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.

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.

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.

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.

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.

Pilot study of DNA methylation, molecular aging markers and measures of health and well-being in aging.

Relations of DNA methylation markers to other biological aging markers and to psychosocial, behavioral, and health measures remain unclear. The sample included 23 participants (n = 11 cases with psychiatric diagnoses and n = 12 controls without current or lifetime psychiatric disorder), balanced by age and sex. Genomic DNA was extracted from blood samples; the following were performed: genome-wide DNA methylation assay using Illumina 850k methylationEPIC; PCR assays for relative telomere length (RTL) and mitochondrial DNA copy number (mtCN). Exposures were: case status; depression and anxiety symptoms; psychosocial support; subjective and objective cognition. Outcomes were: DNA methylation age (DNAm age); RTL; mtCN; extrinsic and intrinsic epigenetic age acceleration (EEAA and IEAA). Stronger correlation with chronological age was observed for DNAm age (ρ = 0.86; p < 0.0001) compared to RTL (ρ = -0.53; p < 0.01); mtCN was not correlated with age. DNAm age was more strongly correlated with behavioral and health variables than RTL or mtCN; e.g., correlations with DNAm age: body mass index (ρ = 0.36; p = 0.10); smoking pack-years (ρ = 0.37; p = 0.08); physical activity (ρ = -0.56; p = 0.01); alcohol intake (ρ = 0.56; p = 0.01). DNAm age was inversely correlated with psychosocial support (ρ = -0.42; p = 0.048) and Modified Mini-Mental State score (ρ = -0.44; p = 0.01). Anxiety, psychosocial support, and objective cognition were significantly related to accelerated aging; depression and subjective cognition were not. In conclusion, DNAm age correlated more strongly with chronological age and key psychosocial, behavioral, and health variables than RTL or mtCN. Signals for associations with epigenetic aging were observed for psychosocial and neurobehavioral variables.

Determinants of the performance of traditional Chinese medicine clinics in Taiwan.

The study attempts to investigate the features and determinants of the performance of Taiwanese Traditional Chinese Medicine (TCM) Clinics with data for 4905 TCM clinics over the 1998 to 2012 period. The empirical results from the fixed effects model and the Hausman-Taylor Model with cluster-robust standard errors reveal several interesting findings. First, consumer characteristics such as the frequency of disabling injuries has positive impacts on the volume of medical services provided by TCM clinics. These results imply that people are likely to select TCM as the option for medical treatment when they face the occurrence of physical injury in Taiwan. In addition, the scale measurements for TCM clinics including the numbers of physicians, medical personnel and divisions have significantly positive effects on the performance of TCM clinics, while their survival length also has the same effect. Finally, the global budget system under the NHI plays a key role in suppressing the revenue of TCM clinics through the peer review mechanism.

Photoperiod during maternal pregnancy and lifetime depression in offspring.

Experimental studies indicate that perinatal light exposure has enduring effects on affective behaviors in rodents; however, insufficient research has explored this hypothesis in humans. We examined photoperiod (i.e., day length) metrics during maternal pregnancy in relation to lifetime depression in the longitudinal Nurses' Health Study (NHS) and NHS II. 160,723 participants reported birth date and birth state (used to derive daily photoperiod based on published mathematical equations), and clinician-diagnosed depression and antidepressant use throughout adulthood. Logistic regression was used to estimate odds ratios (OR) (and 95% confidence intervals [CI]) for depression (defined as clinician diagnosis and antidepressant use) across quintiles of two exposures during maternal pregnancy: 1) total photoperiod (total number of daylight hours) and 2) differences between minimum/maximum photoperiod; each trimester of pregnancy was examined separately. Total photoperiod during maternal pregnancy was not associated with depression overall or by trimester of pregnancy. However, larger differences between minimum/maximum photoperiod during maternal pregnancy were related to lower odds of depression (multivariable [MV]-adjusted OR: 0.86, 95% CI: 0.83, 0.90 comparing extreme quintiles of exposure; p-trend<0.0001); this association appeared specific to the second trimester of pregnancy (MV-adjusted p-trends = 0.03, <0.0001, and 0.3 across the three trimesters, respectively). In addition, birth at higher latitude (where larger differences in minimum/maximum photoperiod exist) was associated with a significant reduction in the lifetime risk of depression. These findings are consistent with an emerging hypothesis in which perinatal light exposure may influence risk of depression, and they might be understood through the conceptual framework of adaptive developmental plasticity.

Polygenic risk score of shorter telomere length and risk of depression and anxiety in women.

Prior studies have reported significant cross-sectional associations between depression or anxiety and shorter telomere lengths, but the temporality of associations is uncertain. Little is known regarding whether shorter telomere length is related to increased risk of developing depression or anxiety. In this study, using the genetic tool of polygenic risk score (PRS), we evaluated the association between genetic predisposition to shorter telomere length and the risks of lifetime clinically significant depression (defined by self-reported clinician/physician diagnosis, antidepressant use, and/or presence of severe depressive symptoms) and of clinically meaningful anxiety symptoms among 17,693 female participants of European ancestry. The weighted PRS of telomere lengths (TLs) combined the dosage of nine alleles that were significantly associated with inter-individual variation in TLs in published genome-wide association studies. Higher score of PRS, corresponding to shorter TL in the literature, was significantly associated with shorter relative TLs (p = 0.008). However, higher PRS was not associated with the lifetime risk of either depression or anxiety. Furthermore, higher PRS was not associated with long-term patterns of depressive symptom trajectories or specifically with later-life onset of depression or anxiety. In summary, this study did not observe a significant association between genetic predisposition to shorter telomere length and risk of depression and anxiety in a large sample of mid-life and older white women. However, these genetic variants jointly account for a limited proportion of interpersonal variation in leukocyte telomere length. Future studies will need to incorporate more genetic variants to improve the accuracy of predicted power, as such data become available.

Prospective study of chronotype and incident depression among middle- and older-aged women in the Nurses' Health Study II.

BACKGROUND: Prior cross-sectional studies have suggested that being a late chronotype is associated with depression and depressive symptoms, but prospective data are lacking. METHODS: We examined the association between chronotype and incident depression (defined as self-reported physician/clinician-diagnosed depression or antidepressant medication use) in 32,470 female participants of the Nurses' Health Study II cohort who self-reported their chronotype (early, intermediate or late) and were free of depression at baseline in 2009 (average age: 55 yrs). Women updated their depression status on biennial questionnaires in 2011 and 2013. We used multivariable (MV)-adjusted Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for incident depression across chronotype categories (i.e., early, intermediate, and late chronotypes). RESULTS: Across a follow-up period of 4 years, we observed 2,581 cases of incident depression in this cohort. Compared to intermediate chronotypes, early chronotypes had a modestly lower risk of depression after MV adjustment (MVHR = 0.88, 95%CI = 0.81-0.96), whereas late chronotypes had a similar risk of 1.06 (95%CI = 0.93-1.20); the overall trend across chronotype categories was statistically significant (ptrend<0.01). Results were similar when we restricted analyses to women who reported average sleep durations (7-8 h/day) and no history of rotating night shift work at baseline. CONCLUSIONS: Our results suggest that chronotype may influence the risk of depression in middle-to older-aged women. Additional studies are needed to confirm these findings and examine roles of both environmental and genetic factors to further our understanding of the role of chronotype in the etiology of mood disorders.

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.

Relation of long-term patterns in caregiving activity and depressive symptoms to telomere length in older women.

BACKGROUND: Research links psychological stress to accelerated cellular aging. Here we examined whether long-term patterns of depression and caregiving burden, forms of chronic psychological stress, were associated with shorter telomere length, a biomarker of cellular aging. METHODS: The study included 1250 healthy older women (mean: 68.0; range: 60-81 years) in the Nurses' Health Study. Long-term patterns in depressive symptoms and caregiving activity (separated into care of children/grandchildren vs. ill or disabled family members/others) incorporated questionnaire data between 1992 and 2000; relative leukocyte telomere lengths (LTLs) were measured in 2000-2001. Least-squares means LTL z-scores were calculated across categories of depression patterns and caregiving intensity. RESULTS: Six empirically-derived latent classes of depressive symptom trajectories were identified: minimal-stable (63.7%), mild-worsening (3.9%), subthreshold-improving (22.8%), subthreshold-worsening (2.7%), clinical range depressive-improving (6.2%), and clinical range depressive-persistent (0.6%). After collapsing trajectory patterns into 4 groups (combining those with minimal and mild symptoms into one group and those with clinical range depressive symptoms into one group) due to very small sample sizes in some groups, we observed marginal associations (p = 0.07): e.g., the least-squares means LTL z-scores were lowest (-0.08; 95% CI: -0.22 to 0.06) for the clinical range depressive symptoms group and highest (0.12; 0.04-0.20) for the subthreshold-improving group (Tukey's post-hoc pairwise p = 0.07). With six depressive symptom trajectories, no significant associations were observed with regard to telomere lengths. There were no significant associations between caregiving intensity and LTLs. CONCLUSIONS: There were no associations between long-term patterns of caregiving burden and telomere lengths among older women. Possible differences in telomere lengths by types of long-term depressive symptom trajectories may warrant further investigation.

Smoking Behavior Changes in the Early Rheumatoid Arthritis Period and Risk of Mortality During Thirty-Six Years of Prospective Followup.

OBJECTIVE: To investigate whether rheumatoid arthritis (RA) diagnosis influences smoking behavior changes and whether these changes were associated with mortality. METHODS: We identified an incident RA cohort in the Nurses' Health Study (NHS; 1976-2012). Behavioral data were collected through biennial questionnaires. We created a comparison cohort, matching RA cases to women without RA by age and calendar year at the index date of RA diagnosis. To investigate smoking behavior changes in the early RA period, sustained cessation was defined as permanently quitting within 4 years of the RA/index date. We used Cox regression to obtain hazard ratios (HRs) for mortality, comparing sustained smoking cessation to continued smoking. RESULTS: Among 121,700 women in the NHS, we identified 938 with incident RA matched to 8,951 non-RA comparators. Among current smokers, 40.0% with RA permanently quit smoking in the early RA period, compared to 36.1% of comparators (odds ratio for sustained cessation 1.18 [95% confidence interval (95% CI) 0.88, 1.58]). There were 313 deaths (33.4%) in the RA cohort and 2,042 (22.8%) among comparators. Compared to continued smoking, sustained cessation was associated with similarly decreased mortality in both the RA (HR 0.58 [95% CI 0.33, 1.01]) and comparison (HR 0.47 [95% CI 0.39, 0.58]) cohorts. Women with RA had higher mortality for >5 post-RA pack-years (HR 3.67 [95% CI 2.80, 4.81]) than comparators with >5 post-index pack-years (HR 1.88 [95% CI 1.62, 2.17]; P < 0.001 for interaction; reference: ever-smoker non-RA women with 0 post-index pack-years). CONCLUSION: Sustained smoking cessation within 4 years of RA diagnosis reduced mortality risk, with a similar effect observed among non-RA comparators. Smoking >5 pack-years after RA diagnosis significantly increased mortality beyond the risk of non-RA comparators.

Weight Change During the Early Rheumatoid Arthritis Period and Risk of Subsequent Mortality in Women With Rheumatoid Arthritis and Matched Comparators.

OBJECTIVE: To investigate whether weight change during the early rheumatoid arthritis (RA) period is associated with subsequent mortality and to evaluate whether there is an RA-specific effect. METHODS: We identified patients with incident RA during the Nurses' Health Study (NHS; 1976-2016) and created a comparison cohort by matching each RA patient with up to 10 non-RA comparators by age and calendar year of the RA diagnosis (index date). To capture weight change around the early RA period ("peri-RA/index"), we used weight measurements collected 2-4 years before and 2-4 years after the index date. We used Cox regression analysis to estimate hazard ratios (HRs) for mortality according to peri-RA/index weight change categories, separately in each cohort and in the combined cohorts, evaluating for an RA-specific effect. RESULTS: Among 121,701 women in the NHS, 902 patients with incident RA were identified and matched to 7,884 non-RA comparators. In the RA cohort, 371 deaths (41.1%) occurred during a mean follow-up of 17.0 years after the early RA period, and 2,303 deaths (29.2%) occurred in the comparison cohort during a mean follow-up of 18.4 years. Weight loss of >30 pounds during the peri-RA period had a hazard ratio (HR) for mortality of 2.78 (95% confidence interval [95% CI] 1.58-4.89) compared to stable weight; results in the comparison cohort were similar (HR 2.16, 95% CI 1.61-2.88). A weight gain of >30 pounds had no association with mortality in patients with RA (HR 1.45, 95% CI 0.69-3.07) or comparators (HR 1.19, 95% CI 0.89-1.59). For mortality, there was no statistically significant interaction between RA/comparator status and weight change category (P = 0.68). CONCLUSION: Severe weight loss during the early RA period was associated with an increased subsequent mortality risk for women with and those without RA. These results extend prior observations by including non-RA comparators and finding no protective association between weight gain and mortality, providing evidence against an RA-specific obesity paradox for mortality.

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.

Association of Trauma and Posttraumatic Stress Disorder With Incident Systemic Lupus Erythematosus in a Longitudinal Cohort of Women.

OBJECTIVE: To conduct the first longitudinal study examining whether trauma exposure and posttraumatic stress disorder (PTSD) are associated with increased risk of incident systemic lupus erythematosus (SLE) in a civilian cohort. METHODS: We examined the association of trauma exposure and PTSD symptoms with SLE incidence over 24 years of follow-up in a US longitudinal cohort of women (n = 54,763). Incident SLE in women meeting ≥4 American College of Rheumatology criteria was ascertained by self-report and confirmed by medical record review. PTSD and trauma exposure were assessed with the Short Screening Scale for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition PTSD and the Brief Trauma Questionnaire, respectively. Women were categorized as having no trauma, trauma and no PTSD symptoms, subclinical PTSD (1-3 symptoms), or probable PTSD (4-7 symptoms). We examined whether longitudinally assessed health risk factors (e.g., smoking, body mass index [BMI], oral contraceptive use) accounted for increased SLE risk among women with trauma exposure and PTSD versus those without. RESULTS: During follow-up, 73 cases of SLE occurred. Compared to women with no trauma, probable PTSD was associated with increased SLE risk (for 4-7 symptoms, hazard ratio [HR] 2.94 [95% confidence interval {95% CI} 1.19-7.26], P < 0.05). Subclinical PTSD was associated with increased SLE risk, although this did not reach statistical significance (for 1-3 symptoms, HR 1.83 [95% CI 0.74-4.56], P = 0.19). Smoking, BMI, and oral contraceptive use slightly attenuated the associations (e.g., for 4-7 symptoms, adjusted HR 2.62 [95% CI 1.09-6.48], P < 0.05). Trauma exposure, regardless of PTSD symptoms, was strongly associated with incident SLE (HR 2.83 [95% CI 1.29-6.21], P < 0.01). CONCLUSION: This study contributes to growing evidence that psychosocial trauma and associated stress responses may lead to autoimmune disease.

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.

Influence of Alcohol Consumption on the Risk of Systemic Lupus Erythematosus Among Women in the Nurses' Health Study Cohorts.

OBJECTIVE: Moderate alcohol consumption has antiinflammatory properties and is associated with reduced cardiovascular disease and rheumatoid arthritis risks. We investigated the association between alcohol consumption and systemic lupus erythematosus (SLE) risk among women followed in the Nurses' Health Study (NHS) cohorts. METHODS: We conducted a prospective cohort analysis among 204,055 women in NHS (1980-2012) and NHSII (1989-2011) who were free of connective tissue disease and provided alcohol information at baseline. Alcohol consumption was assessed using a semiquantitative food frequency questionnaire every 2-4 years. We validated incident SLE through medical record review after self-report. Cox proportional hazards models estimated hazard ratios (HRs) for SLE based on cumulative average alcohol intake, adjusting for potential confounders. Results were meta-analyzed using DerSimonian and Laird random-effects models. We further investigated SLE risk associated with wine, beer, and liquor intake. RESULTS: We identified 125 incident SLE cases in NHS and 119 in NHSII. Mean ± SD age at SLE diagnosis was 55.8 ± 9.5 years in NHS and 43.4 ± 7.7 years in NHSII. Compared to no alcohol intake, the meta-analyzed multivariable HR for cumulative alcohol consumption ≥5 gm/day was 0.61 (95% confidence interval [95% CI] 0.41-0.89). When limiting alcohol exposure to >4 years prior to SLE diagnosis, the multivariable HR was similar: 0.61 (95% CI 0.41-0.91). Women who drank ≥2 servings/week of wine had significantly decreased SLE risk (HR 0.65, 95% CI 0.45-0.96) compared to women who did not drink wine. CONCLUSION: In these large prospective cohorts, we demonstrated an inverse association between moderate alcohol consumption (≥5 grams or 0.5 drink/day) and SLE risk in women.