Computing within-study covariances, data visualization, and missing data solutions for multivariate meta-analysis with metavcov

BackgroundMeta-analyses frequently include studies with small sample sizes. Researchers usually fail to account for sampling error in the reported within-study variances; they model the observed study-specific effect sizes with the within-study variances and treat these sample variances as if they were the true variances. However, this sampling error may be influential when sample sizes are small. This article illustrates that the sampling error may lead to substantial bias in meta-analysis results.MethodsWe conducted extensive simulation studies to assess the bias caused by sampling error. Meta-analyses with continuous and binary outcomes were simulated with various ranges of sample size and extents of heterogeneity. We evaluated the bias and the confidence interval coverage for five commonly-used effect sizes (i.e., the mean difference, standardized mean difference, odds ratio, risk ratio, and risk difference).ResultsSampling error did not cause noticeable bias when the effect size was the mean difference, but the standardized mean difference, odds ratio, risk ratio, and risk difference suffered from this bias to different extents. The bias in the estimated overall odds ratio and risk ratio was noticeable even when each individual study had more than 50 samples under some settings. Also, Hedges’ g, which is a bias-corrected estimate of the standardized mean difference within studies, might lead to larger bias than Cohen’s d in meta-analysis results.ConclusionsCautions are needed to perform meta-analyses with small sample sizes. The reported within-study variances may not be simply treated as the true variances, and their sampling error should be fully considered in such meta-analyses.

Evidence-Synthesis Tools to Inform Evidence-Based Physiatry.

Severe infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza virus can cause patients to be admitted to intensive care units (ICUs). It is necessary to understand the differences in clinical characteristics and outcomes between these two types of critically ill patients. We searched Embase, PubMed, and Web of Science for articles and performed a meta-analysis using Stata 14.0 with a random-effects model. This paper was written in strict accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Thirty-five articles involving 131,692 ICU patients with coronavirus disease 2019 (COVID-19) and 30,286 ICU patients with influenza were included in our meta-analysis. Compared with influenza patients, COVID-19 patients were more likely to be male (odds ratio (OR) = 1.75, 95% CI: 1.54-1.99) and older (standardized mean difference (SMD) = 0.16, 95% CI: 0.03-0.29). In terms of laboratory test results, COVID-19 patients had higher lymphocyte (SMD = 0.38, 95% CI: 0.17-0.59) and platelet counts (SMD = 0.52, 95% CI: 0.29-0.75) but lower creatinine (SMD = -0.29, 95% CI: -0.55-0.03) and procalcitonin levels (SMD = -0.78, 95% CI: -1.11-0.46). Diabetes (SMD = 1.27, 95% CI: 1.08-1.48) and hypertension (SMD = 1.30, 95% CI: 1.05-1.60) were more prevalent in COVID-19 patients, while influenza patients were more likely to have cancer (OR = 0.52, 95% CI: 0.44-0.62), cirrhosis (OR = 0.52, 95% CI: 0.44-0.62), immunodepression (OR = 0.38, 95% CI: 0.25-0.58), and chronic pulmonary diseases (OR = 0.35, 95% CI: 0.24-0.52). We also found that patients with COVID-19 had longer ICU stays (SMD = 0.20, 95% CI: 0.05-0.34), were more likely to develop acute respiratory distress syndrome (OR = 4.90, 95% CI: 2.77-8.64), and had higher mortality (OR = 1.35, 95% CI: 1.17-1.55). There are some differences in the basic characteristics, comorbidities, laboratory test results and complications between ICU patients with COVID-19 and ICU patients with influenza. Critically ill patients with COVID-19 often require more medical resources and have worse clinical outcomes. PROSPERO Registration Number: CRD42023452238.

ObjectiveThis systematic review and meta-analysis aimed to summarize the available evidence regarding circulating kisspeptin and anti-müllerian hormone (AMH) and the homeostasis model assessment of insulin resistance (HOMA-IR) index in adolescents and women with and without polycystic ovary syndrome (PCOS). MethodWe performed a comprehensive literature search in Medline, Embase, Cochrane, Scopus, and Web of Science for studies evaluating circulating kisspeptin levels in women with and without PCOS published until September 24th, 2020. Co-primary outcomes were the HOMA-IR index and AMH. The quality of included studies was assessed using the Newcastle-Ottawa Scale. Random-effects models were used to estimate outcomes, and effects reported as mean difference (MD) or standardized MD (SMD) and their 95 % confidence interval (CI). The systematic review and meta-analysis was registered in the International Prospective Register of Systematic Reviews (PROSPERO) as number CRD42020205030. ResultsWe evaluated 18 studies including, 1282 PCOS cases and 977 controls. Participants with PCOS were younger (MD = −2.38 years, 95 %CI -4.32 to -0.44), with higher BMI (MD = 1.16, 95 % CI 0.54–1.78), waist-to-hip ratio (MD = 0.04, 95 %CI 0.02 to 0.05), circulating kisspeptin (SMD = 1.15, 95 %CI 0.68–1.62), luteinizing hormone (SMD = 1.29, 95 %CI 0.76–1.83), AMH (SMD = 0.97, 95 %CI 0.60–1,34), total testosterone (SMD = 2.48, 95 %CI 1.73–3.23), free testosterone (SMD = 1.37, 95 %CI 0.56–2.17), and dehydroepiandrosterone sulphate (SMD = 0.72, 95 %CI 0.32–1.13) levels, and Ferriman-Gallwey score (SMD = 5.08, 95 %CI 2.76–7.39), and lower sex hormone-binding globulin level (SMD = −1.34, 95 %CI −2.15 to −0.52). Besides, participants with PCOS had higher HOMA-IR index (SMD = 0.76, 95 %CI 0.35–1.17), and circulating insulin (SMD = 0.75, 95 %CI 0.30–1.19), leptin (SMD = 2.82, 95 %CI 1.35–4.29), and triglycerides (SMD = 2.15, 95 %CI 1.08–3.23) levels than participants without the syndrome. The meta-regression did not identify significant factors influencing circulating kisspeptin. ConclusionPatients with PCOS showed higher kisspeptin, LH, insulin, AMH, and androgen levels and HOMA-IR index, and lower sex hormone-binding globulin levels than those without the syndrome.

BackgroundNutrition support is a common means for patients with gastric cancer, especially for those undergoing elective surgery. Recently, enteral immunonutrition (EIN) was increasingly found to be more effective than enteral nutrition (EN) in enhancing the host immunity and eventually improving the prognosis of gastric cancer patients undergoing gastrectomy. However, the results reported were not consistent. This meta-analysis aimed to assess the impact of EIN for patients with GC on biochemical, immune indices and clinical outcomes.MethodsFour electronical databases (Medline, EMBASE, Scopus and Cochrane library) were used to search articles in peer-reviewed, English-language journals. Mean difference (MD), Relative risk (RR), or standard mean difference (SMD) with 95% confidence interval (CI) were calculated. Heterogeneity was assessed by Cochrane Q and I2 statistic combined with corresponding P-value. The analysis was carried out with RevMan 5.3.ResultsSeven studies involving 583 patients were eligible for the pooled analysis. EIN, when beyond a 7-day time-frame post-operatively (D ≥ 7), increased level of CD4+ (SMD = 0.99; 95% CI, 0.65–1.33; P < 0.00001), CD4+/ CD8+ (SMD = 0.34; 95% CI, 0.02–0.67; P = 0.04), the IgM (SMD = 1.15; 95% CI, 0.11–2.20; P = 0.03), the IgG (SMD = 0.98; 95% CI, 0.55–1.42; P < 0.0001), the lymphocyte (SMD = 0.69; 95% CI, 0.32–1.06; P = 0.0003), and the proalbumin (SMD = 0.73; 95% CI, 0.33–1.14; P = 0.0004). However, those increased effects were not obvious within a 7-day time-frame post-operatively (D < 7). The levels of CD8+ and other serum proteins except proalbumin were not improved both on D ≥ 7 and D < 7. Clinical outcomes such as systemic inflammatory response syndrone (SIRS) (MD, - 0.89 days; 95% CI, - 1.40 to - 0.39; P = 0.005), and postoperative complications (RR, 0.29; 95% CI, 0.14–0.60; P = 0.001) were significantly reduced in EIN group. Pulmonary infection and length of hospitalization (LHS) were not improved no matter what time after surgery.ConclusionsEIN was found to improve the cellular immunity, modulate inflammatory reaction and reduce postoperative complication for GC patients undergoing radical gastrointestinal surgery. Exclusion of grey literature and non-English language studies was the key limitation in this study.

IMPACT OF CONTACT FORCE TECHNOLOGY ON ATRIAL FIBRILLATION ABLATION: A META-ANALYSIS

Effectiveness of psychosocial interventions for reducing parental substance misuse.

Heel lance has been the conventional method of blood sampling in neonates for screening tests. Neonates undergoing heel lance experience pain which cannot be completely alleviated. To determine whether venepuncture or heel lance is less painful and more effective for blood sampling in term neonates. Randomized or quasi-randomised controlled trials comparing pain response to venepuncture versus heel lance were identified by searching the Cochrane Central Regsiter of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, CINAHL, and clinical trials registries in May 2011. Trials comparing pain response to venepuncture versus heel lance with or with out the use of a sweet tasting solution as a co-intervention in term neonates. Outcomes included pain response to venepuncture versus heel lance with or without the use of a sweet tasting solution using validated pain measures, the need of repeat sampling and cry characteristics. Analyses included typical relative risk (RR), risk difference (RD), number needed to treat (NNT), weighted mean difference (WMD) and standardized mean difference (SMD) with their 95% confidence intervals (CI). Between study heterogeneity was reported including the I squared (I(2)) test. Six studies (n = 478) of variable quality were included. A composite outcome of Infant Pain Scale (NIPS), Neonatal Facial Action Coding System (NFCS) and/or Premature Infant Pain Profile (PIPP) score was reported in 288 infants, who did not receive a sweet tasting solution. Meta-analysis showed a significant reduction in the venepuncture versus the heel lance group (SMD -0.76, 95% CI -1.00 to -0.52; I(2) = 0%). When a sweet tasting solution was provided the SMD remained significant favouring the venepuncture group (SMD - 0.38, 95% CI -0.69 to -0.07). The typical RD for requiring more than one skin puncture for venepuncture versus heel lance (reported in 4 studies; n = 254) was -0.34 (95% CI -0.43 to -0.25; I(2) = 97%). The NNT to avoid one repeat skin puncture was 3 (95% CI 2 to 4). Cry characteristics favoured the venepuncture group but the differences were reduced by the provision of sweet tasting solutions prior to either procedure. Venepuncture, when performed by a skilled phlebotomist, appears to be the method of choice for blood sampling in term neonates. The use of a sweet tasting solution further reduces the pain.Further well designed randomised controlled trials should be conducted in settings where several individuals perform the procedures.

Involving consumer-providers in mental health teams results in psychosocial, mental health symptom and service use outcomes for clients that were no better or worse than those achieved by professionals employed in similar roles, particularly for case management services.There is low quality evidence that involving consumer-providers in mental health teams results in a small reduction in clients' use of crisis or emergency services. The nature of the consumer-providers' involvement differs compared to professionals, as do the resources required to support their involvement. The overall quality of the evidence is moderate to low. There is no evidence of harm associated with involving consumer-providers in mental health teams.Future randomised controlled trials of consumer-providers in mental health services should minimise bias through the use of adequate randomisation and concealment of allocation, blinding of outcome assessment where possible, the comprehensive reporting of outcome data, and the avoidance of contamination between treatment groups. Researchers should adhere to SPIRIT and CONSORT reporting standards for clinical trials.Future trials should further evaluate standardised measures of clients' mental health, adverse outcomes for clients, the potential benefits and harms to the consumer-providers themselves (including need to return to treatment), and the financial costs of the intervention. They should utilise consistent, validated measurement tools and include a clear description of the consumer-provider role (eg specific tasks, responsibilities and expected deliverables of the role) and relevant training for the role so that it can be readily implemented. The weight of evidence being strongly based in the United States, future research should be located in diverse settings including in low- and middle-income countries.

Does Surgical Approach Affect Outcomes in Total Hip Arthroplasty Through 90 Days of Follow-Up? A Systematic Review With Meta-Analysis

During menopause a decreasing ovarian follicular response generally causes a fluctuation and eventual decrease in estrogen levels. This can lead to the development of various perimenopausal and postmenopausal symptoms (for example hot flushes, night sweats, vaginal dryness). Dehydroepiandrosterone (DHEA) is one of the main precursors of androgens, which in turn are converted to testosterone and estrogens. It is possible that the administration of DHEA may increase estrogen and testosterone levels in peri- and postmenopausal women to alleviate their symptoms and improve general wellbeing and sexual function (for example libido, dyspareunia, satisfaction). Treatment with DHEA is controversial as there is uncertainty about its effectiveness and safety. This review should clearly outline the evidence for DHEA in the treatment of menopausal symptoms and evaluate its effectiveness and safety by combining the results of randomised controlled trials. To assess the effectiveness and safety of administering DHEA to women with menopausal symptoms in the peri- or postmenopausal phase. The databases that we searched (3 June 2014) with no language restrictions applied were the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS. We also searched conference abstracts and citation lists in the ISI Web of Knowledge. Ongoing trials were searched in the trials registers. Reference lists of retrieved articles were checked. We included randomised controlled trials comparing any dose and form of DHEA by any route of administration versus any other active intervention, placebo or no treatment for a minimal treatment duration of seven days in peri- and postmenopausal women. Two authors independently extracted data after assessing eligibility for inclusion and quality of studies. Authors were contacted for additional information. Twenty-eight trials with 1273 menopausal women were included in this review. Data could be extracted from 16 trials to conduct the meta-analysis. The overall quality of the studies was moderate to low with the majority of studies that were included in the meta-analysis having reasonable methodology. Compared to placebo, DHEA did not improve quality of life (standardised mean difference (SMD) 0.16, 95% confidence interval (CI) -0.03 to 0.34, P = 0.10, 8 studies, 287 women (132 from parallel and 155 from crossover trials), I² = 0%, moderate quality evidence; one trial of the nine that reported on this outcome was removed in a sensitivity analysis as it was judged to be at high risk of bias). DHEA was found to be associated with androgenic side effects (mainly acne) (odds ratio (OR) 3.77, 95% CI 1.36 to 10.4, P = 0.01, 5 studies, 376 women, I² = 10%, moderate quality evidence) when compared to placebo. No associations were found with other adverse effects. It was unclear whether DHEA affected menopausal symptoms as the results from the trials were inconsistent and could not easily be pooled to provide an overall effect due to different types of measurement (for example continuous, dichotomous, change and end scores). DHEA was found to improve sexual function (SMD 0.31, 95% CI 0.07 to 0.55, P = 0.01, 5 studies, 261 women (239 women from parallel trials and 22 women from crossover trials), I² = 0%; one trial judged to be at high risk of bias was removed during sensitivity analysis) compared to placebo.There was no difference in the acne associated with DHEA when comparing studies that used oral DHEA (OR 2.16, 95% CI 0.47 to 9.96, P = 0.90, 3 studies, 136 women, I² = 5%, very low quality evidence) to one study that used skin application of DHEA (OR 2.74, 95% CI 0.10 to 74.87, P = 0.90, 1 study, 22 women, very low quality evidence). The effects did not differ for sexual function when studies using oral DHEA (SMD 0.11, 95% CI -0.13 to 0.35, P = 0.36, 5 studies, 340 women, I² = 0) were compared to a study using intravaginal DHEA (SMD 0.42, 95% CI 0.03 to 0.81, 1 study, 218 women). Test for subgroup differences: Chi² = 1.77, df = 1 (P = 0.18), I² = 43.4%. Insufficient data were available to assess quality of life and menopausal symptoms for this comparison.There were insufficient data available to compare the effects of DHEA to hormone therapy (HT) for quality of life, menopausal symptoms, and adverse effects. No large differences in treatment effects were found for sexual function when comparing DHEA to HT (mean difference (MD) 1.26, 95% CI -0.21 to 2.73, P = 0.09, 2 studies, 41 women, I² = 0%). There is no evidence that DHEA improves quality of life but there is some evidence that it is associated with androgenic side effects. There is uncertainty whether DHEA decreases menopausal symptoms, but DHEA may slightly improve sexual function compared with placebo.

BackgroundParkinson disease (PD) impairs gait, balance, and quality of life, and wearable devices have been proposed to support rehabilitation, but evidence for their clinical efficacy remains uncertain.ObjectiveThis study aimed to evaluate, within the International Classification of Functioning, Disability, and Health (ICF) framework, the effects of wearable-device interventions on gait performance, balance, and health-related quality of life in people with PD by conducting a systematic review and meta-analysis of randomized controlled trials (RCTs).MethodsWe searched PubMed, Web of Science, Cochrane Library, Embase, and ClinicalTrials.gov from inception to November 18, 2025, for RCTs in people with PD comparing wearable-device interventions with control conditions. We used Hartung-Knapp random-effects models to pool mean differences (MDs) or standardized mean differences (SMDs) and reported 95% prediction intervals when ≥3 studies were pooled. Risk of bias was assessed using the Cochrane Risk of Bias (RoB) tool, and certainty of evidence was rated using Grading of Recommendations Assessment, Development, and Evaluation (GRADE).ResultsNine RCTs involving 260 participants were included. Wearable devices produced a small improvement in stride length (MD 0.10 meter, 95% CI 0.03-0.17), but there was no clear benefit for the 10-Meter Walk Test time (MD 0.04 second, 95% CI –0.06 to 0.15). Double support time showed no reduction (MD –1.59% gait cycle, 95% CI –3.79 to 0.61). Freezing of gait (Freezing of Gait Questionnaire [FOG-Q] and New Freezing of Gait Questionnaire [NFOG-Q]) did not significantly improve (SMD –0.24, 95% CI –0.72 to 0.24). Motor severity (Unified Parkinson Disease Rating Scale Part III [UPDRS III]) showed a small, nonsignificant trend favoring wearable devices (MD –2.16 points, 95% CI –4.39 to 0.07). For balance, pooled results from the Berg Balance Scale (BBS), Mini Balance Evaluation Systems Test (Mini-BESTest), and Performance-Oriented Mobility Assessment Balance Subscale (POMA balance) suggested a borderline effect (SMD 0.48, 95% CI –0.02 to 0.98). Wearable devices did not meaningfully improve Parkinson Disease Questionnaire (PDQ) scores (SMD –0.28, 95% CI –0.74 to 0.17), EQ-5D utility (MD 0.10, 95% CI –0.24 to 0.44), or Falls Efficacy Scale–International (FES-I) scores (MD –0.04, 95% CI –1.10 to 1.02). Prediction intervals frequently crossed the null, suggesting effects may vary by setting and population.ConclusionsWearable device interventions for Parkinson disease produced a small improvement on average in stride length, with no consistent benefits for other gait outcomes, balance, or patient-centered outcomes. By integrating ICF mapping with Hartung-Knapp meta-analysis, prediction intervals, and GRADE, and avoiding pooling of conceptually distinct gait measures used in prior reviews, this review clarifies where evidence is most consistent, supports using wearables as adjuncts to rehabilitation, and underscores the need for larger, longer RCTs with standardized outcomes to determine who benefits and how to implement them.Trial RegistrationPROSPERO CRD42024585686; https://www.crd.york.ac.uk/PROSPERO/view/CRD42024585686

PurposePrimary hyperparathyroidism (PHPT) is characterized by increased bone remodeling and hypercalcemia. Parathyroidectomy (PTX), the current standard of care, is recommended in all symptomatic and some groups of asymptomatic patients. Anti-resorptive therapies (bisphosphonates and denosumab) have been used in patients where PTX is refused or contraindicated. In this meta-analysis, we investigated the effectiveness of anti-resorptives in preventing/treating PHPT-induced bone loss and mitigating hypercalcemia.MethodPubMed, Scopus, and Cochrane Library databases were searched for articles with keywords containing PHPT, bisphosphonates, and denosumab in various combinations. We extracted and tabulated areal BMD (aBMD), serum mineral, and bone turnover parameters from the qualified studies and used comprehensive meta-analysis software for analysis.ResultsOf the 1,914 articles screened, 13 were eligible for meta-analysis. In the pooled analysis, 12 months of anti-resoptives (bisphosphonates and denosumab) therapy significantly increased aBMD at the lumbar spine (Standard difference in means (SDM)=0.447, 95% CI=0.230 to 0.664, p=0.0001), femoral neck (SDM=0.270, 95% CI=0.049 to 0.491, p=0.017) and increased serum PTH (SDM=0.489, 95% CI=0.139 to 0.839, p=0.006), and decreased serum calcium (SDM=-0.545, 95% CI=-0.937 to -0.154, p=0.006) compared with baseline. 12 months of bisphosphonate use significantly increased aBMD only at the lumbar spine (SDM=0.330, 95% CI=0.088 to 0.571, p=0.007) with a significant increased in serum PTH levels (SDM=0.546, 95% CI= 0.162 to 0.930, p=0.005), and a decreased in serum calcium (SDM=-0.608, 95% CI=-1.048 to -0.169, p=0.007) and bone-turnover markers (BTMs) compared with baseline. Denosumab use for 12 months significantly increased aBMD at both the lumbar spine (SDM=0.828, 95% CI=0.378 to 1.278, p=0.0001) and femur neck (SDM=0.575, 95% CI=0.135 to 1.015, p=0.010) compared with baseline. Mean lumbar spine aBMD (SDM=0.350, 95% CI=0.041 to 0.659, p=0.027) and serum PTH (SDM=0.602, 95% CI= 0.145 to 1.059, p=0.010) were significantly increased after 12 months of alendronate use compared with placebo. When compared with baseline, alendronate significantly decreased BTMs after 12 months and increased aBMD without altering the PTH and calcium levels after 24 months.ConclusionAnti-resorptives are effective in mitigating bone loss and hypercalcemia in PHPT while maintaining or increasing aBMD. PTX reversed all changes in PHPT and normalized PTH levels.

ObjectivesContradictory findings exist in studies comparing salpingectomy and proximal tubal occlusion (PTO) in treating hydrosalpinx patients before in vitro fertilization (IVF). Therefore, this meta-analysis aimed to comprehensively compare ovarian response, pregnancy outcomes, and complications between salpingectomy and PTO in treating these patients.MethodsEmbase, PubMed, and Web of Science were searched to identify relevant articles published from 1980 to August 31, 2020. Eight studies that involve 716 hydrosalpinx patients before IVF were included, among whom 408 patients received salpingectomy and 308 patients received PTO. The data were pooled; the standardized mean difference (SMD) or odds ratio (OR) was calculated.ResultsProximal tubal occlusion-treated patients had higher fertilization rate (SMD = 0.35, 95% CI: 0.11–0.59), while similar days of controlled ovarian hyperstimulation (COH) (SMD: 0.15, 95% CI: −0.36–0.67) and number of retrieved oocytes (SMD = −0.22, 95% CI: −0.54–0.10) compared with salpingectomy-treated patients. Furthermore, no difference of implantation rate (OR = 1.17, 95% CI: 0.62–2.20), clinical pregnancy rate (OR = 0.82, 95% CI: 0.59–1.15), ongoing pregnancy rate (OR = 0.64, 95% CI: 0.36–1.13), or live birth rate (OR = 0.67, 95% CI: 0.16–2.72) was shown between salpingectomy-treated patients and PTO-treated patients. Additionally, ectopic pregnancy rate (OR = 1.13, 95% CI: 0.21–5.92) and miscarriage rate (OR = 0.88, 95% CI: 0.31–2.48) were similar between salpingectomy-treated patients and PTO-treated patients.ConclusionProximal tubal occlusion exhibits a higher fertilization rate but no obvious benefits on days of COH, number of retrieved oocytes, pregnancy outcomes, and complications over salpingectomy in hydrosalpinx patients before IVF.

Moderate- to low-quality evidence suggests that mobile bearing prostheses may have similar effects on knee pain, clinical and functional scores, health-related quality of life, revision surgery, mortality, reoperation rate and other serious adverse events compared with fixed bearing prostheses in posterior cruciate retaining TKA. Therefore we cannot draw firm conclusions. Most (98.5%) participants had OA, so the findings primarily reflect results reported in participants with OA. Future studies should report in greater detail outcomes such as those presented in this systematic review, with sufficient follow-up time to allow gathering of high-quality evidence and to inform clinical practice. Large registry-based studies may have added value, but they are subject to treatment-by-indication bias. Therefore, this systematic review of RCTs can be viewed as the best available evidence.