Consistent Effect Sizes Research Articles

Elevated serum albumin-to-creatinine ratio as a protective factor on clinical outcomes among critically ill patients with sepsis: a retrospective study.

The aim of this study was to examine the prognostic significance of serum albumin-to-creatinine ratio (ACR) in critically ill patients with sepsis. This retrospective study analyzed sepsis cases admitted to the Affiliated Hospital of Jiangsu University between January 2015 and November 2023. The patients were divided into four groups based on their ACR upon admission to the intensive care unit (ICU). Laboratory data were collected at the time of ICU admission, and the primary outcome measure was in-hospital all-cause mortality. Kaplan-Meier survival curves were generated to illustrate the differences in 30-/60-day mortality among the various groups. Multivariate Cox regression models and restricted cubic splines (RCS) were utilized to explore the association between ACR and all-cause mortality in sepsis patients. Subgroup analyses were conducted to examine the impact of other covariates on the relationship between ACR and all-cause mortality. A total of 1,123 eligible patients were included in the study, with a median ACR of 0.169. The in-hospital mortality rate was 33.7%, the ICU mortality rate was 31.9%, and the 30-day mortality rate was 28.1%. Kaplan-Meier survival analysis demonstrated that patients with higher ACR had a significantly lower risk of 30-/60-day mortality (log-rank p < 0.001). Multivariable Cox proportional hazards analyses revealed that ACR was an independent predictor of in-hospital death (HR: 0.454, 95% CI 0.271-0.761, p = 0.003), ICU death (HR: 0.498, 95% CI 0.293-0.847, p = 0.010), and 30-day death (HR: 0.399, 95% CI 0.218-0.730, p = 0.003). For each 1-unit increase in ACR, there was a 1.203-fold decrease in the risk of death during the hospital stay. The RCS curve illustrated a non-linear negative correlation between ACR and in-hospital mortality (p for non-linear =0.018), ICU mortality (p for non-linear =0.005), and 30-day mortality (p for non-linear =0.006). Sensitivity analysis indicated consistent effect sizes and directions in different subgroups, confirming the stability of the results. Low ACR levels were identified as independent risk factors associated with increased in-hospital, ICU, and 30-day mortality in sepsis patients. ACR can serve as a significant predictor of the clinical outcome of sepsis.

Translational Cardiology: Practical Insights into the Coenzyme Q10 Role as Potential Therapeutic Agent for Cardiovascular Disease Treatment via Systematic Review and Meta-Analysis of Prospective Cohort Studies

Background and Objectives: As clinicians seek novel treatment strategies for CVDs, personalized nutrient recommendations are becoming essential. CoQ10, a key component of the mitochondrial electron transport chain, shows promise with proven cardioprotective effects. This systematic review and meta-analysis evaluates the efficacy of CoQ10 supplementation in improving mitochondrial function, systolic performance, and other parameters in CVD. Methods: Analysis included data from PubMed, Embase, and the Cochrane Library up to January 2024. It focused on randomized controlled trials (RCTs) involving adults with cardiovascular diseases (CVDs), comparing CoQ10 with placebo or standard care. Data extraction and quality assessment followed PRISMA guidelines, the Cochrane Collaboration's RoB2 tool, AMSTAR 2, and GRADE. The primary outcome was mitochondrial function (ATP production, respiratory capacity), and the secondary outcome was systolic function (ejection fraction). Findings: CoQ10 supplementation improved ejection fraction (mean difference: 5.6%, 95% CI: 3.2% to 8.0%, p&lt;0.001, I²=25%). The I² statistic for ejection fraction was 25%, indicating low heterogeneity. Mitochondrial function showed increased ATP production (SMD: 0.82, 95% CI: 0.60 to 1.04, p&lt;0.001, I²=30%) and enhanced respiratory capacity (SMD: 0.75, 95% CI: 0.53 to 0.97, p&lt;0.001, I²=28%). The I² statistics for ATP production and mitochondrial respiratory capacity were 30% and 28%, respectively, suggesting low to moderate heterogeneity. Sensitivity analyses confirmed the robustness of the results, with consistent effect sizes and confidence intervals across both fixed-effect and random-effects models, and no significant changes upon excluding high-risk studies. Publication bias was low, as indicated by funnel plots and Egger's test (p=0.12). Limitations: Larger-scale RCTs are needed to confirm findings and determine the optimal dosage and duration of CoQ10 therapy. Conclusion: CoQ10 has been consistently shown to improve mitochondrial function, systolic performance, and other key cardiovascular health parameters in CVD patients. The evidence here presented strongly bridges the gaps between the current research and clinical applications and supports clinicians in implementing the prescription of CoQ10 supplementation as an intervention evidence-based therapeutic agent that effectively improves cardiovascular health outcomes

Genetic susceptibility of urolithiasis: comprehensive results from genome-wide analysis.

The pathogenesis of urolithiasis is multi-factorial and genetic factors have been shown to play a significant role in the development of urolithiasis. We tried to apply genome-wide Mendelian randomization (MR) analysis and figure out reliable gene susceptibility of urolithiasis from the largest samples to date in two independent genome-wide association studies (GWAS) database of European ancestry. We extracted summary statistics of expression quantitative trait locus (eQTL) from eQTLGen consortium. Urolithiasis phenotype information was obtained from both FinnGen Biobank and UK Biobank. Multiple two-sample MR analysis with a Bonferroni-corrected P threshold (P < 2.5e-06) was conducted. The primary endpoint was the causal effect calculated by random-effect inverse variance weighted (IVW) method. Sensitivity analysis, volcano plots, scatter plots, and regional plots were also performed and visualized. After multiple MR tests between 19942 eQTLs and urolithiasis phenotype from both cohorts, 30 common eQTLs with consistent effect size direction were found to be causally associated with urolithiasis risk. Finally only one gene (LMAN2) was simultaneously identified among all top significant eQTLs from both FinnGen Biobank (beta = 0.6758, se = 0.0327, P = 6.775e-95) and UK Biobank (beta = 0.0044, se = 0.0009, P = 2.417e-06). We also found that LMAN2 was with the largest beta effect size on urolithiasis phenotype from the two cohorts. We for the first time implemented genome-wide MR analysis to investigate the genetic susceptibility of urolithiasis in general population of European ancestry. Our results provided novel insights into common genetic variants of urinary stone disease, which was of great help to subsequent researches.

Critical evaluation of the reliability of DNA methylation probes on the Illumina MethylationEPIC v1.0 BeadChip microarrays

ABSTRACT DNA methylation (DNAm) plays a crucial role in a number of complex diseases. However, the reliability of DNAm levels measured using Illumina arrays varies across different probes. Previous research primarily assessed probe reliability by comparing duplicate samples between the 450k-450k or 450k-EPIC platforms, with limited investigations on Illumina EPIC v1.0 arrays. We conducted a comprehensive assessment of the EPIC v1.0 array probe reliability using 69 blood DNA samples, each measured twice, generated by the Alzheimer’s Disease Neuroimaging Initiative study. We observed higher reliability in probes with average methylation beta values of 0.2 to 0.8, and lower reliability in type I probes or those within the promoter and CpG island regions. Importantly, we found that probe reliability has significant implications in the analyses of Epigenome-wide Association Studies (EWAS). Higher reliability is associated with more consistent effect sizes in different studies, the identification of differentially methylated regions (DMRs) and methylation quantitative trait locus (mQTLs), and significant correlations with downstream gene expression. Moreover, blood DNAm measurements obtained from probes with higher reliability are more likely to show concordance with brain DNAm measurements. Our findings, which provide crucial reliability information for probes on the EPIC v1.0 array, will serve as a valuable resource for future DNAm studies.

Lipids, lipid-modifying drug target genes and migraine: a Mendelian randomization study

IntroductionMigraine, a prevalent headache disorder with unclear mechanisms and limited treatments, may be influenced by dyslipidemia and genetic factors. Statins and emerging lipid-modifying agents show potential but lack evidence for migraine management. Mendelian Randomization analysis offers insights into causal relationships and therapeutic targets. This study aims to explore genetically predicted lipid traits, drug targets, and their association with migraine risk.MethodWe conducted Mendelian randomization (MR) analyses utilizing genetic variants associated with lipid traits and variants in genes encoding the protein targets of various classes of lipid-lowering drugs. The specific drug classes investigated included HMGCR, PCSK9, NPC1L1, ABCG5/ABCG8, LDLR, LPL, ANGPTL3, APOB, CETP, and APOC3. To determine the effects on migraine risk, we meta-analyzed MR estimates for regional variants using data from two large sample sets. The genetic variants were weighted based on their associations with specific lipid traits, such as low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), Apolipoprotein A1, and Apolipoprotein B. To obtain association weights, we utilized data from lipid genetics consortia. For lipid-modifying drug targets that exhibited suggestive significance, we further employed expression quantitative trait locus (eQTL) data. Additionally, we performed colocalization analysis to assess genetic confounding.ResultThe use of genetic proxies for HMGCR inhibition demonstrated a significant association with a decreased risk of migraine in the FinnGen dataset (OR = 0.64, 95% CI: 0.46–0.88, p = 0.0006) and a nearly significant association in the Choquet dataset (OR = 0.78, 95% CI: 0.60–1.01, p = 0.06). When pooling the estimates, the overall effect size showed a reduced risk of migraine (OR = 0.73, 95% CI: 0.60–0.89, p = 0.0016). Similarly, genetic mimicry of LPL enhancement was associated with a lower risk of migraine in the FinnGen dataset (OR = 0.82, 95% CI: 0.69–0.96, p = 0.01) and the Choquet dataset (OR = 0.91, 95% CI: 0.83–0.99, p = 0.03). Pooling the estimates showed a consistent effect size (OR = 0.89, 95% CI: 0.83–0.96, p = 0.002). Sensitivity analyses yielded no statistically significant evidence of bias arising from pleiotropy or genetic confounding.ConclusionIn the study, it was observed that among the 10 lipid-lowering drug targets investigated, LPL and HMGCR showed significant associations with migraine risk. These findings indicate that LPL and HMGCR have the potential to serve as candidate drug targets for the treatment or prevention of migraines.

Regulatory Variants on the Leukocyte Immunoglobulin-Like Receptor Gene Cluster are Associated with Crohn's Disease and Interact with Regulatory Variants for TAP2.

Crohn's disease [CD] has a complex polygenic aetiology with high heritability. There is ongoing effort to identify novel variants associated with susceptibility to CD through a genome-wide association study [GWAS] in large Korean populations. Genome-wide variant data from 902 Korean patients with CD and 72 179 controls were used to assess the genetic associations in a meta-analysis with previous Korean GWAS results from 1621 patients with CD and 4419 controls. Epistatic interactions between CD-risk variants of interest were tested using a multivariate logistic regression model with an interaction term. We identified two novel genetic associations with the risk of CD near ZBTB38 and within the leukocyte immunoglobulin-like receptor [LILR] gene cluster [p < 5 × 10-8], with highly consistent effect sizes between the two independent Korean cohorts. CD-risk variants in the LILR locus are known quantitative trait loci [QTL] for multiple LILR genes, of which LILRB2 directly interacts with various ligands including MHC class I molecules. The LILR lead variant exhibited a significant epistatic interaction with CD-associated regulatory variants for TAP2 involved in the antigen presentation of MHC class I molecules [p = 4.11 × 10-4], showing higher CD-risk effects of the TAP2 variant in individuals carrying more risk alleles of the LILR lead variant (odds ratio [OR] = 0.941, p = 0.686 in non-carriers; OR = 1.45, p = 2.51 × 10-4 in single-copy carriers; OR = 2.38, p = 2.76 × 10-6 in two-copy carriers). This study demonstrated that genetic variants at two novel susceptibility loci and the epistatic interaction between variants in LILR and TAP2 loci confer a risk of CD.

Laboratory and demographic predictors of functional assay positive status in suspected heparin-induced thrombocytopenia: A multicenter retrospective cohort study

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated immune response against platelet factor 4 (PF4) bound to heparin anticoagulants. A priori identification of patients at-risk for HIT remains elusive and a number of risk factors have been identified, but these associations and their effect sizes have limited validation in large cohorts of suspected HIT patients. The aim of this study was to investigate existing anti-PF4/heparin antibody thresholds and model the relationship of demographic variables and anti-PF4/heparin antibody levels with functional assay positivity across multiple institutions in the absence of detailed clinical data. In a large collection of suspected HIT patients (n = 8904), we tested for associations between laboratory and demographic variables and functional assay positive status as well as anti-PF4/heparin antibody levels. We also tested for correlation between IgG-specific and polyspecific (IgG/IgA/IgM) anti-PF4/heparin antibody values and their ability to predict functional assay positive status using area under the receiver operating characteristic (AUROC). Logistic regression identified increasing anti-PF4/heparin antibody OD levels (OR = 51.84 [37.27–74.34], p < 2.0 × 10−16) and female sex (OR = 1.47 [1.19–1.82], p = 3.5 × 10−4) as risk factors for positive functional assay in the largest cohort with consistent effect sizes in two other cohorts. In a subset of 1175 patients, polyspecific and IgG-specific anti-PF4/heparin antibody values were heterogeneous (mean coefficient of variation = 31.9 %), but strongly correlated (rho = 0.878; p < 2 × 10−16) with similar prediction of functional assay positivity (polyspecific AUROC = 0.976 and IgG-specific AUROC = 0.980). Thus, we recapitulate previously identified risk factors of functional assay positivity, providing precise effect sizes in a large observational population of suspected HIT patients. Our data reinforce the necessity of functional assay confirmation and suggest that, despite heterogeneity, polyspecific and IgG-specific anti-PF4/heparin antibody assays predict functional assay positive status similarly, even in the absence of 4Ts scores and detailed clinical data.

Intra‐ and interpersonal factors and adolescent wellbeing during COVID‐19 in three countries

AbstractCOVID‐19 has altered adolescents' opportunities for developing and strengthening interpersonal skills and proficiencies. Using data from adolescents in Italy, the United States, and the United Kingdom, we examined the relation between internalizing symptoms assessed pre‐pandemic or when pandemic‐related restrictions were lifted (Time 1) and associated internalizing symptoms during a subsequent restrictive pandemic period (Time 2). Across all 3 countries, we found significant and consistent effect sizes in the relation between Time 1 and Time 2 internalizing symptoms. We further examined the direct and moderating impact of self‐efficacy and contextual supports for adolescents' internalizing symptoms. Higher self‐efficacy was associated with lower levels of internalizing symptoms at Time 2 in all 3 countries. Additionally, the relation between Time 1 and 2 internalizing symptoms was buffered by regulatory self‐efficacy and peer support in Italy, but in the U.S., higher levels of general self‐efficacy instead had an exacerbating effect on the relation between Times 1 and 2 internalizing symptoms. Results are discussed in the context of utilizing cross‐national datasets to examine similarities in adolescent well‐being over time and in the face of varying government responses to the pandemic.

A meta-analysis on the characteristics of placebo effects on urinary function in placebo-controlled clinical trials among Japanese patients.

This study aimed to assess the effect sizes, changes over time, and ethnic differences in placebo effects on urinary function among Japanese patients participating in clinical trials. A meta-analysis of 30 Japanese placebo-controlled clinical trials was conducted to determine the placebo effects on three functions: daily urinary frequency, nocturnal urinary frequency, and average urine volume per void. The I-square heterogeneity values for the basic values of the three functions ranged from 84.5% to 97.9%, with differences among trials. Longitudinal analysis (1 to 12 weeks) indicated an enhanced placebo effect for up to 8 weeks and no consistency among trials on nocturnal urinary frequency (p < 0.01), unlike those on daily urinary frequency and average urine volume per void (p=1.0). Based on the random-effects model, the mean differences in urinary frequency at 4, 8, and 12 weeks were -0.70 (-0.80; -0.60), -1.06 (-1.16; -0.96), and -1.18 (-1.34; -1.01), respectively. Furthermore, the mean difference (95% confidence interval) in nocturnal urinary frequency and volume of urination per void at 12 weeks was -0.63 (-0.94; -0.31) and 9.67 (7.25; 12.1), respectively. My findings suggest an increase in the strength of placebo effects over time (up to 8 weeks). A comparison of my results to those published in previous global reports showed no meaningful differences in placebo effects among ethnic groups. The consistent placebo effect size on urinary function could be an external indicator in clinical trials.

From the Editor-in-Chief's Desk

Journal of Child and Adolescent PsychopharmacologyVol. 33, No. 1 EditorialFree AccessFrom the Editor-in-Chief's DeskHarold S. KoplewiczHarold S. KoplewiczChild Mind Institute, New York, New York, USA.Search for more papers by this authorPublished Online:14 Feb 2023https://doi.org/10.1089/cap.2022.29234.editorialAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail To Our Readers:I hope the beginning of 2023 has brought joy and a renewed sense of purpose to everyone! The first thing I would like to share is an exciting update from the Child Mind Institute. I am pleased to announce our latest initiative in collaboration with the State of California, the Youth Mental Health Academy.In its inaugural year, the academy will identify and support 2500 talented and diverse high school students with an interest in child and adolescent mental health, and engage them in summer internships with stipends, peer mentorship, and professional development. Recruitment for the academy will be from groups under-represented in our field today, including young people of color and LGBT youth. While moving our field toward being more representative and understanding of the populations in need of our services, we will inspire and cultivate the mental health leaders of tomorrow.I would like to highlight two articles in this issue of the journal. In “Efficacy of Amphetamine Extended-Release Oral Suspension in Children with Attention-Deficit/Hyperactivity Disorder: Effect Size Across the Day,” Faraone et al. report evidence of this treatment's usefulness in children ages 6–12 years. Their study applies a post-hoc analysis to a randomized double-blind placebo-controlled assessment to evaluate outcomes at different timepoints from morning through evening.The authors emphasize the need for medication that works throughout the day, pointing out the pervasive effects of attention-deficit/hyperactivity disorder (ADHD) in children's lives both in the classroom and outside of school. The analysis yielded a large and consistent effect size across the day. But they point out two limitations to their promising findings: the nature of the analysis is posthoc and the sample size is relatively small.The second article I would like to highlight discusses a study that sets out to determine any effects on the cognitive, emotional, and physical development of children ages 6–16 years after treatment with sertraline for up to 3 years. In their article titled, “Effects of Long-Term Sertraline Use on Pediatric Growth and Development: The Sertraline Pediatric Registry for The Evaluation of Safety (SPRITES),” Kolitsopoulos et al. explain that their study compared 695 participants who were exposed to sertraline with or without psychotherapy with 245 participants who were exposed to psychotherapy alone.Of the original participants, 432 completed the full 3-year study. A small but statistically significant increase in weight was observed in the participants exposed to sertraline, but otherwise, results for the group exposed to sertraline displayed normal development and showed no significant changes over time.I hope you find the articles in this issue helpful and informative. Welcome to the new year!Harold S. Koplewicz, MDEditor-in-ChiefFiguresReferencesRelatedDetails Volume 33Issue 1Feb 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:Harold S. Koplewicz.From the Editor-in-Chief's Desk.Journal of Child and Adolescent Psychopharmacology.Feb 2023.1-1.http://doi.org/10.1089/cap.2022.29234.editorialPublished in Volume: 33 Issue 1: February 14, 2023PDF download

Efficacy of Amphetamine Extended-Release Oral Suspension in Children with Attention-Deficit/Hyperactivity Disorder: Effect Size Across the Day.

Objective: To evaluate the treatment effect size throughout the day of amphetamine extended-release oral suspension (AMPH EROS; Tris Pharma, Inc., Monmouth Junction, NJ, USA) in a laboratory classroom study conducted in children aged 6-12 years with attention-deficit/hyperactivity disorder (ADHD). Methods: A post hoc analysis was performed to assess the overall effect size as well as the effect size at each time point from early morning through evening (1, 2, 4, 6, 8, 10, 12, and 13 hours postdose) for each efficacy measure evaluated in a 5-week, randomized, dose-optimized, double-blind, placebo-controlled, laboratory classroom assessment, efficacy, and safety study of AMPH EROS (N = 99). Change from baseline of the primary (Swanson, Kotkin, Agler, M-Flynn, Pelham [SKAMP]-C) and key secondary (secondary efficacy assessments included the SKAMP attention [SKAMP-A], SKAMP-deportment subscale [SKAMP-D], Permanent Product Measure of Performance-number of problems attempted [PERMP-A], PERMP-number of problems correct [PERMP-C]) efficacy measures were analyzed using a linear mixed model repeated-measures analysis model. Comparisons among treatments were adjusted for multiple comparisons using the Bonferroni method. The effect size was estimated using Cohen's d, to determine "small," (0.2), "medium," (0.5), or "large" (0.8) magnitudes of treatment effects. Results: Large overall effect sizes were observed for all primary and key secondary efficacy assessments. Moreover, the SKAMP-C, PERMP-number of problems attempted, and PERMP-C scores showed large effect sizes at each time point evaluated across the day, from 1 to 13 hours postdose. The SKAMP-A and SKAMP-D scores showed a medium to large effect size at each time point. Conclusions: AMPH EROS demonstrated a large and consistent effect size across the day, including early in the morning, in the treatment of symptoms of ADHD in children aged 6-12 years. Trial Registration: clinicaltrials.gov identifier: NCT02083783.

Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1–4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.

Navigating the manyverse of skin conductance response quantification approaches - A direct comparison of trough-to-peak, baseline correction, and model-based approaches in Ledalab and PsPM.

Raw data are typically required to be processed to be ready for statistical analyses, and processing pipelines are often characterized by substantial heterogeneity. Here, we applied seven different approaches (trough-to-peak scoring by two different raters, script-based baseline correction, Ledalab as well as four different models implemented in the software PsPM) to two fear conditioning data sets. Selection of the approaches included was guided by a systematic literature search by using fear conditioning research as a case example. Our approach can be viewed as a set of robustness analyses (i.e., same data subjected to different processing pipelines) aiming to investigate if and to what extent these different quantification approaches yield comparable results given the same data. To our knowledge, no formal framework for the evaluation of robustness analyses exists to date, but we may borrow some criteria from a framework suggested for the evaluation of "replicability" in general. Our results from seven different SCR quantification approaches applied to two data sets with different paradigms suggest that there may be no single approach that consistently yields larger effect sizes and could be universally considered "best." Yet, at least some of the approaches employed show consistent effect sizes within each data set indicating comparability. Finally, we highlight substantial heterogeneity also within most quantification approaches and discuss implications and potential remedies.

Toward Pre-Diagnostic Detection of Dementia in Primary Care.

Preventing dementia warrants the pragmatic engagement of primary care. This study predicted conversion to dementia 12 months before diagnosis with indicators that primary care can utilize within the practical constraints of routine practice. The study analyzed data from the Alzheimer's Disease Neuroimaging Initiative (Total sample = 645, converting participants = 54). It predicted the conversion from biological (plasma neurofilament light chain), cognitive (Trails Making Test- B), and functional (Functional Activities Questionnaire) measures, in addition to demographic variables (age and education). A Gradient Booster Trees classifier effectively predicted the conversion, based on a Synthetic Minority Oversampling Technique (n = 1,290, F1 Score = 92, AUC = 94, Recall = 87, Precision = 97, Accuracy = 92). Subsequent analysis indicated that the MCI False Positive group (i.e., non-converting participants with cognitive impairment flagged by the model for prospective conversion) scored significantly lower on multiple cognitive tests (Montreal Cognitive Assessment, p < 0.002; ADAS-13, p < 0.0004; Rey Auditory Verbal Learning Test, p < 0.002/0.003) than the MCI True Negative group (i.e., correctly classified non-converting participants with cognitive impairment). These groups also differed in CSF tau levels (p < 0.04), while consistent effect size differences emerged in the all-pairwise comparisons of hippocampal volume and CSF Aβ1-42. The model effectively predicted 12-month conversion to dementia and further identified non-converting participants with MCI, in the False Positive group, at relatively higher neurocognitive risk. Future studies may seek to extend these results to earlier prodromal phases. Detection of dementia before diagnosis may be feasible and practical in primary care settings, pending replication of these findings in diverse clinical samples.

Sexual discounting: A systematic review of discounting processes and sexual behavior.

Behavioral processes underlying sexual behavior are important for understanding normal human functioning and risk behavior leading to sexually transmitted infections (STIs). This systematic review examines delay and probability discounting in human sexual behavior through synthesis of 50 peer-reviewed, original research articles. Sixteen studies focusing exclusively on monetary delay discounting found small effect size positive correlations with sexual risk behaviors. Eleven studies examined delay or probability discounting of sexual behavior itself using tasks that varied duration, frequency, or quality of sex to determine value. Results show delay and uncertainty of sex causes systematic decreases in value. These studies also show consistent medium effect size relationships between sexual discounting measures and sexual health and substance use, supporting utility above and beyond monetary discounting. Twenty-three studies have modeled clinically relevant decision-making, examining effects of delay until condom availability and STI contraction probability on condom use. Observational and experimental designs found condom-use discounting is elevated in high-risk substance use populations, is sensitive to context (e.g., partner desirability), and is more robustly related to sexual risk compared with monetary discounting or condom use decisions when no delay/uncertainty was involved. Administering cocaine, alcohol, and, for some participants, methamphetamine increased condom-use discounting with minimal effect on monetary discounting or condom use when no delay/uncertainty was involved. Reviewed studies robustly support that sexual behavior is highly dependent on delay and probability discounting, and that these processes strongly contribute to sexual risk. Future research should exploit these systematic relationships to design behavioral and pharmacological approaches to decrease sexual risk behavior. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Singing In The Mask: Effects Of A Variably Occluded Face Mask On Singing

A limitation of traditional semi-occluded vocal tract exercises (SOVTE) is the single sustained vowel task that precludes co-articulated singing. This study investigated immediate effects of a variably occluded face mask (VOFM) on vocal effort, acoustic, and aerodynamic measures in sung low and high pitches of healthy singers. Single-group, pre-post intervention study. The outlet ports of disposable anesthesia facemasks were fitted with plastic caps with two drilled openings sizes (9.6 mm, 6.4 mm). Twenty-three singers with no voice complaints provided baseline vocal effort, acoustic, and aerodynamic measures in high and low pitches. Participants trained in four conditions: two VOFM sizes (9.6 mm, 6.4 mm) in combination with the 20th and 80th percentile of the singer's pitch range. Participants were trained on three phonatory tasks: repeated consonant/vowel syllables, sung sentence, and sustained vowel. Vocal effort before and after training was compared using a visual-analog scale, while standardized mean differences captured acoustic and aerodynamic changes before and after training. Participants reported decreased vocal effort after VOFM training at all occlusion and pitch combinations. On average, consistent beneficial effect sizes were found in cepstral peak prominence (CPP) and cepstral spectral index of dysphonia (CSID) for all 4 occlusion-pitch combinations, and vocal intensity and mean estimated subglottal pressure increased for all 4 occlusion-pitch training combinations. Changes in mean phonatory airflow and resistance were less consistent. There was an immediate effect of decreased vocal effort in singing after VOFM training. Acoustic and aerodynamic effects were variable and modest. Future studies should explore changes in these outcomes after VOFM in singing voice therapy.

Targets for intervention to prevent substance use in young people exposed to childhood adversity: A systematic review.

Background and aimsChildhood adversity is a strong, and concerningly prevalent, risk factor for the later development of substance misuse. Yet despite substantial accumulating evidence for causal mechanisms, there has been little attempt to synthesize the strength of the evidence. Importantly, these mechanisms may be amenable to intervention, providing targets for substance use prevention among those exposed to childhood adversity. The present review aimed to systematically identify mediating and moderating mechanisms operating between childhood adversity and substance use.MethodsA systematic review was conducted. Electronic databases (PubMed, MEDLINE, PsycINFO, Web of Science and CINAHL) were searched from 1998 to 2020 for modifiable mediators and moderators of the relationship between childhood adversity and substance use in people aged 10–24. Data was qualitatively synthesised, using a socio-ecological perspective to group mediators/moderators into individual, interpersonal, community, and public policy/cultural levels of behaviour.ResultsAfter screening against eligibility criteria, 50 studies were included in the current review. The mediators at the individual level of behaviour showing the largest and most consistent effect sizes included externalising behaviour, anger, coping motives for substance use, and post-traumatic stress symptoms. Among individual-level moderators, religiosity, future orientation and depressive symptoms all attenuated the relationship between childhood adversity and substance use. At the interpersonal level, peer relationships and mother-child relationships mediated the effect of adversity on substance use. Moderators included family cohesion and relationship quality. Community factors were less commonly studied, though school mobility and educational achievement mediated 14% and 28% of the total effect of childhood adversity on substance use respectively. No mediators or moderators were identified for public policy/culture.ConclusionsA substantial proportion of the relationship between childhood adversity and substance use in youth is mediated through individual, interpersonal and community factors. Coupled with the knowledge that existing, evidence-based programs effectively address many of the identified mediators and moderators, this review advances knowledge on optimal targets to prevent substance misuse among those exposed to childhood adversity.

Large trans-ethnic meta-analysis identifies AKR1C4 as a novel gene associated with age at menarche.

Does the expansion of genome-wide association studies (GWAS) to a broader range of ancestries improve the ability to identify and generalise variants associated with age at menarche (AAM) in European populations to a wider range of world populations? By including women with diverse and predominantly non-European ancestry in a large-scale meta-analysis of AAM with half of the women being of African ancestry, we identified a new locus associated with AAM in African-ancestry participants, and generalised loci from GWAS of European ancestry individuals. AAM is a highly polygenic puberty trait associated with various diseases later in life. Both AAM and diseases associated with puberty timing vary by race or ethnicity. The majority of GWAS of AAM have been performed in European ancestry women. We analysed a total of 38 546 women who did not have predominantly European ancestry backgrounds: 25 149 women from seven studies from the ReproGen Consortium and 13 397 women from the UK Biobank. In addition, we used an independent sample of 5148 African-ancestry women from the Southern Community Cohort Study (SCCS) for replication. Each AAM GWAS was performed by study and ancestry or ethnic group using linear regression models adjusted for birth year and study-specific covariates. ReproGen and UK Biobank results were meta-analysed using an inverse variance-weighted average method. A trans-ethnic meta-analysis was also carried out to assess heterogeneity due to different ancestry. We observed consistent direction and effect sizes between our meta-analysis and the largest GWAS conducted in European or Asian ancestry women. We validated four AAM loci (1p31, 6q16, 6q22 and 9q31) with common genetic variants at P < 5 × 10-7. We detected one new association (10p15) at P < 5 × 10-8 with a low-frequency genetic variant lying in AKR1C4, which was replicated in an independent sample. This gene belongs to a family of enzymes that regulate the metabolism of steroid hormones and have been implicated in the pathophysiology of uterine diseases. The genetic variant in the new locus is more frequent in African-ancestry participants, and has a very low frequency in Asian or European-ancestry individuals. N/A. Extreme AAM (<9 years or >18 years) were excluded from analysis. Women may not fully recall their AAM as most of the studies were conducted many years later. Further studies in women with diverse and predominantly non-European ancestry are needed to confirm and extend these findings, but the availability of such replication samples is limited. Expanding association studies to a broader range of ancestries or ethnicities may improve the identification of new genetic variants associated with complex diseases or traits and the generalisation of variants from European-ancestry studies to a wider range of world populations. Funding was provided by CHARGE Consortium grant R01HL105756-07: Gene Discovery For CVD and Aging Phenotypes and by the NIH grant U24AG051129 awarded by the National Institute on Aging (NIA). The authors have no conflict of interest to declare.

Cardiac Imaging of Aortic Valve Area From 34 287 UK Biobank Participants Reveals Novel Genetic Associations and Shared Genetic Comorbidity With Multiple Disease Phenotypes.

The aortic valve is an important determinant of cardiovascular physiology and anatomic location of common human diseases. From a sample of 34 287 white British ancestry participants, we estimated functional aortic valve area by planimetry from prospectively obtained cardiac magnetic resonance imaging sequences of the aortic valve. Aortic valve area measurements were submitted to genome-wide association testing, followed by polygenic risk scoring and phenome-wide screening, to identify genetic comorbidities. A genome-wide association study of aortic valve area in these UK Biobank participants showed 3 significant associations, indexed by rs71190365 (chr13:50764607, DLEU1, P=1.8×10-9), rs35991305 (chr12:94191968, CRADD, P=3.4×10-8), and chr17:45013271:C:T (GOSR2, P=5.6×10-8). Replication on an independent set of 8145 unrelated European ancestry participants showed consistent effect sizes in all 3 loci, although rs35991305 did not meet nominal significance. We constructed a polygenic risk score for aortic valve area, which in a separate cohort of 311 728 individuals without imaging demonstrated that smaller aortic valve area is predictive of increased risk for aortic valve disease (odds ratio, 1.14; P=2.3×10-6). After excluding subjects with a medical diagnosis of aortic valve stenosis (remaining n=308 683 individuals), phenome-wide association of >10 000 traits showed multiple links between the polygenic score for aortic valve disease and key health-related comorbidities involving the cardiovascular system and autoimmune disease. Genetic correlation analysis supports a shared genetic etiology with between aortic valve area and birth weight along with other cardiovascular conditions. These results illustrate the use of automated phenotyping of cardiac imaging data from the general population to investigate the genetic etiology of aortic valve disease, perform clinical prediction, and uncover new clinical and genetic correlates of cardiac anatomy.

Genome-wide association study in a Korean population identifies six novel susceptibility loci for rheumatoid arthritis

ObjectiveGenome-wide association studies (GWAS) in rheumatoid arthritis (RA) have discovered over 100 RA loci, explaining patient-relevant RA pathogenesis but showing a large fraction of missing heritability. As a continuous effort,...