prevalence of 38 % , the prevalence at 6 months was 26 % in the advice only group , 17 % in the established group ( P = .01 compared with the advice only group ) , and 12 % in the established plus DASH group ( P<.001 compared with the advice only group ; P = .12 compared with the established group ) . The prevalence of optimal BP ( < 120 mm Hg systolic and < 80 mm Hg diastolic ) was 19 % in the advice only group , 30 % in the established group ( P = .005 compared with the advice only group ) , and 35 % in the established plus DASH group ( P<.001 compared with the advice only group ; P = .24 compared with the established group ) . CONCLUSION Individuals with above-optimal BP , including stage 1 hypertension , can make multiple lifestyle changes that lower BP and reduce their cardiovascular disease risk This study evaluated the effects of written feedback adapted to a self-help mail intervention . The efficacy of the st and ard mail intervention treatment was 37 % at the end of treatment , 22 % at the 3-month follow-up , 19 % at the 6-month follow-up , and 13 % at the 12-month follow-up . In contrast , the st and ard mail program combined with personalized written feedback result ed in an efficacy of 51 % at the end of treatment , 37 % at the 3-month follow-up , 32 % at the 6-month follow-up , and 27 % at the 12-month follow-up . Both groups were significantly different from the control group at the end of treatment ( 0 % ) , at the 3-month follow-up ( 1 % ) , and at the 6-month follow-up ( 1 % ) . There was a significant reduction in the number of cigarettes smoked daily among continuing smokers under both experimental conditions . The authors conclude that written feedback substantially increases abstinence rates when it is applied following similar guidelines to those used in clinical setting Infant procedural distress is largely understudied , and there is a dearth of empirically supported interventions in the child health psychology literature . This study examined nurse-directed distraction for reducing infant immunization distress . Ninety infants and their parents were r and omly assigned to a distraction condition ( i.e. , nurses used stimuli to divert infants ' attention ) or a typical care condition . Outcome measures were an observational scale , parent and nurse ratings , and infant heart rate . Results indicated that infants engaged in distraction and that distraction reduced their behavioral distress ; however , ratings and heart rate were inconclusive . Analyses of procedural phases indicated that infants exhibited elevated distress immediately prior to and during an injection , but this distress was fleeting Adherence to medications for chronic pediatric diseases decreases overtime . This r and omized controlled trial evaluated a clinic-based , nurse-administered educational and behavioral intervention to prevent the anticipated drop in adherence to nonsteroidal medications among newly diagnosed patients with juvenile rheumatoid arthritis . Thirty-four participants completed the study ( mean age = 8.44 years , SD = 3.96 ) , including 19 in the experimental group and 15 in the st and ard-treatment ( education ) control group . There were significant group and Group x Time effects for adherence ( assessed with an electronic monitor over a 13-month period ) favoring the experimental group . In contrast , the groups did not differ significantly in disease activity or functional limitations . Factors that may have prevented detection of differences in these health parameters are dicussed This study assessed whether contingent incentives can be used to reinforce cocaine abstinence in dependent out patients . Seventy cocaine-dependent out patients were r and omized into 2 conditions . All participants received 24 weeks of treatment and 1 year of follow-up . The treatment provided to all participants combined counseling based on the community reinforcement approach with incentives in the form of vouchers exchangeable for retail items . In 1 condition , incentives were delivered contingent on cocaine-free urinalysis results , whereas in the other condition incentives were delivered independent of urinalysis results . Abstinence-contingent incentives significantly increased cocaine abstinence during treatment and 1 year of follow-up compared with noncontingent incentives This study compared 2 minimal interventions for reducing relapse in ex-smokers . One intervention involved 12-month access to a telephone hot line . In the other intervention , 8 relapse-prevention booklets were mailed to participants over 1 year . The 2 interventions were crossed in a 2 x 2 factorial design , yielding control , hot-line-only , mailings-only , and combined conditions . The criterion of at least 1 week of abstinence at baseline was met by 584 participants , 446 of whom also completed a 12-month assessment . Repeated mailings , but not the hot line , reduced relapse for those participants who had been abstinent for less than 3 months at baseline . At follow-up , 12 % of those in the mailings conditions were smoking again compared with 35 % in the nonmailing conditions . As predicted , both interventions were effective at attenuating the association between depressive symptoms and poor outcome found in the control condition CONTEXT High nevus density is a risk factor for cutaneous malignant melanoma . Melanocytic nevi originate in childhood and are largely caused by solar exposure . OBJECTIVE To determine whether use of broad-spectrum , high-sun protection factor ( SPF ) sunscreen attenuates development of nevi in white children . DESIGN R and omized trial conducted June 1993 to May 1996 . SETTING AND PARTICIPANTS A total of 458 Vancouver , British Columbia , schoolchildren in grade s 1 and 4 were r and omized in 1993 . After exclusion of nonwhite children and those lost to follow-up or with missing data , 309 children remained for analysis . Each child 's nevi were enumerated at the start and end of the study in 1996 . INTERVENTION Parents of children r and omly assigned to the treatment group ( n=222 ) received a supply of SPF 30 broad-spectrum sunscreen with directions to apply it to exposed sites when the child was expected to be in the sun for 30 minutes or more . Children r and omly assigned to the control group ( n=236 ) received no sunscreen and were given no advice about sunscreen use . MAIN OUTCOME MEASURE Number of new nevi acquired during the 3 years of the study , compared between treatment and control groups . RESULTS Children in the sunscreen group developed fewer nevi than did children in the control group ( median counts , 24 vs 28 ; P=.048 ) . A significant interaction was detected between freckling and study group , indicating that sunscreen use was much more important for children with freckles than for children without . Modeling of the data suggests that freckled children assigned to a broad-spectrum sunscreen intervention would develop 30 % to 40 % fewer new nevi than freckled children assigned to the control group . CONCLUSIONS Our data indicate that broad-spectrum sunscreens may attenuate the number of nevi in white children , especially if they have freckles . JAMA . 2000 In this 12-month trial st and ard exercise training was compared with a group-mediated cognitive-behavioral ( GMCB ) intervention with respect to effects on long-term adherence and change in physical function of older adults who were either at risk for or had cardiovascular disease . Participants ( 147 older men and women ) were r and omized to the 2 treatments . Outcomes included self-reportedphysical activity , fitness , and self-efficacy . The GMCB treatment produced greater improvements on all outcomes than did st and ard exercise therapy . Regardless of treatment assignment , men had more favorable change on the study outcomes than did women . Analysis of a self-regulatory process measure in the GMCB group revealed that change in barriers efficacy was related to change in physical activity and fitness . Results suggest that teaching older adults to integrate physical activity into their lives via GMCB leads to better long-term outcomes than st and ardized exercise therapy Telephone counseling is a popular modality for smoking cessation treatment ; however , little attention has been paid to evaluating the efficacy of different contents of calls . This study compared 2 types of proactive telephone calls following a group program . Participants were r and omized to receive either : ( a ) basic content , consisting primarily of support ; or ( b ) enhanced content , tailored to the stage of cessation ( still smoking , abstinent , or relapsed ) and targeting factors hypothesized to be related to success ( motivation , self-efficacy , and negative mood ) . There was a significant interaction between treatment condition and gender . For men , the enhanced condition produced better abstinence rates through 15 months and lower relapse rates . For women , the basic condition was better . History of depression did not interact with condition This study examined the effects of matching participants to treatments on the basis of their preferences for either individual or group therapy for obesity . Seventy-five obese adults who expressed a clear preference for either individual or group therapy were r and omly assigned to either their preferred or their nonpreferred treatment modality within a 2 ( individual vs. group therapy ) x 2 ( preferred vs. nonpreferred modality ) factorial design . At posttreatment , group therapy produced significantly greater reductions in weight and body mass than individual therapy , and no significant effects were observed for treatment preference or the interaction for treatment preference by type of therapy . All treatment conditions showed equivalent improvements in psychological functioning . These findings suggest that group therapy produces greater weight loss than individual therapy , even among those clients who express a preference for individual treatment This r and omized clinical trial evaluated an HIV-risk reduction ( HIV-RR ) intervention based on the information-motivation-behavioral skills model . At baseline , 102 women ( M age = 29 years ; 88 % African American ) completed a survey regarding HIV-related knowledge , risk perceptions , behavioral intentions , and risk behavior . Participants were then assigned to either the HIV-RR intervention or a health-promotion control group . Postintervention and follow-up data indicated that women in the HIV-RR program enhanced their knowledge and strengthened their risk reduction intentions relative to controls . Moreover , HIV-RR women who expressed " imperfect " intentions also increased their condom use , talked more with partners about condom use and HIV testing , and were more likely to have refused unprotected sex BACKGROUND A low-calcium diet is recommended to prevent recurrent stones in patients with idiopathic hypercalciuria , yet long-term data on the efficacy of a low-calcium diet are lacking . Recently , the efficacy of a low-calcium diet has been question ed , and greater emphasis has been placed on reducing the intake of animal protein and salt , but again , long-term data are unavailable . METHODS We conducted a five-year r and omized trial comparing the effect of two diets in 120 men with recurrent calcium oxalate stones and hypercalciuria . Sixty men were assigned to a diet containing a normal amount of calcium ( 30 mmol per day ) but reduced amounts of animal protein ( 52 g per day ) and salt ( 50 mmol of sodium chloride per day ) ; the other 60 men were assigned to the traditional low-calcium diet , which contained 10 mmol of calcium per day . RESULTS At five years , 12 of the 60 men on the normal-calcium , low-animal-protein , low-salt diet and 23 of the 60 men on the low-calcium diet had had relapses . The unadjusted relative risk of a recurrence for the group on the first diet , as compared with the group on the second diet , was 0.49 ( 95 percent confidence interval , 0.24 to 0.98 ; P=0.04 ) . During follow-up , urinary calcium levels dropped significantly in both groups by approximately 170 mg per day ( 4.2 mmol per day ) . However , urinary oxalate excretion increased in the men on the low-calcium diet ( by an average of 5.4 mg per day [ 60 micromol per day ] ) but decreased in those on the normal-calcium , low-animal-protein , low-salt diet ( by an average of 7.2 mg per day [ 80 micromol per day ] ) . CONCLUSIONS In men with recurrent calcium oxalate stones and hypercalciuria , restricted intake of animal protein and salt , combined with a normal calcium intake , provides greater protection than the traditional low-calcium diet |
1,990 | 27,009,102 | Although MVR for ischaemic MR has a higher 30-day mortality rate compared with MVRp , MVRp is associated with the higher rate of MR recurrence and the need for reoperation .
MVR remains an attractive option for ischaemic MR | Ischaemic mitral regurgitation ( MR ) is associated with poor survival .
The favoured surgical option remains debatable .
Our aim was to perform a meta- analysis to compare the outcomes of mitral valve repair ( MVRp ) with replacement ( MVR ) . | BACKGROUND Ischemic mitral regurgitation is associated with a substantial risk of death . Practice guidelines recommend surgery for patients with a severe form of this condition but acknowledge that the supporting evidence for repair or replacement is limited . METHODS We r and omly assigned 251 patients with severe ischemic mitral regurgitation to undergo either mitral-valve repair or chordal-sparing replacement in order to evaluate efficacy and safety . The primary end point was the left ventricular end-systolic volume index ( LVESVI ) at 12 months , as assessed with the use of a Wilcoxon rank-sum test in which deaths were categorized below the lowest LVESVI rank . RESULTS At 12 months , the mean LVESVI among surviving patients was 54.6±25.0 ml per square meter of body-surface area in the repair group and 60.7±31.5 ml per square meter in the replacement group ( mean change from baseline , -6.6 and -6.8 ml per square meter , respectively ) . The rate of death was 14.3 % in the repair group and 17.6 % in the replacement group ( hazard ratio with repair , 0.79 ; 95 % confidence interval , 0.42 to 1.47 ; P=0.45 by the log-rank test ) . There was no significant between-group difference in LVESVI after adjustment for death ( z score , 1.33 ; P=0.18 ) . The rate of moderate or severe recurrence of mitral regurgitation at 12 months was higher in the repair group than in the replacement group ( 32.6 % vs. 2.3 % , P<0.001 ) . There were no significant between-group differences in the rate of a composite of major adverse cardiac or cerebrovascular events , in functional status , or in quality of life at 12 months . CONCLUSIONS We observed no significant difference in left ventricular reverse remodeling or survival at 12 months between patients who underwent mitral-valve repair and those who underwent mitral-valve replacement . Replacement provided a more durable correction of mitral regurgitation , but there was no significant between-group difference in clinical outcomes . ( Funded by the National Institutes of Health and the Canadian Institutes of Health ; Clinical Trials.gov number , NCT00807040 . ) Background — When compared to mitral valve replacement ( MVR ) , mitral valve repair ( MVRp ) is associated with better survival in patients with organic mitral regurgitation ( MR ) . However , there is an important controversy about the type of surgical treatment that should be used in patients with ischemic MR . The objective of this study was to compare the postoperative outcome of MVRp versus MVR in patients with ischemic MR . Methods and Results — Preoperative and operative data of 370 patients with ischemic MR who underwent mitral valve surgery were prospect ively collected and retrospectively analyzed . MVRp was performed in 50 % of patients ( n=186 ) and MVR in 50 % ( n=184 ) . Although operative mortality was significantly lower after MVRp compared to MVR ( 9.7 % versus 17.4 % ; P=0.03 ) , overall 6-year survival was not statistically different between procedures ( 73±4 % versus 67±4 % ; P=0.17 ) . After adjusting for other risk factors and propensity score , the type of procedure ( MVRp versus MVR ) did not come out as an independent predictor of either operative ( OR , 1.5 ; 95 % CI , 0.7–2.9 ; P=0.34 ) or overall mortality ( HR , 1.2 ; 95 % CI , 0.7–1.9 ; P=0.52 ) . Conclusion — As opposed to what has been reported in patients with organic MR , the results of this study suggest that MVRp is not superior to MVR with regard to operative and overall mortality in patients with ischemic MR . These findings provide support for the realization of a r and omized trial comparing these 2 treatment modalities BACKGROUND Mitral regurgitation ( MR ) may complicate acute myocardial infa rct ion ( MI ) . However , it is not known whether mild MR is an independent predictor of post-MI outcome . METHODS AND RESULTS The study cohort consisted of 727 Survival and Ventricular Enlargement Study patients who underwent cardiac catheterization , including left ventriculography , up to 16 days after MI . Left ventriculograms were analyzed for diastolic and systolic volumes , global left ventricular sphericity , extent of wall motion abnormality , and endocardial curvature . The presence of MR was related to the risk of developing a cardiovascular event during 3.5 years of follow-up . MR was present in 141 patients ( 19.4 % ) . Severe ( 3 + ) MR was present in only 2 patients . Patients with MR were more likely to have a persistently occluded infa rct artery ( MR versus no MR , 27.3 % versus 15.2 % ; P=.001 ) . Although the ejection fractions were similar , MR patients had larger end-systolic and end-diastolic volumes and more spherical ventricles than patients without MR . Sphericity change from diastole to systole was also significantly reduced in MR patients . Patients with MR were more likely to experience cardiovascular mortality ( 29 % versus 12 % ; P<.001 ) , severe heart failure ( 24 % versus 16 % ; P=.0153 ) , and the combined end point of cardiovascular mortality , severe heart failure , or recurrent myocardial infa rct ion ( 47 % versus 29 % ; P<.001 ) . The presence of MR was an independent predictor of cardiovascular mortality ( relative risk , 2.00 ; 95 % CI , 1.28 to 3.04 ) . CONCLUSIONS Mild MR is an independent predictor of post-MI mortality . As such , it adds important information for risk stratification of post-MI patients OBJECTIVES Mitral valve ( MV ) surgery for ischaemic mitral regurgitation ( IMR ) in patients with depressed left ventricular ejection fraction ( LVEF ) is associated with poor outcomes . The optimal surgical strategy for IMR in these patients remains controversial . The objective of this study was to compare the early mortality and mid-term survival of MV repair versus MV replacement in patients with IMR and depressed LVEF undergoing coronary artery bypass grafting ( CABG ) . METHODS A retrospective , observational , cohort study was undertaken of prospect ively collected data on 126 consecutive CABG patients with IMR and LVEF < 40 % undergoing either MV repair ( n = 98 , 78 % ) or MV replacement ( n = 28 , 22 % ) between July 2002 and February 2011 . RESULTS The overall mortality rate was 7.9 % ( n = 10 ) . MV replacement was associated with a 4-fold increase in the risk of death compared with MV repair [ 17.9 % , n = 5 vs 5.1 % , n = 5 ; odds ratio ( OR ) 4.04 , 95 % confidence interval ( CI ) 1.08 - 15.1 , P = 0.04 ] . However , after adjusting for preoperative risk factors , the type of surgical procedure was not an independent risk factor for early mortality ( OR 0.1 , 95 % CI 0.01 - 31 , P = 0.7 ) . Multivariable analysis showed that preoperative LVEF ( OR 0.8 , 95 % CI 0.6 - 0.9 , P = 0.018 ) , preoperative B-type natriuretic peptide ( BNP ) levels ( OR 1.01 , 95 % CI 1 - 1.02 , P = 0.025 ) , preoperative left ventricle end-systolic diameter ( OR 0.8 , 95 % CI 0.7 - 1.0 , P = 0.05 ) and preoperative left atrial diameter ( OR 1.3 , 95 % CI 1.0 - 1.6 , P = 0.015 ) were independent risk factors of early mortality . At the median follow-up of 45 months ( interquartile range 20 - 68 months ) , the mid-term survival rate was 74 % in the MV repair group and 70 % in the MV replacement group ( P = 0.08 ) . At follow-up , predictors of worse survival were BNP levels [ hazard ratio ( HR ) 1.0 , 95 % CI 1.0 - 1.01 , P = 0.047 ] , preoperative renal failure ( HR 4.6 , 95 % CI 1.1 - 20.3 , P = 0.039 ) and preoperative atrial fibrillation ( HR 3.3 , 95 % CI 1.1 - 10 , P = 0.032 ) . CONCLUSIONS MV repair in CABG patients with IMR and depressed LVEF is not superior to MV replacement with regard to operative early mortality and mid-term survival OBJECTIVE Mitral incompetence is a chronic sequela of myocardial infa rct ion . It is caused by apical displacement and tethering of the mitral valve leaflets after myocardial infa rct ion , result ing in incomplete coaptation . The consensus is for mitral valve surgery in the presence of significant ischemic mitral regurgitation ( IMR ) . Previously , the only option was mitral valve replacement ( MVR ) with a mechanical or tissue valve . The suboptimal results obtained prompted the development of several methods of mitral valve repair . Today , the most commonly used repair is undersized annuloplasty . METHODS We conducted a retrospective nonr and omized study of all patients who underwent operation for coronary artery disease and IMR between 2000 and 2006 . The surgeon chose the surgical method used for the mitral valve procedure . The most commonly used procedures were restrictive mitral valve annuloplasty ( MVP ) and MVR with a mechanical prosthesis . We collected all pertinent preoperative , intraoperative , and early-postoperative data . We followed up with phone interviews of the patients and their relatives and with complete clinical and echocardiography examinations . RESULTS We carried out operations on 138 patients during the study period ( MVR , 52 patients ; MVP , 86 patients ) . The 2 groups had comparable demographic data and risk factors . The 2 groups were significantly different with respect to mean ( + /-SD ) New York Heart Association ( NYHA ) class ( MVP , 2.72 + /- 0.62 ; MVR , 2.48 + /- 0.70 ; P < .01 ) and ejection fraction ( MVP , 29.01 % + /- 11.00 % ; MVR , 35.87 % + /- 11.00 % ; P < /= .01 ) . The 30-day mortality rates for the MVR and MVP groups were significantly different ( 9.61 % and 5.81 % , respectively ; P < .01 ) . Our follow-up included 83 % of the patients and continued for up to 84 months . The 2 groups showed no significant difference in mortality by the end of follow-up ; however , the MVR patients had a better ejection fraction ( 37.79 % versus 29.86 % ) and NYHA functional class ( 1.88 + /- 0.498 versus 2.36 + /- 0.564 ; P < .01 ) . CONCLUSION Correcting chronic IMR with either repair or replacement produces a good mid-term survival rate ( approximately 75 % ) for survivors in NYHA classes I and II . In our study , mortality rates for the MVP and MVR groups were similar , even though the repair group had a lower mean ejection fraction and a higher NYHA class before and after the operation . We therefore conclude that repair is superior to replacement in treating ischemic mitral insufficiency . A prospect i ve r and omized study is needed to better compare these 2 approaches |
1,991 | 27,566,746 | Conclusions : Our findings indicate that IV tPA delivery through telestroke networks is safe and effective in the 3-hour time window . | Objective : The aim of this systematic review and meta- analysis was to evaluate the safety and efficacy of IV thrombolysis ( IVT ) with tissue plasminogen activator ( tPA ) delivered through telestroke networks in patients with acute ischemic stroke . | BACKGROUND AND PURPOSE Telemedicine can disseminate vascular neurology expertise and optimize recombinant tissue plasminogen activator ( rt-PA ) use for acute ischemic stroke in rural underserved communities . The purpose of this study was to prospect ively assess whether telemedicine or telephone was superior for decision-making . METHODS The study design is a pooled analysis of two identically design ed r and omized controlled trials conducted in a multistate hub and spoke telestroke network setting with acute stroke syndrome patients , comparing telemedicine versus telephone-only consultations . From each trial , common data elements were pooled to assess , principally , for correctness of thrombolysis decision-making . Secondary outcomes included rt-PA use rate , 90-day functional outcome , post-thrombolysis intracranial hemorrhage , and data completeness . RESULTS Two hundred seventy-six pooled patients were evaluated . Correct thrombolysis eligibility decisions were made more often with telemedicine ( 96 % telemedicine , 83 % telephone ; odds ratio [ OR ] 4.2 ; 95 % confidence interval [ CI ] 1.69 - 10.46 ; p=0.002 ) . Intravenous rt-PA usage was 26 % ( 29 % telemedicine , 24 % telephone ; OR 1.27 ; 95 % CI 0.71 - 2.25 ; p=0.41 ) . Ninety-day outcomes were not different for Barthel Index , modified Rankin Scale , or mortality . There was no difference in post-thrombolysis intracranial hemorrhage ( 8 % telemedicine , 6 % telephone ; p>0.999 ) . CONCLUSIONS This pooled analysis supports the hypothesis that stroke telemedicine consultations , compared with telephone-only , result in more accurate decision-making . Together with high rt-PA utilization rate , low post-rt-PA intracranial hemorrhage rate , and acceptable patient outcome , the results confirm that telemedicine is a viable consultative tool for acute stroke . The replication of the hub and spoke network infrastructure supports the generalizability of telemedicine when used in broader setting Background and Purpose — Telestroke networks offer an opportunity to increase tissue-type plasminogen activator use in community hospitals . Methods — We compared 83 patients treated with intravenous tissue-type plasminogen activator by telestroke to 59 patients treated after in-person evaluation by the same neurologists at a tertiary care stroke center . Onset and door-to-treatment times and functional outcome at 90 days were obtained prospect ively . Favorable outcome was defined as modified Rankin Scale score ⩽2 . Results — Favorable outcome rates were comparable between the groups ( 42.1 % versus 37.5 % , P=0.7 ) . There was no significant difference in the rate of symptomatic hemorrhage . Conclusions — Telestroke is a viable alternative to in-person evaluation when stroke expertise is not readily available BACKGROUND Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke , but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established . We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke . METHODS After exclusion of patients with a brain hemorrhage or major infa rct ion , as detected on a computed tomographic scan , we r and omly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase ( 0.9 mg per kilogram of body weight ) or placebo . The primary end point was disability at 90 days , dichotomized as a favorable outcome ( a score of 0 or 1 on the modified Rankin scale , which has a range of 0 to 6 , with 0 indicating no symptoms at all and 6 indicating death ) or an unfavorable outcome ( a score of 2 to 6 on the modified Rankin scale ) . The secondary end point was a global outcome analysis of four neurologic and disability scores combined . Safety end points included death , symptomatic intracranial hemorrhage , and other serious adverse events . RESULTS We enrolled a total of 821 patients in the study and r and omly assigned 418 to the alteplase group and 403 to the placebo group . The median time for the administration of alteplase was 3 hours 59 minutes . More patients had a favorable outcome with alteplase than with placebo ( 52.4 % vs. 45.2 % ; odds ratio , 1.34 ; 95 % confidence interval [ CI ] , 1.02 to 1.76 ; P=0.04 ) . In the global analysis , the outcome was also improved with alteplase as compared with placebo ( odds ratio , 1.28 ; 95 % CI , 1.00 to 1.65 ; P<0.05 ) . The incidence of intracranial hemorrhage was higher with alteplase than with placebo ( for any intracranial hemorrhage , 27.0 % vs. 17.6 % ; P=0.001 ; for symptomatic intracranial hemorrhage , 2.4 % vs. 0.2 % ; P=0.008 ) . Mortality did not differ significantly between the alteplase and placebo groups ( 7.7 % and 8.4 % , respectively ; P=0.68 ) . There was no significant difference in the rate of other serious adverse events . CONCLUSIONS As compared with placebo , intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke ; alteplase was more frequently associated with symptomatic intracranial hemorrhage . ( Clinical Trials.gov number , NCT00153036 . Background : IV thrombolysis represents the most effective acute stroke therapy . However , it is almost exclusively performed in stroke centers and is not available in most community areas . The Telemedical Pilot Project for Integrative Stroke Care ( TEMPiS ) was started in February 2003 . Twelve community hospitals with no or very limited stroke thrombolysis experience and two stroke centers were connected via a network providing online neurologic examination and transfer of neuroradiologic scans . Following recently published preliminary results on acute phase safety of telethrombolysis , the present study reports on its long-term functional outcome . Methods : Modified Rankin Scale ( mRS ) , Barthel Index ( BI ) , and mortality rate were prospect ively collected 3 and 6 months after IV thrombolysis in patients of community network hospitals ( telemedical group ) and the stroke centers . Values of 95/100 for the BI and 0/1 for the mRS were defined as a favorable outcome . Results : Over the first 22 months , 170 patients were treated with tPA in the telemedical hospitals and 132 in the stroke center hospitals . Mortality rates were 11.2 % vs 11.5 % at 3 months ( p = 0.55 ) and 14.2 % vs 13 % at 6 months ( p = 0.45 ) . A good functional outcome after 6 months was found in 39.5 % of the telemedical hospitals vs 30.9 % of the stroke centers ( p = 0.10 ) for the mRS and 47.1 % vs 44.8 % ( p = 0.44 ) regarding the BI . Conclusions : Mortality rates and functional outcomes for telemedicine-linked community hospitals and stroke centers were similar and comparable to the results from r and omized trials Background and Purpose — Telemedicine techniques can be used to address the rural – metropolitan disparity in acute stroke care . The Stroke Team Remote Evaluation Using a Digital Observation Camera ( STRokE DOC ) trial reported more accurate decision making for telemedicine consultations compared with telephone-only and that the California-based research network facilitated a high rate of thrombolysis use , improved data collection , low risk of complications , low technical complications , and favorable assessment times . The main objective of the STRokE DOC Arizona TIME ( The Initial Mayo Clinic Experience ) trial was to determine the feasibility of establishing , de novo , a single-hub , multirural spoke hospital telestroke research network across a large geographical area in Arizona by replicating the STRokE DOC protocol . Methods — Methods included prospect i ve , single-hub , 2-spoke , r and omized , blinded , controlled trial of a 2-way , site-independent , audiovisual telemedicine system design ed for remote examination of adult patients with acute stroke versus telephone consultation to assess eligibility for treatment with intravenous thrombolysis . The primary outcome measure was whether the decision to give thrombolysis was correct . Secondary outcomes were rate of thrombolytic use , 90-day functional outcomes , incidence of intracerebral hemorrhages , and technical observations . Results — From December 2007 to October 2008 , 54 patients were assessed , 27 of whom were r and omized to each arm . Mean National Institutes of Health Stroke Scale score at presentation was 7.3 ( SD 6.2 ) points . No consultations were aborted ; however , technical problems ( 74 % ) were prevalent in the telemedicine arm . Overall , the correct treatment decision was established in 87 % of the consultations . Both modalities , telephone ( 89 % correct ) and telemedicine ( 85 % correct ) , performed well . Intravenous thrombolytic treatment was used in 30 % of the telemedicine and telephone consultations . Good functional outcomes at 90 days were not significantly different . There were no statistically significant differences in mortality ( 4 % in telemedicine and 11 % in telephone ) or rates of intracerebral hemorrhage ( 4 % in telemedicine and 0 % in telephone ) . Conclusions — It is feasible to extend the original STRokE DOC trial protocol to a new state and establish an operational single-hub , multispoke rural hospital telestroke research network in Arizona . The trial was not design ed to have sufficient power to detect a difference between the 2 consultative modes : telemedicine and telephone-only . Whether by telemedicine or telephone consultative modalities , there were appropriate treatment decisions , high rates of thrombolysis use , improved data collection , low rates of intracerebral hemorrhage , and equally favorable time requirements . The learning curve was steep for the hub and spoke personnel of the new telestroke network , as reflected by frequent technical problems . Overall , the results support the effectiveness of highly organized and structured stroke telemedicine networks for extending expert stroke care into rural remote communities lacking sufficient neurological expertise Background and Purpose — Systemic thrombolysis is the only therapy proven to be effective for ischemic stroke . Telemedicine may help to extend its use . However , concerns remain whether management and safety of tissue plasminogen activator ( tPA ) administration after telemedical consultation are equivalent in less experienced hospitals compared with tPA administration in academic stroke centers . Methods — During the second year of the ongoing Telemedical Pilot Project for Integrative Stroke Care , all systemic thrombolyses in stroke patients of the 12 regional clinics and the 2 stroke centers were recorded prospect ively . Patients ’ demographics , stroke severity ( National Institutes of Health Stroke Scale ) , frequency of administration , time management , protocol violations , and safety were included in the analysis . Results — In 2004 , 115 of 4727 stroke or transient ischemic attack patients ( 2.4 % ) in the community hospitals and 110 of 1889 patients in the stroke centers ( 5.8 % ) received systemic thrombolysis . Prehospital latencies were shorter in the regional hospitals despite longer distances . Door to needle times were shorter in the stroke centers . Although blood pressure was controlled more strictly in community hospitals , symptomatic intracerebral hemorrhage rate ( 7.8 % ) was higher ( P=0.14 ) than in stroke centers ( 2.7 % ) but still within the range of the National Institute of Neurological Disorders and Stroke trial . In-hospital mortality rate was low in community hospitals ( 3.5 % ) and in stroke centers ( 4.5 % ) . Conclusions — Although with a lower rate of systemic thrombolysis , there was no evidence of lower treatment quality in the remote hospitals . With increasing numbers of tPA administration and growing training effects , the telestroke concept promises better coverage of systemic thrombolysis in nonurban areas Background and Purpose — In acute stroke care , rapid but careful evaluation of patients is m and atory but requires an experienced stroke neurologist . Telemedicine offers the possibility of bringing such expertise quickly to more patients . This study tested for the first time whether remote video examination is feasible and reliable when applied in emergency stroke care using the National Institutes of Health Stroke Scale ( NIHSS ) . Methods — We used a novel multimedia telesupport system for transfer of real-time video sequences and audio data . The remote examiner could direct the set-top camera and zoom from distant overviews to close-ups from the personal computer in his office . Acute stroke patients admitted to our stroke unit were examined on admission in the emergency room . St and ardized examination was performed by use of the NIHSS ( German version ) via telemedicine and compared with bedside application . Results — In this pilot study , 41 patients were examined . Total examination time was 11.4 minutes on average ( range , 8 to 18 minutes ) . None of the examinations had to be stopped or interrupted for technical reasons , although minor problems ( brightness , audio quality ) with influence on the examination process occurred in 2 sessions . Unweighted & kgr ; coefficients ranged from 0.44 to 0.89 ; weighted & kgr ; coefficients , from 0.85 to 0.99 . Conclusions — Remote examination of acute stroke patients with a computer-based telesupport system is feasible and reliable when applied in the emergency room ; interrater agreement was good to excellent in all items . For more widespread use , some problems that emerge from details like brightness , optimal camera position , and audio quality should be solved 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 To increase the effective use of thrombolytics for acute stroke , the expertise of vascular neurologists must be disseminated more widely . We prospect ively assessed whether telemedicine ( real-time , two-way audio and video , and digital imaging and communications in medicine [ DICOM ] interpretation ) or telephone was superior for decision making in acute telemedicine consultations . METHODS From January , 2004 , to August , 2007 , patients older than 18 years who presented with acute stroke symptoms at one of four remote spoke sites were r and omly assigned , through a web-based , permuted blocks system , to telemedicine or telephone consultation to assess their suitability for treatment with thrombolytics , on the basis of st and ard criteria . The primary outcome measure was whether the decision to give thrombolytic treatment was correct , as determined by central adjudication . Secondary outcomes were the rate of thrombolytic use , 90-day functional outcomes ( Barthel index [ BI ] and modified Rankin scale [ mRS ] ) , the incidence of intracerebral haemorrhages , and technical observations . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00283868 . FINDINGS 234 patients were assessed prospect ively . 111 patients were r and omised to telemedicine , and 111 patients were r and omised to telephone consultation ; 207 completed the study . Mean National Institutes of Health stroke scale score at presentation was 9.5 ( SD 8.1 ) points ( 11.4 [ 8.7 ] points in the telemedicine group versus 7.7 [ 7.0 ] points in the telephone group ; p=0.002 ) . One telemedicine consultation was aborted for technical reasons , although it was included in the analyses . Correct treatment decisions were made more often in the telemedicine group than in the telephone group ( 108 [ 98 % ] vs 91 [ 82 % ] , odds ratio [ OR ] 10.9 , 95 % CI 2.7 - 44.6 ; p=0.0009 ) . Intravenous thrombolytics were used at an overall rate of 25 % ( 31 [ 28 % ] telemedicine vs 25 [ 23 % ] telephone , 1.3 , 0.7 - 2.5 ; p=0.43 ) . 90-day functional outcomes were not different for BI ( 95 - 100 ) ( 0.6 , 0.4 - 1.1 ; p=0.13 ) or for mRS score ( 0.6 , 0.3 - 1.1 ; p=0.09 ) . There was no difference in mortality ( 1.6 , 0.8 - 3.4 ; p=0.27 ) or rates of intracerebral haemorrhage after treatment with thrombolytics ( 2 [ 7 % ] telemedicine vs 2 [ 8 % ] telephone , 0.8 , 0.1 - 6.3 ; p=1.0 ) . However , there were more incomplete data in the telephone group than in the telemedicine group ( 12%vs 3 % , 0.2 , 0.1 - 0.3 ; p=0.0001 ) . INTERPRETATION The authors of this trial report that stroke telemedicine consultations result in more accurate decision making compared with telephone consultations and can serve as a model for the effectiveness of telemedicine in other medical specialties . The more appropriate decisions , high rates of thrombolysis use , improved data collection , low rate of intracerebral haemorrhage , low technical complications , and favourable time requirements all support the efficacy of telemedicine for making treatment decisions , and might enable more practitioners to use this medium in daily stroke care Background : Official guidelines on stroke promote the use of telemedicine via bidirectional videoconferencing equipment , which provides a valid and reliable means of facilitating thrombolysis delivery to patients in distant or rural hospitals . Methods : The present prospect i ve cohort study describes the characteristics and 3-month outcome of the thrombolysis patients treated in 5 community hospitals served by the Helsinki University Central Hospital ( HUCH ) in a telestroke network during 2007 to 2009 . The characteristics and outcome of telestroke thrombolysis patients are compared with consecutive thrombolysis patients ( n = 985 ) treated at HUCH . Results : A total of 106 consecutive telestroke consultations in 2 years led to IV thrombolysis in 61 patients ( 57.5 % ) . The median NIH Stroke Scale score was 10 ( range 3–26 ) , onset to treatment time 120 minutes ( interquartile range [ IQR ] 49 ) , length of consultation 25 minutes ( IQR 18 ) if the consultation led to thrombolysis and 15 minutes ( IQR 10 ) if not ( p = 0.032 ) . The rate of symptomatic intracranial bleedings was 6.7 % ( 4/60 ) according to the National Institute of Neurological Disorders and Stroke definition . Half ( 28/57 ) of the thrombolysis patients with complete follow-up data had a favorable outcome ( modified Rankin Scale [ mRS ] 0–2 ) and a third ( 17/57 ) had an excellent recovery ( mRS 0–1 ) . Thus the patients treated with thrombolysis based on teleconsultation had similar outcome with those treated at HUCH ( mRS 0–2 : 49.1 % vs 58.1 % , p = 0.214 and mRS 0–1 : 17/57 [ 29.4 % ] vs 352/957 [ 36.8 % ] , p = 0.289 ) . Conclusions : A special feature of the Finnish pilot is the high percentage of consultations leading to thrombolytic treatment with features and results very similar to on-site thrombolysis at the neurologic emergency room of HUCH |
1,992 | 20,531,073 | DISCUSSION The three selected self-report scales may assist transplant professionals in detecting nonadherence .
However , these scales were only vali date d in patients with HIV . | INTRODUCTION Nonadherence to immunosuppressive therapy is recognized as a key prognostic indicator for poor posttransplantation long-term outcomes .
Several methods aim ing to measure medication nonadherence have been suggested in the literature .
Although combining measurement methods is regarded as the gold st and ard for measuring nonadherence , self-report is generally considered a central component of adherence assessment . | PURPOSE The Comparison of Ophthalmic Medications for Tolerability ( COMTOL ) question naire was developed for use in clinical trials to compare the tolerability of topical ophthalmic medications used in the treatment of glaucoma . The question naire captures the frequency and bother of common side effects ( i.e. , ocular and other local effects , and effects on visual function ) of topical therapy for lowering intraocular pressure . In addition , the question naire measures the extent to which these side effects and any associated limitations in routine living activities interfere with health-related quality of life , medication compliance , and patient satisfaction with the medication . This study was design ed to assess the measurement characteristics of the COMTOL question naire . METHODS The internal consistency , reliability , reproducibility , construct validity , discriminant validity , and responsiveness of the question naire were assessed in 70 adult patients with glaucoma in a clinical trial comparing timolol and pilocarpine . RESULTS The question naire showed good-to-excellent internal consistency ( 0.73 to 0.98 ) , reliability ( 0.76 to 0.94 ) , and reproducibility ( 0.75 to 0.93 ) . In general , there was a strong correlation in the expected direction between the frequency and bother of side effects and patient-perceived global measures . The question naire discriminated between patients receiving timolol and patients receiving pilocarpine . The question naire demonstrated significant responsiveness to change . CONCLUSIONS The COMTOL question naire showed acceptable measurement characteristics for inclusion as a tolerability measure to supplement spontaneous adverse event reporting in clinical trials of topical ophthalmic therapy The relationship between adherence to highly active antiretroviral therapy ( HAART ) and RNA-HIV viral load outcomes has been extensively shown . Although there are different procedures for assessing treatment adherence , there is no ideal method . We present the SERAD ( Self-Reported Adherence ) question naire , a qualitative and quantitative self-reported instrument design ed to provide an easier adherence measurement . We also compared the question naire to three other methods to evaluate adherence to HAART regimens in HIV-infected patients . Two prospect i ve , observational , longitudinal studies were developed : a single-center pilot study followed by a multicenter study . A total of 530 HIV-infected out patients was prospect ively included , 66 in the pilot study and 464 in the multicenter study . Four methods were used to study adherence to HAART regimens : the SERAD question naire , pill count , electronic monitoring , and plasma drug monitoring . Pearson 's correlations and Bl and and Altman 's method were developed . The SERAD question naire showed good feasibility and significant validity . Adequate levels of agreement between methods were observed , particularly when adherence was high . Differences increased as adherence fell . Moreover , the question naire was completed correctly , the interviewers did not report uncovered aspects , and the information was collected easily . Our results suggest that the SERAD question naire is a feasible and useful instrument for assessing adherence to HAART regimens in HIV-infected patients , and makes it possible to obtain reliable qualitative and quantitative information related to treatment adherence Nonadherence to immunosuppressants in renal transplant recipients is a major factor affecting graft survival , but it is difficult to detect accurately in clinical practice . Adherence was measured in 153 adult renal transplant recipients using self-report question naires and interview , clinician rating , and cyclosporine levels . The sensitivity and specificity of these measures were determined by comparison with electronic monitoring in a r and omly selected sub sample of 58 subjects . Measures of adherence in current clinical use do not perform well when tested against electronic monitoring . Self-report at a confidential interview was the best measure of adherence for the detection of both missed doses and erratic timing of medication . However , the use of a confidential interview is not directly applicable to a clinical setting . Further research on how best to facilitate disclosure in clinical setting s may be the best way to develop adherence measures for use in routine practice The Hill-Bone Compliance to High Blood Pressure Therapy Scale assesses patient behaviors for three important behavioral domains of high blood pressure treatment : 1 ) reduced sodium intake ; 2 ) appointment keeping ; and 3 ) medication taking . This scale is comprised of 14 items in three subscales . Each item is a four point Likert type scale . The content validity of the scale was assessed by a relevant literature review and an expert panel , which focused on cultural sensitivity and appropriateness of the instrument for low literacy . Internal consistency reliability and predictive validity of the scale were evaluated using two community based sample s of hypertensive adults enrolled in clinical trials of high blood pressure care and control . The st and ardized alpha for the total scale were 0.74 and 0.84 , and the average interitem correlations of the 14 items were 0.18 and 0.28 , respectively . The construct and predictive validity of the scale was assessed by factor analysis and by testing of theoretically derived hypotheses regarding whether the scale demonstrated consistent and expected relationships with related variables . In this study , high compliance scale scores predicted significantly lower levels of blood pressure and blood pressure control . Moreover , high compliance scale scores at the baseline were significantly associated with blood pressure control at both baseline and at follow up in the two independent sample s. This brief instrument provides a simple method for clinicians in various setting s to use to assess patients ' self reported compliance levels and to plan appropriate interventions Objectives Many question naires on adherence to antiretroviral therapy are in use , but the validity of patients ’ responses has not been tested . The Medication Adherence Self-Report Inventory ( MASRI ) has been developed and tested for its validity against objective measures and treatment outcome . Design Prospect i ve study comparing question naire responses with MEMS TrackCap ( MC , a medication event monitoring system ) , pill count ( PC ) and plasma HIV viraemia in a publicly funded specialist HIV clinic . Participants Patients self-medicating antiretroviral therapy who were not cognitively impaired and were able to read and underst and English . Results Mean adherence by MC of the 78 subjects was 92.9 % ( SE , 1.8 % ) and by PC 96.8 % ( SE , 1.4 % ) . Agreement between MC and responses to items about doses missed 1 , 2 or 3 days ago was low ( κ = 0.23 ( P < 0.03 ) , 0.44 ( P < 0.001 ) and 0.28 ( P < 0.01 ) respectively ) . This improved when these responses were summated ( κ = 0.46;P < 0.001 ) and was similar to that for recall of non-adherence over the preceding 2 weeks ( κ = 0.54;P < 0.001 ) . Mean self-reported adherence by visual analogue scale ( VAS ) over the preceding month was 93.3 % ( SE , 1.2 % ) . This was strongly associated with both MC ( r = 0.63;P < 0.001 ) and PC ( r = 0.75;P < 0.001 ) . On multivariate analysis , the strongest association between a MASRI item and MC was for the VAS . Both the 2 week recall and VAS items were inversely associated with viral load ( P = 0.01 ) . There was no association between dose timing ( measured MC or question naire ) or 3 day self-report and viral load . Conclusions The MASRI provides a means of measuring patient adherence that is valid when compared with objective measures In this prospect i ve study we compared the incidence of late acute rejections ( LAR ) and changes in serum‐creatinine over time between compliers and noncompliers with immunosuppressive therapy more than 1 year post transplantation and explored the relative contribution of non‐compliance and other risk factors in the occurrence of LAR Background . Renal transplant recipients regularly fail to take their prescribed immunosuppressive medications , frequently leading to adverse outcomes . Methods . Medication vials incorporating electronic monitor circuits in their caps compiled prospect i ve data files on the azathioprine dosing patterns of 180 adult renal transplant recipients monitored up to 4 years . These patients were followed for a mean of 8.7 years posttransplantation . Results . Patients were divided into three groups by the medication doses missed during the first 6 months posttransplant . These initial dosing patterns remained remarkably consistent up to 4 years . Patients ( n=47 ) missing the most doses ( ≥5 % ) experienced earlier and more frequent acute rejection episodes ( P=0.025 ) . This group also demonstrated significantly longer interdose intervals ( P=0.005 ) , with more frequent ( P<0.001 ) and longer ( P<0.001 ) “ drug holidays . ” A patient subgroup with early declining medication adherence ( n=23 ) experienced dramatically poorer outcomes , with significantly increased acute rejection ( P<0.001 ) , chronic rejection ( P=0.034 ) , graft loss before death ( P<0.001 ) , and death ( P=0.04 ) . In all tertiles there was a trend toward missing more medication over time . Conclusions . Excellent posttransplant medication adherence is critical to improved outcomes . Individual dosing patterns are established early after hospital discharge and remain remarkably consistent , despite gradual erosion in adherence over time . The later consequences of medication nonadherence , especially early declines in adherence , include increased frequencies of rejection , graft loss , and death BACKGROUND Poor medical compliance has been held responsible for a large proportion of deaths occurring subsequent to initial postoperative recovery . However , beyond clinical reports , there has been little empirical examination of this issue , or of the extent to which major psychiatric disorder and failure to adjust to the transplant predict long-term physical morbidity and mortality . We prospect ively examined whether a full range of compliance behaviors and psychiatric outcomes during the first year post-transplant predicted subsequent mortality and physical morbidity through 3 years post-transplant . METHODS A total of 145 heart recipients who had received detailed compliance and mental health assessment s during the first year post-transplant were followed up at 3 years post-transplant . Interview data and corroborative information from family members were used to determine compliance in multiple domains , psychiatric diagnoses , and psychiatric symptomatology during the first year post-surgery . Medical record review s were performed to abstract data on acute graft rejection episodes , incident cardiac allograft disease ( CAD ) and mortality from 1 to 3 years post-transplant . RESULTS After controlling for known transplant-related predictors of outcome , multivariate analyses yielded the following significant ( p < 0.05 ) results : ( a ) risk of acute graft rejection was 4.17 times greater among recipients who were not compliant with medications ; ( b ) risk of incident CAD was elevated by persistent depression ( Odds Ratio , OR = 4.67 ) , persistent anger-hostility ( OR = 8.00 ) , medication noncompliance ( OR = 6.91 ) , and obesity ( OR = 9.92 ) ; and ( c ) risk of mortality was increased if recipients met criteria for Post-Traumatic Stress Disorder related to the transplant ( OR = 13.74 ) . CONCLUSIONS The findings , plus data we have previously reported that showed which patients are most likely to have compliance and psychiatric problems early post-transplant , suggest that interventions focused on maximizing patients ' psychosocial status in these areas may further improve long-term physical health outcomes in this population The aim of this study was to verify the validity of a new self-reported question naire design ed to assess nonadherence to antiretroviral medication among patients with HIV . Two hundred fifty-six patients from four clinics participated in a prospect i ve longitudinal study . The question naire was design ed to measure if patients with HIV were taking less than the total number of antiretroviral pills prescribed by their physician . Change in viral load was used as the criterion for validity analyses . Self-reported adherence , viral load and CD4 cell count were assessed at T0 ( baseline ) , T3 ( 3-month ) , and T6 ( 6-month ) . The findings indicated that the question naire had adequate validity ( sensitivity , 71 % ; specificity , 72 % ; correct classification , 72 % ; odd ratio , 6.15 ) . These best values were obtained when the analyses excluded individuals with an unstable viral load and a CD4 cell count of less than 200 copies per milliliter over the 6-month follow-up period . This study has shown that this question naire has satisfactory psychometric qualities to assess nonadherence to antiretroviral medication among patients with HIV . The question naire is brief , simple , and can be used in both clinical or research setting s regardless of the patients ' antiretroviral regimens Nonadherence to antiretroviral therapy is a substantial problem in HIV and jeopardizes the success of treatment . Accurate measurement of nonadherence is therefore imperative for good clinical management but no gold st and ard has been agreed on yet . In a single-center prospect i ve study nonadherence was assessed by electronic monitoring : percentage of doses missed and drug holidays and by three self reports : ( 1 ) a visual analogue scale ( VAS ) : percentage of overall doses taken ; ( 2 ) the Swiss HIV Cohort Study Adherence Question naire ( SHCS-AQ ) : percentage of overall doses missed and drug holidays and ( 3 ) the European HIV Treatment Question naire ( EHTQ ) : percentage of doses missed and drug holidays for each antiretroviral drug separately . Virologic failure prospect ively assessed during 1 year , and electronic monitoring were used as reference st and ards . Using virologic failure as reference st and ard , the best results were for ( 1 ) the SHCS-AQ after electronic monitoring ( sensitivity , 87.5 % ; specificity , 78.6 % ) ; ( 2 ) electronic monitoring ( sensitivity , 75 % ; specificity , 85.6 % ) , and ( 3 ) the VAS combined with the SHCS-AQ before electronic monitoring ( sensitivity , 87.5 % ; specificity , 58.6 % ) . The sensitivity of the complex EHTQ was less than 50 % . Asking simple questions about doses taken or missed is more sensitive than complex question ing about each drug separately . Combining the VAS with the SHCS-AQ seems a feasible nonadherence measure for daily clinical practice . Self-reports perform better after electronic monitoring : their diagnostic value could be lower when given independently Objective : Self-report of antiretroviral medications adherence is inexpensive and simple to use in clinical setting s but grossly overestimates adherence . We investigated methods to calibrate patients ' self-reported adherence to match objective ly measured adherence more closely for the purpose of developing a practical and more accurate self-reported adherence measure . Design : Longitudinal cohort design . Methods : Using data from 2 prospect i ve longitudinal clinical investigations conducted at 5 HIV clinics , we examined the discrepancy between self-reported adherence and objective ly measured adherence . We evaluated the relation between attitudinal measures and the degree of discrepancy and used a cross-validation approach to propose c and i date items to improve adherence survey methodology . Results : Among 330 patients , self-reported adherence was consistently higher than objective ly measured adherence . The best calibration models included the patient 's self-reported adherence , duration of the antiretroviral regimen , and attitudinal measures ( ability to take medication as instructed , believing medication can help one to live longer , whether or not it is too troublesome to take antiretrovirals , and feeling things are going the right way ) . Conclusion : The method efficiently identified survey items to improve self-reported adherence measurement . The calibrated measure more closely approximates objective ly measured adherence and is more sensitive for detecting nonadherence . These models merit evaluation in other setting Objective To assess the effectiveness of the simplified medication adherence question naire ( SMAQ ) in identifying non-adherent patients . Design Prospect i ve observational study of adherence . The six-item SMAQ was developed . The following aspects were evaluated : ( i ) criterion validity , comparison with electronic adherence monitoring ; ( ii ) construct validity , association between adherence , as defined by the SMAQ , and virological outcomes ; and ( iii ) reliability , internal consistency and reproducibility . Patients A group of 3004 unselected HIV patients who had initiated nelfinavir therapy combined with other antiretroviral drugs [ 21 % naive , 15 % protease inhibitor (PI)-naive , 64 % PI-experienced ] between January 1998 and December 1999 were enrolled in 69 hospitals in Spain . The SMAQ was administered at months 3 , 6 and 12 . Results The SMAQ showed 72 % sensitivity , 91 % specificity and a likelihood ratio of 7.94 to identified non-adherent patients , compared with the medication-event monitoring system ( 40 patients evaluated ) . At month 12 , 1797 patients were evaluated , of whom 32.3 % were defined as non-adherent ; viral load < 500 copies/ml found in 68.3 % of the adherent , and 46 % of the non-adherent patients . A logistic regression analysis of PI-naive patients was performed , including age , sex , baseline viral load > 5 log10/ml , CD4 cell count < 200 × 106/l , and non-adherence as independent variables . Non-adherence was the only significant risk factor in failing to achieve virological suppression . Cronbach 's alpha internal consistency coefficient was 0.75 , and overall inter-observer agreement was 88.2 % . Conclusion The SMAQ appears to be an adequate instrument with which to assess adherence in HIV-infected patients , and may be applied in most clinical setting |
1,993 | 12,218,839 | Azithromycin and doxycycline are equally efficacious in achieving microbial cure and have similar tolerability . | BACKGROUND Azithromycin and doxycycline are recommended for treatment of genital Chlamydia trachomatis infection .
A systematic review comparing these antibiotics could affect treatment guidelines .
GOAL The goal was to perform a meta- analysis to evaluate the efficacy and tolerance of azithromycin versus doxycycline for genital chlamydial infection . | STUDY GOAL : To compare the efficacy and safety of single 1 g oral azithromycin with doxycycline , 100 mg twice daily for seven days for treatment of uncomplicated urogenital chlamydial infection . STUDY DESIGN : R and omised , unblinded , comparative trial , involving 597 patients demonstrating clinical evidence of genital chlamydia and a positive non-culture assay for Chlamydia trachomatis . RESULTS : Among the azithromycin- and doxycycline-treated patients 61 % and 60 % , respectively , were asymptomatic within one week after the first dose . At two weeks , these figures increased to 86 % and 83 % , respectively . Bacteriological eradication , based on a negative assay , occurred in 338 ( 97 % ) of 347 azithromycin-treated patients and 161 ( 99 % ) of 163 doxycycline-treated patients . CONCLUSION : Treatment of uncomplicated chlamydial cervicitis and urethritis with single 1 g oral azithromycin is equivalent to st and ard therapy with doxycycline . Drug-related adverse events were approximately twice as common as previously reported for both drugs Aims : To identify any differences in follow-up rates or sexual contact attendance rates in men presenting with non-gonococcal urethritis ( NGU ) after treatment by single dose azithromycin rather than longer st and ard duration therapies and to identify patients ' treatment preferences . Methods : A prospect i ve study was performed on 200 consecutive men attending a genito-urinary medicine ( GUM ) clinic with new episode , microscopically confirmed NGU . The first 100 patients were treated with st and ard duration therapy ( Group S ) whilst the second 100 patients received a single 1 g oral dose of azithromycin ( Group A ) . Patient-led contact tracing was arranged and patients were asked to return for review when a test of cure was performed , contact attendance noted and the patient 's treatment preference ascertained . Results : Both groups were predominantly heterosexual and over 60 % gave a history of previous sexually transmitted disease ( STD ) . There were no significant differences in efficacy between Groups S and A. However , the index follow-up rate and percentage of traceable sexual contacts attending was higher in Group A. In both groups contacts of homosexual men were more likely to attend the GUM clinic . More additional visits were made by Group S due to mislaid medication or compliance problems . Over 70 % of patients question ed expressed a preference for single dose therapy . Conclusion : Single dose therapy with 1 g of azithromycin is as efficacious as longer duration therapies with advantages in patient follow-up rates and contact attendance and for the majority of patients would be their treatment of choice . A cost analysis supports the practical application of this regimen & NA ; Pivampicillin and doxycycline were compared in the treatment of chlamydial urethritis in 80 heterosexual men . The trial was carried out in a double‐blind , comparative parallel group fashion . Forty patients were treated with 700 mg of pivampicillin twice daily and another 40 with 200 mg of doxycycline on the first day and thereafter with 100 mg of doxycycline and one placebo tablet daily . Both treatments lasted for 9 days . Follow‐up examinations were carried out 2 weeks ( 14‐16 days ) and 4 weeks ( 26‐30 days ) after the start of treatment . Altogether five ( 12.5 % ) of the forty pivampicillin‐treated patients were clinical failures and three ( 7.5 % ) still harbored Chlamydia trachomatis after treatment . The corresponding figures for the doxycycline‐treated patients were two ( 5.1 % ) and one ( 2.6 % ) . The difference between the treatment results of the two groups did not reach statistical significance Two-hundred patients with confirmed Chlamydia trachomatis infection of the urogenital region were treated with either ciprofloxacin 1.5 g/day or doxycycline 100 mg/day for seven days . One-hundred and fifty-seven patients were males and 43 females . C. trachomatis was isolated prior to treatment from urethra alone in 155 patients , from cervix alone in 27 and from both urethra and cervix in 15 . The first re-examination was carried out at the end of treatment and the second one week later . Six patients in the ciprofloxacin group and three in the doxycycline group never returned for the first re-examination . At the second re-examination there were seven defaulters in the ciprofloxacin group and 11 in the doxycycline group . Altogether there were 12 bacteriological failures in both groups . Clinical failure despite bacteriological cure occurred in 20 patients in the ciprofloxacin group and eight in the doxycycline group . The total number of treatment failures was 32 in the ciprofloxacin group and 20 in the doxycycline group . The results suggested that neither treatment was efficient enough in the treatment of uncomplicated urogenital infections caused by C. trachomatis The effect of doxycycline treatment was studied in 46 men with chlamydial non-gonococcal urethritis . Treatment with 200 mg doxycycline daily for 10 days rendered 22 of 22 patients free of urethritis . The treatment had no effect on the complications of urethritis like prostatitis and Reiter 's syndrome . In the other group where 200 mg doxycycline was given on the first day and 100 mg on the subsequent days for 8 days , urethritis was resolved in 18 of 22 patients . C. trachomatis was not re-isolated from any of the patients after doxycycline treatment We compared a single 1 gm dose of azithromycin with the st and ard 7-day course of doxycycline for the treatment of uncomplicated chlamydial genital infection in sexually active adolescents . Seventy-three adolescents ( 65 female ) with a cervical or urethral culture positive for Chlamydia trachomatis were enrolled in the study ; 46 received azithromycin and 27 received doxycycline . Follow-up evaluations were done 1 , 2 , and 4 weeks after treatment with azithromycin or initiation of treatment with doxycycline . There were four treatment failures ( 8.7 % ) among the patients who received azithromycin and four in the doxycycline-treated group ( 14.8 % ) ; all were female . Six of these girls ( three treated with azithromycin and three with doxycycline ) gave histories of unprotected intercourse with an untreated partner and were probably reinfected . Almost half the patients were clinical ly symptom free . The clinical response rate for the remaining patients with symptoms was 97.4 % at 4 weeks . Nineteen percent of the azithromycin-treated patients and 33.3 % of those treated with doxycycline had mild to moderate drug-related side effects , which were predominantly gastrointestinal . We conclude that treatment with a single oral dose of azithromycin appears to be as safe and efficacious as a 7-day course of doxycycline for the treatment of uncomplicated genital chlamydial infection in adolescents A total of 2124 women who attended the Richmond Family Planning Association Clinic in Melbourne consecutively were screened for the presence or absence of Chlamydia trachomatis . One hundred and three women were found to have Chl . trachomatis infection of the cervix and were invited to participate in a clinical trial of minocycline and doxycycline for the treatment of chlamydial infection . A 10-day course of either drug result ed in a negative result of a chlamydial culture for all patients at the follow-up assessment , which occurred between 11 days to 12 weeks after the therapy . Minocycline and doxycycline showed equal effectiveness in the eradication of mycoplasmas in over 80 % of the treated patients . Minocycline appeared to have a slight advantage with respect to the resolution of the gynaecological symptoms that were associated with the chlamydial infection . The number of adverse events that were recorded during the trial was similar for both treatment regimens . Gynaecological symptoms were associated with chlamydial infection in approximately 50 % of the women in the study . The lack of association between chlamydial infection and gynaecological symptoms has led to the instigation of routine testing for the presence of Chlamydia spp . in young women who have more than one sexual partner OBJECTIVES The heterosexual spread of HIV-1 is occurring at different rates in different parts of the world . The transmission probability of HIV-1 per sexual contact is low , but may be greatly enhanced by several cofactors . Sexually transmitted diseases ( STD ) , especially genital ulcers , may be such factors . So far , epidemiological evidence that other STD facilitate HIV-1 transmission is weak . The objective of this study was to determine whether treatable STD enhanced sexual transmission of HIV-1 in a cohort of female prostitutes in Kinshasa , Zaire . METHODS We conducted a nested case-control study of 431 initially HIV-1-negative women followed prospect ively for a mean duration of 2 years ( with monthly STD check-ups and 3-monthly HIV-1 serology ) . Cases ( seroconverters , n = 68 ) were compared with controls ( women who remained HIV-1-negative , n = 126 ) for incidence of STD and sexual exposure during the presumed period of HIV-1 acquisition . RESULTS The annual incidence of HIV-1 in this cohort was 9.8 % . Seroconverters were younger than HIV-1-negative women ( mean age , 24.6 versus 26.8 years ; P = 0.04 ) . During the period of HIV-1 acquisition , cases had a much higher incidence of gonorrhoea , chlamydial infection and trichomoniasis , and engaged in unprotected sex with clients and partners more frequently than controls . After controlling for sexual exposure by multivariate analysis , adjusted odds ratios for seroconversion were 4.8 [ 95 % confidence interval ( CI ) , 2.4 - 9.8 ] for gonorrhoea , 3.6 ( 95 % CI , 1.4 - 9.1 ) for chlamydial infection and 1.9 ( 95 % CI , 0.9 - 4.1 ) for trichomoniasis . Genital ulcers were more frequent in cases than controls , but much less common than other STD . CONCLUSION Non-ulcerative STD were risk factors for sexual transmission of HIV-1 in women , after controlling for sexual exposure . Because of their high prevalence in some population s , non-ulcerative STD may represent a considerable population -attributable risk in the transmission of HIV-1 worldwide . The identification of treatable STD as risk factors for HIV-1 transmission offers an important additional strategy for the prevention of HIV/AIDS CONTEXT Adolescents are at highest risk for infection with Chlamydia trachomatis , an important preventable cause of pelvic inflammatory disease and subsequent tubal factor infertility in US women . Current guidelines for delivery of adolescent primary care services recommend yearly chlamydia screening for those adolescent females considered to be at risk . OBJECTIVES To describe the epidemiology of prevalent and incident chlamydia infection among adolescent females to assess the appropriate interval for chlamydia screening and to define risk factors that would identify adolescent females to target for screening . DESIGN Prospect i ve longitudinal study . PATIENTS A consecutive sample of 3202 sexually active females 12 through 19 years old making 5360 patient visits over a 33-month period , January 1994 through September 1996 . SETTING Baltimore , Md , family planning , sexually transmitted disease , and school-based clinics . INTERVENTION Testing for C trachomatis by polymerase chain reaction . MAIN OUTCOME MEASURES Prevalence and incidence of C trachomatis infections ; predictors of positive test result for C trachomatis . RESULTS Chlamydia infection was found in 771 first visits ( 24.1 % ) and 299 repeat visits ( 13.9 % ) ; 933 adolescent females ( 29.1 % ) had at least 1 positive test result . Females who were 14 years old had the highest age-specific chlamydia prevalence rate ( 63 [ 27.5 % ] of 229 cases ; P=.01 ) . The chlamydia incidence rate was 28.0 cases per 1000 person-months ( 95 % confidence interval , 24.9 - 31.5 cases ) . The median time was 7.2 months to a first positive chlamydia test result and 6.3 months to a repeat positive test result among those with repeat visits . Independent predictors of chlamydia infection -- reason for clinic visit , clinic type , prior sexually transmitted diseases , multiple or new partners , or inconsistent condom use-failed to identify a subset of adolescent females with the majority of infections . CONCLUSIONS A high prevalence and incidence of C trachomatis infection were found among adolescent females . We , therefore , recommend screening all sexually active adolescent females for chlamydia infection every 6 months , regardless of symptoms , prior infections , condom use , or multiple partner risks BACKGROUND AND OBJECTIVES Single dose regimens have advantages in the treatment of STD . Azithromycin has unique pharmacokinetics that may make single dose regimens feasible . Treatment with a single 1 g dose of azithromycin was compared to 100 mg doxycycline twice daily for seven days . STUDY DESIGN This was a r and omized third-party blinded study on 183 male patients , 176 of whom could be evaluated for efficacy . RESULTS Chlamydia trachomatis was cultured from 148 patients , 79 receiving azithromycin and 69 receiving doxycycline . Six patients receiving azithromycin had positive cultures on follow-up , four were known to have had sexual intercourse with infected partners . Fifty-one patients had gonorrhea ; 28 were treated with azithromycin and 23 with doxycycline . Neisseria gonorrhoeae was eradicated from all patients except one receiving azithromycin . He denied sexual exposure during follow-up . Sixty patients were infected with Ureaplasma urealyticum , 35 were treated with azithromycin and 25 with doxycycline . Five patients in each group had positive cultures on follow up . Three patients receiving azithromycin and two receiving doxycycline were known to have had sexual exposure during follow-up . CONCLUSION A single dose of azithromycin showed similar effectiveness as a 7-day regimen of doxycycline AIM OF STUDY The aim of this study was to compare the clinical and microbiological efficacy of a single 1 gram dose of azithromycin against 1 week of doxycycline at 100 mg twice a day in the treatment of : ( 1 ) uncomplicated non-gonococcal urethritis ( NGU ) in male patients , and ( 2 ) culture proven Chlamydia trachomatis cervicitis in female sex workers . METHOD The subjects were 53 male patients who attended the clinic and were diagnosed to have non gonococcal urethritis based on clinical symptoms and a urethral smear , and 63 female sex workers , who had both a positive enzyme immunoassay ( EIA ) test and Chlamydia trachomatis cultures . Follow-up visits were made at one and two weeks post-treatment to assess efficacy , subsequent relapse and presence of side effects . The male patients were also assessed at four weeks post treatment to determine default and reinfection rates . RESULTS Both azithromycin ( clinical cure rates 62.5 % at one week , 86.4 % at two weeks in male patients ; 96.6 % at two weeks in female sex workers ) and doxycycline ( clinical cure rates 65.4 % at one week , 90.9 % at two weeks in male patients ; 100 % at two weeks in female sex workers ) were effective in treating non-gonococcal urethritis and chlamydial cervicitis . Both drugs were very effective in eradicating proven Chlamydia trachomatis infections , with success in 100 % of cases of Chlamydia trachomatis NGU in males , and 96.6 % and 100 % cure rates , for azithromycin and doxycycline respectively , in female sex workers with cervicitis . There were no statistically significant differences between the two drugs in terms of clinical efficacy , influence on default rates or subsequent risk of reinfection . CONCLUSIONS We conclude that a single dose of azithromycin is as effective as a one week course of doxycycline in treating non-gonococcal urethritis in males and in the elimination of Chlamydia trachomatis in females with cervicitis , with the added advantage of a convenient single dose that can be supervised Background : To treat chlamydial infection , the Centers for Disease Control and Prevention recommends either a single dose of azithromycin or a 7‐day course of doxycycline . Cost is a concern with the single‐dose regimen ; compliance is a concern with the multidose regimen . Goal : To compare the use‐effectiveness of azithromycin and doxycycline for preventing persistence or recurrence of Chlamydia trachomatis infection in women and to evaluate associated risk behaviors . Study Design : One hundred and ninety‐six chlamydia‐infected women and their sex partners were recruited into a r and omized controlled trial of single‐dose versus multidose regimens in seven public health clinics , with no incentives for enrollment , compliance , or follow‐up . The outcome measure was a positive test for C. trachomatis by polymerase chain reaction testing at 1 month after treatment . Results : C. trachomatis positivity at 1 month was similar for women receiving single‐dose ( 5.1 % , 5/98 ) and multidose therapy ( 4.1 % , 4/98 ) . Reported compliance among 73 women taking multidose therapy was 94.5 % . A twofold to threefold increased risk of chlamydial persistence or recurrence was observed among women who were ≤24 and white or who reported : a recent new partner , multiple partners , or a partner who may have had multiple partners at the time of enrollment or that not all partners were treated during the 1‐month follow‐up period after initiation of treatment . Conclusions : The use‐effectiveness of single‐dose and multidose therapy was comparably high . Observed rates of persistence or recurrence were consistent with reported rates of pharmacological treatment failure . However , all women with C. trachomatis detected at 1 month had behavioral risk factors that may have contributed to reinfection One hundred and eighty-two patients were enrolled in a r and omized third-party blinded study to assess the efficacy and safety of azithromycin in the treatment of sexually transmitted diseases . Three regimens of azithromycin , including a single oral dose , were compared with a st and ard treatment with doxycycline . The patients were followed for four weeks . Efficacy was evaluated in 168 patients ( 113 azithromycin , 55 doxycycline ) . Fourteen patients had negative cultures or did not come for all follow-up visits . Of the 168 , 138 were infected with Chlamydia trachomatis , 43 with Neisseria gonorrhoeae , and 45 with Ureaplasma urealyticum . Ninety-six per cent of patients with chlamydial infections and 92 % of those with gonorrhoea were cured with azithromycin . Two patients infected with N. gonorrhoeae , four with C. trachomatis and six with U. urealyticum had positive cultures on follow-up visits after receiving azithromycin . Of these 11 patients with positive cultures on follow-up visits , seven ( five with U. urealyticum and two with C. trachomatis ) violated the protocol by having intercourse with infected individuals during the study . Azithromycin was very well tolerated ; one patient complained of mild abdominal pain shortly after receiving the drug , seven patients complained of mild nausea and two patients had mild diarrhoea OBJECTIVE To evaluate the use of single-dose azithromycin for empirical treatment of nongonococcal urethritis . DESIGN R and omized , double-blind , multicenter trial comparing azithromycin vs doxycycline therapy , with a 2:1 r and omization ratio . Patients were evaluated clinical ly and microbiologically for Chlamydia trachomatis and Ureaplasma urealyticum infection before therapy and at 2 and 5 weeks after study entry . SETTING Eleven sexually transmitted disease clinics throughout the United States . PATIENTS A total of 452 men aged 18 years or older with symptomatic nongonococcal urethritis of less than 14 days ' duration . INTERVENTION Patients were treated with either 1.0 g of azithromycin as a single oral dose or 100 mg of doxycycline taken orally twice daily for 7 days . MAIN OUTCOME MEASURES Clinical resolution of symptoms and signs of nongonococcal urethritis , microbiological cure of C trachomatis and U urealyticum , and occurrence of adverse experiences . RESULTS Of the 452 patients enrolled , 248 in the azithromycin-treated group and 123 in the doxycycline-treated group were evaluable for clinical response . The two treatment groups were comparable in terms of age , weight , ethnic distribution , sexual preference , sexual activity , and history of prior nongonococcal urethritis or gonorrhea . Sixteen percent of the azithromycin group and 24 % of the doxycycline group were culture positive for C trachomatis before therapy , while 38 % and 28 % , respectively , were culture positive for U urealyticum . The cumulative clinical cure rate was 81 % ( 95 % confidence interval [ CI ] , 75 % to 85 % ) in the azithromycin-treated group and 77 % ( 95 % CI , 69 % to 84 % ) in the doxycycline-treated group . Clinical cure rates in the two groups were also comparable when patients were stratified by presence or absence of infection with C trachomatis or U urealyticum prior to therapy . Among those infected with C trachomatis , overall microbiological cure rates were 83 % ( 95 % CI , 65 % to 94 % ) for azithromycin-treated patients ( n = 30 ) and 90 % ( 95 % CI , 68 % to 98 % ) for doxycycline-treated patients ( n = 21 ) . Among those infected with U urealyticum , overall microbiological cure rates were 45 % ( 95 % CI , 34 % to 57 % ) for azithromycin-treated patients ( n = 75 ) and 47 % ( 95 % CI , 30 % to 65 % ) for doxycycline-treated patients ( n = 32 ) . Adverse reactions were generally mild to moderate and occurred in 23 % of the azithromycin-treated group and 29 % of the doxycycline-treated group . CONCLUSIONS For empirical treatment of the acute nongonococcal urethritis syndrome in men , a single oral dose of azithromycin was as effective as a st and ard 7-day course of doxycycline in achieving clinical cure . Further , clinical cure rates were comparable with either regimen , regardless of the presence or absence of Chlamydia or Ureaplasma infection Azithromycin has activity in vitro against Chlamydia trachomatis , and its novel pharmacokinetics suggest that even single doses may be effective in the treatment of non-gonococcal urethritis ( NGU ) . This study compared the efficacy and safety of a single 1 g oral dose of azithromycin versus doxycycline 100 mg bid for seven days in the treatment of NGU . Men with symptoms and /or signs of NGU , and with > or = 5 polymorphonuclear leucocytes/high-power field in a Gram's-stained urethral smear , were recruited . Investigations included endourethral swabs for C. trachomatis cell culture . Patients were r and omized to receive azithromycin or doxycycline , and were re-assessed on day 7 - 10 and on day 14 - 21 . Of the 143 men recruited , C. trachomatis was isolated from 51 ( 40 % ) of the 128 evaluable patients . Both treatments were well tolerated and had comparable cure rates . Azithromycin 1 g appears to be an effective and safe alternative to doxycycline for the treatment of chlamydial and non-chlamydial urethritis , and its single-dose administration is an advantage in terms of patient compliance OBJECTIVE --To compare the efficacy and safety of azithromycin and doxycycline in the treatment of males with uncomplicated urethritis caused by chlamydia trachomatis . DESIGN --A multicentre , double-blind , r and omised treatment study . SUBJECTS--130 male out patients with clinical signs and symptoms of urethritis . SETTING --STD clinics at four Norwegian University Hospitals . METHODS -- Patients were r and omly allocated to 1000 mg azithromycin as single dose or doxycycline 100 mg twice daily for 7 days . Clinical , bacteriological and safety assessment s were made at entry and after 1 and 2 weeks . Safety data were also repeated after 4 weeks . RESULTS --Demographic data were similar in both groups . At the week 1 assessment bacteriological eradication was achieved in 44 of 44 evaluable azithromycintreated patients and in 42 of 42 in the doxycycline group . At the week 2 assessment the corresponding figures were 35 of 35 and 34 of 34 respectively . CONCLUSION --Azithromycin 1000 mg single dose was as effective as doxycycline 100 mg twice daily for 7 days in male patients with chlamydial urethritis At the end of a long week in the office , you sink back into your chair , reflecting on some of the more memorable patients you cared for and counseled . Through gentle history taking , you discovered that urinary incontinence is the underlying cause of an elderly patient 's increasing social isolation . During a careful physical examination , you detected bruising on the torso of a woman with chronic headaches and began to explore the longst and ing abusive relationship between the woman and her alcoholic partner . You discontinued procainamide therapy in a 72-year-old man who had asymptomatic premature ventricular contractions after myocardial infa rct ion . To prevent bleeding from esophageal varices , you started -blocker therapy in a woman with long-st and ing cryptogenic cirrhosis and portal hypertension . In couples ' therapy , discussing the future quality of life of a middle-aged gay man with human immunodeficiency virus infection , you journeyed through emotionally intense dialogue about advance directives . You presented the risk factors for major and minor bleeding to a 39-year-old woman who was considering warfarin therapy because of recently diagnosed atrial fibrillation and valvular heart disease . You listened to , made diagnoses for , treated , advised , and comforted many patients . Yet there were some hiccoughs in your practice along the way . You stumbled while debating the pros and cons of breast cancer screening with a healthy 48-year-old woman who has been staying current with information on the Internet . You question ed the merits of a personalized walking program suggested to you by a motivated 66-year-old man with severe claudication . Explaining that you wanted to review the best current evidence on these issues , you resolved to address your uncertainties before these patients made their next office visits , in a week 's time . Sighing deeply , you acknowledge that you have little time to read . You subscribe to three journals , which you browse months after they arrive-either when your journal stack becomes precariously high or when your guilt is sufficiently motivational . You sometimes find the conclusions of individual articles conflicting or confusing . You know that some of the decisions and suggestions you made this week , specifically your decisions about stopping procainamide therapy and starting -blocker therapy and your advice about bleeding risks from anticoagulant therapy , were based on the best current research evidence [ 1 - 3 ] . On the other h and , your patients ' inquiries about breast cancer screening and exercise treatment for claudication highlight your need for a concise , current , rigorous synthesis of the best available evidence on each of these topics : in brief , a systematic review [ 4 , 5 ] . Incorporating Research Evidence into Clinical Decision Making The foregoing scenario is familiar to practitioners . In a typical week , we encounter patients with diverse problems ; exercise numerous clinical , interpersonal , and technical skills ; and make many decisions . The factors that affect these decisions and their outcomes are complex . For instance , each patient has unique sociodemographic characteristics , cultural circumstances , and personal preferences . Each physician has unique knowledge , experiences , and values . Moreover , practitioners and their patients make decisions within the context of a rapidly changing health care system that influences the availability , accessibility , and cost of diagnostic tests and therapies [ 6 ] . Timely , useful evidence from the biomedical literature should be an integral component of clinical decision making . If one treatment has been shown to be better than another , we need to know , so that we can recommend the treatment to the appropriate patients . The worldwide effort to develop new tests and treatments , and to determine their usefulness , has never been stronger , and our patients and their families expect us to be fonts of the knowledge that results from this effort [ 7 ] . Unfortunately , it is easy for current best research evidence to pass us by [ 8 ] . We may lack the time , motivation , and basic skills needed to find , critically appraise , and synthesize information , all of which we must do if we are to integrate the results of original studies into our practice . Fortunately , several potent methods are emerging that can greatly enhance our ability to interpret and apply research evidence ; foremost among them is the systematic review . This article begins a series in Annals that will examine systematic review s in detail and explore their many applications . Systematic review s represent the best chance that most practitioners will have to underst and and accurately apply the key signals arising from the robust and increasingly productive search for solutions to medical problems . A properly conducted systematic review faithfully summarizes the evidence from all relevant studies on the topic of interest , and it does so concisely and transparently . What Is a Systematic Review ? Systematic review s are scientific investigations in themselves , with pre-planned methods and an assembly of original studies as their subjects . They synthesize the results of multiple primary investigations by using strategies that limit bias and r and om error [ 9 , 10 ] . These strategies include a comprehensive search of all potentially relevant articles and the use of explicit , reproducible criteria in the selection of articles for review . Primary research design s and study characteristics are appraised , data are synthesized , and results are interpreted . When the results of primary studies are summarized but not statistically combined , the review may be called a qualitative systematic review . A quantitative systematic review , or meta- analysis , is a systematic review that uses statistical methods to combine the results of two or more studies . The term overview is sometimes used to denote a systematic review , whether quantitative or qualitative . Summaries of research that lack explicit descriptions of systematic methods are often called narrative review s. Review articles are one type of integrative publication ; practice guidelines , economic evaluations , and clinical decision analyses are others . These other types of integrative articles often incorporate the results of systematic review s. For example , practice guidelines are systematic ally developed statements intended to assist practitioners and patients with decisions about appropriate health care for specific clinical circumstances [ 11 ] . Evidence -based practice guidelines are based on systematic review s of the literature , appropriately adapted to local circumstances and values . Economic evaluations compare both the costs and the consequences of different courses of action ; the knowledge of consequences that are considered in these evaluations is often generated by systematic review s of primary studies . Decision analyses quantify both the likelihood and the valuation of the expected outcomes associated with competing alternatives . Differences between Systematic and Narrative Review s All review s , narrative and systematic alike , are retrospective , observational research studies and are therefore subject to systematic and r and om error . Accordingly , the quality of a review - and thus its worth-depends on the extent to which scientific review methods have been used to minimize error and bias . This is the key feature that distinguishes traditional narrative review s from systematic review s ( Table 1 ) . If a review is prepared according to the steps outlined in the right column of Table 1 , it is more likely to be systematic and to provide unbiased conclusions . If review methods approximate those found in the middle column of Table 1 , the article is more likely to be a narrative review , and the conclusions are less likely to be based on an unbiased summary of all relevant evidence . Table 1 . Differences between Narrative Review s and Systematic Review s Systematic review s are generated to answer specific , often narrow , clinical questions in depth . These questions can be formulated explicitly according to four variables : a specific population and setting ( such as elderly out patients ) , the condition of interest ( for example , hypertension ) , an exposure to a test or treatment ( such as pharmacologic management ) , and one or more specific outcomes ( such as cardiovascular and cerebrovascular events and mortality ) [ 12 ] . Thus , an example of a well-formulated , clinical ly relevant question is , Does pharmacologic treatment of hypertension in the elderly prevent strokes and myocardial infa rct ions or delay death ? If the question that is driving the review is not clear from the title , abstract , or introduction , or if no methods section is included , the paper is more likely to be a narrative review than a systematic review [ 13 ] . Most narrative review articles deal with a broad range of issues related to a given topic rather than addressing a particular issue in depth [ 9 ] . For example , a narrative review on diabetes ( such as that which might be found in a textbook chapter ) might include sections on the physiology and pathophysiology of carbohydrate , lipid , and protein metabolism ; the epidemiology of and prognosis associated with diabetes ; diagnostic and screening approaches ; and preventive , therapeutic , rehabilitative , and palliative interventions . Thus , narrative review s may be most useful for obtaining a broad perspective on a topic ; they are less often useful in furnishing quantitative answers to specific clinical questions . Narrative review s are appropriate for describing the history or development of a problem and its management . Narrative review s may better describe cutting-edge developments if research is scant or preliminary or if studies are very limited by flawed design or execution [ 13 ] . They may be particularly useful for discussing data in light of underlying theory and context . Narrative review s can draw analogies and can conceptually integrate two independent fields of research , such as |
1,994 | 22,235,824 | These findings have been demonstrated in several meta-analyses and systematic review s. These review s have generally found that team-based care can reduce systolic blood pressure by 4 - 10 mm Hg over usual care .
Few cost-effectiveness analyses have been performed but generally have found favorable costs for team-based care when considering the potential to reduce morbidity and mortality . | Team-based care is one of the key components of the patient-centered medical home .
Studies have consistently demonstrated that teams involving pharmacists or nurses in patient management can significantly improve blood pressure control . | BACKGROUND African American men with hypertension in low socioeconomic urban population s achieve poor rates of hypertension control and suffer early from its complications . METHODS In a r and omized clinical trial with 309 hypertensive urban African American men aged 21 to 54 years , we evaluated the effectiveness of a more intensive comprehensive educational-behavioral-pharmacologic intervention by a nurse practitioner-community health worker-physician ( NP/CHW/MD ) team and a less intensive education and referral intervention in controlling blood pressure ( BP ) and minimizing progression of left ventricular hypertrophy ( LVH ) and renal insufficiency . Changes in BP , left ventricular mass ( LVM ) , and serum creatinine from baseline to 36 months were compared between groups . RESULTS At 36 months , the mean systolic BP/diastolic BP change from baseline was -7.5/-10.1 mm Hg for the more intensive group and + 3.4/-3.7 mm Hg for the less intensive group ( P = .001 and .005 for between-group differences in systolic BP and diastolic BP , respectively ) . The proportion of men with controlled BP ( < 140/90 mm Hg ) was 44 % in the more intensive group and 31 % in the less intensive group ( P = .045 ) . The LVM was significantly lower in the more intensive group than in the less intensive group ( more intensive , 274 g ; less intensive , 311 g ; P = .004 ) . There was a trend toward slowing of the progression of renal insufficiency ( incidence of 50 % increase in serum creatinine ) in the more intensive group compared to the less intensive group ( more intensive , 5.2 % ; less intensive , 8.0 % ; P = .08 ) . CONCLUSIONS During 36 months , the more intensive intervention led to a lower BP and decreased progression of LVH in a sample of hypertensive young African American men Background — Secondary prevention by risk factor modification improves patient outcomes , yet it is often not achieved in clinical practice . Reasons for failure stem from challenges of prioritizing risk factor reduction and engaging patients in changing their behaviors . We hypothesize that a novel telemedicine intervention with tailored patient education could improve cardiovascular risk factors . Methods — To evaluate this intervention , we propose enrolling 450 patients with a recent myocardial infa rct ion and hypertension into a 3-arm r and omized , controlled trial . The first arm ( n=150 ) will receive home blood pressure ( BP ) monitors plus a nurse-delivered , telephone-based tailored patient education intervention and will be enrolled into HealthVault , a Microsoft electronic health record platform . The second arm ( n=150 ) will also receive BP monitors plus a tailored patient education intervention and be enrolled in HeartVault . However , the patient education intervention will be delivered by a Web-based program and will cover topics identical to those in the nurse-delivered intervention . Both arms will be compared with a control group receiving st and ard care ( n=150 ) . All participants will have an in-person assessment at baseline and at completion of the study , including st and ardized measurements of BP , LDL cholesterol , and glycosylated hemoglobin ( in diabetic subjects ) . The study design will allow assessment of a telephone-based , nurse-administered disease management program versus st and ard care . The main outcome of interest is the reduction in systolic BP in each intervention group compared with the control group at 12 months . Secondary outcomes assessed will include reductions in LDL cholesterol , body weight , and glycosylated hemoglobin , as well as adherence to evidence -based therapies and improvement in health behaviors . Conclusion — If successful in optimizing BP control , managing other coronary heart disease risk factors , and demonstrating a lower cost , the Web-based disease management tool has the potential to enhance coronary artery disease management , quality of care , and ultimately , patient outcomes . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00901277 OBJECTIVE : To evaluate the effectiveness of a community pharmacist-based home blood pressure ( BP ) monitoring program . DESIGN : Trial of a high-intensity ( HI ) versus low-intensity ( LI ) intervention r and omized in 12 community pharmacies . The HI intervention comprised 4 face-to-face visits with a trained pharmacist . Pharmacists provided patient-specific education about hypertension . Following the first and third visits , patients were provided with a home BP monitoring device and instructed to measure their BP at least once daily for the next month . Home BP readings were used by the pharmacists to develop treatment recommendations for the patient ’s physician . Recommendations were discussed with the physician and , if approved , implemented by the pharmacist . In the LI intervention , pharmacists measured patients BP in the pharmacy and referred them to their physician for evaluation . PARTICIPANTS : Patients with uncontrolled BP at baseline . MEASUREMENTS : The main outcomes were the differences in systolic and diastolic BP ( SBP and DBP ) from baseline to follow-up between the HI and LI patients . RESULTS : The study enrolled 125 patients , 64 in the HI and 61 in the LI group . From baseline , SBP declined 13.4 mmHg in the HI group and 9.0 mmHg in the LI group . At the final visit , the difference in SBP/DBP change between the HI and LI group was −4.5/−3.2 mmHg ( P=.12 for SBP and P=.03 for DBP ) . CONCLUSIONS : The HI intervention achieved a lower DBP and this model could be a strategy for patients with hypertension OBJECTIVE To compare the effectiveness of an evidence -based , systematic approach to hypertension care involving comanagement of patients by primary care physicians and clinical pharmacists versus usual care in reducing blood pressure in patients with uncontrolled hypertension . METHODS Patients in a staff model medical group with uncontrolled hypertension were r and omized to either a usual care ( UC ) or a physician-pharmacist comanagement ( PPCM ) group . All physicians in the study received both group and individual education and participated in the development of an evidence -based hypertension treatment algorithm . Physicians were then given the names of their patients whose medical records documented elevated blood pressures ( defined as systolic > or = 140 mm Hg and /or diastolic > or = 90 mm Hg for patients aged < 65 yrs , and systolic > or = 160 mm Hg and /or diastolic > or = 90 mm Hg for those aged > or = 65 yrs ) . Patients r and omized to the UC group were managed by primary care physicians alone . Those r and omized to the PPCM group were comanaged by their primary care physician and a clinical pharmacist , who provided patient education , made treatment recommendations , and provided follow-up . Blood pressure measurements , antihypertensive drugs , and visit costs/patient were obtained from medical records . RESULTS One hundred ninety-seven patients with uncontrolled hypertension participated in the study . Both PPCM and UC groups experienced significant reductions in blood pressure ( systolic -22 and -11 mm Hg , respectively , p < 0.01 ; diastolic -7 and -8 mm Hg , respectively , p < 0.01 ) . The reduction in systolic blood pressure was greater in the PPCM group after adjusting for differences in baseline blood pressure between the groups ( p < 0.01 ) . More patients achieved blood pressure control in the PPCM than in the UC group ( 60 % vs 43 % , p = 0.02 ) . Average provider visit costs/patient were higher in the UC than the PPCM group ( $ 195 vs $ 160 , p = 0.02 ) . CONCLUSIONS An evidence -based , systematic approach using physician-pharmacist comanagement for patients with uncontrolled hypertension result ed in improved blood pressure control and reduced average visit costs/patient BACKGROUND St and ard office-based approaches to controlling hypertension show limited success . Such suboptimal hypertension control reflects in part the absence of both an infrastructure for patient education and frequent , regular blood pressure ( BP ) monitoring . We tested the efficacy of a physician-directed , nurse-managed , home-based system for hypertension management with st and ardized algorithms to modulate drug therapy , based on patients ' reports of home BP . METHODS We r and omized out patients requiring drug therapy for hypertension according to the Joint National Committee on Prevention , Detection , Evaluation , and Treatment of High Blood Pressure ( JNC VI ) criteria to receive usual medical care only ( UC , n = 76 ) or usual care plus nurse care management intervention ( INT , n = 74 ) over a 6-month period . RESULTS Patients receiving INT achieved greater reductions in office BP values at 6 months than those receiving UC : 14.2 + /- 18.1 versus 5.7 + /- 18.7 mm Hg systolic ( P < .01 ) and 6.5 + /- 10.0 versus 3.4 + /- 7.9 mm Hg diastolic , respectively ( P < .05 ) . At 6 months , we observed one or more changes in drug therapy in 97 % of INT patients versus 43 % of UC patients , and 70 % of INT patients received two or more drugs versus 46 % of UC . Average daily adherence to medication , measured by electronic drug event monitors , was superior among INT subjects ( mean + /- SD , 80.5 % + /- 23.0 % ) than among UC subjects ( 69.2 + /- 31.1 % ; t(113 ) = 2.199 , P = .03 ) . There were no significant adverse drug reactions in either group . CONCLUSIONS Telephone-mediated nurse management can successfully address many of the systems-related and patient-related issues that limit pharmacotherapeutic effectiveness for hypertension BACKGROUND Telemedicine is a promising but largely unproven technology for providing case management services to patients with chronic conditions who experience barriers to access to care or a high burden of illness . METHODS The authors conducted a r and omized , controlled trial comparing telemedicine case management to usual care , with blinding of those obtaining outcome data , in 1,665 Medicare recipients with diabetes , aged 55 years or greater , and living in federally design ated medically underserved areas of New York State . The primary endpoints were HgbA1c , blood pressure , and low-density lipoprotein ( LDL ) cholesterol levels . RESULTS In the intervention group ( n = 844 ) , mean HgbA1c improved over one year from 7.35 % to 6.97 % and from 8.35 % to 7.42 % in the subgroup with baseline HgbA1c > or = 7 % ( n = 353 ) . In the usual care group ( n = 821 ) mean HgbA1c improved over one year from 7.42 % to 7.17 % . Adjusted net reductions ( one-year minus baseline mean values in each group , compared between groups ) favoring the intervention were as follows : HgbA1c , 0.18 % ( p = 0.006 ) , systolic and diastolic blood pressure , 3.4 ( p = 0.001 ) and 1.9 mm Hg ( p < 0.001 ) , and LDL cholesterol , 9.5 mg/dL ( p < 0.001 ) . In the subgroup with baseline HgbA1c > or = 7 % , net adjusted reduction in HgbA1c favoring the intervention group was 0.32 % ( p = 0.002 ) . Mean LDL cholesterol level in the intervention group at one year was 95.7 mg/dL. The intervention effects were similar in magnitude in the subgroups living in New York City and upstate New York . CONCLUSION Telemedicine case management improved glycemic control , blood pressure levels , and total and LDL cholesterol levels at one year of follow-up BACKGROUND A patient-centered medical home ( PCMH ) demonstration was undertaken at 1 healthcare system , with the goals of improving patient experience , lessening staff burnout , improving quality , and reducing downstream costs . Five design principles guided development of the PCMH changes to staffing , scheduling , point-of-care , outreach , and management . OBJECTIVE To report differences in patient experience , staff burnout , quality , utilization , and costs in the first year of the PCMH demonstration . STUDY DESIGN Prospect i ve before and after evaluation . METHODS Baseline ( 2006 ) and 12-month ( 2007 ) measures were compared . Patient and staff experiences were measured using surveys from a r and om sample of patients and all staff at the PCMH and 2 control clinics . Automated data were used to measure and compare change components , quality , utilization , and costs for PCMH enrollees versus enrollees at 19 other clinics . Analyses included multivariate regressions for the different outcomes to account for baseline case mix . RESULTS After adjusting for baseline , PCMH patients reported higher ratings than controls on 6 of 7 patient experience scales . For staff burnout , 10 % of PCMH staff reported high emotional exhaustion at 12 months compared with 30 % of controls , despite similar rates at baseline . PCMH patients also had gains in composite quality between 1.2 % and 1.6 % greater than those of other patients . PCMH patients used more e-mail , phone , and specialist visits , but fewer emergency services . At 12 months , there were no significant differences in overall costs . CONCLUSIONS A PCMH re design can be associated with improvements in patient experience , clinician burnout , and quality without increasing overall cost STUDY OBJECTIVE To assess blood pressure control after discontinuation of a physician-pharmacist collaborative intervention . DESIGN Comparative analysis of data of the patients who received the intervention versus a control group from a prospect i ve , cluster-r and omized , 9-month efficacy trial and the same patients ' data 18 and 27 months after completion of the trial , abstract ed from their medical records . SETTING Five primary care medical offices operated by a university health system . PATIENTS One hundred four patients with hypertension ; 65 were in the intervention group , and 39 were in the control group . MEASUREMENTS AND MAIN RESULTS In the prospect i ve study , patients were r and omized to receive a physician-pharmacist collaborative intervention to improve blood pressure control or to the control group . Systolic and diastolic blood pressures were measured by a research nurse at baseline and at the end of the study ( 9 mo later ) . In the current study , data were abstract ed for blood pressure and blood pressure control at 18 and 27 months ( 9 and 18 mo , respectively , after discontinuation of the study ) . At baseline , mean + /- SD systolic blood pressure was 152.5 + /- 9.5 and 150.1 + /- 9.6 mm Hg in the intervention and control groups , respectively ( p=0.22 ) . At 9 months , systolic blood pressure decreased to 124.5 + /- 10.7 and 132.0 + /- 15.1 mm Hg ( p=0.0038 between groups ) , and blood pressure was controlled in 78.5 % and 48.7 % ( p=0.0017 ) of patients in the intervention and control groups , respectively . By 18 months , systolic blood pressure had deteriorated to 131.0 + /- 12.2 and 143.3 + /- 17.5 mm Hg ( p<0.001 ) , and blood pressure control rates decreased to 53.9 % and 30.8 % ( p=0.02 ) . By 27 months , systolic blood pressure was 131.3 + /- 13.0 and 141.2 + /- 15.8 mm Hg ( p=0.0008 ) , and blood pressure control was 55.4 % and 35.9 % ( p=0.05 ) . CONCLUSION A sustained positive effect on blood pressure control was noted up to 18 months after discontinuation of a physician-pharmacist collaborative intervention , when compared with a control group . Blood pressure control did deteriorate at a similar rate in both the intervention and control groups , but the percentage of patients with controlled blood pressure remained significantly higher in the intervention group . These results suggest that continued interventions by pharmacists may be necessary to maintain high rates of blood pressure control , especially in those patients whose blood pressure begins to increase OBJECTIVE To determine whether a new model of primary care , Chronic Care Clinics , can improve outcomes of common geriatric syndromes ( urinary incontinence , falls , depressive symptoms , high risk medications , functional impairment ) in frail older adults . DESIGN R and omized controlled trial with 24 months of follow-up . Physician practice s were r and omized either to the Chronic Care Clinics intervention or to usual care . SETTING Nine primary care physician practice s that comprise an ambulatory clinic in a large staff-model HMO in western Washington State . PARTICIPANTS Those patients aged 65 and older in each practice with the highest risk for being hospitalized or experiencing functional decline . INTERVENTION Intervention practice s ( 5 physicians , 96 patients ) held half-day Chronic Care Clinics every 3 to 4 months . These clinics included an extended visit with the physician and nurse dedicated to planning chronic disease management ; a pharmacist visit that emphasized reduction of polypharmacy and high-risk medications ; and a patient self-management/support group . Control practice s ( 4 physicians , 73 patients ) received usual care . MEASUREMENTS Changes in self-reported urinary incontinence , frequency of falls , depressive symptoms , physical function , and satisfaction were analyzed using an intention-to-treat analysis adjusted for baseline differences , covariates , and practice -level variation . Prescriptions for high-risk medications and cost/utilization data obtained from administrative data were similarly analyzed . RESULTS After 24 months , no significant improvements in frequency of incontinence , proportion with falls , depression scores , physical function scores , or prescriptions for high risk medications were demonstrated . Costs of medical care including frequency of hospitalization , hospital days , emergency and ambulatory visits , and total costs of care were not significantly different between intervention and control groups . A higher proportion of intervention patients rated the overall quality of their medical care as excellent compared with control patients ( 40.0 % vs 25.3 % , P = .10 ) . CONCLUSIONS Although intervention patients expressed high levels of satisfaction with Chronic Care Clinics , improved outcomes for selected geriatric syndromes were not demonstrated . These findings suggest the need for developing greater system-wide support for managing geriatric syndromes in primary care and illustrate the challenges of conducting practice improvement research in a rapidly changing delivery system CONTEXT Poor medication adherence diminishes the health benefits of pharmacotherapies . Elderly patients with coronary risk factors frequently require treatment with multiple medications , placing them at increased risk for nonadherence . OBJECTIVE To test the efficacy of a comprehensive pharmacy care program to improve medication adherence and its associated effects on blood pressure ( BP ) and low-density lipoprotein cholesterol ( LDL-C ) . DESIGN , SETTING , AND PATIENTS A multiphase , prospect i ve study with an observational phase and a r and omized controlled trial conducted at the Walter Reed Army Medical Center of 200 community-based patients aged 65 years or older taking at least 4 chronic medications . The study was conducted from June 2004 to August 2006 . INTERVENTION After a 2-month run-in phase ( measurement of baseline adherence , BP , and LDL-C ) , patients entered a 6-month intervention phase ( st and ardized medication education , regular follow-up by pharmacists , and medications dispensed in time-specific packs ) . Following the intervention phase , patients were r and omized to continued pharmacy care vs usual care for an additional 6 months . MAIN OUTCOME MEASURES Primary end point of the observation phase was change in the proportion of pills taken vs baseline ; secondary end points were the associated changes in BP and LDL-C. Primary end point of the r and omization phase was the between-group comparison of medication persistence . RESULTS A total of 200 elderly patients ( 77.1 % men ; mean [ SD ] age , 78 [ 8.3 ] years ) , taking a mean ( SD ) of 9 ( 3 ) chronic medications were enrolled . Coronary risk factors included drug-treated hypertension in 184 patients ( 91.5 % ) and drug-treated hyperlipidemia in 162 ( 80.6 % ) . Mean ( SD ) baseline medication adherence was 61.2 % ( 13.5 % ) . After 6 months of intervention , medication adherence increased to 96.9 % ( 5.2 % ; P<.001 ) and was associated with significant improvements in systolic BP ( 133.2 [ 14.9 ] to 129.9 [ 16.0 ] mm Hg ; P = .02 ) and LDL-C ( 91.7 [ 26.1 ] to 86.8 [ 23.4 ] mg/dL ; P = .001 ) . Six months after r and omization , the persistence of medication adherence decreased to 69.1 % ( 16.4 % ) among those patients assigned to usual care , whereas it was sustained at 95.5 % ( 7.7 % ) in pharmacy care ( P<.001 ) . This was associated with significant reductions in systolic BP in the pharmacy care group ( -6.9 mm Hg ; 95 % CI , -10.7 to -3.1 mm Hg ) vs the usual care group ( -1.0 mm Hg ; 95 % CI , -5.9 to 3.9 mm Hg ; P = .04 ) , but no significant between-group differences in LDL-C levels or reductions . CONCLUSIONS A pharmacy care program led to increases in medication adherence , medication persistence , and clinical ly meaningful reductions in BP , whereas discontinuation of the program was associated with decreased medication adherence and persistence . TRIAL REGISTRATION clinical trials.gov Identifier : Background Patient-shared electronic health records provide opportunities for care outside of office visits . However , those who might benefit may be unable to or choose not to use these re sources , while others might not need them . Objective Electronic Communications and Home Blood Pressure Monitoring ( e-BP ) was a r and omized trial that demonstrated that Web-based pharmacist care led to improved blood pressure ( BP ) control . During recruitment we attempted to contact all patients with hypertension from 10 clinics to determine whether they were eligible and willing to participate . We wanted to know whether particular subgroups , particularly those from vulnerable population s , were less willing to participate or unable to because they lacked computer access . Methods From 2005 to 2006 , we sent invitation letters to and attempted to recruit 9298 patients with hypertension . Eligibility to participate in the trial included access to a computer and the Internet , an email address , and uncontrolled BP ( BP ≥ 140/90 mmHg ) . Generalized linear models within a modified Poisson regression framework were used to estimate the relative risk ( RR ) of in eligibility due to lack of computer access and of having uncontrolled BP . Results We were able to contact 95.1 % ( 8840/9298 ) of patients . Those refusing participation ( 3032/8840 , 34.3 % ) were significantly more likely ( P < .05 ) to be female , be nonwhite , have lower levels of education , and have Medicaid insurance . Among patients who answered survey questions , 22.8 % ( 1673/7354 ) did not have computer access . Older age , minority race , and lower levels of education were risk factors for lack of computer access , with education as the strongest predictor ( RR 2.63 , 95 % CI 2.30 - 3.01 for those with a high school degree compared to a college education ) . Among hypertensive patients with computer access who were willing to participate , African American race ( RR 1.22 , 95 % CI 1.06 - 1.40 ) , male sex ( RR 1.28 , 95 % CI 1.18 - 1.38 ) , and obesity ( RR 1.53 , 95 % CI 1.31 - 1.79 ) were risk factors for uncontrolled BP . Conclusion Older age , lower socioeconomic status , and lower levels of education were associated with decreased access to and willingness to participate in a Web-based intervention to improve hypertension control . Failure to ameliorate this may worsen health care disparities . Trial Registration Clinical trials.gov NCT00158639 ; http://www . clinical trials.gov/ct2/show/NCT00158639 ( Archived by WebCite at http://www.webcitation.org/5v1jnHaeo BACKGROUND Studies have demonstrated that blood pressure ( BP ) control can be improved when clinical pharmacists assist with patient management . The objective of this study was to evaluate if a physician and pharmacist collaborative model in community-based medical offices could improve BP control . METHODS This was a prospect i ve , cluster r and omized , controlled clinical trial with clinics r and omized to a control group ( n = 3 ) or to an intervention group ( n = 3 ) . The study enrolled 402 patients ( mean age , 58.3 years ) with uncontrolled hypertension . Clinical pharmacists made drug therapy recommendations to physicians based on national guidelines . Research nurses performed BP measurements and 24-hour BP monitoring . RESULTS The mean ( SD ) guideline adherence scores increased from 49.4 ( 19.3 ) at baseline to 53.4 ( 18.1 ) at 6 months ( 8.1 % increase ) in the control group and from 40.4 ( 22.6 ) at baseline to 62.8 ( 13.5 ) at 6 months ( 55.4 % increase ) in the intervention group ( P = .09 for adjusted between-group comparison ) . The mean BP decreased 6.8/4.5 mm Hg in the control group and 20.7/9.7 mm Hg in the intervention group ( P < .05 for between-group systolic BP comparison ) . The adjusted difference in systolic BP was -12.0 ( 95 % confidence interval [ CI ] , -24.0 to 0.0 ) mm Hg , while the adjusted difference in diastolic BP was -1.8 ( 95 % CI , -11.9 to 8.3 ) mm Hg . The 24-hour BP levels showed similar effect sizes . Blood pressure was controlled in 29.9 % of patients in the control group and in 63.9 % of patients in the intervention group ( adjusted odds ratio , 3.2 ; 95 % CI , 2.0 - 5.1 ; P < .001 ) . CONCLUSIONS A physician and pharmacist collaborative intervention achieved significantly better mean BP and overall BP control rates compared with a control group . Additional research should be conducted to evaluate efficient strategies to implement team-based chronic disease management . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00201019 We evaluated blood pressure control , quality of life , quality of care , and satisfaction of patients who were monitored by specially trained community pharmacists in a group medical practice . After participating in an intensive skill development program , pharmacists performed in an interdisciplinary team in a rural clinic . The primary objective was assessed by evaluating outcome variables at 6 months compared with baseline in 25 patients r and omly assigned to a study group . A control group of 26 patients was also evaluated to determine if outcome variables remained constant from baseline to 6 months . Systolic blood pressure was reduced in the study group ( 151 mm Hg baseline , 140 mm Hg at 6 mo , p<0.001 ) and diastolic blood pressure was significantly lower at 2 , 4 , and 5 months compared with baseline . Ratings from a blinded peer review panel indicated significant improvement in the appropriateness of the blood pressure regimen , going from 8.7 + /- 4.7 to 10.9 + /- 4.5 in the study group ( p<0.01 ) , but they did not change in the control group . Several quality of life scores improved significantly in the study group after 6 months ( p<0.05 ) . These included physical functioning ( 61.6 vs 70.7 ) , physical role limitations ( 56.8 vs 72.8 ) , and bodily pain ( 60.0 vs 71.7 ) at baseline and 6 months , respectively . There were no significant changes in the control group . Patient satisfaction scores were consistently higher in the study group at the end of the study . Our results indicate that when community pharmacists in a clinic setting are trained and included as members of the primary care team , significant improvements in blood pressure control , quality of life , and patient satisfaction can be achieved OBJECTIVE : To assess the effect of a physician and pharmacist teamwork approach to uncontrolled hypertension in a medical resident teaching clinic , for patients who failed to meet the recommended goals of the fifth Joint National Commission on Detection , Evaluation and Treatment of High Blood Pressure . HYPOTHESIS : Physician and pharmacist teamwork can improve the rate of meeting national blood pressure goals in patients with previously uncontrolled hypertension . DESIGN : A single-blinded r and omized controlled trial lasting 6 months . SETTING : A primary care outpatient teaching clinic . PATIENTS : A sample of 95 adult hypertensive patients who failed to meet national blood pressure goals based on three consecutive visits over a 6-month period . INTERVENTION : Patients were r and omly assigned to a control arm of st and ard medical care or to an intervention arm in which a physician and pharmacist worked together as a team . MAIN RESULTS : At study completion , the percentage of patients achieving national goals due to intervention was more than double the percentage in the control arm ( 55 % vs 20 % , p < .001 ) . Systolic blood pressure declined 23 mm Hg in the intervention arm versus 11 mm Hg in the control arm ( p < .01 ) . Diastolic blood pressure declined 14 and 3 mm Hg in the intervention and control arms , respectively ( p < .001 ) . The intervention worked equally as well in men and women and demonstrated noticeable promise in a minority of mixed-ancestry Hawaiians in whom hypertension is of special concern . CONCLUSIONS : Patients who fail to achieve national blood pressure goals under st and ard outpatient medical care may benefit from a program that includes a physician and pharmacist teamwork approach CONTEXT Telemedicine is a promising but largely unproven technology for providing case management services to patients with chronic conditions and lower access to care . OBJECTIVES To examine the effectiveness of a telemedicine intervention to achieve clinical management goals in older , ethnically diverse , medically underserved patients with diabetes . DESIGN , Setting , and Patients A r and omized controlled trial was conducted , comparing telemedicine case management to usual care , with blinded outcome evaluation , in 1,665 Medicare recipients with diabetes , aged > /= 55 years , residing in federally design ated medically underserved areas of New York State . Interventions Home telemedicine unit with nurse case management versus usual care . Main Outcome Measures The primary endpoints assessed over 5 years of follow-up were hemoglobin A1c ( HgbA1c ) , low density lipoprotein ( LDL ) cholesterol , and blood pressure levels . RESULTS Intention-to-treat mixed models showed that telemedicine achieved net overall reductions over five years of follow-up in the primary endpoints ( HgbA1c , p = 0.001 ; LDL , p < 0.001 ; systolic and diastolic blood pressure , p = 0.024 ; p < 0.001 ) . Estimated differences ( 95 % CI ) in year 5 were 0.29 ( 0.12 , 0.46)% for HgbA1c , 3.84 ( -0.08 , 7.77 ) mg/dL for LDL cholesterol , and 4.32 ( 1.93 , 6.72 ) mm Hg for systolic and 2.64 ( 1.53 , 3.74 ) mm Hg for diastolic blood pressure . There were 176 deaths in the intervention group and 169 in the usual care group ( hazard ratio 1.01 [ 0.82 , 1.24 ] ) . CONCLUSIONS Telemedicine case management result ed in net improvements in HgbA1c , LDL-cholesterol and blood pressure levels over 5 years in medically underserved Medicare beneficiaries . Mortality was not different between the groups , although power was limited . Trial Registration http:// clinical trials.gov Identifier : NCT00271739 PURPOSE The present study evaluated whether an intervention using a short message service ( SMS ) by cellular phone and Internet would improve blood pressure , weight control , and serum lipids of obese patients with hypertension during 8 weeks . METHODS This is a quasi-experimental design with pre- and follow-up tests . Participants were recruited from the family medicine outpatient department of tertiary care hospital located in an urban city of South Korea . Twenty-eight patients were assigned to an intervention group and 21 to a control group . The goal of intervention was to bring blood pressure , body weight , and serum lipids levels close to normal ranges . Patients in the intervention group were requested to record their blood pressure and body weight in a weekly web based diary through the Internet or by cellular phones . The research ers sent optimal recommendations as an intervention to each patient , by both cellular phone and Internet weekly . The intervention was applied for 8 weeks . RESULTS Systolic ( SBP ) and diastolic blood pressures ( DBP ) significantly decreased by 9.1 and 7.2 mmHg respectively at 8 weeks from the baseline in the intervention group ( p<0.05 ) . However , after 8 weeks from the baseline both SBP and DBP in the control group had not changed significantly . Yet , There were significant mean decreases in body weight and waist circumference by 1.6 kg ( p<0.05 ) and 2.8 cm ( p<0.05 ) in the intervention group , respectively . In the control group increases in body weight and waist circumference ( p<0.05 ) mean changes were also significant . High density lipoprotein cholesterol ( HDL-C ) significantly increased , with a mean change of 3.7 mg/dl at 8 weeks from baseline in the intervention group ( p<0.05 ) . The mean change of HDL-C in the control group was , however , not significant . CONCLUSION During 8 weeks using this web-based intervention by way of cellular phone and Internet SMS improved blood pressure , body weight , waist circumference , and HDL-C in patients with obese hypertension The medical care system is not very effective in modifying health behavior of individuals , in particular , ensuring patient compliance with medication regimens , healthy diets , regular physical activity , and regular health screening , and in the avoidance of substance abuse . Telephone-Linked Care ( TLC ) is a telecommunications technology that enables computer-controlled telephone counseling with patients in their homes . It has been applied to the task of improving a number of different health behaviors . R and omized controlled studies suggest that use of the system for as little as 3 months is associated with improvement in adherence to medication regimens , dietary change in hypercholesterolemia , and increased physical activity among sedentary individuals . Future work involves applying the technology to other important health behaviors , optimally using health behavior theory in the system design , targeting use of TLC to the most appropriate patient groups , incorporating new computer and telecommunications technology into the system , and interfacing TLC into the health care delivery system We propose evaluation of a multi-component home automated telemanagement system providing integrated support to both clinicians and patients in implementing hypertension treatment guidelines . In a r and omized clinical study , 550 blacks with hypertension are followed for 18 months . The major components of the intervention and control groups are identical and are based on the current st and ard of care . For the purpose of this study , we define " st and ard of care " as the expected evidence -based care provided according to the current hypertension treatment guidelines . Although intervention and control groups are similar in terms of their care components , they differ in the mode of care delivery . For the control group the best attempt is made to deliver all components of a guideline -concordant care in a routine clinical environment whereas for the intervention group the routine clinical environment is enhanced with health information technology that assists clinicians and patients in working together in implementing treatment guidelines . The home automated telemanagement system guides patients in following their individualized treatment plans and helps care coordination team in monitoring the patient progress . The study design is aim ed at addressing the main question of this trial : whether the addition of the information technology-enhanced care coordination in the routine primary care setting can improve delivery of evidence -based hypertension care in blacks . The outcome parameters include quality of life , medical care use , treatment compliance , psychosocial variables , and improvement in blood pressure control rates . The trial will provide insight on the potential impact of information technology-enhanced care coordination in blacks with poorly controlled hypertension BACKGROUND There is increasing interest in developing interventions to promote physical activity ( PA ) that do not involve face-to-face contact with health professionals . We developed a fully automated PA counseling system ( telephone-linked communication , TLC-PA ) that was delivered via telephone . DESIGN A r and omized , controlled trial with 298 adult , sedentary members ( mean age , 45.9 years ; 72 % women ; 45 % white ; and 45 % African American ) of a multi-site medical practice . The comparison group ( TLC-Eat ) received an automated intervention promoting healthy eating , which was also delivered via telephone . INTERVENTION The TLC-PA promoted moderate-intensity PA ( MI-PA ) based on the transtheoretical model of behavior change and social cognitive theory . The system was available to participants for 6 months . MAIN OUTCOMES Energy expenditure in MI-PA , proportion of participants who met recommendations for MI-PA , and motivational readiness for PA . MEASURES Self-reports of PA behavior and motivational readiness at baseline , 3 months , and 6 months . RESULTS At 3 months , intention-to-treat analyses showed that the TLC-PA group was more likely to meet recommendations for MI- or vigorous-intensity PA ( VI-PA ) compared to the TLC-Eat group ( TLC-PA=26 % vs TLC-Eat=19.6 % , p=0.04 ) . Among study completers , TLC-PA subjects reported significantly higher daily kilocalorie energy expenditure in MI-PA ( 2.3 kcal/kg/d vs 2.0 kcal/kg/d , p=0.02 ) ; a larger proportion met recommendations for MI- or VI-PA ( 31.2 % vs 21.3 % , p=0.02 ) and were in more advanced stages of motivational readiness than TLC-Eat subjects ( TLC-PA=52.5 % vs TLC-Eat=42.2 % , p=0.04 ) . Results were not maintained at 6 months . The proportion of TLC-PA users decreased significantly over the intervention period . CONCLUSIONS A fully automated counseling system had positive short-term effects on PA among sedentary adults . Lack of maintenance of effects may be due to a decrease in the number of participants who continued to use the system STUDY OBJECTIVE To measure clinical , economic , and humanistic outcomes associated with a pharmacist-managed hypertension clinic compared with physician-managed clinics . DESIGN Prospect i ve , r and omized , comparative study . SETTING Managed care organization . PATIENTS A total of 330 patients with mild-to-moderate essential hypertension . INTERVENTION Hypertension care provided by either the pharmacist-managed hypertension clinic or physician-managed general medical clinics . MEASUREMENTS AND MAIN RESULTS Baseline and 6-month evaluations consisted of systolic and diastolic blood pressure measurements , a short-form health survey , and collection of health care utilization information . After treatment , blood pressure measurements were significantly lower ( p<0.001 ) in the pharmacist-managed hypertension clinic group than in the physician-managed clinic group . Patient satisfaction was significantly higher in the hypertension clinic group . Total costs for the hypertension clinic group were not different from those of the physician-managed clinic group ( $ 242.46 vs $ 233.20 , p=0.71 ) , but cost : effectiveness ratios were lower in the hypertension clinic group ( $ 27 vs $ 193/mm Hg for systolic blood pressure readings , and $ 48 vs $ 151/mm Hg for diastolic blood pressure readings ) . CONCLUSION In a hypertension clinic , pharmacists can be a cost-effective alternative to physicians in management of patients , and they can improve clinical outcomes and patient satisfaction This was a prospect i ve , cluster r and omized controlled trial in patients with uncontrolled hypertension aged 21 to 85 years ( mean , 61 years ) . Pharmacists made recommendations to physicians for patients in the intervention clinics ( n=101 ) but not patients in the control clinics ( n=78 ) . The mean adjusted difference in systolic blood pressure ( BP ) between the control and intervention groups was 8.7 mm Hg ( 95 % confidence interval [ CI ] , 4.4 - 12.9 ) , while the difference in diastolic BP was 5.4 mm Hg ( CI , 2.8 - 8.0 ) at 9 months . The 24-hour BP levels showed similar effects , with a mean systolic BP level that was 8.8 mm Hg lower ( CI , 5.0 - 12.6 ) and a mean diastolic BP level that was 4.6 mm Hg ( CI , 2.4 - 6.8 ) lower in the intervention group . BP was controlled in 89.1 % of patients in the intervention group and 52.9 % in the control group ( adjusted odds ratio , 8.9 ; CI , 3.8 - 20.7 ; P<.001 ) . Physician/pharmacist collaboration achieved significantly better mean BP values and overall BP control rates , primarily by intensification of medication therapy and improving patient adherence The cost-effectiveness of counseling by telephone and by clinic visit contacts were compared in 40 hypertensive patients each of whom received counseling and reinforcement every three weeks for six months regarding diet , exercise , smoking , and coping with stress . Blood pressure declined significantly in both counseling groups ( N : 10 each ) but not in a control group ( N : 20 ) . The cost per patient under control was $ 82 for the clinic counseling and $ 39 for the telephone counseling strategy , suggesting that telephone counseling was a cost-effective technique BACKGROUND Less than one third of the 65 million Americans with hypertension have adequate blood pressure ( BP ) control . This study examined the effectiveness of 2 interventions for improving patient BP control . METHODS This was a 2-level ( primary care provider and patient ) cluster r and omized trial with 2-year follow-up occurring among patients with hypertension enrolled from a Veterans Affairs Medical Center primary care clinic . Primary care providers ( n = 17 ) in the intervention received computer-generated decision support design ed to improve guideline concordant medical therapy at each visit ; control providers ( n = 15 ) received a reminder at each visit . Patients received usual care or a bimonthly tailored nurse-delivered behavioral telephone intervention to improve hypertension treatment . The primary outcome was proportion of patients who achieved a BP < 140/90 mm Hg ( < 130/85 for diabetic patients ) over the 24-month intervention . RESULTS Of the 816 eligible patients contacted , 190 refused and 38 were excluded . The 588 enrolled patients had a mean age of 63 years , 43 % had adequate baseline BP control , and 482 ( 82 % ) completed the 24-month follow-up . There were no significant differences in amount of change in BP control in the 3 intervention groups as compared to the hypertension reminder control group . In secondary analyses , rates of BP control for all patients receiving the patient behavioral intervention ( n = 294 ) improved from 40.1 % to 54.4 % at 24 months ( P = .03 ) ; patients in the nonbehavioral intervention group improved from 38.2 % to 43.9 % ( P = .38 ) , but there was no between-group differences at the end of the study . CONCLUSION The brief behavioral intervention showed improved outcomes over time , but there were not significant between group differences OBJECTIVES This study reports on Eat for Life , a multicomponent intervention to increase fruit and vegetable consumption among African Americans that was delivered through Black churches . METHODS Fourteen churches were r and omly assigned to 3 treatment conditions : ( 1 ) comparison , ( 2 ) self-help intervention with 1 telephone cue call , and ( 3 ) self-help with 1 cue call and 3 counseling calls . The telephone counseling in group 3 was based on motivational interviewing . The primary outcome , assessed at baseline and 1-year follow-up , was fruit and vegetable intake as assessed by 3 food frequency question naires . RESULTS Change in fruit and vegetable intake was significantly greater in the motivational interviewing group than in the comparison and self-help groups . The net difference between the motivational interviewing and comparison groups was 1.38 , 1.03 , and 1.21 servings of fruits and vegetables per day for the 2-item , 7-item , and 36-item food frequency question naires , respectively . The net difference between the motivational interviewing and self-help groups was 1.14 , 1.10 , and 0.97 servings for the 2-item , 7-item , and 36-item food frequency question naires , respectively . CONCLUSIONS Motivational interviewing appears to be a promising strategy for modifying dietary behavior , and Black churches are an excellent setting to implement and evaluate health promotion programs OBJECTIVE To examine baseline renal screening practice s and the effect of nurse case management of patients with diabetes in a group model health maintenance organization ( HMO ) . RESEARCH DESIGN AND METHODS We performed both 1-year retrospective and 1-year prospect i ve studies of renal assessment practice s and ACE inhibitor usage in a cohort of 133 diabetic patients enrolled in a r and omized controlled trial of a diabetes nurse case management program in a group model HMO . In accordance with American Diabetes Association recommendations , urine dipstick and quantitative protein and microalbuminuria testing rates were calculated . RESULTS At baseline , 77 % of patients were screened for proteinuria with dipsticks or had quantitative urine testing . Of patients with negative dipstick findings , 30 % had appropriate quantitative protein or microalbumin follow-up at baseline . Baseline ACE inhibitor usage was associated with decreased follow-up testing ( relative risk = 0.47 ) . Nurse case management was associated with increased quantitative protein or or microalbumin testing and increased follow-up testing ( relative risk = 1.65 and 1.60 , respectively ) . CONCLUSIONS We found a higher degree of adherence to recommendations for renal testing than has been reported previously . Nurse case management intervention further increased renal screening rates . The inverse association between ACE inhibitor usage and microalbumin testing highlights a potentially ambiguous area of current clinical pathways BACKGROUND Few telemedicine programs have undergone cost analyses , impeding their implementation into practice . We report on the economic analysis of a nurse-administered intervention design ed to improve blood pressure control among hypertensive veterans . METHODS We r and omized hypertensive patients at the Durham Veterans Affairs Medical Center primary care clinic to behavioral ( n = 294 ) or nonbehavioral ( n = 294 ) interventions . Behavioral intervention patients received tailored information bimonthly for 2 years via telephone . To calculate intervention cost , we microcosted the nurse 's labor cost and computer hardware and software costs , applied a direct-to-indirect cost ratio , and distributed the costs over an estimated cohort of patients . We analyzed data from the Veterans Affairs Decision Support System to assess whether the intervention impacted overall health care utilization and costs . We used life expectancy estimates from the literature to develop decision models to calculate cost per life-year saved . RESULTS The mean annual intervention cost was $ 112 ( range $ 61-$259 ) . During 2 years of follow-up , patients in the intervention group incurred $ 7,800 in inpatient costs and $ 9,741 in outpatient costs ; the nonintervention group incurred $ 6,866 in inpatient costs and $ 9,599 in outpatient costs . The total cost difference was not statistically significant ( P = .56 ) . Cost-effectiveness of the behavioral intervention ranged from $ 42,457 per life-year saved for normal-weight women to $ 87,300 per life-year saved for normal-weight men . CONCLUSIONS The study results suggest that a nurse-administered , tailored behavioral intervention can be implemented at nominal cost and be cost-effective ; however , there was no apparent lowering of health care utilization and costs during the 2 years of follow-up Objective The aim of this study is to describe recommendations made by clinical pharmacists when co-managing hypertension with physicians . Setting Two family medicine clinics at a major teaching hospital in the mid-western United States . Method This report details the specific recommendations made by pharmacists during a prospect i ve r and omized controlled clinical trial . Patients with uncontrolled hypertension were enrolled in a 9-month intensive pharmacist – physician co-management study . Clinical pharmacists saw patients at baseline , 2 , 4 , 6 , and 8 month visits . Optional visits were allowed between required visits . Main outcome measure For this analysis , pharmacist recommendations were grouped . Physician acceptance of the pharmacists ’ recommendations was also evaluated . Results Data from 101 patients were included and analyzed in this study . Changes in drug therapy were recommended 267 times for these 101 patients . Most recommendations for a change in treatment involved adding a new antihypertensive medication ( 46.4 % ) or increasing a dose ( 33.3 % ) . The majority of pharmacist recommendations to modify drug therapy were made at the baseline visit ( 41.6 % ) , with 76.8 % of recommendations made by the 2 month visit . Physicians accepted and implemented 95.9 % of the 267 pharmacist recommendations to modify drug therapy . Pharmacists recommended no change in the treatment plan 361 times , most often because the patient ’s blood pressure ( BP ) had achieved the goal . Average BP decreased from 153.1 ± 10.0/84.9 ± 12.0 mmHg ( average ± SD ) at baseline to 124.2 ± 9.7/74.7 ± 9.6 mmHg ( P < 0.001 ) at the end of 9 months , with 89.1 % ( P < 0.001 ) of patients reaching their BP goal . Conclusion Pharmacist recommendations for alterations in drug therapy generally occurred early in the course of the study and were largely to intensify therapy through higher dosages or additional medications . Pharmacist – physician co-management of BP is effective at reducing BP and improving BP control rates Background : Nearly one in three adults in the United States has hypertension . Hypertension is one of the largest risk factors for cardiovascular diseases , and it is growing in prevalence , especially among African Americans . Objectives : To test the hypothesis that individuals who participate in usual care ( UC ) plus blood pressure ( BP ) telemonitoring ( TM ) will have a greater reduction in BP from baseline to 12-month follow-up than would individuals who receive UC only . Methods : A two-group , experimental , longitudinal design with block stratified r and omization for antihypertensive medication use was used . African Americans with hypertension were recruited through free BP screenings offered in the community . Data were collected through a structured interview and brief physical exam . Cross tabs , repeated measures analysis of variance , and independent t tests were used to analyze the study 's hypothesis . Results : The TM intervention group had a greater reduction in systolic BP ( 13.0 mm Hg ) than the enhanced UC group ( 7.5 mm Hg ; t = −2.09 , p = .04 ) from baseline to the 12-month follow-up . Although the TM intervention group had a greater reduction in diastolic BP ( 6.3 mm Hg ) compared with the enhanced UC group ( 4.1 mm Hg ) , the differences were not statistically significant ( t = −1.56 , p = .12 ) . Discussion : Telemonitoring of BP result ed in clinical ly and statistically significant reductions in systolic BP over a 12-month period ; if maintained over a longer period of time , the reductions could improve care and outcomes significantly for African Americans with hypertension The clinical efficacy of using specially trained nurses to treat hypertension at the patient 's place of work was compared in a controlled trial with management by the patient 's family doctor . The 457 study participants were selected from 21 906 volunteers in industry and government whose blood-pressure was screened . The nurses were allowed to prescribe and change drug therapy at the work site without prior physician approval . Patients r and omly allocated to receive care at work were significantly more likely to be put on antihypertensive medications ( 94.7 % vs 62.7 % , to reach goal blood-pressure in the first six months ( 48.5 % vs 27.5 % ) , and to take the drugs prescribed ( 67.6 % vs 49.1 % ) . Only 6 % of patients were dissatisfied with the care provided by the nurses . Thus provision of care at work by specially tranined nurses was well accepted and result ed in significantly improved blood-pressure control and medication compliance among employees with asymptomatic and uncomplicated hypertension BACKGROUND To determine which of 3 interventions was most effective in improving blood pressure ( BP ) control , we performed a 4-arm r and omized trial with 18-month follow-up at the primary care clinics at a Veterans Affairs Medical Center . METHODS Eligible patients were r and omized to either usual care or 1 of 3 telephone-based intervention groups : ( 1 ) nurse-administered behavioral management , ( 2 ) nurse- and physician-administered medication management , or ( 3 ) a combination of both . Of the 1551 eligible patients , 593 individuals were r and omized ; 48 % were African American . The intervention telephone calls were triggered based on home BP values transmitted via telemonitoring devices . Behavioral management involved promotion of health behaviors . Medication management involved adjustment of medications by a study physician and nurse based on hypertension treatment guidelines . RESULTS The primary outcome was change in BP control measured at 6-month intervals over 18 months . Both the behavioral management and medication management alone showed significant improvements at 12 months-12.8 % ( 95 % confidence interval [ CI ] , 1.6%-24.1 % ) and 12.5 % ( 95 % CI , 1.3%-23.6 % ) , respectively-but not at 18 months . In subgroup analyses , among those with poor baseline BP control , systolic BP decreased in the combined intervention group by 14.8 mm Hg ( 95 % CI , -21.8 to -7.8 mm Hg ) at 12 months and 8.0 mm Hg ( 95 % CI , -15.5 to -0.5 mm Hg ) at 18 months , relative to usual care . CONCLUSIONS Overall intervention effects were moderate , but among individuals with poor BP control at baseline , the effects were larger . This study indicates the importance of identifying individuals most likely to benefit from potentially re source intensive programs . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00237692 OBJECTIVE To determine if a multimodal intervention composed of patient education , home blood pressure ( BP ) monitoring , BP measurement reporting to an interactive voice response ( IVR ) phone system , and clinical pharmacist follow-up improves BP control compared with usual care . STUDY DESIGN Prospect i ve study with patient enrollment , medication consultation and adjustment , remote BP monitoring , and follow-up at 6 months . METHODS This r and omized controlled trial was conducted at 3 healthcare systems in Denver , Colorado , including a large health maintenance organization , a Veterans Affairs medical center , and a county hospital . At each site , patients with uncontrolled BP were r and omized to the multimodal intervention vs usual care for 6 months , with the primary end point of BP reduction . RESULTS Of 338 patients r and omized , 283 ( 84 % ) completed the study , including 138 intervention patients and 145 usual care patients . Baseline BP was higher in the intervention group vs the usual care group ( 150.5/89.4 vs 143.8/85.3 mm Hg ) . At 6 months , BPs were similar in the intervention group vs the usual care group ( 137.4 vs 136.7 mm Hg , P = .85 for systolic ; 82.9 vs 81.1 mm Hg , P = .14 for diastolic ) . However , BP reductions were greater in the intervention group vs the usual care group ( −13.1 vs −7.1 mm Hg , P = .006 for systolic ; −6.5 vs −4.2 mm Hg , P = .07 for diastolic ) . Adherence to medications was similar between the 2 groups , but intervention patients had a greater increase in medication regimen intensity . CONCLUSIONS A multimodal intervention of patient education , home BP monitoring , BP measurement reporting to an IVR system , and clinical pharmacist follow-up achieved greater reductions in BP compared with usual care BACKGROUND Web-based personal health records ( PHRs ) have been advocated as a means to improve type 2 diabetes mellitus ( DM ) care . However , few Web-based systems are linked directly to the electronic medical record ( EMR ) used by physicians . METHODS We r and omized 11 primary care practice s. Intervention practice s received access to a DM-specific PHR that imported clinical and medications data , provided patient-tailored decision support , and enabled the patient to author a " Diabetes Care Plan " for electronic su bmi ssion to their physician prior to upcoming appointments . Active control practice s received a PHR to up date and su bmi t family history and health maintenance information . All patients attending these practice s were encouraged to sign up for online access . RESULTS We enrolled 244 patients with DM ( 37 % of the eligible population with registered online access , 4 % of the overall population of patients with DM ) . Study participants were younger ( mean age , 56.1 years vs 60.3 years ; P < .001 ) and lived in higher-income neighborhoods ( median income , $ 53,784 vs $ 49,713 ; P < .001 ) but had similar baseline glycemic control compared with non participants . More patients in the intervention arm had their DM treatment regimens adjusted ( 53 % vs 15 % ; P < .001 ) compared with active controls . However , there were no significant differences in risk factor control between study arms after 1 year ( P = .53 ) . CONCLUSIONS Previsit use of online PHR linked to the EMR increased rates of DM-related medication adjustment . Low rates of online patient account registration and good baseline control among participants limited the intervention 's impact on overall risk factor control . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00251875 This study was conducted to evaluate the effect of automated telephone patient monitoring and counseling on patient adherence to antihypertensive medications and on blood pressure control . A r and omized controlled trial was conducted in 29 greater Boston communities . The study subjects were 267 patients recruited from community sites who were > or= 60 years of age , on antihypertensive medication , with a systolic blood pressure ( SBP ) of > or= 160 mm Hg and /or a diastolic blood pressure ( DBP ) of > or= 90 mm Hg . The study compared subjects who received usual medical care with those who used a computer-controlled telephone system in addition to their usual medical care during a period of 6 months . Weekly , subjects in the telephone group reported self-measured blood pressures , knowledge and adherence to antihypertensive medication regimens , and medication side-effects . This information was sent to their physicians regularly . The main study outcome measures were change in antihypertensive medication adherence , SBP and DBP during 6 months , satisfaction of patient users , perceived utility for physicians , and cost-effectiveness . The mean age of the study population was 76.0 years ; 77 % were women ; 11 % were black . Mean antihypertensive medication adherence improved 17.7 % for telephone system users and 11.7 % for controls ( P = .03 ) . Mean DBP decreased 5.2 mm Hg in users compared to 0.8 mm Hg in controls ( P = .02 ) . Among nonadherent subjects , mean DBP decreased 6.0 mm Hg for telephone users , but increased 2.8 mm Hg for controls ( P = .01 ) . For telephone system users , mean DBP decreased more if their medication adherence improved ( P = .03 ) . The majority of telephone system users were satisfied with the system . Most physicians integrated it into their practice s. The system was cost-effective , especially for nonadherent patient users . Therefore , weekly use of an automated telephone system improved medication adherence and blood pressure control in hypertension patients . This system can be used to monitor patients with hypertension or with other chronic diseases , and is likely to improve health outcomes and reduce health services utilization and costs M eeting the complex needs of patients with chronic illness or impairment is the single greatest challenge facing organized medical practice . Usual care is not doing the job ; dozens of surveys and audits have revealed that sizable proportions of chronically ill patients are not receiving effective therapy , have poor disease con- trol , and are unhappy with their care ( 1 ) . Results of r and omized trials also show that effective disease management programs can achieve substantially better outcomes than usual care , the control intervention . These trials , along with the ideas and efforts for improvement discussed in this issue , show that we can improve care and outcomes . As the articles suggest , these improvements will not come easily . If we are to improve care for most patients with chronic illness , the evidence strongly suggests that we reshape our ambulatory care systems for this purpose . Pri- mary care practice was largely design ed to provide ready access and care to patients with acute , varied problems , with an emphasis on triage and patient flow ; short appointments ; diagnosis and treatment of symptoms and signs ; reliance on laborato- ry investigations and prescriptions ; brief , didactic patient education ; and patient- initiated follow-up . Patients and families struggling with chronic illness have differ- ent needs , and these needs are unlikely to be met by an acute care organization and culture . They require planned , regular interactions with their caregivers , with a focus on function and prevention of exacerbations and complications . This interac- tion includes systematic assessment s , attention to treatment guidelines , and behav- iorally sophisticated support for the patient 's role as self-manager . These interactions must be linked through time by clinical ly relevant information systems and continu- ing follow-up initiated by the medical practice . Comprehensive System CONTEXT Studies have suggested that the quality of primary care delivered by nurse practitioners is equal to that of physicians . However , these studies did not measure nurse practitioner practice s that had the same degree of independence as the comparison physician practice s , nor did previous studies provide direct comparison of outcomes for patients with nurse practitioner or physician providers . OBJECTIVE To compare outcomes for patients r and omly assigned to nurse practitioners or physicians for primary care follow-up and ongoing care after an emergency department or urgent care visit . DESIGN R and omized trial conducted between August 1995 and October 1997 , with patient interviews at 6 months after initial appointment and health services utilization data recorded at 6 months and 1 year after initial appointment . SETTING Four community-based primary care clinics ( 17 physicians ) and 1 primary care clinic ( 7 nurse practitioners ) at an urban academic medical center . PATIENTS Of 3397 adults originally screened , 1316 patients ( mean age , 45.9 years ; 76.8 % female ; 90.3 % Hispanic ) who had no regular source of care and kept their initial primary care appointment were enrolled and r and omized with either a nurse practitioner ( n = 806 ) or physician ( n = 510 ) . MAIN OUTCOME MEASURES Patient satisfaction after initial appointment ( based on 15-item question naire ) ; health status ( Medical Outcomes Study Short-Form 36 ) , satisfaction , and physiologic test results 6 months later ; and service utilization ( obtained from computer records ) for 1 year after initial appointment , compared by type of provider . RESULTS No significant differences were found in patients ' health status ( nurse practitioners vs physicians ) at 6 months ( P = .92 ) . Physiologic test results for patients with diabetes ( P = .82 ) or asthma ( P = .77 ) were not different . For patients with hypertension , the diastolic value was statistically significantly lower for nurse practitioner patients ( 82 vs 85 mm Hg ; P = .04 ) . No significant differences were found in health services utilization after either 6 months or 1 year . There were no differences in satisfaction ratings following the initial appointment ( P = .88 for overall satisfaction ) . Satisfaction ratings at 6 months differed for 1 of 4 dimensions measured ( provider attributes ) , with physicians rated higher ( 4.2 vs 4.1 on a scale where 5 = excellent ; P = .05 ) . CONCLUSIONS In an ambulatory care situation in which patients were r and omly assigned to either nurse practitioners or physicians , and where nurse practitioners had the same authority , responsibilities , productivity and administrative requirements , and patient population as primary care physicians , patients ' outcomes were comparable OBJECTIVES A r and omized controlled trial involving a nurse administered patient-tailored intervention is being conducted to improve blood pressure ( BP ) control . METHODS Veterans with hypertension from an outpatient primary care clinic completed a baseline assessment and were r and omly allocated to either a nurse administered intervention or to usual care . In this ongoing study , intervention patients receive the tailored intervention bi-monthly for 2 years via telephone ; the goal of the intervention is to promote adherence with medication and improve health behaviors . Patient factors targeted for intervention include perceived risk of hypertension , memory , literacy , social support , patients ' relationship with their health care provider , side effects of therapy , pill refill , missed appointments , and health behaviors . RESULTS The sample r and omized to the nurse intervention consisted of 294 veterans with hypertension ( average age = 63 years ; 41 % African-American ) . A comparable sample of veterans was assigned to usual care ( n = 294 ) . We have maintained a 97 % retention rate for the first 12 months of the study . The average phone call has lasted 3.7 min ranging from less than 1 to 40 min . At 6-month post-enrollment , individuals receiving the nurse intervention had a greater increase in confidence with following hypertension treatment ( P < 0.007 ) than the usual care group . DISCUSSION The intervention is easily implemented and is design ed to enhance adherence with prescribed hypertension regimen . The study includes both general and patient-tailored information based upon need assessment . The study design ensures internal validity as well as the ability to generalize study findings to the clinic setting CONTEXT Medicare expenditures of patients with chronic illnesses might be reduced through improvements in care , patient adherence , and communication . OBJECTIVE To determine whether care coordination programs reduced hospitalizations and Medicare expenditures and improved quality of care for chronically ill Medicare beneficiaries . DESIGN , SETTING , AND PATIENTS Eligible fee-for-service Medicare patients ( primarily with congestive heart failure , coronary artery disease , and diabetes ) who volunteered to participate between April 2002 and June 2005 in 15 care coordination programs ( each received a negotiated monthly fee per patient from Medicare ) were r and omly assigned to treatment or control ( usual care ) status . Hospitalizations , costs , and some quality -of-care outcomes were measured with cl aims data for 18 309 patients ( n = 178 to 2657 per program ) from patients ' enrollment through June 2006 . A patient survey 7 to 12 months after enrollment provided additional quality -of-care measures . INTERVENTIONS Nurses provided patient education and monitoring ( mostly via telephone ) to improve adherence and ability to communicate with physicians . Patients were contacted twice per month on average ; frequency varied widely . MAIN OUTCOME MEASURES Hospitalizations , monthly Medicare expenditures , patient-reported and care process indicators . RESULTS Thirteen of the 15 programs showed no significant ( P<.05 ) differences in hospitalizations ; however , Mercy had 0.168 fewer hospitalizations per person per year ( 90 % confidence interval [ CI ] , -0.283 to -0.054 ; 17 % less than the control group mean , P=.02 ) and Charlestown had 0.118 more hospitalizations per person per year ( 90 % CI , 0.025 - 0.210 ; 19 % more than the control group mean , P=.04 ) . None of the 15 programs generated net savings . Treatment group members in 3 programs ( Health Quality Partners [ HQP ] , Georgetown , Mercy ) had monthly Medicare expenditures less than the control group by 9 % to 14 % ( -$84 ; 90 % CI , -$171 to $ 4 ; P=.12 ; -$358 ; 90 % CI , -$934 to $ 218 ; P=.31 ; and -$112 ; 90 % CI , -$231 to $ 8 ; P=.12 ; respectively ) . Savings offset fees for HQP and Georgetown but not for Mercy ; Georgetown was too small to be sustainable . These programs had favorable effects on none of the adherence measures and only a few of many quality of care indicators examined . CONCLUSIONS Viable care coordination programs without a strong transitional care component are unlikely to yield net Medicare savings . Programs with substantial in-person contact that target moderate to severe patients can be cost-neutral and improve some aspects of care . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00627029 CONTEXT Treating hypertension decreases mortality and disability from cardiovascular disease , but most hypertension remains inadequately controlled . OBJECTIVE To determine if a new model of care that uses patient Web services , home blood pressure ( BP ) monitoring , and pharmacist-assisted care improves BP control . DESIGN , SETTING , AND PARTICIPANTS A 3-group r and omized controlled trial , the Electronic Communications and Home Blood Pressure Monitoring study was based on the Chronic Care Model . The trial was conducted at an integrated group practice in Washington state , enrolling 778 participants aged 25 to 75 years with uncontrolled essential hypertension and Internet access . Care was delivered over a secure patient Web site from June 2005 to December 2007 . INTERVENTIONS Participants were r and omly assigned to usual care , home BP monitoring and secure patient Web site training only , or home BP monitoring and secure patient Web site training plus pharmacist care management delivered through Web communications . MAIN OUTCOME MEASURES Percentage of patients with controlled BP ( < 140/90 mm Hg ) and changes in systolic and diastolic BP at 12 months . RESULTS Of 778 patients , 730 ( 94 % ) completed the 1-year follow-up visit . Patients assigned to the home BP monitoring and Web training only group had a nonsignificant increase in the percentage of patients with controlled BP ( < 140/90 mm Hg ) compared with usual care ( 36 % [ 95 % confidence interval { CI } , 30%-42 % ] vs 31 % [ 95 % CI , 25%-37 % ] ; P = .21 ) . Adding Web-based pharmacist care to home BP monitoring and Web training significantly increased the percentage of patients with controlled BP ( 56 % ; 95 % CI , 49%-62 % ) compared with usual care ( P < .001 ) and home BP monitoring and Web training only ( P < .001 ) . Systolic BP was decreased stepwise from usual care to home BP monitoring and Web training only to home BP monitoring and Web training plus pharmacist care . Diastolic BP was decreased only in the pharmacist care group compared with both the usual care and home BP monitoring and Web training only groups . Compared with usual care , the patients who had baseline systolic BP of 160 mm Hg or higher and received home BP monitoring and Web training plus pharmacist care had a greater net reduction in systolic BP ( -13.2 mm Hg [ 95 % CI , -19.2 to -7.1 ] ; P < .001 ) and diastolic BP ( -4.6 mm Hg [ 95 % CI , -8.0 to -1.2 ] ; P < .001 ) , and improved BP control ( relative risk , 3.32 [ 95 % CI , 1.86 to 5.94 ] ; P<.001 ) . CONCLUSION Pharmacist care management delivered through secure patient Web communications improved BP control in patients with hypertension . Trial Registration clinical trials.gov Identifier : NCT00158639 BACKGROUND The Take Control of Your Blood Pressure trial evaluated the effect of a multicomponent telephonic behavioral lifestyle intervention , patient self-monitoring , and both interventions combined compared with usual care on reducing systolic blood pressure during 24 months . The combined intervention led to a significant reduction in systolic blood pressure compared with usual care alone . We examined direct and patient time costs associated with each intervention . METHODS We conducted a prospect i ve economic evaluation alongside a r and omized controlled trial of 636 patients with hypertension participating in the study interventions . Medical costs were estimated using electronic data representing medical services delivered within the health system . Intervention-related costs were derived using information collected during the trial , administrative records , and published unit costs . RESULTS During 24 months , patients incurred a mean of $ 6,965 ( s.d . , $ 22,054 ) in inpatient costs and $ 8,676 ( s.d . , $ 9,368 ) in outpatient costs , with no significant differences among the intervention groups . With base-case assumptions , intervention costs were estimated at $ 90 ( s.d . , $ 2 ) for home blood pressure monitoring , $ 345 ( s.d . , $ 64 ) for the behavioral intervention ( $ 31 per telephone encounter ) , and $ 416 ( s.d . , $ 93 ) for the combined intervention . Patient time costs were estimated at $ 585 ( s.d . , $ 487 ) for home monitoring , $ 55 ( s.d . , $ 16 ) for the behavioral intervention , and $ 741 ( s.d . , $ 529 ) for the combined intervention . CONCLUSIONS Our analysis demonstrated that the interventions are cost-additive to the health-care system in the short term and that patients ' time costs are nontrivial Team-based care can improve hypertension control . The purpose of the present study was to evaluate blood pressure ( BP ) control 18 months following the discontinuation of a physician-pharmacist collaborative intervention . This was a retrospective analysis of patients who had previously participated in a prospect i ve , cluster r and omized , controlled clinical trial . Six community-based family medicine offices were r and omized to control or intervention groups . Research nurses measured BPs using an automated device during the prospect i ve trial . The research nurses then abstract ed data from medical records , including BPs , medications , changes in therapy , and laboratory values for 18 months following the discontinuation of the 6-month prospect i ve trial . The study included 228 patients in the control ( n = 146 ) or intervention ( n = 82 ) groups . The control group contained more patients with diabetes or chronic kidney disease ( P < .013 ) , were older ( P = .047 ) , and had more coexisting conditions ( P < .001 ) than the intervention group . Systolic BP 9 months following discontinuation of the physician-pharmacist intervention was 137.2 ± 18.2 mm Hg and 129.8 ± 13.3 mm Hg in the control and intervention groups , respectively ( P = .0015 ) . BP control was maintained in 61 ( 41.8 % ) control patients and 55 ( 67.1 % ) intervention patients ( P = .0003 ) . At 18 months post-intervention , systolic BP was 138.1 ± 20.4 mm Hg and 130.0 ± 16.0 mm Hg in the control and intervention groups , respectively ( P = .023 ) . BP control was maintained in 53 ( 36.3 % ) control patients and 55 ( 67.1 % ) intervention patients at 18 months post-intervention ( P < .0001 ) . A sensitivity analysis was conducted to address the uneven distribution of patients with diabetes or chronic kidney disease , and the differences between groups were still significant . BP control rates remained significantly higher following a physician-pharmacist intervention compared with usual care for 18 months after discontinuation of the intervention . This model has the potential value as a useful long-term strategy to benefit patients with hypertension |
1,995 | 30,383,278 | Conclusions Postintervention GFR comparisons indicate that HP diets result in higher GFRs ; however , when changes in GFR were compared , dietary protein had no effect .
Our analysis indicates that HP intakes do not adversely influence kidney function on GFR in healthy adults | Abstract Background Higher-protein ( HP ) diets are advocated for several reasons , including mitigation of sarcopenia , but their effects on kidney function are unclear .
Objective This meta- analysis was conducted to determine the effect of HP intakes on kidney function in healthy adults . | BACKGROUND A dietary protein intake higher than the Recommended Dietary Allowance during an energy deficit helps to preserve lean body mass ( LBM ) , particularly when combined with exercise . OBJECTIVE The purpose of this study was to conduct a proof-of-principle trial to test whether manipulation of dietary protein intake during a marked energy deficit in addition to intense exercise training would affect changes in body composition . DESIGN We used a single-blind , r and omized , parallel-group prospect i ve trial . During a 4-wk period , we provided hypoenergetic ( ~40 % reduction compared with requirements ) diets providing 33 ± 1 kcal/kg LBM to young men who were r and omly assigned ( n = 20/group ) to consume either a lower-protein ( 1.2 g · kg(-1 ) · d(-1 ) ) control diet ( CON ) or a higher-protein ( 2.4 g · kg(-1 ) · d(-1 ) ) diet ( PRO ) . All subjects performed resistance exercise training combined with high-intensity interval training for 6 d/wk . A 4-compartment model assessment of body composition was made pre- and postintervention . RESULTS As a result of the intervention , LBM increased ( P < 0.05 ) in the PRO group ( 1.2 ± 1.0 kg ) and to a greater extent ( P < 0.05 ) compared with the CON group ( 0.1 ± 1.0 kg ) . The PRO group had a greater loss of fat mass than did the CON group ( PRO : -4.8 ± 1.6 kg ; CON : -3.5 ± 1.4 kg ; P < 0.05 ) . All measures of exercise performance improved similarly in the PRO and CON groups as a result of the intervention with no effect of protein supplementation . Changes in serum cortisol during the intervention were associated with changes in body fat ( r = 0.39 , P = 0.01 ) and LBM ( r = -0.34 , P = 0.03 ) . CONCLUSIONS Our results showed that , during a marked energy deficit , consumption of a diet containing 2.4 g protein · kg(-1 ) · d(-1 ) was more effective than consumption of a diet containing 1.2 g protein · kg(-1 ) · d(-1 ) in promoting increases in LBM and losses of fat mass when combined with a high volume of resistance and anaerobic exercise . Changes in serum cortisol were associated with changes in body fat and LBM , but did not explain much variance in either measure . This trial was registered at clinical trials.gov as NCT01776359 Abstract Increased protein intake versus maltodextrin intake for 4 weeks lowers blood pressure . Concerns exist that high‐protein diets reduce renal function . Effects of acute and 4‐week protein intake versus maltodextrin intake on renal acid load , glomerular filtration rate and related parameters were compared in this study . Seventy‐nine overweight individuals with untreated elevated blood pressure and normal kidney function were r and omized to consume a mix of protein isolates ( 60 g/day ) or maltodextrin ( 60 g/day ) for 4 weeks in energy balance . Twenty‐four‐hour urinary potential renal acid load ( uPRAL ) was compared between groups . A subgroup ( maltodextrin N = 27 , protein mix N = 25 ) participated in extra test days investigating fasting levels and postpr and ial effects of meals supplemented with a moderate protein‐ or maltodextrin‐load on glomerular filtration rate , effective renal plasma flow , plasma renin , aldosterone , pH , and bicarbonate . uPRAL was significantly higher in the protein group after 4 weeks ( P ≤ 0.001 ) . Postpr and ial filtration fraction decreased further after the protein‐supplemented breakfast than after the maltodextrin‐supplemented breakfast after 4 weeks of supplementation ( P ≤ 0.001 ) . Fasting and postpr and ial levels of glomerular filtration rate , effective renal plasma flow , renin , aldosterone , angiotensin‐converting enzyme , pH and bicarbonate did not differ between groups . In conclusion , 4 weeks on an increased protein diet ( 25 % of energy intake ) increased renal acid load , but did not affect renal function . Postpr and ial changes , except for filtration fraction , also did not differ between groups . These data suggest that a moderate increase in protein intake by consumption of a protein mix for 4 weeks causes no ( undesirable ) effects on kidney function in overweight and obese individuals with normal kidney function Although popular and effective for weight loss , low-carbohydrate , high-protein , high-fat ( Atkins ) diets have been associated with adverse changes in blood and renal biomarkers . High-protein diets low in fat may represent an equally appealing diet plan but promote a more healthful weight loss . Healthy adults ( n = 20 ) were r and omly assigned to 1 of 2 low-fat ( < 30 % energy ) , energy-restricted groups : high-protein ( 30 % energy ) or high-carbohydrate ( 60 % energy ) ; 24-h intakes were strictly controlled during the 6-wk trial . One subject from each group did not complete the trial due to out-of-state travel ; two subjects in the high-carbohydrate group withdrew from the trial due to extreme hunger . Body composition and metabolic indices were assessed pre- and post-trial . Both diets were equally effective at reducing body weight ( -6 % , P < 0.05 ) and fat mass ( -9 to -11 % , P < 0.05 ) ; however , subjects consuming the high-protein diet reported more satisfaction and less hunger in mo 1 of the trial . Both diets significantly lowered total cholesterol ( -10 to -12 % ) , insulin ( -25 % ) , and uric acid ( -22 to -30 % ) concentrations in blood from fasting subjects . Urinary calcium excretion increased 42 % in subjects consuming the high-protein diet , mirroring the 50 % increase in dietary calcium with consumption of this diet ; thus , apparent calcium balance was not adversely affected . Creatinine clearance was not altered by diet treatments , and nitrogen balance was more positive in subjects consuming the high-protein diet vs. the high-carbohydrate diet ( 3.9 + /- 1.4 and 0.7 + /- 1.7 g N/d , respectively , P < 0.05 ) . Thus , low-fat , energy-restricted diets of varying protein content ( 15 or 30 % energy ) promoted healthful weight loss , but diet satisfaction was greater in those consuming the high-protein diet BACKGROUND Acute consumption of fat-free fluid milk after resistance exercise promotes a greater positive protein balance than does soy protein . OBJECTIVE We aim ed to determine the long-term consequences of milk or soy protein or equivalent energy consumption on training-induced lean mass accretion . DESIGN We recruited 56 healthy young men who trained 5 d/wk for 12 wk on a rotating split-body resistance exercise program in a parallel 3-group longitudinal design . Subjects were r and omly assigned to consume drinks immediately and again 1 h after exercise : fat-free milk ( Milk ; n = 18 ) ; fat-free soy protein ( Soy ; n = 19 ) that was isoenergetic , isonitrogenous , and macronutrient ratio matched to Milk ; or maltodextrin that was isoenergetic with Milk and Soy ( control group ; n = 19 ) . RESULTS Muscle fiber size , maximal strength , and body composition by dual-energy X-ray absorptiometry ( DXA ) were measured before and after training . No between-group differences were seen in strength . Type II muscle fiber area increased in all groups with training , but with greater increases in the Milk group than in both the Soy and control groups ( P < 0.05 ) . Type I muscle fiber area increased after training only in the Milk and Soy groups , with the increase in the Milk group being greater than that in the control group ( P < 0.05 ) . DXA-measured fat- and bone-free mass increased in all groups , with a greater increase in the Milk group than in both the Soy and control groups ( P < 0.05 ) . CONCLUSION We conclude that chronic postexercise consumption of milk promotes greater hypertrophy during the early stages of resistance training in novice weightlifters when compared with isoenergetic soy or carbohydrate consumption BACKGROUND The metabolic effects of diets high in vegetable protein have not been assessed despite much recent interest in the effect of soy proteins in reducing serum cholesterol . OBJECTIVE We assessed the metabolic effects of diets high in vegetable protein ( specifically , wheat gluten ) on serum lipids , uric acid concentrations , and renal function . DESIGN Twenty hyperlipidemic men and women consumed isoenergetic test ( high-protein ) and control metabolic diets for 1 mo in a r and omized crossover design . In the high-protein diet , 11 % of the total dietary energy from starch in the control bread was replaced by vegetable protein ( wheat gluten ) , result ing in 27 % of total energy from protein compared with 16 % in the control diet . In other respects , the 2 diets were identical . RESULTS Compared with the control , the high-protein diet result ed in lower serum concentrations of triacylglycerol ( by 19.2 + /- 5.6 % ; P = 0.003 ) , uric acid ( by 12.7 + /- 2.0 % ; P < 0.001 ) , and creatinine ( by 2.5 + /- 1.1 % ; P = 0.035 ) and higher serum concentrations of urea ( by 42.2 + /- 5.8 % ; P < 0.001 ) and a higher 24-h urinary urea output ( by 99.2 + /- 17.2 % ; P < 0.001 ) . No significant differences were detected in total or HDL cholesterol or in the renal clearance of creatinine . LDL oxidation , assessed as the ratio of conjugated dienes to LDL cholesterol in the LDL fraction , was lower with the high-protein diet ( by 10.6 + /- 3.6 % ; P = 0.009 ) . CONCLUSIONS High intakes of vegetable protein from gluten may have beneficial effects on cardiovascular disease risk by reducing oxidized LDL , serum triacylglycerol , and uric acid . Further studies are required to assess the longer-term effects on renal function BACKGROUND When substituted for carbohydrate in an energy-reduced diet , dietary protein enhances fat loss in women . It is unknown whether the effect is due to increased protein or reduced carbohydrate . OBJECTIVE We compared the effects of 2 isocaloric diets that differed in protein and fat content on weight loss , lipids , appetite regulation , and energy expenditure after test meals . DESIGN This was a parallel , r and omized study in which subjects received either a low-fat , high-protein ( LF-HP ) diet ( 29 + /- 1 % fat , 34 + /- 0.8 % protein ) or a high-fat , st and ard-protein ( HF-SP ) diet ( 45 + /- 0.6 % fat , 18 + /- 0.3 % protein ) during 12 wk of energy restriction ( 6 + /- 0.1 MJ/d ) and 4 wk of energy balance ( 7.4 + /- 0.3 MJ/d ) . Fifty-seven overweight and obese [ mean body mass index ( in kg/m(2 ) ) : 33.8 + /- 0.9 ] volunteers with insulin concentrations > 12 mU/L completed the study . RESULTS Weight loss ( LF-HP group , 9.7 + /- 1.1 kg ; HF-SP group , 10.2 + /- 1.4 kg ; P = 0.78 ) and fat loss were not significantly different between diet groups even though the subjects desired less to eat after the LF-HP meal ( P = 0.02 ) . The decrease in resting energy expenditure was not significantly different between diet groups ( LF-HP , -342 + /- 185 kJ/d ; HF-SP , -349 + /- 220 kJ/d ) . The decrease in the thermic effect of feeding with weight loss was smaller in the LF-HP group than in the HF-SP group ( -0.3 + /- 1.0 % compared with -3.6 + /- 0.7 % ; P = 0.014 ) . Glucose and insulin responses to test meals improved after weight loss ( P < 0.001 ) with no significant diet effect . Bone turnover , inflammation , and calcium excretion did not change significantly . CONCLUSION The magnitude of weight loss and the improvements in insulin resistance and cardiovascular disease risk factors did not differ significantly between the 2 diets , and neither diet had any detrimental effects on bone turnover or renal function Calcium balance is decreased by an increased intake of purified proteins , although the effects of common dietary sources of protein ( like meat ) on calcium economy remain controversial . We compared the effects of several weeks of controlled high and low meat diets on body calcium retention , using sensitive radiotracer and whole body scintillation counting methodology . Healthy postmenopausal women ( n = 15 ) consumed diets with similar calcium content ( approximately 600 mg ) , but either low or high in meat ( 12 vs. 20 % of energy as protein ) for 8 wk each , in a r and omized crossover design . After 4 wk of equilibration of each diet , calcium retention was measured by extrinsically labeling the 2-d menu with (47)Ca , followed by whole body scintillation counting for 28 d. Urinary and blood indicators of bone metabolism were also determined for each diet . Calcium retention was not different during the high and low meat dietary periods ( d 28 , mean + /- pooled SD : 17.1 and 15.6 % , + /-0.6 % , respectively ; P = 0.09 ) . An initially higher renal acid excretion in subjects consuming the high meat compared with the low meat diet decreased significantly with time . The diets did not affect urinary calcium loss or indicators of bone metabolism . In conclusion , under controlled conditions , a high meat compared with a low meat diet for 8 wk did not affect calcium retention or biomarkers of bone metabolism in healthy postmenopausal women . Calcium retention is not reduced when subjects consume a high protein diet from common dietary sources such as meat BACKGROUND Changes in dietary protein in adults are associated with changes in urinary calcium excretion . The mechanisms underlying this effect are not completely understood , but alterations in intestinal absorption of calcium are not thought to be involved . OBJECTIVE We reexamined this mechanism by evaluating the effect of 2 amounts of dietary protein ( low : 0.7 g/kg ; and high : 2.1 g/kg ) on fractional calcium absorption in 7 healthy , young women . DESIGN The experiment consisted of 2 wk of a well-balanced diet containing moderate amounts of calcium , sodium , and protein followed by 5 d of an experimental diet that contained 1 of 2 amounts of protein and constant amounts of other nutrients known to influence calcium metabolism . Seven subjects received both amounts of dietary protein in r and om order . Blood and urine were sample d at baseline and on day 4 . Fractional calcium absorption was measured by dual-stable calcium isotopes on day 5 . In a second study of 5 additional women , we evaluated the effects of dietary fiber on calcitropic hormones . RESULTS Subjects developed hypocalciuria and secondary hyperparathyroidism on day 4 of the low-protein diet . Urinary calcium excretion and the glomerular filtration rate were elevated significantly by day 4 of the high-protein compared with the low-protein diet . Fractional calcium absorption after the low-protein diet was 0.19+/-0.03 , which was significantly lower than that after the high-protein diet ( 0.26+/-0.03 , P=0.05 ) . CONCLUSION These data provide evidence that depressed intestinal calcium absorption explains , in part , low-protein-induced secondary hyperparathyroidism BACKGROUND : Due to the high satiating effect of protein , a high-protein diet may be desirable in the treatment of obesity . However the long-term effect of different levels of protein intake on renal function is unclear . OBJECTIVE : To assess the renal effects of high vs low protein contents in fat-reduced diets . DESIGN : R and omized 6 months dietary intervention study comparing two controlled ad libitum diets with 30 energy ( E% ) fat content : high-protein ( HP ; 25 E% ) or low-protein , ( LP , 12 E% protein ) . All food was provided by self- selection in a shop at the department , and high compliance to the diet composition was confirmed by measurements of urinary nitrogen excretion . SUBJECTS : 65 healthy , overweight and obese ( 25<body mass index ( BMI ) < 34 kg/m2 ) . RESULTS : Dietary protein intake changed from 91.1 g/d to a 6 months intervention average of 70.4 g/d ( P<0.05 ) in the LP group and from 91.4 g/d to 107.8 g/d ( P<0.05 ) in the HP group , producing changes in glomular filtration rate ( GFR ) of −7.1 ml/min in the LP group and + 5.2 ml/min in the HP group ( group effect : P<0.05 ) . Kidney volume decreased by −6.2 cm3 in the LP group and increased by + 9.1 cm3 in the HP group ( P<0.05 ) , whereas albuminuria remained unchanged in all groups . CONCLUSION : Moderate changes in dietary protein intake cause adaptive alterations in renal size and function without indications of adverse effects OBJECTIVE : To study the effect on weight loss in obese subjects by replacement of carbohydrate by protein in ad libitum consumed fat-reduced diets . DESIGN : R and omized dietary intervention study over six months comparing two ad libitum fat reduced diets ( 30 % of total energy ) strictly controlled in composition : High-carbohydrate ( HC , protein 12 % of total energy ) or high-protein ( HP , protein 25 % of total energy ) . SETTING AND PARTICIPANTS : Subjects were 65 healthy , overweight and obese subjects ( 50 women , 15 men , aged 18–55 y ) r and omly assigned to HC ( n=25 ) , HP ( n=25 ) or a control group ( C , n=15 ) . All food was provided by self- selection in a shop at the department , and compliance to the diet composition was evaluated by urinary nitrogen excretion . MAIN OUTCOME MEASURE : Change in body weight , body composition and blood lipids . RESULTS : More than 90 % completed the trial . Weight loss after six months was 5.1 kg in the HC group and 8.9 kg in the HP group ( difference 3.7 kg , 95 % confidence interval (CI)(1.3–6.2 kg ) P<0.001 ) , and fat loss was 4.3 kg and 7.6 kg , respectively ( difference 3.3 kg ( 1.1–5.5 kg ) P<0.0001 ) , whereas no changes occurred in the control group . More subjects lost > 10 kg in the HP group ( 35 % ) than in the HC group ( 9 % ) . The HP diet only decreased fasting plasma triglycerides and free fatty acids significantly . CONCLUSIONS : Replacement of some dietary carbohydrate by protein in an ad libitum fat-reduced diet , improves weight loss and increases the proportion of subjects achieving a clinical ly relevant weight loss . More freedom to choose between protein-rich and complex carbohydrate-rich foods may allow obese subjects to choose more lean meat and dairy products , and hence improve adherence to low-fat diets in weight reduction programs OBJECTIVE : To compare the long-term compliance and effects of two low-fat diets differing in carbohydrate to protein ratio on body composition and biomarkers of cardiovascular disease risk in obese subjects with hyperinsulinemia . DESIGN : Outpatient , parallel , clinical intervention study of two groups of subjects r and omly assigned to either a st and ard protein ( SP ; 15 % protein , 55 % carbohydrate ) or high-protein ( HP ; 30 % protein , 40 % carbohydrate ) diet , during 12 weeks of energy restriction ( ∼6.5 MJ/day ) and 4 weeks of energy balance ( ∼8.3 MJ/day ) . Subsequently , subjects were asked to maintain the same dietary pattern for the succeeding 52 weeks with minimal professional support . SUBJECTS : A total of 58 obese , nondietetic subjects with hyperinsulinemia ( 13 males/45 females , mean age 50.2 y , mean body mass index ( BMI ) 34.0 kg/m2 , mean fasting insulin 17.8 mU/l ) participated in the study . MEASUREMENTS : Body composition , blood pressure , blood lipids , fasting glucose , insulin , CRP and sICAM-1 were measured at baseline and at weeks 16 and 68 . Urinary urea/creatinine ratio was measured at baseline , week 16 and at 3 monthly intervals thereafter . RESULTS : In total , 43 subjects completed the study with similar dropouts in each group ( P=0.76 ) . At week 68 , there was net weight loss ( SP −2.9±3.6 % , HP −4.1±5.8 % ; P<0.01 ) due entirely to fat loss ( P<0.001 ) with no diet effect . Both diets significantly increased HDL cholesterol concentrations ( P<0.001 ) and decreased fasting insulin , insulin resistance , sICAM-1 and CRP levels ( P<0.05 ) . Protein intake was significantly greater in HP during the initial 16 weeks ( P<0.001 ) , but decreased in HP and increased in SP during 52-week follow-up , with no difference between groups at week 68 , indicating poor long-term dietary adherence behaviour to both dietary patterns . CONCLUSION : Without active ongoing dietary advice , adherence to dietary intervention is poor . Nonetheless , both dietary patterns achieved net weight loss and improvements in cardiovascular risk factors BACKGROUND Limited evidence suggests that a higher ratio of protein to carbohydrate during weight loss has metabolic advantages . OBJECTIVE The objective was to evaluate the effects of a diet with a high ratio of protein to carbohydrate during weight loss on body composition , cardiovascular disease risk , nutritional status , and markers of bone turnover and renal function in overweight women . DESIGN The subjects were r and omly assigned to 1 of 2 isocaloric 5600-kJ dietary interventions for 12 wk according to a parallel design : a high-protein ( HP ) or a high-carbohydrate ( HC ) diet . RESULTS One hundred women with a mean ( + /-SD ) body mass index ( in kg/m(2 ) ) of 32 + /- 6 and age of 49 + /- 9 y completed the study . Weight loss was 7.3 + /- 0.3 kg with both diets . Subjects with high serum triacylglycerol ( > 1.5 mmol/L ) lost more fat mass with the HP than with the HC diet ( x + /- SEM : 6.4 + /- 0.7 and 3.4 + /- 0.7 kg , respectively ; P = 0.035 ) and had a greater decrease in triacylglycerol concentrations with the HP ( -0.59 + /- 0.19 mmol/L ) than with the HC ( -0.03 + /- 0.04 mmol/L ) diet ( P = 0.023 for diet x triacylglycerol interaction ) . Triacylglycerol concentrations decreased more with the HP ( 0.30 + /- 0.10 mmol/L ) than with the HC ( 0.10 + /- 0.06 mmol/L ) diet ( P = 0.007 ) . Fasting LDL-cholesterol , HDL-cholesterol , glucose , insulin , free fatty acid , and C-reactive protein concentrations decreased with weight loss . Serum vitamin B-12 increased 9 % with the HP diet and decreased 13 % with the HC diet ( P < 0.0001 between diets ) . Folate and vitamin B-6 increased with both diets ; homocysteine did not change significantly . Bone turnover markers increased 8 - 12 % and calcium excretion decreased by 0.8 mmol/d ( P < 0.01 ) . Creatinine clearance decreased from 82 + /- 3.3 to 75 + /- 3.0 mL/min ( P = 0.002 ) . CONCLUSION An energy-restricted , high-protein , low-fat diet provides nutritional and metabolic benefits that are equal to and sometimes greater than those observed with a high-carbohydrate diet Decline in muscle mass , protein synthesis , and mitochondrial function occurs with age , and amino acids are reported to enhance both muscle protein synthesis and mitochondrial function . It is unclear whether increasing dietary protein intake corrects postabsorptive muscle changes in aging . We determined whether a 10-day diet of high [ HP ; 3.0 g protein x kg fat-free mass (FFM)(-1 ) x day(-1 ) ] vs. usual protein intake ( UP ; 1.5 g protein x kg FFM(-1 ) x day(-1 ) ) favorably affects mitochondrial function , protein metabolism , and nitrogen balance or adversely affects insulin sensitivity and glomerular filtration rate ( GFR ) in 10 healthy younger ( 24+/-1 yr ) and 9 older ( 70+/-2 yr ) participants in a r and omized crossover study . Net daily nitrogen balance increased equally in young and older participants , but postabsorptive catabolic state also increased , as indicated by higher whole body protein turnover and leucine oxidation with no change in protein synthesis . Maximal muscle mitochondrial ATP production rate was lower in older people , with no change occurring in diet . GFR was lower in older people , and response to HP was significantly different between the two groups , with a significant increase occurring only in younger people , thus widening the differences in GFR between the young and older participants . In conclusion , a short-term high-protein diet increased net daily nitrogen balance but increased the postabsorptive use of protein as a fuel . HP did not enhance protein synthesis or muscle mitochondrial function in either young or older participants . Additionally , widening differences in GFR between young and older patients is a potential cause of concern in using HP diet in older people The purpose of this investigation was to determine the effects of a high protein diet over a one-year period . Fourteen healthy resistance-trained men completed the study ( mean ± SD ; age 26.3 ± 3.9 yr ; height 178.5 ± 8.4 cm ; and average years of training 8.9 ± 3.4 yr ) . In a r and omized crossover design , subjects consumed their habitual or normal diet for 2 months and 4 months and alternated that with a higher protein diet ( > 3 g/kg/d ) for 2 months and 4 months . Thus , on average , each subject was on their normal diet for 6 months and a higher protein diet for 6 months . Body composition was assessed via the Bod Pod ® . Each subject provided approximately 100–168 daily dietary self-reports . During the subjects ' normal eating phase , they consumed ( mean ± SD ) 29.94 ± 5.65 kcals/kg/day and 2.51 ± 0.69 g/kg/day of protein . This significantly increased ( p < 0.05 ) during the high protein phase to 34.37 ± 5.88 kcals/kg/day and 3.32 ± 0.87 g/kg/day of protein . Our investigation discovered that , in resistance-trained men that consumed a high protein diet ( ~2.51–3.32 g/kg/d ) for one year , there were no harmful effects on measures of blood lipids as well as liver and kidney function . In addition , despite the total increase in energy intake during the high protein phase , subjects did not experience an increase in fat mass Background Eight weeks of a high protein diet ( > 3 g/kg/day ) coupled with a periodized heavy resistance training program has been shown to positively affect body composition with no deleterious effects on health . Using a r and omized , crossover design , resistance-trained male subjects underwent a 16-week intervention ( i.e. , two 8-week periods ) in which they consumed either their normal ( i.e. , habitual ) or a higher protein diet ( > 3 g/kg/day ) . Thus , the purpose of this study was to ascertain if significantly increasing protein intake would affect clinical markers of health ( i.e. , lipids , kidney function , etc . ) as well as performance and body composition in young males with extensive resistance training experience . Methods Twelve healthy resistance-trained men volunteered for this study ( mean ± SD : age 25.9 ± 3.7 years ; height 178.0 ± 8.5 cm ; years of resistance training experience 7.6 ± 3.6 ) with 11 subjects completing most of the assessment s. In a r and omized crossover trial , subjects were tested at baseline and after two 8-week treatment periods ( i.e. , habitual [ normal ] diet and high protein diet ) for body composition , measures of health ( i.e. , blood lipids , comprehensive metabolic panel ) and performance . Each subject maintained a food diary for the 16-week treatment period ( i.e. , 8 weeks on their normal or habitual diet and 8 weeks on a high protein diet ) . Each subject provided a food diary of two weekdays and one weekend day per week . In addition , subjects kept a diary of their training regimen that was used to calculate total work performed . Results During the normal and high protein phase of the treatment period , subjects consumed 2.6 ± 0.8 and 3.3 ± 0.8 g/kg/day of dietary protein , respectively . The mean protein intake over the 4-month period was 2.9 ± 0.9 g/kg/day . The high protein group consumed significantly more calories and protein ( p < 0.05 ) than the normal protein group . There were no differences in dietary intake between the groups for any other measure . Moreover , there were no significant changes in body composition or markers of health in either group . There were no side effects ( i.e. , blood lipids , glucose , renal , kidney function etc . ) regarding high protein consumption . Conclusion In resistance-trained young men who do not significantly alter their training regimen , consuming a high protein diet ( 2.6 to 3.3 g/kg/day ) over a 4-month period has no effect on blood lipids or markers of renal and hepatic function . Nor were there any changes in performance or body composition . This is the first crossover trial using resistance-trained subjects in which the elevation of protein intake to over four times the recommended dietary allowance has shown no harmful effects OBJECTIVE To assess the effect of replacing red meat with chicken in the usual diet and the effect of a low-protein diet on glomerular filtration rate ( GFR ) , urinary albumin excretion rate ( UAER ) , and lipid levels in patients with type 2 diabetes . RESEARCH DESIGN AND METHODS A r and omized , crossover , controlled trial was conducted with 28 patients with type 2 diabetes ( seven women ; mean age 58.1 years ) : 15 patients were normoalbuminuric ( UAER < 20 microg/min ) , and 13 patients were microalbuminuric ( UAER 20 - 200 microg/min ) . A chicken-based diet ( red meat replaced with chicken ) and a low-protein diet were compared with the patients ' usual diet . Patients followed each diet for 4 weeks with a 4-week washout period between . GFR ( (51)Cr-EDTA single-injection technique ) , 24-h UAER ( immunoturbidimetry ) , apolipoprotein B , total cholesterol , LDL cholesterol , HDL cholesterol , and triglycerides were measured after each diet . RESULTS Normoalbuminuric and microalbuminuric patients with diabetes were analyzed separately . In normoalbuminuric patients , GFR after the chicken ( 101.3 + /- 22.9 ml x min(-1 ) x 1.73 m(-2 ) ) and low-protein diets ( 93.8 + /- 20.5 ml x min(-1 ) x m(-2 ) ) was lower than after the usual diet ( 113.4 + /- 31.4 ml x min(-1 ) x 1.73 m(-2 ) ; P < 0.05 ) . In microalbuminuric patients , apolipoprotein B levels were lower after the chicken ( 113.5 + /- 36.0 mg/dl ) and low-protein diets ( 103.5 + /- 40.1 mg/dl ) than after the usual diet ( 134.3 + /- 30.7 mg/dl ; P < 0.05 ) . Only the chicken diet reduced UAER ( median 34.3 microg/min ) compared with the low-protein ( median 52.3 microg/min ) and usual ( median 63.8 microg/min ) diets ( P < 0.05 ) . Glycemic control and blood pressure did not change after the diets . CONCLUSIONS A normoproteic diet with chicken as the only source of meat may represent an alternative strategy for treatment of patients with type 2 diabetes and microalbuminuria A frequently cited concern of very-low-carbohydrate diets is the potential for increased risk of renal disease associated with a higher protein intake . However , to date , no well-controlled r and omized studies have evaluated the long-term effects of very-low-carbohydrate diets on renal function . To study this issue , renal function was assessed in 68 men and women with abdominal obesity ( age 51.5+/-7.7 years , body mass index [ calculated as kg/m(2 ) ] 33.6+/-4.0 ) without preexisting renal dysfunction who were r and omized to consume either an energy-restricted ( approximately 1,433 to 1,672 kcal/day ) , planned isocaloric very-low-carbohydrate ( 4 % total energy as carbohydrate [ 14 g ] , 35 % protein [ 124 g ] , 61 % fat [ 99 g ] ) , or high-carbohydrate diet ( 46 % total energy as carbohydrate [ 162 g ] , 24 % protein [ 85 g ] , 30 % fat [ 49 g ] ) for 1 year . Body weight , serum creatinine , estimated glomerular filtration rate and urinary albumin excretion were assessed before and after 1 year ( April 2006-July 2007 ) . Repeated measures analysis of variance was conducted . Weight loss was similar in both groups ( very-low-carbohydrate : -14.5+/-9.7 kg , high-carbohydrate : -11.6+/-7.3 kg ; P=0.16 ) . By 1 year , there were no changes in either group in serum creatinine levels ( very-low-carbohydrate : 72.4+/-15.1 to 71.3+/-13.8 mumol/L , high-carbohydrate : 78.0+/-16.0 to 77.2+/-13.2 mumol/L ; P=0.93 time x diet effect ) or estimated glomerular filtration rate ( very-low-carbohydrate : 90.0+/-17.0 to 91.2+/-17.8 mL/min/1.73 m(2 ) , high-carbohydrate : 83.8+/-13.8 to 83.6+/-11.8 mL/min/1.73 m(2 ) ; P=0.53 time x diet effect ) . All but one participant was classified as having normoalbuminuria at baseline , and for these participants , urinary albumin excretion values remained in the normoalbuminuria range at 1 year . One participant in high-carbohydrate had microalbuminuria ( 41.8 microg/min ) at baseline , which decreased to a value of 3.1 microg/min ( classified as normoalbuminuria ) at 1 year . This study provides preliminary evidence that long-term weight loss with a very-low-carbohydrate diet does not adversely affect renal function compared with a high-carbohydrate diet in obese individuals with normal renal function Due to the shortage of organs , living donor acceptance criteria are becoming less stringent . An accurate determination of the glomerular filtration rate ( GFR ) is critical in the evaluation of living kidney donors and a value exceeding 80 ml/min per 1.73 m(2 ) is usually considered suitable . To improve strategies for kidney donor screening , an underst and ing of factors that affect GFR is needed . Here we studied the relationships between donor GFR measured by (125)I-iothalamate clearances ( mGFR ) and age , gender , race , and decade of care in living kidney donors evaluated at the Clevel and Clinic from 1972 to 2005 . We report the normal reference ranges for 1057 prospect i ve donors ( 56 % female , 11 % African American ) . Females had slightly higher mGFR than males after adjustment for body surface area , but there were no differences due to race . The lower limit of normal for donors ( 5th percentile ) was less than 80 ml/min per 1.73 m(2 ) for females over age 45 and for males over age 40 . We found a significant doubling in the rate of GFR decline in donors over age 45 as compared to younger donors . The age of the donors and body mass index increased over time , but their mGFR , adjusted for body surface area , significantly declined by 1.49+/-0.61 ml/min per 1.73 m(2 ) per decade of testing . Our study shows that age and gender are important factors determining normal GFR in living kidney donors Aims /hypothesisShort-term dietary studies suggest that high-protein diets can enhance weight loss and improve glycaemic control in people with type 2 diabetes . However , the long-term effects of such diets are unknown . The aim of this study was to determine whether high-protein diets are superior to high-carbohydrate diets for improving glycaemic control in individuals with type 2 diabetes . Methods Overweight/obese individuals ( BMI 27–40 kg/m2 ) with type 2 diabetes ( HbA1c 6.5–10 % ) were recruited for a 12 month , parallel design , dietary intervention trial conducted at a diabetes specialist clinic ( Melbourne , VIC , Australia ) . Of the 108 initially r and omised , 99 received advice to follow low-fat ( 30 % total energy ) diets that were either high in protein ( 30 % total energy , n = 53 ) or high in carbohydrate ( 55 % total energy , n = 46 ) . Dietary assignment was done by a third party using computer-generated r and om numbers . The primary endpoint was change in HbA1c . Secondary endpoints included changes in weight , lipids , blood pressure , renal function and calcium loss . Study endpoints were assessed blinded to the diet group , but the statistical analysis was performed unblinded . This study used an intention-to-treat model for all participants who received dietary advice . Follow-up visits were encouraged regardless of dietary adherence and last measurements were carried forward for study non-completers . Results Ninety-nine individuals were included in the analysis ( 53 in high protein group , 46 in high carbohydrate group ) . HbA1c decreased in both groups over time , with no significant difference between groups ( mean difference of the change at 12 months ; 0.04 [ 95 % CI −0.37 , 0.46 ] ; p = 0.44 ) . Both groups also demonstrated decreases over time in weight , serum triacylglycerol and total cholesterol , and increases in HDL-cholesterol . No differences in blood pressure , renal function or calcium loss were seen . Conclusions /interpretationThese results suggest that there is no superior long-term metabolic benefit of a high-protein diet over a high-carbohydrate in the management of type 2 diabetes . Trial registration ACTRN12605000063617 ( www.anzctr.org.au ) . Funding This study was funded by a nutritional research grant from Meat and Livestock Australia ( MLA ) . J.E. Shaw is supported by NHMRC Fellowship 586623 OBJECTIVE : To study the effect of diet composition on diet-induced thermogenesis ( DIT ) over 24 h in a respiration chamber . SUBJECTS : Eight healthy female volunteers ( age 27±3 y ; body mass index , BMI 23±3 kg/m2).DIETS : A high protein and carbohydrate ( HP/C ) ( 60:10:30 ; percentage energy (E%)carbohydrate , fat and protein , respectively ) and high fat ( HF ) ( 30:60:10 respectively ) diet , both isoenergetic , isovolumetric , composed of normal food items and matched for organoleptic properties ( taste , smell , appearance ) . DESIGN : Subjects spent two 36 h periods each in a respiration chamber consuming both test diets in r and om order . Components of 24 h energy expenditure ( 24 h EE ) : sleeping metabolic rate , DIT and activity induced energy expenditure were measured . RESULTS : DIT was higher in all subjects while on the HP/C diet ( 1295 kJ/d vs 931 kJ/d ; 14.6 % vs 10.5 % of energy intake ; P<0.02 ) . There was no significant difference in other components or total 24 h EE , although there was a trend towards higher EE on the HP/C diet . CONCLUSION : A high protein and carbohydrate diet induces a greater thermic response in healthy individuals when compared to a high fat diet Weight loss can have substantial health benefits for overweight or obese persons ; however , the ratio of fat : lean tissue loss may be more important . We aim ed to determine how daily exercise ( resistance and /or aerobic ) and a hypoenergetic diet varying in protein and calcium content from dairy foods would affect the composition of weight lost in otherwise healthy , premenopausal , overweight , and obese women . Ninety participants were r and omized to 3 groups ( n = 30/group ) : high protein , high dairy ( HPHD ) , adequate protein , medium dairy ( APMD ) , and adequate protein , low dairy ( APLD ) differing in the quantity of total dietary protein and dairy food- source protein consumed : 30 and 15 % , 15 and 7.5 % , or 15 and < 2 % of energy , respectively . Body composition was measured by DXA at 0 , 8 , and 16 wk and MRI ( n = 39 ) to assess visceral adipose tissue ( VAT ) volume at 0 and 16 wk . All groups lost body weight ( P < 0.05 ) and fat ( P < 0.01 ) ; however , fat loss during wk 8–16 was greater in the HPHD group than in the APMD and APLD groups ( P < 0.05 ) . The HPHD group gained lean tissue with a greater increase during 8–16 wk than the APMD group , which maintained lean mass and the APLD group , which lost lean mass ( P < 0.05 ) . The HPHD group also lost more VAT as assessed by MRI ( P < 0.05 ) and trunk fat as assessed by DXA ( P < 0.005 ) than the APLD group . The reduction in VAT in all groups was correlated with intakes of calcium ( r = 0.40 ; P < 0.05 ) and protein ( r = 0.32 ; P < 0.05 ) . Therefore , diet- and exercise-induced weight loss with higher protein and increased dairy product intakes promotes more favorable body composition changes in women characterized by greater total and visceral fat loss and lean mass gain 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 Background Little is known about optimal protein intake after transplantation . The aim of this study was to prospect ively investigate associations of urinary urea excretion , a marker for protein intake , with graft failure and mortality in renal transplant recipients ( RTR ) and potential effect modification by body mass index ( BMI ) and estimated glomerular filtration rate ( eGFR ) . Methods Urinary urea excretion was measured in repeated 24-hr urine collection s between 6 and 18 months after transplantation . Results In total , 940 RTR were included . During 4.4 ( 2.3–7.8 ) years of follow-up for graft failure and 4.8 ( 2.5–8.3 ) years for all-cause mortality , 78 RTR developed graft failure and 158 RTR died . Urinary urea excretion was not associated with graft failure in the overall population , but was inversely associated with graft failure in RTR with BMI less than 25 kg/m2 ( hazard ratio [ HR ] , 0.64 [ 0.28–1.50 ] and 0.27 [ 0.09–0.83 ] for the second and third tertiles , respectively , P < 0.001 ) , and in RTR with eGFR of 45 mL per min per 1.73 m2 or higher ( HR , 0.34 [ 0.15–0.79 ] , P = 0.015 and HR , 0.31 [ 0.11–0.86 ] , P = 0.025 for the second and third tertiles , respectively ) , both independent of potential confounders . Compared to the first tertile , RTR in the second and third tertiles of urinary urea excretion were at a lower risk of all-cause mortality ( HR , 0.47 [ 0.32–0.69 ] ; P < 0.001 and HR , 0.42 [ 0.26–0.68 ] ; P < 0.001 , respectively ) , independent of potential confounders . Body mass index and eGFR did not influence this association . Conclusion Urinary urea excretion , a marker for protein intake , was inversely related to graft failure in RTR with BMI less than 25 kg/m2 and in RTR with an eGFR of 45 mL per min per 1.73 m2 or higher . In addition , urinary urea excretion was inversely related to mortality BACKGROUND AND OBJECTIVES Concerns exist about deleterious renal effects of low-carbohydrate high-protein weight loss diets . This issue was addressed in a secondary analysis of a parallel r and omized , controlled long-term trial . DESIGN , SETTING , PARTICIPANTS , AND MEASUREMENTS Between 2003 and 2007 , 307 obese adults without serious medical illnesses at three United States academic centers were r and omly assigned to a low-carbohydrate high-protein or a low-fat weight-loss diet for 24 months . Main outcomes included renal filtration ( GFR ) indices ( serum creatinine , cystatin C , creatinine clearance ) ; 24-hour urinary volume ; albumin ; calcium excretion ; and serum solutes at 3 , 12 , and 24 months . RESULTS Compared with the low-fat diet , low-carbohydrate high-protein consumption was associated with minor reductions in serum creatinine ( relative difference , -4.2 % ) and cystatin C ( -8.4 % ) at 3 months and relative increases in creatinine clearance at 3 ( 15.8 ml/min ) and 12 ( 20.8 ml/min ) months ; serum urea at 3 ( 14.4 % ) , 12 ( 9.0 % ) , and 24 ( 8.2 % ) months ; and 24-hour urinary volume at 12 ( 438 ml ) and 24 ( 268 ml ) months . Urinary calcium excretion increased at 3 ( 36.1 % ) and 12 ( 35.7 % ) months without changes in bone density or clinical presentations of new kidney stones . CONCLUSIONS In healthy obese individuals , a low-carbohydrate high-protein weight-loss diet over 2 years was not associated with noticeably harmful effects on GFR , albuminuria , or fluid and electrolyte balance compared with a low-fat diet . Further follow-up is needed to determine even longer-term effects on kidney function BACKGROUND It is important for clinical end users of MEDLINE to be able to retrieve articles that are both scientifically sound and directly relevant to clinical practice . The use of method ologic search filters ( such as " r and om allocation " for sound studies of medical interventions ) has been advocated to improve the accuracy of search ing for such studies . Method ologic search filters have been tested in previous MEDLINE files but indexing continues to evolve and the operating characteristics of these search filters in current MEDLINE files are unknown . OBJECTIVE To determine the robustness of empirical search strategies developed in 1991 for detecting clinical content in MEDLINE in the year 2000 . DESIGN A survey based on a h and search of 171 core health care journals using predetermined quality indicators for scientific merit and clinical relevance . METHODS 6 trained , experienced research assistants read all issues of 171 journals for the publishing year 2000 . Each article was rated using purpose and quality indicators and categorized into clinical ly relevant original studies , review articles , general papers , or case reports . The original and review articles were then categorized as ' pass ' or ' fail ' for method ologic rigor in the areas of therapy/ quality improvement , diagnosis , prognosis , causation , economics , clinical prediction , and qualitative and review articles . Search strategies developed in 1991 were tested in the 2000 data base . MAIN OUTCOME MEASURES Sensitivity , specificity , precision , and accuracy of the search strategies . RESULTS Search strategies developed in 1991 generally performed at least as well in 2000 for both best single terms and combinations of terms for high-sensitivity MEDLINE search es for studies of treatment , prognosis , etiology and diagnosis . For example , the accuracy of " clinical trial ( pt ) " rose from 91.6 % to 94.4 % ( P<0.05 ) for retrieving high- quality studies of treatments . CONCLUSION Most MEDLINE search strategies developed in 1991 are robust when search ing in the publishing year 2000 BACKGROUND Consumption of a diet high in protein can cause glomerular hyperfiltration , a potentially maladaptive response , which may accelerate the progression of kidney disease . STUDY DESIGN An ancillary study of the OmniHeart trial , a r and omized 3-period crossover feeding trial testing the effects of partial replacement of carbohydrate with protein on kidney function . SETTING & PARTICIPANTS Healthy adults ( N=164 ) with prehypertension or stage 1 hypertension at a community-based research clinic with a metabolic kitchen . INTERVENTION Participants were fed each of 3 diets for 6 weeks . Feeding periods were separated by a 2- to 4-week washout period . Weight was held constant on each diet . The 3 diets emphasized carbohydrate , protein , or unsaturated fat ; dietary protein was either 15 % ( carbohydrate and unsaturated fat diets ) or 25 % ( protein diet ) of energy intake . OUTCOMES Fasting serum creatinine , cystatin C , and β2-microglobulin levels , estimated glomerular filtration rate ( eGFR ) . MEASUREMENTS Serum creatinine , cystatin C , and β2-microglobulin collected at the end of each feeding period . RESULTS Baseline cystatin C-based eGFR was 92.0±16.3 ( SD ) mL/min/1.73 m(2 ) . Compared with the carbohydrate and unsaturated fat diets , the protein diet increased cystatin C-based eGFR by ~4 mL/min/1.73 m(2 ) ( P < 0.001 ) . The effects of the protein diet on kidney function were independent of changes in blood pressure . There was no significant difference between the carbohydrate and unsaturated fat diets . LIMITATIONS Participants did not have kidney disease at baseline . CONCLUSIONS A healthy diet rich in protein increased eGFR . Whether long-term consumption of a high-protein diet leads to kidney disease is uncertain |
1,996 | 30,324,797 | Conclusion We found no evidence from controlled experimental and observational studies that compared with no treatment , the use of GnRH analogs improved AH in girls with EP | Objective We assessed the effectiveness of puberty blockade with a gonadotropin-releasing hormone ( GnRH ) analog in increasing adult height ( AH ) in girls with puberty onset between 7 and 10 years of age . | OBJECTIVE To study the effectiveness of luteinising hormone releasing hormone ( LHRH ) analogues in improving final height in girls affected by early puberty . PATIENTS Forty six consecutive girls with onset of puberty aged 7.5–8.5 years r and omly divided into two groups : one treated with 3.75 mg triptorelin intramuscularly every four weeks ( group 1 ) ; and the other with no treatment ( group 2 ) . RESULTS Mean ( SD ) chronological age at onset of menarche was significantly higher in group 1 than in group 2 ( 11.9 ( 1.0 ) v 10.8 ( 0.7 ) years ) . However , mean ( SD ) height at menarche ( 152.7 (7.2)v 152.5 ( 5.7 ) cm ) and mean ( SD ) growth after menarche ( 4.9 ( 3.0 ) v 5.4 ( 2.2 ) cm ) were similar in both groups . The mean ( SD ) final height was similar in the two groups ( group 1 , 158.1 ( 6.2 ) cm ; group 2 , 158.6 ( 6.0 ) cm ) and not significantly different from target height . Fourteen of 20 patients in group 1 and 12 of 18 patients in group 2 showed final height equal to or higher than target height . Final heights of girls with poor initial height prognosis were significantly lower than those of girls with good prognosis , but in patients with the same initial height prognosis , both groups showed final heights similar and not significantly different from their target heights . CONCLUSIONS LHRH analogue has no apparent effect on final height in subjects with onset of puberty between 7.5 and 8.5 years Early and fast puberty ( EFP ) in girls , defined as pubertal onset at age 8 - 9 yr , with an accelerated course , may cause compromised final height ( FHt ) and psychosocial distress . Treatment with a gonadotropin-suppressive agent is controversial , because the improvement in FHt is equivocal and there may be risk of obesity . We analyzed the data of 126 girls with EFP : 63 treated with GnRH analog ( GnRHA ) since Tanner stage 3 , for 2 - 4 yr ; and 63 untreated . Age at onset of puberty ; accelerated time of transition from Tanner stage 2 to 3 ( < 1.3 yr ) ; and clinical , hormonal and sonographic findings were similar in the 2 groups . The girls given GnRHA treatment had a significantly prolonged pubertal course , compared with the accelerated course in the untreated girls ( 4.7 + /- 0.4 vs. 2.45 + /- 0.4 yr , P < 0.001 ) . After therapy , they reached Tanner stages 4 and 5 and FHt at a significantly older age than the untreated group ( P < 0.001 ) , and their menarche was delayed ( 12.8 + /- 0.6 vs. 10.8 + /- 0.5 yr , P < 0.001 ) . However , the different pace of puberty in the 2 groups did not change the total pubertal growth and the bone maturation rate . The Ht gain from Tanner stage 3 to 4 ( 10.4 + /- 2.7 vs. 11.2 + /- 3.1 cm ) and from Tanner stage 4 to FHt ( 8.2 + /- 2.7 vs. 8.8 + /- 3.6 cm ) was similar in the treated and untreated girls , as were absolute Ht and bone age at each pubertal stage . The weight gain of the treated girls was more pronounced during treatment ( P = 0.0016 ) , but it was arrested after discontinuation of therapy ; and by the time FHt was reached , the body mass index was similar in the 2 groups . The treated and untreated girls achieved a similar mean FHt , which was not significantly different from their respective mean target Ht ( THt ) . Individual analysis revealed that 70 % of the treated girls and 67 % of the untreated girls attained their THt range ( THt + /- 0.5 SD ) or surpassed it . In conclusion , treatment with GnRHA affected only the pace of EFP . The similar Ht gain and bone maturation rate at each pubertal stage in the treated and untreated girls may suggest that the total pubertal growth is not dependent on pubertal duration and pace and is probably determined already at the onset of the normal pubertal development . The treatment did not compromise the FHt and did not cause long-lasting obesity . Therefore , GnRHA therapy may be suggested for use in girls who have psychosocial difficulties in coping with EFP Twenty-two girls affected by sexual precocity with impaired final height prognosis were followed until they achieved final height . Twelve of them were treated with an intranasal (D-Ser6)-gonadotrophin-releasing hormone ( GnRH ) analogue ( buserelin ) administered at a mean dose of 25 micrograms/kg/day ( range 20 - 32 ) for a mean period of 14 months ( range 8 - 18 ) . Ten girls refused treatment . Mean final height of the treated girls was 157.3 + /- 8.2 cm , significantly ( p = 0.03 ) higher than the 149.7 + /- 5.5 cm of untreated patients . Treated girls surpassed midparental height ( + 1.7 cm ) while untreated girls reached the lower part of target zone ( -3.5 cm ) . Our data suggest that intranasal buserelin treatment preserves final height in girls with sexual precocity and initially impaired height prognosis Objective : To investigate the effects of treatment with gonadotropin-releasing hormone analog ( GnRHa ) on final height in girls who experienced moderately early puberty with symptoms beginning at 7 - 8.5 years of age . Methods : Female cases diagnosed with moderately early puberty which had started between ages 7 to 8.5 years were included in the study . In the treatment groups , all cases with a bone age ≤10.5 years constituted group 1 ( n=18 ) and those with a bone age > 10.5 years constituted group 2 ( n=23 ) . The 8 patients for which treatment approval could not be obtained constituted group 3 . The 49 cases in all three groups were observed until they reached their final height . Results : Target height , target height st and ard deviation score ( SDS ) , final height , and final height SDS values were similar in all 3 groups . Final height showed a significant positive correlation with target height ( p=0.000 , r=0.54 ) and height at diagnosis ( p=0.003 , r=0.467 ) in all groups . Linear regression analysis revealed that a 1 cm longer height at diagnosis increased the final height 0.213 fold , and a 1 cm longer target height at diagnosis increased the final height 0.459 fold . Conclusion : We found that GnRHa did not make a positive contribution to final height in cases of moderately early puberty BACKGROUND We analysed the effectiveness of therapy with LHRH analogues in girls with a puberty onset at age 8 years . PATIENTS AND METHOD We performed a non-r and omised clinical study of 32 girls with advanced puberty . These included 16 treated with triptorelin LHRH analogue(3.75 mg/month during 1 year ) and 16 control subjects . We carried out anthropometric measurements and determined the pubertal height growth ( gain in height from the puberty onset up to the final height ) and the pubertal duration ( time in years from the puberty onset up to the age at which final height is attained ) . RESULTS Treatment with LHRH analogue delayed the menarche age ( 11.5 [1.46]vs 10.37 [ 0.67 ] years of age ; p = 0.03 ) , led to an involution in secondary sexual characteristics and a temporary decrease ingrowth rate , and delayed skeletal maturation . However , pubertal duration , pubertal height growth and final height were all similar in both groups . In addition , no significant differences in body fat mass were observed . CONCLUSIONS Treatment with LHRH analogues in advanced puberty modifies pubertal development , without modifying pubertal duration or pubertal height growth . Furthermore , this treatment does not improve final height Puberty is a period characterized by growth spurt and rapid change in body composition . The effect of GnRH agonist therapy for central precocious puberty on bone mineral density is unclear . We demonstrated changes in bone mineral density in subjects with central precocious puberty , who were treated with GnRH agonist for more than 3 years OBJECTIVE To evaluate prospect ively pubertal and predicted adult height progression until final height ( FH ) or near FH in girls with apparent idiopathic precocious puberty who were not treated . STUDY DESIGN The decision not to treat at the time of initial evaluation was based on evidence of slowly progressive puberty as shown by bone age ( BA ) advancement < 2 years above the chronologic age , whatever the hypothalamic pituitary ovarian axis activation , or no evidence of hypothalamic pituitary ovarian axis activation , whatever the BA advancement . During follow-up , patients who showed a significant decrease in predicted FH were treated with gonadotropin-releasing hormone agonist . RESULTS Twenty-six girls with idiopathic precocious puberty were studied at a mean chronologic age of 7.4 + /- 0.9 years during a follow-up period of 6.6 + /- 2.2 years until FH or near FH . During the first 2 years of follow-up , most of the patients ( group 1 , n = 17 ; 65 % of the cases ) showed no substantial changes in predicted FH . They never required treatment , and menarche occurred at a mean chronologic age of 11.9 + /- 0.6 years . Their mean FH ( or near FH ) at 160.7 + /- 5.7 cm was close to their target height ( 161.3 + /- 4.7 cm ) . On the other h and , after a mean follow-up period of 1.4 + /- 0.8 years , 9 patients ( group 2 ) had acceleration of bone maturation and deterioration of their predicted FH ( from 162.1 + /- 6 . 2 cm to 155.3 + /- 5.6 cm ; P < .01 ) , which was at that time significantly lower than their target height ( P < .05 ) ( mean target height = 159.8 + /- 4.6 cm ) . They received a gonadotropin-releasing hormone agonist for 2.1 + /- 0.7 years , result ing in a restoration of growth prognosis ( mean FH or near FH = 160.2 + /- 6.7 cm ) . CONCLUSIONS This study demonstrates that not all patients with apparent idiopathic precocious puberty require medical treatment , notably when there is no evidence of hypothalamo-pituitary ovarian activation or no significantly advanced BA to impair height potential . Most show a slowly progressing puberty . However , careful follow-up of these patients is necessary up to at least 9 years of age , because until then height prediction may deteriorate , necessitating gonadotropin-releasing hormone agonist treatment in one third of the cases BACKGROUND To evaluate the effect of GnRH-analogue triptoreline on the predicted adult height and final height in central precocious puberty ( CPP ) . PATIENTS AND METHODS The study included 14 girls with CPP treated for 1 - 6 years with triptoreline depot ( 75 micrograms/kg/28 days/i.m . ; group 1 ) . The criteria for diagnosis included the following : compelling evidence of rapid progression of puberty , with a bone age ( BA ) greater than 2 SD above the mean value for chronological age ( CA ) associated with poor initial predicted final height and growth speed greater than 2 SD above the mean value for age . In addition we obtained data from 6 untreated girls with advanced puberty and good predicted adult height followed during the same period of time ( group II ) . 7 of 14 girls of group I and 5 of 6 girls of group II attained final height . RESULTS A decrease in growth speed and an increase and in CA/BA ratio were observed after three years of treatment ( + 4.9 + /- 0.7 SD to -1.45 + /- 2.63 SD and 0.62 + /- 0.14 to 0.74 + /- 0.09 respectively ; P = 0.034 ; n = 6 ) . The predicted adult height increased significantly after two years of treatment ( 153.1 + /- 4.49 to 156.94 + /- 5 cm ; p = 0.041 ; n = 10 ) and was more evident after three years of treatment ( 153.84 + /- 5.77 to 160.7 + /- 7.5 cm ; p = 0.03 ; n = 6 ) . The final height of 7 girls of group I who attained it was similar to target height ( 161 + /- 3.1 vs. 159 + /- 1.3 cm ; NS ) and greater than initial predicted adult height ( 161 + /- 3.1 vs. 154 + /- 2.1 cm ; p = 0.044 ) and than final height of the 5 girls of group II ( 161 + /- 3.1 vs. 154.28 + /- 6.1 cm ) . CONCLUSIONS Triptorelin depot improves predicted adult height and final height of girls with early central puberty may be over their target height In order to evaluate the effects of two long‐acting luteinizing hormone‐releasing hormone agonists on growth , bone maturation and final height in girls with central precocious puberty , we analyzed growth data from 40 girls ( 15 treated with buserelin intranasal spray ( group A ) , 15 treated with triptorelin depot i m every 28 days ( group B ) and 10 untreated ( group C ) ) . Patients in group A started treatment when chronological age ( CA ) was 7.7 ± 0.9 years , bone age ( BA ) was 10.2 ± 1.1 years and height was 131.9 ± 5.0 cm . Patients in group B started therapy when CA was 7.6 ± 0.5 years , BA 9.8 ± 1.0 years and height 133.2 ± 7.6 m. The diagnosis of untreated patients ( group C ) was made when CA was 7.2 ± 0.9 years , BA 9.6 ± 2.2 years and height 130.2 ± 8.6 cm . Both luteinizing hormone‐releasing hormone agonists appeared to control precocious puberty . Final height in group B ( 160.6 ± 5.7 cm ) was significantly higher than that of group A ( 153.2 ± 5.0 cm : p < 0.05 ) and group C ( 149.6 ± 6.3 ; p < 0.01 ) , whereas the difference between groups A and C was not statistically significant . In group B a positive difference was observed between final height ( 160.6 ± 5.7 cm ) and target height ( 157.6 ± 5.9 cm ) ( ns ) ; on the contrary , in groups A and C , final height was lower than target height ( 155.5 ± 5.3 and 156.4 ± 1.3 cm , respectively ) , but only in group C the difference was statistically significant ( p < 0.01 ) . The best results regarding final height obtained by slow‐release depot i m therapy may be associated with more stable agonist blood levels during treatment We design ed a prospect i ve study of height potential in girls with idiopathic precocious puberty , comparing the presenting features of girls with and without evidence of reduced adult height potential . The 14 girls with impaired adult height prognoses ( group 1 ) were reexamined after treatment with a gonadotropin releasing hormone agonist , nafarelin . The seven girls with the prognosis of unimpaired height ( group 2 ) were followed without therapy . We found that the group could be distinguished at initial examination by the greater bone age/height age ratio of group 1 ( mean + /- SEM : 1.4 + /- 0.06 vs 1.0 + /- 0.05 ; p less than 0.005 ) and by the greater difference between predicted height and target height in group 1 . The mean predicted height in group 1 was significantly less than the mean target height ( 150.7 + /- 2.1 vs 165.4 + /- 3.0 cm ; p less than 0.005 ) , whereas the mean predicted and target heights in group 2 were similar ( 165.4 + /- 3.0 vs 164.3 + /- 2.1 cm ) . Initial estradiol levels were also greater in group 1 than in group 2 ( 21.6 vs 10.6 pg/ml ; p less than 0.05 ) , although this difference was not sustained during follow-up . In group 1 , nafarelin therapy suppressed the pituitary-gonadal axis , and although there was a transient reduction in height potential in girls with the youngest bone ages during the first 6 months of therapy , 2 years of treatment slightly improved predicted heights from 150.7 + /- 2.1 to 152.7 + /- 2.0 cm ( p less than 0.05 ) . Height predictions also increased without therapy during the 2-year observation period in group 2 , from 165.4 + /- 3.0 to 168.7 + /- 4.1 cm ( p less than 0.05 ) . Our data indicate that gonadotropin releasing hormone agonist therapy preserves height potential in girls with an initially impaired height prognosis , and that height potential is preserved without therapy in those with a good initial height prognosis OBJECTIVES To distinguish which children with precocious puberty ( PP ) and early puberty ( EP ) should be treated and which followed without therapy . To determine the effect of GnRH analog treatment on the final height of treated patients and compare the effect of two different analogs on gonadotropin suppression and final height . STUDY DESIGN Sixteen females with PP or EP with a mean chronological age ( CA ) of 8.8 + /- 1.4 years and a mean bone age ( BA ) of 10.8 + /- 1.3 years were treated for a mean of 2.7 + /- 1.0 years with a GnRH analog ( triptorelin or leuprolide acetate ; group A ) , while 21 girls with a mean CA of 8.5 + /- 1.0 years , a mean BA of 9.7 + /- 1.4 years and a predicted adult height of > 155 cm were followed without therapy ( group B ) . Criteria for treatment were one of : a. predicted adult height ( PAH ) of < 155 cm initially or at any time during follow up ; b. PAH over 155 cm with a dramatic decrease in PAH over a 6-month follow-up period ; c. advanced and rapidly progressing breast development for age ( Tanner 3 before the age of 9 years ) . RESULTS GnRHa therapy suppressed gonadotropins in group A , while gonadotropins increased gradually in group B. Height velocity ( HV ) decreased in group A , while it remained accelerated in group B ; BA increased a mean of 1.7 + /- 0.5 years in group A and 3.2 + /- 0.3 years in group B. This result ed in a height increase in group A from a baseline PAH of 153.7 + /- 1.2 cm to a final height ( FH ) of 160.9 + /- 4.0 cm ( p < 0.001 ) , clearly above their target height ( TH ) of 157.7 + /- 4.2 cm . The height of group B children did not change over time ( 164.1 + /- 4.1 cm before therapy and 166.0 + /- 6.0 cm at FH ) , both above their TH . The mean leuprolide acetate dose utilized in this study decreased during treatment , while both the initial and final triptorelin dose remained unchanged . Adequate gonadotropin suppression ( peak level of LH and FSH of < 2 IU/l after i.v . GnRH stimulation ) was noted with both leuprolide acetate and triptorelin , although LH suppression was slightly more pronounced with triptorelin . BA advanced 1.8 + /- 0.4 years during leuprolide acetate treatment and 1.5 + /- 0.3 years with triptorelin , so that FH increased a mean of 5.5 + /- 1.3 cm with leuprolide acetate and 8.7 + /- 2.2 cm with triptorelin . CONCLUSIONS PAH of < 155 cm before or during therapy , PAH of > 155 cm with a dramatic decrease in predicted height over a 6-month follow-up period and /or advanced and rapidly progressing breast development in girls with PP or EP were useful parameters in deciding which patients to treat . GnRHa therapy suppressed gonadotropins , HV and bone maturation in children with an accelerated form of PP or EP , result ing in a significant height increase . Final height remained stable over time in untreated patients . Adequate gonadotropin suppression was noted with both analogs , although with the doses of analog used in our study , LH and BA suppression were more pronounced with triptorelin , result ing in a larger height gain GnRH agonists improve final height in girls with " true " precocious puberty . To test if a comparable effect can be obtained in older girls , we performed a long-term controlled study in 30 caucasian girls whose puberty started between 8.4 and 10 yr ( 9.4 + /- 0.1 yr ) , a variant of normal called " advanced " puberty . At entry into trial , these girls had clinical , biological , and sonographic manifestations of puberty and a bone age greater than 10.9 yr . They were r and omized 2:1 to receive 3.75 mg triptorelin i m every 4 weeks for 2 yr ( n = 20 , group I ) or no treatment ( n = 10 , group II ) . Mean height at inclusion was 135.2 + /- 4.3 cm ( + 0.6 SDS ) in group I , 136.1 + /- 4.2 cm ( + 0.8 SDS ) in group II , with target height 157.6 + /- 4.3 cm ( group I ) and 157.8 + /- 4.7 cm ( group II ) , and predicted height ( Bayley-Pinneau ) 154.1 + /- 3.9 cm and 155.2 + /- 3.7 cm . Although GnRH agonists transiently delayed sexual maturation as well as bone age and growth rate , they had no clear-cut long-st and ing effect , and final height was comparable in treated ( 157.6 + /- 4.0 cm ) and untreated girls ( 156.1 + /- 5.3 cm ) ( NS ) To evaluate the effect of central precocious puberty ( CPP ) and its treatment with gonadotropin-releasing hormone ( GnRH ) analogues on final height and peak bone mass ( PBM ) , we measured lumbar bone mineral density ( BMD ) in 23 girls at final height . Patients were distributed in two groups . Group 1 : 14 patients with progressive CPP were treated with GnRH analogues ; seven patients received buserelin ( 1600 μg/daily ) , subsequently switched to depot triptorelin ( 60 μg/kg/26–28 days ) ; seven patients were treated with depot triptorelin ( 60 μg/kg/26–28 days ) ; mean age of treatment was 6.2 years ( range 2.7–7.8 years ) ; the treatment was discontinued at the mean age of 10.1 years ( range 8.7–11.3 years ) ; final height was reached at the mean age 13.4 years ( range 12.0–14.9 years ) . Group 2 : 9 patients ( mean age 6.5 years , range 4.8–7.7 years ) with a slowly progressing variant of CPP were followed without treatment ; final height was reached at the mean age 13.6 years ( range 12.5–14.8 years ) . Lumbar BMD ( L2–L4 by dual energy X-ray absorptiometry ) was measured in all patients at final height . In group 1 , final height ( 158.9 ± 5.4 cm ) was significantly greater than the pre-treatment predicted height ( 153.5 ± 7.2 cm , P < 0.001 ) , but significantly lower than mid-parental height ( 163.2 ± 6.2 cm , P < 0.005 ) . Subdividing the girls of group 1 according to the bone age at discontinuation of therapy ( i.e. ≤11.5 years , n = 5 , or ≥12.0 years , n = 9 ) , the former patients had a final height significantly higher than the latter ( 163.7 ± 3.9 cm vs 156.5 ± 4.6 cm , P < 0.02 ) . In group 2 , final height ( 161.8 ± 4.6 cm ) was similar to the pre-treatment predicted height ( 163.1 ± 6.2 cm , P = NS ) and was not significantly different from mid-parental height ( 161.0 ± 5.9 cm ) . BMD values ( group 1 : 1.11 ± 0.14 g/cm2 , group 2 : 1.22 ± 0.08 g/cm2 ) were not significantly different from those of a control group ( 1.18 ± 0.10 g/cm2 ; n = 20 , age 16.3–20.5 years ) and the patients ’ mothers ( group 1 : 1.16 ± 0.07 g/cm2 , n = 11 , age 32.9–45.1 years ; group 2 : 1.20 ± 0.08 g/cm2 , n = 7 , age 33.5–46.5 years ) . In group 1 , the girls who stopped therapy at a bone age ≤11.5 years had significantly higher BMD ( 1.22 ± 0.10 g/cm2 ) compared to those who discontinued therapy at a bone age ≥12.0 years ( 1.04 ± 0.12 g/ cm2 , P < 0.05 ) . Conclusion In girls with progressive CPP , long-term treatment with GnRH analogues improves final height . A subset of patients with CPP does not require treatment because good statural outcome ( slowly progressing variant ) . In CPP , the abnormal onset of puberty and the long-term GnRH analogue treatment do not impair the achievement of PBM . In GnRH treated patients , the discontinuation of therapy at an appropriate bone age for pubertal onset may improve both final height and PBM The impact of treatment of central precocious puberty ( CPP ) with GnRH agonists on final statural height ( FH ) remains controversial , and guidelines on the optimal time point for interruption of these treatments have not been established . We analyzed the long term results of 58 girls and 8 boys uniformly treated with triptorelin slow release formulation ( Decapeptyl , triptorelin-SR ) for CPP and compared their FH with predicted height before treatment and with the FH of a historical group of patients not treated with GnRH agonist . The FH SD score was close to 0 and was not different from the genetic target height . In girls , FH was improved by 4.8 + /- 5.8 cm compared with predicted height before treatment and by 8.3 cm by comparison with a historical group . In boys , comparison with a historical group revealed a 13.7-cm improvement , whereas predicted height before treatment was similar to FH . Three variables were independently associated with FH in girls : the bone age/statural age ratio at the onset of treatment ( negatively ) , the height SD score at the end of treatment , and the posttreatment growth spurt ( delta FH - height at the end of treatment ) . The influence of the posttreatment growth spurt , itself dependent on age and bone age at the interruption of treatment , suggests that continuing treatment beyond the age of 11 yr in girls does not improve and could actually decrease FH . This point should be evaluated in a formal controlled trial This study was design ed to determine the benefit of therapy on final height ( FHt ) in girls with central precocious puberty ( CPP ) . A total of 102 patients were evaluated--28 untreated , 26 treated with cyproterone acetate ( CyA ) , and 48 treated with GnRH analogue (GnRHA)- and their achieved FHt was compared to the respective target height ( THt ) . Of the untreated girls , half ( 14/28 ) had a slow course of puberty and reached THt + /- 0.5 SD ( FHt 160.2 + /- 7.1 , THt 159.5 + /- 6.6 cm ) ; the other half ( 14/28 ) had an accelerated course of puberty with a FHt well below THt ( FHt 150.8 + /- 4.3 , THt , 159.2 + /- 5.9 cm ) and in most cases ( 14/28 ) below the height-SDS of both parents . The treated girls ( both regimens ) reached THt above ( CyA group : FHt 157.8 + /- 5.1 , THt 156.8 + /- 5.1 cm ; GnRHA group : 159.6 + /- 6.3 , THt 157.7 + /- 5.7 cm ) . We conclude that without treatment the FHt of girls with CPP may be significantly compromised and that therapy is more beneficial if started before bone age exceeds 12 years . Our data also showed that for final height predictions in CPP the Bayley and Pinneau tables for average children should be used , regardless of the advanced bone age of the patients |
1,997 | 22,938,627 | Studies with SSRIs examined effects of sertraline , paroxetine , and citalopram .
CONCLUSIONS Evidence is strong that pharmacology and CAM may improve depression .
Moderate evidence supports the use of exercise .
A strong body of evidence indicates that disease management programs do not improve depression . | OBJECTIVE We sought to conduct a systematic review to evaluate the effects of interventions on depression in adults with heart failure ( HF ) . | Abstract Background : Disease management programmes ( DMPs ) improve quality of care for patients with heart failure ( HF ) . However , only a limited number of trials have studied the efficacy of such programmes for patients with heart failure with preserved ejection fraction ( HFPEF ) . Objective : To estimate the impact of a structured , nurse-led patient education programme and care plan in general practice on outcome parameters and events in patients with HFPEF . Methods : Single blinded r and omized clinical trial with an intervention over six months and a follow-up during 12 additional months . In the control group , the patients ( n = 41 ) were managed according to Russian national guidelines . Patients in the intervention group ( n = 44 ) received education on individual lifestyle changes and modifications of cardiovascular disease ( CVD ) risk factors , home-based exercise training and weekly nurse consultations in addition to usual care . Results : Six months after their inclusion , patients in the intervention group significantly improved body mass index , waist circumference , six-min walk test distance , total cholesterol , low-density lipoprotein , left ventricular end-diastolic volume index , quality of life and level of anxiety . After 18 months , there were 11 deaths ( 25 % ) or hospitalizations in the intervention group and 12 ( 29 % ) in the control group ( P = 0.134 ) . Cardiovascular mortality and readmission rate were not reduced significantly after six months of follow-up : the hazard ratio was 0.47 ( 95 % CI : 0.17–1.28 ; P = 0.197 ) . After 18 months , this was 0.85 ( 0.42–1.73 ; P = 0.658 ) . Conclusion : This primary care based DMP for patients with HFPEF improved the patients ’ emotional status and quality of life , positively influenced body weight , functional capacity and lipid profile , and attenuated heart remodelling BACKGROUND Preliminary evidence suggests that meditative exercise may have benefits for patients with chronic systolic heart failure ( HF ) ; this has not been rigorously tested in a large clinical sample . We sought to investigate whether tai chi , as an adjunct to st and ard care , improves functional capacity and quality of life in patients with HF . METHODS A single-blind , multisite , parallel-group , r and omized controlled trial evaluated 100 out patients with systolic HF ( New York Heart Association class I-III , left ventricular ejection fraction ≤40 % ) who were recruited between May 1 , 2005 , and September 30 , 2008 . A group-based 12-week tai chi exercise program ( n = 50 ) or time-matched education ( n = 50 , control group ) was conducted . Outcome measures included exercise capacity ( 6- minute walk test and peak oxygen uptake ) and disease-specific quality of life ( Minnesota Living With Heart Failure Question naire ) . RESULTS Mean ( SD ) age of patients was 67 ( 11 ) years ; baseline values were left ventricular ejection fraction , 29 % ( 8 % ) and peak oxygen uptake , 13.5 mL/kg/min ; the median New York Heart Association class of HF was class II . At completion of the study , there were no significant differences in change in 6-minute walk distance and peak oxygen uptake ( median change [ first quartile , third quartile ] , 35 [ -2 , 51 ] vs 2 [ -7 , 54 ] meters , P = .95 ; and 1.1 [ -1.1 , 1.5 ] vs -0.5 [ -1.2 , 1.8 ] mL/kg/min , P = .81 ) when comparing tai chi and control groups ; however , patients in the tai chi group had greater improvements in quality of life ( Minnesota Living With Heart Failure Question naire , -19 [ -23 , -3 ] vs 1 [ -16 , 3 ] , P = .02 ) . Improvements with tai chi were also seen in exercise self-efficacy ( Cardiac Exercise Self-efficacy Instrument , 0.1 [ 0.1 , 0.6 ] vs -0.3 [ -0.5 , 0.2 ] , P < .001 ) and mood ( Profile of Mood States total mood disturbance , -6 [ -17 , 1 ] vs -1 [ -13 , 10 ] , P = .01 ) . CONCLUSION Tai chi exercise may improve quality of life , mood , and exercise self-efficacy in patients with HF . Trial Registration clinical trials.gov Identifier : NCT00110227 Heart failure ( HF ) is the leading cause of rehospitalization in older adults . The purpose of this pilot study was to examine whether telemonitoring by an advanced practice nurse reduced subsequent hospital readmissions , emergency department visits , costs , and risk of hospital readmission for patients with HF . One hundred two patient/caregiver dyads were r and omized into 2 groups postdischarge ; 84 dyads completed the study . Hospital readmissions , emergency department visits , costs , and days to readmission were abstract ed from medical records . Participants were interviewed soon after discharge and 3 months later about effects of telemonitoring on depressive symptoms , quality of life , and caregiver mastery . There were no significant differences due to telemonitoring for any outcomes . Caregiver mastery , informal social support , and electronic home monitoring were not significant predictors for risk of hospital readmission . Further studies should address the interaction between the advanced practice nurse and follow-up intervention with telemonitoring of patients with HF to better target those who are most likely to benefit AIMS Supervised exercise can benefit selected patients with heart failure , however the effectiveness of home-based exercise remains uncertain . We aim ed to assess the effectiveness of a home-based exercise programme in addition to specialist heart failure nurse care . METHODS AND RESULTS This was a r and omized controlled trial of a home-based walking and resistance exercise programme plus specialist nurse care ( n=84 ) compared with specialist nurse care alone ( n=85 ) in a heart failure population in the West Midl and s , UK . PRIMARY OUTCOME Minnesota Living with Heart Failure Question naire ( MLwHFQ ) at 6 and 12 months . SECONDARY OUTCOMES composite of death , hospital admission with heart failure or myocardial infa rct ion ; psychological well-being ; generic quality of life ( EQ-5D ) ; exercise capacity . There was no statistically significant difference between groups in the MLwHFQ at 6 month ( mean , 95 % CI ) ( -2.53 , -7.87 to 2.80 ) and 12 month ( -0.55 , -5.87 to 4.76 ) follow-up or secondary outcomes with the exception of a higher EQ-5D score ( 0.11 , 0.04 to 0.18 ) at 6 months and lower Hospital Anxiety and Depression Scale score ( -1.07 , -2.00 to -0.14 ) at 12 months , in favour of the exercise group . At 6 months , the control group showed deterioration in physical activity , exercise capacity , and generic quality of life . CONCLUSION Home-based exercise training programmes may not be appropriate for community-based heart failure patients AIM One of the major treatment goals in congestive heart failure ( CHF ) is to preserve the functional level of the patient and to improve psychosocial factors . For these purpose s , exercise training is recommended for the management of CHF . With this background , the aim of this study is to investigate the effects of aerobic exercise on quality of life , depression and anxiety levels in a Turkish patient population with CHF . METHODS Sixty patients with CHF in stage II-III according to NYHA were included . Patients were r and omly assigned either to a cardiac rehabilitation group or to a control group . Twenty-seven patients were allocated to a weekly aerobic walking program on treadmill , thrice a week for 8 weeks , and 26 patients did not receive any exercise training . Both groups were assessed by an ergospirometric exercise test , Hacettepe Quality of Life Question naire ( HQoL ) , Beck Depression Inventory ( BDI ) , Spielberger Trait Anxiety Inventory ( STAI ) at baseline and at the end . RESULTS Forty-four patients ( treatment group : 23 ) completed the study . In the treatment group , significant increases in peak oxygen consumption , exercise time and metabolic equivalents ( MET ) levels were attained ( P=0.001 , P=0.001 , P=0.003 , respectively ) . Significant decreases in BDI ( P=0.004 ) and STAI subgroups ( P=0.049 , P=0.023 , respectively ) were observed , whereas there was no change in HQoL scores . In the control group , there was no difference between baseline and 8th week evaluation in all parameters . CONCLUSIONS Patients with CHF tolerated aerobic exercise programs well . This result ed with improvement in both physical and psychologic wellbeing , but not in quality of life in the short term The purpose of this study was to evaluate the effect of stress management training on quality of life , functional capacity , and heart rate variability in elderly patients with New York Heart Association class I-III congestive heart failure ( CHF ) . While substantial research exists on stress management training for patients with coronary heart disease , there are few data on the value of psychosocial training on patients with CHF . Thirty-three multiethnic patients ( mean age , 66+/-9 years ) were assigned through incomplete r and omization to one of two treatment groups or a wait-listed control group . The 14 participants who completed the treatment attended eight training sessions during a 10-week period . The training consisted of 75-minute sessions adapted from the Freeze-Frame stress management program developed by the Institute of HeartMath . Subjects were assessed at baseline and again at the completion of the training . Depression , stress management , optimism , anxiety , emotional distress , and functional capacity were evaluated , as well as heart rate variability . Significant improvements ( p<0.05 ) were noted in perceived stress , emotional distress , 6-minute walk , and depression , and positive trends were noted in each of the other psychosocial measures . The 24-hour heart rate variability showed no significant changes in autonomic tone . The authors noted that CHF patients were willing study participants and their emotional coping and functional capacity were enhanced . This program offers a simple and cost-effective way to augment medical management of CHF . Given the incompleteness of CHF medical management and the exploding interest in complementary medical intervention , it seems imperative that further work in psychosocial treatment be undertaken Objectives : To evaluate the feasibility of screening and recruiting patients with major depression and congestive heart failure ( CHF ) in a tertiary care cardiology hospital and to obtain preliminary efficacy , tolerability , and safety data for nefazodone treatment of a major depressive episode in CHF patients . Method : We conducted a 12-week , open-label trial of nefazodone given in dosages up to 600 mg daily . We assessed patients at baseline , 1 , 2 , 4 , 8 , and 12 weeks . Measures used were the 17-item Hamilton Depression Rating Scale ( HDRS ) , the Clinical Global Impression Scale , the Beck Depression Inventory , Spielberger 's State-Trait Anxiety Inventory , and the Minnesota Living with Heart Failure Question naire . We also obtained pre- and post study ECGs , 24-hour Holter monitor recordings , and plasma levels of norepinephrine . Results : After screening 443 CHF patients , 28 patients with major depression met study eligibility criteria . The 23 patients who completed 4 or more weeks of medication showed significant improvement on all depression scales and in quality of life . Of 19 subjects who completed the full 12-week trial , 74 % experienced a decline of 50 % or more on HDRS scores . The completers also showed a significant reduction in heart rate , an increase in QT intervals ( but not in the QTc ) , and a marginally significant decrease in plasma norepinephrine . There were no changes in heart rate variability . Conclusions : It is feasible to screen and recruit CHF patients with major depression for an antidepressant trial . Nefazodone seems sufficiently safe , tolerable , and efficacious to justify a larger , placebo-controlled trial Purpose To compare the effects of home-based and hospital-based exercise programs on exercise capacity , quality of life , psychological symptoms , and hemodynamic parameters in heart failure ( HF ) patients . Methods Seventy-four patients were r and omized into either a hospital-based exercise ( Group 1 ) or a home-based exercise ( Group 2 ) group . Prior to and after the 8-week rehabilitation program , the two groups were compared with respect to their functional capacity [ maximal oxygen uptake ( pVO2 ) and 6-min walk test ( 6MWT ) ] , quality of life ( Medical Outcomes Study and the 36-item Short Form Survey , SF-36 ) , psychological symptoms [ Beck Depression Inventory ( BDI ) and State-Trait Anxiety Inventory ] , and hemodynamic parameters [ ( left ventricular diastolic diameter in diastole , left ventricular diameter in systole , Mitral Early diastolic peak flow velocity (E)/late diastolic peak flow velocity ( A ) , Mitral E/Mitral early peak velocity ( Em ) , Tei index , right ventricular systolic peak velocity ( Sm ) , tricuspid annular plane systolic excursion , systolic pulmonary arterial pressure ( SPAP ) , and left and right ventricular ejection fraction ( LVEF and RVEF ) ] . Results After the exercise programs , significant improvement was observed in pVO2 , 6MWT and subscales of physical function , general health , and vitality of SF 36 , as well as BDI and LVEF in both groups ( P < 0.05 ) . A comparison of the two exercise groups revealed no significant differences between them regarding the analyzed variables ( P > 0.05 ) . Conclusion Both the hospital-based and home-based exercise groups improved significantly in functional capacity , quality of life , depression symptoms , and LVEF . Based on these results , we believe that physicians can recommend home-based exercise under strict supervision for stable HF patients . However , additional research should be conducted in this area BACKGROUND Heart failure is a common and important cause of morbidity and mortality . Disease management offers promise in reducing the need for hospitalization and improving quality of life for heart failure patients , but experimental data on the efficacy of such programs are limited . METHODS AND RESULTS A total of 151 patients hospitalized with heart failure were r and omized to usual care or scheduled telephone calls by specially trained nurses promoting self-management and guideline -based therapy as prescribed by primary physicians . Nurses also screened patients for heart failure exacerbations , which they managed with supplemental diuretics or by contacting the primary physician for instructions . Outcomes included time to hospital encounter , mortality , number and cost of hospitalizations , functional status , and satisfaction with care . Intervention patients had a longer time to encounter ( hazard ratio [ HR ] = 0.67 ; 95 % confidence interval [ CI ] 0.47 - 0.96 ; P = .029 ) , hospital readmission ( HR = 0.67 ; CI 0.46 - 0.99 ; P = .045 ) , and heart failure-specific readmission ( HR = 0.62 ; CI 0.38 - 1.03 ; P = .063 ) . The number of admissions , hospital days , and hospital costs were significantly lower during the first 6 months after intervention but not at 1 year . The intervention had little effect on functional status , mortality , and satisfaction with care . CONCLUSION A nurse-administered , telephone-based disease management program delayed subsequent health care encounters , but had minimal impact on other outcomes CONTEXT Motivating patients with heart failure to adhere to medical advice has not translated into clinical benefit , but past trials have had method ological limitations . OBJECTIVE To determine the value of self-management counseling plus heart failure education , compared with heart failure education alone , for the primary end point of death or heart failure hospitalization . DESIGN , SETTING , AND PATIENTS The Heart Failure Adherence and Retention Trial ( HART ) , a single-center , multiple-hospital , partially blinded behavioral efficacy r and omized controlled trial involving 902 patients with mild to moderate heart failure and reduced or preserved systolic function , r and omized from the Chicago metropolitan area between October 2001 and October 2004 and undergoing follow-up for 2 to 3 subsequent years . INTERVENTIONS All patients were offered 18 contacts and 18 heart failure educational tip sheets during the course of 1 year . Patients r and omized to the education group received tip sheets in the mail and telephone calls to check comprehension . Patients r and omized to the self-management group received tip sheets in groups and were taught self-management skills to implement the advice . MAIN OUTCOME MEASURE Death or heart failure hospitalization during a median of 2.56 years of follow-up . RESULTS Patients were representative of typical clinical population s ( mean age , 63.6 years ; 47 % women , 40 % racial/ethnic minority , 52 % with annual family income less than $ 30,000 , and 23 % with preserved systolic function ) . The rate of the primary end point in the self-management group was no different from that in the education group ( 163 [ 40.1 % ) ] vs 171 [ 41.2 % ] , respectively ; odds ratio , 0.95 [ 95 % confidence interval , 0.72 - 1.26 ] ) . There were no significant differences on any secondary end points , including death , heart failure hospitalization , all-cause hospitalization , or quality of life . CONCLUSIONS Compared with an enhanced educational intervention alone , the addition of self-management counseling did not reduce death or heart failure hospitalization in patients with mild to moderate heart failure . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00018005 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 BACKGROUND many heart failure disease management programs are primarily conducted in the male population . An approach incorporating disciplines such as physiotherapy , occupational therapy , social work , dietary and pharmacy in a st and ardized clinical pathway merits further investigation in older women with HF . METHODS in this r and omized controlled trial , female patients in the intervention group received the multidisciplinary clinical pathway consisting of a series of 12 visits over a 6-week period in an outpatient clinic . RESULTS ninety-one community dwelling female patients aged 63 to 89 were r and omized . Comparison of change between the two groups from baseline in the Minnesota Living with Heart Failure Question naire score did not show a difference ( P<0.470 ) . There was also no difference between the two groups in functional outcome as measured by change from baseline by the Physical Self-Maintenance Scale ( P<0.321 ) . The treatment group had significantly more hospitalizations , and cardiologist visits during the study period ( P < 0.0001 ) . CONCLUSION It is feasible to conduct a r and omized study in a frail community-based older female population and to test a complex multidisciplinary pathway . Future studies should provide insight into the optimal intensity and duration of heart failure management programs with optimal targeting OBJECTIVE To determine whether clinical trials originating in certain countries always have positive results . DATA SOURCES Abstract s of trials from Medline ( January 1966-June 1995 ) . STUDY SELECTION Two separate studies were conducted . The first included trials in which the clinical outcome of a group of subjects receiving acupuncture was compared to that of a group receiving placebo , no treatment , or a nonacupuncture intervention . In the second study , r and omized or controlled trials of interventions other than acupuncture that were published in China , Japan , Russia/USSR , or Taiwan were compared to those published in Engl and . DATA EXTRACTION Blinded review ers determined inclusion and outcome and separately classified each trial by country of origin . DATA SYNTHESIS In the study of acupuncture trials , 252 of 1085 abstract s met the inclusion criteria . Research conducted in certain countries was uniformly favorable to acupuncture ; all trials originating in China , Japan , Hong Kong , and Taiwan were positive , as were 10 out of 11 of those published in Russia/USSR . In studies that examined interventions other than acupuncture , 405 of 1100 abstract s met the inclusion criteria . Of trials published in Engl and , 75 % gave the test treatment as superior to control . The results for China , Japan , Russia/USSR , and Taiwan were 99 % , 89 % , 97 % , and 95 % , respectively . No trial published in China or Russia/USSR found a test treatment to be ineffective . CONCLUSIONS Some countries publish unusually high proportions of positive results . Publication bias is a possible explanation . Research ers undertaking systematic review s should consider carefully how to manage data from these countries BACKGROUND Diastolic heart failure ( DHF ) is common in older women . There have been no clinical trials that have identified therapies to improve symptoms in these patients . A total of 32 women with New York Heart Association class II and III DHF ( left ventricular ejection fraction > 45 % and symptoms of dyspnea or fatigue ) were r and omized into a 12-week home-based , low-to-moderate intensity ( 40 % and 60 % , respectively ) exercise and education program ( intervention ) or education only program ( control ) . Methods and results The intervention group improved in the 6-minute walk test from 840 + /- 366 ft to 1043 + /- 317 ft versus 824 + /- 367 ft to 732 + /- 408 ft in the control group ( P = .002 ) . Quality of life also improved in the intervention group compared with the control group as measured by the Living with Heart Failure Question naire ( 41 + /- 26 to 24 + /- 18 vs 27 + /- 18 to 28 + /- 22 at 12 weeks , P = .002 ; 24 + /- 18 to 19 + /- 18 vs 28 + /- 22 to 32 + /- 27 at the 3-month follow-up , P = .014 ) and the Geriatric Depression Scale ( 6 + /- 4 to 4 + /- 4 vs 5 + /- 3 to 7 + /- 5 at 12 weeks , P = .012 ; 4 + /- 4 to 4 + /- 4 vs 7 + /- 5 to 7 + /- 5 at the 3-month follow-up , P = .009 ) . CONCLUSIONS Women with DHF exhibit significant comorbidities and physical limitations . Home-based , low-to-moderate intensity exercise , in addition to education , is an effective strategy for improving the functional capacity and quality of life in women with DHF . Further study is needed to assess the long-term effect of exercise on clinical outcomes OBJECTIVES The objective was to test the hypothesis that heart failure ( HF ) patients treated with sertraline will have lower depression scores and fewer cardiovascular events compared with placebo . BACKGROUND Depression is common among HF patients . It is associated with increased hospitalization and mortality . METHODS The SADHART-CHF ( Sertraline Against Depression and Heart Disease in Chronic Heart Failure ) trial was a r and omized , double-blind , placebo-controlled trial of sertraline 50 to 200 mg/day versus matching placebo for 12 weeks . All participants also received nurse-facilitated support . Eligible patients were age 45 years or older with HF ( left ventricular ejection fraction < or = 45 % , New York Heart Association functional class II to IV ) and clinical depression ( Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria for current major depressive disorder ) . Those with significant cognitive impairment , psychosis , recent alcohol or drug dependence , bipolar or severe personality disorder , active suicidal ideation , and current antipsychotic or antidepressant medications were excluded . Primary end points were change in depression severity ( Hamilton Depression Rating Scale total score ) and composite cardiovascular status at 12 weeks . RESULTS A total of 469 patients were r and omized ( n = 234 sertraline , n = 235 placebo ) . The mean + /- SE change from baseline to 12 weeks in the Hamilton Depression Rating Scale total score was -7.1 + /- 0.5 ( sertraline ) and -6.8 + /- 0.5 ( placebo ) ( p < 0.001 from baseline , p = 0.89 between groups , mean change between groups -0.4 ; 95 % confidence interval : -1.7 to 0.92 ) . The proportions whose composite cardiovascular score worsened , improved , or was unchanged were 29.9 % , 40.6 % , and 29.5 % , respectively , in the sertraline group and 31.1 % , 43.8 % , and 25.1 % , respectively , in the placebo group ( p = 0.78 ) . CONCLUSIONS Sertraline was safe in patients with significant HF . However , treatment with sertraline compared with placebo did not provide greater reduction in depression or improved cardiovascular status among patients with HF and depression . ( Antidepressant Medication Treatment for Depression in Individuals With Chronic Heart Failure [ SADHART-CHF ] ; NCT00078286 ) BACKGROUND The aim of this study was to determine the effects of a home-based exercise program on clinical outcomes . Exercise training improves exercise capacity in patients with heart failure ( HF ) but the long-term effects on clinical outcomes remain unknown . METHODS We r and omized 173 patients with systolic HF to control ( n = 87 ) or home-based exercise ( n = 86 ) . The primary end point was a composite of all-cause hospitalizations , emergency department admissions , urgent transplantation , and death at 12 months . Functional performance ( as assessed by cardiopulmonary exercise testing and the 6-minute walk test ) , quality of life , and psychological states were measured at baseline , 3 months , and 6 months . RESULTS There was no significant difference between experimental and control groups in the combined clinical end point at 12 months and in functional status , quality of life , or psychological states over 6 months . Patients in the exercise group had a lower incidence of multiple ( 2 or more ) hospitalizations compared with the control group : 12.8 % versus 26.6 % , respectively ( P = .018 ) . CONCLUSIONS A home-based walking program that incorporated aerobic and resistance exercise did not result in improved clinical outcomes at 1-year follow-up in this cohort of patients with systolic HF . However , the exercise program result ed in reduced rehospitalization rates BACKGROUND Exercise programs for patients with heart failure have often enrolled and evaluated relatively healthy , young patients . They also have not measured the impact of exercise performance on daily activities and quality of life . METHODS AND RESULTS We investigated the impact of a 6-month supervised and grade d exercise program in 33 elderly patients with moderate to severe heart failure r and omized to usual care or an exercise program . Six of 17 patients did not tolerate the exercise program . Of those who did , peak oxygen consumption increased by 2.4 + /- 2.8 mL/kg/min ( P < .05 ) and 6-minute walk increased by 194 ft ( P < .05 ) . However , outpatient energy expenditure did not increase , as measured by either the doubly labeled water technique or Caltrac accelerometer . Perceived quality of life also did not improve , as measured by the Medical Outcomes Study , Functional Status Assessment , or Minnesota Living With Heart Failure question naires . CONCLUSION Elderly patients with severe heart failure can safely exercise , with an improvement in peak exercise tolerance . However , not all patients will benefit , and daily energy expenditure and quality of life do not improve to the same extent as peak exercise BACKGROUND Depression impairs health status among patients with coronary disease . The effect of depression on patients with heart failure has been studied to date only in hospitalized patients . METHODS AND RESULTS Prospect i ve cohort study of 113 out patients with advanced heart failure . At baseline , 19 % ( n = 21 ) had major depression or dysthymia , 9 % ( n = 10 ) had minor depression , and 72 % ( n = 82 ) had no current depression diagnosis . Repeated measures analyses of covariance adjusting for demographic and clinical differences demonstrated that the depression groups differed on observed function ( 6-minute walk distance [ F = 4.8 , P = .01 ] ) , and self-reported generic ( SF-36 ) and disease-specific ( Kansas City Cardiomyopathy Question naire ) health status . Depression groups also differed in severity of self-reported breathlessness , chest pain , and fatigue . Subject- and spouse-reported role function also differed between the groups . Partial correlation ( controlling for the same covariates ) between baseline Hamilton Depression Scale scores and these outcomes was highly significant at baseline and follow-up . CONCLUSIONS Depression is prospect ively associated with poorer health status in patients with advanced heart failure . Physical and role function , symptom severity , and quality of life are all significantly affected The course of depression and the economic consequences in the 6-month period after hospitalization for congestive heart failure were examined in a prospect i ve observational cohort study involving 203 older adults ( mean age=76.8 years , SD=7.8 ) . At discharge , 73 of 203 subjects ( 36 % ) were depressed according to the screening criteria of the Geriatric Depression Scale , and 44 ( 22 % ) were depressed according to the Structured Clinical Interview for DSM-III-R-Non-Patient Edition . The proportions were 33 % and 20 % of 166 subjects , respectively , at 4 weeks and 26 % and 17 % of 113 subjects , respectively , at 24 weeks . Depressed patients used more medical re sources after discharge than nondepressed patients . Additional research is required to determine whether the optimal time to identify and treat depressed older adults with congestive heart failure is during a hospital stay or after discharge AIMS To determine the effects of a nurse-led intervention design ed to improve self-management of patients with heart failure in a primary health care setting regarding health-related quality of life and depression . METHODS Patients at eight primary health care centres were screened by the Diagnosis Related Groups registry for the diagnosis of heart failure and eligibility for a cluster r and omised study . A total of 153 patients were included ( n=78 in the intervention group , 54 % males , mean age 79 years , 59 % in New York Heart Association class III-IV ) . The intervention involved patient and family education about heart failure and self-management and monthly telephone follow-up during 12 months by a primary health care nurse . RESULTS The effects of the nurse-led intervention were limited . Significant differences were found in the physical dimension measured by the SF-36 health survey , and in depression measured by the Zung Self-rating Depression Scale . In comparison within groups at the 3 and 12-month follow-up , the intervention group significantly maintained their health-related quality of life measured by the SF-36 health survey , and their experience of depression measured by the Zung Self-rating Depression Scale to a greater extent than in the control group , especially among women . CONCLUSION A nurse-led intervention directed toward patients with heart failure in a primary health care setting result ed in limited effects between the groups , although the physical and mental status were retained during 12 months of follow-up to a greater extent than in the control group Objective Anemia is a frequent comorbidity in chronic heart failure ( CHF ) adversely affecting patients ’ prognosis . Erythropoietin seems to improve exercise capacity in CHF patients . This study investigates the effects of recombinant human erythropoietin analog darbepoetin-α on quality of life and emotional stress , evaluated by relevant question naires in patients with CHF and anemia . Methods Forty-one CHF patients [ New York Heart Association class : II-III ; left ventricular ( LV ) ejection fraction ( EF ) ≤40 % ; hemoglobin < 12.5 g/dl ; serum creatinine < 2.5 mg/dl ] were r and omized ( 1:1 ) to receive either 3-month darbepoietin-α at 1.5 μg/Kg every 20 days plus iron orally ( n = 21 ) or placebo plus iron orally ( n = 20 ) . Echocardiographic LVEF , question naires addressing quality of life ( Kansas City Cardiomyopathy Question naire , functional and overall , Duke 's Activity Status Index ) and emotional stress [ Zung self-rating depression scale ( SDS ) , Beck Depression Inventory ] , as well as plasma b-type natriuretic peptide and 6-min walking distance ( 6MWT as a marker of exercise capacity ) were assessed at baseline and posttreatment . Results A significant improvement in LVEF ( 32 ± 6 from 26 ± 6 % , P < 0.001 ) , 6MWT ( 274 ± 97 from 201 ± 113 m , P < 0.01 ) , hemoglobin ( 12.8 ± 1.4 from 10.9 ± 1.0 g/dl , P < 0.001 ) and plasma b-type natriuretic peptide ( 517 ± 579 from 829 ± 858 pg/ml , P = 0.002 ) was observed posttreatment only in darbepoetin-treated group . Kansas City Cardiomyopathy Question naire functional ( 78 ± 14 from 57 ± 24 % , P < 0.01 ) and overall ( 68 ± 20 from 47 ± 22 , P < 0.001 ) , Duke 's Activity Status Index ( 19 ± 11 from 14 ± 9 , P < 0.05 ) , Zung SDS ( 38 ± 10 from 47 ± 11 , P < 0.05 ) and Beck Depression Inventory ( 11 ± 9 from 16 ± 10 , P < 0.05 ) scores also improved in darbepoetin-treated patients , whereas they remain unchanged in the placebo group except for the Zung SDS which worsened ( P≤0.05 ) . A significant correlation between drug-induced percent changes in 6MWT and Zung SDS ( r = –0.627 , P < 0.05 ) was also observed . Conclusions Darbepoetin-α improves quality of life and emotional stress in CHF patients with anemia , with a parallel increase in exercise capacity Background : Chronic heart failure ( CHF ) will become one of the greatest medical challenges during the next decades . This is especially true with regard to elderly patients . Besides medical diagnostics and drug therapy , efficient treatment of CHF must also include exercise training . Aims : The purpose of our study was 1 ) to record health-related quality of life ( QOL ) in elderly patients with CHF and 2 ) to assess the efficacy of a training program , as well as to evaluate any changes detected during a six month follow-up . Methods : In our non-r and omized study , 116 patients , divided according to age into Group 1 ( > 70 years ) and Group 2 ( < 70 years ) , took part in a 4-week training program . Results : There were differences in the clinical parameters and the QOL between the older and the younger patients both after 4 weeks and at the follow-up . After six months , however , the older patients again recorded having an inferior QOL to that of the younger patients . Conclusion : Elderly patients can also benefit from physical exercise training , with improvement in clinical parameters and QOL . In order to maintain the subjectively improved QOL in the long term , however , continued special heart failure education and support is required OBJECTIVES The purpose of this study was to assess whether depressive symptoms are independently associated with changes in heart failure (HF)-specific health status . BACKGROUND Depression is common in patients with HF , but the impact of depressive symptoms on the health status of these patients over time is unknown . METHODS We conducted a multicenter prospect i ve cohort study of out patients with HF . Data from 460 patients who completed a baseline Medical Outcomes Study -Depression Question naire and both a baseline and follow-up ( 6 + /- 2 weeks ) Kansas City Cardiomyopathy Question naire ( KCCQ ) were analyzed . The KCCQ measures HF-specific health status , including symptoms , physical and social function , and quality of life . Multivariable regression was used to evaluate depressive symptoms as a predictor of change in KCCQ scores , adjusting for baseline KCCQ scores and other patient variables . The primary outcome was change in KCCQ summary scores ( range 0 to 100 ; higher scores indicate better health status ; 5 points is a clinical ly meaningful change ) . RESULTS Approximately 30 % ( 139/460 ) of the patients had significant depressive symptoms at baseline . Depressed patients had markedly lower baseline KCCQ summary scores ( beta = -19.6 ; p < 0.001 ) . After adjustment for potential confounders , depressed patients were at risk for significant worsening of their HF symptoms , physical and social function , and quality of life ( average change in KCCQ summary score = -7.1 points ; p < 0.001 ) . Depressive symptoms were the strongest predictor of decline in health status in the multivariable models . CONCLUSIONS Depressive symptoms are a strong predictor of short-term worsening of HF-specific health status . The recognition and treatment of depression may be an important component of HF care Background : Heart failure ( HF ) has clinical ly significant psychological and physical consequences for older persons , and hospitalization for HF is frequent and costly to the Medicare program . As HF is the most common primary Medicare home care diagnosis , there is a critical need to develop home care services that improve heath-related outcomes for this population . The primary aim of this pilot study was to develop , implement , and test the initial feasibility and potential efficacy of the Home-Care Education , Assessment , Remote-Monitoring , and Therapeutic Activities ( HEART ) trial , a nurse-directed multicomponent home care intervention . Observed outcomes were quality of life ( QOL ) , depressive symptoms , and 90-day hospitalization . Methods : Twenty-four patients with a primary diagnosis of HF were assigned to the intervention ( n = 12 ) or control group ( n = 12 ) according to geographical location in a large multibranch Medicare-certified home health agency . Intervention group patients received 8 structured nurse education visits using evidence -based protocol s design ed in previous trials to teach HF self-management and to prevent/reduce depression , as well as a telemonitoring system . Control group patients received usual care and telemonitoring . Quality of life was assessed using the Minnesota Living With Heart Failure question naire . Depressive symptoms were assed using the Patient Health Question naire 9 at baseline and 90-day study end point . Results : Study protocol s and instrumentation were found to be feasible and effective . Examination of enrollment data led to a reevaluation of eligibility criteria . Patients participating in the HEART intervention demonstrated significantly improved QOL ( F = 8.99 , P = .007 ) and significantly reduced depressive symptoms ( F = 35.10 , P = .001 ) in comparison to control group patients at the study end point . There was a trend toward lower hospital readmission rates in the intervention group ( 16 % vs 25 % ) , but this was not statistically significant . Conclusion : This pilot study suggests that a full-scale trial of the HEART intervention is feasible BACKGROUND Disease management is effective in the general population , but it has not been tested prospect ively in a sample of solely Hispanics with heart failure ( HF ) . We tested the effectiveness of telephone case management in decreasing hospitalizations and improving health-related quality of life ( HRQL ) and depression in Hispanics of Mexican origin with HF . METHODS AND RESULTS Hospitalized Hispanics with chronic HF ( n = 134 ) were enrolled and r and omized to intervention ( n = 69 ) or usual care ( n = 65 ) . The sample was elderly ( 72 + /- 11 years ) , New York Heart Association class III/IV ( 81.3 % ) , and poorly educated ( 78.4 % less than high school education ) . Most ( 55 % ) were unacculturated into US society . Bilingual/bicultural Mexican-American registered nurses provided 6 months of st and ardized telephone case management . Data on hospitalizations were collected from automated systems at 1 , 3 , and 6 months after the index hospital discharge . Health-related quality of life and depression were measured by self-report at enrollment , 3 , and 6 months . Intention to treat analysis was used . No significant group differences were found in HF hospitalizations , the primary outcome variable ( usual care : 0.49 + /- 0.81 [ CI 0.25 - 0.73 ] ; intervention : 0.55 + /- 1.1 [ CI 0.32 - 0.78 ] at 6 months ) . No significant group differences were found in HF readmission rate , HF days in the hospital , HF cost of care , all-cause hospitalizations or cost , mortality , HRQL , or depression . CONCLUSION These results have important implication s because of the current widespread enthusiasm for disease management . Although disease management is effective in the mainstream HF patient population , in Hispanics this ill , elderly , and poorly educated , a different approach may be needed Decreased HRV has been consistently associated with increased cardiac mortality and morbidity in HF patients . The aim of this study is to determine if a 6-week course of heart rate variability ( HRV ) biofeedback and breathing retraining could increase exercise tolerance , HRV , and quality of life in patients with New York Heart Association Class I-III heart failure ( HF ) . Participants ( N = 29 ) were r and omly assigned to either the treatment group consisting of six sessions of breathing retraining , HRV biofeedback and daily practice , or the comparison group consisting of six sessions of quasi-false alpha-theta biofeedback and daily practice . Exercise tolerance , measured by the 6-min walk test ( 6MWT ) , HRV , measured by the st and ard deviation of normal of normal beats ( SDNN ) , and quality of life , measured by the Minnesota Living with Congestive Heart Failure Question naire , were measured baseline ( week 0 ) , post ( week 6 ) , and follow-up ( week 18 ) . Cardiorespiratory biofeedback significantly increased exercise tolerance ( p = .05 ) for the treatment group in the high ( ≥31 % ) left ventricular ejection fraction ( LVEF ) category between baseline and follow-up . Neither a significant difference in SDNN ( p = .09 ) nor quality of life ( p = .08 ) , was found between baseline and follow-up . A combination of HRV biofeedback and breathing retraining may improve exercise tolerance in patients with HF with an LVEF of 31 % or higher . Because exercise tolerance is considered a strong prognostic indicator , cardiorespiratory biofeedback has the potential to improve cardiac mortality and morbidity in HF patients Objective : To study the effect of Tai Chi on exercise tolerance in patients with moderate heart failure . Design : R and omised parallel group study balanced for baseline variables . Setting : Cardiology Department , Royal Hallamshire Hospital . Patients and methods : 52 patients 42 men , mean age 68.9 years , range 4690 years , and 10 women , mean age 70.0 years , range 5882 with chronic heart failure New York Heart Association symptom class IIIII were studied . Patients were r and omised to Tai Chi Chuan twice a week for 16 weeks or to st and ard medical care without exercise rehabilitation . Main outcome measures : The primary outcome measure was the change in the distance walked in the shuttle walk test . Secondary outcome measures were changes in symptom scores and quality of life indices . Results : Objective measures of exercise tolerance did not improve significantly with Tai Chi , but patients having Tai Chi exercise had an improvement in symptom scores of heart failure measured by the Minnesota Living with Heart Failure Question naire comparison of deltas , 2.4 control vs 14.9 ; p0.01 , and depression scores measured by the SCL-90-R question naire 2.9 vs 6.8 ; p0.12 compared with those patients in the control group . Conclusion : In patients with chronic heart failure , 16 weeks of Tai Chi training was safe , with no adverse exercise related problems . It was enjoyed by all taking part and led to significant improvements in symptoms and quality of life OBJECTIVES To explore associations between psychiatric comorbidity and rehospitalization risk , length of hospitalization , and costs . DESIGN Cross-sectional study of 1-year hospital administrative data . SETTING Cl aims -based study of older adults hospitalized in the United States . PARTICIPANTS Twenty-one thous and four hundred twenty-nine patients from a 5 % national r and om sample of U.S. Medicare beneficiaries aged 65 and older , with at least one acute care hospitalization in 1999 with a Diagnostic-Related Group of congestive heart failure . MEASUREMENTS The number of hospitalizations , mean length of hospital stay , and total hospitalization costs in calendar year 1999 . RESULTS Overall , 15.8 % of patients hospitalized for heart failure ( HF ) had a coded psychiatric comorbidity ; the most commonly coded comorbid psychiatric disorder was depression ( 8.5 % of the sample ) . Most forms of psychiatric comorbidity were associated with greater inpatient utilization , including risk of additional hospitalizations , days of stay , and hospitalization charges . Additional hospitalization costs associated with psychiatric comorbidity ranged up to $ 7,763 , and additional days length of stay ranged up to 1.4 days . CONCLUSION Psychiatric comorbidity appears in a significant minority of patients hospitalized for HF and may affect their clinical and economic outcomes . The associations between psychiatric comorbidity and use of inpatient care are likely to be an underestimate , because psychiatric illness is known to be underdetected in older adults and in hospitalized medical patients BACKGROUND Depression is frequently observed in patients with heart failure and is associated with poor quality of life and adverse prognosis . However , the prevalence of depression in heart failure could be overestimated because symptoms of depression overlap with those of heart failure . Similarly , the importance of depression may be overestimated if depression merely reflects worse heart failure . Because the response to depression treatment has not been evaluated in this patient population , we evaluated the efficacy of controlled-release paroxetine ( paroxetine CR ) , a selective serotonin reuptake inhibitor , on depression and quality of life in chronic heart failure . METHODS A double-blind , r and omized , placebo-controlled design was used to evaluate reductions in depression following 12 weeks of treatment with paroxetine CR ( n = 14 , age 62.1 + /- 12.3 years ) or placebo ( n = 14 , age = 61.9 + /- 9.0 years ) . Patients with symptomatic congestive heart failure and a score of at least 10 on the Beck Depression Inventory ( BDI ) were eligible . Beck Depression Inventory was obtained at baseline and 4 , 8 , and 12 weeks of follow-up . Quality of life was assessed using the Medical Outcomes Study Short Form and the Minnesota Living with Heart Failure Question naire . RESULTS Controlled-release paroxetine result ed in significantly more recovery from depression ( BDI < 10 ) than placebo ( 69 % vs 23 % , P = .018 ) and result ed in lower continuous BDI scores throughout the intervention ( P = .024 ) . Controlled-release paroxetine was associated with higher general health levels compared with placebo on the Medical Outcomes Study 36-Item Short Form survey ( 38 + /- 10 vs 30 + /- 6 , P = .016 ) at 12 weeks of follow-up . Reductions in depression were correlated with improvements in psychological aspects of quality of life ( P < .05 ) but not with physical quality of life measures ( P > .10 ) . CONCLUSION Antidepressant therapy with paroxetine CR results in significant reductions in depression among patients with heart failure . The reductions in depression with paroxetine CR are accompanied by improvements in psychological aspects of quality of life . Larger controlled trials are needed to further document the effectiveness of paroxetine CR and other selective serotonin reuptake inhibitors in patients with heart failure and to determine patient subgroups that are most likely to benefit from antidepressive interventions This study assessed the feasibility of a telephonic nurse double-disease management program ( DDMP ) for patients with depression and congestive heart failure . Thirty-five patients with depression and congestive heart failure were entered into a novel DDMP modeled after Wagner 's chronic illness care model and implemented as part of a 13-month Breakthrough Series Collaborative administered by the Institute of Healthcare Improvement . Twenty-four patients remained in the program long enough to complete at least one follow-up assessment ( ie , 6 weeks or longer ) . Patients were entered into the program based on depression severity scores from either the interactive voice response ( IVR ) version of the Hospital Anxiety and Depression Scale ( HADS ) or the self-administered ( or telephonic ) Patient Health Question naire ( PHQ ) . Because use of the IVR version of the HADS was eliminated after several weeks into the program ( because of poor patient acceptance ) , 19 patients had both entry and follow-up scores on the same instrument ( PHQ ) . Depression " response " was defined as a 50 % improvement in PHQ score . Mixed models regression was used to test the statistical significance of change in PHQ scores over time . Patient and clinician reports were obtained to evaluate program acceptability and satisfaction . Eighty-two percent of patients ( n = 11 ) with Major Depressive Disorder ( MDD ) responded , and 75 % of patients ( n = 8) with " other depression " ( PHQ score < 10 ) responded . Mean change in PHQ scores for the sample as a whole improved significantly over the 24 weeks of the program ( p < 0.0003 ) , as well as for those with major depression and other depression considered separately ( p < 0.01 for both ) . In some patients who refused medication , depression seemed to respond to self-management support interventions of the care manager . Based on patient acceptance and clinicians ' reports , the program appeared feasible and possibly effective . DDMP appears feasible and possibly effective . Future clinical trials are warranted BACKGROUND Although there are limited clinical data to support the use of exercise training as a means to reduce mortality and morbidity in patients with heart failure , current guidelines state that exercise is beneficial . TRIAL DESIGN The objective of this trial is to determine whether exercise training reduces all-cause mortality or all-cause hospitalization for patients with left ventricular systolic dysfunction and heart failure symptoms . After undergoing baseline assessment s to determine whether they can safely exercise , patients are r and omized to either usual care or exercise training . Patients in the exercise training arm attend 36 supervised facility-based exercise training sessions . Exercise modalities are cycling or walking . After completing 18 sessions , patients initiate home-based exercise and then transition to solely home-based exercise after completing all 36 sessions . Patients return for facility-based training every 3 months to reinforce their exercise training program . Patients are followed for up to 4 years . Physiologic , quality -of-life , and economic end points that characterize the effect of exercise training in this patient population will be measured at baseline and at intervals throughout the trial . Blood sample s will be collected to examine biomarkers such as brain natriuretic peptide , tumor necrosis factor , and C-reactive protein . CONCLUSIONS Because of its relatively low cost , high availability , and ease of use , exercise training is an intervention that could be accessible to most patients with heart failure . The HF-ACTION trial is design ed to definitively assess the effect of exercise training on the clinical ly relevant end points of mortality , hospitalization , and quality of life in patients with heart failure BACKGROUND Due to dyspnea and fatigue , patients with chronic heart failure ( CHF ) are often restricted in the performance of everyday activities , which gradually may lead to hypoactivity . AIMS To assess whether aerobic training leads to a more active lifestyle and improved quality of life ( QoL ) in patients with CHF . METHODS Patients with stable CHF ( NYHA II/III ; 59 ( 11 ) years ) were r and omly assigned to a training group ( n=18 ; 3-month aerobic program above st and ard treatment ) or control group ( n=16 ; st and ard treatment without special advice for exercise ) . Measurements were performed on level of everyday physical activity ( PA , novel accelerometry-based activity monitor ) and QoL , and on several related parameters . RESULTS Training did not result in a more active lifestyle or improved QoL , but improved ( P<0.05 ) peak power ( 17 % ) , 6-min walk distance ( 10 % ) , muscle strength ( 13 - 15 % ) and depression ( -1.3 unit ) . Changes in level of everyday PA were related to changes in peak Vo(2 ) ( r=0.58 , P=0.01 ) and knee extension strength ( r=0.48 , P=0.05 ) . CONCLUSIONS At group level training did not result in a more active lifestyle or improved QoL. However , correlations between training-related changes in parameters suggest that aerobic training has the potential to increase levels of everyday PA in CHF OBJECTIVE To assess the physiological and psychosocial effects of exercise training in chronic heart failure . SUBJECTS/ PATIENTS Twenty-six men with heart failure ( New York Heart Association functional classes II and III ) aged 52.5 ( SD 9.8 ) years , were studied . METHODS The subjects were r and omized either to rehabilitation group ( Group A : 16 patients ) , participating in a 6-month exercise training program , or to control group ( Group B : 10 patients ) . A psychosocial assessment , which included affective ( Beck Depression Inventory and Hospital Anxiety and Depression Scale ) , quality of life ( Quality of Life Index , Minnesota Living with Heart Failure Question naire and the Scale of Life Satisfaction ) and personality ( Eysenck Personality Question naire ) parameters , was performed at the beginning and the end of the study . RESULTS After training VO2 peak increased by 36 % and exercise time by 35 % , p < 0.05 . A significant decrease in anxiety and depression was also observed . Moreover , trained patients demonstrated a significant improvement in quality of life . No significant correlations were found between deltaVO2 peak and all psychosocial parameter gains . However , the more depressed patients showed the largest physiological responses . CONCLUSION An exercise rehabilitation program in patients with chronic heart failure is useful for improving their work capacity and psychosocial status . Improvements in psychological status seem to be independent of the aerobic gains Depression is common in patients with heart failure ( HF ) , prognostic for adverse outcomes and purportedly related to disease severity . Psychological and physiologic factors relevant to HF were assessed in HF-ACTION , a large r and omized study of aerobic exercise training in patients with systolic HF . The relation of objective and subjective parameters was compared with scores on the Beck Depression Inventory ( BDI ) to examine the hypothesis that depressive symptoms are better associated with perception of disease severity than with objective markers of HF severity . At baseline , 2,322 of 2,331 subjects entered into HF-ACTION completed question naires to assess depression ( BDI ) and quality of life ( Kansas City Cardiomyopathy Question naire [ KCCQ ] ) . Objective markers of HF severity included ejection fraction , B-type natriuretic peptide , and peak oxygen consumption ( using cardiopulmonary exercise testing , with evaluation of duration and respiratory exchange ratio also performed ) . Measures more likely to be affected by perceived functional status included New York Heart Association ( NYHA ) classification and the 6-minute walk test . Objective assessment s of disease severity were slightly related ( peak oxygen consumption ) or not related ( B-type natriuretic peptide and ejection fraction ) to BDI scores . Using multivariate analysis ( KCCQ not included ) , only age , gender , cardiopulmonary exercise testing duration , NYHA class , 6-minute walk distance , and peak respiratory exchange ratio independently correlated with BDI scores . In conclusion , depression was minimally related to objective assessment s of severity of disease in patients with HF , but was associated with patient ( and clinician ) perceptions of disease severity . Addressing depression might improve symptoms in patients with HF CONTEXT Findings from previous studies of the effects of exercise training on patient-reported health status have been inconsistent . OBJECTIVE To test the effects of exercise training on health status among patients with heart failure . DESIGN , SETTING , AND PATIENTS Multicenter , r and omized controlled trial among 2331 medically stable out patients with heart failure with left ventricular ejection fraction of 35 % or less . Patients were r and omized from April 2003 through February 2007 . INTERVENTIONS Usual care plus aerobic exercise training ( n = 1172 ) , consisting of 36 supervised sessions followed by home-based training , vs usual care alone ( n = 1159 ) . R and omization was stratified by heart failure etiology , which was a covariate in all models . MAIN OUTCOME MEASURES Kansas City Cardiomyopathy Question naire ( KCCQ ) overall summary scale and key subscales at baseline , every 3 months for 12 months , and annually thereafter for up to 4 years . The KCCQ is scored from 0 to 100 with higher scores corresponding to better health status . Treatment group effects were estimated using linear mixed models according to the intention-to-treat principle . RESULTS Median follow-up was 2.5 years . At 3 months , usual care plus exercise training led to greater improvement in the KCCQ overall summary score ( mean , 5.21 ; 95 % confidence interval , 4.42 to 6.00 ) compared with usual care alone ( 3.28 ; 95 % confidence interval , 2.48 to 4.09 ) . The additional 1.93-point increase ( 95 % confidence interval , 0.84 to 3.01 ) in the exercise training group was statistically significant ( P < .001 ) . After 3 months , there were no further significant changes in KCCQ score for either group ( P = .85 for the difference between slopes ) , result ing in a sustained , greater improvement overall for the exercise group ( P < .001 ) . Results were similar on the KCCQ subscales , and no subgroup interactions were detected . CONCLUSIONS Exercise training conferred modest but statistically significant improvements in self-reported health status compared with usual care without training . Improvements occurred early and persisted over time . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00047437 OBJECTIVE To assess whether language of publication restrictions impact the estimates of an intervention 's effectiveness , whether such impact is similar for conventional medicine and complementary medicine interventions , and whether the results are influenced by publication bias and statistical heterogeneity . STUDY DESIGN AND SETTING We set out to examine the extent to which including reports of r and omized controlled trials ( RCTs ) in language s other than English ( LOE ) influences the results of systematic review s , using a broad data set of 42 language -inclusive systematic review s , involving 662 RCTs , including both conventional medicine ( CM ) and complementary and alternative medicine ( CAM ) interventions . RESULTS For CM interventions , language -restricted systematic review s , compared with language -inclusive ones , did not introduce biased results , in terms of estimates of intervention effectiveness ( r and om effects ration of odds rations ROR=1.02 ; 95 % CI=0.83 - 1.26 ) . For CAM interventions , however , language -restricted systematic review s result ed in a 63 % smaller protective effect estimate than language -inclusive review s ( r and om effects ROR=1.63 ; 95 % CI=1.03 - 2.60 ) . CONCLUSION Language restrictions do not change the results of CM systematic review s but do substantially alter the results of CAM systematic review s. These findings are robust even after sensitivity analyses , and do not appear to be influenced by statistical heterogeneity and publication bias Background : Effective management of heart failure relies on optimal use of non-pharmacological therapy alongside medical treatment . Yet , there is an inadequate use of non-pharmacological therapy in caring for older people with heart failure . Objective : To examine the effects of relaxation therapy and exercise training on psychological outcomes and disease-specific quality of life of older heart failure patients . Methods : Subjects undertook relaxation ( n = 59 ) , exercise training ( n = 32 ) or received attention placebo ( n = 62 ) for 12 weeks . The relaxation group attended two training sessions , one revision workshop , and continued with twice-daily taped-directed home relaxation practice , with support from the intervener through bi-weekly telephone contact , for 12 weeks . The exercise group undertook 12 weekly sessions of resistance training and aerobic exercise and thrice weekly home exercise . The control group received regular telephone calls for general ‘ greetings ’ . Results : The relaxation and exercise groups reported a significantly greater improvement in psychological [ F(2 , 149 ) = 6.69 , p = 0.002 ] and various disease-specific quality of life outcomes [ dyspnea : F(2 , 149 ) = 5.72 , p = 0.004 ; fatigue : F(2 , 149 ) = 3.78 , p = 0.25 ; emotion : F(2 , 149 ) = 6.68 , p = 0.001 ] , compared with those who received the attention placebo . While relaxation therapy was more effective to reduce psychological distress , with depression in particular ( p < 0.001 ) , exercise therapy worked better to control fatigue symptoms ( p = 0.03 ) . Conclusion : Relaxation therapy and exercise training are effective to improve the psychological and physical health of older heart failure patients . They should be used as an individual treatment modality , or as care components of a disease management program BACKGROUND Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease . Although darbepoetin alfa can effectively increase hemoglobin levels , its effect on clinical outcomes in these patients has not been adequately tested . METHODS In this study involving 4038 patients with diabetes , chronic kidney disease , and anemia , we r and omly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo , with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter . The primary end points were the composite outcomes of death or a cardiovascular event ( nonfatal myocardial infa rct ion , congestive heart failure , stroke , or hospitalization for myocardial ischemia ) and of death or end-stage renal disease . RESULTS Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo ( hazard ratio for darbepoetin alfa vs. placebo , 1.05 ; 95 % confidence interval [ CI ] , 0.94 to 1.17 ; P=0.41 ) . Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo ( hazard ratio , 1.06 ; 95 % CI , 0.95 to 1.19 ; P=0.29 ) . Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo ( hazard ratio , 1.92 ; 95 % CI , 1.38 to 2.68 ; P<0.001 ) . Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo ( P<0.001 ) . There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group . CONCLUSIONS The use of darbepoetin alfa in patients with diabetes , chronic kidney disease , and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes ( either death or a cardiovascular event or death or a renal event ) and was associated with an increased risk of stroke . For many persons involved in clinical decision making , this risk will outweigh the potential benefits . ( Clinical Trials.gov number , NCT00093015 . 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 |
1,998 | 24,129,886 | AUTHORS ' CONCLUSIONS We found low- to moderate- quality evidence that behavioural therapies and other psychological therapies are equally effective . | BACKGROUND Behavioural therapies represent one of several categories of psychological therapies that are currently used in the treatment of depression .
However , the effectiveness and acceptability of behavioural therapies for depression compared with other psychological therapies remain unclear .
OBJECTIVES 1 .
To examine the effects of all BT approaches compared with all other psychological therapy approaches for acute depression.2 .
To examine the effects of different BT approaches ( behavioural therapy , behavioural activation , social skills training and relaxation training ) compared with all other psychological therapy approaches for acute depression.3 .
To examine the effects of all BT approaches compared with different psychological therapy approaches ( CBT , third wave CBT , psychodynamic , humanistic and integrative psychological therapies ) for acute depression . | Outcomes of seven treatment trials comparing cognitive behavioral therapy to treatment with tricyclic antidepressant medication in major depressive disorder have been quite similar to one another . This led us to question whether treatment outcome in time-limited studies reflected a unique effect of cognitive behavioral therapy . To test the uniqueness hypothesis , relaxation training , a nonpharmacologic , noncognitive treatment , was chosen as a comparison for cognitive behavioral therapy as well as drug therapy . Treatment duration was 16 weeks . The sample of 37 patients treated for major depressive disorder was less depressed than those previously studied . For both cognitive behavioral therapy and relaxation training , outcome of depression was superior to that of tricyclic antidepressant medication by endpoint analysis . The posttreatment scores on the Beck Depression Inventory of 82 % of the group receiving cognitive behavioral therapy improved to a Beck Depression Inventory score ≤9 which was not significantly greater than that for the group receiving relaxation training.(73 % ) , so a unique effect was not demonstrated for cognitive behavioral therapy . The outcome for tricyclic antidepressant medication ( 29 % improved to criteria ) was significantly worse than that for cognitive behavioral therapy . The patient 's pretreatment initial expectancy was not predictive 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 Psychotherapy 's equivalence paradox is that treatments tend to have equivalently positive outcomes despite non-equivalent theories and techniques . We replicated an earlier comparison of treatment approaches in a sample four times larger and restricted to primary -care mental health . METHOD Patients ( n=5613 ) who received cognitive-behavioural therapy ( CBT ) , person-centred therapy ( PCT ) or psychodynamic therapy ( PDT ) at one of 32 NHS primary -care services during a 3-year period ( 2002 - 2005 ) completed the Clinical Outcomes in Routine Evaluation - Outcome Measure ( CORE-OM ) at the beginning and end of treatment . Therapists indicated which approaches were used on an End of Therapy form . We compared outcomes of groups treated with CBT ( n=1045 ) , PCT ( n=1709 ) , or PDT ( n=261 ) only or with one of these plus one additional approach ( e.g. integrative , supportive , art ) , design ated CBT+1 ( n=1035 ) , PCT+1 ( n=1033 ) , or PDT+1 ( n=530 ) , respectively . RESULTS All six groups began treatment with equivalent CORE-OM scores , and all averaged marked improvement ( overall pre/post effect size=1.39 ) . Neither treatment approach nor degree of purity ( ' only ' v. ' + 1 ' ) had a statistically significant effect . Distributions of change scores were all similar . CONCLUSIONS Replicating the earlier results , the theoretically different approaches tended to have equivalent outcomes . Caution is warranted because of limited treatment specification , non-r and om assignment , incomplete data , and other issues . Insofar as these routine treatments appear effective for patients who complete them , those who fail to complete ( or to begin ) treatment deserve attention by research ers and policymakers In a study design ed to maximize the effectiveness of treatment by allowing participants to select the target of treatment , 40 depressed older adults were r and omly assigned to a waiting-list control condition or to conditions in which the target of treatment was either chosen or assigned . All participants received self-management therapy and the choice was between changing behavior or changing cognition . It was found that individually administered self-management therapy was effective in treating depression for older adults . There were no differences in outcome between versions of self-management therapy that targeted behavioral or cognitive change . Among those who completed treatment , there were no differences in outcome between those who received a choice and those who did not . Individuals who were given a choice of treatment options , however , were less likely to drop out of treatment prematurely BACKGROUND cognitive impairment is an important part of the diagnostic criteria for dementia . The Mini-Mental State Examination ( MMSE ) is recommended to test for cognitive impairment and to monitor medication response . OBJECTIVES we examined the prevalence of cognitive impairment in the UK and assessed associations with cognitive impairment . DESIGN cross-sectional survey as part of a cluster r and omised trial . SUBJECTS representative sample of people aged 75 years and over . METHODS all subjects had a detailed baseline health assessment including the MMSE . RESULTS a total of 15,051 subjects completed the assessment ( 71.9 % ) . Almost two-thirds of subjects were female ( 61.5 % ) and almost half were aged between 75 and 79 years ( 47.0 % ) . The prevalence of cognitive impairment was 18.3 % ( 95 % confidence intervals ( CI ) = 16.0 - 20.9 ) at a cut-off of 23/24 , and 3.3 % ( 95 % CI = 2.8 - 4.0 ) at 17/18 . Those with impairment ( MMSE 23/24 ) were significantly more likely to have hearing ( odds ratio ( OR ) 1.7 ) , vision ( OR 1.7 ) and urinary incontinence problems ( OR 1.3 ) , have two or more falls in the previous 6 months ( OR 1.4 ) , and report poorer health ( OR 1.9 ) . Almost half the participants lived alone ( n = 7,073 ; 47.0 % ) and of these almost one-fifth were impaired ( MMSE 23/24 ; 19.4 % ) . CONCLUSIONS there was a high prevalence of cognitive impairment . This representative sample demonstrates the potential burden of disease and service dem and s. It supports the need for a broader assessment of functioning as recommended by the National Service Framework for Older People , particularly in people with cognitive impairment OBJECTIVE Different studies show the negative effects on caregivers ' health of maladaptive thoughts and the positive effects of engaging in pleasurable activities on distress . The aim of this study is to ( a ) test the efficacy of a cognitive-behavioral intervention aim ed at training caregivers to flexibilize maladaptive thoughts regarding caregiving and increasing their leisure activities and to ( b ) analyse the mediator role in the effects of the intervention of caregivers ' change in dysfunctional thoughts and behavioral activation . METHODS A total of 170 caregivers were contacted and r and omly distributed to the intervention condition or to the control group . Depression , behavioral activation , and dysfunctional thoughts were assessed at baseline and post-intervention by ' blinded ' interviewers . The intervention consisted in twelve group based sessions in which in addition to cognitive-behavioral techniques , caregivers ' were trained in basic principles for caring for a relative with dementia . RESULTS Significant intervention by time effects were found for depression , dysfunctional thoughts and frequency of leisure activities . Only significant positive effects were found for the intervention group . The regression analysis for testing mediational effects of dysfunctional thoughts and leisure activities on the relationship between participating on the intervention and changes in depressive symptomatology show that mediation is established in both cases . CONCLUSIONS The results of our study contribute to the literature on interventions for dementia caregivers highlighting the positive mediator effect that modifying caregivers ' dysfunctional thoughts and increasing their behavioral activation has on caregivers ' depressive symptomatology Older adults who met criteria for major depressive disorder were r and omly assigned to behavioral , cognitive , or brief dynamic therapy . Symptoms were equally reduced across the three treatment conditions . Early in treatment , alliance ratings were obtained from both therapists and patients and were related to outcome . We calculated one therapist alliance composite score and five patient alliance factor scores . In general , no agreement was found between therapists ' and patients ' judgments of alliance . Levels of alliance were found to be not significantly different across the three treatment conditions . For the sample as a whole , only the patient factor of Patient Commitment was found to be associated with depressive symptoms after treatment , with the strongest findings in the cognitive therapy condition . The Patient Commitment factor uniquely contributed to outcome over and above the contribution of initial symptomatology and symptomatic change at midpoint in therapy . Expected trends of association with outcome were observed for the therapist alliance composite score in brief dynamic therapy and for the patient factor of Patient Working Capacity in both cognitive and brief dynamic therapy . Findings are discussed in terms of their theoretical and clinical implication OBJECTIVES To describe the patterns of self-reported medication use , including both prescription and non-prescription drugs , for older people in five areas in Engl and and Wales , and to identify the effects of socio-demographic features on medication use . DESIGN A cross-sectional survey on population r and om sample s of people aged 65 and over . The survey is a part of the screening interviews at the first stage of the Medical Research Council Cognitive Function and Ageing Study ( MRC CFAS ) carried out between 1991 and 1994 . The sample was stratified to provide equal numbers in the 65 - 74 years and 75 years and over age groups . SETTING Three urban ( Newcastle , Nottingham and Oxford ) and two rural ( Cambridgeshire and Gwynedd ) centres . Older people living in both the general community and institutions were included . PARTICIPANTS 12489 older people whose medication data were collected among the 13009 participants of the CFAS , of which the participation rate is 80 % . RESULTS Overall prevalence of medication use was 75 % ( 95 % confidence interval 74 - 76 % ) for people aged 65 - 74 and 84 % ( 83 - 85 % ) for people aged 75 and over , with a mean number of 2.03 ( st and ard deviation 1.95 ) and 2.47 ( 2.02 ) drugs reported per respondent in each group , respectively . Concurrent use of five or more drugs ( polypharmacy ) was found in 11 % ( 10 - 12 % ) of people in the 65 - 74 age group and in 15 % ( 14 - 16 % ) in the 75 and over age group . People aged 75 and over were more likely to be taking at least one drug than people aged 65 - 74 ( OR=1.69 , 1.54 - 1.85 ) , and women were more likely to be so compared with men ( OR=1.43 , 1.30 - 1.56 ) . Centre variation was found but none of the centres consistently showed higher or lower usage of medications across the major drug categories . People living in institutions were more likely to be taking gastrointestinal drugs , central nervous system drugs and experience polypharmacy . The use of respiratory and central nervous system drugs ( except hypnotics and anxiolytics ) increased in lower social class and decreased in people attending full-time education for 10 years or more . The use of haematology/dietetic drugs ( 85 % of which were vitamin and mineral preparations ) decreased in lower social class . CONCLUSION This study provides representative estimates of medication usage among older people in Engl and and Wales and identified associated factors and regional variations for medication use in a category-specific manner . The findings , suggesting the existence of centre variation and the association between type of accommodation , social class and medication use warrant further investigation Cross-sectional and longitudinal data are presented from a 2-year follow-up study of 91 older adults , initially diagnosed as in an episode of major depressive disorder ( MDD ) , who were treated with brief cognitive , behavioral , or psychodynamic psychotherapy . Using research diagnostic criteria ( RDC ) , 52 % , 58 % , and 70 % of the sample did not meet criteria for any RDC depressive disorder at posttherapy , and 12- and 24-month follow-ups , respectively . There were no significant differences in response rate by therapy modality . Using Longitudinal Interval Follow-up Evaluation ( LIFE ; Shapiro & Keller , 1979 ; Keller et al. , 1987 ) methodology , we noted that patients not depressed at posttreatment remained depression-free for longer time periods than those who were minor or MDD . These rates compare favorably with published reports on younger depressed patients OBJECTIVE Clinical guidelines recommend that antidepressant treatment should be continued for a minimum of 6 months following response in depression and anxiety disorders . However , adherence to antidepressants is low . This prospect i ve cohort study investigated the influence of patients ' antidepressant concerns , treatment preferences , and illness perceptions on adherence to antidepressants over a 6-month period . METHOD A cohort of 178 patients aged 18 to 74 years and newly issued with a prescription for antidepressants to treat any condition was followed up prospect ively at 5 primary care practice s in Southeast Engl and . Adherence was measured through self-report and prescription refill data . Patient perceptions were quantified using vali date d outcome measures , the Beliefs about Medicine Question naire and the Illness Perception Question naire , at 4 timepoints . Patient treatment preferences were recorded using a specially design ed question naire . Data collection took place between September 2000 and May 2002 . RESULTS Of 147 participants ( 83 % ) who completed the study , 19 % persisted with antidepressants in accordance with guideline recommendations throughout the 6-month period . Specific concern about antidepressant side effects ( OR = 3.30 , 95 % CI = 2.20 to 4.97 ) and general worry about taking antidepressants ( OR = 1.65 , 95 % CI = 1.13 to 2.40 ) were independent predictors of antidepressant nonuse . Preference for different treatment/uncertainty about preferred treatment was also a strong predictor ( OR = 3.82 , 95 % CI = 1.35 to 10.77 ) . However , illness perceptions were not associated with adherence . CONCLUSIONS Concerns about antidepressants and a mismatch between patients ' preferred and prescribed treatment act as significant barriers to sustained adherence . This study highlights the central role of the patient-physician partnership in exploring antidepressant concerns , working with treatment preferences , and providing supportive continued management . The findings may inform the development of interventions within primary care programs to enhance commitment to treatment for common mental disorders Abstract People who have recovered from an episode of clinical depression have an elevated risk for developing a new episode of depression compared with those not previously depressed . One possible explanation for this finding is that depression may leave ‘ scars’—enduring psychological changes result ing from depression . This hypothesis was examined for a set of interpersonal variables which measured self-perceptions , behavior observed in dyadic and group interactions , and ratings by peers and coders based on those interactions . The ‘ scar ’ pattern was defined as a deficit observed during depression which remained after the depressive episode ended . Data for 21 patients who improved during psychotherapy , 20 patients who did not improve , and 80 nondepressed participants were examined . No variables fit the ‘ scar ’ pattern . Seven variables were identified as concomitants of depression . Nine variables provided predictive information , in that patients who subsequently improved in treatment significantly differed at pre-test from patients who subsequently failed to improve . The failure to support the scar hypothesis is discussed , along with alternative explanation for the higher risk for a new depressive episode seen in the previously depressed . The importance of the finding that some measures of interpersonal behavior predict response to treatment is also discussed The authors contrasted four treatments for unipolar ( nonpsychotic ) depression : 1 ) amitriptyline , 2 ) social skills training plus amitriptyline , 3 ) social skills training plus placebo , and 4 ) psychotherapy plus placebo . They studied 72 female out patients , 52 of whom completed the 12 weeks of treatment . The four treatments , conducted by experienced clinicians , were not substantially different from one another . Each treatment produced significant and clinical ly meaningful changes in symptomatology and social functioning . However , the authors identified several notable differences across groups : a significant difference in dropout rates ( from a high of 55.6 % for the amitriptyline group to a low of 15 % for the social skills plus placebo group ) and a significant difference in the proportion of patients who were substantially improved . The social skills plus placebo treatment was the most effective treatment on this dimension Work in 1985 by Simons , Lustman , Wetzel , and Murphy showed that a patient 's score on Rosenbaum 's self-control scale predicted differential response to treatments for depression , with a high score predicting a good outcome with talking therapy and a low score a good outcome with drug therapy . This study of 37 patients did not replicate those findings . Using the same paradigm , we predicted response correctly 7 times and incorrectly 16 times , a clear failure . A valid method for choosing the best treatment for a patient with major depression remains to be found The brief behavioral activation treatment for depression ( BATD ) is a relatively uncomplicated , time-efficient , and cost-effective method for treating depression . Because of these features , BATD may represent a practical intervention within managed care-driven , inpatient psychiatric hospitals . Based on basic behavioral theory and empirical evidence supporting activation strategies , we design ed a treatment to increase systematic ally exposure to positive activities and thereby help to alleviate depressive affect . This study represents a pilot study that extends research on this treatment into the context of an inpatient psychiatric unit . Results demonstrate effectiveness and superiority of BATD as compared with the st and ard supportive treatment provided within the hospital . A large effect size was demonstrated , despite a limited sample size . The authors discuss the limitations of the study and future directions Antidepressant medication is considered the current st and ard for severe depression , and cognitive therapy is the most widely investigated psychosocial treatment for depression . However , not all patients want to take medication , and cognitive therapy has not demonstrated consistent efficacy across trials . Moreover , dismantling design s have suggested that behavioral components may account for the efficacy of cognitive therapy . The present study tested the efficacy of behavioral activation by comparing it with cognitive therapy and antidepressant medication in a r and omized placebo-controlled design in adults with major depressive disorder ( N = 241 ) . In addition , it examined the importance of initial severity as a moderator of treatment outcome . Among more severely depressed patients , behavioral activation was comparable to antidepressant medication , and both significantly outperformed cognitive therapy . The implication s of these findings for the evaluation of current treatment guidelines and dissemination are discussed BACKGROUND The age of onset of major depression may produce divergent profiles of recovery after treatment . METHODS Symptom level and course trajectories of with early- and adult-onset of major depression were followed prospect ively over 2 years in 62 adult out patients who recovered from DSM-III-R unipolar major depression after cognitive behavior therapy . We compared individuals with depression onset before age 20 ( n = 31 ) with those with onset after age 20 ( n = 31 ) , controlling for current age , education , and history of depression , and accounting for their return to mental health treatment . Participants completed psychiatric and psychosocial assessment s before and after treatment , and every 6 months for 2 years post-treatment . We analyzed severity and changes of weekly depressive symptoms to construct profiles of recovery for the early- and adult-onset groups . RESULTS Our data indicated : ( a ) on average , the early-onset group experienced consistently more depressive symptoms than the adult-onset group ; ( b ) the pattern of symptoms remained level for both groups during the 2-year follow-up ; ( c ) both groups maintained parallel and stable course profiles over the 2-year follow-up ; and , ( d ) early age of onset was associated with higher rate of depressive relapse . LIMITATIONS Accuracy of the ratings of depressive symptoms may have been limited by the retrospective nature of the psychiatric status ratings . CONCLUSIONS Results suggest that among our recovered participants , early age of onset is associated with shorter time to relapse , more residual symptoms over the follow-up , and a stable and linear course of residual symptoms during the 2-year follow-up This was a non-analogue study of the effects of assertion training on depression . Twenty-six moderately depressed females ( X = 21.3 years ) were assigned r and omly to assertion training or delay-control groups . Results partially supported the effectiveness of treatment . Experimental Ss became significantly more assertive and engaged in significantly more activities than controls , and effects of treatment continued after treatment ended . Eight weeks after treatment , the experimental Ss ' scores indicated significantly less depression than at posttesting . Both experimental Ss and delya controls reported a significant decrease in depression from pre- to posttest . The two groups were not significantly different in reported depression at posttesting . Other findings included : ( 1 ) significant negative correlations between measures of depression and assertiveness ; ( 2 ) no significant interactions between S type ( client and volunteer ) and outcome ; and ( 3 ) no significant interactions between length of time depressed and outcome This study presents 2-year follow-up data of a comparison between complete cognitive-behavioral therapy for depression ( CT ) and its 2 major components : behavioral activation and behavioral activation with automatic thought modification . Data are reported on 137 participants who were r and omly assigned to 1 of these 3 treatments for up to 20 sessions with experienced cognitive-behavioral therapists . Long-term effects of the therapy were evaluated through relapse rates , number of asymptomatic or minimally symptomatic weeks , and survival times at 6- , 12- , 18- , and 24-month follow-ups . CT was no more effective than its components in preventing relapse . Both clinical and theoretical implication s of these findings are discussed |
1,999 | 28,779,802 | In 2017 , it is not clear if an anterolateral ligament reconstruction is needed in the setting of primary anterior cruciate ligament reconstruction | null | null |
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