Effect of L-carnitine and/or L-acetyl-carnitine in nutrition treatment for male infertility: a systematic review

The aim of this systematic review was to quantify the efficacy of L-carnitine (LC) and/or L-acetyl-carnitine (LAC) in nutrition treatment for male infertility according to present clinical evidence. Biomedical databases were searched to collect related clinical trials and nine relevant randomized controlled trials (RCTs) were included. The quality of the RCTs was assessed based on their performance in randomization, blinding, and allocation concealment. The meta-analysis compared LC and /or LAC therapy to placebo treatment found significant improvement in pregnancy rate (OR = 4.10, 95% CI (2.08, 8.08), p< 0.0001), total sperm motility (WMD = 7.43, 95% CI (1.72, 13.14), p = 0.04, forward sperm motility (WMD = 11.83, 95% CI (0.49, 23.16), p = 0.04) and atypical sperm cell (WMD = -5.72, 95% CI (-7.89, -3.56), p< 0.00001). However, no significant difference was found in the sperm concentration (WMD = 5.69, 95% CI (-4.47, 15.84), p = 0.27) and semen volume (WMD = 0.28, 95% CI (-0.02, 0.58), p = 0.07). In conclusion, the administration of LC and/or LAC may be effective in improving pregnancy rate and sperm kinetic features in patients affected by male infertility. However, the exact efficacy of carnitines on male infertility needs to be confirmed by further investigations.     

Published methodological quality of randomized controlled trials does not reflect the actual quality assessed in protocols

ObjectivesTo assess whether the reported methodological quality of randomized controlled trials (RCTs) reflects the actual methodological quality and to evaluate the association of effect size (ES) and sample size with methodological quality.Study Design and SettingSystematic review. This is a retrospective analysis of all consecutive phase III RCTs published by eight National Cancer Institute Cooperative Groups up to 2006. Data were extracted from protocols (actual quality) and publications (reported quality) for each study.ResultsFour hundred twenty-nine RCTs met the inclusion criteria. Overall reporting of methodological quality was poor and did not reflect the actual high methodological quality of RCTs. The results showed no association between sample size and actual methodological quality of a trial. Poor reporting of allocation concealment and blinding exaggerated the ES by 6% (ratio of hazard ratio [RHR]: 0.94; 95% confidence interval [CI]: 0.88, 0.99) and 24% (RHR: 1.24; 95% CI: 1.05, 1.43), respectively. However, actual quality assessment showed no association between ES and methodological quality.ConclusionThe largest study to date shows that poor quality of reporting does not reflect the actual high methodological quality. Assessment of the impact of quality on the ES based on reported quality can produce misleading results.     

An analysis of general medical and specialist journals that endorse CONSORT found that reporting was not enforced consistently

BACKGROUND: We aimed to determine if specialist journals implement specific Consolidated Standards for Reporting Trials (CONSORT) recommendations to the same extent as general medical journals. METHODS: Analysis of random controlled trials (RCTs) in five general medical journals (n=100) and 10 specialist journals (n=100), all endorsing CONSORT. We evaluated the likelihood of reporting important methodologic criteria. Analyses controlled for the nested effect of journal within each journal type. RESULTS: General medical journals published, on average, more CONSORT items per RCT than specialist journals (7.9 [SD 1.8] vs. 6.5 [SD 2.2] out of 11 possible items, P=.02). When compared with specialist journals, RCTs in general medical journals published a participant flow diagram more frequently (83 vs. 42%, odds ratio [OR] 6.7, 95% confidence interval [CI] 3.4-12.9) and more likely to report the method of randomization (78 vs. 55%, OR 2.9, 95% CI 1.5-5.3) and allocation concealment (48 vs. 26%, OR 2.6, 95% CI 1.4-4.7); they were less likely to publish RCTs reporting adverse events (58 vs. 78%, OR 0.3, 95% CI 0.2-0.7). Both page length and impact factor were weakly associated with number of CONSORT items reported. CONCLUSION: General medical and specialist journals that endorse CONSORT do not enforce reporting issues consistently, with specialty journals lagging behind general medical journals.     

Discrepancy between published report and actual conduct of randomized clinical trials

Randomized clinical trial (RCT) publications with inappropriate random-sequence generation, lack of allocation concealment, or imperfect blinding yield inflated estimates of effect compared to those in which adequate methods are described. RCTs that do not state methods used yield similar effect estimates, suggesting that inadequate methods were used. We compared RCT publications with investigator reports of actual practice for 40 rheumatology RCTs published in 1997/1998. In RCTs in which these methods were not described in the trial reports and would thus have been characterized as "inadequate," investigators reported using methods of random-sequence generation and allocation concealment that would be considered adequate in 77.4 and 78.1% of RCTs, respectively. This suggests that, in contrast to previous reports, inadequate random-sequence generation and allocation concealment, per se, may not be a major problem in RCTs. Characterizing RCTs as "good" or "poor" quality based on the published report is likely to be inappropriate.     

Specific instructions for estimating unclearly reported blinding status in randomized trials were reliable and valid

ObjectiveTo test the reliability and validity of specific instructions to classify blinding, when unclearly reported in randomized trials, as “probably done” or “probably not done.”Study Design and SettingWe assessed blinding of patients, health care providers, data collectors, outcome adjudicators, and data analysts in 233 randomized trials in duplicate and independently using detailed instructions. The response options were “definitely yes,” “probably yes,” “probably no,” and “definitely no.” We contacted authors for data verification (46% response). For each of the five questions, we assessed reliability by calculating the agreement between the two reviewers and validity by calculating the agreement between reviewers’ consensus and verified data.ResultsThe percentage with unclear blinding status varied between 48.5% (patients) and 84.1% (data analysts). Reliability was moderate for blinding of outcome adjudicators (κ = 0.52) and data analysts (κ = 0.42) and substantial for blinding of patients (κ = 0.71), providers (κ = 0.68), and data collectors (κ = 0.65). The raw agreement between the consensus record and the author-verified record varied from 84.1% (blinding of data analysts) to 100% (blinding of health care providers).ConclusionWith the possible exception of blinding of data analysts, use of “probably yes” and “probably no” instead of “unclear” may enhance the assessment of blinding in trials.     

The risk of unblinding was infrequently and incompletely reported in 300 randomized clinical trial publications

ObjectivesTo assess the proportion of clinical trials explicitly reporting the risk of unblinding, to evaluate the completeness of reporting on unblinding risk, and to describe the reported procedures involved in assessing unblinding.Study Design and SettingWe sampled at random 300 blinded randomized clinical trials indexed in PubMed in 2010. Two authors read the trial publications and extracted data independently.ResultsTwenty-four trial publications, or 8% (95% confidence interval [CI], 5, 12%), explicitly reported the risk of unblinding, of which 16 publications, or 5% (95% CI, 3, 8%), reported compromised blinding; and 8 publications, or 3% (95% CI, 1, 5%), intact blinding. The reporting on risk of unblinding in the 24 trial publications was generally incomplete. The median proportion of assessments per trial affected by unblinding was 3% (range 1–30%). The most common mechanism for unblinding was perceptible physical properties of the treatments, for example, a difference in the taste and odor of a typhoid vaccine compared with its placebo.ConclusionPublished articles on randomized clinical trials infrequently reported risk of unblinding. This may reflect a tendency for avoiding reporting actual or suspected unblinding or a genuine low risk of unblinding.     

Instruments for Assessing Risk of Bias and Other Methodological Criteria of Published Animal Studies: A Systematic Review

Background: Results from animal toxicology studies are critical to evaluating the potential harm from exposure to environmental chemicals or the safety of drugs prior to human testing. However, there is significant debate about how to evaluate the methodology and potential biases of the animal studies. There is no agreed-upon approach, and a systematic evaluation of current best practices is lacking.Objective: We performed a systematic review to identify and evaluate instruments for assessing the risk of bias and/or other methodological criteria of animal studies.Method: We searched Medline (January 1966–November 2011) to identify all relevant articles. We extracted data on risk of bias criteria (e.g., randomization, blinding, allocation concealment) and other study design features included in each assessment instrument.Discussion: Thirty distinct instruments were identified, with the total number of assessed risk of bias, methodological, and/or reporting criteria ranging from 2 to 25. The most common criteria assessed were randomization (25/30, 83%), investigator blinding (23/30, 77%), and sample size calculation (18/30, 60%). In general, authors failed to empirically justify why these or other criteria were included. Nearly all (28/30, 93%) of the instruments have not been rigorously tested for validity or reliability.Conclusion: Our review highlights a number of risk of bias assessment criteria that have been empirically tested for animal research, including randomization, concealment of allocation, blinding, and accounting for all animals. In addition, there is a need for empirically testing additional methodological criteria and assessing the validity and reliability of a standard risk of bias assessment instrument.Citation: Krauth D, Woodruff TJ, Bero L. 2013. Instruments for assessing risk of bias and other methodological criteria of published animal studies: a systematic review. Environ Health Perspect 121:985–992 (2013); http://dx.doi.org/10.1289/ehp.1206389     

Influence of trial registration on reporting quality of randomized trials: Study from highest ranked journals

ObjectiveTo evaluate the reporting quality of key methodological items of randomized control trials (RCTs) in 55 of the highest ranked journals.Study Design and SettingA list of the highest top ranked journals was identified, and a search for detecting RCTs in those journals was made. Two hundred sixty four journals were screened and 55 of them were identified having at least one RCT. Three RCTs were randomly selected a priori from each journal; 148 RCTs were finally included. RCTs were assessed by two reviewers using the Consolidated Standards of Reporting Trials (CONSORT) statement.ResultsOnly 11 (8%) RCTs had all items adequately reported. In addition, 36% of RCTs reported that the study was registered in any trial registry. We found a significant difference in the quality of reporting for baseline characteristics, recruitment, participant's flow, and randomization implementation between those studies having reported the registration of their RCT in a trial registry and those that have not. Adherence to key methodological items of the CONSORT statement was as follows: sample size determination (60%), sequence generation (49%), allocation concealment (40%), and blinding (25%).ConclusionsReporting of varied CONSORT items remains suboptimal. Registration in a trial registry was associated with improved reporting. Further efforts to enhance RCT registration could contribute to this improvement.     

Lack of blinding of outcome assessors in animal model experiments implies risk of observer bias

ObjectivesTo examine the impact of not blinding outcome assessors on estimates of intervention effects in animal experiments modeling human clinical conditions.Study Design and SettingWe searched PubMed, Biosis, Google Scholar, and HighWire Press and included animal model experiments with both blinded and nonblinded outcome assessors. For each experiment, we calculated the ratio of odds ratios (ROR), that is, the odds ratio (OR) from nonblinded assessments relative to the corresponding OR from blinded assessments. We standardized the ORs according to the experimental hypothesis, such that an ROR <1 indicates that nonblinded assessor exaggerated intervention effect, that is, exaggerated benefit in experiments investigating possible benefit or exaggerated harm in experiments investigating possible harm. We pooled RORs with inverse variance random-effects meta-analysis.ResultsWe included 10 (2,450 animals) experiments in the main meta-analysis. Outcomes were subjective in most experiments. The pooled ROR was 0.41 (95% confidence interval [CI], 0.20, 0.82; I² = 75%; P < 0.001), indicating an average exaggeration of the nonblinded ORs by 59%. The heterogeneity was quantitative and caused by three pesticides experiments with very large observer bias, pooled ROR was 0.20 (95% CI, 0.07, 0.59) in contrast to the pooled ROR in the other seven experiments, 0.82 (95% CI, 0.57, 1.17).ConclusionLack of blinding of outcome assessors in animal model experiments with subjective outcomes implies a considerable risk of observer bias.     

Randomized trials published in higher vs. lower impact journals differ in design,conduct, and analysis

ObjectiveTo compare methodological characteristics of randomized controlled trials (RCTs) published in higher vs. lower impact Core Clinical Journals.Study Design and SettingWe searched MEDLINE for RCTs published in 2007 in Core Clinical Journals. We randomly sampled 1,140 study reports in a 1:1 ratio in higher (five general medicine journals with the highest total citations in 2007) and lower impact journals.ResultsFour hundred sixty-nine RCTs proved eligible: 219 in higher and 250 in lower impact journals. RCTs in higher vs. lower impact journals had larger sample sizes (median, 285 vs. 39), were more likely to receive industry funding (53% vs. 28%), declare concealment of allocation (66% vs. 36%), declare blinding of health care providers (53% vs. 41%) and outcome adjudicators (72% vs. 54%), report a patient-important primary outcome (69% vs. 50%), report subgroup analyses (64% vs. 26%), prespecify subgroup hypotheses (42% vs. 20%), and report a test for interaction (54% vs. 27%); P < 0.05 for all differences.ConclusionRCTs published in higher impact journals were more likely to report methodological safeguards against bias and patient-important outcomes than those published in lower impact journals. However, sufficient limitations remain such that publication in a higher impact journal does not ensure low risk of bias.     

Blinding was judged more difficult to achieve and maintain in nonpharmacologic than pharmacologic trials

OBJECTIVE: To compare the feasibility of blinding and the perceived risk of unblinding in trials evaluating pharmacologic (PT) and nonpharmacologic treatments (NPT) of hip or knee osteoarthritis. STUDY DESIGN AND SETTING: Two independent reviewers assessed the feasibility of blinding patients, care providers, and outcome assessors, the perceived risk of unblinding, and whether blinding was reported in 110 reports of randomized controlled trials (RCTs) evaluating PT and NPT in patients with hip or knee osteoarthritis. RESULTS: Blinding was considered to be possible less often in NPT trials than in PT trials for patients (42 vs. 96%; P <.001), care providers (12 vs. 96%; P <.001), and outcome assessors (34 vs. 98%; P <.001). When blinding was judged feasible, the perceived risk of unblinding was more often considered moderate or important in NPT than PT trials for patients (35 vs. 14%, P=.02) and outcome assessors (44 vs. 10%, P=.0004). When blinding was judged feasible, it was reported less often in NPT reports than in PT reports for patients (46 vs. 98%, P <.001), care providers (43 vs. 83%, P=.03), and outcome assessors (72 vs. 98%, P=.0006). CONCLUSION: Blinding appears to be more difficult to achieve and unblinding may occur more often in NPT than PT trials.     

Use of a Mendelian randomization approach to assess the causal relation of gamma-Glutamyltransferase with blood pressure and serum insulin levels

Elevated levels of γ-glutamyltransferase (GGT) have been associated with elevated blood pressure (BP) and diabetes. However, the causality of these relations has not been addressed. The authors performed a cross-sectional analysis (2003-2006) among 4,360 participants from the population-based Cohorte Lausannoise (CoLaus) Study (Lausanne, Switzerland). The rs2017869 variant of the γ-glutamyltransferase 1 (GGT1) gene, which explained 1.6% of the variance in GGT levels, was used as an instrument for Mendelian randomization (MR). Sex-specific GGT quartiles were strongly associated with both systolic and diastolic BP (all P's < 0.0001). After multivariable adjustment, these relations were attenuated but remained significant. Using MR, the authors observed no positive association of GGT with BP (systolic: β -5.68, 95% confidence interval (CI): -11.51, 0.16 (P = 0.06); diastolic: β = -2.24, 95% CI: -5.98, 1.49 (P = 0.24)). The association of GGT with insulin was also attenuated after multivariable adjustment but persisted in the fully adjusted model (β = 0.07, 95% CI: 0.04, 0.09; P < 0.0001). Using MR, the authors also observed a positive association of GGT with insulin (β = 0.19, 95% CI: 0.01, 0.37; P = 0.04). In conclusion, the authors found evidence for a direct causal relation of GGT with fasting insulin but not with BP.     

Lung cancer risk in painters: a meta-analysis

We conducted a meta-analysis to quantitatively compare the association between occupation as a painter and the incidence or mortality from lung cancer. PubMed and the reference lists of pertinent publications were searched and reviewed. For the meta-analysis, we used data from 47 independent cohort, record linkage, and case-control studies (from a total of 74 reports), including > 11,000 incident cases or deaths from lung cancer among painters. Three authors independently abstracted data and assessed study quality. The summary relative risk (meta-RR, random effects) for lung cancer in painters was 1.35 [95% confidence interval (CI), 1.29-1.41; 47 studies] and 1.35 (95% CI, 1.21-1.51; 27 studies) after controlling for smoking. The relative risk was higher in never-smokers (meta-RR = 2.00; 95% CI, 1.09-3.67; 3 studies) and persisted when restricted to studies that adjusted for other occupational exposures (meta-RR = 1.57; 95% CI, 1.21-2.04; 5 studies). These results support the conclusion that occupational exposures in painters are causally associated with the risk of lung cancer.     

Antihypertensive Medication Classes and the Risk of Dementia: A Systematic Review and Network Meta-Analysis

ObjectivesTo systematically review and synthesize the evidence on differential associations between antihypertensive medication (AHM) classes and the risk of incident dementia.DesignSystematic review and random effects frequentist network meta-analysis. Embase, MEDLINE, and the Cochrane library were searched from origin to December 2019.Setting and participantsRandomized controlled trials (RCTs) and prospective cohort studies that compared associations of different AHM classes with incident all-cause dementia and/or Alzheimer's disease over at least 1 year of follow-up.MeasuresAll cause dementia and/or Alzheimer's disease.ResultsFifteen observational studies and 7 RCTs were included. Data on AHM classes were available for 649,790 participants and dementia occurred in 19,600 (3.02%). Network meta-analysis showed that in observational studies, treatment with either calcium channel blockers (CCBs) or angiotensin II receptor blockers (ARBs) was associated with lower dementia risks than treatment with other antihypertensives: CCBs vs angiotensin converting enzyme inhibitors (ACE inhibitors) (HR=0.84, 95% CI 0.74-0.95), beta blockers (HR=0.83, 95% CI 0.73-0.95) and diuretics (HR=0.89, 95% CI 0.78-1.01) and ARBs vs ACE inhibitors (HR=0.88, 95% CI 0.81-0.97), beta blockers (HR=0.87, 95% CI 0.77-0.99), and diuretics (HR=0.93, 95% CI 0.83-1.05). There were insufficient RCTs to create a robust network based on randomized data alone.Conclusions and ImplicationsRecommending CCBs or ARBs as preferred first-line antihypertensive treatment may significantly reduce the risk of dementia. If corroborated in a randomized setting, these findings reflect a low-cost and scalable opportunity to reduce dementia incidence worldwide.     

Selective decontamination of the digestive tract reduces bacterial bloodstream infection and mortality in critically ill patients. Systematic review of randomized, controlled trials

A systematic review and meta-analysis of randomized controlled trials (RCTs) of selective decontamination of the digestive tract (SDD) was undertaken to evaluate the impact of this procedure on bacterial bloodstream infection and mortality. Data sources were Medline, Embase, Cochrane Register of Controlled Trials, previous meta-analyses, and conference proceedings, without restriction of language or publication status. RCTs were retrieved that compared oropharyngeal and/or intestinal administration of antibiotics as part of the SDD protocol, with or without a parenteral component, with no treatment or placebo in the controls. The three outcome measures were patients with bloodstream infection, causative micro-organisms, and total mortality. Fifty-one RCTs conducted between 1987 and 2005, comprising 8065 critically ill patients were included in the review; 4079 patients received SDD and 3986 were controls. SDD significantly reduced overall bloodstream infections [odds ratio (OR), 0.73; 95% confidence interval (CI), 0.59-0.90; P=0.0036], gram-negative bloodstream infections (OR, 0.39; 95% CI, 0.24-0.63; P<0.001) and overall mortality (OR, 0.80; 95% CI, 0.69-0.94; P=0.0064), without affecting gram-positive bloodstream infections (OR, 1.06; 95% CI, 0.77-1.47). The subgroup analysis showed an even larger impact of SDD using parenteral and enteral antimicrobials on overall bloodstream infections, bloodstream infections due to gram-negative bacteria and overall mortality with ORs of 0.63 (95% CI, 0.46-0.87; P=0.005), 0.30 (95% CI, 0.16-0.56; P<0.001), and 0.74 (95% CI, 0.61-0.91; P=0.0034), respectively. Twenty patients need to be treated with SDD to prevent one gram-negative bloodstream infection and 22 patients to prevent one death.     

大豆异黄酮对代谢综合征患者干预效果的Meta分析

目的　研究大豆异黄酮对代谢综合征患者多项指标的影响。方法　检索PubMed、中国知网、中国生物医学文献数据库、万方医学数据库和重庆维普数据库,搜索有关大豆异黄酮与代谢综合征的随机对照试验。采用RevMan5.3软件进行Meta分析。结果　纳入9项研究,有395例代谢综合征患者参与。Meta分析结果显示大豆异黄酮干预能提高患者高密度脂蛋白胆固醇水平［SMD=0.32,95%CI（0.16,0.48）,P<0.0001］,降低腰围［SMD=-0.56,95%CI（-1.07,-0.04）,P=0.0200］、甘油三酯［SMD=-0.56,95%CI（-0.94,-0.18）,P=0.0040］、总胆固醇［SMD=-3.39,95%CI（-4.76,-2.01）,P＜0.0001］、低密度脂蛋白胆固醇［SMD=-1.42,95%CI（-2.23,-0.61）,P=0.0006］、收缩压［SMD=-0.33,95%CI (-0.51, -0.15),P=0.0004］、舒张压［SMD=-0.28,95%CI (-0.46, -0.10),P=0.0030］及空腹血糖水平［SMD=-1.12,95%CI（-2.02,-0.23）,P=0.0100］。结论　大豆异黄酮能够有效改善代谢综合症患者多项指标。