International Immunopharmacology

Abstract Background: Mean platelet volume (MPV) is a simple, low-cost biomarker that reflects platelet activation. Its prognostic value in septic shock remains controversial. We aimed to determine whether MPV at intensive care unit (ICU) admission is associated with hospital mortality in patients with septic shock. Methods: Retrospective cohort study of consecutive adults with septic shock (Sepsis-3 criteria) admitted to a single ICU. MPV, severity scores (SOFA, APACHE II, SAPS II), procalcitonin, and clinical data were collected. The primary outcome was in-hospital mortality. Spearman correlation, univariate and multivariate logistic regression (with Firth's correction), ROC curves, and subgroup analyses were performed. Results: Fifty-eight patients were included; mortality was 58.6%. MPV did not differ between non-survivors and survivors (13.09 {+/-} 1.37 vs. 12.66 {+/-} 1.45 fL, p = 0.259). MPV showed a weak correlation with procalcitonin ({rho} = 0.394, p = 0.002) but not with severity scores. In multivariate analysis adjusting for age, sex, SOFA and comorbidity count, MPV was not an independent predictor of mortality (OR 1.075, 95% CI 0.682-1.755, p = 0.749). The area under the ROC curve for MPV was 0.598 (95% CI 0.444-0.752), significantly lower than that of SOFA (0.837) and procalcitonin (0.836). Subgroup analyses showed no significant association between MPV and mortality in any stratum. Conclusions: In this cohort of septic shock patients, MPV at ICU admission was not associated with hospital mortality and had poor discriminative ability. Widely used severity scores and procalcitonin remain superior prognostic markers. MPV should not be used as a prognostic tool in septic shock. Keywords: Septic shock, Mean platelet volume, Mortality, SOFA, Procalcitonin, Biomarker

In some countries, melatonin is sold without a physician prescription and dosage is unregulated. Transdermal products have become popular including those marketed for children. We measured consumer assumptions about these products among adult residents of the United States, analyzed lot-to-lot variability, and compared the pharmacokinetics of melatonin administered in oral, lotion, and bath product forms. Survey respondents (n=199) believed oral melatonin was more effective than transdermal products and that all melatonin products were relatively safe. Melatonin lotion products analyzed by HPLC displayed lot-to-lot variability as well as changes in formulation and product claims. To determine pharmacokinetics, three different treatments (oral tablets, lotion, and bath immersion) were administered to twelve undergraduate participants in a randomized, crossover design. Five additional participants completed bath product treatment only. Participants collected saliva samples up to 48 hours after administration, which were analyzed for melatonin by enzyme-linked immunosorbent assay. Oral (n=11) and lotion formulations (n=12) caused maximum salivary melatonin levels within 30 minutes after administration, but bath immersion did not cause increases in saliva melatonin (n=17). The half-life of oral melatonin was 1.17 [0.69 -- 1.65] hours versus 5.72 [3.75 -- 7.68] hours for lotion treatment (p = 0.011, effect size r = 0.770). Melatonin lotion may pose a risk to consumers who assume it is safe and less effective than oral tablets, when in fact it may be very potent and remain at high physiological levels into the following day. This study is registered on clinicaltrials.gov (NCT06382610) and was funded by the Sleep Research Society.

ABSTRACT Background: Self medication with analgesics and non steroidal anti inflammatory drugs (NSAIDs) is common in low- and middle income countries and may expose users to preventable adverse outcomes. Evidence from Guinea remains scarce. This study aimed to estimate the prevalence of self medication with analgesics and NSAIDs among pharmacy clients in urban Conakry, identify associated factors, and describe clinical risk situations. Methods: We conducted a pharmacy based analytical cross sectional study in 30 private pharmacies across Conakry, Guinea. A total of 1,032 participants seeking analgesics or NSAIDs were enrolled between November 3, 2012, and April 5, 2013. Self-medication was defined as acquisition or use without a valid medical prescription. Factors associated with self-medication were analysed using multivariable logistic regression. Results: Among 1,032 participants, 603 reported self medication (prevalence 58.4%). Previous unsupervised use was reported by 78.7%. The most frequently used medicines were paracetamol (56.9%, n=587), diclofenac (21.3%, n=220), ibuprofen (17.9%, n=185), and aspirin (3.9%, n=40). Overall, 68.0% (n=702) reported no knowledge of potential adverse effects. Clinical risk situations were frequent: gastrointestinal disorders (41.3%, n=426), hypertension (9.2%, n=95), and pregnancy exposure among reproductive age women (26.0%). In multivariable analysis, self medication was independently associated with previous analgesic/NSAID use (aOR = 2.8, 95% CI: 2.1 to 3.6), lack of knowledge of adverse effects (aOR = 1.9, 95% CI: 1.4 to 2.5), informal occupation (aOR = 1.6, 95% CI: 1.2 to 2.2), and age 18 to 59 years (aOR = 1.5, 95% CI: 1.1 to 2.1). Conclusions: In this pharmacy based study conducted in urban Conakry, self medication with analgesics and NSAIDs was common and frequently associated with limited awareness of potential adverse effects. These findings support the need for strengthened pharmaceutical regulation, pharmacist-led counselling, health literacy interventions, and improved access to primary care. Keywords: self medication; analgesics; NSAIDs; paracetamol; diclofenac; ibuprofen; pharmacy; Guinea; Conakry; drug safety; public health.

Background: Non-invasive diagnosis, reliable recurrence surveillance remain critical unmet needs in gliomas. Glioma induces profound systemic immune alterations despite its anatomical confinement to the central nervous system. Circulating immune cells, particularly monocytes, are key mediators of tumor-host crosstalk and may retain tumor-induced transcriptional imprints. However, their potential clinical utility as blood-based biomarkers for detection and monitoring, remain largely unexplored. Methods and findings: In this study, we performed integrated single-cell RNA sequencing of blood immune cells and demonstrated that circulating CD14+ monocytes are significantly expanded in glioma patients, exhibiting features of differentiation arrest and increased transcriptional plasticity. These cells harbor glioma-specific molecular signatures distinct from those observed in healthy controls and patients with other tumors. Leveraging these findings, we developed an ensemble machine learning diagnostic model based on transcriptomic profiles of circulating CD14+ monocytes (training cohort, n=107), which achieved a mean area under the receiver operating characteristic curve (AUC) of 0.971 during cross-validation. In an independent cohort of 567 participants, the model maintained high diagnostic accuracy, yielding an AUC of 0.877 for distinguishing glioma from controls and other tumors. And it achieved a recurrence detection AUC of 0.969 in 51 postoperative samples. Moreover, in a prospective follow-up study involving 30 glioma patients, lower model-derived scores of postoperation were significantly associated with prolonged progression-free survival (log-rank test, P=0.043), supporting its prognostic utility. Conclusion: We demonstrate circulating CD14+ monocytes undergo glioma-specific transcriptional reprogramming, generating systemic tumor-associated signal captured via transcriptomic profiling. This blood-based diagnostic model provides non-invasive, scalable approach for glioma detection, recurrence surveillance, outcome prediction.

Robot-assisted hematoma puncture has seen significant development in primary hospitals across the country. Sino Plan software system is the core of the intelligent surgical robot, independently developed by Sinovation.We conducted a comparative study of imaging indicators, such as residual hematoma volume and hematoma clearance rate, as well as prognostic indicators, in patients who underwent hematoma puncture at our hospital over a 9-year period, before and after the introduction of Sino Plan.The results indicated that following the application of Sino Plan, the hematoma clearance rate was significantly enhanced, and the residual hematoma volume was markedly reduced. Regarding patient prognosis, there was no significant difference in GCS scores between the two groups, but the incidence of adverse prognostic events was lower in patients where Sino Plan was utilized.In conclusion, this 9-year retrospective analysis at our hospital reveals that Sino Plan offers distinct advantages. However, its application in certain special cases suggests that further improvements to the software are warranted to better meet the demands of more specific clinical scenarios.

Resuscitation in the oldest old at the end of life is associated with potential harm, raising concerns about misalignment with patients goals of care. This study aimed to elucidate changes in the use of resuscitation among the oldest old in Japan following the revision of the national guideline on end-of-life care which explicitly incorporates the concept of advance care planning. We conducted a repeated cross-sectional study using the National Database of Health Insurance Claims Open Data, including adults aged [≥]85 years, from April 2014 to March 2024. The annual number of resuscitation procedures per 100,000 individuals aged [≥]85 years was used as the measure of frequency. Resuscitation included closed-chest cardiopulmonary resuscitation (CPR) and endotracheal intubation. Interrupted time series analysis was used to examine changes following the 2018 revision of the national end-of-life care guideline. The frequencies of CPR and endotracheal intubation declined before 2018 (CPR: age 85-89, -68.4 [-87.9 to -48.8]; age [≥]90, -106.7 [-131.5 to -82.0]; intubation: age 85-89, -57.5 [-71.8 to -43.2]; age [≥]90, -69.5 [-80.7 to -58.3]), but the decline attenuated thereafter (CPR: age 85-89, +56.2 [28.0 to 84.5]; age [≥]90, +84.1 [50.7 to 117.6]; intubation: age 85-89, +36.6 [8.5 to 64.7]; age [≥]90, +38.3 [23.8 to 52.8]). These findings provide insight into the changes in resuscitation trends following policy interventions supporting end-of-life decision-making. Further studies are needed to better understand the mechanisms underlying this change.

Background: Community-acquired pneumonia (CAP) remains a major global health burden disproportionately affecting older adults and people with comorbidities, with Streptococcus pneumoniae as one of the leading bacterial causes in Europe. The Hungarian Occurrence and Burden of PnEumonia (Hungarian-HOPE) study examined the incidence, hospitalization rates, and mortality of CAP between 2016 and 2020 in Hungary. Methods: The National Health Insurance Fund database was used to identify adult CAP patients (all-cause) based on ICD-10 codes J10-18. Outcomes included CAP incidence, 0-15-day hospitalization, and 0-30-day mortality after hospitalization, stratified by age, sex, and comorbidities (chronic obstructive pulmonary disease [COPD], asthma, cardiovascular disease [CVD], and type 1 and 2 diabetes [T1DM, T2DM]). Risk maps visualized relative risk gradients across population strata. Results: During the pre-pandemic period (2016-2019), over 100,000 CAP cases and more than 50,000 hospitalizations were recorded annually. In 2020, recorded cases fell to approximately 98,000, while hospitalizations increased to 66,200. Hospitalization rates increased from 25.1% in 2016 to 29.1% in 2019, then increased to 43.1% in 2020. The 30-day mortality among hospitalized patients rose from 22.7% in 2016 to 23.6% in 2019. Incidence, hospitalization, and mortality all increased with age. Relative to healthy males aged 30-39 years, CAP risk escalated steeply in the [≥]80 years cohort (incidence 5-15-fold; hospitalization >3-fold; mortality 11-24-fold) and was further amplified by COPD, CVD, or T2DM, with a lesser effect for T1DM. Conclusions: The results highlight the substantial age- and comorbidity-driven CAP burden in Hungary and support prioritization of preventive strategies including pneumococcal vaccination for older adults and high-risk groups.

Purpose: To characterize peripheral immune alterations in treated birdshot uveitis (BU) patients using high-dimensional mass cytometry and multiplex serology. Design: Cohort study. Subjects: 36 BU patients on immunomodulatory treatment (IMT) and 31 healthy controls (HCs). Methods: Detailed ophthalmologic examinations were performed, and peripheral blood and serum samples were collected for immune profiling using mass cytometry and multiplex cytokine analysis. Main Outcome Measures: Imaging-based indicators of ocular inflammation; peripheral immune cell frequencies; serum cytokine levels. Results: Compared to HCs, BU patients showed increased frequencies of Th17, CD146+ T cells, intermediate effector/central memory T cells co-expressing CXCR3 and CCR4, CD56dim NK cells and elevated IL-18 levels. Patients were clinically stratified by an expert ophthalmologist into three disease activity groups: Inactive, Active (comprising combinations of surface retina, deep retina and choroid activity) and Burned-out. Inactive patients harbored more quiescent effector T cells, e.g. Tim-3+ Tc17-Tc22 intermediates and more CD8+ TSCM, potentially representing a resting pool of autoimmune T cells. Active patients exhibited increased in vivo activation of relevant T cells, with stronger HLA-DR, CD38 or PD-1 expression, and highest levels of CD56dim NK cells. Immune profiles were also linked to treatment subgroups: csDMARDs (conventional synthetic disease-modifying antirheumatic drugs) were associated with higher CD56bright NK frequencies, and absence of therapy showed elevated PD-1/SLAMF7 Tc17+1 and PD-1CD57 CD8 TEMRA cells. IL-6R blockade (tocilizumab) resulted in loss of IL-6R T-cells accompanied by increased SLAMF7 T cells, due to epitope masking. Conclusions: Peripheral CyTOF profiling anchored to thorough clinical stratification revealed disease activity-associated immune signatures and therapy-associated imprints in BU.

Biological aging is heterogeneous across organ systems, yet whether CT-derived abdominal aging provides prognostic value beyond routine clinical data and whether organ decomposition adds beyond a unified estimate remains untested. We developed and evaluated organ-specific and ensemble biological age models from radiomic features across five abdominal organs in 68,675 CT scans from 32,883 subjects, evaluated on alignment with chronological age of healthy subjects (nested cross validation: MAE=3.68 years, R^2=0.90). In sequential analyses restricted to adults aged 20-60 years which is the stratum of strongest BAG-disease association, ensemble biological age gaps provided incremental prognostic value beyond demographic covariates for all-cause disease and mortality (Delta C-index=0.141, 0.051) and beyond routine blood biomarkers (Delta C-index=0.048), confirming CT-derived aging captures structural information beyond laboratory markers. Organ-specific biological age added incremental prognostic value beyond ensemble selectively for focal diseases: cardiovascular (aorta, Delta C-index=0.091) and hepato-pancreatic (pancreas, Delta C-index=0.096). These findings establish a hierarchical organization of CT-derived biological aging, positioning routine CT as a source that adds prognostic value to existing clinical biomarkers.

Background: Frontotemporal dementia (FTD) lacks widely accessible disease-specific biomarkers. Optical coherence tomography (OCT) and OCT angiography (OCTA) may provide non-invasive measures of retinal changes associated with neurodegeneration. We conducted a systematic review and meta-analysis evaluating retinal biomarkers in FTD compared with Alzheimer disease (AD) and controls. Methods: A systematic search of PubMed and Embase was conducted through April 25, 2026 according to PRISMA guidelines. Studies evaluating OCT/OCTA biomarkers in FTD with comparator groups were included. Inverse weighted random-effects models, publication bias assessments, and meta-regressions were performed. Results: Ten studies involving 139 individuals with FTD, 87 with AD, 29 with mild cognitive impairment, 14 with TDP-43 proteinopathy, 5 with tauopathy, and 255 controls were included in the systematic review; five studies were eligible for meta-analysis. Compared with AD, individuals with FTD demonstrated significantly thinner retinal nerve fiber layer (RNFL) thickness (SMD = -0.61, 95% CI -0.98, -0.24). Compared with controls, individuals with FTD exhibited significantly thinner ganglion cell layer-inner plexiform layer (GCL-IPL) thickness (SMD = -0.55, 95% CI -1.02, -0.08), whereas pooled analyses across multiple retinal biomarkers were non-significant (SMD = -0.19, 95% CI -0.52, 0.14). RNFL thickness correlated negatively with female % in FTD and positively with age in both AD and controls. Conclusions: Individuals with FTD exhibit lower RNFL thickness than AD and lower GCL-IPL thickness than controls, suggesting retinal alterations may reflect neurodegeneration. However, larger longitudinal studies with standardized OCT/OCTA protocols are needed to determine the diagnostic and prognostic utility of retinal biomarkers in FTD

ABSTRACT OBJECTIVE: We performed a systematic review and meta-analysis (SRMA) of post-surgical outcomes, comparing chlorhexidine gluconate (CHG) versus povidone iodine (PI) for vaginal antisepsis of major gynecologic procedures. DATA SOURCES: Ovid Medline, Embase, Scopus, Embase, Cochrane, and Clinicaltrials.gov were searched between 1986 and December 2023, for studies comparing CHG with PI for vaginal antisepsis of major gynecologic operations. STUDY ELIGIBILITY CRITERIA: We included Randomized Controlled Trials (RCTs) and non-RCTs comparing CHG to PI for vaginal antisepsis of major gynecologic operations. The primary outcome was surgical site infections (SSIs) and the secondary outcome was urinary tract infections (UTIs) and vaginal irritation. METHODS: Summary estimates were calculated by fixed effects models when I2 [≤] 25% and by random effects models when I2 > 25%. Statistical analysis was performed using RevMan 5.4.1. The protocol for this systematic review was registered on PROSPERO (ID CRD42022378101). RESULTS: Nine studies met the inclusion criteria, four of which were randomized controlled trials (RCTs). 9538 patients were included, 4300 (45%) of whom were allocated to CHG and 5238 (55%) to PI. No statistically significant difference in SSI incidence was found for vaginal antisepsis with CHG versus PI in pooled analyses (n= 9538 patients; RR 1.20; 95% CI 0.92-1.57; I2 =0%). In contrast, a significantly higher risk of UTIs was observed for vaginal antisepsis with CHG than with PI (n=6061 patients; RR 1.48 95% CI 1.03-2.14; I2 = 0%). CONCLUSION: In our SRMA, there were no significant differences in SSI risk when either CHG or PI was utilized for antiseptic vaginal preparation. Interestingly, vaginal antisepsis with PI was associated with a lower incidence of post-operative UTIs following major gynecologic surgery. Our findings support current guidelines that form of vaginal antisepsis can be used for SSI prevention. They also suggest that PI may result in fewer postoperative UTIs but further randomized studies are needed to support these findings. Key words: surgical site infection, surgical wound infection, urinary tract infection, urogynecologic surgery, Chlorhexidine, Povidone Iodine, surgical antiseptic,

Background Artificial intelligence-enhanced electrocardiography (AI-ECG) enables scalable, low-cost cardiac dysfunction screening, but existing models are annotation-intensive and predominantly adult-derived, leaving paediatric generalizability uncertain. Paediatric cohorts exhibit highly variable cardiac morphology and function compared to adults, which may be useful for learning generalizable AI-ECG models. Methods We pretrained ECG-Fyler on a predominantly paediatric, all-age cohort at Boston Children's Hospital (1992-2023), annotated with a cardiology-specific coding system (Fyler codes), and evaluated it on assessments from echocardiography (echo) and cardiac magnetic resonance (CMR) studies. We validated on an external adult cohort from Columbia University Irving Medical Center. Performance was benchmarked against several AI-ECG foundation models by AUROC across age groups, lesion types, and limited-data scenarios. Findings The pretraining cohort comprised 782,138 ECGs from 255,271 patients (median age: 10.9 years, IQR: [2.8-16.8]). Internal evaluation included 178,495 ECG-echo pairs (median age: 10.9 [3.7-17.0]) and 8,584 ECG-CMR pairs (median age: 20.7 [15.6-29.6]). External validation included 82,543 ECG-echo pairs from adults (median age: 64.0 [52.0-74.0]). ECG-Fyler improved AUROC across biventricular dysfunction and dilation tasks, with the largest gains in low-data settings. In internal validation, ECG-Fyler detected low left ventricular ejection fraction (LVEF [&le;] 40%) from only 100 fine-tuning samples (AUROC: 0.80, 95% CI: [0.78-0.80]), outperforming other models (AUROC < 0.65) and improving with additional fine-tuning (AUROC: 0.94 [0.93-0.94]). Similar improvements were observed for CMR-derived LVEF, RVEF, and ventricular dilation. In external validation on adults, ECG-Fyler exhibited an AUROC of 0.83 (CI: [0.82-0.85]) for LVEF [&le;] 40%. After fine-tuning on less than 10% of external data, LVEF [&le;] 45% performance (AUROC: 0.87 [0.86-0.88]) outperformed a fully trained, site-specific prior model (AUROC: 0.85 [0.84-0.87]). Interpretation Pretraining on richly annotated, paediatric-dominant ECGs yields models that transfer efficiently across institutions and ages, supporting AI-ECG screening and triage when labels or imaging access are limited. Funding National Institutes of Health (R01LM012973); Kostin Innovation Fund, Boston Children's Hospital

The Epic Sepsis Model version 2 (ESMv2) is a prediction model embedded into the electronic medical record used to warn clinicians which hospitalized patients are at risk for sepsis. We conducted a retrospective cohort study of 31,951 hospitalizations of 25,760 patients to compare analyses conducted at the commonly used patient-level (where a maximum prediction prior to the onset of sepsis is used to measure performance) vs novel prediction-level (where each prediction is used to measure performance). Sepsis, defined by the Sepsis 3 criteria occurred during 1,049 hospitalizations (3.3%). Patient-level analyses suggested excellent discrimination AUC 0.86; [IQR 0.85, 0.87], whereas prediction-level analyses demonstrated lower performance AUC 0.62; [IQR 0.57, 0.65]. Low estimates of the positive predictive value (14.5% at the patient level vs 4% at the prediction level) imply a high number of false alerts. Common evaluation approaches may overstate the performance of dynamic prediction models and mislead clinical decision-making.

Background: Despite the success of combination antiretroviral therapy (cART), vascular comorbidities, including cerebrovascular disease, are more prominent in people living with HIV (PLWH) compared to people without HIV (PWOH). However, quantitative assessments of cerebrovascular morphometry and their associations with cognitive outcomes in the context of HIV are still limited. In this study, we explore this missing link. Methods: Magnetic Resonance Angiography (MRA) data, blood markers, and neurocognitive assessments were collected from 73 PWOH subjects (male: 57, female: 16; age: 53 {+/-} 16) and 99 PLWH subjects (male: 66, female: 30, age: 53 {+/-} 11). Vessel morphometric features were quantified using intraCranial Artery Feature Extraction (iCafe) to investigate associations between vessel morphometry, markers of monocytes, endothelial cell activation, and cognitive performance. Results: HIV status predicted a lower total number of branches ({beta} = -0.224, p = 0.001, d = -0.517) and shorter total distal length ({beta} = -0.173, p = 0.021, d = -0.370) with a moderate effect size. Total branch number was found to be negatively associated with plasma levels of monocyte markers (sCD14: r = -0.167, p = 0.033; sCD163: r = -0.157, p = 0.045) and positively correlated with white matter cerebral blood flow (r = 0.550; p [&le;] 0.05). HIV status was the strongest predictor of overall cognitive performance in ANCOVA model ({beta} = -0.219, p = 0.006, d = -0.453). Conclusions: Our results suggest that cognitive impairment in PLWH is associated with vessel morphology metrics. Monocyte immune activation may contribute to changes in vessel morphology.

Patients with primary immunodeficiency (PID) often face prolonged diagnostic delays and may increasingly turn to large language models (LLMs) to interpret their symptoms during this period. We evaluated whether an LLM could recognize PID from symptom descriptions derived from interviews with 21 PID patients. In a prior study, we showed that GPT-4o identified PID in 96% of cases when prompted with physician-written patient histories (Rider et al., JACI, 2024). Here, when prompted with symptom descriptions in patients' own words, GPT-5 identified PID in only 7 cases (33%), although it more broadly suggested immune system issues in 18 cases (81%). The gap between these findings indicates that LLMs are sensitive to the language and framing of symptom descriptions, performing substantially worse when patients describe their own symptoms in everyday language than when clinicians summarize patient histories in structured medical terms. This study underscores the need to carefully evaluate how LLMs are used in patient-facing applications.

Background Atrial fibrillation (AF) is a leading cause of stroke, cardiovascular morbidity, and mortality. Atrial myopathy, characterized by progressive metabolic, electrical, and structural changes, creates the arrhythmogenic substrate that drives AF. Defining the key drivers of atrial myopathic processes is essential for targeted therapies that can mitigate AF progression. Here we explore how reduced ERBB4 expression contributes to the development of left atrial myopathy. Methods We analyzed the Cleveland Clinic Biobank to compare left atrial ERBB4 levels in patients grouped by AF diagnosis. To investigate the impact of reduced ERBB4 levels on atrial tissue substrate, we created mouse models of cardiac-specific Erbb4 deficiency using Mlc2a (myosin light chain 2a)-Cre. Comprehensive physiological assessments were performed. Transcriptomic analyses of the left atrium were performed in an Erbb4 haploinsufficient mouse model and compared with human atrial datasets. Molecular validation of key dysregulated pathways was performed. Results We found that left atrial ERBB4 levels are reduced in patients with AF. Adult cardiomyocyte-specific Erbb4 heterozygous (Erbb4fl/+;Mlc2a-Cre) mice exhibited prolonged P-wave duration in the absence of ventricular dysfunction. Left atrial transcriptomic analysis in Erbb4 haploinsufficient mice showed upregulation of pathways related to fibrosis, apoptosis, and coagulation, and downregulation of pathways related to fatty acid metabolism and mitochondrial function, mirroring changes observed in pressure overload mouse models. A cross-species transcriptomic comparison revealed significant overlap between ERBB4-correlated gene expression and functional pathways in adult human atria and mice with Erbb4 haploinsufficiency. Validating the transcriptomic data, protein and functional assays demonstrated increased fibrosis, apoptosis, and oxidative stress in the mutant left atrial tissue. Conclusion Left atrial ERBB4 levels are reduced in AF patients. A mouse model of Erbb4 deficiency and human atrial transcriptomic analyses highlight a role for ERBB4 in supporting normal atrial metabolism while protecting against inflammation, apoptosis, and fibrosis.

Intro: Characteristics of the pulse wave transmitted through the carotid arteries are predictive of cognitive decline and cerebrovascular health in humans. This study aimed to identify risk factor trajectories in childhood, adolescence and early adulthood that are associated with forward compression wave intensity (FCWI) in the common carotid artery in adults aged 28 years. Methods: Systolic blood pressure (SBP), body mass index (BMI) and fasting blood glucose (FBG) measured at multiple time-points when participants were aged between 8-20 years were included in a trajectory analysis. At age 28 years, FCWI was measured in 402 (M=206, F=196) participants who underwent a Duplex ultrasound assessment of the common carotid artery. Statistical analysis assessed differences in FCWI between each trajectory group for males and females separately. Results: In males, four trajectory groups were identified for BMI, three for SBP, and two for FBG. In females, three trajectory groups were identified for BMI, SBP, and FG. In males, having higher BMI (P=0.006), SBP (P=0.021) and FBG (P=0.002) from ages 8-20 years was associated with greater FCWI at age 28 years. In females, no associations were found between FCWI at age 28-years and trajectory groups for BMI (P=0.185), SBP (P=0.289) or FBG (P=0.070). Conclusion: Having high BMI, SBP and FBG throughout childhood, adolescence and early adulthood was associated with higher FCWI in the carotid artery at age 28 years in males, but not females. This may have a direct impact on the etiology of cognitive decline and cerebrovascular disease in later life.

Lead is a toxic metal ubiquitous in our environment. While dramatic reductions in lead sources have paralleled equivalent decreases in lead-poisoning rates, chronic lead exposure remains a critical public health concern. Childhood lead exposure (at its lowest levels) is liked to changes in cognitive development but less is known about lead's effects on children's brain structure, especially as a result of in utero exposure. We measured prenatal and early-postnatal lead exposure in shed deciduous teeth of 448 9- and 10-year-old children (from 20 United States cities) and linked those lead levels to childhood brain structure, cognition/behavior, and neighborhood- and family-level socioeconomic characteristics. Here we show negative associations between tooth-lead levels and the thickness of the brain's cortex, particularly in regions linked to language processing. With increasing tooth-lead levels, children of lower-income (versus higher-income) families showed steeper declines in receptive vocabulary. Caregiver-reported behavioral problems exhibited similar associations. With in utero exposure linked to adverse neurodevelopmental outcomes (well before lead exposure and its risks are evaluated by healthcare professionals), prenatal screening of maternal lead levels/exposure, coupled with recommended strategies to reduce its placental transmission, may help reduce lead's effects on future generations.

Background: Conventional psychiatric screening instruments summarize symptoms within individual scales and prioritize cases with high single-instrument additive score severity. This design treats items as independent within instruments and ignores cross-instrument covariance structure, making it insensitive to respondents whose responses are distributed across multiple domains in unusual combinations that remain below threshold on every individual scale. Methods: We analyzed two cohorts spanning older and younger adults. Item prompts from depression, stress, anxiety, and sleep instruments were embedded into a shared semantic space using a pretrained sentence encoder. Principal component analysis of the item-prompt embeddings alone---with no use of respondent data at this stage---was used to construct a low-dimensional subspace retaining 80\% of variance in the item embedding matrix. Normalized participant responses were then projected into this subspace, with Jaccard-based stability analysis used as a check on dimensional robustness. Multivariate deviation from the cohort norm was quantified with Mahalanobis distance using Ledoit-Wolf covariance regularization. Candidate outliers were defined by the empirical 95th percentile of the cohort-specific distance distribution. To isolate response configurations not already captured by conventional single-instrument extreme-value logic, we excluded all outlier respondents who had endorsed any individual item at the maximum value of its Likert scale on any instrument. For the remaining outliers, anomalous components were backtracked to their original item loadings for interpretation. Results: In the older-adult Health and Retirement Study (HRS) cohort, principal component analysis of 27 item-prompt embeddings showed that a 10-dimensional subspace provided a stable representation of cross-instrument semantic structure. In the younger-adult Xinxiang cohort the corresponding stable solution was 16-dimensional. In each cohort, seven respondents remained as multivariate outliers despite falling below every single-instrument extreme-value threshold. These cases were not characterized by uniformly severe symptom scores but by unusual cross-domain response configurations that became visible only in the shared semantic covariance subspace. The response structure of the retained configurations differed across cohorts: older-adult cases more often involved weak endorsement of mood-labeled items alongside nonzero body- and sleep-related responses, whereas younger-adult cases more often involved incomplete response configurations spanning mood, sleep, stress, and self-harm-related items. Conclusions: A semantically aligned, auditable covariance subspace provides a practical tool for flagging unusual multivariate response configurations that single-instrument additive screening may not flag. The method is interpretable at the level of original item contributions. It should be understood as a hypothesis-generating screen for unusual response configurations requiring further clinical assessment, not as a diagnostic instrument. Outcome validity remains to be established by prospective study.

Hybrid mechanistic-statistical models offer interpretability and adaptability for short-term seasonal epidemic forecasting, but it remains unclear whether their accuracy depends more on increased biological complexity or on the assimilation of richer data. Using eight retrospective influenza seasons in North Carolina, we evaluate whether training on historical data and assimilating auxiliary emergency department (ED) visit data improves four-week-ahead hospital admission forecasts more than adding biological complexity (multi-subtype structure and cross-season immunity). Hierarchical Bayesian training on historical data improves accuracy by 22.4 % (95 % CI: 16.4-28.1 %), and inclusion of ED visit data yields a further 5.3 % (95 % CI: 3.0-7.6 %) improvement, whereas added biological complexity produces diminishing or null gains. We further observe a substitution effect in which ED visit data partially compensates for omitted biological structure. We deployed a simplified model variant in the 2025-2026 CDC FluSight Challenge and ranked among the top ensemble performers, supporting the robustness of Bayesian hierarchical training in real time. Together, these findings indicate that short-term forecast accuracy is driven more by historical learning and assimilating auxiliary signals than by biological fidelity, with implications for how forecasting systems should balance mechanistic complexity.