Journal of Internal Medicine

Background: This study investigates whether proteomic aging clocks (PACs) are associated with cerebral small vessel disease (CSVD). Methods: We included participants from two US community-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study and the Multi-Ethnic Study of Atherosclerosis (MESA) Study. These analyses leveraged PACs that were developed in ARIC using proteomics measured by SomaScan in midlife (Visit 2; mean age 56 y; n=1,486) and late-life (Visit 5; mean age 76 y; n=1,496), trained on chronological age. Proteomic age acceleration (PAA) was calculated as residuals from regressing PACs on chronological age. 3T brain MRI data were collected in late-life. We examined associations of PAA with log-transformed white matter hyperintensity (WMH) volume using linear regression and with the presence of microbleeds, and subcortical, lacunar, and cortical infarcts using logistic regression. Associations of PACs with WMH volume and microbleeds were tested in MESA using proteins measured at Exam 1 (mean age 57 y; n=932) and Exam 5 (mean age 66 y; n=934). All associations were quantified per 5-year increase in PAA. All models were adjusted for demographics and cardiovascular risk factors. Results: In ARIC, higher midlife PAA was associated with greater WMH volume (percent difference: 25% [95% CI: 13%, 39%]) and higher odds of subcortical infarcts (OR: 1.24 [1.02, 1.51]). Late-life PAA was associated with all CSVD markers: WMH volume (percent difference: 20% [8%, 34%]), cerebral microbleeds (OR: 1.40 [1.15, 1.69]), subcortical (OR: 1.80 [1.47, 2.22]), lacunar (OR: 1.80 [1.46, 2.23]), and cortical infarcts (OR: 1.39 [1.07, 1.82]). In MESA, higher late-life PAA was associated with greater WMH volume (28% [3%, 58%]) but not with microbleeds. Conclusion: Accelerated proteomic aging is associated with a higher prevalence of MRI markers of CSVD, most predominantly in late-life. Understanding this relationship may help stratify those at higher risk of CSVD at an early stage.

Background Cardiac MRI (CMR) is often utilized for patients with suspected cardiac amyloidosis (CA). However, data are lacking for use in patients with advanced renal dysfunction (ARD) (GFR<30 mL/min/1.73 m2, dialysis dependent, or renal transplant). This study evaluates the utility of CMR for diagnosis of CA in this population. Methods Patients with ARD who underwent CMR in a 3T field for suspicion of CA between 2010 and 2024 at our institution were included. A diagnosis of CA was made if any of the following were present a)?PYP scintigraphy grade ? 2, b) positive endomyocardial biopsy, or c) positive extracardiac biopsy with clinical features of CA. Two CMR-trained physicians independently assessed T1 relaxation time, ECV, Ti scout, LGE, and overall likelihood of CA. Results Out of the 65 patients included 14 (22%) had a diagnosis of CA. Although T1 time [1352 (1276-1428) ms] and ECV (40.3% +/- 9.1%) were elevated across the cohort, they were significantly higher in patients with CA (p<0.001 for both). Both ECV and T1 time reliably predicted CA (AUC of 0.87 and 0.88 respectively). ECV of ?45% had 75% sensitivity and 80% specificity for CA. A T1 time ? 1390 ms had 75% sensitivity and 85% specificity for CA. LGE was prevalent and was seen in 86% and 84% patients with and without CA respectively. Of the 31 patients deemed to be unlikely CA by a CMR reader, 6% had CA. However, of the 34 patients read as possible/likely CA, only 35% had confirmed CA. Conclusions In this understudied population of ARD, CMR parametric mapping exhibits high negative predictive value (NPV) for CA and improved positive predictive value (PPV) when higher cutoffs are used for T1 time and ECV. CMR reader overall impression exhibits high NPV but low PPV for CA.

Rationale: Sepsis is a life-threatening syndrome causing significant morbidity and mortality especially in the aging population. Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition of clonal expansion of hematopoietic stem cells harboring somatic mutations associated with increased incidence of chronic illness and all-cause mortality. Objective: Evaluate the association of pre-illness CHIP with mortality and morbidity in patients admitted to the ICU with sepsis. Methods: We performed a retrospective study using a de-identified electronic health record linked with a DNA biorepository. We identified adult patients with sepsis who had DNA collected prior to ICU admission. We tested the association between CHIP status, determined from whole-genome sequencing, and ICU mortality, organ support-free days, and long-term survival adjusting for age, sex, race and Sequential Organ Failure Assessment (SOFA) score on ICU admission. Measurements and Main Results: Pre-illness CHIP was associated with increased sepsis mortality (OR = 1.54, 95% CI 1.13 to 2.07, P = 0.005) and fewer days alive and free of organ support (-1.7 days, 95% CI -3.2 to -0.2, P = 0.028) after adjusting for age, sex, race, and SOFA score. In sepsis survivors, CHIP was also associated with increased long-term mortality after discharge (HR 1.40, 95% CI 1.01 to 1.93, P = 0.041). Conclusions: Pre-illness CHIP was independently associated with increased mortality and morbidity in critically-ill adults with sepsis. These findings suggest that CHIP is a risk factor for sepsis severity. Elucidating the mechanism underlying this association could uncover new therapeutic interventions for sepsis.

BackgroundPleuroparenchymal fibroelastosis (PPFE) is a rare, fibrotic lung disease with poor prognosis, usually affecting adults which most commonly occurs idiopathically. Biallelic pathogenic variants in DGUOK cause mitochondrial DNA (mtDNA) depletion syndrome, predominantly affecting infants with severe hepatic and neurological symptoms. Detailed description of pulmonary manifestations with late-onset presentation have not been reported. MethodsWe describe nine patients with PPFE and DGUOK-associated mitochondriopathy. Clinical, radiological, histopathological, and genetic data were systematically collected from all patients. Functional studies, single nucleus RNA sequencing (snRNAseq), immunofluorescence staining, transmission electron microscopy and respiratory chain enzyme activity assays were conducted on patient-derived fibroblasts, muscle or lung tissues. mtDNA content quantification was performed on whole genome sequencing (WGS) data. ResultsAll patients (ages 5-36) presented with progressive dyspnea, weight loss and some with spontaneous pneumothoraces. Chest computed tomography and lung biopsies showed features of PPFE. Biallelic pathogenic DGUOK variants were identified in all patients, seven of them carry an unreported intronic variant leading to mtDNA depletion. snRNAseq of lung tissue from four pediatric patients identified Aberrant Basaloid cells and intermediate cells as their precursor localized at the fibrotic edge. Mitochondrial alterations were identified by electron microscopy. ConclusionPPFE in children and young adults is associated with DGUOK-related mitochondriopathy. For the first time, we demonstrate Aberrant Basaloid cells in pediatric fibrotic lung tissue. Since pulmonary involvement may be underrecognized or misinterpreted and the clinical presentation may not always be typical of a mitochondriopathy, we recommend genetic testing in all patients with PPFE of unknown origin.

Background: Itch in systemic sclerosis (SSc) is thought to be most significant in early disease, but no longitudinal studies have examined itch course. We estimated itch presence and severity from SSc disease onset, accounting for participant age and time since onset at each assessment. Methods: People with SSc from the multinational Scleroderma Patient-centred Intervention Network Cohort completed past-week itch severity assessments (0 to 10 numerical rating scale) at enrolment and longitudinally at 3-month intervals. To estimate itch probability (score > 0) and, if present, itch severity, we used two-stage mixed effects models with basis splines to address non-linearity. The primary predictor was age at each assessment, partitioned into age at non-Raynaud phenomenon symptom onset and time since onset. We estimated prevalence and severity for onset ages of 20, 30, 40, 50 and 60 years and, for each onset age, at 2 years, 3 years, 4 years, 5 years, 7 years, and 5-year intervals 10 years to 35 years post-onset. Findings: We included 2173 participants with 19 733 itch assessments (mean [standard deviation] 9.1 [6.9] assessments). 1896 of 2173 (87.3%) participants were women. Mean age at enrolment was 54.7 (SD 12.7) years. 873 (40.2%) participants had diffuse cutaneous SSc. Predicted itch probability was between 35.0% (95% CI 31.8% to 38.5%) and 36.8% (95% CI 33.3% to 40.4%) at all onset age and disease duration combinations. Mean itch severity, when present, was moderate, between 4.1 (95% CI 4.1 to 4.1) and 4.4 (95% CI 4.3 to 4.4), for all age and duration combinations. Interpretation: Itch prevalence and mean severity were stable across onset ages and over time within onset ages. Findings suggest that itch is common in SSc and not as closely related to disease duration as previously thought. Research is needed to elucidate itch pathophysiology and identify effective management strategies.

Objectives: Juvenile systemic lupus erythematosus (JSLE) and juvenile dermatomyositis (JDM) are systemic autoimmune rheumatic diseases (RMDs) with childhood-onset associated with increased risk of damage accumulation and cardiovascular disease (CVD) over the life course. Methods: Damage associated with JSLE and JDM has been assessed using validated outcome measures in a longitudinal single-centre cohort study with long-term follow-up, involving data collected both retrospectively and prospectively. Descriptive statistics, sensitivity and regression analyses have been used to evaluate predictors of damage and CVD-risk. Results: We assessed comparatively a JSLE cohort (n=76), with a mean age of 24.3 +/- 4.2 years and a JDM cohort (n=79) with a mean 20.1 +/-5.0 years (p<0.001), with matched duration of follow-up (10.0 +/- 4.2 vs. 11.0 +/- 5.1, respectively, p=0.68). Traditional CVD-risk factors, including hypertension (p=0.02), dyslipidaemia (p=0.0005), and higher total cholesterol (p=0.01) and LDL-cholesterol (p=0.02) levels at the last assessment were higher in JSLE vs. JDM. Over the disease course, 39 (51.3%) AYA with JSLE vs. 47 (59.4%) AYA with JDM accumulated damage (p=0.307), which was independently predicted by the body mass index in both cohorts (p=0.038 and p=0.026, respectively). The PDAY score was the only tool able to stratify AYA based on CVD-risk (median = 5 (4-13) points in JSLE vs. 0 (0-3) points in JDM, p=0.0001), as all the adult CVD-risk scores were very low in both cohorts. Conclusions: This is the first comparative evaluation of JSLE vs. JDM in adulthood, which highlighted increased damage burden and CVD-risk in JSLE that warrants further investigation.

Background Group A streptococcus (GAS) infections have been associated with neuropsychiatric disorders in epidemiologic studies and animal models, but data in US health care populations are limited. GAS is also associated with autoimmune sequelae, including acute rheumatic fever (ARF)/Sydenham chorea (SC), poststreptococcal reactive arthritis (PSRA), poststreptococcal glomerulonephritis (PSGN), and guttate psoriasis (GP). Epstein-Barr virus (EBV) has been linked to systemic lupus erythematosus (SLE) and multiple sclerosis (MS) and the complexity of these associations parallels that of GAS-associated conditions, providing a useful comparison. Objectives 1) Assess the association between a positive GAS test and incident neuropsychiatric diagnoses within 1 year in a large US health care database. 2) Assess the validity of the same database in detecting well-established disease associations while avoiding false associations. Design, Setting, Participants Retrospective cohort study using TriNetX data from US health care organizations. Patients with positive or negative tests were propensity score-matched (GAS cohort n=178,301; EBV cohort n=64,854). Patients with documented neuropsychiatric diagnoses prior to testing were excluded. To approximate a primary care population, inclusion required at least one well-visit. Exposures Positive vs negative GAS test; positive vs negative EBV test (separate cohorts). Main Outcomes and Validations Main outcome: incident neuropsychiatric diagnoses within 1 year of GAS testing. Positive control outcomes: ARF/SC, PSRA, PSGN, and GP (for GAS cohort); SLE and MS (for EBV cohort). Negative control outcomes: conditions without known association with GAS. Results After matching, a positive GAS test was associated with attention-deficit/hyperactivity disorder (ADHD) (RR: 1.09; 95% CI: 1.03-1.15). Among established poststreptococcal conditions, only GP was associated with prior GAS (RR: 1.75; 95% CI: 1.06-2.89). Case counts were insufficient to evaluate ARF/SC, PSRA, and PSGN. Negative control outcomes showed no association. In the EBV cohort, no association was observed with SLE, and MS showed a decreased risk. Conclusions and Relevance A positive GAS test was associated with ADHD but not with other neuropsychiatric disorders. The database detected poststreptococcal GP but did not identify most established postinfectious autoimmune associations, likely reflecting rarity, heterogeneity, and diagnostic complexity. These findings begin to describe the range of real-world health care databases to evaluate postinfectious neuropsychiatric risk.

Background: immune dysregulation underlies cardiovascular risk excess in systemic autoimmune diseases, such as rheumatoid arthritis (RA) and Sjogren disease (SjD). However, exact mediators are unknown. Regulatory autoantibodies targeting G protein coupled receptors, including CXCR3, have emerged as modulators of immune and vascular homeostasis, but their role in autoimmunity remains ill defined. Our aim was to evaluate antiCXCR3 levels in systemic autoimmunity and their potential value as biomarkers. Methods: antiCXCR3 IgG serum levels were quantified in early RA (n=84), clinically suspect arthralgia (n=12), and controls (n=65). Established RA (n=103) and SjD (n=44) were recruited for validation. Atherosclerosis was assessed by carotid ultrasound. Cytokines were measured by multiplex immunoassays. Cardiometabolic related proteins were evaluated using high-throughput targeted proteomics. Publicly available datasets were used for validation. Results: antiCXCR3 antibodies were significantly reduced in early RA and arthralgia compared with controls, independently of disease activity, autoantibodies, or systemic inflammation. This finding was confirmed in validation cohorts. AntiCXCR3 were negatively associated with good therapeutic outcomes upon csDMARD at 6 and 12 months. Lower anti-CXCR3 levels were independently associated with atherosclerosis occurrence and extent across conditions. Incorporating antiCXCR3 into mSCORE improved risk stratification. AntiCXCR3 were related to proteomic signatures linked to immune activation and to apoptosis, chemotaxis, and cell adhesion in an atherosclerosis dependent manner. Transcriptomic analyses indicated compartment specific CXCR3 dysregulation. Conclusion: reduced antiCXCR3 antibodies represent a shared hallmark bridging systemic autoimmunity and atherosclerosis burden, shaping our understanding on the regulatory role of antibodies at the vascular immune interface. Clinical translation of anti-CXCR3 antibodies hold promise to improve risk stratification.

Purpose: To evaluate whether chest radiograph-derived age acceleration is associated with incident lung cancer and whether it improves discrimination beyond established lung cancer risk factors. Materials and Methods: This retrospective analysis used prospectively collected data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Baseline digitized chest radiographs from the initial screening year were analyzed using a previously validated deep learning model that estimates chest radiograph-derived age (Xp-age). Age acceleration (AgeAccel) was defined as the residual of Xp-age after calibration to chronological age using a regression model from the development dataset. A 1-year landmark design excluded participants diagnosed with lung cancer or censored within 1 year of baseline. Associations with incident lung cancer were assessed using multivariable Cox proportional-hazards models adjusted for prespecified demographic and clinical predictors, including smoking variables used in the PLCOm2012 risk prediction model. Discrimination was evaluated using the concordance index and 6-year time-dependent area under the receiver-operating-characteristic curve. Results: The analytic cohort included 23,213 participants (mean age, 62.5 years); 790 developed incident lung cancer after the landmark (mean follow-up, 16.7 years). Higher AgeAccel was associated with increased lung cancer incidence (hazard ratio, 1.10 per 1-SD increase; 95% confidence interval: 1.03- 1.17); however, addition of AgeAccel to an established risk factor model resulted in minimal change in discrimination (C-index, 0.840 vs. 0.839; time-dependent AUC at 6 years, 0.852 vs. 0.852). Attribution maps emphasized the aortic arch/mediastinal region with similar spatial patterns across smoking and lung cancer strata. Conclusion: Chest radiograph-derived age acceleration was independently associated with future lung cancer incidence.

Background: Elevated lipoprotein(a) [Lp(a)] is a known risk factor for several cardiovascular-related diseases established from multiple genetic and observational studies. However, the underlying mechanisms mediating the effects of Lp(a) levels on cardiovascular disease risk and major adverse cardiovascular events (MACE) are unclear. The aim of this study was to identify proteins downstream of Lp(a) using mendelian randomization (MR) - a genetic causal inference approach. Methods: A two-sample MR was performed by initially identifying Lp(a) genetic instruments based on data from genome wide association studies (GWAS) of Lp(a) blood concentrations. These instruments were then tested for association with proteins from proteomic pQTL data (Olink from UK Biobank, 2940 proteins and SomaScan from deCODE, 4907 proteins). Results: A total of 521 proteins associated with Lp(a) were identified. Using pathway enrichment analysis, the following MACE-relevant pathways were identified comprising a total of 91 Lp(a) downstream proteins: oxidized phospholipid-related, chemotaxis of immune cells and endothelial cell activation, pro-inflammatory monocyte activation, neutrophil activity, coagulation, and lipid metabolism. Conclusion: The results suggest that the influence of Lp(a) treatments is primarily through modifying inflammation rather than lipid-lowering, thus providing insight into the mechanistic framework which mediates the effects of elevated Lp(a) on atherosclerotic cardiovascular disease.

Sickle cell disease (SCD) is associated with substantial cardiovascular morbidity, but echocardiographic data from Latin American populations remain scarce. We aimed to characterise the structural, functional, and haemodynamic echocardiographic profile of adults with SCD attending a tertiary referral centre in Cali, Colombia. We conducted an observational, cross-sectional study based on systematic review of medical records and transthoracic echocardiography reports of consecutive adult patients ([&ge;]18 years) with confirmed SCD evaluated between January 2022 and December 2024. Patients with complex congenital heart disease, severe valvular disease of unrelated aetiology, pregnancy, or echocardiograms of insufficient quality were excluded. Of 669 patients screened, 57 met inclusion criteria. Reporting followed STROBE recommendations. The median age was 24 years (interquartile range [IQR] 21-32) and 59.6% were female; the SS genotype was the most frequent (76.4%) and 71.4% were on hydroxyurea. Median haemoglobin was 10.2 g/dL (IQR 9.3-11.4) and median NT-proBNP 491 pg/mL (IQR 98-1290). Most patients had preserved left ventricular dimensions and systolic function (median ejection fraction 63%, IQR 57-66.5; mean global longitudinal strain -18.9% {+/-} 2.9). Right ventricular function was preserved (mean tricuspid annular plane systolic excursion 25.4 {+/-} 4.6 mm). Left ventricular geometry was normal in 42.1%, with concentric remodelling in 24.6%, concentric hypertrophy in 21.1%, and eccentric hypertrophy in 12.3%. Diastolic function was normal in 71.4%. Valvular disease, when present, was predominantly mild. Tricuspid regurgitation velocity exceeded 2.5 m/s in 29.8% of patients and exceeded 3.0 m/s in 10.5%, identifying a substantial subgroup at intermediate-to-high probability of pulmonary hypertension. In this Colombian cohort of relatively young adults with SCD, cardiac structure and biventricular function were largely preserved, but nearly one-third of patients had echocardiographic findings suggestive of pulmonary hypertension. These findings support the routine use of transthoracic echocardiography as an accessible tool for early cardiovascular risk stratification in adults with SCD in low- and middle-income settings.

Abstract Background Spontaneous coronary artery dissection (SCAD) is a well-recognised cause of acute coronary syndrome particularly among women without conventional cardiovascular risk factors. Increasing evidence indicates a genetic contribution; however, the underlying genetic architecture of SCAD remains insufficiently understood. Objective The aim of this study was to assess the prevalence of rare variants in previously reported SCAD associated genes and to explore the potential presence of novel genetic alterations in well-characterised Swedish patients with SCAD. Methods The study comprised 201 patients enrolled in SweSCAD, a national project examining the clinical characteristics, aetiology, and outcomes of SCAD. All individuals had a confirmed diagnosis based on invasive coronary angiography. Comprehensive exome sequencing was performed to identify rare variants contributing to disease susceptibility. Results Genetic variants that have been associated with SCAD according to current clinical genetics practice for variant reporting were identified in approximately 4 % of patients. In addition, rare potentially relevant variants were detected in almost 60 % of patients in genes associated with vascular integrity and vascular remodelling. Conclusion This study supports SCAD as a genetically complex arteriopathy, driven by rare high?impact variants together with broader polygenic susceptibility. Variants in collagen, vascular extracellular matrix, and oestrogen?responsive pathways provide biologically plausible links to female?predominant disease. Although the diagnostic yield of clearly actionable variants is modest, these findings support broader genomic evaluation beyond overt syndromic presentations and highlight the need for larger integrative genomic and functional studies to refine risk stratification and management.

Objective: To investigate overall and neighborhood socioeconomic deprivation moderated associations between glycemic control and brain structure in youth. Research Design and Methods: This was a cross-sectional study of 705 healthy 11-12-year-olds across 21 study sites in the United States. Data was obtained from the Adolescent Brain and Cognitive Development (ABCD) Study(R). Glycemic control was assessed using hemoglobin A1c (HbA1c), brain structure was evaluated via MRI, and neighborhood deprivation was measured with the Area Deprivation Index (ADI). Mixed effects models were used to examine relationships between HbA1c, brain structure and ADI controlling for sociodemographic covariates. Stratified analysis was performed by tertiles of ADI. Results: Higher HbA1c was associated with lower mean cortical thickness (CT) and smaller total cortical gray matter volume (GMV). One percent increase in HbA1c corresponded to a 0.024 mm reduction in mean CT and a 9,611 mm3 reduction in total cortical GMV. Regionally, higher HbA1c was associated with thinner cortex and smaller gray matter volumes primarily in the frontal, cingulate and occipital areas. There was a significant interaction of HbA1c and ADI on total GMV, which was driven by significant negative associations of HbA1c with total GMV in the high ADI group, and medium ADI group, but not the low ADI group. Conclusions: Mild elevations in HbA1c, even within the non-diabetic range, are linked to early brain structural changes, particularly in youth from neighborhoods with greater socioeconomic deprivation. These results highlight the interplay between metabolic health and neighborhood deprivation on shaping brain development in youth.

ImportanceAge-related eye diseases, such as cataract, glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy (DR), are leading causes of irreversible vision loss globally. Chronic inflammation is a shared pathogenic pathway, but the role of systemic inflammatory drivers like clonal hematopoiesis of indeterminate potential (CHIP) is unknown. ObjectiveTo investigate the association of CHIP, including its major genetic subtypes and clone sizes, with the risk of four major age-related eye diseases. Design, Setting, and ParticipantsThis was a prospective cohort study conducted using data from the UK Biobank, a large-scale, population-based cohort. A total of 436,469 participants free of the four eye diseases at baseline were included in the analysis. Data were collected from 2006 to 2010, with follow-up extending to March 2022. ExposuresCHIP status was ascertained from whole-exome sequencing data, defined by the presence of a somatic driver mutation with a variant allele fraction of 2% or greater. Main Outcomes and MeasuresThe primary outcomes were incident cases of cataract, glaucoma, AMD, and DR, identified through linked electronic health records. Associations were assessed using multivariable Cox proportional hazards regression models. ResultsOf 436,469 participants (mean [SD] age, 56.4 [8.1] years; 54.5% women), 14,110 (3.2%) had CHIP. Over a median follow-up of 13.1 years, CHIP was significantly associated with an increased risk of incident cataract (Hazard Ratio [HR], 1.08; 95% CI, 1.03-1.14), AMD (HR, 1.12; 95% CI, 1.04-1.21), and DR (HR, 1.41; 95% CI, 1.20-1.64). No significant association was found with glaucoma (HR, 1.08; 95% CI, 0.99-1.17). The risk for AMD was primarily associated with smaller clones (VAF <10%), while the risk for DR was highest with non-DNMT3A mutations. Systemic inflammation, particularly neutrophil count, partially mediated the associations. Conclusions and RelevanceIn this study, CHIP was independently associated with a higher risk of developing cataract, AMD, and DR, but not glaucoma. These findings establish a link between hematopoietic somatic mutations and the pathogenesis of several major age-related eye diseases, suggesting that CHIP-driven inflammation is a potential target for risk stratification and prevention. Key PointsO_ST_ABSQuestionC_ST_ABSIs clonal hematopoiesis of indeterminate potential (CHIP) associated with the risk of major age-related eye diseases? FindingsIn this cohort study of 436,469 participants, CHIP was associated with an increased risk of incident cataract (HR, 1.08; 95% CI, 1.03-1.14), age-related macular degeneration (HR, 1.12; 95% CI, 1.04-1.21), and diabetic retinopathy (HR, 1.41; 95% CI, 1.20-1.64), but not glaucoma. MeaningThese findings identify CHIP as an independent, non-ocular risk factor for cataract, AMD, and diabetic retinopathy, suggesting that systemic inflammation driven by CHIP contributes to the pathogenesis of these conditions and may represent a novel target for preventive strategies.

BackgroundAcute basilar artery occlusion (BAO) causes devastating strokes. Despite the benefit of endovascular treatment, the optimal management remains sometimes controversial, such as for patients with mild deficits, and would benefit from robust prognostic tools. Given the dense white matter networks within the posterior fossa, we tested whether quantifying disconnections from acute diffusion-weighted imaging (DWI) could improve outcome prediction and responders to recanalization compared with conventional metrics. MethodsWe conducted a secondary analysis from a prospective multicenter stroke registry, including consecutive patients (2017-2024) with BAO and admission MRI. Ultra-high-resolution diffusion MRI was acquired in healthy participants to build normative tractograms with optimized posterior fossa quality. Patient infarcts delineated on DWI were projected onto these tractograms to estimate disconnected fiber volume. The primary outcome was 90-day modified Rankin Scale (mRS) 0-3 vs 4-6. Predictive performance of disconnected fiber volume was compared with baseline NIHSS, infarct volume, and posterior circulation ASPECTS (pc-ASPECTS) using logistic regressions and areas under receiver operating characteristic curves (AUC). Ordinal regressions tested associations across the full mRS spectrum, stratified by recanalization status. Analyses were repeated in patients with NIHSS [&le;]10. ResultsAmong 201 patients (median age 70; NIHSS 10), 97 (48.3%) had poor outcome. Despite small median infarct volume (4.75 mL), disconnected fiber volume was substantial (median 25.15 mL). Disconnected fiber volume achieved an AUC of 0.84, outperforming NIHSS (0.67; p<0.0001), infarct volume (0.75; p=0.00059), and pc-ASPECTS (0.76; p=0.0127). Low disconnected fiber volume predicted better outcomes across the full mRS (OR=0.12 [95% CI, 0.065-0.204]) and greater benefit from successful recanalization (OR=0.33 [95% CI, 0.15-0.70]). In patients with NIHSS [&le;]10 (n=102), disconnected fiber volume remained the strongest predictor (AUC=0.83). ConclusionsDisconnected fiber volume derived indirectly is a robust prognostic marker of BAO outcomes that outperforms conventional predictors and may support future treatment decisions. Registrationhttps://clinicaltrials.gov - NCT03776877.

Background. Patients with heart failure and reduced ejection fraction (HFrEF) commonly show signs of systemic inflammation. Interleukin-1 (IL-1) is a pro-inflammatory cytokine, known to modulate cardiac function. We aimed to determine the effects of treatment with anakinra, recombinant IL-1 receptor antagonist (IL-1Ra), on plasma IL-1Ra levels. Methods. We measured IL-1Ra levels at baseline and longest available follow-up to 24 weeks in 63 patients (44 males, 40 self-identified Black-Americans) with recent hospitalization for HFrEF, and systemic inflammation (C reactive protein [CRP] levels >2 mg/L) who were assigned to anakinra (N=42 [66.7%]) or placebo (N=21 [33.3%]) as part of the REDHART2 clinical trial (NCT0014686). Cardiorespiratory fitness was measured as peak oxygen consumption (peak VO2). Results. Baseline plasma IL-1Ra levels were 380 pg/ml (290 to 1046). On-treatment IL-1Ra levels were significantly higher in the patients treated with anakinra vs placebo (3,994 pg/ml [3,372 to 5,000] vs 492 pg/ml [304 to 1370], P<0.001). The longest available follow-up was 6 weeks in 10 patients (15.9%), 12 weeks in 12 patients (19%) and 24 weeks in 41 patients (65.1%). On-treatment IL-1Ra levels and interval change in IL-1Ra showed a modest inverse correlation with on-treatment CRP levels (R=-0.269, P=0.033 and R=-0.355, P=0.004, respectively) and no statistically significant correlations with peak VO2 values (P>0.05). Conclusions. Patients with recently decompensated HFrEF and systemic inflammation treated with recombinant IL-1Ra, anakinra, have a significant several-fold increase in plasma IL-1Ra levels. On-treatment IL-1Ra levels however show only a modest correlation with CRP levels and not with peak VO2.

Background Hyperlipidemia is a major risk factor for cardiovascular disease and is increasingly linked to depression, which is associated with adverse cardiovascular prognosis. As proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are increasingly used for lipid lowering, their neuropsychiatric safety profile compared with established therapies remains uncertain. Objectives This study aimed to compare the risk of incident depression associated with initiation of PCSK9 inhibitor therapy vs statin therapy among adults with hyperlipidemia. Methods In this population-based cohort study, we emulated a target trial using a new-user active-comparator design and real-world data from the TriNetX research network from July 1, 2020, to June 30, 2025. Adults with hyperlipidemia who newly initiated PCSK9 inhibitors or statins were included. The exposure was initiation of PCSK9 inhibitor therapy versus statin therapy. Propensity score matching was performed, yielding 17,805 patients in each group. The primary outcome was incident depression. Cumulative incidence was estimated using the Kaplan-Meier method, and hazard ratios (HRs) with 95% confidence intervals (Cis) were estimated using Cox proportional hazards models. Results Among 35 610 propensity score-matched patients, the mean age was 65.4 (10.6) years and 46.7% were female. During a mean follow-up of 35.0 (21.2) months, incident depression occurred in 546 patients (3.1%) initiating PCSK9 inhibitors and 981 patients (5.5%) initiating statins. The 5-year cumulative incidence of depression was 5.84% for PCSK9 inhibitor initiators and 7.91% for statin initiators. PCSK9 inhibitor initiation was associated with a lower risk of incident depression (HR, 0.74; 95% CI, 0.67-0.82), corresponding to a 5-year number needed to treat of 46. The association was observed for major depressive disorder (HR, 0.71; 95% CI, 0.63-0.80) but not for dysthymic disorder or adjustment disorder. Consistent associations were observed across prespecified subgroups and sensitivity analyses, and the lower depression risk associated with PCSK9 inhibitor initiation remained regardless of comparator statin intensity or lipophilicity. Conclusions In this real-world target trial emulation, initiation of PCSK9 inhibitor therapy was associated with a lower risk of incident depression compared with statin therapy among adults with hyperlipidemia. Further prospective studies are warranted to confirm these findings and clarify underlying mechanisms.

Background: SARS-CoV-2 infection is an established prothrombotic trigger, yet the population-level temporal relationship between circulating viral activity and pulmonary embolism (PE) remains poorly characterized. We aimed to evaluate the short-term association between respiratory viral activity and PE hospitalizations, accounting for specific temporal lags. Methods: We conducted a population-level time-series analysis of incident PE hospitalizations in Ontario, Canada, from 2011 to 2024. Using distributed lag non-linear models, we assessed the association between standardized weekly activity levels of SARS-CoV-2, influenza A/B, and respiratory syncytial virus (RSV) and PE risk over a 5-week lag period. Relative risks (RR) per standard deviation (SD) increase in viral activity were estimated via negative binomial regression using cross-basis terms to account for both exposure-response and lag-response non-linearities. Models were adjusted for Fourier seasonal terms and secular trends. Findings: Among 70,670 incident PE cases identified between 2011 and 2024, SARS-CoV-2 activity demonstrated a significant temporal association with PE. A cumulative RR increase of 20% per SD in SARS-CoV-2 activity was observed over the five weeks following exposure (RR 1.20; 95% CI 1.05-1.37). The risk followed a distinct delay trajectory: weekly cumulative RRs peaked at week 3 (RR 1.21; 95% CI 1.01-1.45). For the 2020-2024 period, influenza A also showed an association peaking at week 3 without statistical significance (RR 1.17; 95% CI 0.95-1.45). Interpretation: Increased population-level SARS-CoV-2 activity is associated with a heightened risk of PE, peaking at approximately the third week. This delayed peak suggests a protracted thrombo-inflammatory window, likely driven by sustained endothelial injury. These findings highlight the vascular burden of COVID-19 and suggest that infection prevention measures, including vaccination, may provide significant downstream protection against thromboembolic disease.

Introduction Lung cancer is rare before age 45, and its inherited genetic basis remains poorly defined. Methods We performed whole-genome sequencing in 171 predominantly young-onset lung cancer patients and integrated these data with whole-exome sequencing from six major lung cancer consortia, yielding 9,065 patients. After quality control, analyses focused on 6,545 individuals of European ancestry, the largest ancestral group. We compared the prevalence of rare pathogenic and likely pathogenic (P/LP) germline variants between 186 young-onset (age <45 years) and 6,359 older patients at gene and gene-set levels using Fisher's exact test, stratified by histology, sex, and smoking status. Polygenic risk scores (PRS) derived from common variants were also evaluated. Results Young-onset patients carried a higher burden of rare germline P/LP variants in DNA damage response (DDR) genes (including BRIP1, ERCC6, MSH5), and in cilia-related genes, notably GPR161. At the pathway level, DDR genes were significantly enriched (OR=1.66, p=0.007), with the strongest signal in the Fanconi Anemia pathway and among females (OR=1.96, p=0.01). Enrichment was also observed in inborn errors of immunity pathways, with strongest signals in antibody deficiency and the complement system genes. Young-onset patients additionally exhibited higher lung cancer PRS. Conclusion Young-onset lung cancer exhibits a distinct germline genetic architecture, characterized by enrichment of rare P/LP variants in DDR, cilia-related, and immune pathways, and an elevated lung cancer PRS. These findings support a greater role for inherited susceptibility in early-onset disease and have implications for risk stratification, earlier screening, and precision prevention.

BackgroundTBX4 variants are a recognised cause of paediatric pulmonary hypertension (PH), often associated with interstitial lung disease (ILD). Evidence for ILD-directed therapy in this group is lacking. MethodsWe conducted a retrospective study of children ([&le;]18 years) with TBX4-associated PH at a national centre (2001-2025). ILD was defined using ChILD-EU criteria. Patients treated with pulsed intravenous methylprednisolone were assessed for response using ChILD-EU categories. Secondary outcomes included respiratory severity score (RSS), functional class (FC), echocardiographic measures, and NT-proBNP. ResultsOf 21 children, 11 (52%) had ILD; 9 received corticosteroids. Median age at treatment was 0.8 years. A clear or best response occurred in 7/9 (78%). RSS improved in 6/9 (p=0.02), with all children on respiratory support showing partial or complete weaning. Functional class improved in all with FC III/IV at baseline (p=0.02). Right ventricular function improved (TAPSE z-score +1.65, p=0.04), and elevated NT-proBNP normalised. Key clinical milestones included ECMO weaning, transplant delisting, and discontinuation of prostacyclin therapy. No significant adverse effects were observed. Untreated children showed no early improvement. ConclusionsCorticosteroids were associated with meaningful improvements in respiratory and PH outcomes in TBX4-associated PH with ILD. Prospective evaluation is warranted.