Individual Participant Data Meta-analysis Research Articles

The role of endometrial scratching in IVF/ICSI: a critical appraisal of individual participant data meta-analysis.

The role of endometrial scratching in IVF/ICSI: a critical appraisal of individual participant data meta-analysis.

Comparison of Patient Health Questionnaire-9, Edinburgh Postnatal Depression Scale and Hospital Anxiety and Depression – Depression subscale scores by administration mode: An individual participant data differential item functioning meta-analysis

Administration mode of patient-reported outcome measures (PROMs) may influence responses. We assessed if Patient Health Questionnaire-9 (PHQ-9), Edinburgh Postnatal Depression Scale (EPDS) and Hospital Anxiety and Depression Scale – Depression subscale (HADS-D) item responses and scores were associated with administration mode. We compared (1) self-administration versus interview-administration; within self-administration (2) research or medical setting versus private; and (3) pen-and-paper versus electronic; and within interview-administration (4) in-person versus phone. We analysed individual participant data meta-analysis datasets with item-level data for the PHQ-9 (N = 34,529), EPDS (N = 16,813), and HADS-D (N = 16,768). We used multiple indicator multiple cause models to assess differential item functioning (DIF) by administration mode. We found statistically significant DIF for most items on all measures due to large samples, but influence on total scores was negligible. In 10 comparisons conducted across the PHQ-9, EPDS, and HADS-D, Pearson's correlations and intraclass correlation coefficients between latent depression symptom scores from models that did or did not account for DIF were between 0.995 and 1.000. Total PHQ-9, EPDS, and HADS-D scores did not differ materially across administration modes. Researcher and clinicians who evaluate depression symptoms with these questionnaires can select administration methods based on patient preferences, feasibility, or cost.

Systematic review: Patient-related, microbial, surgical, and histopathological risk factors for endoscopic post-operative recurrence in patients with Crohn's disease.

Risk stratification for endoscopic post-operative recurrence (ePOR) in Crohn's disease (CD) is required to identify patients who would benefit most from initiation of prophylactic medication and intensive monitoring of recurrence. To assess the current evidence on patient-related, microbial, surgical and histopathological risk factors for ePOR in patients with CD after ileocolic (re-)resection. Multiple online databases (Embase, MEDLINE, Web of Science and Cochrane Library) were searched up to March 2024. Studies with reported associations of patient-related, microbial, surgical and/or histopathological factors for ePOR (i.e., Rutgeerts' score ≥i2 or modified Rutgeerts' score ≥i2a) were included. The risk of bias was assessed with the Newcastle-Ottawa Scale for observational cohort studies and case-control studies. In total, 47 studies were included (four RCTs, 29 cohort studies, 12 case-control studies, one cross-sectional study and one individual participant data meta-analysis) including 6006 patients (median sample size 87 patients [interquartile range 46-170]). Risk of bias assessment revealed a poor quality in 41% of the studies. An association was reported in multiple studies of ePOR with active smoking at and post-surgery, male sex and prior bowel resection. A heterogeneous association with ePOR was reported for other risk factors included in the current guidelines (penetrating disease, perianal disease, younger age, extensive small bowel disease and presence of granulomas in the resection specimen or myenteric plexitis in the resection margin), and other patient-related, microbial, surgical and histopathological factors. Risk factors for ePOR in international guidelines are not consistently reported as risk factors in current literature except for active smoking and prior bowel resection. To develop evidence-based, personalised strategies, large prospective studies are warranted to identify risk factors for ePOR. Validation studies of promising (bio)markers are also required.

Allergic Contact Dermatitis to Topical Preparations Containing Minoxidil: A Systematic Review and Individual Participant Data Meta-Analysis.

Topical minoxidil is generally well tolerated, yet there have been a few reports of allergic contact dermatitis (ACD) confirmed through patch testing. This systematic review and individual participant data meta-analysis sought to elucidate the primary allergens in patients exhibiting ACD in response to topical minoxidil formulations and to ascertain the appropriate testing concentrations and vehicles of minoxidil itself. A comprehensive search was conducted across the PubMed, Scopus, and Embase databases utilizing the keywords "minoxidil" and "contact dermatitis," or "contact allergy," or "contact eczema." Studies documenting ACD in patients using topical minoxidil confirmed by patch testing were deemed eligible. Our analysis included 46 studies encompassing 99 patients with patch-test-confirmed ACD to minoxidil-based topical treatments. The majority of these patients (93.9%) were exposed to minoxidil without additional active components. Minoxidil itself was identified as the primary allergen in 74.7% of the patients, with propylene glycol being the next most common allergen at 17.1%. Other allergens identified included estradiol, butylene glycol, methylchloroisothiazolinone/methylisothiazolinone, canrenone, and latanoprost. The most effective concentration was found to be 2% minoxidil in propylene glycol, which yielded a 100% positivity rate. The findings indicate that minoxidil is the predominant allergen in ACD reactions to its topical formulations, followed by propylene glycol. For the accurate diagnosis of ACD related to minoxidil, patch testing with 2% minoxidil in propylene glycol is recommended, as are separate tests for propylene glycol and other potential allergenic ingredients.

409-P: Evaluating the Agreement between CKD-EPI Calculated eGFR and mGFR in People with Diabetes—An International Individual Participant Data Meta-analysis

409-P: Evaluating the Agreement between CKD-EPI Calculated eGFR and mGFR in People with Diabetes—An International Individual Participant Data Meta-analysis

Validation of the Health Assessment Tool (HAT) based on four aging cohorts from the Swedish National study on Aging and Care

BackgroundAs global aging accelerates, routinely assessing the functional status and morbidity burden of older patients becomes paramount. The aim of this study is to assess the validity of the comprehensive clinical and functional Health Assessment Tool (HAT) based on four cohorts of older adults (60 + years) from the Swedish National study on Aging and Care (SNAC) spanning urban, suburban, and rural areas.MethodsThe HAT integrates five health indicators (gait speed, global cognition, number of chronic diseases, and basic and instrumental activities of daily living), providing an individual-level score between 0 and 10. The tool was constructed using nominal response models, first separately for each cohort and then in a harmonized dataset. Outcomes included all-cause mortality over a maximum follow-up of 16 years and unplanned hospital admissions over a maximum of 3 years of follow-up. The predictive capacity was assessed through the area under the curve (AUC) using logistic regressions. For time to death, Cox regressions were performed, and Harrell’s C-indices were reported. Results from the four cohorts were pooled using individual participant data meta-analysis and compared with those from the harmonized dataset.ResultsThe HAT demonstrated high predictive capacity across all cohorts as well as in the harmonized dataset. In the harmonized dataset, the AUC was 0.84 (95% CI 0.81–0.87) for 1-year mortality, 0.81 (95% CI 0.80–0.83) for 3-year mortality, 0.80 (95% CI 0.79–0.82) for 5-year mortality, 0.69 (95% CI 0.67–0.70) for 1-year unplanned admissions, and 0.69 (95% CI 0.68–0.70) for 3-year unplanned admissions. The Harrell’s C for time-to-death throughout 16 years of follow-up was 0.75 (95% CI 0.74–0.75).ConclusionsThe HAT is a highly predictive, clinically intuitive, and externally valid instrument with potential for better addressing older adults’ health needs and optimizing risk stratification at the population level.

The effect of balanced energy-protein supplementation provided to lactating women on maternal and infant outcomes: study protocol for a prospectively planned individual patient data (IPD) meta-analysis

Abstract* Background The high prevalence of infant stunting and maternal undernutrition in low- and middle-income countries poses a significant public health threat. The World Health Organization recommends balanced energy-protein (BEP) supplementation to pregnant women from populations with a high prevalence of underweight (prepregnancy BMI <18.5 kg/m2), leaving a notable gap in guidance for lactating women. Therefore, we established the Maternal BEP Studies Harmonization Initiative (BEP Initiative) to investigate the impact of BEP supplementation given to pregnant and/or lactating women on maternal and infant outcomes by synthesizing data from multiple clinical trials. This is a study protocol for our prospective individual participant data (IPD) meta-analysis on BEP lactation trials. Methods Data from four randomized controlled trials that include mother-infant dyads in India (n=816), Pakistan (n=957), Burkina Faso (n=800), and Nepal (n=726) will be pooled and analysed. Women were randomized to BEP (one trial had a third arm with maternal BEP plus infants receiving azithromycin) or control groups at baseline (during the first week) and received the intervention through six months postpartum. A one-stage IPD meta-analysis will be done using mixed-effects linear and log-binomial regression models to account for between-trial heterogeneity. The primary outcome of infant length-for-age z scores (LAZ) and secondary outcomes of maternal and infant indicators of nutritional status, all at six months of age, will be examined. Also, we will assess baseline characteristics as covariates and effect modifiers for the BEP to outcome relationship. Discussion This prospective IPD meta-analysis uses a one-stage IPD meta-analysis, which allows for higher statistical power to examine outcomes, more flexibility in defining variables, and can examine effect modifiers, which could inform which individuals or populations may benefit more from BEP given during lactation.

Deferred Cord Clamping, Cord Milking, and Immediate Cord Clamping at Preterm Birth: A Systematic Review and Individual Participant Data Meta-analysis

(Abstracted from Lancet 2023;402:2209–2222) Deferring or delaying umbilical cord clamping for at least 60 seconds is an increasingly common practice for infants. For term neonates, this practice has been shown to improve hemoglobin and hematocrit levels and lower the risk of iron deficiency.

Enhancing oncology research through data sharing and re-use: A five-year review of Vivli's global data platform.

e13670 Background: The last decade has seen a paradigm shift in clinical research with the accessibility of trial data, facilitating secondary analyses and the development of novel predictive models. Vivli a non-profit entity established in 2018, epitomizes this movement with its global platform (vivli.org) dedicated to the facilitating access to and re-use of individual participant data from completed clinical trials for use by researchers worldwide. Methods: Commencing with approximately 2,500 trials from 15 members, Vivli has expanded over five years to encompass more than 7,000 trials involving 3.6 million participants across 50 members who contribute trial data from various sectors (industry, academic, government and non-profit foundation). Results: Oncology trials constitute 11% of the Vivli data pool of 7,000 trials, constituting 36% of Vivli’s research proposals due to the therapeutic area's high-impact potential. Researchers accessing data in the Vivli platform have produced a significant body of scientific work, with 74 oncology-focused publications emerging from their analyses. Notably, Roche's data has been a key resource, denoted by the 28% of all Vivli proposals requesting access to Roche data. Fifty-eight publications have resulted from secondary analysis of Roche oncology data. The motivation for secondary analyses in oncology have been predominantly for new research into treatment effectiveness or safety (39%). Other reasons include confirmation of existing research (15%), individual participant data (IPD) meta-analysis (14%), statistical method (10%), clinical trial design (5%), and summary-level meta-analysis (4%), training/testing (7%), other (5%). Conclusions: The Vivli platform has proven to be a key resource in recent years for the oncology community enabling the integration and publication of new insights. The sharing of IPD is in part motivated to ensure reproducibility of findings; our experience demonstrates that a minority of researchers are interested in reproducibility analysis but the majority of research is focused on new insight generation. The platform's success in facilitating the findability, accessibility and reuse of patient level data is signified by ever increasing numbers of scientific publications emerging from analyses on the Vivli platform and this underscores its role in advancing scientific discovery and development within the field of oncology.

Outcome of emergency neurosurgery in patients with refractory and super-refractory status epilepticus: a systematic review and individual participant data meta-analysis.

Refractory (RSE) and super-refractory status epilepticus (SRSE) are serious neurological conditions requiring aggressive management. Beyond anesthetic agents, there is a lack of evidence guiding management in these patients. This systematic review and individual participant data meta-analysis (IPDMA) seeks to evaluate and compare the currently available surgical techniques for the acute treatment of RSE and SRSE. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Individual Participant Data (PRISMA-IPD). Only patients who underwent surgery while in RSE and SRSE were included. Descriptive statistics were used to compare various subgroups. Multivariable logistic regression models were constructed to identify predictors of status epilepticus (SE) cessation, long-term overall seizure freedom, and favorable functional outcome (i.e., modified Rankin score of 0-2) at last follow-up. A total of 87 studies including 161 participants were included. Resective surgery tended to achieve better SE cessation rate (93.9%) compared to non-resective techniques (83.9%), but this did not reach significance (p = 0.071). Resective techniques were also more likely to achieve seizure freedom (69.1% vs. 34.4%, p = <0.0001). Older age at SE (OR = 1.384[1.046-1.832], p = 0.023) was associated with increased likelihood of SE cessation, while longer duration of SE (OR = 0.603[0.362-1.003], p = 0.051) and new-onset seizures (OR = 0.244[0.069-0.860], p = 0.028) were associated with lower likelihood of SE cessation, but this did not reach significance for SE duration. Only shorter duration of SE prior to surgery (OR = 1.675[1.168-2.404], p = 0.0060) and immediate termination of SE (OR = 3.736 [1.323-10.548], p = 0.014) were independently associated with long-term seizure status. Rates of favorable functional outcomes (mRS of 0-2) were comparable between resective (44.4%) and non-resective (44.1%) techniques, and no independent predictors of outcome were identified. Our findings suggest that emergency neurosurgery may be a safe and effective alternative in patients with RSE/SRSE and may be considered earlier during the disease course. However, the current literature is limited exclusively to small case series and case reports with high risk of publication bias. Larger clinical trials assessing long-term seizure and functional outcomes are warranted to establish robust management guidelines.

Cost effectiveness analysis of a fixed dose combination pill for primary prevention of cardiovascular disease from an individual participant data meta-analysis

Cardiovascular disease (CVD) continues to impart a large burden on the global population, especially in lower income countries where affordability limits the use of cardiovascular medicines. A fixed dose combination strategy of at least 2 blood pressure lowering medications and a statin with aspirin in a single pill has been shown to reduce the risk of incident CVD by 38% in primary prevention in a recent meta-analysis. We report the in-trial (median follow-up: 5 years) cost-effectiveness of a fixed dose combination (FDC) pill in different income groups based on data from that meta-analysis. Countries were categorized using World Bank economic groups: Lower Middle Income Countries (LMIC), Upper Middle Income Countries (UMIC) and High Income Countries (HIC). Country specific costs were obtained for hospitalized events, procedures, and non-study medications (2020 USD). FDC price was based on the cheapest equivalent substitute (CES) for each component. For the CES-FDC pill versus control the difference in cost was $346 (95% CI: $294-$398) per participant in Lower Middle Income Countries, $838 (95% CI: $781-$895) in Upper Middle Income Countries and $42 (95% CI:-$155 to $239) (cost-neutral) in High Income Countries. During the study period the CES-FDC pill was associated with incremental gain in quality-adjusted life years of 0.06 (95% CI: 0.04-0.08) resulting in an incremental cost-effectiveness ratio (ICER) of $5767 (95% CI: 5735-$5799), $13,937 (95% CI: $13,893-$14,041) and $700 (95% CI: $662-$738) respectively. In subgroups analyses, the highest 10 years CVD risk subgroup had ICERs of $2033, $7322 and-$6000/QALY. A FDC pill produced at CES costs is cost-neutral in HIC. Governments of LMI and UMI countries should assess these results based on the ICER threshold accepted in their own country and own specific health care priorities but should consider prioritizing this strategy for patients with high 10 years CVD risk as a first step. Population Health Research Institute.

How well do participants in clinical trials represent the U.S. population with chronic neck or back pain?

Randomized clinical trials (RCTs) are the gold standard for assessing treatment effectiveness; however, they have been criticized for generalizability issues such as how well trial participants represent those who receive the treatments in clinical practice. We assessed the representativeness of participants from eight RCTs for chronic spine pain in the U.S., which were used for an individual participant data meta-analysis on the cost-effectiveness of spinal manipulation for spine pain. In these clinical trials, spinal manipulation was performed by chiropractors. We conducted a retrospective secondary analysis of RCT data to compare trial participants' socio-demographic characteristics, clinical features, and health outcomes to a representative sample of (a) U.S. adults with chronic spine pain and (b) U.S. adults with chronic spine pain receiving chiropractic care, using secondary data from the National Health Interview Survey (NHIS) and Medical Expenditure Panel Survey (MEPS). We assessed differences between trial and U.S. spine populations using independent t-tests for means and z-tests for proportions, accounting for the complex multi-stage survey design of the NHIS and MEPS. We found the clinical trials had an under-representation of individuals from health disparity populations with lower percentages of racial and ethnic minority groups (Black/African American 7% lower, Hispanic 8% lower), less educated (No high school degree 19% lower, high school degree 11% lower), and unemployed adults (25% lower) with worse health outcomes (physical health scores 2.5 lower and mental health scores 5.3 lower using the SF-12/36) relative to the U.S. population with spine pain. While the odds of chiropractic use in the U.S. are lower for individuals from health disparity populations, the trials also under-represented these populations relative to U.S. adults with chronic spine pain who visit a chiropractor. Health disparity populations are not well represented in spine pain clinical trials. Embracing key community-based approaches, which have shown promise for increasing participation of underserved communities, is needed.

Heterogeneity of European farmers’ risk preferences: an individual participant data meta-analysis

Abstract We present a new approach to establish an empirical overview of farmers’ risk preferences and the characteristics associated with these preferences. We rely on an Individual Participant Data Meta-analysis whereby we identify studies eliciting risk preferences through self-assessments and Holt and Laury lotteries, and construct and analyse a unique dataset of 5,157 farmers from 19 studies in 13 European countries. Our results reveal significant heterogeneity in risk preferences across elicitation methods, within and across studies, risk domains and farm and farmer characteristics. European farmers are on average risk-averse when risk preferences are elicited by lotteries, and on average risk-neutral when elicited by self-assessments. Beyond differences in the average risk aversion, there are distributional differences pointing to a limited convergence between elicitation methods and a larger explanatory power of farm and farmer characteristics to determine risk preferences elicited with self-assessments compared to lotteries.

#2801 Which patients may benefit most from hemodiafiltration compared with hemodialysis: prediction of the individualized treatment effect

Abstract Background and Aims Haemodiafiltration (HDF) with an appropriate dosing reduces death from any cause based on an individual participant data meta-analysis and aggregated data meta-analyses of available randomized trials. No differences in treatment effect are reported for specific patient populations when defined on a single characteristic in subgroup analyses. Yet, it is unclear to what extent individual patients, characterized by a combination of clinical characteristics, may benefit from HDF. This study aimed to develop and internally validate a treatment effect prediction model to determine which individual patients would benefit most from well dosed HDF, compared with haemodialysis (HD), in terms of survival. Method Individual participant data from five randomized controlled trials (CONTRAST, ESHOL, Turkish HDF study, French HDF study, CONVINCE) comparing HDF with HD on all-cause mortality were used to derive a Royston-Parmar model for exploring the prediction of absolute treatment effect of HDF based on pre-specified patient and disease characteristics, notably age, sex, body mass index, diabetes mellitus, history of cardiovascular disease, creatinine levels, and c-reactive protein levels. Internal validation of the model was performed using internal-external cross validation. Results Among 4153 participants, with a median follow-up of 30 months (Q1-Q3: 24-36), death from any cause occurred in 558 patients (27.2%). The median predicted survival benefit of HDF compared with HD was 6.9 (Q1–Q3: 5.6–9.0) months, with a range of 2 to 42 months. Patients who were predicted to benefit most from HDF were younger, less likely to have diabetes or a cardiovascular history and had higher serum creatinine levels. Internal-external cross validation showed adequate discrimination and calibration. Conclusion All-cause mortality is reduced by HDF compared with HD in ESKD patients. Yet, the absolute survival benefit seems to considerably differ between individual patients. Our results suggest that the effects of HDF on absolute survival can be predicted accurately using a combination of readily available patient and disease characteristics. This prediction model approach exemplifies the potential of prediction algorithms in supporting clinical decision-making for the choice of treatment options. Validation and potential updates to the presented algorithm are necessary, along with a preferable randomized evaluation of its clinical impact before widespread implementation.

#1399 Hemodiafiltration or haemodialysis for kidney failure: updated systematic review and individual participant data meta-analysis

Abstract Background and Aims A recent large European randomised controlled trial (RCT) showed a 23% reduction in all-cause mortality in favour of high dose haemodiafiltration (HDF) compared to high flux haemodialysis (HD). Several reactions critically questioned the main outcome and subgroup results and thereby its implications. Implications, however, should not be viewed based on results of one trial, but rather on the combined available evidence. Therefore, we set out to update our previous 2016 individual patient data meta-analysis (IPA-MA). An IPA-MA was chosen over an aggregated data meta-analysis as it allows more powerful and uniformly consistent analyses of subgroups and outcomes. Method The study was conducted according to PRISMA-IPD guidelines. We performed searches in MEDLINE, Embase and CENTRAL to identify RCTs in kidney failure patients with at least one year follow-up after randomisation, comparing on-line HDF with HD on mortality outcomes. Investigators were invited to share participant level data. The primary outcome was all-cause mortality. Secondary outcomes were cause-specific death (cardiovascular, only cardiac, only non-cardiac, infection-related, sudden death). We ran Cox proportional hazards models using intention to treat samples with a random effect for study, reporting hazard ratios (HR) and 95% confidence intervals (95% CI), overall and stratified by several predefined patient characteristics. Also, we ran Cox models using HDF patient data to estimate relations between achieved convective volume and mortality outcomes. Results Data from five European RCTs (i.e. ESHOL, CONTRAST, French HDF Study, Turkish HDF Study, and CONVINCE) were included, comprising 4153 patients. After a median follow-up of 30 months (Q1-Q3: 24-36), death from any cause occurred in 558 patients (27.2%) in the HD group and in 477 patients (23.3%) in the HDF group (HR: 0.84; 95% CI: 0.74 to 0.95). There was no evidence for a differential effect across subgroups. Cause specific analyses showed, compared to the HD, a lower risk of cardiovascular death in the HDF group (HR: 0.78; 95% CI: 0.63 to 0.96), which seemed to be driven by a lower risk for cardiac death (HR: 0.67, 95% CI: 0.50 to 0.89). The largest survival benefit was found for patients achieving a convective volume of 23 L or above, with a multivariable adjusted HR of 0.63 (95% CI: 0.50 to 0.79) for all-cause death, of 0.58 (95% CI: 0.40 to 0.85) for cardiovascular death and of 0.51 (0.28 – 0.93) for infection related death. The relation between achieved convection volume and mortality outcomes seemed gradual: the higher achieved the volume, the lower the risk compared to HD. Conclusion The combined available individual patient data from RCTs indicate that on-line HDF treatment improves survival with, at present, no clear differences across patient subgroups, when identified based on single characteristics. Our finding “the higher dose of HDF achieved, the lower the risk” seems congruent with that reported previously from observation studies.

Rethinking causal assumptions about maternal BMI, gestational weight gain, and adverse pregnancy outcomes

BackgroundThe aim of this study was to evaluate commonly assumed causal relationships between body mass index (BMI), gestational weight gain (GWG), and adverse pregnancy outcomes, which have formed the basis of guidelines and interventions aimed at limiting GWG in women with overweight or obesity. We explored relationships between maternal BMI, total GWG (as a continuous variable and as ‘excessive’ GWG), and pregnancy outcomes (including infant birthweight measures and caesarean birth).MethodsAnalysis of individual participant data (IPD) from the i-WIP (International Weight Management in Pregnancy) Collaboration, from randomised trials of diet and/or physical activity interventions during pregnancy reporting GWG and maternal and neonatal outcomes.Women randomised to the control arm of 20 eligible randomised trials (4370 of 8908 participants) from the i-WIP dataset of 36 randomised trials (total 12,240 women). The main research questions were to characterise the relationship between maternal BMI and (a) total GWG, (b) the risk of ‘excessive’ GWG (using the Institute of Medicine’s guidelines), and (c) adverse pregnancy outcomes as mediated via GWG versus other pathways to determine the extent to which the observed effect of maternal BMI on pregnancy outcomes is mediated via GWG. We utilised generalised linear models and regression-based mediation analyses within an IPD meta-analysis framework.ResultsMean GWG decreased linearly as maternal BMI increased; however, the risk of ‘excessive’ GWG increased markedly at BMI category thresholds (i.e. between the normal and overweight BMI category threshold and between the overweight and obese BMI category threshold). Increasing maternal BMI was associated with increased risk of all pregnancy outcomes assessed; however, there was no evidence that this effect was mediated via effects on GWG.ConclusionsThere is evidence of a meaningful relationship between maternal BMI and GWG and between maternal BMI and adverse pregnancy outcomes. There is no evidence that the effect of maternal BMI on outcomes is via an effect on GWG. Our analyses also cast doubt on the existence of a relationship between ‘excessive’ GWG and adverse pregnancy outcomes. Our findings challenge the practice of actively managing GWG throughout pregnancy.

Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. To clarify associations of sex hormones with these outcomes. Systematic literature review to July 2019, with bridge searches to March 2024. Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. Observational study design, heterogeneity among studies, and imputation of missing data. Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Laryngeal features in Lipoid proteinosis: a systematic review and meta-analysis of individual participant data.

Lipoid proteinosis (LP) or Urbach-Wiethe disease (OMIM 247100) is a rare syndrome characterised by early vocal folds infiltration and subsequent multi-organ involvement. LP is often unrecognised and its associated hoarseness is overlooked. The main objective of the study was to investigate hoarseness in LP and implement a diagnosis among otolaryngologists. PubMed/MEDLINE and OMIM databases were systematically searched. Authors concentrated the search on published articles starting from the discovery of the pathogenesis of LP by Hamada et al. in 2002. Only cases in which a diagnosis was reported both clinically and through biopsy and/or genetic molecular testing were included. Characteristics of the LP cases were extracted from each included study. Results were obtained through Generalized Estimating Equations. The search strategy yielded 217 articles, of which 74 (34.1%) met the selection criteria. A total of 154 cases were included. Hoarseness was described in all LP cases and clearly stated as the onset symptom in 68.8%. The onset was on average at 19months of age (CI: 3.00-20.00), while the mean age at diagnosis was 15years (CI: 10.00-30.00). Therefore, the diagnostic delay amounted to 13.42years (CI: 8.00-23.83). Hoarseness alone was responsible for an LP diagnosis in only 14.3% of cases. In 43.5% of cases, genetic analysis of the ECM1 gene was performed and exon 6 was the most frequently altered portion. Analysing the largest number of published cases, the study underlined that hoarseness is the key symptom for diagnosing LP since early childhood, though frequently overlooked.

Obesity in women with polycystic ovary syndrome -an individual participant data meta-analysis of well characterised, unselected populations

Obesity in women with polycystic ovary syndrome -an individual participant data meta-analysis of well characterised, unselected populations

150 Development of a leaky gut model: Meta-analysis of plasma and fecal markers of leaky gut

Abstract Intestinal integrity can be compromised in livestock and poultry species during stress events, including off-feed events. To develop a leaky gut model, weanling barrows 26 to 28 d old [n = 307; Duroc terminal line Fast genetics, initial body weight (BW) = 5.90 ± 0.47 kg), were used in a total of 6 randomized complete block experiments at the NutriQuest modeling center (Fergus Falls, MN). All trials included positive control (PC) and negative control (NC) treatments. The other treatments evaluated (n = 8) were various strains and levels of direct-fed microbial (DFM) products. With the exception of PC, all treatments had complete 24-h feed restriction (FR) approximately 18 d after arrival. Pigs assigned to PC had ad libitum access to feed. Pigs were housed 3 pigs per pen in 1 of 30 pens, and all pigs were fed a common high-quality basal diet. For 3 trials, pigs received Excede (Zoetis; Parsipanny, NJ) IM upon arrival and were provided gentamycin via water for 3 d post-arrival. For 3 trials, no prophylactic antibiotics were administered. Eighteen days post-arrival, fecal and plasma samples were collected from all pigs and feed was removed from FR pens. After 24 h, plasma and fecal samples were collected from all pigs, and one-half of the pigs per trial were harvested for tissue collection. Four days after FR, samples were collected similarly, and the remaining pigs were harvested. Plasma samples were analyzed for LPS binding protein concentrations (LBP), and fecal samples were analyzed for myeloperoxidase (MPO) concentrations. Data from the PC (n = 90) and NC (n = 92) treatments only were analyzed as Individual Participant Data meta-analysis using PROC MIXED of SAS. Data from all pigs (n = 307) were analyzed using PROC REG of SAS with forward step-wise selection to determine relationships between response variables. Plasma LBP concentrations did not differ between PC and NC 24 h after FR (P = 0.14). However, change in LBP concentrations and the ratio of LBP immediately before and after FR, differed between PC and NC (P &amp;lt; 0.001). For NC, LBP concentrations decreased, and for PC, LBP concentrations increased (Table 1). There was no effect of treatment on fecal MPO concentrations. Using the broader dataset (n = 307), variables that were predictive of plasma LBP concentrations immediately following FR were trial (P &amp;lt; 0.001), treatment (P &amp;lt; 0.001), and fecal MPO concentrations (P &amp;lt; 0.05). Variables that were predictive of change in LBP concentrations before and after FR were trial (P &amp;lt; 0.001), treatment (P &amp;lt; 0.001), and initial BW (P &amp;lt; 0.01). These data, taken with data presented in a companion abstract on ileal tight junction gene expression, suggest that plasma LBP concentrations immediately following a FR event are a useful marker of leaky gut. Fecal MPO concentrations do not consistently respond to FR.