The emergence of viruses with reduced susceptibility to antivirals poses an ongoing risk which could limit their effectiveness. Here we report a cluster of A(H3N2) viruses detected in Tasmania, Australia, with a PA gene mutation A37T that showed mild reductions in susceptibility in vitro to baloxavir (3.47- to 16.33-fold increased EC₅₀) when compared to wild-type influenza A(H3N2) viruses. When the PA-A37T and PA-I38T substitutions were combined and tested in IRINA assay, eightfold higher inhibition was seen compared to PA-I38T alone. On-going monitoring of influenza viruses for reduced susceptibility to antivirals remains an important part of seasonal and zoonotic influenza surveillance.

A key problem underlying COPD is the severe and irreversible lung tissue damage (emphysema) as consequence of hampered repair. Available therapies do not halt or reverse disease progression, and novel therapeutic strategies aimed at tissue repair are urgently awaited. To address this unmet need, ongoing research aims to provide insight into the cellular/molecular mechanisms underpinning defective lung repair in emphysema. Healthy lungs possess an intrinsic regenerative capacity based on alveolar epithelial progenitor cells that reside in their niche, which is composed of a supporting extracellular matrix, stromal cells and immune cells. While this stromal niche is vital for appropriate regenerative responses, emerging studies show that interactions within the stromal niche are defective in COPD, hampering alveolar repair. This review addresses the novel concept that restoring disrupted interactions within the diseased stromal niche may lead to repair of damaged lung tissue in COPD. The unavailability of successful strategies to achieve stromal health and support lung tissue repair may be due to an incomplete insight into the complex interactions within the alveolus. Moreover, inadequate delivery methods, with uncontrolled release and rapid clearance of regenerative compounds and therapeutic cells, contribute to the failed translation of novel findings into effective strategies. This review provides an overview of the current state of the field, including novel insights into the defective interactions that have been identified within the alveolar niche in COPD. Moreover, advanced models to study the alveolar niche and innovative strategies to therapeutically target this niche and restore stromal health in COPD are discussed.

RNU4ATAC-opathy is a rare autosomal recessive disorder characterized by a wide clinical spectrum, including brain anomalies, seizures, strokes, immunodeficiency, and cardiac defects. Other manifestations include ophthalmologic, dermatologic, renal, gastrointestinal, auditory, and endocrine involvement. Here, we report the identification of pathogenic RNU4ATAC variants through whole exome sequencing in an infant presenting with microcephaly, growth failure, and immunodeficiency.

We describe an 11-month-old infant who had been followed since 4 months of age for growth failure and developmental delay. During follow-up, the patient experienced episodes of neurological deterioration triggered by febrile illnesses associated with SARS-CoV-2 and respiratory syncytial virus infections (RSV) at 9 and 11 months of age, respectively. Immunological evaluation showed normal immunoglobulin levels, a marked reduction in switched memory and memory B cells, impaired T-cell activation, and decreased T-cell subpopulations, suggesting combined immunodeficiency that may have contributed to increased susceptibility to viral infections. Whole exome sequencing subsequently identified compound heterozygous pathogenic variants in the RNU4ATAC gene, confirming the diagnosis of RNU4ATAC-opathy.

RNU4ATAC-opathy should be considered in cases with microcephaly, growth failure, immunodeficiency, and skeletal abnormalities. Our case shows that RNU4ATAC-opathy may present as infection-related encephalopathy, together with combined T- and B-cell dysfunction. Early immunological assessment and timely initiation of prophylactic therapy could play a key role in improving survival. Genetic and immunological evaluations are essential for accurate diagnosis, early intervention, and effective management. Further research is needed to clarify the syndrome's impact on immune function and guide targeted therapies.

The ubiquitin-proteasome system (UPS) plays a pivotal role in the precise regulation of innate immunity. Within the spatiotemporal framework of coronavirus (CoV) infection, the UPS emerges as a critical arena and a molecular switch, dynamically mediating the balance between host antiviral defense and viral replication alongside immune evasion. The host leverages the UPS to activate interferon (IFN) signaling pathways and to directly target viral proteins for degradation. Conversely, CoVs have developed sophisticated mechanisms to exploit this system, either by degrading antiviral proteins or by encoding viral deubiquitinases (DUBs) to counteract host ubiquitination signals. Notably, CoV proteins themselves undergo ubiquitination, which can lead to either their functional activation or proteasomal degradation, underscoring the dual-edged nature of the UPS. In this review, we initially examined the mechanisms by which the UPS regulates the IFN system. Subsequently, we highlighted the strategies employed by CoVs to inhibit the IFN system through the manipulation of the UPS. Thirdly, we synthesized findings regarding how the UPS specifically targets and degrades the principal virulence proteins of CoVs. Finally, we investigated the potential of the UPS as a therapeutic target for developing resistance against CoV infections.

Antidepressants (ADs) have been associated with adverse cardiovascular effects, including cardiac arrhythmias. Evidence on the association between AD use and the risk of atrial fibrillation (AF) and ventricular arrhythmia/sudden cardiac death (VA/SCD) remains inconsistent. This systematic review and meta-analysis aimed to evaluate the relationship between AD use and the risk of AF and VA/SCD.

A detailed search was conducted in PubMed, Scopus, and Web of Science till June 2026. Cohort and case-control studies comparing AD users with non-users and reporting AF, VA, or SCD as outcomes were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model.

Twelve studies with 9,619,278 participants were included. AD use was associated with a significantly increased risk of VA/SCD (9 studies, 6,373,522 participants, OR = 1.34, 95% CI: 1.15-1.55; I² = 90.5%). The association remained significant for both SSRIs and TCAs. For AF, no overall significant association emerged (3 Studies, 3,245,756 participants, OR = 1.75, 95% CI: 0.84-3.62; I² = 98.1%). However, sensitivity analysis excluding one influential study showed a significant association with AF (2 Studies, 18,109 participants, OR = 1.27, 95% CI: 1.07-1.50) and eliminated heterogeneity (I² = 0%).

This meta-analysis suggests an association between AD use and an increased risk of VA/SCD, while evidence for AF remains uncertain because the results were influenced by a single study. Future large observational studies that better address confounding by indication and adequately adjust for depression are needed to provide more robust evidence.

Angio FFR has attracted attention as a method for assessing the functional severity of intermediate coronary artery stenosis. However, detailed comparisons with wire-based FFR in terms of radiation dose and procedural efficiency remain limited. This study aimed to compare examination-related parameters and procedural efficiency between the two methods and to evaluate the clinical utility of angio FFR.

This retrospective clinical study included patients who underwent functional assessment of coronary artery stenosis using either angio FFR or wire-based FFR during cardiac catheterization. The evaluated parameters were reference-point air kerma at the patient entrance reference point (K_a,r), air kerma-area product (P_KA), fluoroscopy time, contrast volume, number of images, and angiography room stay time. Continuous variables were compared using median values and interquartile ranges.

Compared with the wire-based FFR group, the angio FFR group showed significantly lower K_a,r, fluoroscopy time, contrast volume, and angiography room stay time (p<0.05). No significant differences were observed in P_KA (p=0.95) or the number of images (p=0.27).

Angio FFR was associated with lower K_a,r and improved procedural efficiency compared with wire-based FFR, suggesting its potential utility in functional assessment of coronary artery stenosis.

As Japan faces a heart failure (HF) pandemic, geriatric health service facilities (GHSFs) are vital for transitional HF care from hospital to home. This study investigated HF care practices, challenges, and support needs in Japanese GHSFs.

We conducted a cross-sectional web-based survey of 171 GHSFs. We analyzed current management practices, perceived difficulties, and support needs regarding HF care in GHSFs. Concerns over high medication costs for HF were the primary reason for admission refusal (49.7%). Although daily symptom assessments, including dyspnea and edema were common, weight monitoring was conducted only monthly in 50.3% of facilities. HF care infrastructure was inadequate: 99.4% of GHSFs had no specialized staff (e.g., certified HF educators), only 38.0% had access to expert consultation, and only 56.7% provided HF-specific rehabilitation. Consequently, 44.4% of representatives reported significant perceived difficulty in HF care, primarily in judging consultation timing (75.0%). Facilities reporting low/neutral satisfaction with information desired advance care planning (ACP) and consultation criteria. HF patients had significantly lower home discharge rates than the overall facility residents (median [interquartile range] 20.0% [4.1-34.6%] vs. 34.0% [19.0-49.0%]; P<0.01).

Concerns over financial barriers, along with structural and communication barriers in GHSFs, drive admission refusals and complicate HF management, potentially limiting home discharge. Improving transitional HF care requires addressing these financial concerns, providing standardized staff education and specialized support, and bridging information gaps, specifically regarding ACP and consultation criteria, between hospitals and facilities.

To map the existing evidence on shared decision-making (SDM) in stroke care across four dimensions (clinical contexts, decision support tools, influencing factors and implementation outcomes) and to identify key research gaps.

Scoping review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR).

A systematic search was conducted in PubMed, Web of Science, Embase, China National Knowledge Infrastructure and Wanfang Database from inception to 15 September 2025.

Studies were included if they focused on patients with stroke; involved SDM (defined as a collaborative process in which patients and healthcare professionals make health-related decisions together, integrating the best available evidence with patient values and preferences) or decision-support interventions in clinical management; and reported on applications, processes or outcomes of SDM. Both qualitative and quantitative studies were considered.

Data were charted using a predefined form and synthesised through a narrative and thematic analysis to map application scenarios, implementation formats and influencing factors.

Seventeen studies were included. SDM was applied across multiple stroke care processes, including acute thrombolysis, secondary prevention and discharge planning. Implementation formats varied, including paper-based tools, visual decision aids, web-based platforms and computer-assisted systems. Influencing factors were identified at multiple levels, including patient-related factors, healthcare professional engagement, characteristics of decision-support tools and organisational processes. Overall, SDM showed potential benefits in improving patient involvement and decision quality, although evidence remained heterogeneous and limited.

SDM shows a promising but underdeveloped application in stroke care. Existing evidence is fragmented, with variability in implementation approaches and limited high-quality evaluation. Future research should focus on establishing standardised definitions and outcome measures for SDM, developing decision-support tools that can be adapted to diverse stroke care processes and evaluating SDM implementation across the full continuum of care, which would help strengthen the evidence base in this field.

To investigate associations between current use of menopausal hormone therapy and development of venous thromboembolism, ischaemic stroke, and myocardial infarction.

Nationwide nested case-control study.

National Danish health registries.

9807 women with venous thromboembolism, 18 460 women with ischaemic stroke, and 11 974 women with myocardial infarction were identified in a cohort of women of 50-69 years living in Denmark between 2003 and 2021 without a medical history of venous thrombosis, arterial thrombosis, cancer, liver disease, thrombophilia, oophorectomy, infertility treatment, endometriosis, or polyendocrine metabolic ovarian syndrome (PMOS, previously known as polycystic ovary syndrome). Cases were matched by birth year to a total of 49 035, 92 300, and 59 870 women without thrombotic disease, respectively.

Receiving a first time diagnosis of venous thromboembolism, ischaemic stroke, or myocardial infarction.

Among women who had not used menopausal hormone therapy, incidence rates of venous thromboembolism, ischaemic stroke, and myocardial infarction per 10 000 person years were 15.8, 20.3, and 13.0, respectively. Compared with no current use, current use of oral oestrogen therapy (alone or combined with progestin) was associated with increased rates of venous thromboembolism (hazard ratio 1.6, 95% CI 1.5 to 1.8), ischaemic stroke (1.3, 1.2 to 1.4), and myocardial infarction (1.2, 1.1 to 1.3). The absolute risk increase per year was 0.09% (95% confidence interval (CI) 0.08 to 0.13%) for venous thromboembolism, 0.06% (0.04 to 0.08%) for ischaemic stroke, and 0.03% (0.01 to 0.04%) for myocardial infarction, corresponding to numbers needed to harm for one year of use of 1055 (95% CI 791 to 1266), 1642 (1232 to 2463), and 3846 (2564 to 7692), respectively.Use of oral forms of oestradiol was consistently associated with increased venous thromboembolic risk compared with no current use. Oral oestradiol doses >1 mg/day used for more than one year was associated with increased risks of ischaemic stroke and myocardial infarction, with risks increasing with treatment duration (stroke hazard ratio 1.8, 95% CI 1.4 to 2.2 and myocardial infarction hazard ratio 1.8, 1.4 to 2.4 for >5 years of use compared with no current use).Transdermal therapy was not associated with increased thrombotic rates compared with no current use, with the exception of increased risk of myocardial infarction with transdermal combined cyclic therapy (hazard ratio 2.1, 95% CI 1.1 to 4.1).

Compared with no current use of any hormone therapy, oral menopausal hormone therapy was associated with increased venous thromboembolic risk regardless of dosage and treatment duration, while prolonged use of high dose oral oestradiol (>1 mg/day) showed elevated risks of ischaemic stroke and myocardial infarction. No increased thrombotic risks were observed with transdermal therapy.

To compare the effect of specific antidepressants with placebo on heart rate corrected QT interval (QTc) during the first eight weeks of treatment for major depressive disorder in adults, and to investigate whether antidepressant use is associated with early major cardiovascular adverse events (MACE).

Individual participant data (IPD) network meta-regression and aggregate pairwise meta-analysis.

Individual and aggregate level data from randomised controlled trials identified through Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS, Medline, Medline In-Process, PsycINFO, the websites of regulatory agencies, and international registers.

IPD were harmonised to enhance comparability and analysed using network meta-regressions to explore the interplay with baseline QTc, age, sex assigned at birth, body mass index, serum potassium level, and estimated glomerular filtration rate. The primary outcome was changes in QTc Fridericia (QTcF) associated with specific antidepressants and placebo after taking into account modifiable and non-modifiable risk factors. Aggregate data on early MACE were analysed using pairwise meta-analysis comparing antidepressants with placebo.

Double blind randomised trials of adults (≥18 years) with major depressive disorder diagnosed according to standardised, operationalised criteria.

Of 130 unique randomised controlled trials identified, 35 (27%) included individual level data (8679 participants) on QTc with placebo and 10 antidepressants (amitriptyline, bupropion, duloxetine, escitalopram, fluoxetine, mirtazapine, paroxetine, trazodone, venlafaxine, vortioxetine). Compared with placebo, escitalopram and amitriptyline were associated with increased QTc intervals (8.7 milliseconds (ms), 95% credibility interval (CrI) 1.6 to 15.8, and 5.3 ms, 0.8 to 9.8, respectively). When risk factors were considered, amitriptyline and escitalopram were also associated with the highest QTc prolongations (58.8% and 21.3%, respectively), whereas venlafaxine and vortioxetine were often associated with the lowest QTc intervals (24.1% and 9.7%, respectively). Important variability of effects was observed, especially for escitalopram, fluoxetine, and mirtazapine. An aggregate analysis of 139 trials (52 398 participants) did not identify an association between antidepressant use and increased rates of early MACE and non-suicidal death compared with placebo (risk difference 0.01%, 95% CrI -0.01% to 0.02%).

The effect of specific antidepressants on QTc interval differed between adults with depression. No evidence associated antidepressant use with early MACE and non-suicidal sudden death. To support shared decision making and taking into account the trade-off between benefits and harms, individual modifiable and non-modifiable risk factors should be considered when choosing antidepressants.

Open Science Framework https://osf.io/c8k65/.