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PubMed2026

Effect of Peer Comparison Feedback and Professional Norms on Vitamin D Testing and Generic Medication Prescribing.

BACKGROUND: Organization for Economic Cooperation and Development (OECD) estimates suggest that 20% of health care spending is wasteful or even harmful. Previous interventions have had limited success in discouraging low-value care in medical practice. METHODS: We conducted a nationwide randomized controlled trial among primary care physicians (PCPs) in Switzerland (November 2020-December 2021). We randomly assigned PCPs to one of three intervention groups related to low-value care (vitamin D testing, generic prescribing, or a cost intervention) or a control group. This article reports results for the vitamin D testing and generic prescribing interventions compared with the common control group. PCPs in the intervention groups received a personalized information letter combining professional norms and peer comparison feedback about the low-value service (either vitamin D testing or prescribing of nongeneric medications). Primary endpoints were (1) the number of vitamin D tests per 100 patients and (2) the share of generic medications prescribed. We estimated average treatment effects using linear regression and assessed effect heterogeneity with a causal forest. RESULTS: A total of 618 PCPs were randomly assigned to the vitamin D intervention, 597 to the generic prescribing intervention and 601 to the common control group. The intervention reduced average vitamin D testing by 3.66 tests per 100 patients (95% confidence interval [CI], -5.42 to -1.89; P<0.001). The intervention did not increase average generic medication prescribing (mean difference, +0.57 percentage points; 95% CI, -0.68 to +1.81 percentage points; P=0.37). Heterogeneity analysis suggested that reductions in vitamin D testing among physician subgroups ranged from one to seven per 100 patients and that higher baseline generic prescribing rates were associated with increases in generic substitution following the intervention. No increases in low-value care were seen among those physicians with low baseline levels. CONCLUSIONS: Peer comparison letters emphasizing professional norms reduced vitamin D testing but did not increase generic medication prescribing. (Funded by the Swiss National Science Foundation; AEA Randomized Controlled Trials Registry no., AEARCTR-0004747.).

Humans↗

PubMed2026

Characteristics of p53 and Smad4 immunohistochemistry in pancreatic ductal adenocarcinoma and validation by next-generation sequencing.

BACKGROUND: Mutations in four major driver genes -KRAS, CDKN2A, TP53, and SMAD4- are central to the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) and critically inform diagnosis, therapeutic decision-making, and prognostic assessment. Although next-generation sequencing (NGS) is widely regarded as the gold standard for detecting these mutations, its clinical application is often limited by suboptimal analytical efficiency and substantial economic cost. Among these genes, immunohistochemical (IHC) staining for the proteins encoded by TP53 and SMAD4 has been extensively adopted in routine pathology practice. However, standardized IHC pattern classification schemes and rigorous validation of their predictive accuracy for underlying genomic alterations remain lacking in PDAC. METHODS: We retrospectively enrolled 63 PDAC patients and systematically characterized the typical IHC expression patterns of p53 and Smad4. Targeted NGS was subsequently performed on all available tumor specimens, and the resulting mutational profiles were correlated with corresponding IHC findings. Diagnostic performance including sensitivity, specificity and accuracy of p53 IHC for predicting TP53 mutations and of Smad4 IHC for predicting SMAD4 mutations was rigorously evaluated. RESULTS: Among the four canonical driver genes, co-occurring double- or triple-gene mutations were prevalent; within TP53 and SMAD4, missense mutations constituted the most frequent variant type. Using NGS as the reference standard, we validated the diagnostic utility of a three-tiered p53 IHC classification system, particularly in fine-needle biopsy (FNB) specimens. Furthermore, we proposed a novel, refined Smad4 IHC pattern classification that incorporates an "intermediate" category, thereby expanding upon conventional binary interpretation. This new scheme achieved markedly improved mutation prediction accuracy (0.76) compared with traditional approaches (0.57). CONCLUSION: Our study highlights the complementary diagnostic value of p53 and Smad4 IHC relative to molecular testing in PDAC, especially when tissue is limited, as commonly encountered in FNB specimens. The newly established Smad4 IHC classification system, which integrates an intermediate expression category into the conventional two-tier framework, demonstrates superior clinical utility and enhances predictive accuracy for SMAD4 genomic alterations.

Humans↗

PubMed2026

Effects of acute hypoxia followed by reoxygenation on intestinal histomorphology, oxidative stress and hypoxia signaling biomarkers, and microbiota in pikeperch (Sander lucioperca).

In aquatic environments, natural and anthropogenic factors commonly reduce dissolved oxygen (DO) and trigger hypoxia, which threatens the health and survival of aquatic organisms. As an important economic fish species in China, pikeperch (Sander lucioperca) is extremely sensitive to hypoxia. However, there are relatively few reports on how hypoxia and reoxygenation affect its intestinal physiology and microbial community. Three treatment groups were set for pikeperch: normoxia (DO = 8.5 ± 0.5 mg/L), 48 h hypoxia (DO = 2.5 ± 0.1 mg/L), and reoxygenation (48 h hypoxia followed by 6 h reoxygenation at normal DO), to evaluate alterations in intestinal histopathology, tight junction gene expression, oxidative stress, hypoxia signaling molecules and intestinal microbiota composition. The results showed that hypoxia significantly decreased muscularis thickness by approximately 32.5% and reduced the expression of tight junction genes (Occludin, Claudin2, and ZO-2). Moreover, hypoxia significantly increased oxidative stress index levels (GSH-Px, CAT, and MDA), markedly upregulated the expression of Bax, Caspase3, and HIF-1α, while significantly downregulating the expression of Bcl-2, Egln1, and Egln2. Notably, reoxygenation elicited partial compensatory effects against these hypoxia-induced changes. 16S rRNA sequencing analysis revealed that hypoxic stress altered the intestinal microbial community composition of pikeperch and increased its diversity. In the hypoxia group, the abundance of the phylum Bacillota, along with the genera Halomonas and Acinetobacter, was significantly elevated, whereas in the reoxygenation group, the genus Lactobacillus increased approximately 180-fold. The results indicated that hypoxia caused intestinal oxidative damage, cell apoptosis, and intestinal microbiota dysbiosis in pikeperch, while short-term reoxygenation achieved partial recovery from these hypoxia-triggered intestinal injuries. The present research provides valuable references for in-depth exploration of the molecular mechanisms behind the response of pikeperch to acute hypoxia and reoxygenation stress, while also offering a novel perspective to understand the mechanism by which hypoxia impacts intestinal health in fish.

Animals↗

PubMed2026

Feasibility and effectiveness of the Bergen 4-Day Treatment for obsessive-compulsive disorder in Australia: A pilot comparison with 3-week inpatient obsessive-compulsive disorder treatment.

OBJECTIVES: Obsessive-compulsive disorder is a debilitating and chronic condition that, when untreated or unresponsive to treatment, imposes a significant health and economic burden on individuals and families. This prospective non-randomised inpatient study compared the acceptability and clinical outcomes of the Bergen 4-Day Treatment programme with those of a standard 3-week specialised treatment programme for obsessive-compulsive disorder in Australia. METHOD: Twenty-five participants diagnosed with obsessive-compulsive disorder were non-randomly assigned to Bergen 4-Day Treatment (n = 12) or a 3-week standard (n = 13) inpatient programme. Independent assessments were completed at pre-treatment, 10 days post treatment and at 3-month follow-up. The Yale-Brown Obsessive-Compulsive Scale was rated to assess obsessive-compulsive disorder severity, while secondary measures of depression, anxiety, obsessive beliefs and wellbeing were self-rated by participants. RESULTS: Baseline characteristics of both groups were comparable, with obsessive-compulsive disorder symptom severity within the moderate to severe range. After treatment, obsessive-compulsive disorder symptoms as well as secondary depression and anxiety symptoms were reduced in both treatment groups. Participants receiving Bergen 4-Day Treatment had significantly lower Yale-Brown Obsessive-Compulsive Scale scores at 10 days (M = 13.46) and 3 months (M = 11.84), compared to standard treatment (M = 19.04 and M = 19.15, respectively). Response (91.9%) and remission (45.8%) rates for the Bergen 4-Day Treatment group were significantly higher at both post-treatment timepoints, compared to the standard treatment group. No dropouts occurred in the Bergen 4-Day Treatment group, and participant satisfaction was high. CONCLUSION: The findings of this pilot open-label study suggest that Bergen 4-Day Treatment shows promise as an acceptable, efficient and effective treatment for obsessive-compulsive disorder, warranting further investigation as a scalable alternative for improving access to specialised obsessive-compulsive disorder treatment in Australia.

Humans↗

PubMed2026

Stratified medicine with eplerenone for myocardial infarction or injury and no obstructive coronary arteries: A registry-based basket trial.

BACKGROUND: Myocardial Infarction with No Obstructive Coronary Arteries (MINOCA) or Nonischemic Myocardial Injury affects approximately 1 in 9 patients presenting with acute coronary syndrome, yet evidence-based therapies are lacking. Coronary microvascular dysfunction is implicated in the pathogenesis of suspected MINOCA, but its prevalence, prognostic implications and treatment are uncertain. The objectives are, first, to assess the prevalence of coronary microvascular dysfunction in patients with suspected MINOCA and, second, to implement endotype-informed stratified medicine involving patients with coronary microvascular dysfunction to treatment with eplerenone, a cardio- and vasculo-protective mineralocorticoid receptor antagonist. METHODS: This is a prospective, registry-based, multicenter, diagnostic study and nested, randomized, controlled, open-label, blinded-endpoint (PROBE) basket trial. Up to 400 patients with clinically suspected MINOCA and one or more cardiovascular risk factors will be enrolled into a registry-based diagnostic study. Coronary microvascular function will be assessed during invasive angiography using thermodilution. Patients with an index of coronary microvascular resistance (IMR) ≥ 25 will be randomized 1:1 to eplerenone (25-50 mg daily for 6 months) or standard care without eplerenone (control group) (n = 150 randomized). Final endotypes will be centrally adjudicated by a panel of blinded cardiologists. The primary outcome of the diagnostic study is the proportion of patients with IMR ≥ 25 during index coronary angiography. Secondary outcomes include coronary flow reserve, cardiovascular MRI parameters, patient-reported outcome measures, biomarkers of myocardial fibrosis and vascular inflammation, health outcomes and health economic assessments. The primary outcome of the randomized trial is the within-individual change in NT-proBNP at baseline, 1 month, and 6 months, based on intention-to-treat. Secondary outcomes include mechanistic blood biomarkers and patient-reported outcome measures. VALUE: This registry-based randomized trial will provide novel evidence on endotype-informed secondary prevention therapy with eplerenone for suspected MINOCA.

Humans↗

PubMed2026

Effects of positive psychotherapy on anxiety and quality of life in chronic Urticaria.

INTRODUCTION: Individual, social, and economic consequences including anxiety and poor quality of life are recognised to result from allergic disorders. A positive, realistic viewpoint that emphasises balance and the body is provided by positive psychotherapy. The purpose of this randomized, controlled intervention study was to investigate how counseling based on positive psychotherapy affected anxiety and quality of life. METHODS: Patients in the intervention group had eight sessions of individual counseling based on positive psychotherapy in addition to standard treatment. Other than standard care, the members of the control group received no interventions. The Dermatological Quality of Life Scale (DYQS), Urticaria Activity Score, State-Trait Anxiety Scale, and Personal Information Form were employed as data collection instruments. The study had 66 patients with Chronic Spontaneous Urticaria (CSU), 32 of whom were in the intervention group and 34 of whom were in the control group. RESULTS: The mean scores of the intervention group decreased significantly from pre-test to post-test for urticaria activity (UAS7: 28.22 ± 11.17 to 4.22 ± 4.30, p < 0.001), dermatological quality of life (DLQI: 38.63 ± 7.61 to 5.09 ± 6.19, p < 0.001), situational anxiety (61.63 ± 7.73 to 26.03 ± 4.71, p < 0.001), and trait anxiety (61.56 ± 7.90 to 25.13 ± 3.66, p < 0.001). Furthermore, post-test scores between the intervention and control groups showed statistically significant differences in favor of the intervention group in all primary outcomes, including the total UAS7 score (intervention: 4.22 ± 4.30 vs. control: 21.56 ± 11.81, p < 0.001) and the total dermatological quality of life score (intervention:5.09 ± 6.19 vs. control:30.85 ± 10.17, p < 0.001). CONCLUSIONS: Counseling based on positive psychotherapy has been shown to improve people's quality of life while lowering anxiety and urticaria symptoms. This study demonstrates how these treatments can enhance the quality of life for patients with chronic urticaria by lowering their anxiety and illness symptoms.

Humans↗

PubMed2026

Prevalence and risk factors of red blood cell alloimmunization among sickle cell disease patients in resource-limited countries: A systematic review and meta-analysis.

BACKGROUND: Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by hemoglobin S production, in which homozygous individuals (HbSS) develop a broad range of acute and chronic complications. While disease-modifying and curative therapies are increasingly available in high-income settings, red blood cell (RBC) transfusion remains the mainstay of treatment in resource-limited countries and is associated with high rates of alloimmunization. This systematic review and meta-analysis aimed to estimate the prevalence of alloimmunization and identify associated risk factors among patients with SCD living in resource-limited settings. METHODS: Africa Journals Online (AJOL), Embase, PubMed, Scopus, and Web of Science were searched for original studies published from inception to December 15, 2025. Only studies conducted in low- and lower-middle-income countries (LMICs) were included. Eligible studies evaluated the prevalence of alloimmunization in patients with SCD receiving RBC transfusions. A random-effects meta-analysis of proportions was performed to pool quantitative data, while qualitative findings were systematically summarized in tabular form. Statistical heterogeneity was assessed using the I² statistic and further explored using Baujat plots, leave-one-out analyses, and meta-regression. RESULTS: Our analysis included 27 studies conducted in Africa (n = 23) and Asia (n = 4), predominantly from lower-middle-income countries (n = 19) and mainly employing a cross-sectional design (n = 20), comprising 3128 previously transfused patients with SCD. The pooled prevalence of RBC alloimmunization was 8.76% (95% CI: 6.71-11.37%; I² = 75%). Higher alloimmunization rates were observed in West and North Africa, particularly in Côte d'Ivoire, Egypt, and Nigeria, whereas lower rates were reported in Asia and East Africa. The most frequently identified antibodies belonged to the Rh blood group system (n = 153), followed by the Kell system (n = 65). CONCLUSION: In resource-limited settings, RBC alloimmunization is a frequent and clinically significant complication in patients with SCD, contributing to increased morbidity and potential mortality. Targeted and economically viable antigen matching may reduce alloimmunization rates and improve transfusion safety in LMICs.

Humans↗

PubMed2026

Emergence of Babesia naoakii infection in Indonesian domestic cattle, a new host record in water buffaloes, and characterization of complete mitochondrial protein-coding genes.

Babesia (B.) naoakii, previously referred to as Babesia sp. Mymensingh, is a recently characterized tick-borne haemoprotozoan parasite of cattle. In Indonesia, we first reported its presence in 2022 from clinically affected cattle in Central Java. To investigate the wider epidemiology of this neglected ruminant-associated Babesia species, we surveyed apparently healthy cattle (Bos indicus) and water buffaloes (Bubalus bubalis) across three districts of Java, Indonesia. A PCR assay targeting the B. naoakii-specific apical membrane antigen 1 (ama1) gene detected the parasite occurrence in 34.39% of assessed cattle (87/253; 95% CI: 28.80-40.44%) and 30.77% of water buffaloes (12/39; 95% CI: 18.47-46.52%). These results represent the first record of B. naoakii infection in water buffaloes in the country and confirm that the parasite circulates in subclinically infected bovine hosts. To characterise this apicomplexan parasite further at the molecular level, we assembled in full length the three mitochondrial protein-coding genes (PCGs): cytochrome c oxidase subunits 1 (cox1) and 3 (cox3), as well as cytochrome b (cytb). These genes were reconstructed by next-generation sequencing of blood DNA collected during the acute haemolytic-phase of B. naoakii infection, from calves that subsequently succumbed to the disease in the endemic area. Phylogenetic analyses of the concatenated amino-acid sequences of cox1, cox3, and cytb placed the Indonesian isolates within a well-supported monophyletic clade, distinct from all previously characterised ruminant-associated Babesia species and sister to the Babesia bigemina/Babesia ovata lineage. This placement confirmed species identity and reinforced the genetic distinctiveness of B. naoakii in Indonesia. Notably, although B. naoakii circulates in peripheral blood and mirrors the diagnostic behaviour of the mild pathogen B. bigemina, its clinical impact more closely resembles that of the severe pathogenic B. bovis, particularly in young animals. This diagnostic-clinical discordance highlights the need for B. naoakii-specific molecular surveillance and species-level differentiation in regions of co-endemicity. Given the high prevalence in subclinically B. naoakii-infected adults, the documented severity of babesiosis in calves, and the potential for substantial economic losses, broader epidemiological investigations and species-specific control measures for B. naoakii are urgently performed. The same holds true for future epizootiological investigations of underdiagnosed B. naoakii-infections possibly circulating in Indonesian endemic ruminant bovids such as the banteng (Bos javanicus), the lowland anoa (Bubalus depressicornis) and the tamaraw (Bubalus mindorensis).

Animals↗

PubMed2026

International study of coronary microvascular angina (iCorMicA): A registry-based diagnostic study and nested randomized trial.

BACKGROUND: Angina is a debilitating condition caused by coronary artery disease and microvascular dysfunction. Following coronary angiography angina and no obstructive coronary arteries is a common outcome, and women are disproportionately affected. The objectives are first, to assess causes of angina in patients undergoing invasive management; and second, to assess effects of coronary function test-guided management on clinical outcomes. METHODS: This is an international, multicenter, prospective, registry-based study and nested, randomized, controlled, triple-blind, and endpoint trial. Participants, community care providers, and outcomes assessors are masked. Consented participants enter the registry. Participants without obstructive coronary artery disease (luminal stenosis <50%, or fractional flow reserve >0.80) are eligible for randomization. Index of microcirculatory resistance (IMR; abnormal ≥25) and coronary flow reserve (CFR; abnormal <2.0; gray zone 2.0-2.5) are measured by bolus thermodilution, and results are disclosed (intervention) or not (control group) to the attending cardiologist. RESULTS: The primary outcome of the registry is the Seattle Angina Questionnaire summary score at baseline described by coronary artery disease status. Secondary outcomes include the prevalence of obstructive coronary artery disease, patient reported outcome measures and clinical outcomes. The primary outcome of the randomized trial is the within-individual change in Seattle Angina Questionnaire summary score at 12-months from baseline. Secondary outcomes include safety, diagnostic accuracy, patient reported outcome measures for quality of life, physical and psychological function, cardiovascular risk, clinical outcomes, health economics and mechanistic biomarkers. The first patient was screened on December 18, 2020 and the last patient was enrolled on June 30, 2026. Forty sites were included in the United Kingdom (n = 35), Republic of Ireland (n = 2), Holland (n = 2), and Poland (n = 1). In total, 1,483 participants were enrolled into the registry of whom 1,047 were randomized and 386 were not randomized (registry-only). CONCLUSION: This international, registry-based clinical trial will provide novel evidence on the natural history of angina and stratified therapy for angina with no obstructive coronary arteries. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT04674449. UNIQUE IDENTIFIER: NCT04674449.

Humans↗

PubMed2026

Integrative genomic and transcriptomic analyses identify key regulators of skin pigmentation in Larimichthys crocea.

The yellow body coloration of large yellow croaker (Larimichthys crocea) constitutes a crucial economic trait, yet its underlying genetic regulatory mechanisms remain poorly understood. This study systematically elucidated the molecular basis of body color variation by integrating genome resequencing and skin transcriptome analyses, combined with the contextual analysis of key pigmentation-related genes and phenotypic histological validation. 200 phenotyped individuals (including yellow-selected lines, F1 progeny, and normal control groups, all derived from a well-characterized aquaculture stock) identified 39 significantly associated SNPs (-log₁₀(P) ≥ 6), mapping to multiple candidate genes. These genes were significantly enriched in pathways related to pigment deposition (GO:0033059), melanosome organization (GO:0032438), melanogenesis, and tyrosine metabolism. Cross-developmental stage transcriptome analysis revealed 2395 differentially expressed genes (DEGs). Multi-omics integration identified eight overlapping candidate genes, including tyrp1, slc45a2, oca2, and dgat2, among which tyrp1 was prioritized for in-depth validation based on its core regulatory role in eumelanin synthesis, significant SNP association signal, and consistent downregulation in transcriptomic data. Experimental validation demonstrated that the g.895C > T mutation in exon 2 of tyrp1b was strongly significantly associated with the yellow phenotype: the frequency of mutant genotypes (TT/CT) reached 92.86%in the yellow-selected group, whereas the control group exclusively exhibited the wild-type genotype (CC). qPCR confirmed significantly downregulated tyrp1b expression in the skin of yellow individuals, consistent with the transcriptome trend. Histological and stereomicroscopic observations of skin tissues further validated the physiological basis of the yellow phenotype, revealing a significant reduction in melanophore number and abnormal melanosome morphology in yellow-phenotype individuals, accompanied by increased xanthophore density. These results suggest that tyrp1b mutation is strongly associated with the yellow phenotype. However, the presence of a wild-type CC individual in the yellow group indicates that this mutation is not strictly required for yellow coloration, suggesting that other genetic or environmental factors may also contribute to the phenotype, Additionally, downregulation of the carotenoid metabolism gene bco2 coupled with upregulation of xdh, together with the functional changes of slc45a2 and oca2, may synergistically promote xanthophore pigment deposition, contributing to the yellow phenotype. As melanin synthesis in large yellow croaker relies on the conserved tyrosinase pathway and transporter proteins, mutations in associated genes (tyrp1b, slc45a2, oca2) represent a primary underlying cause for the loss of melanin-based coloration and transition to a yellow phenotype in L. crocea. These findings provide key molecular targets and a theoretical foundation for molecular breeding of body color in this species, and also enrich the understanding of xanthism regulatory mechanisms in teleosts.

Animals↗

PubMed2026

Efficacy, acceptability, and related outcomes of pharmacological interventions for acute bipolar mania: a systematic review and dose-related network meta-analysis across different age groups.

BACKGROUND: Acute bipolar mania carries negative social and economic consequences. We investigated the comparative efficacy/response/acceptability of pharmacological interventions for acute bipolar mania, considering dose effects across different age groups. METHODS: We conducted a network meta-analysis (NMA) to search for randomized controlled trials (RCTs) comparing pharmacological interventions with one another or placebo in acute bipolar mania patients, indexed in PubMed/MEDLINE, Embase, Web of Science, and Scopus (from inception through 2025.12.24). Co-primary outcomes were change in manic symptoms/response/and acceptability. Tolerability/remission and rate of adverse events were secondary outcomes. Confidence-In-Network-Meta-Analysis was likewise appraised. RESULTS: 113 RCTs, encompassing 49 distinct treatment combinations, included 20,666 participants. Sensitivity analysis retaining only low-risk-of-bias studies and excluding outliers for possible effect modifiers indicated that risperidone 3 mg/day(SMD = -7.57;95%C.I. = -8.25;-5.85); tamoxifen 160 mg/day(SMD = -1.73;95%C.I. = -2.32;-1.13); rivastigmine 3 mg/day(SMD = -1.13;95%C.I. = -1.06;-0.58); haloperidol 30 mg/day(SMD = -0.96;95%C.I. = -1.25;-0.75); valproate 750 mg/day(SMD = -0.76;95%C.I. = -1.48;-0.58); tamoxifen 40 mg/day(SMD = -0.75;95%C.I. = -1.41;-0.59); celecoxib 400 mg/day(SMD = -0.74;95%C.I. = -1.20;-0.38); paliperidone extended-release 12 mg/day(SMD = -0.62; 95%C.I. = -0.91;-0.32); olanzapine 15 mg/day(SMD = -0.59;95%C.I. = -0.60;-0.38); olanzapine 20 mg/day(SMD = -0.52;95%C.I. = -0.66;-0.38); risperidone 4 mg/day(SMD = -0.53;95%C.I. = -0.76;-0.29); allopurinol 600 mg/day(SMD = -0.54;95%C.I. = -0.67;-0.22); cariprazine 12 mg/day(SMD = -0.49;95%C.I. = -0.66;-0.33); risperidone 4.2 mg/day(SMD = -0.46;95%C.I. = -0.75;-0.17); lithium 1500 mg/day(SMD = -0.42;95%C.I. = -0.57;-0.28); ziprasidone 160 mg/day(SMD = -0.49;95%C.I. = -0.68;-0.31); asenapine 20 mg/day(SMD = -0.38;95%C.I. = -0.53;-0.22); haloperidol 8 mg/day(SMD = -0.34;95%C.I. = -0.63;-0.05); aripiprazole 15 mg/day(SMD = -0.33;95%C.I. = -0.61;-0.06) outperformed placebo. Ziprasidone 160 mg/day, celecoxib 200 mg/day, asenapine 20 mg/day, and asenapine 10 mg/day proved more efficacious than placebo in children. No statistically significant differences were reported between treatments and placebo for response/remission/acceptability/tolerability, and manic/hypomanic switch. A meta-regression of efficacy effect sizes against the adapted AMSTAR-Plus content scores showed that larger SMDs were associated with lower AMSTAR scores, indicating lower study quality, warranting further caution for such large efficacy estimates. CONCLUSIONS: Our findings are consistent with previous NMAs and current guidelines, expanding the current knowledge base while concurrently appraising different drugs, doses, and age groups.

Humans↗

PubMed2026

Statistical test to compare the linkage model and the admixture model based on central limit results.

In the Admixture Model, the probability that an individual carries a certain allele at a specific marker depends on the allele frequencies in K ancestral populations and the proportion of the individual's genome originating from these populations. The markers are assumed to be independent. The Linkage Model is a Hidden Markov Model that extends the Admixture Model by incorporating linkage between neighboring loci. We prove consistency and asymptotic normality of maximum likelihood estimators for the ancestry of individuals in the Linkage Model, complementing earlier results by (Pfaff et al., 2004; Pfaffelhuber and Rohde, 2022; Heinzel, 2025) for the Admixture Model. These results are used to prove that a statistical test that allows for model selection between the Admixture Model and the Linkage Model is an asymptotic level-α-test. Finally, we demonstrate the practical relevance of our results by applying the test to real-world data from The 1000 Genomes Project Consortium (2015).

Genetic Linkage↗

PubMed2026

Modelling the effects of biological intervention in a dynamical gene network.

Cellular response to environmental and internal signals can be modeled by dynamical gene regulatory networks (GRN). In the literature, three main classes of gene network models can be distinguished: (1) non-quantitative (or data-based) models which do not describe the probability distribution of gene expressions; (2) quantitative models which fully describe the probability distribution of all genes co-expression; and (3) mechanistic models which allow for a causal interpretation of gene interactions. We propose two rigorous frameworks to model gene alteration in a dynamical GRN, depending on whether the network model is quantitative or mechanistic. We explain how these models can be used for design of experiment, or, if additional alteration data are available, for validation purposes or to improve the parameter estimation of the original model. We apply these methods to the Gaussian graphical model, which is quantitative but non-mechanistic, and to mechanistic models of Bayesian networks and penalized linear regression.

Gene Regulatory Networks↗

PubMed2026

The landscape of pruning for large language models: A systematic review and unified taxonomy.

Confronting the inherent tension between the exceptional capabilities and the immense computational costs of Large Language Models (LLMs), pruning has become a crucial technique for achieving efficient deployment. However, a systematic analytical framework dedicated specifically to LLM pruning remains absent. In this paper, we aim to bridge this gap. We first elucidate the theoretical foundations that underpin the effectiveness of pruning, namely overparameterization and redundancy, and then propose a multidimensional taxonomy that organizes existing approaches along the axes of granularity, timing, and criteria. Building upon this unified perspective, we further analyze performance recovery mechanisms and the broader evaluation ecosystem, while also exploring forward-looking challenges such as interpretability, automation, and hardware-algorithm co-design. Through this comprehensive synthesis, we seek to provide an integrated and coherent analytical lens for advancing both research and practice in LLM pruning.

Large Language Models↗

PubMed2025

An integrated multiscale air quality modelling framework for industrial park pollution: Linking local emissions to regional transport.

Capturing the spatiotemporal distribution of pollutants in industrial parks remains challenging for regional air quality models because of their coarse resolution (3 km), resulting in uncertainties in local emission quantification. To address this, we developed the Integrated Multiscale Air Quality Modelling System for Industry (IAQMS-Industry), coupling the regional Nested Air Quality Prediction Modelling System (NAQPMS) with a city-scale chemical transport model. This framework integrates point-source locations and Gaussian plume dispersion to simulate particulate matter with a diameter smaller than 2.5 micrometres (PM2.5) at 100 m resolution. Applied to the Beijing Yi Zhuang and Tangshan industrial parks and evaluated against observations. The coupled model achieved a normalized mean bias (NMB) ranging from 3.1 % to 6.2 %, improving upon NAQPMS (-16.9 % to -7.7 %). Spatial analysis revealed that coarse regional grids underestimated the PM2.5 concentrations at industrial sites by smoothing gradients, whereas IAQMS-Industry successfully resolved spatial patterns. Industrial point emissions accounted for 22.9 %-26.4 % of PM2.5 in the coupled model, which was significantly greater than the regional model estimates of 1.6 %-13.7 %. These findings indicate that regional models overestimate pollutant dispersion processes in industrial parks while underestimating local industrial impacts. By explicitly resolving point-source dynamics and linking them to regional transport, IAQMS-Industry provides a robust tool for designing targeted emission controls in industrial cities and balancing local air quality improvements with minimized regional pollution outflow. This study underscores the necessity of multiscale modelling for accurate source apportionment and informed environmental governance in industrial zones.

Air Pollution↗

PubMed2026

Snow carps as an emerging model for polyploid genome evolution.

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Editorial↗

PubMed2026

Penalized Cumulative Probability Model for a Continuous Outcome Subject to Detection Limits.

Mixed-type outcome data occur when the outcome variable's distribution is a mixture of both continuous and discrete ordinal variables. Such mixed-type outcomes are common in biomedical, psychological, and the health sciences, particularly for variables having either a detection or quantitation limit. When interest lies in identifying a combination of genomic features associated with a mixed-type outcome, any method used would require a variable selection strategy for high-dimensional data. Unfortunately, few variable selection methods exist for modeling a mixed-type outcome when the covariate space is high dimensional. This study develops a high-dimensional penalized cumulative probability model (CPM), to allow for the identification of genomic features associated with mixed-type outcome of interest. We demonstrated how such model may be estimated using the iterative penalization procedure-the generalized monotone incremental forward stagewise (GMIFS) algorithm. The Model-X knockoffs procedure was combined with the estimation algorithm to control the false discovery rates (FDR) when performing variable selection. Through extensive simulation studies, our penalized CPM was shown to outperform alternative methods in terms of controlled variable selection performance by achieving high statistical power with the FDR being controlled at the target level. We demonstrate the utility of our method by applying it to predict estimated glomeruli filtration rate (eGFR) in kidney transplant recipients at 24 months post-transplant using baseline gene expression data as predictors. Our CPM model identified five genes associated with this mixed-type outcome which have important links to renal disease, which may provide prognostic guidance for kidney transplantation recipients.

Models, Statistical↗

PubMed2026

Construction of precision clinical-proteomics risk model based on machine learning for predicting heart failure in type II diabetes mellitus.

BACKGROUND AND AIMS: Heart failure (HF) is a severe complication in type 2 diabetes mellitus (T2DM), but current risk stratification scores have limited predictive accuracy. We aimed to develop novel prediction tools integrating clinical variables with proteomics to improve risk stratification of hospitalization for HF in T2DM. METHODS AND RESULTS: In this study, we included 2111 UK Biobank participants with T2DM but no prior HF, and profiled 2920 proteins to predict 10-year incident HF hospitalization. Participants were randomly divided into training (70%), tuning (10%), and validation (20%) sets.Three prediction models were developed: a Clinical model based on demographic characteristics, comorbidities, medication use, and laboratory indices; a Protein model based on 40 proteins selected by the Light Gradient Boosting Machine (LGBM); and the Clinical OMics and Protein ASSessment for Heart Failure (COMPASS-HF) model, which integrated both clinical variables and the LGBM-selected proteins. Models were evaluated for area under the curve (AUC), sensitivity, and specificity. During follow-up, 168 participants (7.96%) developed incident HF. The COMPASS-HF model showed better discrimination than the Clinical model, with an AUC of 0.897 (95% CI: 0.850-0.945) versus 0.790 (95% CI: 0.723-0.856). It also demonstrated higher sensitivity (0.882; 95% CI: 0.725-0.967) and consistent performance in subgroups. COMPASS-HF effectively stratified risk of hospitalization for HF, with cumulative incidence rates of 31.9% in the high-risk group and 1.2% in the low-risk group. CONCLUSIONS: By combining clinical and proteomic variables, we developed a high-performance HF prediction model for T2DM, enabling precise risk stratification and informing early intervention strategies.

Humans↗