Journal of Internal Medicine

IntroductionPneumonia is a common source of sepsis and carries significant morbidity and mortality. Prior research suggests patients with severe mental illness may receive disparate care and experience worse outcomes from infectious and cardiovascular conditions. Whether mental illness influences the radiographic presentation of pneumonia-related sepsis, which can guide antimicrobial selection and clinical decision making, remains poorly-understood. MethodsThis retrospective study examined chest imaging findings in 202 adult septic patients with respiratory source infection presenting to a large tertiary care emergency department between December 2017 and December 2019. Patients were stratified by the presence (n = 51, 25.2%) or absence (n = 151, 74.8%) of a comorbid mental illness, defined broadly to include neurocognitive, mood, personality, psychotic, and substance use disorders. Radiographic findings, including parenchymal abnormalities, pleural effusions, and laterality, were systematically abstracted from the medical record and compared between groups using Chi-squared testing. ResultsPatients with mental illness were more likely to have at least one radiographic finding (84% vs. 74%), though this difference did not reach statistical significance (p = 0.14). The average number of findings per patient was nearly identical between groups (3.14 vs. 3.12, p = 0.38), and no individual radiographic feature differed significantly between cohorts. DiscussionThese findings suggest that, contrary to our hypothesis, mental illness may not be associated with the radiographic appearance of pneumonia in septic patients. Larger, diagnosis-specific studies are needed to evaluate whether specific psychiatric subgroups exhibit distinct imaging patterns.

BackgroundAntiphospholipid syndrome (APS) complicating pregnancy carries significant obstetric morbidity. Secondary APS, arising in the context of systemic autoimmune disease, may confer worse outcomes than primary APS due to additional inflammatory and immunological mechanisms. This study aimed to compare pregnancy outcomes between autoimmune rheumatic disease-associated secondary APS and primary APS managed at a quaternary care hospital in Chennai. MethodsA retrospective observational study analysed 82 pregnancies (secondary APS n=46; primary APS n=36) managed between January 2025 and March 2026. Outcomes including live birth rate, miscarriage, fetal death, preterm birth, pre-eclampsia, and intrauterine growth restriction (IUGR) were compared using chi-square test, Fisher exact test, and independent t-test. Multivariable logistic regression identified independent predictors of adverse outcomes. ResultsLive birth rate was significantly lower in secondary APS compared to primary APS (69.6% vs 86.1%; p=0.048). Triple antiphospholipid antibody positivity was more prevalent in secondary APS (47.8% vs 25.0%; p=0.032). On multivariable analysis, secondary APS (aOR 2.71; 95% CI 1.08-6.81; p=0.033), triple positivity (aOR 3.45; 95% CI 1.39-8.57; p=0.007), and lupus anticoagulant (aOR 2.62; 95% CI 1.01-6.76; p=0.047) independently predicted adverse outcomes. Hydroxychloroquine (aOR 0.39; p=0.038) and combination aspirin plus low-molecular-weight heparin (aOR 0.31; p=0.019) were independently protective. ConclusionSecondary APS is associated with significantly worse pregnancy outcomes than primary APS. Triple antiphospholipid positivity and lupus anticoagulant independently increase obstetric risk. Hydroxychloroquine and combination antithrombotic therapy significantly improve live birth rates. Early rheumatology referral and multidisciplinary obstetric management are essential.

ImportanceCardiovascular disease (CVD) is a major cause of morbidity/mortality in juvenile-onset systemic lupus erythematosus (JSLE), yet no reliable tools exist to stratify CVD-risk. ObjectiveTo identify serum biomarkers associated with atherosclerosis progression and response to atorvastatin. Design/SettingWe used data/samples from a sub-cohort of the APPLE trial (2009) which investigated atorvastatin vs. placebo to reduce atherosclerosis progression in JSLE, measured by change in carotid intima-media thickness (CIMT), and conducted a baseline autoantibody diagnostic-accuracy biomarker study. Participants/ExposureAPPLE trial participants (randomized 1:1 to atorvastatin vs. placebo) with matched baseline serum samples and stratified based on 36-month CIMT progression were included in the analysis. Main Outcomes and MeasuresBaseline serum autoantibodies were profiled using a functional proteomic platform (Sengenics, N=94). Empirical Bayes moderated t-test and Receiver Operating Characteristic (ROC) based logistic regression were applied to identify autoantibody signatures predictive of high vs. low atherosclerosis progression. ResultsNinety-four children and young people with JSLE (age mean [SD] =15.3 [2.4] years; 73 [78%] female, 8 [8.5%] Asian, 23 [24.5%] Black, 43 [45.7%] White, and 20 [21.3%] Other) were evaluated. Autoantibody levels against six novel autoantigens (STK24, RAD23B, HDAC4, STAT4, SEPTIN9, NFIA) classified high vs. low CIMT progression in the placebo arm (combined AUC 0.87, 95% CI -0.75 to 0.96). In the atorvastatin arm, autoantibodies to eight autoantigens (ABI1, ATP5B, CSNK2A2, NRIP3, PRKAR1A, PDK4, BATF, NUDT2), distinguished the statin responders vs. non-responders (combined AUC 0.96, 95% CI -0.88 to 1). An additional 27-autoantibody signature predicted response/partial response to atorvastatin (AUC 0.88, 95% CI - 0.76 to 0.97). Protein-protein interaction analysis identified endothelial disruption and lipid infiltration as key atherosclerosis mechanisms in atorvastatin non-responders. Combining the autoantibody prediction models with disease parameters and a metabolic signature did not increase model performance in either placebo (AUC 0.81, 95% CI - 0.68 to 0.94 vs. 0.87, 95% CI -0.75 to 0.96) or sttin arms (AUC 0.84, 95% CI -0.73 to 0.95 vs. 0.88, 95% CI -0.76 to 0.97). Conclusions and RelevanceThis study identified novel autoantibody signatures for atherosclerosis progression and statin response in JSLE, with potential utility for precision medicine approaches for CVD-risk management. Key PointsO_ST_ABSQuestionC_ST_ABSCan functional proteomic analyses identify autoantibody signatures predictive of atherosclerosis progression and response to statin treatment in children and young people with juvenile-onset systemic lupus erythematosus? FindingsUsing baseline samples from the APPLE trial (1:1 RCT of atorvastatin vs placebo), we identified novel autoantibody profiles that accurately distinguished individuals with high versus low carotid intima-media thickness progression over three years in both placebo (AUC 0.87, 95% CI-0.75 to 0.96) and atorvastatin groups (AUC 0.96, 95% CI-0.88 to 1). MeaningAutoantibody signatures show strong potential for early risk stratification and for identifying those most likely to benefit from statin therapy.

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.

RationaleSepsis 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. ObjectiveEvaluate the association of pre-illness CHIP with mortality and morbidity in patients admitted to the ICU with sepsis. MethodsWe 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 ResultsPre-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). ConclusionsPre-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.

The causes of severe neuropsychiatric deteriorations among patients with previously stable autism spectrum disorder (ASD) are poorly understood and present substantial challenges for care. We aimed to characterize the prevalence of autoimmune and inflammatory conditions and markers, as well as musculoskeletal findings, among youth with ASD experiencing a suspected post-infectious neuropsychiatric deterioration. The Stanford Immune Behavioral Health (IBH) Clinic is a specialty program for youth with neuropsychiatric deteriorations that are suspected to be post-infectious (non-psychosocial). We report findings for 43 consecutive patients with ASD (70% male [30 of 43]) evaluated in the IBH Clinic. The average (SD) age at clinical presentation was 12.0 (4.0) years. Juvenile arthritis was diagnosed in 15 patients (35%), predominantly enthesitis-related arthritis (ERA) and psoriatic arthritis (PsA). Seven patients had ultrasonographic evidence of joint effusions and/or synovitis without meeting juvenile idiopathic arthritis (JIA) criteria. Autoimmune conditions other than arthritis were observed in 9 patients (21%). The mean (SD) age at arthritis and other autoimmune condition diagnoses were 16.2 (5.5) and 12.7 (4.9) years, respectively. We observe markers of immune activation during neuropsychiatric deteriorations in over half of patients (60% [26 of 43]), including markers of autoimmunity (33% [12 of 36]), complement activation (41% [13 of 32]), immune dysregulation/inflammation (11% [4 of 37]), and vasculopathy (30% [13 of 43]). One-third (37% [16 of 43]) demonstrated two or more markers. These data underscore the importance of targeted immune evaluation--including musculoskeletal imaging and inflammatory marker screening--in ASD patients who have had a suspected post-infectious behavioral regression. Lay SummaryIn this cohort study of 43 patients with autism spectrum disorder (ASD) and suspected post-infectious deteriorations, more than half had laboratory markers of immune activation (using a limited panel), one-third had joint inflammation (confirmed by ultrasound), and additional autoimmune conditions were observed in 21%. From this, we conclude that patients with ASD who experience a suspected post-infectious neuropsychiatric deterioration may have underlying inflammation which may contribute to neuropsychiatric and behavioral regressions, highlighting the importance of immunologic and rheumatologic evaluation in clinical assessment.

ABSTRACT/SUMMARYPulmonary arteriovenous malformations (PAVMs) larger than 4mm in size are estimated to affect 38 per 100,000 individuals [95% confidence intervals 18-76]. They provide an anatomical right-to-left shunt such that each heartbeat, a proportion of the cardiac output bypasses the pulmonary capillary bed, preventing essential processing functions such as gas exchange and filtration of blood-borne emboli. Although large cohort series were published in earlier decades, more recent data series have been scant. To support modern educational platforms, here we report features of 1149 consecutive patients with imaging-proven PAVMs, reviewed at a single UK centre between 1984-2026, including 813 (71%) with clinical and/or genetically confirmed hereditary haemorrhagic telangiectasia (HHT). The median age was 47y, and 735 (64%) were female. We report 4348 oxygen saturation measurements at presentation and follow-up, and 810 pulmonary artery pressure (PAP) measurements made at angiography prior to treatment of PAVMs by embolisation. Together, these confirm that there is no risk of hypoxic pulmonary hypertension, with PAP measurements higher in patients with higher SaO2. Massive haemoptysis or haemothorax occurred in 18 patients [0.009, 0.023], of which 7/18 [95% CI 0.01, 0.64] events were pregnancy-associated. Ischaemic strokes affected 125 patients [0.09, 0.13], brain abscess 107 patients [0.08, 0.11] patients, and haemorrhagic strokes 29 patients [0.02, 0.03] patients. These data will inform design of future work to evaluate aetiologies, associations and implications for clinical practice.

Background: Before transcatheter aortic valve replacement (TAVR), patients with severe aortic valve stenosis are at an increased risk of developing fluid volume overload and heart failure, which is associated with subsequent adverse outcomes after TAVR. Purpose: To quantify fluid volume status as whole-body fast-exchange extracellular volume (FE-ECV) in patients undergoing TAVR compared to healthy reference values using photon-counting CT (PCCT). Methods: Consecutive patients referred for TAVR and healthy living kidney donor candidates, respectively, underwent PCCT including the pelvis. FE-ECV (mL) was quantified using venous hematocrit, injected iodinated contrast concentration and volume, and blood iodine concentration and urinary bladder excreted iodine mass quantified in iodine map regions of interest from the inferior vena cava and covering the urinary bladder, acquired at one time point 6-10 minutes after intravenous iodinated contrast administration. Results: The study included 156 subjects (healthy: n=51, age 47{+/-}9 years, 55% female; TAVR: n=105, age 78{+/-}6 years, 39% female). In healthy subjects, FE-ECV was 160{+/-}22 mL/kg lean body mass (LBM), 95% limits 116-204 mL/kg LBM, and was independent of age, sex, contrast agent type, and scan delay time after contrast injection (p>0.66 for all). Compared to healthy subjects, FE-ECV in patients referred for TAVR was higher (174{+/-}34 mL/kg LBM, p=0.01), with 19 patients (18%) exceeding the normal range. Conclusion: One in five patients referred for TAVR demonstrated increased FE-ECV, revealing a substantial prevalence of fluid overload detectable by single-time point late-phase PCCT iodine mapping.

Background: Anemia is an established marker of cardiovascular disease severity and risk which leads to elevations in resting myocardial blood flow (MBF) and impaired myocardial flow reserve (MFR) in patients without obstructive coronary artery disease (CAD). Anemia can potentially be detected opportunistically from blood pool density changes on computed tomography (CT) imaging. Objectives: We evaluated relationships between chamber density measurements with hemoglobin, positron emission tomography (PET) findings, and cardiovascular events. Methods: We included 33460 patients from 13 sites in the REFINE-PET who underwent PET and 24368 patients undergoing lung cancer screening chest CT. A deep learning model segmented cardiac chambers from CT images, then quantified chamber density. We evaluated the relationship between chamber density measures with resting MBF and MFR, as well as associations with death or myocardial infarction (MI). Results: We included a total of 57,828 patients. A higher density in myocardium compared to left ventricle blood pool was associated with reduced MFR (adjusted odds ratio 3.02 per SD increase, 95% confidence interval[CI] 2.72 - 3.38) and an increased risk of death or MI in (adjusted hazard ratio[HR] 1.38 per SD increase, 95% CI 1.26-1.51). Having myocardial density higher than blood pool density was also associated with cardiovascular death in patients undergoing low-dose chest CT (adjusted HR 1.73, 95% CI 1.20-2.52). Conclusions: In a large multimodality dataset, lower cardiac chamber density is associated with impaired MFR and independently associated with cardiovascular events. These biomarkers can be automatically extracted from CT to provide physiologic insights and potentially guide patient care.

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.

Clonal hematopoiesis of indeterminate potential (CHIP) represents the age-related expansion of hematopoietic stem cells with preleukemic mutations. However, its association with all-cause and cause-specific mortality has not been well characterized in older adults. We aimed to evaluate whether CHIP is associated with all-cause and cause-specific mortality in a population of older women in the United States. Our study included 6,704 participants in the Women?s Health Initiative Long Life Study (WHI-LLS) without hematologic malignancy. The co-primary exposures were any CHIP (variant allele frequency [VAF] [&ge;] 2%) and large CHIP (VAF [&ge;] 10%), and the primary outcome was all-cause mortality. Multivariable-adjusted Cox proportional hazards models tested the associations of CHIP and CHIP subtypes with all-cause and cause-specific mortality. Any CHIP and large CHIP were independently associated with all-cause mortality, with multivariable-adjusted hazard ratios (aHRs) of 1.12 (95% confidence interval [CI] 1.04-1.21; P = 0.003) and 1.28 (95% CI 1.15-1.43; P < 0.001), respectively. In gene-specific analyses, non-DNMT3A CHIP was associated with all-cause mortality (aHR: 1.22 [95% CI: 1.12-1.34], P < 0.001), while DNMT3A CHIP was not (aHR: 1.07 [95% CI: 0.98-1.18], P = 0.13). Furthermore, large CHIP was associated with cardiovascular (aHR: 1.29 [95% CI: 1.08-1.55], P = 0.006), cancer (aHR: 1.49 [95% CI: 1.11-2.02], P = 0.009), and neurologic (aHR: 1.40 [95% CI: 1.07-1.84], P = 0.02) death. In this cohort of older women, CHIP, particularly large clones and non-DNMT3A CHIP, was associated with all-cause and cause-specific mortality. These findings suggest that clonal size and subtype may differentially influence mortality risk.

Background: Alpha-1 antitrypsin deficiency (AATD) caused by the PI*ZZ mutation (Glu342Lys) results in hepatic accumulation of misfolded AAT-Z protein and reduced circulating AAT levels, leading to progressive liver disease and emphysema. Gene correction therapy represents a potentially curative approach by directly correcting the underlying genetic defect. We report the first case of successful hepatic gene correction with early histological and functional assessment. Methods/Case presentation: We report the case of a 66-year-old male patient with PI*ZZ AATD who underwent gene correction therapy within the YOLT-202 phase I/Ia clinical trial (clinical trial.gov ID NCT07193615). Ten weeks post treatment a liver biopsy was performed to re-evaluate pre-existing F2 liver fibrosis as measured by elastography before entering the study. Serum samples allowed functional assessment of the AAT-mediated elastase inhibition. Results: Liver biopsy did not show signs of hepatic inflammation and demonstrated 54% (Sanger) and 57% (Illumina) gene correction rate of the PI*ZZ variant on the DNA level with no bystander edits or off-target effects. Following a transient elevation of transaminases during the early post-treatment period, liver enzymes normalized. Monthly serum AAT measurements demonstrated biologically active and stable therapeutic levels throughout follow-up. Conclusions: This case demonstrates efficient and precise hepatic gene correction without concerning histological alterations and with substantial improvement of functional parameters, supporting the feasibility and safety of gene editing approaches for AATD.

BackgroundGroup 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. Objectives1) 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, ParticipantsRetrospective 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. ExposuresPositive vs negative GAS test; positive vs negative EBV test (separate cohorts). Main Outcomes and ValidationsMain 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. ResultsAfter 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 RelevanceA 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 and aimsCurrent FH VCEP specifications of ACMG/AMP guidelines for familial hypercholesterolemia (FH) variant interpretation assign a higher evidence weight to functional data obtained with flow cytometry than microscopy assays, due to lack of existing evidence. This restricts the use of microscopy-derived functional data for variant classification. We aimed to systematically compare functional data of LDLR variants obtained by high-content microscopy and flow cytometry to determine their concordance and assess whether microscopy-based assays could support a higher evidence level. MethodsFifty LDLR variants with available flow cytometry and high-content microscopy data were compared for LDL uptake activity, including 21 newly characterized variants by microscopy in this study. Variants were grouped by FH VCEP functional thresholds (<70% activity, abnormal function; >90% activity, normal function) and results were integrated with UK Biobank data to assess associations with lipid traits. ResultsFirst, we validated our scalable microscopy assay with FH VCEP-classified control variants. Then we compared functional activity measured by microscopy and flow cytometry assays for 50 variants, which showed significant correlation (r = 0.66, p<0.0001) and a close average agreement (Bland-Altman bias = -0.05). Applying FH VCEP functional classification thresholds yielded broadly consistent classification in both methods, with minor shifts among categories. Integration with UK Biobank data showed that carriers of variants with reduced LDLR activity (<70% and <50%) had higher LDL-C, total cholesterol and ApoB levels compared to those with normal activity (>90%) for both microscopy and flow cytometry assays, with more pronounced differences observed at the <50% LDLR activity threshold. ConclusionHigh-content microscopy provides reliable and scalable measurements of LDLR function, showing high concordance with flow cytometry and consistent associations with lipid phenotypes. These findings support reconsideration of the evidence weight assigned to validated microscopy assays within FH VCEP variant classification frameworks, namely to Strong (Level 1).

Background. Tethered cord syndrome (TCS) is classically associated with a low-lying conus medullaris, yet many surgically treated children have a normally positioned conus (occult TCS). Large-scale normative data on conus position in children, and the diagnostic value of quantitative conus assessment, are limited. Purpose. To establish a large-cohort reference distribution for conus medullaris termination level in children, to quantify conus position in children surgically treated for presumed (occult) TCS, and to test whether automated conus segmentation and radiomics can distinguish TCS from normal. Materials and Methods. In this retrospective single-center study, conus termination level was extracted from structured radiology reports of consecutive pediatric lumbosacral MRI examinations and encoded numerically (L1 = 1, L2 = 2, etc.). Children surgically treated for tethered cord were identified by linkage to an operative registry (name and date of birth) and restricted to preoperative examinations. A deep-learning model (nnU-Net) was trained for conus segmentation on axial T2-weighted images. IBSI-compliant radiomic features were extracted; reproducibility was assessed by intra- and inter-observer intraclass correlation (ICC). A case-control radiomics analysis used batch-only ComBat harmonization and cross-validated L1-penalized logistic regression; discrimination was compared with conus level by paired bootstrap. Results. Among 9,808 examinations with a parseable conus level (98.5% of reports; parser validated against dual blinded annotation, 99.4% agreement, weighted kappa 0.946), the conus terminated in the L1 region in 85.7% and the L2 region in 14.3% of the reference cohort (postoperative examinations excluded, n = 9,655); a low-lying conus (>=L3) occurred in only 0.05% (5/9,655), and remained rare (0.14%, 14/9,808) including operated examinations (median L1; mean 1.13 +/- 0.33). A slightly more cephalad position was seen with increasing age (negligible correlation). Among 475 preoperative children surgically treated for tethered cord, 99.6% had a normally positioned conus (<=L2) and only 0.4% were low-lying. Automated conus segmentation achieved a held-out Dice of 0.85. Conus radiomics likewise did not distinguish TCS from controls (equivalence-tested null; full segmentation/radiomics pipeline reported in the companion methodological paper). Conclusion. In children, the conus medullaris terminates at L1-L2 in more than 99% of cases and is normally positioned in virtually all children surgically treated for TCS. Within the conus, neither position nor texture (radiomics) identifies tethered cord; whether the filum terminale carries a diagnostic signal was not tested here.

BackgroundElevated 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. MethodsA 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). ResultsA 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. ConclusionThe 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.

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.

Background: The importance of lactate trajectory during the first day of cardiogenic shock is increasingly recognized. We aimed to assess the association between admission-day lactate trajectory and in-hospital mortality, and to identify same-day interventions predictive of lactate clearance. Methods: We analyzed adult patients admitted with cardiogenic shock between October 2015 and June 2023, using the Vizient(R) Clinical Data Base. Early lactate clearance was defined as lactate <2.5 mmol/L by the end of the admission day. We used multivariable logistic regression to assess the association between lactate change and in-hospital mortality, and to identify interventions associated with lactate clearance. Results: Among 40,434 patients with cardiogenic shock, 30.1% achieved same-day lactate normalization, which was associated with lower in-hospital mortality (aOR 0.51; 95% CI 0.48-0.54). Lactate change showed the greatest prognostic importance, with observed mortality exceeding 80% among those with lactate increase >5 mmol/L regardless of baseline values. After adjustment, lactate change showed a positive exponential relationship with mortality, with aORs ranging from 0.25 (95% CI 0.23-0.27) for a -10 mmol/L change to 3.99 (95% CI 3.58-4.40) for a +10 mmol/L change. The intervention most strongly associated with early lactate clearance was pulmonary artery catheter (PAC; aOR 1.28 [95% CI 1.19-1.37]). Conclusions: Nearly 1 in 3 patients with cardiogenic shock achieved early lactate clearance, which was associated with lower mortality. The magnitude of lactate change had profound prognostic implications regardless of the initial value. Among day 1 interventions, PAC use had the strongest association with lactate clearance.

Purpose: Polypharmacy is highly prevalent among critically ill patients, yet it's independent impact on intensive care unit (ICU) outcomes in sepsis remains critically unexplored. We aimed to evaluate whether pre-admission polypharmacy independently predicts ICU mortality and provides incremental prognostic value using the medication reconciliation module of the MIMIC-IV-ED linked database. Materials and Methods: We conducted a retrospective cohort study of 3,347 adults admitted to the ICU who met Sepsis-3 criteria. Pre-admission polypharmacy was categorized as none (0-4), standard (5-9), or high (>=10 medications). Multivariable logistic regression, propensity score matching, and reclassification analyses (NRI/IDI) were performed. The primary outcome was in-hospital ICU mortality. Results: High polypharmacy was present in 58.9% of patients. Crude ICU mortality increased sequentially: 18.5% (none), 26.0% (standard), and 27.5% (high; p < 0.001). After multivariable adjustment, high polypharmacy independently predicted in-hospital ICU mortality (aOR 1.45, 95% CI (1.10-1.91)), and 28-day mortality (aOR 1.47). Drug-class analysis identified statins as significantly protective (aOR 0.56), whereas RAS blockers combined with diuretics increased acute kidney injury risk (aOR 1.49). Propensity matching confirmed the primary mortality association (matched aOR 1.28). Conclusions: By utilizing the ED medication reconciliation table, this study proves high polypharmacy represents a distinct 'pharmacologic frailty', independent of acute severity. Available instantly at triage, this zero-latency metric provides significant early prognostic value (SOFA NRI = 0.24) and identifies actionable high-risk interactions (e.g., RAS blockers plus diuretics) for immediate, targeted pharmacist-led intervention upon ICU admission.