Social Integration and Reduced Risk of Coronary Heart Disease in Women: The Role of Lifestyle Behaviors.

RATIONALE: Higher social integration is associated with lower cardiovascular mortality; however, whether it is associated with incident coronary heart disease (CHD), especially in women, and whether associations differ by case fatality are unclear. OBJECTIVES: This study sought to examine the associations between social integration and risk of incident CHD in a large female prospective cohort. METHODS AND RESULTS: Seventy-six thousand three hundred and sixty-two women in the Nurses' Health Study, free of CHD and stroke at baseline (1992), were followed until 2014. Social integration was assessed by a simplified Berkman-Syme Social Network Index every 4 years. End points included nonfatal myocardial infarction and fatal CHD. Two thousand three hundred and seventy-two incident CHD events occurred throughout follow-up. Adjusting for demographic, health/medical risk factors, and depressive symptoms, being socially integrated was significantly associated with lower CHD risk, particularly fatal CHD. The most socially integrated women had a hazard ratio of 0.55 (95% confidence interval, 0.41-0.73) of developing fatal CHD compared with those least socially integrated (P for trend <0.0001). When additionally adjusting for lifestyle behaviors, findings for fatal CHD were maintained but attenuated (P for trend =0.02), whereas the significant associations no longer remained for nonfatal myocardial infarction. The inverse associations between social integration and nonfatal myocardial infarction risk were largely explained by health-promoting behaviors, particularly through differences in cigarette smoking; however, the association with fatal CHD risk remained after accounting for these behaviors and, thus, may involve more direct biological mechanisms. CONCLUSIONS: Social integration is inversely associated with CHD incidence in women, but is largely explained by lifestyle/behavioral pathways.

The relation of telomere length at midlife to subsequent 20-year depression trajectories among women.

BACKGROUND: Telomeres cap and protect DNA but shorten with each somatic cell division. Aging and environmental and lifestyle factors contribute to the speed of telomere attrition. Current evidence suggests a link between relative telomere length (RTL) and depression but the directionality of the relationship remains unclear. We prospectively examined associations between RTL and subsequent depressive symptom trajectories. METHODS: Among 8,801 women of the Nurses' Health Study, depressive symptoms were measured every 4 years from 1992 to 2012; group-based trajectories of symptoms were identified using latent class growth-curve analysis. Multinomial logistic models were used to relate midlife RTLs to the probabilities of assignment to subsequent depressive symptom trajectory groups. RESULTS: We identified four depressive symptom trajectory groups: minimal depressive symptoms (62%), worsening depressive symptoms (14%), improving depressive symptoms (19%), and persistent-severe depressive symptoms (5%). Longer midlife RTLs were related to significantly lower odds of being in the worsening symptoms trajectory versus minimal trajectory but not to other trajectories. In comparison with being in the minimal symptoms group, the multivariable-adjusted odds ratio of being in the worsening depressive symptoms group was 0.78 (95% confidence interval, 0.62-0.97; p = 0.02), for every standard deviation increase in baseline RTL. CONCLUSIONS: In this large prospective study of generally healthy women, longer telomeres at midlife were associated with significantly lower risk of a subsequent trajectory of worsening mood symptoms over 20 years. The results raise the possibility of telomere shortening as a novel contributing factor to late-life depression.

Prospective association of depression and phobic anxiety with changes in telomere lengths over 11 years.

BACKGROUND: Although depression and anxiety have been associated with shorter telomeres in cross-sectional studies, the data regarding the prospective relations of depression and anxiety to accelerated telomere length shortening are limited and findings are mixed. We prospectively examined relations of baseline depression and phobic anxiety to subsequent 11-year change in relative leukocyte telomere lengths (LTLs). METHODS: We selected 1,250 women from a subcohort of the Nurses' Health Study who provided blood specimens at both blood collections (1989-1990 and 2000-2001). Depression was defined by self-reported regular antidepressant use or presence of severe depressive symptoms; anxiety symptoms were assessed using the Crown-Crisp Experiential Index. Using quantitative real-time polymerase chain reaction assay, LTLs were measured as the copy number ratio of telomere repeat to a single control gene. Changes in LTLs were defined in three ways: absolute change, symmetrized percent change, and decile shift. RESULTS: Overall, there were no statistically significant associations of depression or phobic anxiety to subsequent 11-year LTL shortening, despite a point estimates in the direction of greater telomere shortening among participants with versus without depression, across all three metrics of telomere change. The strongest predictor of LTL change was baseline telomere length, and regression-to-the-mean was observed. CONCLUSION: Baseline depression and phobic anxiety were not significantly associated with 11-year attrition in LTLs among 1,250 mid-life and older women. However, a suggestion of depression and greater subsequent LTL attrition, while not statistically significant, may warrant further inquiry, particularly in prospective studies with larger sample sizes and broader windows of the lifespan.

Patterns of late-life depressive symptoms and subsequent declines in cognitive domains.

BACKGROUND: Depression frequently co-occurs with cognitive decline, but the nature of this association is unclear. We examined relations of late-life depressive symptom patterns to subsequent domain-specific cognitive changes. METHODS: Depressive symptoms were measured at up to 3 timepoints among 11,675 Nurses' Health Study participants prior to cognitive testing. Depressive symptom patterns were categorized as non-depressed, variable or persistent, based on published severity cutpoints. Outcomes were global, verbal, and executive function-attention composite scores. RESULTS: Participants with persistent depressive symptoms had worse executive function-attention decline compared with non-depressed participants (multivariable-adjusted mean difference = -0.03 units/year, 95% CI: -0.05, -0.01; p = 0.003); this difference was comparable with 8 years of aging. However, being in the persistent versus non-depressed group was not significantly related to verbal (p = 0.71) or global score (p = 0.09) decline. By contrast, compared with the non-depressed group, those with variable depressive symptoms had worse verbal memory decline (multivariable-adjusted mean difference = -0.01 units/year, 95% CI: -0.02, -0.002; p = 0.03); this group showed no differences for global or executive function-attention decline. CONCLUSIONS: A variable pattern of depressive symptom severity related to subsequent decline in verbal memory, while a persistent pattern related to decline in executive function-attention. Findings could signal differences in underlying neuropathologic processes among persons with differing depression patterns and late-life cognitive decline. Copyright © 2016 John Wiley & Sons, Ltd.

Racial Variation in Depression Risk Factors and Symptom Trajectories among Older Women.

OBJECTIVE: To assess racial variation in depression risk factors and symptom trajectories among older women. METHODS: Using Nurses' Health Study data, participants (29,483 non-Hispanic white and 288 black women) aged 60 years or older, free of depression in 2000, were followed until 2012. Data on race and risk factors, selected a priori, were obtained from biennial questionnaires. Incident depression was defined as depression diagnosis, antidepressant use, or presence of severe depressive symptoms. Group-based trajectories of depressive symptoms were determined using latent variable modeling approaches. RESULTS: Black participants had lower risk (hazard ratio: 0.76; 95% confidence interval: 0.57-0.99) of incident late-life depression compared with whites. Although blacks had higher prevalence than whites of some risk factors at study baseline, distributions of major contributors to late-life depression risk (low exercise, sleep difficulty, physical/functional limitation, pain) were comparable. There was evidence of effect modification by race for relations of region of birth (Southern birthplace), smoking, and medical comorbidity to depression risk; however, wide confidence intervals occurred among blacks because of smaller sample size. Four trajectories were identified: minimal symptoms-stable (58.3%), mild symptoms-worsening (31.4%), subthreshold symptoms-worsening (4.8%), and subthreshold symptoms-improving (5.5%). Probabilities of trajectory types were similar for blacks and whites. CONCLUSION: Although overall trajectories of late-life depressive symptoms were comparable by race, there was racial variation in depression risk estimates associated with less-studied factors, such as U.S. region of birth. Future work may address unmeasured health and resilience determinants that may underlie observed findings and that could inform clinical assessment of late-life depression risk factors.

Religious Service Attendance and Lower Depression Among Women-a Prospective Cohort Study.

OBJECTIVE: Previous studies on the association between religious service attendance and depression have been mostly cross-sectional, subject to reverse causation, and did not account for the potential feedback between religious service attendance and depression. We prospectively evaluated evidence whether religious service attendance decreased risk of subsequent risk of depression and whether depression increased subsequent cessation of service attendance, while explicitly accounting for feedback with potential effects in both directions. METHOD: We included a total of 48,984 US nurses who were participants of the Nurses' Health Study with mean age 58 years and who were followed up from 1996 to 2008. Religious service attendance was self-reported in 1992, 1996, 2000, and 2004. Depression was defined as self-reported physician-diagnosed clinical depression, regular anti-depressant use, or severe depressive symptoms. Multivariate logistic regression and marginal structural models were used to estimate the odds ratio of developing incident depression, adjusted for baseline religious service attendance, baseline depression, and time-varying covariates. RESULTS: Compared with women who never attended services, women who had most frequent and recent religious service attendance had the lowest risk of developing depression (odds ratio [OR] = 0.71, 95 % confidence interval [CI] 0.62-0.82). Compared with women who were not depressed, women with depression were less likely to subsequently attend religious services once or more per week (OR = 0.74, 95 % CI 0.68-0.80). CONCLUSIONS: In this study of US women, there is evidence that higher frequency of religious service attendance decreased the risk of incident depression and women with depression were less likely to subsequently attend services.

Risk factors for late-life depression: A prospective cohort study among older women.

Depression prevention requires identifying key risk contributors. Prior studies have identified several factors related to late-life depression but have seldom addressed factors jointly or in dose-response fashion. This study aimed to examine a wide range of potential predisposing factors and to estimate individual and joint contributions to risk of late-life depression in women. A total of 21,728 women aged ≥65years, without prior depression, in the Nurses' Health Study conducted in the United States were followed from 2000 to 2010. Demographic, social, lifestyle/behavioral and health variables were selected a priori from the literature or previous findings in this cohort. Depression was defined as physician/clinician-diagnosed depression, regular antidepressant use, or the presence of severe depressive symptoms. During 10-year follow-up, 3945 incident cases were identified. After simultaneous multivariable-adjustment, multiple factors in the domains of social stress (lower self-rated societal position and high volume of caregiving to disabled/ill relatives), unfavorable lifestyle (smoking, physical inactivity, heavy or binge drinking), and poor physical health (multiple comorbidity burden, excessive sleep, difficulty falling/staying asleep, bodily pain, and physical/functional limitation or disability) were significantly associated with higher depression risk; many featured dose-response relationships. Sensitivity analyses that excluded outcomes within 2years yielded similar estimates. The total population attributable fraction for all factors was 55.5%. Physical/functional limitation accounted for one-quarter of population attributable fraction, followed by problematic sleep, inadequate exercise, and pain (combining for one-third of population attributable fraction). Efforts to remediate or prevent these factors may contribute to an efficient strategy for late-life depression prevention in women.

Diabetic Phenotypes and Late-Life Dementia Risk: A Mechanism-specific Mendelian Randomization Study.

BACKGROUND: Mendelian Randomization (MR) studies have reported that type 2 diabetes (T2D) was not associated with Alzheimer disease (AD). We adopted a modified, mechanism-specific MR design to explore this surprising result. METHODS: Using inverse-variance weighted MR analysis, we evaluated the association between T2D and AD using data from 39 single nucleotide polymorphisms (SNPs) significantly associated with T2D in DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) and the corresponding associations of each SNP with AD risk obtained from the International Genomics of Alzheimer's Project (IGAP, n=17,008 AD cases and n=37,154 controls). We evaluated mechanism-specific genetic subscores, including ß-cell function, insulin sensitivity, and adiposity, and repeated analyses in 8501 Health and Retirement Study participants for replication and model validation. RESULTS: In IGAP, the overall T2D polygenic score did not predict AD [odds ratio (OR) for the T2D polygenic score=1.01; 95% confidence interval (CI), 0.96, 1.06] but the insulin sensitivity polygenic score predicted higher AD risk (OR=1.17; 95% CI, 1.02, 1.34). In the Health and Retirement Study, polygenic scores were associated with T2D risk; the associations between insulin sensitivity genetic polygenic score and cognitive phenotypes were not statistically significant. CONCLUSIONS: Evidence from polygenic scores suggests that insulin sensitivity specifically may affect AD risk, more than T2D overall.

Helicobacter pylori test-and-treat program can be cost-effective to prevent gastric cancer in Taiwanese adults: referred to the nationwide reimbursement database.

BACKGROUND: Helicobacter pylori infection increases the risk of gastric cancer. The study aimed to compare cost-effectiveness ratios of H. pylori test-and-treat programs to prevent gastric cancer in Taiwan, referring to the nationwide reimbursement database and expected years of life lost. MATERIALS AND METHODS: During 1998-2009, there were 12,857 females and 24,945 males with gastric adenocarcinoma in Taiwan National Cancer Registry. They were followed up to 2010 and linked to the reimbursement database of National Health Insurance and the national mortality registry to determine lifetime health expenditures and expected years of life lost. Cost-effectiveness ratios of H. pylori test-and-treat programs for prevention of gastric adenocarcinoma were compared between screenings with (13) C-urea breath test and with anti-H. pylori IgG. RESULTS: The test-and-treat program with anti-H. pylori IgG to prevent gastric adenocarcinoma had lower incremental cost-effectiveness ratios than that with (13) C-urea breath test in both sexes (females: 244 vs 1071 US dollars/life-year; males: 312 vs 1431 US dollars/life-year). Cost saving would be achieved in an endemic area where H. pylori prevalence was >73.5%, or by selecting subpopulations with high absolute risk reduction rates of cancer after eradication. Moreover, expected years of life lost of gastric adenocarcinoma were higher and the incremental cost-effectiveness ratios of test-and-treat programs were more cost-effective in young adults (30-69 y/o) than in elders (≥70 y/o). CONCLUSIONS: The test-and-treat program with anti-H. pylori IgG shall be cost-effective to prevent gastric adenocarcinoma in a high endemic area, especially beginning at 30 years of age when H. pylori prevalence rates become stabilized.

Revisiting Mendelian randomization studies of the effect of body mass index on depression.

Mendelian Randomization studies, which use genetic instrumental variables (IVs) as quasi-experiments to estimate causal effects, report inconsistent findings regarding effects of body mass index (BMI) on mental health. We used genetic IV to estimate effects of BMI on depression and evaluated validity of a commonly used IV. Female Nurse's Health Study participants (n=6989, average age 56.4, [Standard Deviation 6.91] years at first depression assessment) self-reported BMI, which was averaged across eight reports prior to depression assessment (mean=24.96, SD 4.50). Genetic instruments included fat mass and obesity-associated protein (FTO) alleles, melanocortin receptor 4 (MC4R) alleles, and polygenic risk scores based on 32 established polymorphisms for BMI. Depression was assessed using multiple symptom measures, scaled to the Geriatric Depression Scale 15, averaged across up to 7 biennial waves. We used over-identification tests to assess the validity of genetic IVs. In conventional estimates, each additional BMI point predicted 0.024 (95% Confidence Interval (CI): 0.020-0.029) higher average depression scores. Genetic IV estimates were not significant when based on FTO (beta: 0.064, CI: -0.014, 0.142), MC4R (beta: 0.005, CI: -0.146, 0.156), polygenic score excluding FTO (beta=-0.003, 95%-CI -0.051, 0.045), or mechanism-specific scores. The over-identification test comparing IV estimates based on FTO to estimates based on the polygenic score excluding FTO rejected equality of estimated effects (P=0.014). Results provide no evidence against a null effect of BMI on depression and call into question validity of FTO as an instrument for BMI in Mendelian Randomization studies.

The natural history and burden of illness of metachromatic leukodystrophy: a systematic literature review.

BACKGROUND: Metachromatic leukodystrophy (MLD; OMIM 250100 and 249900) is a rare lysosomal storage disease caused by deficient arylsulfatase A activity, leading to accumulation of sulfatides in the nervous system. This systematic literature review aimed to explore the effect of MLD on the lives of patients. METHODS: The Ovid platform was used to search Embase, MEDLINE, and the Cochrane Library for articles related to the natural history, clinical outcomes, and burden of illness of MLD; congress and hand searches were performed using 'metachromatic leukodystrophy' as a keyword. Of the 531 publications identified, 120 were included for data extraction following screening. A subset of findings from studies relating to MLD natural history and burden of illness (n = 108) are presented here. RESULTS: The mean age at symptom onset was generally 16-18 months for late-infantile MLD and 6-10 years for juvenile MLD. Age at diagnosis and time to diagnosis varied widely. Typically, patients with late-infantile MLD presented predominantly with motor symptoms and developmental delay; patients with juvenile MLD presented with motor, cognitive, and behavioral symptoms; and patients with adult MLD presented with cognitive symptoms and psychiatric and mood disorders. Patients with late-infantile MLD had more rapid decline of motor function over time and lower survival than patients with juvenile MLD. Commonly reported comorbidities/complications included ataxia, epilepsy, gallbladder abnormalities, incontinence, neuropathy, and seizures. CONCLUSIONS: Epidemiology of MLD by geographic regions, quantitative cognitive data, data on the differences between early- and late-juvenile MLD, and humanistic or economic outcomes were limited. Further studies on clinical, humanistic (i.e., quality of life), and economic outcomes are needed to help inform healthcare decisions for patients with MLD.

A systematic review on the birth prevalence of metachromatic leukodystrophy.

BACKGROUND: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency in arylsulfatase A (ASA) activity arising primarily from ASA gene (ARSA) variants. Late-infantile, juvenile and adult clinical subtypes are defined by symptom onset at ≤ 2.5, > 2.5 to < 16 and ≥ 16 years, respectively. Epidemiological data were sought to address knowledge gaps and to inform decisions regarding the clinical development of an investigational drug. METHODS: To synthesize all available estimates of MLD incidence and birth prevalence worldwide and in selected countries, Ovid MEDLINE and Embase were searched systematically (March 11, 2022) using a population, intervention, comparator, outcome, time and setting framework, complemented by pragmatic searching to reduce publication bias. Where possible, results were stratified by clinical subtype. Data were extracted from non-interventional studies (clinical trials, non-clinical studies and case reports were excluded; reviews were used for snowballing only). RESULTS: Of the 31 studies included, 14 reported birth prevalence (13 countries in Asia-Pacific, Europe, the Middle East, North America and South America), one reported prevalence and none reported incidence. Birth prevalence per 100,000 live births ranged from 0.16 (Japan) to 1.85 (Portugal). In the three European studies with estimates stratified by clinical subtypes, birth prevalence was highest for late-infantile cases (0.31-1.12 per 100,000 live births). The distribution of clinical subtypes reported in cases diagnosed over various time periods in 17 studies varied substantially, but late-infantile and juvenile MLD accounted for at least two-thirds of cases in most studies. CONCLUSIONS: This review provides a foundation for further analysis of the regional epidemiology of MLD. Data gaps indicate the need for better global coverage, increased use of epidemiological measures (e.g. prevalence estimates) and more stratification of outcomes by clinical and genetic disease subtype.

Adcyap1r1 genotype, posttraumatic stress disorder, and depression among women exposed to childhood maltreatment.

BACKGROUND: A growing literature indicates that genetic variation, in combination with adverse early life experiences, shapes risk for later mental illness. Recent work also suggests that molecular variation at the ADCYAP1R1 locus is associated with posttraumatic stress disorder (PTSD) in women. We sought to test whether childhood maltreatment (CM) interacts with ADCYAP1R1 genotype to predict PTSD in women. METHODS: Data were obtained from 495 adult female participants from the Detroit Neighborhood Health Study. Genotyping of rs2267735, an ADCYAP1R1 variant, was conducted via TaqMan assay. PTSD, depression, and CM exposure were assessed via structured interviews. Main and interacting effects of ADCYAP1R1 and CM levels on past month PTSD and posttraumatic stress (PTS) severity were examined using logistic regression and a general linear model, respectively. As a secondary analysis, we also assessed main and interacting effects of ADCYAP1R1 and CM variation on risk of past-month depression diagnosis and symptom severity. RESULTS: No significant main effects were observed for ADCYAP1R1 genotype on either PTSD/PTS severity. In contrast, a significant ADCYAP1R1 × CM interaction was observed for both past month PTSD and PTS severity, with carriers of the "C" allele showing enhanced risk for these outcomes among women exposed to CM. No significant main or interaction effects were observed for past month depression/depression severity. CONCLUSIONS: Genetic variation at the ADCYAP1R1 locus interacts with CM to shape risk of later PTSD, but not depression, among women. The molecular mechanisms contributing to this interaction require further investigation.

Sex-specific association of a common variant of the XG gene with autism spectrum disorders.

Autism spectrum disorders (ASD) are much more common in males than in females. Studies using both linkage and candidate gene association approaches have identified genetic variants specific to families in which all affected cases were male, suggesting that sex may interact with or otherwise influence the expression of specific genes in association with ASD. In this study, we specifically evaluated the sex-specific genetic effects of ASD with a family-based genome-wide association study approach using the data from the Autism Genetic Resource Exchange repository. We evaluated the male-specific genetic effects of ASD in 374 multiplex families of European ancestry in which all affected were male (male-only; MO) and identified a novel genome-wide significant association in the pseudoautosomal boundary on chromosome Xp22.33/Yp11.31 in the MO families of predominantly paternal origin (rs2535443, p = 3.8 × 10(-8) ). Five markers that reside within a 550 kb intergenic region on chromosome 13q33.3, between the MYO16 and IRS2 genes, also showed suggestive association with ASD in the MO families (p = 3.3 × 10(-5) to 5.3 × 10(-7) ). In contrast, none of these markers appeared to be associated with ASD in the families containing any affected females. Our results suggest that the pseudoautosomal boundary on Xp22.33/Yp11.31 may harbor male-specific genetic variants for ASD.

Global Incidence and Prevalence of Gaucher Disease: A Targeted Literature Review.

Incidence and prevalence estimates for Gaucher disease (GD) are scarce for this rare disease and can be variable within the same region. This review provides a qualitative synthesis of global GD incidence and prevalence estimates, GD1-3 type-specific and overall, published in the last 10 years. A targeted literature search was conducted across multiple databases from January 2011 to September 2020, including web-based sources and congress proceedings to May 2021. Searches yielded 490 publications, with 31 analyzed: 20 cohort studies (15 prospective, 5 retrospective), 6 cross-sectional studies, 5 online reports (most from Europe (n = 11) or North America (n = 11); one multiregional). Across all GD types, incidence estimates ranged 0.45-25.0/100,000 live births (16 studies), lowest for Asia-Pacific. Incidence of GD1: 0.45-22.9/100,000 live births (Europe and North America) and GD3: 1.36/100,000 live births (Asia-Pacific only). GD type-specific prevalence estimates per 100,000 population were GD1: 0.26-0.63; GD2 and GD3: 0.02-0.08 (Europe only); estimates for GD type unspecified or overall ranged 0.11-139.0/100,000 inhabitants (17 studies), highest for North America. Generalizability was assessed as "adequate"or "intermediate" for all regions with data. GD incidence and prevalence estimates for the last 10 years varied considerably between regions and were poorly documented outside Europe and North America. Data for GD2 and GD3 were limited.

Early Diagnosis of Primary Immunodeficiency Disease Using Clinical Data and Machine Learning.

BACKGROUND: Primary immunodeficiency diseases (PIDD) are a group of immune-related disorders that have a current median delay of diagnosis between 6 and 9 years. Early diagnosis and treatment of PIDD has been associated with improved patient outcomes. OBJECTIVE: To develop a machine learning model using elements within the electronic health record data that are related to prior symptomatic treatment to predict PIDD. METHODS: We conducted a retrospective study of patients with PIDD identified using inclusion criteria of PIDD-related diagnoses, immunodeficiency-specific medications, and low immunoglobulin levels. We constructed a control group of age-, sex-, and race-matched patients with asthma. The primary outcome was the diagnosis of PIDD. We considered comorbidities, laboratory tests, medications, and radiological orders as features, all before diagnosis and indicative of symptom-related treatment. Features were presented sequentially to logistic regression, elastic net, and random forest classifiers, which were trained using a nested cross-validation approach. RESULTS: Our cohort consisted of 6422 patients, of whom 247 (4%) were diagnosed with PIDD. Our logistic regression model with comorbidities demonstrated good discrimination between patients with PIDD and those with asthma (c-statistic: 0.62 [0.58-0.65]). Adding laboratory results, medications, and radiological orders improved discrimination (c-statistic: 0.70 vs 0.62, P < .001), sensitivity, and specificity. Extending to the advanced machine learning models did not improve performance. CONCLUSIONS: We developed a prediction model for early diagnosis of PIDD using historical data that are related to symptomatic care, which has potential to fill an important need in reducing the time to diagnose PIDD, leading to better outcomes for immunodeficient patients.

Trends in characteristics and outcomes among US adults hospitalised with COVID-19 throughout 2020: an observational cohort study.

OBJECTIVES: To examine the temporal patterns of patient characteristics, treatments used and outcomes associated with COVID-19 in patients who were hospitalised for the disease between January and 15 November 2020. DESIGN: Observational cohort study. SETTING: COVID-19 subset of the Optum deidentified electronic health records, including more than 1.8 million patients from across the USA. PARTICIPANTS: There were 51 510 hospitalised patients who met the COVID-19 definition, with 37 617 in the laboratory positive cohort and 13 893 in the clinical cohort. PRIMARY AND SECONDARY OUTCOME MEASURES: Incident acute clinical outcomes, including in-hospital all-cause mortality. RESULTS: Respectively, 48% and 49% of the laboratory positive and clinical cohorts were women. The 50- 65 age group was the median age group for both cohorts. The use of antivirals and dexamethasone increased over time, fivefold and twofold, respectively, while the use of hydroxychloroquine declined by 98%. Among adult patients in the laboratory positive cohort, absolute age/sex standardised incidence proportion for in-hospital death changed by -0.036 per month (95% CI -0.042 to -0.031) from March to June 2020, but remained fairly flat from June to November, 2020 (0.001 (95% CI -0.001 to 0.003), 17.5% (660 deaths /3986 persons) in March and 10.2% (580/5137) in October); in the clinical cohort, the corresponding changes were -0.024 (95% CI -0.032 to -0.015) and 0.011 (95% CI 0.007 0.014), respectively (14.8% (175/1252) in March, 15.3% (189/1203) in October). Declines in the cumulative incidence of most acute clinical outcomes were observed in the laboratory positive cohort, but not for the clinical cohort. CONCLUSION: The incidence of adverse clinical outcomes remains high among COVID-19 patients with clinical diagnosis only. Patients with COVID-19 entering the hospital are at elevated risk of adverse outcomes.

SLC6A4 methylation modifies the effect of the number of traumatic events on risk for posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a common and debilitating mental disorder that occurs following exposure to a traumatic event. However, most individuals do not develop PTSD following even a severe trauma, leading to a search for new variables, such as genetic and other molecular variation, associated with vulnerability and resilience in the face of trauma exposure. METHOD: We examined whether serotonin transporter (SLC6A4) promoter genotype and methylation status modified the association between number of traumatic events experienced and PTSD in a subset of 100 individuals from the Detroit Neighborhood Health Study. RESULTS: Number of traumatic events was strongly associated with risk of PTSD. Neither SLC6A4 genotype nor methylation status was associated with PTSD in main effects models. However, SLC6A4 methylation levels modified the effect of the number of traumatic events on PTSD after controlling for SLC6A4 genotype. Persons with more traumatic events were at increased risk for PTSD, but only at lower methylation levels. At higher methylation levels, individuals with more traumatic events were protected from this disorder. This interaction was observed whether the outcome was PTSD diagnosis, symptom severity, or number of symptoms. CONCLUSIONS: Gene-specific methylation patterns may offer potential molecular signatures of increased risk for and resilience to PTSD.

Common genetic variation in the GAD1 gene and the entire family of DLX homeobox genes and autism spectrum disorders.

Biological and positional evidence supports the involvement of the GAD1 and distal-less homeobox genes (DLXs) in the etiology of autism. We investigated 42 single nucleotide polymorphisms in these genes as risk factors for autism spectrum disorders (ASD) in a large family-based association study of 715 nuclear families. No single marker showed significant association after correction for multiple testing. A rare haplotype in the DLX1 promoter was associated with ASD (P-value = 0.001). Given the importance of rare variants to the etiology of autism revealed in recent studies, the observed rare haplotype may be relevant to future investigations. Our observations, when taken together with previous findings, suggest that common genetic variation in the GAD1 and DLX genes is unlikely to play a critical role in ASD susceptibility.

Evaluation of machine learning methodology for the prediction of healthcare resource utilization and healthcare costs in patients with critical limb ischemia-is preventive and personalized approach on the horizon?

BACKGROUND: Critical limb ischemia (CLI) is a severe stage of peripheral arterial disease and has a substantial disease and economic burden not only to patients and families, but also to the society and healthcare systems. We aim to develop a personalized prediction model that utilizes baseline patient characteristics prior to CLI diagnosis to predict subsequent 1-year all-cause hospitalizations and total annual healthcare cost, using a novel Bayesian machine learning platform, Reverse Engineering Forward Simulation™ (REFS™), to support a paradigm shift from reactive healthcare to Predictive Preventive and Personalized Medicine (PPPM)-driven healthcare. METHODS: Patients ≥ 50 years with CLI plus clinical activity for a 6-month pre-index and a 12-month post-index period or death during the post-index period were included in this retrospective cohort of the linked Optum-Humedica databases. REFS™ built an ensemble of 256 predictive models to identify predictors of all-cause hospitalizations and total annual all-cause healthcare costs during the 12-month post-index interval. RESULTS: The mean age of 3189 eligible patients was 71.9 years. The most common CLI-related comorbidities were hypertension (79.5%), dyslipidemia (61.4%), coronary atherosclerosis and other heart disease (42.3%), and type 2 diabetes (39.2%). Post-index CLI-related healthcare utilization included inpatient services (14.6%) and ≥ 1 outpatient visits (32.1%). Median annual all-cause and CLI-related costs per patient were $30,514 and $2196, respectively. REFS™ identified diagnosis of skin and subcutaneous tissue infections, cellulitis and abscess, use of nonselective beta-blockers, other aftercare, and osteoarthritis as high confidence predictors of all-cause hospitalizations. The leading predictors for total all-cause costs included region of residence and comorbid health conditions including other diseases of kidney and ureters, blindness of vision defects, chronic ulcer of skin, and chronic ulcer of leg or foot. CONCLUSIONS: REFS™ identified baseline predictors of subsequent healthcare resource utilization and costs in CLI patients. Machine learning and model-based, data-driven medicine may complement physicians' evidence-based medical services. These findings also support the PPPM framework that a paradigm shift from post-diagnosis disease care to early management of comorbidities and targeted prevention is warranted to deliver a cost-effective medical services and desirable healthcare economy.