Paraneoplastic autoimmunity develops as consequences of immune reactions to cancer and exhibits a wide range of clinical manifestations. The autoimmune signs are often visible before the underlying malignancy is diagnosed, and a prompt diagnosis of paraneoplasia is crucial to enable early tumor detection. We characterized the immune responses underlying the severe mucocutaneous blistering disease paraneoplastic pemphigus. We used a two-step approach to proteome-wide autoantibody repertoire analysis and independent validation in patients with paraneoplastic pemphigus (n = 84) and non-paraneoplastic autoimmune blistering diseases (n = 103). Our findings reveal that paraneoplastic pemphigus features a broad repertoire of disease-specific autoantibodies that mainly target tissue-specific proteins in the skin and mucous membranes. Importantly, we identify SERPINB3 as a major autoantibody target with an expression pattern and clinical association suggesting a role in bronchiolitis obliterans. Autoantibody profiles are similar across neoplasias, except in thymoma patients, who additionally express multiple cytokine autoantibodies. Our findings reveal a disease-defining autoantibody repertoire in paraneoplastic pemphigus that corresponds with clinical manifestations and holds high potential for early cancer detection in patients with blistering disease.

Systematic profiling of plasma proteins in population studies offers a complementary approach to discovery of novel risk factors and may provide new insights into the causes of coronary heart disease. To explore relationships between the circulating proteome and coronary heart disease (CHD), we evaluated associations of 4780 plasma proteins with incident CHDin the Cardiovascular Health Study (CHS, N=2856,575CHD events) and replicated significant associations in the Atherosclerosis Risk in Communities Study (ARIC, N = 10456; 1375 events). We find that 11 proteins significantly associate with incident CHD after adjusting for risk factors; and eight significantly replicated in ARIC. Several proteins correlate with carotid intimal medial thickness and CHD associations are attenuated in participants without subclinical atherosclerosis. Macrophage metalloelastase (MMP12) is the strongest observed association (Hazard Ratio, 1.31; 95% Confidence Interval, 1.19-1.44). Mendelian randomization (MR) identifies a causal relationship between higher MMP12 and lower CHD (Odds Ratio, OR 0.94) and ischemic stroke (OR 0.90) risk, while reverse MR found that genetic propensity to CHD increased MMP12. Taken together, multivariable MR confirms a direct protective effect of higher plasma MMP12 on CHD risk and a genetic effect of atherosclerosis and CHD on elevating MMP12. Proteomic analyses reveal associations with incident CHD and genomic evidence suggests that therapeutic MMP12 inhibition may confer adverse cardiovascular effects.

Antiretroviral therapy (ART) in human immunodeficiency virus (HIV) markedly improved life expectancy in persons living with HIV (PLWH), but cardiac disease has emerged as the leading cause of death in this population. The prevalence of impaired diastolic function and heart failure with preserved ejection fraction (HFpEF) is higher among PLWH on ART. However, the specific role that HIV itself, and/or ART may have on the cardiomyocyte phenotype is unknown. We investigated modified molecular pathways in cardiomyocytes after exposure to serum from the same patients who were initially ART-naïve and then subsequently ART-treated. Rat cardiomyocytes were treated for 24 hours with serum obtained longitudinally from PLWH (N = 10) before and after being on ART for 6 months. Transcriptomic changes were determined by RNA sequencing. Measures of apoptosis, calcium handling, and extracellular matrix remodeling were analyzed using TUNEL assay and western blot. Here we show that exposure to serum from ART-naïve PLWH increases cardiomyocyte cell death. In contrast, exposure to serum obtained from the same PLWH after six months on ART results in altered expression of calcium-handling proteins and upregulation of profibrotic and extracellular matrix-related markers, indicating altered contraction and relaxation, and adverse cardiac remodeling. These findings demonstrate dysregulated molecular pathways in cardiomyocytes following exposure to untreated HIV serum versus ART-treated HIV serum from patients followed longitudinally. Altogether, these data suggest that HIV infection and ART contribute to changes seen in the cardiomyocyte phenotype and play complementary roles in the pathogenesis of diastolic dysfunction and HFpEF in PLWH.

BackgroundMental health disorders and metabolic dysfunction-associated steatotic liver disease (MASLD) represent substantial global public health challenges. The precise relationship between mental health parameters and MASLD development remains poorly characterized.MethodsUsing data from the UK Biobank cohort, we conducted a prospective cohort study to evaluate participants’ anxiety, depression, mania, and trauma exposure scores using standardized psychometric instruments. Metabolic signatures were derived through elastic net regularization coupled with Cox proportional hazards modeling. Mediation analyses quantified the proportion of mental health-MASLD associations attributable to metabolic pathway alterations.ResultsThe analytical cohort comprises 55,012 participants with trauma assessments, 15,318 with mania evaluations, 30,798 with depression metrics, and 17,596 with anxiety profiles. Multivariable-adjusted analyses reveal significant dose-response relationships between mental health burden and MASLD incidence: anxiety (HR = 1.13, 95%CI 1.08–1.18, P < 0.05), depression (HR = 1.06, 95%CI 1.03–1.10, P < 0.05), mania (HR = 1.15, 95%CI 1.06–1.24, P < 0.05), and trauma (HR = 1.22, 95%CI 1.11–1.34, P < 0.05). Metabolic analyses indicate that creatinine, glutamine, and the triglyceride fraction of very low-density lipoprotein (VLDL-triglyceride%) serve as key mediators in the pathway through which mental health influences MASLD incidence. The derived metabolic signature demonstrates significant mediation effects across all psychological domains (anxiety: 12.7%, depression: 15.7%, mania: 11.5%, trauma: 11.2%).ConclusionsThis large-scale cohort study establishes clinically significant mental health conditions as risk factors for MASLD development, with metabolic dysregulation serving as a partial mediator of this association. The identified metabolite panel, particularly perturbations in nitrogen metabolism and lipid partitioning, provides mechanistic insights into psychosomatic pathways influencing hepatic steatosis, suggesting potential targets for interdisciplinary intervention strategies.

Most noninvasive blood glucose technologies, especially wearable photoplethysmography devices, require multiple calibrations and are often limited to narrow cohorts such as unmedicated or mild cases. We assess whether a single pretest once per month can meet clinical accuracy while broadening applicability through cohort-specific models. We develop models for three groups: (i) individuals not using antidiabetic drugs, (ii) those using oral antidiabetic drugs only, and (iii) those using antidiabetic drugs in combination with other medications. Models are trained on cohort data with and without the monthly pretest and are then applied directly to personal testing without retraining. Inputs include dual-channel photoplethysmography signals and an inferred HbA1c (glycated hemoglobin) feature. Accuracy is summarized by mean absolute relative difference, clinical safety by the Parkes Error Grid, and improvements by a nonparametric rank-sum test. Here, we show that the best models using a single monthly pretest achieve mean absolute relative differences of 9.59, 12.23, and 16.40% for groups (i), (ii), and (iii), respectively. In the most complex group (iii), prediction errors are significantly lower than our earlier work according to the rank-sum test. The single-pretest models produce no clinically unacceptable readings on the Parkes Error Grid, likely due to dual-channel input and the inferred glycated-hemoglobin feature. A single monthly pretest enables accurate and clinically safe noninvasive glucose measurement across diverse patient groups. The approach operates without retraining or fine-tuning and can adapt to new users and devices through edge computing, supporting integration into current wearables for everyday diabetes management and public-health prevention.

BackgroundElectronic health records are increasingly used to conduct pregnancy-related research as pregnant women are under-represented in research. Creating a register of pregnancies by combining data from primary and secondary care will further facilitate research in pregnancy. This work describes the construction of an algorithm to create a unified pregnancy cohort in the QResearch database during the emergency phase of the COVID-19 pandemic.MethodsNational primary care records in the QResearch® database were linked to patient-level data from Hospital Episode Statistics (HES) datasets. Females aged 15-50 years with a pregnancy outcome recorded between 30 December 2020 and 30 September 2022 were included. Pregnancy (delivery/loss) episodes were identified and cohort demographics reported using a three-stage algorithm. Pregnancy start dates were derived using a combination of HES and primary care data, or individually estimated where no corresponding date could be identified.Results266,758 women with 279,027 pregnancies are captured in the register. 232,673 pregnancies (83.4%) are deliveries (99.5% livebirths and 0.5% stillbirths) and 46,354 (16.6%) pregnancies are pregnancy losses. Pregnancy losses are highest amongst those of Caribbean (23.1%; n = 781) ethnicity and lowest in those of Pakistani ethnicity (13.9%, n = 1,579). 82.4% of pregnancies are derived from HES maternity records, 10.6% from primary care records, 3.4% from HES Admissions, and 3.6% from HES Procedures.ConclusionThe construction of a pregnancy register in QResearch® offers a valuable resource for future research. Its methodology can be adapted to construct new cohorts over any period, providing a comprehensive resource on pregnancy outcomes and events.

Healthcare professionals experience high levels of burnout and chronic stress, which further jeopardizes their optimism and mental resilience. The study involved 175 health professionals (46 doctors, 56 nurses, 27 nursing assistants, 23 ward assistants, 23 paramedical workers) of the Sismanogleio General Hospital of Athens, aged 26-65. Participants were administered an electronic questionnaire, which included socio-demographic data and work-related information, the Revised Life Orientation Test (LOT-R) and the Connor-Davidson Resilience Scale (CD-RISK-25). The data analysis was conducted using SPSS, with Descriptive and Inferential Statistics methods. The results reveal moderate levels of mental resilience (Mean=65.23, Std. Dev.=15.44) and moderate levels of optimism (Mean=12.75, Std. Dev.=2.89) among participants. Health professionals' levels of optimism are positively correlated with their levels of mental resilience (rho = 0.208, p = 0.006). The levels of optimism and mental resilience do not differ according to gender, marital status, or years of work experience (p = 0.612, p = 0.458, p = 0.214, respectively), but differ according to age (p < 0.001). Health professionals aged 60+ show the highest levels of mental resilience, while paramedical workers demonstrate greater optimism compared to physicians. The development of targeted training and support programs aimed at strengthening optimism and mental resilience among healthcare professionals may be beneficial.

Infection by human T-cell lymphotropic virus type 1 (HTLV-1) affects millions of people worldwide and causes severe diseases. To date, no specific treatment is available for HTLV infection. The purpose of this study was to determine the impact of Dolutegravir use in reducing HTLV-1 proviral load (PVL) in HIV-HTLV1 coinfected subjects on stable antiretroviral therapy. In this cross-sectional study we quantified HTLV-1 PVL in HIV-HTLV1 coinfected patients and HTLV-1 mono-infected ones. We compared HTLV-1 proviral load across groups, adjusting for age and sex, antiretroviral therapy use and CD4/CD8 cells count. We used a propensity score derived from a regression model for Dolutegravir use and HTLV-1 PVL, that included covariates like age and antiretroviral therapy duration. Eighty-eight patients were included, 44 coinfected by HIV and HTLV-1 and 44 controls. Linear regression shows an association between Dolutegravir use and lower HTLV-1 proviral load values (p = 0.042). Participants using Dolutegravir are significantly more likely to have an HTLV-1 proviral load below the median (205 DNA copies/mm3) than those antiretroviral therapy -naïve (p = 0.003). In logistic regression, Dolutegravir use is significantly associated with undetectable HTLV-1 proviral load (<50 DNA copies/mm3, p = 0.015), and HTLV-1 proviral load lower than quartile 75 values (945 DNA copies/mm3, p = 0.021). Dolutegravir use is consistently associated with lower HTLV-1 proviral load in HIV-HTLV-1 coinfected patients. This indicates that Dolutegravir may be an effective treatment for HTLV-1 infection.

BackgroundAlthough a short cervix in the mid-trimester of pregnancy is one of the strongest predictors of preterm birth (i.e., parturition before 37 completed weeks), there is limited understanding of how the dynamics of cervical remodeling (i.e., changes in cervical length) leading up to labor and delivery can inform obstetrical risk.MethodsIn this study, latent growth curve analysis was applied to serial cervical length measurements across pregnancy (median per subject = 6; IQR = 3–8) to quantify characteristics of cervical change in a cohort of 5111 singleton pregnancies carried by Black American women.ResultsA conditional mediation model including nine common maternal risk factors of spontaneous preterm birth as exogenous predictors accounts for 26.5% of the variability in gestational duration. The collective evidence supports the conclusion that the effect of common maternal characteristics on spontaneous preterm birth is mediated through cervical length change. Specifically, previous preterm birth, pre-pregnancy BMI, parity, and previous abortion are shown to have unique influences on preterm birth risk that likely operate, in part, through linear changes in the cervix across pregnancy.ConclusionsThis study provides an account of the intermediary role of cervical dynamics in associations between known maternal risk factors and gestational age at delivery. Although these findings may not be generalizable to all populations, they have the potential to enhance screening efforts for women who are disproportionately affected by health disparities related to preterm birth.

Blood-based biomarkers hold promise as a minimally invasive tool for identifying early signs of Alzheimer's disease pathology and neurodegeneration. We investigated associations between plasma biomarkers of amyloid-beta, tau, neuroaxonal injury, and glial activation with cognitive performance among community-dwelling Hispanic/Latino adults in the United States. We analyzed cross-sectional data from 5730 adults aged 50 years and older (unweighted; mean [SD], 63.5 [8.2] years) in the Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA; 2016-2018). Plasma concentrations of amyloid-beta (Aβ42/40), phosphorylated tau-181 (pTau-181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were quantified (Quanterix Simoa HD-X) and log-transformed (ln). Cognitive performance was assessed across domain-specific scores (learning, memory, verbal fluency, and executive functioning/processing speed) used to calculate global cognitive performance. Survey-weighted linear regression models were used to examine associations between plasma biomarkers and cognitive performance, adjusting for sociodemographic, cardiometabolic, kidney, and APOE ε4 covariates. Here we show higher ln(pTau-181) and ln(NfL) are associated with lower global cognitive performance (bpTau-181 = -0.06; 95%CI = [-0.12;-0.01]; p = 0.022; bNfL = -0.07; 95%CI = [-0.12;-0.02]; p = 0.005). Lower ln(Aβ42/40) is associated with poorer verbal fluency, higher ln(pTau-181) is associated with poorer learning and memory, and higher ln(NfL) is associated with learning and executive functioning/processing speed. We find ln(GFAP) is not significantly associated with cognitive performance. Plasma biomarkers related to Alzheimer's disease pathophysiology and broader neurodegenerative processes are associated with cognitive performance among Hispanic/Latino adults. These findings highlight the potential utility of blood-based biomarkers for identifying early cognitive vulnerability in this population.