Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination.

During the SARS-CoV-2 pandemic, novel and traditional vaccine strategies have been deployed globally. We investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including third-dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. We analyzed human lymph nodes after infection or mRNA vaccination for correlates of serological differences. Antibody breadth against viral variants is lower after infection compared with all vaccines evaluated but improves over several months. Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens. In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases. SARS-CoV-2 antibody specificity, breadth, and maturation are affected by imprinting from exposure history and distinct histological and antigenic contexts in infection compared with vaccination.

Spheromers reveal robust T cell responses to the Pfizer/BioNTech vaccine and attenuated peripheral CD8+ T cell responses post SARS-CoV-2 infection.

T cells are a critical component of the response to SARS-CoV-2, but their kinetics after infection and vaccination are insufficiently understood. Using "spheromer" peptide-MHC multimer reagents, we analyzed healthy subjects receiving two doses of the Pfizer/BioNTech BNT162b2 vaccine. Vaccination resulted in robust spike-specific T cell responses for the dominant CD4+ (HLA-DRB1∗15:01/S191) and CD8+ (HLA-A∗02/S691) T cell epitopes. Antigen-specific CD4+ and CD8+ T cell responses were asynchronous, with the peak CD4+ T cell responses occurring 1 week post the second vaccination (boost), whereas CD8+ T cells peaked 2 weeks later. These peripheral T cell responses were elevated compared with COVID-19 patients. We also found that previous SARS-CoV-2 infection resulted in decreased CD8+ T cell activation and expansion, suggesting that previous infection can influence the T cell response to vaccination.

A hormone complex of FABP4 and nucleoside kinases regulates islet function.

The liberation of energy stores from adipocytes is critical to support survival in times of energy deficit; however, uncontrolled or chronic lipolysis associated with insulin resistance and/or insulin insufficiency disrupts metabolic homeostasis1,2. Coupled to lipolysis is the release of a recently identified hormone, fatty-acid-binding protein 4 (FABP4)3. Although circulating FABP4 levels have been strongly associated with cardiometabolic diseases in both preclinical models and humans4-7, no mechanism of action has yet been described8-10. Here we show that hormonal FABP4 forms a functional hormone complex with adenosine kinase (ADK) and nucleoside diphosphate kinase (NDPK) to regulate extracellular ATP and ADP levels. We identify a substantial effect of this hormone on beta cells and given the central role of beta-cell function in both the control of lipolysis and development of diabetes, postulate that hormonal FABP4 is a key regulator of an adipose-beta-cell endocrine axis. Antibody-mediated targeting of this hormone complex improves metabolic outcomes, enhances beta-cell function and preserves beta-cell integrity to prevent both type 1 and type 2 diabetes. Thus, the FABP4-ADK-NDPK complex, Fabkin, represents a previously unknown hormone and mechanism of action that integrates energy status with the function of metabolic organs, and represents a promising target against metabolic disease.

Systems vaccinology of the BNT162b2 mRNA vaccine in humans.

The emergency use authorization of two mRNA vaccines in less than a year from the emergence of SARS-CoV-2 represents a landmark in vaccinology1,2. Yet, how mRNA vaccines stimulate the immune system to elicit protective immune responses is unknown. Here we used a systems vaccinology approach to comprehensively profile the innate and adaptive immune responses of 56 healthy volunteers who were vaccinated with the Pfizer-BioNTech mRNA vaccine (BNT162b2). Vaccination resulted in the robust production of neutralizing antibodies against the wild-type SARS-CoV-2 (derived from 2019-nCOV/USA_WA1/2020) and, to a lesser extent, the B.1.351 strain, as well as significant increases in antigen-specific polyfunctional CD4 and CD8 T cells after the second dose. Booster vaccination stimulated a notably enhanced innate immune response as compared to primary vaccination, evidenced by (1) a greater frequency of CD14+CD16+ inflammatory monocytes; (2) a higher concentration of plasma IFNγ; and (3) a transcriptional signature of innate antiviral immunity. Consistent with these observations, our single-cell transcriptomics analysis demonstrated an approximately 100-fold increase in the frequency of a myeloid cell cluster enriched in interferon-response transcription factors and reduced in AP-1 transcription factors, after secondary immunization. Finally, we identified distinct innate pathways associated with CD8 T cell and neutralizing antibody responses, and show that a monocyte-related signature correlates with the neutralizing antibody response against the B.1.351 variant. Collectively, these data provide insights into the immune responses induced by mRNA vaccination and demonstrate its capacity to prime the innate immune system to mount a more potent response after booster immunization.

HER2-driven breast cancer suppression by the JNK signaling pathway.

The HER2+ subtype of human breast cancer is associated with the malignant transformation of luminal ductal cells of the mammary epithelium. The sequence analysis of tumor DNA identifies loss of function mutations and deletions of the MAP2K4 and MAP2K7 genes that encode direct activators of the JUN NH2-terminal kinase (JNK). We report that in vitro studies of human mammary epithelial cells with CRISPR-induced mutations in the MAPK and MAP2K components of the JNK pathway caused no change in growth in 2D culture, but these mutations promoted epithelial cell proliferation in 3D culture. Analysis of gene expression signatures in 3D culture demonstrated similar changes caused by HER2 activation and JNK pathway loss. The mechanism of signal transduction cross-talk may be mediated, in part, by JNK-suppressed expression of integrin α6ß4 that binds HER2 and amplifies HER2 signaling. These data suggest that HER2 activation and JNK pathway loss may synergize to promote breast cancer. To test this hypothesis, we performed in vivo studies using a mouse model of HER2+ breast cancer with Cre/loxP-mediated ablation of genes encoding JNK (Mapk8 and Mapk9) and the MAP2K (Map2k4 and Map2k7) that activate JNK in mammary epithelial cells. Kaplan-Meier analysis of tumor development demonstrated that JNK pathway deficiency promotes HER2+-driven breast cancer. Collectively, these data identify JNK pathway genes as potential suppressors for HER2+ breast cancer.

Climate change and public health: The effects of global warming on the risk of allergies and autoimmune diseases: The effects of global warming on the risk of allergies and autoimmune diseases.

Global climate change and extreme weather events are associated with epigenetic modifications in immune cells, leading to the possible increased risk and prevalence of allergies and autoimmune diseases.

Phosphorylation of RXRα mediates the effect of JNK to suppress hepatic FGF21 expression and promote metabolic syndrome.

The cJun NH2-terminal kinase (JNK) signaling pathway in the liver promotes systemic changes in metabolism by regulating peroxisome proliferator-activated receptor α (PPARα)-dependent expression of the hepatokine fibroblast growth factor 21 (FGF21). Hepatocyte-specific gene ablation studies demonstrated that the Mapk9 gene (encoding JNK2) plays a key mechanistic role. Mutually exclusive inclusion of exons 7a and 7b yields expression of the isoforms JNK2α and JNK2ß. Here we demonstrate that Fgf21 gene expression and metabolic regulation are primarily regulated by the JNK2α isoform. To identify relevant substrates of JNK2α, we performed a quantitative phosphoproteomic study of livers isolated from control mice, mice with JNK deficiency in hepatocytes, and mice that express only JNK2α or JNK2ß in hepatocytes. We identified the JNK substrate retinoid X receptor α (RXRα) as a protein that exhibited JNK2α-promoted phosphorylation in vivo. RXRα functions as a heterodimeric partner of PPARα and may therefore mediate the effects of JNK2α signaling on Fgf21 expression. To test this hypothesis, we established mice with hepatocyte-specific expression of wild-type or mutated RXRα proteins. We found that the RXRα phosphorylation site Ser260 was required for suppression of Fgf21 gene expression. Collectively, these data establish a JNK-mediated signaling pathway that regulates hepatic Fgf21 expression.

Glucagon-like peptide-1 receptor agonists reverse nerve morphological abnormalities in diabetic peripheral neuropathy.

AIMS/HYPOTHESIS: Diabetic peripheral neuropathy (DPN) is a highly prevalent cause of physical disability. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are used to treat type 2 diabetes and animal studies have shown that glucagon-like peptide-1 (GLP-1) receptors are present in the central and peripheral nervous systems. This study investigated whether GLP-1 RAs can improve nerve structure. METHODS: Nerve structure was assessed using peripheral nerve ultrasonography and measurement of tibial nerve cross-sectional area, in conjunction with validated neuropathy symptom scores and nerve conduction studies. A total of 22 consecutively recruited participants with type 2 diabetes were assessed before and 1 month after commencing GLP-1 RA therapy (semaglutide or dulaglutide). RESULTS: There was a pathological increase in nerve size before treatment in 81.8% of the cohort (n=22). At 1 month of follow-up, there was an improvement in nerve size in 86% of participants (p<0.05), with 32% returning to normal nerve morphology. A 3 month follow-up study (n=14) demonstrated further improvement in nerve size in 93% of participants, accompanied by reduced severity of neuropathy (p<0.05) and improved sural sensory nerve conduction amplitude (p<0.05). CONCLUSIONS/INTERPRETATION: This study demonstrates the efficacy of GLP-1 RAs in improving neuropathy outcomes, evidenced by improvements in mainly structural and morphological measures and supported by electrophysiological and clinical endpoints. Future studies, incorporating quantitative sensory testing and measurement of intraepidermal nerve fibre density, are needed to investigate the benefits for small fibre function and structure.

Mosquito thermal tolerance is remarkably constrained across a large climatic range.

How mosquitoes may respond to rapid climate warming remains unknown for most species, but will have major consequences for their future distributions, with cascading impacts on human well-being, biodiversity and ecosystem function. We investigated the adaptive potential of a wide-ranging mosquito species, Aedes sierrensis, across a large climatic gradient by conducting a common garden experiment measuring the thermal limits of mosquito life-history traits. Although field-collected populations originated from vastly different thermal environments that spanned over 1200 km, we found limited variation in upper thermal tolerance between populations. In particular, the upper thermal limits of all life-history traits varied by less than 3°C across the species range and, for most traits, did not differ significantly between populations. For one life-history trait-pupal development rate-we did detect significant variation in upper thermal limits between populations, and this variation was strongly correlated with source temperatures, providing evidence of local thermal adaptation for pupal development. However, we found that maximum environmental temperatures across most of the species' range already regularly exceed the highest upper thermal limits estimated under constant temperatures. This result suggests that strategies for coping with and/or avoiding thermal extremes are likely key components of current and future mosquito thermal tolerance.

Trans-Synaptic Degeneration Following Acute Optic Neuritis in Multiple Sclerosis.

OBJECTIVE: To explore longitudinal changes in brain volumetric measures and retinal layer thicknesses following acute optic neuritis (AON) in people with multiple sclerosis (PwMS), to investigate the process of trans-synaptic degeneration, and determine its clinical relevance. METHODS: PwMS were recruited within 40 days of AON onset (n = 49), and underwent baseline retinal optical coherence tomography and brain magnetic resonance imaging followed by longitudinal tracking for up to 5 years. A comparator cohort of PwMS without a recent episode of AON were similarly tracked (n = 73). Mixed-effects linear regression models were used. RESULTS: Accelerated atrophy of the occipital gray matter (GM), calcarine GM, and thalamus was seen in the AON cohort, as compared with the non-AON cohort (-0.76% vs -0.22% per year [p = 0.01] for occipital GM, -1.83% vs -0.32% per year [p = 0.008] for calcarine GM, -1.17% vs -0.67% per year [p = 0.02] for thalamus), whereas rates of whole-brain, cortical GM, non-occipital cortical GM atrophy, and T2 lesion accumulation did not differ significantly between the cohorts. In the AON cohort, greater AON-induced reduction in ganglion cell+inner plexiform layer thickness over the first year was associated with faster rates of whole-brain (r = 0.32, p = 0.04), white matter (r = 0.32, p = 0.04), and thalamic (r = 0.36, p = 0.02) atrophy over the study period. Significant relationships were identified between faster atrophy of the subcortical GM and thalamus, with worse visual function outcomes after AON. INTERPRETATION: These results provide in-vivo evidence for anterograde trans-synaptic degeneration following AON in PwMS, and suggest that trans-synaptic degeneration may be related to clinically-relevant visual outcomes. ANN NEUROL 2023;93:76-87.

Elucidating allergic reaction mechanisms in response to SARS-CoV-2 mRNA vaccination in adults.

BACKGROUND: During the COVID-19 pandemic, novel nanoparticle-based mRNA vaccines were developed. A small number of individuals developed allergic reactions to these vaccines although the mechanisms remain undefined. METHODS: To understand COVID-19 vaccine-mediated allergic reactions, we enrolled 19 participants who developed allergic events within 2 h of vaccination and 13 controls, nonreactors. Using standard hemolysis assays, we demonstrated that sera from allergic participants induced stronger complement activation compared to nonallergic subjects following ex vivo vaccine exposure. RESULTS: Vaccine-mediated complement activation correlated with anti-polyethelyne glycol (PEG) IgG (but not IgM) levels while anti-PEG IgE was undetectable in all subjects. Depletion of total IgG suppressed complement activation in select individuals. To investigate the effects of vaccine excipients on basophil function, we employed a validated indirect basophil activation test that stratified the allergic populations into high and low responders. Complement C3a and C5a receptor blockade in this system suppressed basophil response, providing strong evidence for complement involvement in vaccine-mediated basophil activation. Single-cell multiome analysis revealed differential expression of genes encoding the cytokine response and Toll-like receptor (TLR) pathways within the monocyte compartment. Differential chromatin accessibility for IL-13 and IL-1B genes was found in allergic and nonallergic participants, suggesting that in vivo, epigenetic modulation of mononuclear phagocyte immunophenotypes determines their subsequent functional responsiveness, contributing to the overall physiologic manifestation of vaccine reactions. CONCLUSION: These findings provide insights into the mechanisms underlying allergic reactions to COVID-19 mRNA vaccines, which may be used for future vaccine strategies in individuals with prior history of allergies or reactions and reduce vaccine hesitancy.

Systematic review and meta-analysis of birth weight and perfluorohexane sulfonate exposures: examination of sample timing and study confidence.

We examined the association between mean birth weight (BW) differences and perfluorohexane sulfonate (PFHxS) exposure biomarkers.We fit a random effects model to estimate the overall pooled effect and for different strata based on biomarker sample timing and overall study confidence. We also conducted an analysis to examine the impact of a continuous measure of gestational age sample timing on the overall pooled effect.We detected a -7.9 g (95% CI -15.0 to -0.7; pQ=0.85; I2=0%) BW decrease per ln ng/mL PFHxS increase based on 27 studies. The 11 medium confidence studies (ß=-10.0 g; 95% CI -21.1 to 1.1) showed larger deficits than 12 high (ß=-6.8 g; 95% CI -16.3 to 2.8) and 4 low confidence studies (ß=-1.5 g; 95% CI -51.6 to 48.7). 10 studies with mid-pregnancy to late-pregnancy sampling periods showed smaller deficits (ß=-3.9 g; 95% CI -17.7 to 9.9) than 5 post-partum studies (ß=-28.3 g; 95% CI -69.3 to 12.7) and 12 early sampling studies (ß=-7.6 g; 95% CI -16.2 to 1.1). 6 of 12 studies with the earliest sampling timing showed results closer to the null.Overall, we detected a small but statistically significant BW deficit across 27 studies. We saw comparable BW deficit magnitudes in both the medium and high confidence studies as well as the early pregnancy group. Despite no definitive pattern by sample timing, larger deficits were seen in postpartum studies. We also saw results closer to the null for a subset of studies restricted to the earliest biomarker collection times. Serial pregnancy sampling, improved precision in gestational age estimates and more standardised reporting of sample variation and exposure units in future epidemiologic research may offer a greater understanding of the relationship between PFHxS on BW and any potential impact of pregnancy haemodynamics.

Passive sensing of smartphone use, physical activity and sedentary behavior among adolescents and young adults during the COVID-19 pandemic.

The research that links excessive screen time to adverse health outcomes is based on self-reported screen use. Few studies have documented how passively-sensed smartphone and app use relate to health behaviors like activity and sitting. Furthermore, they have not considered that daily fluctuations in smartphone/app use may have different relationships to these behaviors than a person's usual smartphone/app use. This study evaluated whether physical activity or sedentary (sitting) behavior are associated with either smartphone screen time or specific smartphone app use by adolescents and young adults during the COVID-19 pandemic. Adolescents and young adults aged 13-29 years wore activPAL4 micro activity monitors while their smartphones logged daily screen time and app use durations for nine days. Data were collected in 2020-2021 and analyzed in 2022-2023. Participants (N = 125) had a mean (SD) age of 19.7 (4.3) years. Participants' usual smartphone screen time was negatively associated with daily step counts. Daily deviations in smartphone screen time were negatively associated with daily step counts and moderate-vigorous physical activity durations. Time spent on Instagram, YouTube and, to a lesser extent, TikTok were linked with reduced activity levels. Daily sedentary behavior was not associated with usual or daily screen time. Interventions to promote physical activity during the transition into adulthood may benefit from limiting excessive smartphone screen time. Specific intervention targets could include limiting use of apps with infinite scrolling feeds algorithmically tuned to maintain user engagement, such as Instagram, YouTube and TikTok.

Sympathetic tone dictates the impact of lipolysis on FABP4 secretion.

Levels of circulating fatty acid binding protein 4 (FABP4) protein are strongly associated with obesity and metabolic disease in both mice and humans, and secretion is stimulated by ß-adrenergic stimulation both in vivo and in vitro. Previously, lipolysis-induced FABP4 secretion was found to be significantly reduced upon pharmacological inhibition of adipose triglyceride lipase (ATGL) and was absent from adipose tissue explants from mice specifically lacking ATGL in their adipocytes (ATGLAdpKO). Here, we find that upon activation of ß-adrenergic receptors in vivo, ATGLAdpKO mice unexpectedly exhibited significantly higher levels of circulating FABP4 as compared with ATGLfl/fl controls, despite no corresponding induction of lipolysis. We generated an additional model with adipocyte-specific deletion of both FABP4 and ATGL (ATGL/FABP4AdpKO) to evaluate the cellular source of this circulating FABP4. In these animals, there was no evidence of lipolysis-induced FABP4 secretion, indicating that the source of elevated FABP4 levels in ATGLAdpKO mice was indeed from the adipocytes. ATGLAdpKO mice exhibited significantly elevated corticosterone levels, which positively correlated with plasma FABP4 levels. Pharmacological inhibition of sympathetic signaling during lipolysis using hexamethonium or housing mice at thermoneutrality to chronically reduce sympathetic tone significantly reduced FABP4 secretion in ATGLAdpKO mice compared with controls. Therefore, activity of a key enzymatic step of lipolysis mediated by ATGL, per se, is not required for in vivo stimulation of FABP4 secretion from adipocytes, which can be induced through sympathetic signaling.

Quantum bit error rate timing jitter dependency on multi-mode fibers.

The full time-jitter response of a single-photon detector can make a significant contribution to the quantum bit error rate (QBER) of high repetition rate quantum key distribution (QKD) implementations. Although there have been studies into understanding the contribution for single-mode optical fiber coupled single-photon detectors, the contribution of larger, multimode core diameters to the QBER have not been explored in detail. With the growing importance of free-space QKD, which typically use multimode fibers to reduce coupling loss, it is vitally important to understand how the multimode fiber coupling will impact the total QBER. This work studies the impact of the time-jitter contribution to QBER when coupling a commercial off-the-shelf silicon single-photon avalanche diode with various multimode fibers while simulating operating at 1 GHz with empirical measurements taken at 1 MHz repetition rate. It was found that step-index multimode fibers can significantly increase the QBER, while graded-index fibers can provide an QBER contribution similar to a single-mode fiber. The results highlight that there is a significant benefit in using graded index multimode fibers for a free-space QKD receiver, particularly for high repetition rate applications.

The Epidemiology of Smoking in Older Adults: A National Cohort Study.

BACKGROUND: Older smokers account for the greatest tobacco-related morbidity and mortality in the USA, while quitting smoking remains the single most effective preventive health intervention for reducing the risk of smoking-related illness. Yet, knowledge about patterns of smoking and smoking cessation in older adults is lacking. OBJECTIVE: Assess trends in prevalence of cigarette smoking between 1998 and 2018 and identify patterns and predictors of smoking cessation in US older adults. DESIGN: Retrospective cohort study PARTICIPANTS: Individuals aged 55+ enrolled in the nationally representative Health and Retirement Study, 1998-2018 MAIN MEASURES: Current smoking was assessed with the question: "Do you smoke cigarettes now?" Quitting smoking was defined as having at least two consecutive waves (between 2 and 4 years) in which participants who were current smokers in 1998 reported they were not currently smoking in subsequent waves. KEY RESULTS: Age-adjusted smoking prevalence decreased from 15.9% in 1998 (95% confidence interval (CI) 15.2, 16.7) to 11.2% in 2018 (95% CI 10.4, 12.1). Among 2187 current smokers in 1998 (mean age 64, 56% female), 56% of those living to age 90 had a sustained period of smoking cessation. Smoking less than 10 cigarettes/day was strongly associated with an increased likelihood of quitting smoking (subdistribution hazard ratio 2.3; 95% CI 1.9, 2.8), compared to those who smoked more than 20 cigarettes/day. CONCLUSIONS: Smoking prevalence among older persons has declined and substantial numbers of older smokers succeed in quitting smoking for a sustained period. These findings highlight the need for continued aggressive efforts at tobacco cessation among older persons.

Pseudomonas aeruginosa lasR mutant fitness in microoxia is supported by an Anr-regulated oxygen-binding hemerythrin.

Pseudomonas aeruginosa strains with loss-of-function mutations in the transcription factor LasR are frequently encountered in the clinic and the environment. Among the characteristics common to LasR-defective (LasR-) strains is increased activity of the transcription factor Anr, relative to their LasR+ counterparts, in low-oxygen conditions. One of the Anr-regulated genes found to be highly induced in LasR- strains was PA14_42860 (PA1673), which we named mhr for microoxic hemerythrin. Purified P. aeruginosa Mhr protein contained the predicted di-iron center and bound molecular oxygen with an apparent Kd of ∼1 µM. Both Anr and Mhr were necessary for fitness in lasR+ and lasR mutant strains in colony biofilms grown in microoxic conditions, and the effects were more striking in the lasR mutant. Among genes in the Anr regulon, mhr was most closely coregulated with the Anr-controlled high-affinity cytochrome c oxidase genes. In the absence of high-affinity cytochrome c oxidases, deletion of mhr no longer caused a fitness disadvantage, suggesting that Mhr works in concert with microoxic respiration. We demonstrate that Anr and Mhr contribute to LasR- strain fitness even in biofilms grown in normoxic conditions. Furthermore, metabolomics data indicate that, in a lasR mutant, expression of Anr-regulated mhr leads to differences in metabolism in cells grown on lysogeny broth or artificial sputum medium. We propose that increased Anr activity leads to higher levels of the oxygen-binding protein Mhr, which confers an advantage to lasR mutants in microoxic conditions.

Temporal trends in associations between severe mental illness and risk of cardiovascular disease: A systematic review and meta-analysis.

BACKGROUND: Severe mental illness (SMI; schizophrenia, bipolar disorders (BDs), and other nonorganic psychoses) is associated with increased risk of cardiovascular disease (CVD) and CVD-related mortality. To date, no systematic review has investigated changes in population level CVD-related mortality over calendar time. It is unclear if this relationship has changed over time in higher-income countries with changing treatments. METHODS AND FINDINGS: To address this gap, a systematic review was conducted, to assess the association between SMI and CVD including temporal change. Seven databases were searched (last: November 30, 2021) for cohort or case-control studies lasting ≥1 year, comparing frequency of CVD mortality or incidence in high-income countries between people with versus without SMI. No language restrictions were applied. Random effects meta-analyses were conducted to compute pooled hazard ratios (HRs) and rate ratios, pooled standardised mortality ratios (SMRs), pooled odds ratios (ORs), and pooled risk ratios (RRs) of CVD in those with versus without SMI. Temporal trends were explored by decade. Subgroup analyses by age, sex, setting, world region, and study quality (Newcastle-Ottawa scale (NOS) score) were conducted. The narrative synthesis included 108 studies, and the quantitative synthesis 59 mortality studies (with (≥1,841,356 cases and 29,321,409 controls) and 28 incidence studies (≥401,909 cases and 14,372,146 controls). The risk of CVD-related mortality for people with SMI was higher than controls across most comparisons, except for total CVD-related mortality for BD and cerebrovascular accident (CVA) for mixed SMI. Estimated risks were larger for schizophrenia than BD. Pooled results ranged from SMR = 1.55 (95% confidence interval (CI): 1.33 to 1.81, p < 0.001), for CVA in people with BD to HR/rate ratio = 2.40 (95% CI: 2.25 to 2.55, p < 0.001) for CVA in schizophrenia. For schizophrenia and BD, SMRs and pooled HRs/rate ratios for CHD and CVD mortality were larger in studies with outcomes occurring during the 1990s and 2000s than earlier decades (1980s: SMR = 1.14, 95% CI: 0.57 to 2.30, p = 0.71; 2000s: SMR = 2.59, 95% CI: 1.93 to 3.47, p < 0.001 for schizophrenia and CHD) and in studies including people with younger age. The incidence of CVA, CVD events, and heart failure in SMI was higher than controls. Estimated risks for schizophrenia ranged from HR/rate ratio 1.25 (95% CI: 1.04 to 1.51, p = 0.016) for total CVD events to rate ratio 3.82 (95% CI: 3.1 to 4.71, p < 0.001) for heart failure. Incidence of CHD was higher in BD versus controls. However, for schizophrenia, CHD was elevated in higher-quality studies only. The HR/rate ratios for CVA and CHD were larger in studies with outcomes occurring after the 1990s. Study limitations include the high risk of bias of some studies as they drew a comparison cohort from general population rates and the fact that it was difficult to exclude studies that had overlapping populations, although attempts were made to minimise this. CONCLUSIONS: In this study, we found that SMI was associated with an approximate doubling in the rate ratio of CVD-related mortality, particularly since the 1990s, and in younger groups. SMI was also associated with increased incidence of CVA and CHD relative to control participants since the 1990s. More research is needed to clarify the association between SMI and CHD and ways to mitigate this risk.

Comparing Machine Learning to Regression Methods for Mortality Prediction Using Veterans Affairs Electronic Health Record Clinical Data.

BACKGROUND: It is unclear whether machine learning methods yield more accurate electronic health record (EHR) prediction models compared with traditional regression methods. OBJECTIVE: The objective of this study was to compare machine learning and traditional regression models for 10-year mortality prediction using EHR data. DESIGN: This was a cohort study. SETTING: Veterans Affairs (VA) EHR data. PARTICIPANTS: Veterans age above 50 with a primary care visit in 2005, divided into separate training and testing cohorts (n= 124,360 each). MEASUREMENTS AND ANALYTIC METHODS: The primary outcome was 10-year all-cause mortality. We considered 924 potential predictors across a wide range of EHR data elements including demographics (3), vital signs (9), medication classes (399), disease diagnoses (293), laboratory results (71), and health care utilization (149). We compared discrimination (c-statistics), calibration metrics, and diagnostic test characteristics (sensitivity, specificity, and positive and negative predictive values) of machine learning and regression models. RESULTS: Our cohort mean age (SD) was 68.2 (10.5), 93.9% were male; 39.4% died within 10 years. Models yielded testing cohort c-statistics between 0.827 and 0.837. Utilizing all 924 predictors, the Gradient Boosting model yielded the highest c-statistic [0.837, 95% confidence interval (CI): 0.835-0.839]. The full (unselected) logistic regression model had the highest c-statistic of regression models (0.833, 95% CI: 0.830-0.835) but showed evidence of overfitting. The discrimination of the stepwise selection logistic model (101 predictors) was similar (0.832, 95% CI: 0.830-0.834) with minimal overfitting. All models were well-calibrated and had similar diagnostic test characteristics. LIMITATION: Our results should be confirmed in non-VA EHRs. CONCLUSION: The differences in c-statistic between the best machine learning model (924-predictor Gradient Boosting) and 101-predictor stepwise logistic models for 10-year mortality prediction were modest, suggesting stepwise regression methods continue to be a reasonable method for VA EHR mortality prediction model development.