Unclear Allocation Concealment Research Articles

Platelet-Rich Plasma Injections Were Not Better Than Hyaluronic Acid Injections for Knee Joint Degeneration.

Filardo G, Di Matteo B, Di Martino A, Merli ML, Cenacchi A, Fornasari P, Marcacci M, Kon E. Platelet-rich plasma intra-articular knee injections show no superiority versus viscosupplementation: a randomized controlled trial. Am J Sports Med. 2015 Jul;43(7):1575-82. ### Question: In patients with knee joint degeneration, how do injections of platelet-rich plasma (PRP) compare with those of hyaluronic acid (HA)? ### Design: Randomized (unclear allocation concealment), blinded (patients and outcome assessors), controlled trial with 12 months of follow-up. ### Setting: A specialized referral center for orthopaedics in Bologna, Italy. ### Patients: 192 patients with chronic knee pain lasting ≤4 months or swelling and imaging findings of cartilage degeneration indicating chondropathy or osteoarthritis. Exclusion criteria were an age 3, major axial deviation, focal chondral or osteochondral lesion, concomitant knee lesion causing pain or swelling, inflammatory arthropathy, hematological or severe cardiovascular diseases, infection, immunodepression, treatment with anticoagulants or nonsteroidal anti-inflammatory drugs, or decreased hemoglobin or platelet counts. 183 patients (mean age, 55 years; 61% men) completed follow-up. ### Intervention: Patients were allocated …

Transperitoneal versus retroperitoneal approach for elective open abdominal aortic aneurysm repair.

There has been extensive debate in the surgical literature regarding the optimum surgical access approach to the infrarenal abdominal aorta during an operation to repair an abdominal aortic aneurysm. The published trials comparing retroperitoneal (RP) and transperitoneal (TP) aortic surgery show conflicting results. To assess the effectiveness and safety of the transperitoneal versus retroperitoneal approach for elective open abdominal aortic aneurysm repair on mortality, complications, hospital stay and blood loss. The Cochrane Vascular Trials Search Co-ordinator searched the Cochrane Vascular Specialised Register (last searched May 2015) and CENTRAL (2015, Issue 4) and trials databases (May 2015). The review authors searched the Chinese Biomedical Literature Database and other resources including clinical trials registers. We included randomized controlled trials (RCTs) that assessed the TP approach versus the RP approach for elective open abdominal aortic aneurysm (AAA) repair. We evaluated the outcomes of mortality, complications, intensive care unit (ICU) stay, hospital stay, blood loss, aortic cross-clamp time and operating time. Two review authors independently selected RCTs against the inclusion criteria. We resolved any disagreements by discussion with a third review author. Two review authors independently extracted data from the included trials. We resolved any disagreements by discussion with a third review author. Two review authors independently assessed the risk of bias according to a standard quality checklist provided by Cochrane Vascular. We included four RCTs, with a combined total of 129 participants, that assessed the TP approach versus the RP approach for elective open AAA repair. The overall quality of the evidence was low to very low because of the low methodological quality of the included trials (unclear random sequence generation method and allocation concealment, and no blinding of outcome assessors), small sample sizes, small number of events, high heterogeneity and inconsistency between the included trials, no power calculations and relatively short follow-up. There were no differences between the RP approach and the TP approach regarding mortality (odds ratio (OR) 0.32, 95% CI 0.01 to 8.25; 110 participants; four trials; P = 0.49; I² statistic = 0%; very low quality evidence). However, the RP approach may increase complications, such as hematoma (OR 0.90, 95% CI 0.13 to 6.48; 75 participants; two trials; P = 0.92; very low quality evidence), chronic wound pain (OR 2.20, 95% CI 0.36 to 13.34; 48 participants; one trial; P = 0.39; very low quality evidence) and abdominal wall hernia (OR 10.76, 95% CI 0.55 to 211.78; 48 participants; one trial; P = 0.12; very low quality evidence) compared with the TP approach in the patients for elective open AAA repair, but the confidence intervals (CIs) were wide. The RP approach reduced the blood loss (mean difference (MD) -504.87 mL, 95% CI -779.19 to -230.56; 129 participants; four trials; P = 0.003; very low quality evidence), ICU stay (MD -19.00 hours, 95% CI -31.41 to -6.59; 83 participants; two trials; P = 0.003; low quality evidence) and hospital stay (MD -3.14 days, 95% CI -4.82 to -1.45; 129 participants; four trials; P = 0.0003; low quality evidence). There were no differences between the RP approach and the TP approach regarding aortic cross-clamp time (MD 0.69 mins, 95% CI -7.23 to 8.60; 129 participants; four trials; P = 0.86; very low quality evidence) and operating time (MD -15.94 mins, 95% CI -34.76 to 2.88; 129 participants; four trials; P = 0.10; very low quality evidence). Very low quality evidence from four small RCTs indicates that the RP approach did not have advantages over the TP approach for elective open AAA repair in terms of mortality. Moreover, the RP approach may increase the risk of postoperative wound complications although the CIs were wide.Low quality evidence shows that the RP approach could reduce blood loss, hospital stay and ICU stay compared with the TP approach. Very low quality evidence shows no differences between the RP approach and TP approaches in aortic cross-clamp time and operating time.Further large-scale RCTs of the RP approach versus TP approach for elective open AAA repair are required.

Antenatal dietary supplementation with myo-inositol in women during pregnancy for preventing gestational diabetes.

Antenatal dietary supplementation with myo-inositol in women during pregnancy for preventing gestational diabetes.

Fornix-based versus limbal-based conjunctival trabeculectomy flaps for glaucoma.

Fornix-based versus limbal-based conjunctival trabeculectomy flaps for glaucoma.

Peribulbar versus retrobulbar anaesthesia for cataract surgery.

Cataract is a major cause of blindness worldwide. Unless medically contraindicated, cataract surgery is usually performed under local (regional) anaesthesia. Local anaesthesia involves the blockage of a nerve subserving a given part of the body. It involves infiltration of the area around the nerve with local anaesthetic. The two main approaches in the eye are retrobulbar and peribulbar. There is debate over whether the peribulbar approach provides more effective, safer anaesthesia for cataract surgery than retrobulbar block. The objective of this review was to assess the effects of peribulbar anaesthesia (PB) compared to retrobulbar anaesthesia (RB) on pain scores, ocular akinesia, patient acceptability and ocular and systemic complications. In the previous version of our review, we searched the databases until December 2007. In this updated version, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (March 2015); MEDLINE (1960 to March 2015); and EMBASE (1980 to March 2015). We included randomized controlled clinical trials comparing peribulbar anaesthesia and retrobulbar anaesthesia for cataract surgery. Two authors independently assessed trial quality and extracted data. We contacted trial authors for additional information, study methodology and missing data. We carried out a descriptive narrative of results as the included studies used varied methods for reporting the outcomes. We performed a subgroup analysis for globe akinesia. We included six trials involving 1438 participants. Three of the six trials had adequate sequence generation while all the trials had unclear allocation concealment There was no evidence of any difference in pain perception during surgery with either retrobulbar or peribulbar anaesthesia. Both were largely effective. There was no evidence of any difference in complete akinesia or the need for further injections of local anaesthetic. Conjunctival chemosis was more common after peribulbar block (relative risk (RR) 2.11, 95% confidence interval (CI) 1.46 to 3.05) and lid haematoma was more common after retrobulbar block (RR 0.36, 95% CI 0.15 to 0.88). Retrobulbar haemorrhage was uncommon and occurred only once, in a patient who had a retrobulbar block. There is little to choose between peribulbar and retrobulbar block in terms of anaesthesia and akinesia during surgery measuring acceptability to patients, need for additional injections and development of severe complications. Severe local or systemic complications were rare for both types of block.

Incision in the Quadriceps of >4 cm Delayed Recovery of Strength After Total Knee Replacement.

Chareancholvanich K, Pornrattanamaneewong C. Does the Length of Incision in the Quadriceps Affect the Recovery of Strength After Total Knee Replacement? A Prospective Randomised Clinical Trial. Bone Joint J. 2014 Jul;96-B(7):902-6. ### Question: In patients having total knee replacement, does the length of incision in the quadriceps affect the time to recover the preoperative quadriceps strength? ### Design: Randomized (unclear allocation concealment), blinded (patients and outcome assessor), controlled trial with 12 months of follow-up. ### Setting: A university hospital in Bangkok, Thailand. ### Patients: 60 patients (mean age, 68 years; 87% women) who were undergoing total knee replacement for late-stage primary osteoarthritis. Exclusion criteria were varus or valgus deformity of >20°, flexion contracture of >30°, range of flexion of <60°, or previous knee surgery. All patients completed follow-up. ### Intervention: Patients were allocated to quadriceps incisions measuring 2 cm (n = 20), 4 cm (n = 20), and 6 cm (n = 20) in length. Total knee replacement was performed by 1 surgeon with the patient under regional anesthesia with use of a tourniquet at 350 mm Hg of pressure. The quadriceps incision …

Monitoring of stimulated cycles in assisted reproduction (IVF and ICSI).

Traditional monitoring of ovarian hyperstimulation during in vitro fertilisation (IVF) and intra-cytoplasmic sperm injection (ICSI) treatment has included transvaginal ultrasonography (TVUS) plus serum estradiol levels to ensure safe practice by reducing the incidence and severity of ovarian hyperstimulation syndrome (OHSS) whilst achieving the good ovarian response needed for assisted reproduction treatment. The need for combined monitoring (using TVUS and serum estradiol) during ovarian stimulation in assisted reproduction is controversial. It has been suggested that combined monitoring is time consuming, expensive and inconvenient for women and that simplification of IVF and ICSI therapy by using TVUS only should be considered. To assess the effect of monitoring controlled ovarian hyperstimulation (COH) in IVF and ICSI cycles in subfertile couples with TVUS only versus TVUS plus serum estradiol concentration, with respect to rates of live birth, pregnancy and OHSS. We searched the Menstrual Disorders and Subfertility Group Specialised Register of controlled trials, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, PsycINFO, the National Research Register, and web-based trial registers such as Current Controlled Trials. The last search was conducted in May 2014. There was no language restriction applied. All references in the identified trials and background papers were checked and authors were contacted to identify relevant published and unpublished data. Only randomised controlled trials that compared monitoring with TVUS only versus TVUS plus serum estradiol concentrations in women undergoing COH for IVF and ICSI treatment were included. Three review authors independently selected the studies, extracted data and assessed risk of bias. They resolved disagreements by discussion with the rest of the authors. Outcomes data were pooled and summary statistics were presented when appropriate. The quality of the evidence was rated using the GRADE methods. With this update, four new studies were identified resulting in a total of six trials including 781 women undergoing monitoring of COH with either TVUS alone or a combination of TVUS and serum estradiol concentration during IVF or ICSI treatment.None of the six studies reported our primary outcome of live birth rate. Pooled data showed no evidence of a difference in clinical pregnancy rate per woman between monitoring with TVUS only and combined monitoring (odds ratio (OR) 1.10; 95% confidence interval (CI) 0.79 to 1.54; four studies; N = 617; I² = 5%; low quality evidence). This suggests that compared with women with a 34% chance of clinical pregnancy using monitoring with TVUS plus serum estradiol, the clinical pregnancy rate in women using TVUS only was between 29% and 44%.There was no evidence of a difference between the groups in the reported cases of OHSS (OR 1.03; 95% CI 0.48 to 2.20; six studies; N = 781; I² = 0%; low quality evidence), suggesting that compared with women with a 4% chance of OHSS using monitoring with TVUS plus serum estradiol, the OHSS rate in women monitored by TVUSS only was between 2% and 8%.There was no evidence of a difference between the groups in the mean number of oocytes retrieved pre woman (mean difference (MD) 0.32; 95% CI -0.60 to 1.24; five studies; N = 596; I² = 17%; low quality evidence).The evidence was low quality for all comparisons. Limitations included imprecision and potential bias due to unclear randomisation methods, allocation concealment and blinding, as well as differences in treatment protocols. Quality assessment was hampered by the lack of methodological descriptions in several studies. This review update found no evidence from randomised trials to suggest that combined monitoring by TVUS and serum estradiol is more efficacious than monitoring by TVUS alone with regard to clinical pregnancy rates and the incidence of OHSS. The number of oocytes retrieved appeared similar for both monitoring protocols. The data suggest that both these monitoring methods are safe and reliable. However, these results should be interpreted with caution because the overall quality of the evidence was low. Results were compromised by imprecision and poor reporting of study methodology. A combined monitoring protocol including both TVUS and serum estradiol may need to be retained as precautionary good clinical practice and as a confirmatory test in a subset of women to identify those at high risk of OHSS. An economic evaluation of the costs involved with the two methods and the views of the women undergoing cycle monitoring would be welcome.

Amnioinfusion for third trimester preterm premature rupture of membranes.

Preterm premature rupture of membranes (PPROM) is a leading cause of perinatal morbidity and mortality. Amnioinfusion aims to restore amniotic fluid volume by infusing a solution into the uterine cavity. The objective of this review was to assess the effects of amnioinfusion for PPROM on perinatal and maternal morbidity and mortality. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (2 December 2013). Randomised trials of amnioinfusion compared with no amnioinfusion in women with PPROM. Three review authors independently assessed trials for inclusion. Two review authors independently assessed trial quality and extracted data. Data were checked for accuracy. We included five trials, of moderate quality, but we only analysed data from four studies (with a total of 241 participants). One trial did not contribute any data to the review.Transcervical amnioinfusion improved fetal umbilical artery pH at delivery (mean difference 0.11; 95% confidence interval (CI) 0.08 to 0.14; one trial, 61 participants) and reduced persistent variable decelerations during labour (risk ratio (RR) 0.52; 95% CI 0.30 to 0.91; one trial, 86 participants).Transabdominal amnioinfusion was associated with a reduction in neonatal death (RR 0.30; 95% CI 0.14 to 0.66; two trials, 94 participants), neonatal sepsis (RR 0.26; 95% CI 0.11 to 0.61; one trial, 60 participants), pulmonary hypoplasia (RR 0.22; 95% CI 0.06 to 0.88; one trial, 34 participants) and puerperal sepsis (RR 0.20; 95% CI 0.05 to 0.84; one trial, 60 participants). Women in the amnioinfusion group were also less likely to deliver within seven days of membrane rupture (RR 0.18; 95% CI 0.05 to 0.70; one trial, 34 participants). These results should be treated with circumspection as the positive findings were mainly due to one trial with unclear allocation concealment. These results are encouraging but are limited by the sparse data and unclear methodological robustness, therefore further evidence is required before amnioinfusion for PPROM can be recommended for routine clinical practice.

A systematic review of therapeutic hypothermia for adult patients following traumatic brain injury.

IntroductionResearch into therapeutic hypothermia following traumatic brain injury has been characterised by small trials of poor methodological quality, producing variable results. The Cochrane review, published in 2009, now requires updating. The aim of this systematic review is to assess the effectiveness of the application of therapeutic hypothermia to reduce death and disability when administered to adult patients who have been admitted to hospital following traumatic brain injury.MethodsTwo authors extracted data from each trial. Unless stated in the trial report, relative risks and 95% confidence intervals (CIs) were calculated for each trial. We considered P < 0 · 05 to be statistically significant. We combined data from all trials to estimate the pooled risk ratio (RR) with 95% confidence intervals for death, unfavourable outcome, and pneumonia. All statistical analyses were performed using RevMan 5.1 (Cochrane IMS, Oxford, UK) and Stata (Intercooled Version 12.0, StataCorp LP). Pooled RRs were calculated using the Mantel-Haenszel estimator. The random effects model of DerSimonian and Laird was used to estimate variances for the Mantel-Haenszel and inverse variance estimators.ResultsTwenty studies are included in the review, while 18 provided mortality data. When the results of 18 trials that evaluated mortality as one of the outcomes were statistically aggregated, therapeutic hypothermia was associated with a significant reduction in mortality and a significant reduction in poor outcome. There was a lack of statistical evidence for an association between use of therapeutic hypothermia and increased onset of new pneumonia.ConclusionsIn contrast to previous reviews, this systematic review found some evidence to suggest that therapeutic hypothermia may be of benefit in the treatment of traumatic brain injury. The majority of trials were of low quality, with unclear allocation concealment. Low quality trials may overestimate the effectiveness of hypothermia treatment versus standard care. There remains a need for more, high quality, randomised control trials of therapeutic hypothermia after traumatic brain injury.PROSPERO Systematic Review Registration Number 2012: CRD42012002449.

Metformin and gonadotropins for ovulation induction in patients with polycystic ovary syndrome: a systematic review with meta-analysis of randomized controlled trials

The current systematic review with meta-analysis of randomized controlled trials (RCTs) was aimed to evaluate the effects of metformin on reproductive outcomes in patients with polycystic ovary syndrome (PCOS) who receive gonadotropins for ovulation induction. After systematic review of electronic databases and websites for registration of RCTs, a total of 7 RCTs reporting data on 1023 cycles were included in the final analysis. Descriptive data showed an overall low studies’ quality due to unclear sequence generation and allocation concealment, lack of blinding procedure, incomplete outcome data and several biases and/or confounders. Data synthesis showed that metformin improved live-birth (odds ratio [OR] = 1.94, 95% confidence interval [CI] 1.10 to 3.44; P = 0.020) and pregnancy (OR = 2.25, 95% CI 1.50 to 3.38; P < 0.0001) rates, without significant heterogeneity across the studies (P = 0.230, estimation of inconsistency = 30%; and P = 0.710, estimation of inconsistency = 0%, respectively, for live-birth and pregnancy rates). A significant reduction of cancellation rate was observed after metformin administration (OR = 0.41, 95% CI 0.24 to 0.72, P = 0.002) without significant heterogeneity across the studies (P = 0.500, estimation of inconsistency = 0%). Metformin administration influenced or did not influence other secondary endpoints assessed with a significant heterogeneity. In conclusion, metformin administration increases the live-birth and pregnancy rate in PCOS patients who receive gonadotropins for ovulation induction. Further well designed, blinded, placebo-controlled, and adequately powered RCTs are need to confirm that metanalytic results.

Bortezomib for patients with previously untreated multiple myeloma: a systematic review and meta-analysis of randomized controlled trials

Multiple myeloma (MM) is an incurable disease with a poor survival, which has not been affected even by high-dose chemotherapy. This systematic review was performed to assess the efficacy and safety of the novel agent bortezomib for patients with previously untreated MM. We systematically searched biomedical literature databases and identified randomized controlled trials (RCTs) comparing bortezomib with placebo, no bortezomib, or other active agents for patients with previously untreated MM. Overall survival (OS), reported as hazard ratio (HR) with 95% confidence interval (CI), was the primary outcome measure. The secondary outcomes included time to progression (TTP), progression-free survival (PFS), and response rates. Five RCTs involving 2,728 patients were included. Three trials compared bortezomib with no bortezomib, and two compared bortezomib with other active agents (vincristine ± adriamycin-based chemotherapy). All included RCTs had methodological shortcomings, including no or unclear allocation concealment and blinding. Compared with no bortezomib or vincristine-based chemotherapy, the bortezomib-based regimen significantly improved the OS of patients with previously untreated MM. HR was 0.71 (95% CI 0.55-0.93) and 0.77 (95% CI 0.60-0.99), respectively. However, when compared with the vincristine + adriamycin-based regimen, the OS was similar (HR = 0.87, 95% CI 0.57-1.33). TTP, PFS, and response rates were also improved in patients receiving bortezomib-based regimen. However, the risk of peripheral neuropathy was found to be significantly higher. In summary, bortezomib appears to improve survival and response rates of patients with previously untreated MM in spite of higher risk of peripheral neuropathy.

Aspirin reduced recurrence of venous thromboembolism (VTE) after a first-ever, unprovoked VTE

Abstract QUESTION Does aspirin reduce recurrence of venous thromboembolism (VTE) after a course of oral vitamin K antagonist therapy in adults with a first-ever, unprovoked VTE? METHODS DESIGN Randomized placebo-controlled trial (Aspirin for the Prevention of Recurrent Venous Thromboembolism [Warfarin and Aspirin {WARFASA}] study). ClinicalTrials.gov NCT00222677. ALLOCATION Unclear allocation concealment.† BLINDING Blinded† (patients, clinicians, {data collectors}*, outcome adjudicators, {data analysts, safety committee, and manuscript writers}*). FOLLOW-UP PERIOD Median 25 months. SETTING {25 centers in Austria and Italy}*. PATIENTS 403 patients g 18 years of age (mean age 62 y, 64% men) who had a first-ever, objectively confirmed, symptomatic, unprovoked (without known risk factors), proximal deep venous thrombosis (DVT), pulmonary embolism (PE), or both; received oral vitamin K antagonists for 6 to 18 months (target international normalized ratio of 2.0 to 3.0), and were randomized within 2 weeks of anticoagulant withdrawal. {Exclusion criteria included cancer, major thrombophilia, other indications for long-term anticoagulant therapy, active or high risk for bleeding, or bleeding during anticoagulant therapy}.‡ INTERVENTION Aspirin, 100 mg once daily (n = 205), or placebo (n = 198) for 2 years. OUTCOMES Primary efficacy outcome was symptomatic, objectively verified, recurrence of VTE (composite of DVT or PE). Primary safety outcome was major bleeding (fatal, occurring in a critical site, ≥ 2.0-g/dL decrease in hemoglobin, or transfusion of ≥ 2 units of whole blood or red cells). Secondary outcomes included DVT; PE; clinically relevant, nonmajor bleeding; and mortality. PATIENT FOLLOW-UP 98% (modified intention-to-treat analysis including patients who received ≥ 1 dose of study drug). MAIN RESULTS Aspirin reduced recurrent VTE and DVT more than placebo (Table). Groups did not differ for PE, bleeding, or mortality (Table). CONCLUSION After discontinuation of anticoagulant therapy for a first-ever, unprovoked venous thromboembolism, aspirin reduced recurrence.Aspirin vs placebo after discontinuation of anticoagulant therapy for a first-ever, unprovoked VTE§OutcomesEvent ratesAt 2 yAspirinPlaceboRRR (95% CI)NNT (CI)Recurrent VTE14%22%44% (14 to 65)11 (8 to 34)Pulmonary embolism5.4%7.1%29% (-51 to 67)Not significantDeep venous thrombosis7.8%14%47% (6 to 71)15 (10 to 127)Bleeding||1.95%2.03%2% (-284 to 76)Not significantRRI (CI)NNH (CI)Mortality2.9%2.5%4% (-231 to 68)Not significant§Abbreviations defined in Glossary; RRR, RRI, NNT, NNH, and CI calculated from control event rates and hazard ratios (HR) in article. HR for recurrent VTE was adjusted for age, sex, type of index event, and duration of anticoagulation therapy before randomization.||Includes major bleeding (1 event per group) and clinically relevant nonmajor bleeding events.

Influence of Reported Study Design Characteristics on Intervention Effect Estimates From Randomized, Controlled Trials

Published evidence suggests that aspects of trial design lead to biased intervention effect estimates, but findings from different studies are inconsistent. This study combined data from 7 meta-epidemiologic studies and removed overlaps to derive a final data set of 234 unique meta-analyses containing 1973 trials. Outcome measures were classified as "mortality," "other objective," "or subjective," and Bayesian hierarchical models were used to estimate associations of trial characteristics with average bias and between-trial heterogeneity. Intervention effect estimates seemed to be exaggerated in trials with inadequate or unclear (vs. adequate) random-sequence generation (ratio of odds ratios, 0.89 [95% credible interval {CrI}, 0.82 to 0.96]) and with inadequate or unclear (vs. adequate) allocation concealment (ratio of odds ratios, 0.93 [CrI, 0.87 to 0.99]). Lack of or unclear double-blinding (vs. double-blinding) was associated with an average of 13% exaggeration of intervention effects (ratio of odds ratios, 0.87 [CrI, 0.79 to 0.96]), and between-trial heterogeneity was increased for such studies (SD increase in heterogeneity, 0.14 [CrI, 0.02 to 0.30]). For each characteristic, average bias and increases in between-trial heterogeneity were driven primarily by trials with subjective outcomes, with little evidence of bias in trials with objective and mortality outcomes. This study is limited by incomplete trial reporting, and findings may be confounded by other study design characteristics. Bias associated with study design characteristics may lead to exaggeration of intervention effect estimates and increases in between-trial heterogeneity in trials reporting subjectively assessed outcomes.

Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials: combined analysis of meta-epidemiological studies.

The design of randomised controlled trials (RCTs) should incorporate characteristics (such as concealment of randomised allocation and blinding of participants and personnel) that avoid biases resulting from lack of comparability of the intervention and control groups. Empirical evidence suggests that the absence of such characteristics leads to biased intervention effect estimates, but the findings of different studies are not consistent. To examine the influence of unclear or inadequate random sequence generation and allocation concealment, and unclear or absent double blinding, on intervention effect estimates and between-trial heterogeneity, and whether or not these influences vary with type of clinical area, intervention, comparison and outcome measure. Data were combined from seven contributing meta-epidemiological studies (collections of meta-analyses in which trial characteristics are assessed and results recorded). The resulting database was used to identify and remove overlapping meta-analyses. Outcomes were coded such that odds ratios < 1 correspond to beneficial intervention effects. Outcome measures were classified as mortality, other objective or subjective. We examined agreement between assessments of trial characteristics in trials assessed in more than one contributing study. We used hierarchical Bayesian bias models to estimate the effect of trial characteristics on average bias [quantified as ratios of odds ratios (RORs) with 95% credible intervals (CrIs) comparing trials with and without a characteristic] and in increasing between-trial heterogeneity. The analysis data set contained 1973 trials included in 234 meta-analyses. Median kappa statistics for agreement between assessments of trial characteristics were: sequence generation 0.60, allocation concealment 0.58 and blinding 0.87. Intervention effect estimates were exaggerated by an average 11% in trials with inadequate or unclear (compared with adequate) sequence generation (ROR 0.89, 95% CrI 0.82 to 0.96); between-trial heterogeneity was higher among such trials. Bias associated with inadequate or unclear sequence generation was greatest for subjective outcomes (ROR 0.83, 95% CrI 0.74 to 0.94) and the increase in heterogeneity was greatest for such outcomes [standard deviation (SD) 0.20, 95% CrI 0.03 to 0.32]. The effect of inadequate or unclear (compared with adequate) allocation concealment was greatest among meta-analyses with a subjectively assessed outcome intervention effect (ROR 0.85, 95% CrI 0.75 to 0.95), and the increase in between-trial heterogeneity was also greatest for such outcomes (SD 0.20, 95% CrI 0.02 to 0.33). Lack of, or unclear, double blinding (compared with double blinding) was associated with an average 13% exaggeration of intervention effects (ROR 0.87, 95% CrI 0.79 to 0.96), and between-trial heterogeneity was increased for such studies (SD 0.14, 95% CrI 0.02 to 0.30). Average bias (ROR 0.78, 95% CrI 0.65 to 0.92) and between-trial heterogeneity (SD 0.37, 95% CrI 0.19 to 0.53) were greatest for meta-analyses assessing subjective outcomes. Among meta-analyses with subjectively assessed outcomes, the effect of lack of blinding appeared greater than the effect of inadequate or unclear sequence generation or allocation concealment. Bias associated with specific reported study design characteristics leads to exaggeration of beneficial intervention effect estimates and increases in between-trial heterogeneity. For each of the three characteristics assessed, these effects were greatest for subjectively assessed outcomes. Assessments of the risk of bias in RCTs should account for these findings. Further research is needed to understand the effects of attrition bias, as well as the relative importance of blinding of patients, care-givers and outcome assessors, and thus separate the effects of performance and detection bias. National Institute for Health Research Health Technology Assessment programme.

Splinting for carpal tunnel syndrome.

Carpal tunnel syndrome (CTS) is a condition where one of two main nerves in the wrist is compressed, which can lead to pain in the hand, wrist and sometimes arm, and numbness and tingling in the thumb, index and long finger. Splinting is usually offered to people with mild to moderate symptoms. However, the effectiveness and duration of the benefit of splinting for this condition remain unknown. To compare the effectiveness of splinting for carpal tunnel syndrome with no treatment, placebo or another non-surgical intervention. We searched the Cochrane Neuromuscular Disease Group Specialized Register (10 January 2011), CENTRAL, NHSEED and DARE (The Cochrane Library 2011, Issue 4), MEDLINE (January 1966 to December 2011), EMBASE (January 1980 to January 2012), AMED (January 1985 to January 2012), and CINAHL Plus (January 1937 to January 2012), using no time limits. We searched the reference lists of all included trials and relevant reviews for further relevant studies. All randomised and quasi-randomised trials comparing splinting with no treatment (or a placebo) or with other non-surgical treatments were eligible for inclusion. We also included studies comparing one splint type or regimen versus another. We excluded studies comparing splinting with surgical treatment. There were no language restrictions. We included all patients diagnosed with carpal tunnel syndrome unless they had undergone surgical release. Two review authors independently selected trials for inclusion, and performed data extraction. Two authors also independently performed the assessment of risk of bias. We calculated measures of effect as risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CI) reported and statistical significance set at P < 0.05 for all outcome comparisons. The review included 19 studies randomising 1190 participants with carpal tunnel syndrome. Two studies compared splinting with no treatment, five compared different splint designs, one compared different splint-wearing regimens, seven compared splint delivered as a single intervention with another non-surgical intervention, and five compared splint delivered alongside other non-surgical interventions with another non-surgical intervention. Only three studies reported concealing the allocation sequence, and only one reported blinding of participants. Three studies measured the primary outcome, short-term overall improvement at three months or less. One low quality study with 80 wrists found that compared to no treatment, splints worn at night more than tripled the likelihood of reporting overall improvement at the end of four weeks of treatment (RR 3.86, 95% CI 2.29 to 6.51). However, the lack of patient blinding and unclear allocation concealment suggests this result should be interpreted with caution. A very low quality quasi-randomised trial with 90 wrists found that wearing a neutral splint more than doubled the likelihood of reporting 'a lot or complete relief' at the end of two weeks of treatment compared with an extension splint (RR 2.43, 95% CI 1.12 to 5.28). The third study which measured short-term overall improvement did not report outcome data separately per group. Nine studies measured adverse effects of splinting and all found either no or few participants reporting discomfort or swelling due to splinting; however, the precision of all RRs was very low. Differences between groups in the secondary outcomes - symptoms, function, and neurophysiologic parameters - were most commonly small with 95% CIs incorporating effects in either direction. Overall, there is limited evidence that a splint worn at night is more effective than no treatment in the short term, but there is insufficient evidence regarding the effectiveness and safety of one splint design or wearing regimen over others, and of splint over other non-surgical interventions for CTS. More research is needed on the long-term effects of this intervention for CTS.

Randomisation to protect against selection bias in healthcare trials.

Randomised trials use the play of chance to assign participants to comparison groups. The unpredictability of the process, if not subverted, should prevent systematic differences between comparison groups (selection bias). Differences due to chance will still occur and these are minimised by randomising a sufficiently large number of people. To assess the effects of randomisation and concealment of allocation on the results of healthcare studies. We searched the Cochrane Methodology Register, MEDLINE, SciSearch and reference lists up to September 2009. In addition, we screened articles citing included studies (ISI Science Citation Index) and papers related to included studies (PubMed). Eligible study designs were cohorts of studies, systematic reviews or meta-analyses of healthcare interventions that compared random allocation versus non-random allocation or adequate versus inadequate/unclear concealment of allocation in randomised trials. Outcomes of interest were the magnitude and direction of estimates of effect and imbalances in prognostic factors. We retrieved and assessed studies that appeared to meet the inclusion criteria independently. At least two review authors independently appraised methodological quality and extracted information. We prepared tabular summaries of the results for each comparison and assessed the results across studies qualitatively to identify common trends or discrepancies. A total of 18 studies (systematic reviews or meta-analyses) met our inclusion criteria. Ten compared random allocation versus non-random allocation and nine compared adequate versus inadequate or unclear concealment of allocation within controlled trials. All studies were at high risk of bias.For the comparison of randomised versus non-randomised studies, four comparisons yielded inconclusive results (differed between outcomes or different modes of analysis); three comparisons showed similar results for random and non-random allocation; two comparisons had larger estimates of effect in non-randomised studies than in randomised trials; and two comparisons had larger estimates of effect in randomised than in non-randomised studies.Five studies found larger estimates of effect in trials with inadequate concealment of allocation than in trials with adequate concealment. The four other studies did not find statistically significant differences. The results of randomised and non-randomised studies sometimes differed. In some instances non-randomised studies yielded larger estimates of effect and in other instances randomised trials yielded larger estimates of effect. The results of controlled trials with adequate and inadequate/unclear concealment of allocation sometimes differed. When differences occurred, most often trials with inadequate or unclear allocation concealment yielded larger estimates of effects relative to controlled trials with adequate allocation concealment. However, it is not generally possible to predict the magnitude, or even the direction, of possible selection biases and consequent distortions of treatment effects from studies with non-random allocation or controlled trials with inadequate or unclear allocation concealment.

Meta-analysis of the evidence for a partially hydrolyzed 100% whey formula for the prevention of allergic diseases

Objective:Infants with a documented hereditary risk of atopy (i.e., an affected parent and/or sibling) who cannot be breastfed exclusively are recommended to receive a formula with confirmed reduced allergenicity, i.e., a partially or extensively hydrolyzed formula (pHF and eHF, respectively), as a means of preventing allergic reactions. The efficacy of each hydrolyzed formula for the prevention of allergic diseases should be established separately, as factors such as the protein source, hydrolysis method and degree of hydrolysis that often depend on the manufacturer contribute to differences among hydrolysates. The aim was to systematically review data on the efficacy of a partially hydrolyzed 100% whey formula (pHF) in reducing the risk of allergy in healthy infants at high risk for allergy.Methods:The Cochrane Library, MEDLINE, EMBASE, and CINAHL databases were searched in September 2009 (from inception to September 2009) for randomized and quasi-randomized controlled trials (RCTs); additional references were obtained from reviewed articles. The company that manufactures the pHF used was contacted for unpublished data.Results:The search yielded 84 citations. Fifteen RCTs were included, some of which had potential methodological limitations such as unclear or inadequate allocation concealment, no intention-to-treat analysis, and no true blinding. For primary outcomes, i.e., all allergic diseases and atopic eczema/atopic dermatitis, use of the pHF compared with standard formula (SF) was associated with reduced risks (incidence, cumulative incidence, period prevalence) that were statistically significant for most, albeit not all, time points. Comparison of groups who received the pHF versus extensively hydrolyzed (eH) whey formula revealed no significant differences in outcomes except for reductions in the cumulative incidences of all allergic diseases at 0 to 36 months of age. Comparison of groups who received the pHF versus eH casein formula revealed no significant difference in outcomes between groups.Conclusions:The use of the pHF compared to SF is effective in allergy prevention in children at high risk for allergy at most time points. These results should be interpreted with caution due to a lack of methodological rigor in many trials. Reassuringly, the strongest evidence comes from a well-designed and conducted, independently funded RCT.

WITHDRAWN: Surgical versus non-surgical management of pleural empyema.

Pleural empyema is a collection of pus between the lungs and the chest wall. There is debate about treatment options with the advent of both fibrinolytic enzymes to facilitate tube drainage and less invasive video-assisted thoracoscopic surgery (VATS). To determine which was more effective: surgical (using thoracoscopy or thoracotomy) or non-surgical techniques (thoracocentesis, chest tube drainage); and to establish whether there was an optimum time for intervention. In this updated review we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, issue 3) which contains the Acute Respiratory Infections Group's specialized register; MEDLINE (January 2002 to July Week 4, 2005); and EMBASE (January 2001 to 3rd Quarter 2005). Bibliographies, reference lists of identified studies and review articles were handsearched. Personal communication with authors is ongoing. There were no language restrictions. Randomised controlled trials (RCTs) of surgical techniques versus non-surgical approaches for treatment of pus in the pleural cavity in children and adults but not neonates. Studies of empyema associated with tuberculosis or malignancy were excluded. Trial quality was assessed using Jadad criteria (Jadad 1996). Authors were contacted for missing information. The primary outcomes were death or resolution of the empyema. Secondary outcomes addressed the length of time chest tubes were required, pain, hospital stay and any complications. Only one small randomised study was identified. Some methodological quality considerations cast doubt on the validity of the study with regard to patient selection, unclear allocation concealment and outcome assessor blinding and it scored 'B' overall (Jadad score 3). When compared with chest tube drainage combined with streptokinase, video-assisted thoracoscopic surgery (VATS) had a significantly higher primary treatment success and patients spent less time in hospital. Each treatment group suffered one mortality. The latest search revealed no further published randomised studies but communication with authors revealed two ongoing studies comparing conventional chest tube drainage plus antibiotics with and without fibrinolytics with video-assisted thorascopic surgery (VATS). A small unpublished study is awaiting assessment that compared chest tube drainage and antibiotics with thoracoscopy or thoracotomy plus antibiotics. It seems that for large, loculated pleural empyemas VATS is superior to chest tube drainage in terms of duration of chest tubes in situ and length of hospital stay. However, there are questions about validity in the one study which met the inclusion criteria and the study has too few participants to draw conclusions. There are risks of complications (associated with all treatments) which may not be apparent with small numbers. Larger studies are needed.

Active cooling in traumatic brain‐injured patients: a questionable therapy?

Hypothermia is shown to be beneficial for the outcome after a transient global brain ischaemia through its neuroprotective effect. Whether this is also the case after focal ischaemia, such as following a severe traumatic brain injury (TBI), has been investigated in numerous studies, some of which have shown a tendency towards an improved outcome, whereas others have not been able to demonstrate any beneficial effect. A Cochrane report concluded that the majority of the trials that have already been published have been of low quality, with unclear allocation concealment. If only high-quality trials are considered, TBI patients treated with active cooling were more likely to die, a conclusion supported by a recent high-quality Canadian trial on children. Still, there is a belief that a modified protocol with a shorter time from the accident to the start of active cooling, longer cooling and rewarming time and better control of blood pressure and intracranial pressure would be beneficial for TBI patients. This belief has led to the instigation of new trials in adults and in children, including these types of protocol adjustments. The present review provides a short summary of our present knowledge of the use of active cooling in TBI patients, and presents some tentative explanations as to why active cooling has not been shown to be effective for outcome after TBI. We focus particularly on the compromised circulation of the penumbra zone, which may be further reduced by the stress caused by the difference in thermostat and body temperature and by the hypothermia-induced more frequent use of vasoconstrictors, and by the increased risk of contusional bleedings under hypothermia. We suggest that high fever should be reduced pharmacologically.

Music during caesarean section under regional anaesthesia for improving maternal and infant outcomes

Evidence on the benefits of music during caesarean section under regional anaesthesia to improve clinical and psychological outcomes for mothers and infants has not been established. To evaluate the effectiveness of music during caesarean section under regional anaesthesia for improving clinical and psychological outcomes for mothers and infants. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2008). We included randomised controlled trials comparing music added to standard care during caesarean section under regional anaesthesia to standard care alone. Two review authors, Malinee Laopaiboon and Ruth Martis, independently assessed eligibility, risk of bias in included trials and extracted data. We analysed continuous outcomes using a mean difference (MD) with a 95% confidence interval (CI). One trial involving 76 women who planned to have their babies delivered by caesarean section met the inclusion criteria, but data were available for only 64 women. This trial was of low quality with unclear allocation concealment and only a few main clinical outcomes reported for the women. The trial did not report any infant outcomes. It appears that music added to standard care during caesarean section under regional anaesthesia had some impact on pulse rate at the end of maternal contact with the neonate in the intra-operative period (MD -7.50 fewer beats per minute, 95% CI -14.08 to -0.92) and after completion of skin suture for the caesarean section (MD -7.37 fewer beats per minute, 95% CI -13.37 to -1.37). There was also an improvement in the birth satisfaction score (maximum possible score of 35) (MD of 3.38, 95%CI 1.59 to 5.17). Effects on other outcomes were either not significant or not reported in the one included trial. The findings indicate that music during planned caesarean section under regional anaesthesia may improve pulse rate and birth satisfaction score. However, the magnitude of these benefits is small and the methodological quality of the one included trial is questionable. Therefore, the clinical significance of music is unclear. More research is needed to investigate the effects of music during caesarean section under regional anaesthesia on both maternal and infant outcomes, in various ethnic pregnant women, and with adequate sample sizes.