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PubMed2026

Impact of smoking on structural failure after arthroscopic rotator cuff repair: a systematic review and meta-analysis.

BACKGROUND: Rotator cuff tears cause significant shoulder pain and functional limitation. Arthroscopic rotator cuff repair improves symptoms, yet structural failure rates remain substantial. Smoking may impair tendon-to-bone healing, but clinical studies report mixed findings due to heterogeneous methodology. Therefore, a systematic synthesis of imaging-confirmed outcomes is needed to clarify the association between smoking and structural failure after arthroscopic rotator cuff repair. METHODS: This review followed PRISMA 2020 and was registered in PROSPERO (CRD420251246197). PubMed, Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception to 12 December 2025. Comparative clinical studies of adults undergoing arthroscopic rotator cuff repair that reported imaging-confirmed structural integrity (magnetic resonance imaging or ultrasonography) at ≥6 months were included. Two reviewers independently screened studies, extracted data, and assessed quality using the Newcastle-Ottawa Scale. The primary outcome (structural failure) was pooled as risk ratios using a random-effects model with the restricted maximum likelihood estimator and Hartung-Knapp adjustment. Secondary continuous outcomes were synthesized using Bayesian random-effects models; subgroup, sensitivity, and meta-regression analyses explored heterogeneity. RESULTS: Ten cohort studies (1,683 shoulders) were included. Smoking was associated with a higher risk of imaging-confirmed structural failure (risk ratio 1.53; 95% confidence interval 1.13-2.08; P = .011) with low heterogeneity (I2 = 24.7%). Subgroup and sensitivity analyses supported robustness, with no evidence of effect modification by region, follow-up duration, tear size, or smoking definition. Meta-regression showed no significant influence of age, smoking prevalence, or diabetes prevalence on the pooled effect. Secondary outcomes (3 studies) suggested slightly lower postoperative American Shoulder and Elbow Surgeons scores among smokers, while visual analog scale pain scores and forward flexion showed no clear between-group differences. No publication-bias signals were detected for the primary outcome. CONCLUSION: Smoking is associated with a higher risk of imaging-confirmed structural failure after arthroscopic rotator cuff repair. Functional outcomes were broadly similar between groups, with only a small, likely clinically negligible reduction in American Shoulder and Elbow Surgeons scores among smokers. These findings support careful smoking history assessment and perioperative risk modification, including smoking cessation strategies.

Humans↗

PubMed2026

A conserved distal-tail helical extension defines a tailspike attachment architecture in Gram-negative siphophages.

Rapid growth of bacteriophage genome collections has outpaced functional annotation of tail-tip proteins, limiting comparative analysis of host-recognition structures. Starting from a shared distal-tail gene organization in the Salmonella phages 9NA and Jersey, I developed a morphogenetic bioinformatic framework integrating gene synteny, sequence comparison, profile hidden Markov model (HMM) screening, structural evidence, structure-aware searching, and AlphaFold modeling. Comparison with the experimentally characterized lambda and Sf11 tail assemblies identified a predominantly alpha-helical C-terminal extension of the distal-tail (DT) protein associated with tailspike attachment, termed the distal-tail helical extension (DT-helix). Screening 541,986 proteins from 5167 complete NCBI RefSeq tailed-phage genomes, followed by evidence-based evaluation of sequence, genomic context, and structural architecture, identified 165 curated DT-helical-extension-associated phages. Their DT proteins segregated into six sequence groups. In the four principal multi-member groups, cognate tailspikes showed group-specific conservation in proximal N-terminal regions but substantially greater downstream diversity, consistent with sequence constraint at the DT-tailspike attachment boundary. A complementary ProstT5/Foldseek search supported the established groups but revealed no convincing additional highly divergent family. Together with the experimentally characterized Sf11 attachment interface, these findings define a recurrent morphogenetic architecture linking conserved distal-tail scaffolds to more variable receptor-binding proteins across siphophages infecting Gram-negative bacteria. Although universal exchangeability is not established, the identified scaffold-receptor-binding boundaries provide a framework for molecular characterization and rational phage engineering. Accession-level information for the 165 curated phages is available through PhageTailDB.

Viral Tail Proteins↗

PubMed2026

Mortality of Individuals With PRNP Variants Associated With Prion Disease in the United States, 1998-2024.

BACKGROUND AND OBJECTIVES: To characterize the survival of individuals with pathogenic PRNP variants-including to estimate annual hazards, to judge the accuracy of previously reported survival data, and to evaluate the utility of public record searches in determining vital status. METHODS: In this single-center cohort study, we gathered data on individuals who received positive antemortem PRNP genetic tests at the US National Prion Disease Pathology Surveillance Center (NPDPSC), including both diagnostic tests in symptomatic individuals, and predictive tests in asymptomatic individuals. Genetic test and autopsy results were queried from the NPDPSC database, and public record searches were conducted using online tools. RESULTS: Four hundred four individuals received positive genetic test results. Of 206 cases symptomatic at the time of genetic testing, 188 are likely now deceased based on typical disease duration for their genetic variants. Combined autopsy and public record searches in combination confirmed 174 of these deaths, for an estimated 92.6% sensitivity. We evaluated the age-dependent penetrance of the reportedly highly penetrance variants D178N and E200K and the reportedly low-penetrance variant V210I. Among 99 initially asymptomatic individuals with the pathogenic E200K variant, more than 936 person-years of follow-up, 18 deaths were observed, significantly fewer than 27.4 expected according to life tables based on retrospective data. The age-dependent penetrance of E200K calculated from these longitudinal data was significantly lower than that from retrospective data, with 69% penetrance by age 80 and a median age at death of 75. For the pathogenic D178N variant, the median age at death was 57, which was numerically later, but not significantly different from, that seen in retrospective data. For V210I, just 2 deaths occurred, both after age 90, consistent with minimal penetrance. DISCUSSION: Our data support high penetrance of PRNP D178N and E200K variants and low penetrance of V210I. For E200K, the age at onset distribution appears to be shifted slightly later, and lifetime risk slightly lower, than previously reported. Autopsy data and public death records in combination were sensitive and concordant for determining long-term outcomes, but additional prospective data should be gathered to support future preventive trials.

Journal Article↗

PubMed2026

Experimental evolution reveals contrasting adaptive landscapes in lab and field environments.

Experimental evolution is widely used to infer microbial responses to environmental change, yet most laboratory studies impose constant, well-mixed conditions that differ fundamentally from fluctuating, spatially structured field environments. We compared genomic evolution in the leaf litter-associated bacterium Curtobacterium strain MMLR14_002 under control and warming treatments in laboratory culture and in a complementary field experiment. Laboratory-derived isolates accumulated more mutations per genome and exhibited stronger locus-level parallelism, with mutations recurring in a small number of coding loci. Field-derived isolates accumulated fewer mutations per genome, and these mutations rarely occurred in the same coding loci across replicate populations. Instead, field isolates exhibited a higher proportion of intergenic mutations, with mutations recurring in the same intergenic regions across independent field deployments. When coding mutations were detected in the field, they were distributed across functionally diffuse targets and more often involved metabolic pathways than the core cellular processes repeatedly targeted during laboratory evolution. Warming itself did not consistently influence mutation accumulation or the genomic distribution of mutations; instead, laboratory and field contexts primarily shaped the accumulation, targets, and repeatability of genomic change. These results suggest that laboratory thermal evolution identifies adaptive routes favored under sustained selection but may overestimate coding-level parallelism under heterogeneous field conditions. Bridging laboratory and field evolution will likely require experimental designs that incorporate temporal variability and spatial heterogeneity characteristic of natural systems.IMPORTANCEA central goal of experimental evolution is to infer how microbes evolve in nature from laboratory studies. Here, we evaluate this assumption by comparing genomic evolution of a leaf litter-associated Curtobacterium strain in laboratory and field warming experiments to identify broad patterns rather than isolate the contribution of any single environmental factor. We find that the strong parallelism at coding loci observed under laboratory conditions is reduced in the field, while mutations recurring in the same intergenic regions across field deployments suggest that parallel evolution in nature may more often involve regulatory noncoding regions rather than coding targets. These results show that environmental context reshapes adaptive landscapes and may limit the parallelism of coding-level genomic responses inferred from homogeneous laboratory conditions.

experimental evolution↗

PubMed2026

Could the preoperative urethral curve be used to predict immediate urinary continence following Retzius-sparing robot-assisted radical prostatectomy? A retrospective multi-center study.

PURPOSE: Immediate urinary continence (UC) recovery following Retzius-sparing robot-assisted radical prostatectomy (RS-RARP) remains highly variable, highlighting the need for reliable preoperative prediction. We aimed to develop and validate models to identify patients likely to achieve immediate UC recovery following RS-RARP. MATERIALS AND METHODS: A total of 580 prostate cancer patients who underwent RS-RARP from four medical centers were assigned to a training set (n=348), an internal validation set (n=103) and an external validation set (n=129). Independent predictors were identified through univariate analysis and LASSO regression. A nomogram was constructed using multivariate logistic regression. Its performance was evaluated with receiver operating characteristic (ROC) curve, calibration curves, and decision curve analysis. RESULTS: Immediate UC recovery was observed in 84.5% (294/348) of patients in the training cohort, 80.6% (83/103) in the internal validation cohort, and 81.4% (105/129) in the external validation cohort, respectively. Multivariate analysis identified membranous urethral length (MUL) (OR=1.23, P=0.029) and urethral curvature (OR=2.84, P<0.001) as independent predictors, while prostate volume (PV) (OR=0.84, P <0.001) as a protective factor. The nomogram integrating MUL, PV, and urethral curvature demonstrated superior predictive accuracy, with an AUC of 0.87 (95% CI, 0.83-0.91) in the training cohort. The bootstrap-corrected calibration slope was 0.96, and the Brier score was 0.08. Calibration curves and decision curve analysis confirmed the predictive accuracy and clinical utility of the nomogram. CONCLUSIONS: Our study introduces a novel quantitative method for assessing urethral curvature. The mpMRI-based model, integrating urethral curvature and prostate spatial configuration, offers enhanced predictive accuracy for postoperative immediate UC recovery.

Humans↗

PubMed2026

Oxidative potential of fresh vs. O₃-aged PM2.5 across urban and rural sources in China.

Fine particulate matter (PM2.5) is a major health risk, yet its impacts are still largely assessed using mass concentration, which does not capture toxicity. Recently, oxidative potential (OP) has emerged as a more relevant metric, reflecting the ability of particles to generate reactive oxygen species. A current challenge, especially in China, is understanding how emission sources and ozone (O3) aging affect PM2.5 toxicity, given that O3 is an increasingly important pollutant there. A work by Ma and co-workers published in J. Environ. Sci. (doi.org/10.1016/j.jes.2024.04.023) addressed this by evaluating the OP of fresh and O3-aged PM2.5 from multiple sources in China using the dithiothreitol (DTT) assay. Biomass burning particles exhibited the highest OP, up to 35 times greater than suburban PM2.5, driven by water-soluble organics and transition metals. While O3 aging generally reduced OP, it also induced complex chemical transformations. These findings highlight that PM2.5 toxicity is dynamic and source-dependent, underscoring the need to move beyond mass-based air quality metrics.

Particulate Matter↗

PubMed2026

Phenotypic and transcriptomic characterization of biallelic RNU2-2 developmental and epileptic encephalopathy.

OBJECTIVE: A significant proportion of individuals with suspected genetic developmental and epileptic encephalopathies (DEEs) remain unsolved following whole genome sequencing (WGS). Here we describe biallelic RNU2-2 variants causing a recently reported, severe, recessive DEE. METHODS: We screened individuals who have received WGS analyses at the Genomic Medicine Centre Karolinska for Rare Diseases for biallelic RNU2-2 variants. Deep phenotyping was performed through reviewing entire medical histories and phenotypic traits were transcribed to their corresponding Human Phenotype Ontology (HPO) term. HPO terms were used to generate pairwise phenotypic similarity scores and assess for significantly shared phenotype enrichment in the RNU2-2 sub-cohort. RNA sequencing analyses were performed in fibroblast and blood tissues to compare splicing events between RNU2-2 individuals and two independent control groups. RESULTS: We identified 14 individuals from nine families with 12 ultra-rare biallelic RNU2-2 variants clustering in the conserved 5' domains. Genotype data from 13 of 14 individuals has been reported previously as part of a larger cohort. All individuals presented with a highly concordant, severe DEE, characterized by severe to profound intellectual disability, inability to walk or communicate, hyperkinesia, and refractory seizures. Infantile spasms and tonic seizures were the predominant seizure types and a Lennox-Gastaut syndrome-like phenotype was common. These individuals had a significantly similar phenotypic signature when compared with 703 individuals with complex pediatric epilepsies (two-sided Monte Carlo permutation test, p = .005). RNA sequencing analyses showed aberrant splicing, with the most pronounced effects in fibroblast tissues in mutually exclusive exon and alternate 3' splice-site events, which were not detectable in blood. SIGNIFICANCE: We present deep phenotyping data and transcriptomic analyses that provide support for rare, 5' clustering biallelic RNU2-2 variants causing this novel, severe DEE. We propose an RNA sequencing methodology on fibroblast tissue for future validation of RNU2-2 variants.

autosomal recessive disease↗

PubMed2026

Intravenous Nicorandil in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary PCI: The CLEAN Randomized Clinical Trial.

BACKGROUND: Nicorandil, an adenosine triphosphate-sensitive potassium-channel opener with nitrate-like properties, may reduce reperfusion injury and microvascular obstruction in ST-segment elevation myocardial infarction (STEMI), but large-scale randomized evidence on long-term clinical outcomes is inconclusive. OBJECTIVES: The CLEAN trial aimed to assess whether adjunctive intravenous nicorandil improves 12-month clinical outcomes in patients with STEMI undergoing primary percutaneous coronary intervention. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial conducted at 49 hospitals in China, patients aged 18 to 80 years with STEMI within 12 hours of symptom onset were randomly assigned (1:1) to receive intravenous nicorandil (6 mg bolus before reperfusion followed by 6 mg/h infusion for 48 h) or matching placebo. Oral nicorandil was prohibited during follow-up. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, target vessel revascularization, or unplanned hospitalization for heart failure within 12 months. RESULTS: Between January 2021 and December 2023, 1,503 patients were enrolled and randomly assigned to nicorandil (n = 748) or placebo (n = 755). The primary composite outcome occurred in 98 patients (13.1%) in the nicorandil group (113 events over 717.2 person-years) and 99 (13.1%) in the placebo group (136 events over 710.3 person-years), with no significant difference between groups (rate ratio: 0.869; 95% CI: 0.650-1.162; P = 0.3429). Among secondary outcomes, nominal reductions were observed in cardiovascular death (1.9% vs 3.6%; HR: 0.515; 95% CI: 0.269-0.983) and target-vessel revascularization (1.1% vs 3.0%; HR: 0.322; 95% CI: 0.143-0.727), whereas rates of nonfatal myocardial infarction and unplanned hospitalization for heart failure were similar between groups. Adverse events did not differ between groups. CONCLUSIONS: In patients with STEMI undergoing primary percutaneous coronary intervention, adjunctive intravenous nicorandil did not significantly reduce the 12-month primary composite outcome. These findings do not support routine use of intravenous nicorandil in unselected patients with STEMI. (Clinical Efficacy and sAfety of Intravenous Nicorandil; NCT04665648).

Humans↗

PubMed2026

High-dose radiotherapy in patients with high-risk prostate cancers treated with long-term androgen deprivation therapy (GETUG AFU 18): a randomised, phase 3 trial.

BACKGROUND: For patients with high-risk prostate cancer, the role of dose-escalated radiotherapy in combination with long-term androgen deprivation treatment (ADT) is controversial, without any demonstrated benefit on cancer-specific or overall survival. We aimed to evaluate the effect of a 10 Gy dose increase, from 70 Gy to 80 Gy, on progression-free survival in men with high-risk prostate cancer. METHODS: In this multicentre, open-label, randomised, phase 3 trial, we enrolled patients with high-risk prostate cancer, defined as prostate-specific antigen of 20 ng/mL or more, Gleason score of at least 8, or clinical stage T3-T4, from 25 centres in France. Participants were randomly assigned (1:1) by minimisation, stratified by centre and previous pelvic lymph node dissection, to receive prostate-targeted dose-escalated external beam radiotherapy (80 Gy; 2 Gy per fraction for 8 weeks) or standard-dose external beam radiotherapy (70 Gy; 2 Gy per fraction for 7 weeks), combined with long-term ADT. Neither the participants nor the investigators were masked to the allocated treatment. The primary endpoint was 5-year progression-free survival defined as the time from randomisation to first biochemical (defined as prostate-specific antigen >nadir plus 2 ng/mL) or clinical (ie, local, regional, or metastatic) disease progression, analysed in the intention-to-treat population, with 197 events required. 5-year progression-free survival was the prespecified endpoint, and 10-year progression-free survival was additionally reported (post hoc) in view of the low number of events at 5 years. The trial is registered at ClinicalTrials.gov, NCT00967863, and is complete. FINDINGS: Between April 6, 2009, and Jan 24, 2013, 505 patients with high-risk prostate cancer were enrolled; 250 were assigned to receive dose-escalated radiotherapy (80 Gy) and 255 to receive standard dose radiotherapy (70 Gy). All participants were male and ethnicity data were not collected. At a median follow-up of 9·5 years (IQR 8·5-10·3), 5-year progression-free survival was 91·4% (95% CI 87·0-94·4) in the dose-escalation group versus 88·1% (83·2-91·6) in the control group, and 10-year progression-free survival was 83·6% (77·8-88·0) versus 72·2% (65·3-78·0; stratified HR 0·56, 95% CI 0·40-0·78, p<0·0001). Grade 3 or worse adverse events assessed at 6 months (acute toxicity) were observed in 60 (24%) of patients in the dose-escalation group and 62 (25%) in the control group. The most frequent grade 3 or worse adverse events were sexual disorders (28 [11%] in the dose-escalation group vs 20 [8%] in the control group) and bladder or urethra disorders (12 [5%] vs 19 [8%]). Adverse events assessed at 5 years (late toxicity) occurred in 118 (70%) of 168 in the dose-escalation group and 122 (73%) of 168 in the control group; grade 3 or worse late toxicities occurred in 19 (8%) participants in the dose-escalated radiotherapy group versus 17 (7%) participants in the control group. The most common late grade 3 adverse event was bladder or urethra disorders (seven [4%] vs three [2%], respectively). Serious adverse events occurred in nine (4%) patients in the dose escalation group and nine (4%) in the control group; none were considered to be treatment related. There were no treatment-related deaths. INTERPRETATION: For patients with high-risk prostate cancer, radiotherapy at a total dose of 80 Gy, in combination with long-term ADT, improved progression-free survival and could be a potential option in this situation. However, given the low number of events, further research is needed to consolidate and confirm the benefit in dose-escalation in prostate cancer-specific survival and overall survival. FUNDING: French National Cancer Institute and AstraZeneca.

Aged↗

PubMed2026

The impact of sex, age, and genetic ancestry on DNA methylation across tissues.

Understanding the consequences of individual DNA methylation variation is crucial for advancing our knowledge of human biology and disease, yet the collective impact of individual traits on DNA methylation and their downstream effects on gene expression across human tissues remains poorly understood. Here, we quantify the contributions of sex, age, genetic ancestry, and BMI on autosomal DNA methylation variation across nine human tissues and 424 individuals from the Genotype-Tissue Expression project. We show that genetic ancestry and age have a greater impact on DNA methylation compared with sex, with aging effects being more widespread but less pronounced. On average, <10% of the gene expression variation in sex, age, and ancestry is mediated by DNA methylation differences, with ancestry showing the largest proportion of mediation. We further show that ancestry-associated DNA methylation differences accumulate at CpG sites with extreme methylation states and are largely under genetic control. The female autosomal genome exhibits consistent hypermethylation across tissues at Polycomb-repressed regions. Ultimately, we show that age-related Polycomb target hypermethylation is observed across multiple tissues but not in the gonads. Our multi-individual, multitissue approach defines the key drivers of human DNA methylation variation in healthy conditions, establishing a baseline for the interpretation of DNA methylation changes in disease contexts.

Humans↗

PubMed2026

Pairwise Comparative Safety and Effectiveness of Anti-TNF Blockers, Vedolizumab, and Ustekinumab During Pregnancy: A Systematic Review and Meta-Analysis.

PURPOSE: Biologic therapies, including tumor necrosis factor (TNF) blockers, vedolizumab (VDZ), and ustekinumab (UST), are generally considered safe during pregnancy in patients with inflammatory bowel disease (IBD), though comparative data remain limited. This meta-analysis examines their safety and effectiveness. METHODS: A systematic search of MEDLINE, EMBASE, CINAHL, Cochrane, and Web of Science was conducted through July 2025. Eligible studies reported maternal or neonatal outcomes in pregnant IBD patients treated with biologics. Studies were pooled using a random-effects model to calculate risk ratios (RRs) with 95% confidence intervals. Heterogeneity was assessed using I2. Primary outcomes were preterm birth and disease activity; secondary outcomes included pregnancy and neonatal outcomes. RESULTS: Nine observational studies (n = 6,054) were included. Compared to TNF blockers, VDZ was associated with a higher risk of preterm delivery (RR = 1.35, 95% CI 1.04-1.75, I2 = 0%) and active disease (RR = 1.55, 95% CI 1.01-2.40, I2 = 50%). UST was associated with a higher risk of active disease (RR = 1.30, 95% CI 1.06-1.60, I2 = 0%) and congenital anomalies (RR = 2.08, 95% CI 1.30-3.32, I2 = 0%) compared to TNF blockers. Compared to UST, VDZ was linked to increased risks of preterm birth (RR = 2.60, 95% CI 1.03-6.57, I2 = 0%) and low birth weight (RR = 2.38, 95% CI 1.01-5.60, I2 = 0%). No significant differences were observed for live births, abortions, hospitalizations, or neonatal infections. CONCLUSION: TNF blockers showed a favorable safety and effectiveness profile, VDZ and UST performed broadly similar, and all three biological classes appeared compatible with safe use in pregnancy to maintain effective disease control. Observed differences reflect that VDZ and UST cohorts likely had longer disease duration, prior biologic exposure, and more active disease. The results of this meta-analysis support the continuation of biologic therapy for disease control in pregnant patients with IBD. Treatment decisions should be individualized and tailored to each patient's clinical context.

Female↗

PubMed2026

Artificial intelligence-supported double reading in European population breast cancer screening: A systematic review and meta-analysis of prospective programs.

BACKGROUND: Most European population mammography screening programs rely on double reading with arbitration, a model that delivers mortality benefit but is increasingly challenged by radiologist workload, variable specificity, and interval cancers. Artificial intelligence (AI) is being evaluated to support or optimize these established European screening pathways. PURPOSE: To synthesize prospective or program-embedded evaluations of AI conducted within European-style population screening programs and to estimate exploratory program-level absolute risk differences (RDs) per 1000 examinations for cancer detection rate (CDR) and recall. MATERIALS AND METHODS: We performed a prespecified, focused evidence synthesis of three large studies embedded within routine population screening programs operating under European-relevant workflows: MASAI (randomized AI-supported risk triage within a national program), ScreenTrustCAD (prospective paired-reader evaluation with AI as an independent reader in a double-reading framework), and PRAIM (nationwide decision-referral implementation). Outcomes were harmonized as AI-control RDs per 1000 examinations. Random-effects pooling used Hartung-Knapp-Sidik-Jonkman models. For the paired-reader design, sensitivity analyses applied a Kish effective sample-size approach across plausible within-examination correlations (ρ = 0.3-0.8). Positive predictive value (PPV) and workflow/time outcomes were summarized descriptively. RESULTS: Across 597,419 examinations, the pooled CDR RD was +0.9 per 1000 (95% CI -0.0 to +1.8; I2 ≈ 12%), consistent with a modest directional increase with borderline statistical uncertainty. The pooled recall RD was -0.6 per 1000 (95% CI -3.1 to +2.1; I2 ≈ 41-43%), indicating no consistent recall increase across screening programs. Where reported, PPV was higher with AI-supported screening. Efficiency signals included 44.3% fewer total readings in MASAI and shorter reading times for AI-normal examinations in PRAIM; in PRAIM, a program-level safety-net mechanism recovered 204 cancers that would otherwise have been missed. CONCLUSION: In European population screening programs characterized by double reading and arbitration, prospective program-embedded evidence suggests that AI integration may yield a small absolute increase in cancer detection (≈1/1000) without a consistent increase in recall, alongside improved PPV and efficiency signals. These findings suggestAI primarily as a complementary reader within European screening workflows, with implementation requiring explicit quality assurance and monitoring of interval cancers and stage distribution.

Humans↗

PubMed2026

Comparing trajectories of cognitive functioning in treatment-resistant and non-resistant depression: a multicentre linear mixed-effects analysis.

BACKGROUND: Impaired cognitive functioning is a severe symptom in major depressive disorder (MDD). Recent evidence suggests it may be a central characteristic in its treatment resistant form (TRD), potentially constituting a clinical marker for treatment resistance and a target amenable to intervention. To date, cognitive functioning in TRD remains poorly understood and longitudinal investigations are scarce. METHODS: This observational prospective cohort study, including 320 patients diagnosed with MDD from the multicentre PROMPT study, examined differences in cognitive functioning between 118 TRD and 202 non-TRD patients over a period of twelve weeks in a real-world setting, using linear mixed modelling. Patients that failed to respond to at least two prior antidepressants trials at baseline were classified as TRD. RESULTS: TRD patients showed significantly poorer baseline performances than non-TRD patients in attention/processing speed (β = -0.45; 95%CI[-0.70, -0.19]; FDR-p = 0.003) and verbal memory (β = -0.45; 95%CI[-0.72, -0.18]; FDR-p = 0.003). Significant time × group interactions were observed in motor speed and verbal fluency tasks. Post-hoc-analyses revealed stagnation in TRD patients and significant improvement in non-TRD patients. Across all other tasks improvement was observed in both groups, and random effects showed large heterogeneity between patients, indicating notable individual differences in cognitive performances. CONCLUSIONS: The results suggest distinct recovery patters between non-TRD and TRD patients, and diminished functioning in TRD patients at the domain level. However, intact and diminished performances likely occur in both groups, warranting further investigation of cognitive heterogeneity. These short-term findings highlight the need for more comprehensive longitudinal research on cognition in TRD.

Humans↗

PubMed2026

Bioepidemiology of cardiac amyloidosis.

BACKGROUND: Cardiac amyloidosis, primarily due to immunoglobulin light chain (AL) or transthyretin (ATTR) amyloid, is an increasingly recognized cause of heart failure. Modern diagnostic advances suggest that ATTR, particularly in older adults, may be more prevalent than historically reported. METHODS: All Olmsted County decedents aged ≥40 years from 1970 to 1976 were identified. Available ventricular myocardium from retained paraffin blocks was screened histologically for amyloid using sulfated Alcian blue staining; positive cases underwent grading and proteomic typing by laser microdissection coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Beyond prevalence estimation, this analysis characterizes amyloid type, deposition grade and distribution, associated comorbidities, and cause-of-death patterns, comparing amyloid-positive decedents with age- and sex-matched controls. RESULTS: Of 2,566 eligible deaths, 1,028 autopsy cases with evaluable myocardium formed the study cohort (mean age 70.5 years; 61.1% male; 97% White). Cardiac amyloid was present in 52 cases giving an overall prevalence of 5.1% (95% CI: 3.8-6.6, which rose from 0% under age 60 to 37.5% (95% CI: 21.1-56.3) in those ≥90 years (p < 0.001). While prevalence estimates were higher in men above age 80 compared to women, there was no evidence of an interaction of age and sex (p = 0.90). The quantity of amyloid was sufficient for typing in 38 cases: ATTR (84.2%), AL (7.9%), serum amyloid A (5.3%), and apolipoprotein A-IV (2.6%). Adjusted estimates assuming untyped mild cases were ATTR-type increased ATTR prevalence to 4.5% (95% CI: 3.3-5.9) overall. Comorbidity profiles were similar between amyloid-positive and negative groups, though syncope and leg weakness were more common in amyloid-positive decedents. CONCLUSIONS: In an unselected autopsy cohort, cardiac amyloid was common, particularly ATTR in older adults. Prevalence increased steeply after age 80. These findings suggest that ATTR amyloidosis is not rare and is likely underdiagnosed and has similar prevalence in women and men, despite the male predominance reported in the literature.

Humans↗

PubMed2025

The effect of penile tourniquet and continuous artificial erection on penile erectile tissues: An experimental study.

INTRODUCTION: Penile tourniquet (PT) is known to cause ischemic injury, which worsens with prolonged application. Artificial erection (AE), formed by intracorporal saline injection mostly under PT, has been practiced for decades to evaluate penile curvature, yet its effect on erectile tissues has never been investigated. In this study, we examined a modified approach, continuous artificial erection (CAE), and investigated its effects on erectile tissues. OBJECTIVE: This study aims to investigate the histopathological and immunohistochemical effects of CAE on penile erectile tissues. STUDY DESIGN: Thirty-five rats were randomized into five groups. Four experiment groups received 20 or 40 min of isolated PT (20T and 40T) or PT with CAE (20T&E and 40T&E). CAE was achieved through continuous intracavernosal saline injection. Penectomy was performed three weeks post-procedure in the experiment groups and directly in the control group. Erectile tissue samples were evaluated using light microscopy for histopathological parameters including inflammation, neovascularization and fibrosis, and by immunohistochemistry. Endothelial function was assessed by eNOS and e-selectin staining, while ICAM-1 staining was used to assess chronic inflammation. RESULTS: 40T showed the highest levels of inflammation, fibrosis, and endothelial dysfunction. 20T had significantly less inflammation than 40T, with a non-significant increase in fibrosis and alteration of endothelial markers. 40T&E displayed the second-highest fibrosis rate (adjusted p > 0.05), while 20T&E showed complete absence of fibrosis. Both 40T&E and 20T&E preserved strong eNOS and e-selectin expression, identical to controls. ICAM-1 expression in 20T&E was also consistent with the control group. The most significant difference in erectile tissue damage was noted between 40T and 20T&E. CONCLUSION: This is the first study to evaluate the effects of AE on erectile tissues. Findings of this experimental model support that, CAE does not increase the tissue damage that is already caused by PT, but rather reduces it, likely through the washout of blood elements contributing to reperfusion injury. CAE possibly provides a protective effect on erectile tissues by preserving endothelial function, reducing inflammation and fibrosis, especially under 20 minutes of duration. These findings may support that AE maneuvers such as "artificial erection test" and CAE are potentially safe, while further studies are needed to assess the detailed effects of CAE.

Male↗

PubMed2026

Evaluation of the difference between automated and measured QTc intervals in children.

BACKGROUND: The corrected QT interval (QTc) is obtained through automated ECG computations or manual physician measurements. We hypothesized that differences exist in children between the measured and automated QTc intervals within and between Healthy and hypertrophic cardiomyopathy (HCM) subjects with greater differences for HCM due to structural abnormalities. METHODS: QT measurements - Bazett correction- automated (aQTc) and measured (mQTc), were extracted from the GE MUSE database for 385 Healthy pediatric (single ECG) and 208 HCM subjects (2 ECGs), stratified by age < 12 and ≥ 12 yrs., sex, race, and ethnicity. QTc means (SD), automated and measured differences, and the difference of the differences of aQTc and mQTc were analyzed overall and by subgroups. All ECGs were read by one pediatric cardiologist with a second cardiologist reading a random subset of HCM ECGs to evaluate intraclass correlations and agreement. RESULTS: The mQTc intervals were shorter than aQTc intervals within Healthy (p < 0.001) and within first HCM ECGs (p < 0.001) with both aQTc and mQTc shorter in Healthy than HCM (p < 0.001). The difference in these differences was significant overall using HCM ECG 1 but not HCM ECG 2. Healthy subject aQTc and mQTc intervals differed by age, sex, and race (p < 0.002). HCM ECG 1 aQTc- mQTc intervals differed for age < 12 yrs., as well as by sex and race. HCM ECG 2 intervals differed only for age < 12 yrs. CONCLUSIONS: Compared to measured values, automated QTc values were significantly longer in both Healthy and HCM subjects. Automated measurements may overestimate the QTc.

Humans↗

PubMed2026

Effect of demographic characteristics on the outcome of prostate cancer salvage radiotherapy: Analysis from a randomized controlled trial.

BACKGROUND: This study investigated the impact of advanced molecular imaging, race, socioeconomic status, and metabolic dysregulation on the outcome of salvage radiotherapy (sRT) for prostate cancer recurrence in a clinical trial setting. METHODS: The authors randomized post-prostatectomy men with detectable prostate-specific antigen to sRT guided by conventional imaging (arm A) or 18F-fluciclovine-positron emission tomography/computed tomography (arm B) and followed them up for up to 48 months to determine failure-free survival (FFS). The authors computed socioeconomic status (SES) and allostatic load (AL) scores to quantify socioeconomic status and level of metabolic dysregulation. They stratified patients by race as African American men (AAM) versus men of other races (MOR) and compared FFS between them using the z-test. RESULTS: Eighty-one (AAM = 29, MOR = 52) and 76 (AAM = 26, MOR = 50) men completed per-protocol sRT in arms A and B, respectively. Across study arms, AAM showed a higher FFS rate than MOR (72.8% [95% CI, 53.8%-85.0%] vs. 58.7% [95% CI, 46.6%-68.9%]; p = .002). In arm A, FFS rate was better for AAM than MOR, (64.0% [95% CI, 34.4%-82.9%] vs. 45.3% [95% CI, 28.8%-60.4%]; p = .008). In arm B, FFS improved for both groups but less so for AAM, (81.5% [95% CI, 57.2%-92.7%] vs. 73.0% [95% CI, 56.3%-84.1%]; p = .131). The authors found lower SES scores and higher AL scores for AAM in both study arms than MOR. CONCLUSION: Despite lower socioeconomic status and higher burden of metabolic dysregulation, in a clinical trial setting that controls for disparities in health care access, AAM have a more favorable sRT outcome than MOR.

Humans↗

PubMed2026

Malaria rapid diagnostic tests: performance, pitfalls, and progress.

PURPOSE OF REVIEW: Malaria rapid diagnostic tests (RDTs) have revolutionized malaria diagnosis in endemic settings. RDTs are simple to use and accurate for clinical cases, although sensitivity is reduced at parasite densities below 200 parasites/μl. However, increasing prevalence of hrp2/3 gene deletions in certain areas threaten utility of histidine-rich protein 2 (HRP2)-based RDTs, and lingering HRP2 antigenemia can generate false-positive results after parasite clearance. This review summarizes current performance of malaria RDTs, threats to their validity, and recent innovations to improve their performance and continued role in malaria diagnosis. RECENT FINDINGS: Most World Health Organization (WHO) prequalified RDTs perform well for clinical diagnosis, with only occasional exceptions, including a recently reported issue affecting several countries. RDT sensitivity is generally related to malaria transmission intensity, with higher proportions of false-negative results in lower-transmission areas. Newly prequalified lactate dehydrogenase (pLDH)-based RDTs perform well for both Plasmodium falciparum in areas with >5% hrp2/3 gene deletions and for Plasmodium vivax diagnosis. Several point-of-care alternatives to RDTs, including micro-fluidic devices, hemozoin-detecting devices, and automated hematology analyzers, have shown promising results in small studies, but require larger-scale trials before widespread use. SUMMARY: RDTs remain a critical tool in clinical diagnosis of malaria, and newer pLDH-based tests perform well in areas where hrp2/3 gene deletions threaten validity of HRP2-based RDTs.

Humans↗