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PubMed1979

A modified approach to small area estimation.

The ever-growing need for good estimates of the health, social, political, and economic parameters of local areas has served as the motivating force for new developments in methodology. Due to the constraints of sample size, design, and cost, accessible data from large areas for criterion variables of interest is often used jointly with local data on symptomatic variables. Furthermore, several procedures have derived local area estimators by combining symptomatic information and sample data into a multiple regression format. In those situations where assumptions are too strict or unrealistic, as when a nonlinear model is more appropriate, the merits of a more flexible approach are obvious. Our research focuses upon a further investigation of an alternative strategy for which the most limiting assumption is the availability of good symptomatic information. A more formal representation of the model is developed within the framework of a poststratification scheme. The methodology involves ratio estimation of the respective stratum means via indicator variables which serve the purpose of classification. To determine the accuracy of the proposed small area estimator and allow for comparisons of precision with respect to other strategies, we express the relationship between criterion and symptomatic variables by relevant continuous multivariate distributions. Specifically, comparisons are made with the results obtained using a regression estimator which is applicable to the same general setting. The theoretical framework considers multivariate stratification, where boundary determination is achieved by application of practical methods which use minimum variance stratification as a criterion.

Demography↗
PubMed1976

Some barriers to effective alcoholism research.

Barriers to effective alcoholism research include the search for unitary etiological factors, the difficulties in assembling homogeneous samples of subjects for study, the lack of widespread multidisciplinary efforts, and uncertainty about the goals of treatment for alcoholism. Innovative research approaches are needed for alcoholism prevention in order to preclude the proliferation of patterns of alcohol abuse.

Alcoholism↗
PubMed2026

Multisensory stimulation for promoting development and preventing morbidity in preterm infants.

RATIONALE: Multisensory stimulation is a structured, developmentally appropriate intervention that provides simultaneous or sequential stimulation of two or more senses (e.g. tactile, auditory, visual, or vestibular) in a controlled and non-stressful manner, with the aim of supporting early neurodevelopment in preterm infants. It has the potential to enhance physiological regulation in preterm infants by stabilizing key functions, such as respiratory patterns, heart rate, and oxygen saturation; reducing the need for respiratory support; and improving feeding performance and sleep regulation. Targeted multisensory interventions have also been associated with improved neurodevelopmental outcomes, including enhanced psychomotor development and visual function. OBJECTIVES: To assess the benefits and harms of multisensory stimulation compared to any single sensory intervention or standard care on major neurodevelopmental disability, mortality, and growth in preterm infants. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Emcare, CINAHL, Epistemonikos, two trial registries, and conference abstracts up to 28 November 2025. We checked reference lists of included trials, and systematic reviews on sensory interventions. ELIGIBILITY CRITERIA: We included 18 randomized controlled trials (RCTs) comparing multisensory stimulation in preterm infants with no intervention (placebo or standard care), and one RCT comparing multisensory stimulation with single-sense stimulation (tactile stimulation). OUTCOMES: Our critical outcomes were major neurodevelopmental disability at 18 to 24 months: cerebral palsy (CP), developmental delay, intellectual impairment, blindness, sensorineural deafness; death during initial hospitalization; and total weight gain (grams), assessed at discharge. When comparing multisensory stimulation with single-sense intervention, we also included weight gain during the intervention, an outcome added during the post-hoc analysis. Important outcomes were duration of hospital stay, of NICU stay, and of respiratory support; and time until full oral feeding. RISK OF BIAS: We used the Cochrane tool, RoB 2. SYNTHESIS METHODS: We conducted meta-analyses using fixed-effect models to calculate risk ratios (RR) for dichotomous data, and mean differences (MDs) for continuous data, each with its 95% confidence intervals (CIs). We assessed statistical heterogeneity by calculating the I2 statistic when we included more than two trials in a meta-analysis. We evaluated the certainty of evidence using GRADE. INCLUDED STUDIES: We included 19 trials (1554 newborn infants): 18 studies compared multisensory stimulation with standard care; one compared multisensory stimulation with single-sensory stimulation (tactile). In 10 studies, the primary aim was to assess the neurobehavioral outcomes of multisensory stimulation on preterm neo-nates. The other nine studies aimed to assess the impact of multisensory stimulation on weight gain during the intervention, weight gain until hospital discharge, length of neonatal intensive care unit (NICU) stay, length of hospital stay, time until full oral feeding, length of respiratory support, or a combination. In the abstract we report results for the critical outcomes only. We identified 13 ongoing studies. Four studies are awaiting assessment. SYNTHESIS OF RESULTS: Multisensory stimulation compared to standard care No studies reported on these major neurodevelopmental disabilities, assessed at 18 to 24 months' corrected age (CA): developmental delay, intellectual impairment, blindness, or sensorineural deafness. One study reported on rates of CP at 12 months of age. The evidence is very uncertain about the effect of multisensory stimulation on CP (RR 0.67, 95% CI 0.28 to 1.58; I² not applicable; 1 study, 18 participants; very low-certainty evidence). The evidence suggests that multisensory stimulation may result in little to no difference in death during initial hospitalization (RR 0.97, 95% CI 0.54 to 1.73; I² not applicable; 1 study, 395 participants; low-certainty evidence). Multisensory stimulation may increase total weight gain prior to discharge (MD 72.67, 95% CI 68.23 to 77.12; I² = 0%; 3 studies, 474 participants; low-certainty evidence). Multisensory stimulation compared to single-sense (tactile) stimulation No studies reported on major neurodevelopmental disability, assessed at 18 to 24 months' CA, or death during initial hospitalization. The evidence is very uncertain about the effect of multisensory stimulation compared to tactile stimulation on weight gain during the intervention (MD -175.00, 95% CI -376.60 to 26.60; I² not applicable; 1 study, 20 participants; very low-certainty evidence). The certainty of the evidence was low to very low across outcomes, primarily due to risk of bias, imprecision from small sample sizes and wide CIs, and in some cases, inconsistency. The evidence base was also limited by the lack of reporting of relevant outcomes and reliance on surrogate outcomes or shorter follow-up periods. AUTHORS' CONCLUSIONS: The available evidence on multisensory stimulation in preterm infants is limited and of low to very low certainty. No included studies reported on major neurodevelopmental disabilities at 18 to 24 months' CA, which represented a critical outcome for this review. Evidence regarding the effect of multisensory stimulation on CP is very uncertain, as it is based on a single small study reporting a surrogate outcome at 12 months. Multisensory stimulation may result in little to no difference in mortality during the initial hospitalization. It may increase total weight gain prior to discharge. However, the clinical significance of this finding is uncertain, particularly given the low certainty of the evidence and the multifactorial nature of growth in preterm infants. The evidence is very uncertain about the effect of multisensory stimulation compared to single-sense (tactile) stimulation on weight gain during the intervention. The only included study did not report major neurodevelopmental disabilities at 18 to 24 months' CA, mortality during the initial hospitalization, or total weight gain prior to discharge, which represented the critical outcomes for this review. Overall, the current evidence does not allow firm conclusions about the effectiveness of multisensory stimulation in promoting development or preventing morbidity in preterm infants. Future studies on multisensory stimulation should use more rigorous designs, larger samples, and report interventions using the template for intervention description and replication (TIDieR) checklist to ensure transparency. They should also report essential outcomes, such as neonatal death, major neurodevelopmental disabilities, length of hospital and NICU stay, time to full oral feeding, duration of respiratory support, and weight gain, to better assess the long‑term effects of multisensory stimulation in preterm infants. FUNDING: This Cochrane review had no dedicated funding. REGISTRATION: Protocol available via DOI: 10.1002/14651858.CD016073.

Humans↗
PubMed2026

Systemic biomarkers of treatment response to methotrexate in people with painful knee osteoarthritis: A biological substudy of the PROMOTE randomised controlled clinical trial.

OBJECTIVE: Stratification of therapeutic responses may help identify efficacious therapies for osteoarthritis (OA). In the PROMOTE randomised trial, participants with elevated baseline high-sensitivity C-reactive protein (hs-CRP) showed greater pain reduction after methotrexate treatment. We set out to interrogate a broader panel of serum/plasma inflammatory response markers relevant to methotrexate actions as potential biomarkers of therapeutic effect. Our objectives were to: (i) characterize changes in these systemic markers during methotrexate treatment; determine whether (ii) baseline levels or (iii) changes in any marker during treatment were associated with treatment response; and (iv) compare these findings with the more established clinical inflammatory marker, hs-CRP. DESIGN: Plasma/serum samples from participants in PROMOTE's biological substudy were analysed for 35 inflammatory markers at baseline (pre-treatment) and at 6-months (post-treatment), by MesoScale V-plex multiplex assay. Those with paired biological and clinical data at both baseline and 6-months were included in the substudy analysis set. Relationships between markers and overall data structure were assessed by Pearson correlation and Principal Component analysis. Associations between markers (baseline levels or change over time) and change in average knee pain severity in past week (numerical rating scale, NRS) were evaluated by univariable linear regression, adjusting for baseline age, sex, and body mass index. Least Absolute Shrinkage and Selection Operator (LASSO) regression with bootstrap resampling enabled marker selection. Benjamini-Hochberg correction adjusted for multiple testing (Padj). RESULTS: 87 participants with paired blood marker and clinical data were eligible for substudy analysis. 18/35 markers were quantifiable and analysed. Systemic IL-8 and TNF-α levels decreased (Padj=0.015, 0.048 respectively) while IL-15 increased (Padj=0.033) with methotrexate treatment over 6-months. Analysing within this active treatment randomised arm, higher baseline IFN-γ was associated with greater reduction in NRS pain change (0.66 [0.01, 1.31], P=0.047), as was decreasing TNF-α over 6-months (2.25 [0.00, 4.5], P=0.049). LASSO identified higher IFN-γ, lower plasma IL-15 and IL-16, and younger age as the most important baseline predictors of pain improvement. hs-CRP was highly selected by LASSO for treatment response in both arms. In a secondary univariate treatment arm-by-biomarker interaction analysis, of the 19 markers, only hs-CRP showed consistent effects in adjusted models (at baseline, coeffic. 2.34 [0.53, 4.15], P=0.001; change over 6-months, (0.36 [0.06, 0.66], P=0.018). CONCLUSIONS: Blood measurement of IFN-γ, TNF-α, IL-15 and IL-16 as well as hs-CRP could act as potential markers to stratify the treatment response by average knee pain to methotrexate in knee osteoarthritis.

Humans↗
PubMed2026

Gubernacular discontinuity and abnormal distal fixation in cryptorchidism: Challenging the classical concept.

BACKGROUND: The gubernaculum is essential for testicular descent, but its detailed surgical anatomy remains poorly understood. We have previously identified an unrecognized anatomy of the round ligament in female patients with sliding inguinal hernias. OBJECTIVE: This study investigated whether comparable anatomical features exist in the gubernaculum of male cryptorchidism patients, as compared to those identified in female sliding hernias. MATERIALS AND METHODS: We retrospectively analyzed undescended testes located in the inguinal canal that underwent open inguinal orchidopexy between 2016 and 2025. Laparoscopically managed nonpalpable testes and those with suprascrotal testes were excluded. To ensure consistent anatomical evaluation, a standardized surgical protocol supervised by the senior author was applied to all cases. Findings were verified using operative reports and video recordings. After dissecting the processus vaginalis along the internal spermatic fascia (transversalis fascia), the pars infravaginalis gubernaculi were exposed. The relationship between the plica gubernaculi and pars infravaginalis gubernaculi, as well as the site of distal gubernacular fixation, was assessed. RESULTS: A total of 64 undescended testes of 56 patients were included. Video recordings were available for 45 of these 64 testes (70%). A patent processus vaginalis was observed in 60 out of 64 testes (94%), while it was obliterated in two ascending testes and unknown in two. In all 64 testes (100%), the pars infravaginalis gubernaculi was not continuous with the plica gubernaculi, with the transversalis fascia interposed between them. This configuration closely resembled that described previously for sliding inguinal hernias in women. Distal gubernacular fixation was located lateral to the scrotum in 49 testes (77%), at the upper scrotal border in 14 testes (22%), and absent in one testis (1.6%). DISCUSSION: Cryptorchidism is associated with a previously unrecognized discontinuity of the gubernaculi and common abnormal distal gubernacular fixation. These findings challenge the conventional views on gubernacular invagination and suggest that abnormal distal fixation may contribute to failed testicular descent. The study was limited by its single-center, retrospective design, small sample size, and lack of a control group. CONCLUSION: This study identified a previously unrecognized discontinuity of the gubernaculi in cryptorchidism. These findings deepen the understanding of the pathophysiology of testicular descent.

Humans↗
PubMed2026

A systematic review and meta-analysis of the late positive potential and internalizing psychopathology.

The present study leveraged the Hierarchical Taxonomy of Psychopathology (HiTOP) framework to conduct a systematic meta-analysis to determine the association between the late positive potential (LPP) index of emotional reactivity and internalizing psychopathology. PRISMA guidelines were followed. Articles were identified through PubMed, APA PsycInfo, and Web of Science online platforms in May 2025. Included articles examined associations between the LPP to positive and/or negative stimuli and internalizing psychopathology. Risk of bias and publication bias were assessed. Results were examined for individual disorders, distress and fear subfactors, and the internalizing spectrum using two approaches: standard analyses that examined aggregate effects and hierarchical analyses that examined direct and indirect relationships. We conducted moderator analyses for sample, task design, LPP quantification, and psychopathology measurement. We included 63 studies across 5,360 participants (Mage = 19.65, SD = 11.1; 58.7% female). In standard meta-analyses, depression was associated with a smaller LPP to positive stimuli (r = -.06, 95% confidence interval [CI; -.12, -.003]). Specific phobia was associated with a larger LPP to negative stimuli (r = .21, 95% CI [.02, .37]). Distress was associated with a smaller LPP to both positive (r = -.12) and negative (r = -.11) stimuli when measured via clinical interview, and fear was associated with a larger LPP to negative stimuli (r = .10, 95% CI [.03, .16]). Hierarchical analyses indicated that the depression results were specific to the disorder, whereas the fear disorder-level results were due to the higher order fear subfactor. The LPP demonstrates discriminant relationships with distress and fear disorders and subfactors. Results were largely robust against methodological factors. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Humans↗
PubMed2025

Systematic discovery of CRISPR-boosted CAR T cell immunotherapies.

Chimeric antigen receptor (CAR) T cell therapy has shown remarkable success in treating blood cancers, but CAR T cell dysfunction remains a common cause of treatment failure1. Here we present CELLFIE, a CRISPR screening platform for enhancing CAR T cells across multiple clinical objectives. We performed genome-wide screens in human primary CAR T cells, with readouts capturing key aspects of T cell biology, including proliferation, target cell recognition, activation, apoptosis and fratricide, and exhaustion. Screening hits were prioritized using a new in vivo CROP-seq2 method in a xenograft model of human leukaemia, establishing several gene knockouts that boost CAR T cell efficacy. Most notably, we discovered that RHOG knockout is a potent and unexpected CAR T cell enhancer, both individually and together with FAS knockout, which was validated across multiple in vivo models, CAR designs and sample donors, and in patient-derived cells. Demonstrating the versatility of the CELLFIE platform, we also conducted combinatorial CRISPR screens to identify synergistic gene pairs and saturation base-editing screens to characterize RHOG variants. In summary, we discovered, validated and biologically characterized CRISPR-boosted CAR T cells that outperform standard CAR T cells in widely used benchmarks, establishing a foundational resource for optimizing cell-based immunotherapies.

Humans↗
PubMed2025

Genetic Differences in Reactivity to the Environment Impact Psychotic-Like and Affective Reactivity in Daily Life.

BACKGROUND AND HYPOTHESIS: Consistent with diathesis-stress models, psychosis research has focused on genetic moderation of adverse environmental exposures. In contrast, the Differential Susceptibility (DS) model suggests that the same genetic variants that increase risk-inducing effects of adverse experiences also enhance beneficial effects from positive experiences. This study examined whether individuals with high genetic susceptibility to the environment showed differential psychotic-like and affective reactivity in response to positive and negative events in daily life. STUDY DESIGN: Experience sampling methodology assessed context (positive and stressful) and momentary levels of paranoia, psychotic-like experiences (PLE), and positive (PA) and negative affect (NA) in 217 non-clinical adults oversampled for schizotypy. Linear mixed models examined whether Polygenic Risk Scores of Environmental Sensitivity (PRS-ES) moderated the impact of current context on subsequent experiences. STUDY RESULTS: PRS-ES moderated positive, but not stressful, context on subsequent levels of momentary paranoia, NA, and PA, but not PLE. Genetic and environmental (G × E) interactions indicated diathesis-stress at lower thresholds of PRS-ES, but a DS model at the highest threshold of the PRS-ES. Participants with elevated PRS-ES showed increased paranoia and NA and decreased PA in subsequent assessments when reporting low levels of positive situations, but also decreased paranoia and NA and increased PA when rating contexts as positive. CONCLUSIONS: Findings support the influence of genetic sensitivity to the environment on psychotic-like and affective reactivity in daily life, particularly in response to positive contexts. This highlights the transdiagnostic protective role of positive experiences and informs ecological momentary interventions.

Humans↗
PubMed2025

Exploring the causal association between television viewing and meniscal injuries: A two-sample Mendelian randomization analysis.

The aim of this study was to assess whether there is a potential causal relationship between sedentary behavior and meniscal injuries based on the Mendelian randomization (MR) method. This study used a two-sample MR design to integrate pooled data from a large-scale genome-wide association studies (GWAS). Single nucleotide polymorphisms (SNPs) that were significantly associated with sedentary behavior (represented by daily TV-viewing time) and independent of each other were selected as instrumental variables, while focusing on data from populations of European ancestry. To ensure the robustness and reliability of the analyses, 3 mainstream MR analysis methods were combined in this study: inverse variance weighted (IVW), weighted median estimation (WME) and MR-Egger regression. Heterogeneity test, horizontal multivariate analysis, and leave-one-out sensitivity test were also conducted to further validate the stability of causal estimation. The results of the IVW method showed that sedentary behavior was significantly associated with the risk of meniscus injury, with an OR (95% CI) of 2.93 (1.89-4.52), and a P-value of&#x2005;<&#x2005;.001, suggesting that sedentary behavior may be an important risk factor for meniscus injury. No significant bias was found in the heterogeneity test and the assessment of multiple validity, and the sensitivity analysis showed that the effect of individual SNPs on the overall estimation was small, and the results had good robustness. This study provides genetic epidemiological evidence of a positive causal effect of sedentary behavior on meniscal injuries based on a causal inference approach with genetic instrumental variables. The results suggest that reducing sedentary time, especially prolonged TV watching behavior, may reduce the risk of meniscus injury to some extent.

Humans↗
PubMed2026

Identification and genetic validation of potential therapeutic targets for pulmonary hypertension through multi-omics causal inference.

Pulmonary hypertension (PH) underscores the urgent need for novel therapeutic targets. This study aimed to employ a proteome-wide Mendelian randomization (MR) approach to systematically identify circulating proteins causally associated with PH, thereby providing genetically validated candidate targets for drug development. We adopted a 2-sample MR design, integrating large-scale plasma proteomic quantitative trait loci (pQTL) data (encompassing 4148 proteins) and summary statistics from a large-scale PH genome-wide association study (2047 cases, 8301 controls). Candidate targets were screened through a multilayered analytical pipeline comprising proteomic MR, transcriptomic MR, and summary-data-based Mendelian randomization. The ultimately identified MR-Identified Causal Candidate Targets (MR-ICTs) underwent rigorous Bayesian colocalization analysis, followed by biological characterization through functional enrichment analysis, single-cell transcriptomics, and phenome-wide association studies. Through robust genetic causal inference, this study provides that circulating proteins such as LYZ, GREM2, NID1, and PF4V1 play causal roles in PH pathogenesis. These findings offer a set of rigorously genetically validated, high-priority therapeutic targets for developing novel PH treatments, specifically addressing key pathological mechanisms such as innate immunity, BMP signaling pathway dysregulation, and platelet activation. Our multi-dimensional analysis ultimately identified 6 MR-ICTs causally associated with PH. Notably, the causal associations for lysozyme C (LYZ), gremlin-2 (GREM2), nidogen-1 (NID1), and platelet factor 4 variant 1 (PF4V1) were stringently validated by Bayesian colocalization analysis (posterior probability for hypothesis 4 [PPH4], indicating a shared causal variant, > 0.99). Functional enrichment analysis revealed significant involvement of these targets in immune response and TGF-&#x3b2; signaling pathways. Single-cell analysis further elucidated their cell-type-specific expression, with LYZ predominantly expressed in monocytes and PF4V1 almost exclusively in platelets.

Hypertension, Pulmonary↗
PubMed2025

Novel Protein-Altering Variants in Cleft Genes Transmitted in Families With NSCL&#xb1;P.

BACKGROUND: Pathogenic protein-altering variants play a role in the etiology of nonsyndromic cleft lip with or without palate (nsCL&#xb1;P), one of the most common craniofacial anomalies. However, the genetic basis of many cases remains unclear, complicating risk prediction for affected families. PURPOSE: This study utilized whole-genome sequencing (WGS) of 150 case-families with nsCL&#xb1;P from sub-Saharan Africa to identify pathogenic risk variants. STUDY DESIGN, SETTING, SAMPLE: This study utilized whole-genome sequencing (WGS) of 150 case-families with nsCL&#xb1;P from sub-Saharan Africa to identify risk variants. PREDICTOR/EXPOSURE/INDEPENDENT VARIABLE: Genetic variants. MAIN OUTCOME VARIABLES: Nonsyndromic cleft lip with or without palate (nsCL&#xb1;P). ANALYSES: Genomes were sequenced at a mean &#xd7;30 coverage, and variants were prioritized using CADD (&#x2265;20), REVEL (&#x2265;0.5), and ACMG/AMP clinical significance criteria. RESULTS: We identified pathogenic protein-altering variants in CHD7 (p.Arg1345His), LRP2 (p.Asp3245Asn), RYR1 (p.Arg2163Leu, p.Pro2903Thr), SHH (p.Met114Val), and WNT3 (p.Ser112Pro) highlighting the role of hedgehog signaling pathway (FDR=5.32e-12) in nsCL&#xb1;P. These variants were inherited from unaffected parents suggesting an incomplete penetrance of the variant effect. Although mouse data showed that knockout of these genes produces cleft phenotypes, in vivo studies will help us better understand how the consequences of these variants differ from benign mutations. The presence of these protein-altering variants in unaffected parents-incomplete penetrance, provides additional evidence supporting the trait complexity. CONCLUSIONS AND RELEVANCE: This study identified rare, pathogenic protein-altering variants in genes involved in key developmental pathways in African families affected by nsCL&#xb1;P. These findings highlight the critical role of the hedgehog signaling pathway and related networks in the etiology of nsCL&#xb1;P. These findings underscore the importance of whole-genome sequencing in genetically diverse populations to uncover novel risk variants. These findings enhance our understanding of the genetic etiology of nsCL&#xb1;P, particularly in under-represented African populations and support the multifactorial inheritance and the involvement of developmental pathways, such as hedgehog signaling in the etiology of clefting.

Humans↗
PubMed2025

CAUSAL ASSOCIATION BETWEEN SEPSIS AND FIBROBLAST GROWTH FACTORS AS WELL AS THEIR RECEPTORS LEVELS: A TWO-SAMPLE MENDELIAN RANDOMIZATION STUDY.

Objective: The potential association between sepsis risk and circulating levels of fibroblast growth factors (FGFs) and their receptors (FGFRs) has been a focus of research; however, the causal relationship between them remains to be elucidated. We hypothesize a causal association between genetically predicted FGFs, FGFRs, and sepsis risk, and we conduct a Mendelian randomization (MR) study to validate this hypothesis. Methods: We utilized a two-sample MR design to assess the effect of genetic variants associated with various FGFs (FGF1, FGF2, FGF7, FGF16, FGF19, FGF21, FGF23, FGF5) and FGFRs (FGFR1, FGFR2, FGFR3, &#x3b1;-Klotho) on sepsis risk, using genome-wide association study summary statistics. Our MR analyses employed the inverse-variance weighted (IVW) method, along with weighted median, weighted mode, and MR-Egger regression, supplemented by sensitivity analyses to ensure robustness. Results: The MR analysis identified an unequal number of instrumental variables ranging from 2 to 17 for FGFs and FGFRs when sepsis was the outcome. No significant correlation was found between genetically determined FGF levels and sepsis risk by IVW analysis (all P > 0.05). Correspondingly, similar nonsignificant associations were observed for FGFRs (all P > 0.05). Other MR methods corroborated the IVW findings. Sensitivity analyses, including Cochran's Q test, MR-Egger, and MR pleiotropy residual sum and outlier, indicated no significant heterogeneity or pleiotropy in the relationships, with the exception of a nonsignificant correlation between FGFR1 and sepsis that persisted after the exclusion of an outlier (odds ratio, 0.84; P = 0.34). Conclusion: The analysis found no significant causal associations between FGFs, their receptors, and sepsis risk, indicating a need for further research on their complex interactions.

Humans↗
PubMed2022

Adolescents hospitalised for suicidality: biomarkers, social and affective predictors: a cohort study.

OBJECTIVES: The present research examines genomics and in vivo dynamics of family context and experienced affect following discharge from psychiatric hospitalisation for suicidal thoughts and behaviours (STBs). The purpose of this paper is to provide an overview of a new model, description of model-guided integration of multiple methods, documentation of feasibility of recruitment and retention and a description of baseline sample characteristics. DESIGN: The research involved a longitudinal, multimethod observational investigation. SETTING: Participants were recruited from an inpatient child and adolescent psychiatric hospital. 194 participants ages 13-18 were recruited following hospitalisation for STB. PRIMARY AND SECONDARY OUTCOME MEASURES: Participants underwent a battery of clinical interviews, self-report assessments and venipuncture. On discharge, participants were provided with a phone with (1) the electronically activated recorder (EAR), permitting acoustic capture later coded for social context, and (2) ecological momentary assessment, permitting assessment of in vivo experienced affect and STB. Participants agreed to follow-ups at 3 weeks and 6 months. RESULTS: A total of 71.1% of approached patients consented to participation. Participants reported diversity in gender identity (11.6% reported transgender or other gender identity) and sexual orientation (47.6% reported heterosexual or straight sexual orientation). Clinical interviews supported a range of diagnoses with the largest proportion of participants meeting criteria for major depressive disorder (76.9%). History of trauma/maltreatment was prevalent. Enrolment rates and participant characteristics were similar to other observational studies. CONCLUSIONS: The research protocol characterises in vivo, real-world experienced affect and observed family context as associated with STB in adolescents during the high-risk weeks post discharge, merging multiple fields of study.

Adolescent↗
PubMed2026

Comparison of endothelin-1 levels in plasma from human coronary arteries measured by enzyme linked immunosorbent assay and Olink high-throughput proteomics platform.

Endothelin-1 (ET-1) antagonists are increasingly being approved for new treatments for cardiovascular disease, where elevated ET-1 levels contribute to increased vasoconstriction. Further therapeutic targets, including coronary artery disease, are under investigation. The Olink Explore 3072 Proximity Extension Assay platform enables multiplexed high-throughput measurement of ~3000 plasma proteins, from minimal (&#x2264;6&#x2009;&#xb5;L) sample volumes. However, it is not known if the two oligonucleotide-tagged antibodies raised against preproET-11-212, used in this Olink assay, specifically measure biologically active ET-1 or the other inactive EDN1-encoded peptides, also secreted by human endothelial cells. Paired plasma samples from 29 patients with coronary artery disease were obtained, using a specialised intra-coronary sampling catheter, designed to obtain site specific biochemical information from within coronary arteries. We compared ET-1 concentrations measured with an ET-1 specific ELISA, demonstrated to have no cross-reactivity with other EDN1-encoded peptides versus values obtained using Olink Explore platform. Olink-measured ET-1 correlated significantly with ELISA-derived ET-1 levels (r&#xa0;=&#xa0;0.53, p&#xa0;=&#xa0;0.003), and Olink values predicted ELISA results. Olink ET-1 concentrations also correlated with ETB receptor levels (r&#xa0;=&#xa0;0.40, p&#xa0;<&#xa0;0.05). These findings indicate that the Olink Explore platform can detect relative changes in biologically active ET-1, supporting its use as a biomarker tool in clinical and translational studies.

Humans↗
PubMed2026

Mendelian Randomization Analysis of NETs-Associated Inflammatory Traits and Type 2 Diabetes and its Complications.

Neutrophil extracellular traps (NETs) -associated inflammatory traits play a significant role in type 2 diabetes mellitus (T2DM) and its complications. Notably, IL-6, a key inflammatory cytokine, is intricately linked to the formation of NETs and the pathogenesis of T2DM and its complications. This study aimed to explore the causal association between NETs-associated inflammatory traits and T2DM, as well as its complications, using a Mendelian Randomization (MR) approach. This study utilized a two-sample MR design with data from Genome-Wide Association Studies (GWAS), comprising a large European population-based meta-analysis for T2DM and its complications. The primary method of analysis was the inverse variance weighted (IVW) approach, complemented by MR-Egger regression, weighted median, and weighted mode methods. Sensitivity analyses included MR-Egger, MR-PRESSO, Cochran's Q, and leave-one-out methods to assess the robustness of the findings. The study indicated that genetically predicted levels of interleukin-6 (IL-6) were inversely associated with diabetic coronary artery disease (CAD) (OR = 0.8997, 95% CI: 0.8257-0.9803, P = 0.0158). Additionally, NETs showed significant associations with T2DM with renal complications (OR=0.97, 95% CI 0.9428-0.998, P = 0.0358) and T2DM with peripheral circulatory complications(OR = 1.0342, 95% CI 1.002-1.0673, P = 0.037). The significant IVW associations showed no evidence of heterogeneity or horizontal pleiotropy. This study suggests that genetically predicted NETs-associated inflammatory traits are associated with specific T2DM complications. Genetically predicted IL-6 was inversely associated with diabetic CAD, whereas NETs were associated with renal and peripheral circulatory complications in T2DM.

Diabetes Mellitus, Type 2↗