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PubMed2026

High-frequency contralesional dorsal premotor cortex and low-frequency contralesional primary motor cortex rTMS in subacute stroke with severe upper limb impairment: comparable motor outcomes and differential regional degree centrality changes.

BACKGROUND: The contralesional dorsal premotor cortex has been proposed as a potential neuromodulatory target for patients with severe upper limb impairment due to subacute ischemic stroke. This proof-of-concept study aimed to compare behavioral outcomes and resting-state neuroimaging findings between high-frequency repetitive transcranial magnetic stimulation (rTMS) over the contralesional dorsal premotor cortex and guideline-supported low-frequency stimulation over the contralesional primary motor cortex. METHODS: In this randomized trial, 46 patients with severe upper limb impairment in the subacute stage after ischemic stroke were randomly assigned to receive either high-frequency rTMS over the contralesional dorsal premotor cortex or low-frequency rTMS over the contralesional primary motor cortex. Low-frequency stimulation over the contralesional primary motor cortex served as an evidence-supported active comparator for poststroke upper limb motor recovery. Stimulation was administered five times per week for two weeks using magnetic resonance imaging-guided neuronavigation. All participants received concurrent standard rehabilitation therapy. The primary outcome was the Fugl-Meyer Assessment for Upper Extremity. Secondary outcomes included the Arm Subscore of the Motricity Index, the Hong Kong version of the Functional Test for the Hemiplegic Upper Extremity, the Modified Barthel Index, and resting-state functional magnetic resonance imaging-derived degree centrality. RESULTS: Both groups showed significant improvements in the primary and secondary behavioral measures (p < 0.01), with no significant between-group differences in the magnitude of change (p > 0.05). In neuroimaging analyses, patients receiving high-frequency rTMS over the contralesional dorsal premotor cortex showed significantly greater degree centrality changes in the ipsilesional middle occipital gyrus, contralesional medial superior frontal gyrus, and contralesional middle frontal gyrus than those receiving low-frequency rTMS over the contralesional primary motor cortex (p < 0.05). Within the high-frequency stimulation group, degree centrality changes in the ipsilesional middle occipital gyrus were positively correlated with improvements in the Fugl-Meyer Assessment for Upper Extremity (r = 0.619, false discovery rate-corrected p = 0.018). CONCLUSIONS: High-frequency rTMS over the contralesional dorsal premotor cortex produced behavioral improvements comparable to guideline-supported low-frequency rTMS over the contralesional primary motor cortex, without establishing superiority or formal non-inferiority. Exploratory neuroimaging analyses showed greater degree centrality changes in the ipsilesional middle occipital gyrus after high-frequency premotor stimulation, and these changes correlated with upper-limb motor improvement. These findings support further investigation of contralesional dorsal premotor cortex-targeted high-frequency rTMS for severe subacute post-stroke upper limb impairment. REGISTRATION: URL: http://www.chictr.org.cn; Unique identifier: ChiCTR2000038049.

Humans↗

PubMed2026

Clinically Relevant Pharmacogenomic Variant Frequencies in Kazakh, Russian, and Uzbek Population Groups Residing in Kazakhstan.

Central Asian populations remain underrepresented in pharmacogenomic research, limiting the availability of population-specific data for genotype-informed prescribing and precision medicine. This study analyzed clinically relevant pharmacogenomic variant frequencies in Kazakh, Russian, and Uzbek population groups residing in Kazakhstan using genome-wide genotype data from 1301 individuals: Kazakh (n = 1111), Russian (n = 156), and Uzbek (n = 34). ClinPGx, a PharmGKB-based clinical annotation framework that prioritizes variant-drug associations according to levels of evidence, was used to select variants with evidence levels 1A, 1B, and 2A. In total, 112 directly genotyped variants were retained for population-specific allele and genotype frequency analysis. All 112 variants were queried against the gnomAD v4.1 genome and exome reference datasets. Of these, matching allele-frequency data for the predefined reported allele were available in at least one of the two gnomAD datasets for 103 variants, whereas for 9 variants the VEP-based query did not return a matching gnomAD frequency for that allele. Frequencies were reported for the same predefined reported allele across all groups, and differences between the study groups were assessed using 95% confidence intervals, Fisher's exact tests, and false discovery rate correction. Genotype counts and the proportions of individuals carrying at least one copy of the reported allele were also summarized for all selected variants. Several pharmacogenomic variants showed population-specific frequency patterns, including NUDT15 rs116855232, SLCO1B1 rs4149056, VKORC1 rs9934438, and UGT1A1 rs10929302. Comparison with gnomAD showed that the observed frequencies were variant-specific and could not be consistently approximated by a single broad genetic ancestry group. Reference-based population structure analysis provided additional ancestry context and supported separate reporting by population group. The study did not evaluate clinical outcomes or make individual prescribing recommendations, and the small Uzbek sample size limits the precision of frequency estimates for this group, particularly for rare variants. Overall, this study provides a clinically prioritized pharmacogenomic frequency resource for underrepresented population groups in Kazakhstan and supports broader Central Asian representation in pharmacogenomic implementation research.

Central Asia↗

PubMed2025

Mediating effects of waist circumference and BMI on the association between meal frequency and mortality.

OBJECTIVE: To examine the potential indirect effect of meal frequency on mortality via obesity indices. DESIGN: Prospective cohort study. SETTING: Korean Genome and Epidemiology Study. PARTICIPANTS: This cohort study involved 148 438 South Korean adults aged 40 years and older. RESULTS: Meal frequency at the baseline survey was assessed using a validated FFQ. Outcomes included all-cause mortality, cancer mortality and CVD mortality. Cox proportional hazards regression models were employed to examine the relationship between meal frequency and the risk of mortality. Mediation analyses were performed with changes in obesity indices (BMI and weight circumference (WC)) as mediators. In comparison to the three-time group, the once-per-day and four-times-per-day groups had a higher risk for all-cause mortality. The irregular frequency group had a higher risk for CVD mortality. Both once-per-day and four-times-per-day groups exhibited higher risks for cancer mortality. The effect of meal frequency on all-cause mortality was partially mediated by WC. For specific-cause mortality, similar mediation effects were found. CONCLUSIONS: The data suggests that three meals per day have a lower mortality and longer life expectancy compared with other meal frequencies. Increased waist circumference partially mediates this effect. These findings support the implementation of a strategy that addresses meal frequency and weight reduction together.

Humans↗

PubMed2026

Occupationally relevant vibrations and the brain: frequency-dependent proteomics signatures in a rat model.

INTRODUCTION: Occupational exposure to whole-body vibration (WBV), particularly in agricultural environments, has been associated with adverse cognitive and physiological effects. This study examined the neurophysiological impact of WBV in a rat model at 4 Hz and 30 Hz, frequencies representative of off-road and on-road vehicle operation. METHODOLOGY: Forty-four Sprague-Dawley rats were assigned to control (0 Hz), low-frequency (4 Hz), or high-frequency (30 Hz) vibration conditions. After three days of exposure, brain tissues were collected and analyzed using mass spectrometry-based proteomics to identify differentially expressed proteins. RESULTS: Proteomic profiling revealed distinct, frequency-dependent alterations in brain protein expression. Compared with controls, 32 cognition-related proteins were differentially regulated at 4 Hz and 29 at 30 Hz, with 13 differing between the two vibration conditions. Principal component analysis showed clear separation among groups, indicating unique proteomic signatures for each exposure frequency. Functional enrichment and protein-protein interaction analyses demonstrated involvement of synaptic plasticity, cytoskeletal organization, calcium regulation, and neurotransmitter release. Exposure to 4 Hz was associated with the upregulation of proteins involved in calcium homeostasis and synaptic integrity, suggesting potential disruption of cognitive processes. In contrast, 30 Hz increased the expression of proteins related to axonal guidance and neuroprotection, indicating a less clearly adverse response that may reflect adaptive or potentially beneficial effects. DISCUSSION: These findings provide new insight into biological mechanisms underlying WBV-induced cognitive changes and underscore the importance of vibration frequency in shaping neurophysiological outcomes. They also establish a foundation for future studies integrating proteomics with behavioural assessments in animals and humans.

Animals↗

PubMed2026

Simultaneous quantitative detection of multiple low-frequency variants by high-dynamic-range capillary electrophoresis.

Sensitive and quantitative detection of low-frequency variants across multiple loci is critical for nucleic acid-based diagnostics, yet clinical implementation requires a balance among sensitivity, multiplexing capacity, cost, and operational simplicity. We previously developed a high-dynamic-range capillary electrophoresis system capable of detecting variants at allele frequencies below 1%; however, its application was limited to single-locus analysis. Here, we expanded this platform to multiplex detection by incorporating mobility-shift strategies into the assay design. This approach enabled simultaneous analysis of 15 hotspot variants across three clinically relevant loci: KRAS codons 12 and 13 and GNAS codon 201. Validation using synthetic oligonucleotides, formalin-fixed paraffin-embedded tissue, and liquid specimens demonstrated high quantitative accuracy over clinically relevant variant allele frequency ranges, with measured values closely matching expected values (R2 > 0.97). The assay showed high concordance with targeted amplicon sequencing and digital polymerase chain reaction for all variants at variant allele frequencies ≥1%, while also detecting selected variants below this threshold. Collectively, these results establish a multiplexed high-dynamic-range capillary electrophoresis assay for simultaneous, quantitative detection of low-frequency variants, offering a scalable and cost-effective approach for disease-focused gene panels in clinical laboratory settings.

HiDy↗

PubMed2026

Infra-low-frequency neurofeedback alters EEG network efficiency: exploratory evidence from healthy volunteers.

Infra-Low-Frequency Neurofeedback (ILF-NFB) combines classic frequency-band (FB) and infra-low-frequency (ILF) EEG components in implicit training protocols and is increasingly applied in clinical contexts. Yet, the neurophysiological mechanisms underlying ILF-NFB remain to be further elucidated. In this randomized, sham-controlled and double-blind study, we explored the online impact of a one-session ILF-NFB application on EEG correlates in healthy participants (39 analyzed datasets). Continuous 31-channel EEG was recorded during verum and sham feedback in a double-blind, randomized crossover design. In this exploratory analysis approach, functional connectivity was estimated using the debiased weighted phase-lag index (dwPLI) and analyzed with graph-theoretical measures. The results revealed higher global efficiency during verum compared to sham in the Beta1 band (12-15 Hz), reaching significance in the primary comparison but not surviving Bonferroni correction across the five tested bands; block-wise follow-ups showed a significant verum-sham difference in the first half of the neurofeedback session and a directionally consistent pattern in the second half. The Condition × Block interaction was not significant. No consistent differences were observed in other frequency bands, nor for betweenness centrality. While preliminary, these exploratory results point to possible network-level effects during ILF-NFB and motivate further confirmatory work in extended training protocols and clinical populations.

Humans↗

PubMed2026

Frequency and clinical features of germline pathogenic variants in sarcoma: a case-control study.

BACKGROUND: Germline multigene panel testing is not yet integrated into standard care for patients with sarcoma. This study aimed to assess the frequency and distribution of germline pathogenic variants in patients with sarcoma compared with cancer-free controls and identify differences between patients with and without germline pathogenic variants. METHODS: This retrospective cohort included 488 sarcoma patients and 2440 cancer-free controls matched 1:5 by age, sex, and ethnicity. Multigene panel testing was performed between 2016 and 2024 at a single germline testing laboratory. The frequency of germline pathogenic variants in selected genes was compared using Fisher exact test with odds ratios (ORs) and 95% confidence intervals. Additionally, within the case-only cohort, clinical characteristics were evaluated to assess associations with the presence of germline pathogenic variants in any gene. RESULTS: Among 488 patients with sarcoma, 67.8% (n = 331) were female, with a median age at sarcoma diagnosis of 47 years (range = 0.5-87.5 years). Cases had a higher frequency of germline pathogenic variants compared with controls (26.2% vs 10.5%; OR = 3.05, P < .001). We observed a higher frequency of germline pathogenic variants in TP53, BRCA2, CHEK2, NF1, SDHA, BRIP1, POT1, RB1, and CDH1 among patients with sarcoma compared with controls. Age at sarcoma diagnosis did not differ between groups. CONCLUSIONS: This study confirms the high detection rate of germline pathogenic variants in patients with sarcoma and describes several associated genes. These findings indicate that age at sarcoma diagnosis may not reliably predict germline pathogenic variants. Expanding germline testing for patients with sarcoma would enhance personalized treatment strategies and familial risk assessment.

Humans↗

PubMed2026

HLA Allele and Haplotype Frequencies Among Registered Unrelated Donors in the Western Region of Saudi Arabia.

The Saudi stem cell donor registry (SSCDR) has successfully recruited over 92,000 unrelated potential stem cell donors through nationwide campaigns. The Western region of Saudi Arabia is characterized by its unique ethnic diversity, shaped by centuries of immigration and pilgrimage. This study aimed to determine the distribution of HLA alleles and haplotypes among donors from this region. A total of 1112 donors registered with SSCDR were included, all recruited during campaigns conducted in the Western region between 2019 and 2021. Participants provided ancestry information to confirm their city of origin. High-resolution HLA typing for loci A, B, C, DRB1 and DQB1 was performed using sequence-based typing (SBT). Allele and haplotype frequencies were estimated for each subgroup using Arlequin 3.5 software. Distinct haplotype patterns were observed across cities. The most common haplotypes in the 1112 potential stem cell donors in the Western Region of Saudi Arabia were HLA-A*02:01∼C*07:02∼B*07:02∼DRB1*15:01∼DQB1*06:02 and HLA-A*02:01∼C*06:02∼B*50:01∼DRB1*07:01∼DQB1*02:01 in Jeddah; A*23:01∼C*06:02∼B*50:01∼DRB1*07:01∼DQB1*02:01 in Al-Madinah; HLA-A*26:01∼C*07:02∼B*08:01∼DRB1*03:01∼DQB1*02:01, HLA-A*30:01∼C*06:02∼B*13:02∼DRB1*07:01∼DQB1*02:01 and HLA-A*02:01∼C*06:02∼B*50:01∼DRB1*07:01∼DQB1*02:01 in Makkah; HLA-A*02:01∼C*15:02∼B*51:01∼DRB1*13:01∼DQB1*06:03 and HLA-A*02:01∼C*07:02∼B*07:02∼DRB1*15:01∼DQB1*06:02 in Al-Baha; and HLA-A*31:01∼C*15:02∼B*51:01∼DRB1*13:01∼DQB1*06:03 in Taif. HLA data are available in the Allele Frequencies Net Database (AFND: 3854, 3855, 3856, 3857 and 3858) under the population name 'Saudi Western Region'. In western Saudi Arabia, HLA allele and haplotype distributions demonstrate marked city-specific variation. Our research identifies DR7-, DR13- and DR15-based haplotypes as the most prevalent across the region. These findings are critical for optimizing unrelated donor searches for patients lacking compatible familial matches. Understanding these local frequencies allows for more targeted recruitment and better matching probabilities in stem cell registries.

Humans↗

PubMed2026

Genetic Ancestry and Carrier Variant Frequency Enrichment in a Colombian Andean Population: Insights From the Eje Cafetero.

Colombia is one of the most genetically diverse populations in Latin America, and its demographic process has promoted the persistence and local enrichment of deleterious alleles, increasing the frequency of autosomal recessive disorders, particularly in semi-isolated Andean populations such as the Eje Cafetero. However, exome-based reference data from this region remain scarce, limiting ancestry-aware variant interpretation and carrier screening strategies. We aimed to characterize the ancestry proportions of this population using exome data, and to estimate the carrier frequency and distribution of pathogenic and likely pathogenic (P/LP) variants in clinically relevant recessive genes. We conducted a cross-sectional study with whole-exome sequencing (WES) in 316 unrelated individuals from the Colombian Eje Cafetero. P/LP variants were evaluated in 454 genes associated with autosomal recessive disorders. The global ancestry proportions were estimated using a validated panel of 250 exome-compatible ancestry-informative markers. Carrier frequencies were compared against Non-Finnish Europeans (NFE) and Admixed Americans (AMX) from gnomAD v4. The cohort showed predominant European ancestry (mean 51%), followed by Native American (36%) and African (13%) components. We identified 151 carriers of 89 distinct pathogenic variants across autosomal recessive genes. The most frequent variants were SERPINA1 c.863A>T (5.5%), CFTR c.1210-11T>G (3.5%), and PYGM c.1094C>T (1.5%). Also, recurrent variants were significantly enriched compared with both NFE and AMX populations, supporting regional founder effects. This study represents one of the most comprehensive exome-based genetic characterizations of the Colombian Eje Cafetero, revealing ancestry-specific enrichment of clinically relevant autosomal recessive variants driven by founder effects.

Female↗

PubMed2026

Physiological and molecular responses of coelomocytes to low- to mid-frequency acoustic exposure in the sea urchin Strongylocentrotus intermedius.

Underwater noise is a widespread environmental pollutant in marine ecosystems, yet the effects of low- to mid-frequency acoustic exposure on immune physiology and molecular responses in echinoderms remain unclear. In this study, the sea urchin Strongylocentrotus intermedius was exposed to continuous pure-tone acoustic stimulation at 80, 125, 250, 500, 750, and 1000 Hz for 3 h. Results showed that acoustic exposure significantly affected redox homeostasis, energy metabolism, and immune function in S. intermedius coelomocytes: the antioxidant system and glutathione redox balance were altered, as indicated by increased superoxide dismutase (SOD) and catalase (CAT) activities, elevated reduced glutathione (GSH) content, and a higher GSH/GSSG ratio; glycolysis-related enzyme activities were enhanced, with increased pyruvate kinase (PK) activity under 125-500 Hz exposure and elevated hexokinase (HK) activity at 250 Hz; and immune function was impaired, as shown by increased coelomocyte mortality, reduced phagocytic activity, and inhibited acid phosphatase (ACP) and alkaline phosphatase (AKP) activities, whereas respiratory burst activity showed no significant change. Among all treatments, 250 Hz induced the most pronounced physiological responses. Transcriptomic analysis of coelomocytes from the 250 Hz group identified 663 differentially expressed genes, including 537 upregulated and 126 downregulated genes, mainly enriched in pathways related to apoptosis, phagosome, lysosome, glutathione metabolism, arachidonic acid metabolism, and carbohydrate metabolism. These findings indicate that low- to mid-frequency acoustic exposure can act as a physiological and molecular stressor to S. intermedius coelomocytes by affecting redox homeostasis, enhancing energy metabolism, and suppressing immune effector processes, with 250 Hz showing the strongest effect under the present exposure conditions. This study provides experimental evidence for evaluating the potential biological effects of low- to mid-frequency acoustic exposure on benthic echinoderms.

Animals↗

PubMed2024

Estimation of carrier frequencies of autosomal and X-linked recessive genetic conditions based on gnomAD v4.0 data in different ancestries.

PURPOSE: Monogenic rare diseases contribute significantly to infant deaths and pediatric hospitalizations and cause burden to the patients and their families. The American College of Medical Genetics and Genomics recommended in 2021 that carrier screening of autosomal recessive and X-linked conditions with a carrier frequency of ≥1/200 and a severe or moderate phenotype should be offered when planning or during pregnancy. In November 2023 gnomAD v4.0 was released. It contains in total 807,162 individuals, being nearly 5× larger than previous versions, which have been used to estimate gene carrier frequencies (GCF). METHODS: We utilized gnomAD v4.0 (GRCh38) to calculate the GCFs for available genetic ancestry groups for variants having pathogenic or likely pathogenic classification (>80% of submissions) in ClinVar. We calculated GCF separately for exomes and genomes, combined data, and at-risk couple frequencies (ACF) per genetic ancestry group. RESULTS: In total, 324 genes had a GCF ≥1/200 in at least 1 ancestry subgroup. The number of genes with GCF ≥1/200 varied greatly between subgroups. ACFs were more similar, Ashkenazi Jewish having the highest ACF of 6.11%. CONCLUSION: Improved understanding of carrier risks and updated carrier screening content would allow patients to make more informed reproductive decisions.

Humans↗

PubMed2026

Effect of intraoperative 40-hz gamma-frequency auditory stimulation on postoperative delirium in older adults undergoing major surgery: a randomized clinical trial protocol.

INTRODUCTION: Postoperative delirium (POD) is a common and clinically significant complication among older adults undergoing major surgery under general anesthesia. Gamma-frequency (40-Hz) auditory stimulation has demonstrated potential neuroprotective and cognition-enhancing effects, suggesting a plausible role in perioperative delirium prevention. However, direct clinical evidence supporting intraoperative 40-Hz auditory stimulation in reducing POD remains limited, warranting rigorous evaluation in a randomized trial. PATIENTS AND METHODS: This prospective, parallel-group, randomized controlled trial will enroll 550 older adults scheduled for major noncardiac, nonneurosurgical surgery under general anesthesia. Participants will be randomized in a 1:1 ratio to either the active stimulation group, receiving intraoperative 40-Hz gamma-frequency auditory stimulation delivered via headphones for 2 h following successful anesthesia induction, or the sham stimulation group, wearing headphones without active auditory output. The primary outcome is the incidence of POD on postoperative day 1 though 3, assessed using the Confusion Assessment Method (CAM) or the CAM for the ICU (CAM-ICU). Secondary outcomes include POD severity, sleep quality, pain scores, analgesic consumption, the incidence of postoperative nausea and vomiting (PONV), rescue antiemetic use, duration of post-anesthesia care unit (PACU) stay, length of hospital stay, quality of postoperative recovery, incidence of perioperative adverse events; postoperative morbidity, health-related quality of life, and all-cause 30-day mortality. DISCUSSION: This trial will determine whether intraoperative 40-Hz gamma-frequency auditory stimulation reduces the incidence of POD among older adults undergoing major surgery under general anesthesia. If efficacious, this noninvasive intervention could constitute a feasible perioperative strategy to mitigate delirium risk and enhance postoperative recovery. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2500115156).

Humans↗

PubMed2026

needLR: long-read structural variant annotation with population-scale frequency estimation.

SUMMARY: We present needLR, a structural variant (SV) annotation tool that can be used for filtering and prioritization of candidate pathogenic SVs from long-read sequencing data using population allele frequencies, annotations for genomic context, and gene-phenotype associations. When using population data from 500 presumably healthy individuals to evaluate nine test cases with known pathogenic SVs, needLR assigned allele frequencies to over 97.5% of all detected SVs and reduced the average number of novel genic SVs to 121 per case while retaining all known pathogenic variants. AVAILABILITY AND IMPLEMENTATION: needLR is implemented in bash with dependencies including Truvari v4.2.2, BEDTools v2.31.1, and BCFtools v1.19. Source code, documentation, and pre-computed population allele frequency data are freely available at https://github.com/jgust1/needLR under an MIT license and archived on Zenodo at https://zenodo.org/records/19463479.

Software↗

PubMed2025

Frequency and Distribution of KIR Genotypes of Donors-Recipient Pairs in the Haploidentical Haematopoietic Stem Cell Transplantation Setting: Collaborative Study by the Spanish Working Group in Histocompatibility and Transplant Immunology (GETHIT) and the Spanish Haematopoietic Transplantation and Cell Therapy Group (GETH-TC).

There is limited information regarding the influence of KIR genotype, compared to the HLA system, in haploidentical haematopoietic stem cell transplantation (haplo-HSCT). This study aimed to determine the frequencies of KIR genotypes in Spanish haematologic patients undergoing haplo-HSCT. A study was conducted on 113 oncohaematological patients and their donors, treated across five centres that are members of the Spanish Working Group in Histocompatibility and Transplant Immunology (GETHIT) and the Spanish Haematopoietic Transplantation and Cell Therapy Group (GETH-TC). KIR typing was performed using PCR-rSSO or PCR-SSP. KIR genotypes were identified using the KIR Allele Frequency Net Database. Among donors, the most frequent KIR genotypes were Type 1 (28.3%), Type 2 (12.4%) and Type 4 (10.6%). In patients, Genotypes 1 (23.9%), 4 (23%) and 2 (14.2%) were most prevalent. Donors exhibited AA centromeric (46%) and telomeric (59.3%) types, while patients had a higher AB centromeric frequency (52.2%). Differences were observed in the BB centromeric type (3.5% patients; 16.8% donors, p = 0.002). The AB KIR genotype was the most common (70.8% donors; 75.2% patients). Most were classified as 'neutral' (61.9% donors; 73.5% patients). B-content score1 was the most common (48.7% patients; 33.6% donors). Notably, classification as best was rare (2.7% patients; 16.8% donors, p = 0.002). The study highlights the distribution of KIR genotypes in haplo-HSCT patients and donors, with Genotypes 1, 2 and 4 being the most prevalent. AB KIR genotypes and B-content score 1 were dominant. Moreover, KIR genotypes ID may serve as criteria for future investigation about the immunogenetic predisposition to malignant haematological diseases.

Humans↗

PubMed2026

Transcriptome-based high-frequency recurrence index predicts frequent recurrence in non-muscle-invasive bladder cancer after Bacillus Calmette-Guérin therapy.

BACKGROUND: High-frequency recurrence (HfR, ≥ 2 recurrences) in non-muscle-invasive bladder cancer (NMIBC) poses a significant clinical burden. Current risk models, such as the European Organization for Research and Treatment of Cancer (EORTC), the European Association of Urology (EAU), and the UROMOL classification, offer limited predictive accuracy for identifying patients at risk for frequent recurrence despite appropriate treatment. METHODS: A 75-gene high-frequency recurrence index (HfRI) was constructed by selecting recurrence-associated genes using differential expression and Cox regression analyses. The HfRI was computed as a weighted sum of normalized gene expression values. The model was trained on a discovery cohort and validated in multiple cohorts (n = 1379) using machine-learning approaches. Clinical relevance was assessed using recurrence-free survival (RFS) and Cox models, and predictive performance was compared with that of the EORTC, EAU, and UROMOL classifications using the area under the curve (AUC) and the concordance index (c-index). RESULTS: The HfRI robustly stratified patients into high-risk and low-risk groups across six independent NMIBC cohorts. Patients classified as HfRI-high had a significantly greater likelihood of experiencing ≥ 2 recurrences (χ2, p = 0.001) and showed markedly reduced RFS (log-rank test, p < 0.001). The adverse prognostic effect of the HfRI persisted even among patients treated with BCG therapy (log-rank test, p = 0.02). Multivariate analysis revealed that the HfRI was an independent predictor of HfR (HR = 2.82, 95% CI = 1.89-4.20, p < 0.001). Compared with established clinical risk classifiers, the HfRI demonstrated superior predictive performance (AUC = 0.736, c-index = 0.673) in terms of the EORTC (AUC = 0.594), EAU (AUC = 0.557) risk groups, and UROMOL2021 (AUC = 0.596) classification. Pathway analysis revealed that HfRI-high tumors were characterized by upregulation of cell cycle progression and DNA replication pathways, accompanied by suppression of immune signaling pathways. These biological features provide a mechanistic explanation for the reduced responsiveness to intravesical BCG therapy, underscoring the role of HfRI not only as a predictor of recurrence risk but also as a biomarker capable of identifying patients unlikely to benefit from standard BCG treatment. CONCLUSIONS: HfRI represents a robust, transcriptome-based tool for predicting frequent recurrence in NMIBC patients. The HfRI supports earlier identification of patients at risk of high-frequency recurrence, thereby supporting personalized treatment strategies.

Humans↗

PubMed2026

Sperm subpopulations differing in mitochondrial abundance show divergent nuclear allele frequencies.

Mammalian ejaculates contain heterogeneous sperm subpopulations that differ in subcellular architecture and developmental history, despite appearing morphologically uniform. The extent to which this cellular heterogeneity reflects underlying nuclear genomic structure within a sire remains largely unexplored. Mitochondrial architecture in sperm is established during spermatogenesis, with final assembly and organization occurring during spermiogenesis under nuclear genomic control, positioning variation in mitochondrial abundance and organization as a potential phenomic indicator of within-sire allelic segregation. Here, we tested whether sperm subpopulations defined by differing mitochondrial abundance exhibit systematic differences in nuclear allele representation. Boar sperm were resolved into low and high mitochondrial subpopulations using fluorescence-activated cell sorting based on MitoTracker™ Green fluorescence while excluding debris, doublets, and non-viable cells. Epifluorescence microscopy confirmed that high MitoTracker™ Green fluorescence sperm possessed longer mitochondrial sheaths, validating a structural distinction between subpopulations. Whole-genome sequencing of paired mitochondrial subpopulations from three boars was performed, and allelic ratio distortion was evaluated relative to heterozygous baseline populations. Analyses across heterozygous loci genome-wide identified candidate allele frequency shifts between mitochondrial-defined subpopulations, suggesting non-random segregation of alleles within ejaculates. Using a minimum sequencing depth of 30 reads in both sorted fractions, 182 candidate SNPs were identified with evidence of allele-frequency differences between mitochondrial fluorescence-defined subpopulations. These findings suggest that sperm mitochondrial abundance can potentially serve as an indirect, high-throughput marker of nuclear genomic heterogeneity within sires. This proof-of-concept framework establishes a foundation for future studies integrating sperm phenotyping, genome-wide allele-frequency analysis and functional validation to better characterize gamete-level heterogeneity.

Male↗

PubMed2026

Effects of Moderate-Frequency Resistance Training on Cardiometabolic Risk Factors in Adults With Overweight or Obesity: A Systematic Review and Meta-Analysis.

BACKGROUND: Resistance training (RT) effectively manages cardiometabolic risk factors in adults, but the specific effects of moderate-frequency RT (2-3 sessions/week) in adults with overweight or obesity are understudied. OBJECTIVE: This study aimed to evaluate moderate-frequency RT's effects on cardiometabolic risk factors in this population and quantify effect sizes. DATA SOURCES: PubMed, Web of Science, EMBASE, and Cochrane Library searched up to July 2025. ELIGIBILITY: English randomized controlled trials (RCTs) comparing RT (≥ 7 weeks) to nonexercise control; nonathletic adults ≥ 18 years with BMI ≥ 25 kg/m2. PARTICIPANTS: 454 participants across 12 RCTs (mean age 58.93 ± 12.87 years; mean BMI 31.2 ± 3.5 kg/m2; ~50% female). RESULTS: RT significantly reduced diastolic blood pressure (MD = -1.53 mmHg; 95% CI: -2.16 to -0.91; p < 0.01), LDL-C (MD = -0.25 mmol/L; 95% CI: -0.41 to -0.08; p < 0.01), and triglycerides (MD = -0.17 mmol/L; 95% CI: -0.30 to -0.04; p = 0.01). No significant effects on systolic blood pressure, mean arterial pressure, waist circumference, glycemic markers, total cholesterol, or HDL-C. Subgroup analyses showed larger LDL-C/triglyceride improvements with concurrent dietary control. CONCLUSION: Moderate-frequency RT inconsistently improves cardiometabolic risk factors, benefiting diastolic blood pressure, LDL-C, and triglycerides but not glycemic or other parameters. Combining with dietary control may enhance benefits, supporting RT as a complementary strategy in multimodal lifestyle interventions. TRIAL REGISTRATION PROSPERO: CRD42022343167.

Humans↗

PubMed2026

Whole-genome sequencing implicates rare, low-frequency and structural non-coding variation at the SCN5A locus in Brugada syndrome.

Brugada syndrome (BrS) is an inherited cardiac condition characterized by a hallmark ECG pattern and an increased risk of sudden cardiac death. Central to the aetiology of BrS, the SCN5A region harbours both common non-coding risk variants and rare coding variants that are causative in approximately 20% of patients. However, rare non-coding genetic variation in this region remains largely unexplored. Here, we used whole-genome sequencing (WGS) of 752 European-ancestry BrS cases and 1,827 ancestry-matched controls to identify BrS-associated rare non-coding genetic variation at the SCN5A locus. Sliding-window and cis-regulatory element (CRE)-based rare-variant aggregate testing implicated three conserved CREs, including a dense aggregation of case singleton variants within a 178 bp enhancer in intron 17 of SCN5A which replicated in an independent BrS cohort. Prioritised BrS-associated rare and low-frequency non-coding variants within these elements were predicted to alter cardiac transcription factor motifs, and altered CRE activity in hiPSC-CM luciferase assays or were associated with BrS-relevant ECG endophenotypes in the UK Biobank. Single-variant analysis across the region identified a Bonferroni-significant five-fold case-enriched low-frequency variant within a known CRE in intron 1 of SCN5A, which replicated, was associated with slower cardiac conduction in the UK Biobank and accounted for part of the BrS GWAS signal at this locus. Structural variant analyses identified a 10.5 kb deletion upstream of SCN5A in a BrS case that encompassed a cardiac CRE and reduced sodium current density in a hiPSC-CM model, as well as a 6 kb BrS-enriched retrotransposon insertion in SCN5A that appeared to underlie part of the GWAS signal in this region. Together, these findings implicate rare and low-frequency non-coding variation at the SCN5A locus in BrS susceptibility and demonstrate the value of targeted WGS analysis of key disease loci.

Journal Article↗