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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.

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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13167-019-00196-9) contains supplementary material, which is available to authorized users.

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.To develop a machine learning model using elements within the electronic health record data that are related to prior symptomatic treatment to predict PIDD.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.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.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.

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.

States of matter that break time-reversal symmetry are invariably associated with magnetism or circulating currents. Recently, one of us proposed a phase, the directional scalar spin chiral order (DSSCO), as an exception: it breaks time-reversal symmetry via chiral ordering of spins along a particular direction, but is spin-rotation symmetric. In this work we prove the existence of this state via state-of-the-art density matrix renormalization group (DMRG) analysis on a spin-1 chain with nearest-neighbor bilinear-biquadratic interactions and additional third-neighbor ferromagnetic Heisenberg exchange. Despite the large entanglement introduced by the third-neighbor coupling, we are able to access system sizes up to $L=918$ sites. We find first-order phase transitions from the DSSCO into the famous Haldane phase as well as a spin-quadrupolar phase where spin nematic correlations dominate. In the Haldane phase we demonstrate a method for detecting the topological edge states using DMRG that could be useful for other topological phases too. This method can be understood as the well-known active operators applied only at the boundary.

ObjectivesTo 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.DesignObservational cohort study.SettingCOVID-19 subset of the Optum deidentified electronic health records, including more than 1.8 million patients from across the USA.ParticipantsThere 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 measuresIncident acute clinical outcomes, including in-hospital all-cause mortality.ResultsRespectively, 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.ConclusionThe 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.

Objective: Past studies have reported associations between pesticide exposure and the risk of systemic lupus erythematosus (SLE). Residential pesticide exposure has been less well studied than agricultural exposure. The purpose of this study was to assess SLE risk associated with residential pesticide exposure in an urban population of predominantly African-American women. Methods: Adult women with SLE were identified from six hospital databases and community screening in three neighborhoods in Boston, Massachusetts, USA. Controls were adult women volunteers from the same neighborhoods who were screened for the absence of connective tissue disease and anti-nuclear antibodies. Subjects were considered exposed to pesticides if they had ever had an exterminator for an ant, cockroach, or termite problem prior to SLE diagnosis or corresponding reference age in controls. Risks associated with pesticide exposure were analyzed using multivariable logistic regression models, adjusted for sociodemographic factors. Results: We identified 93 SLE subjects and 170 controls with similar baseline characteristics. Eighty-three per cent were African-American. Pesticide exposure was associated with SLE, after controlling for potential confounders (odds ratio 2.24, 95% confidence interval 1.28–3.93). Conclusion: Residential exposure to pesticides in an urban population of predominantly African-American women was associated with increased SLE risk. Additional studies are needed to corroborate these findings.

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

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.

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.

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 ρ = −0.53; p 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.

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.

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.

Background: The impact of dietary flavonoid intakes on risk of depression is unclear. Objective: We prospectively examined associations between estimated habitual intakes of dietary flavonoids and depression risk. Design: We followed 82,643 women without a previous history of depression at baseline from the Nurses' Health Study [(NHS) aged 53-80 y] and the Nurses' Health Study II [(NHSII) aged 36-55 y]. Intakes of total flavonoids and subclasses (flavonols, flavones, flavanones, anthocyanins, flavan-3-ols, polymeric flavonoids, and proanthocyanidins) were calculated from validated foodfrequency questionnaires collected every 2-4 y. Depression was defined as physician- or clinician-diagnosed depression or antidepressant use and was self-reported in response to periodic questionnaires. Cox proportional hazards models were performed to examine associations. Results: A total of 10,752 incident depression cases occurred during a 10-y follow-up. Inverse associations between flavonol, flavone, and flavanone intakes and depression risk were observed. Pooled multivariable- Adjusted HRs (95% CIs) were 0.93 (0.88, 0.99), 0.92 (0.86, 0.98), and 0.90 (0.85, 0.96) when comparing the highest (quintile 5) with the lowest (quintile 1) quintiles, respectively, with evidence of linear trends across quintiles (P- Trend = 0.0004-0.08). In flavonoid-rich food-based analyses, the HR was 0.82 (95% CI: 0.74, 0.91) among participants who consumed $2 servings citrus fruit or juices/d compared with ,1 serving/wk. In the NHS only, total flavonoids, polymers, and proanthocyanidin intakes showed significantly (9-12%) lower depression risks. In analyses among late-life NHS participants (aged $65 y at baseline or during follow-up), for whom we were able to incorporate depressive symptoms into the outcome definition, higher intakes of all flavonoid subclasses except for flavan-3-ols were associated with significantly lower depression risk; flavones and proanthocyanidins showed the strongest associations (HR for both: 0.83; 95% CI: 0.77, 0.90). Conclusions: Higher flavonoid intakes may be associated with lower depression risk, particularly among older women. Further studies are needed to confirm these associations. Am J Clin Nutr 2016;104:704-14.

Objective To examine whether genetic, environmental, and serologic rheumatoid arthritis (RA) risk factors are associated with inflammatory joint signs in a cohort of first-degree relatives (FDRs) of RA patients. Methods We evaluated RA risk factors and inflammatory joint signs in a prospective cohort of FDRs without RA in the Studies of the Etiology of RA. Genetic factors included 5 HLA-DRB1 shared epitope alleles and 45 RA-associated single-nucleotide polymorphisms; loci were combined using genetic risk scores weighted by RA risk. Environmental factors (smoking, body mass index, education, and parity) and RA-related autoantibodies were assessed at baseline. Physical examination was performed at baseline and 2-year follow-up, by observers who were blinded with regard to autoantibody status, to assess inflammatory joint signs as tender or swollen joints at sites typical for RA. Logistic regression was performed to evaluate associations of genetic, environmental, and serologic factors with inflammatory joint signs. Results We analyzed 966 non-Hispanic white FDRs at baseline and 262 at 2-year follow-up after excluding those with inflammatory joint signs at baseline. The mean ± SD age was 47.2 ± 15.5 years, 71% were female, and 55% were shared epitope positive. Smoking >10 pack-years was associated with inflammatory joint signs at baseline (odds ratio [OR] 1.89 [95% confidence interval (95% CI) 1.26-2.82]) and at 2 years (OR 2.66 [95% CI 1.01-7.03]), compared to never smokers. There was a significant interaction between smoking and age with regard to risk of inflammatory joint signs (P = 0.02). FDRs younger than 50 years with >10 pack-years had the highest risk of inflammatory joint signs (OR 4.39 [95% CI 2.22-8.66], compared to never smokers younger than 50 years). Conclusion In a high-risk cohort of FDRs, smoking and age were associated with both prevalent and incident inflammatory joint signs at sites typical for RA. Further prospective investigations of the factors affecting the transitions between preclinical RA phases are warranted.

This study first features 334,781 job openings required certificate from Taiwan’s two largest human source agencies and then evaluates the market value of certificates for occupational safety and health management. We utilize demand, supply and an intermediary unit as the three main criteria while ten sub-criteria and five alternatives are chosen as well. The study utilizes multi-criteria decision making (MCDM) methods, such as Fuzzy AHP, Fuzzy ANP and VIKOR as the tools for evaluating and analyzing the market value of the certificates. The qualitative analysis results suggest that the demand aspect is more important than the supply and intermediary unit aspects, that “fit between certificates and industries” in relation to supply is the most important sub-criterion, and that “government and regulations” for the intermediary unit has the second highest weight. Finally, “level A technician for occupational safety management”, “level A technician for occupational health management” and “higher examination for industrial safety” have significant market value in occupational safety and health management. We use the hybrid FMCDM model in this study to provide help to industries, the government, examinees and other interested parties to find out the factors affecting the supply of and demand for certificates.

Objective To evaluate rheumatoid arthritis (RA) and mortality risk among women followed prospectively in the Nurses’ Health Study (NHS). Methods We analyzed 119,209 women in the NHS who reported no connective tissue disease at enrollment in 1976. Comorbidity and lifestyle data were collected through biennial questionnaires. Incident RA cases were validated by medical records review. Cause of death was determined by death certificate and medical records review. Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (95% CIs) for all-cause, cardiovascular disease (CVD), cancer, and respiratory disease mortality for women with RA compared to those without RA. Results We validated 964 incident RA cases and identified 28,808 deaths during 36 years of prospective follow-up. Of 307 deaths among women with RA, 80 (26%) were from cancer, 70 (23%) were from CVD, and 44 (14%) were from respiratory causes. Women with RA had increased total mortality (HR 1.40, 95% CI 1.25–1.57) compared to those without RA, independent of mortality risk factors, including smoking. RA was associated with significantly increased respiratory disease mortality (HR 2.06, 95% CI 1.51–2.80) and cardiovascular disease mortality (HR 1.45, 95% CI 1.14–1.83), but not cancer mortality (HR 0.93, 95% CI 0.74–1.15). For women with seropositive RA, respiratory disease mortality was nearly 3-fold higher than among non-RA women (HR 2.67, 95% CI 1.89–3.77). Conclusion Women with RA had significantly increased mortality compared to those without RA. Respiratory disease and cardiovascular disease mortality were both significantly elevated for women with RA. The nearly 3-fold increased relative risk of respiratory disease mortality was observed only for those with seropositive RA.

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 β-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.

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

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.

This study aims to construct the business model for firms in Taiwan's e-book industry.This study applied a hybrid fuzzy MCDM approach including FAHP, VIKOR, GRA, and TOPSIS to achieve the aim.This study provides a complete analysis of e-book business model selection. This study evaluates an appropriate business model for e-book firms in Taiwan. We apply expert questionnaires to calculate the weights, which contain five criteria, namely, business strategy (BS), finance characteristics (FC), market characteristics (MC), quality measurements of product and service (QS) and implementation (IM) (BCCSM) for the capability of developing the firms' business. Then, a fuzzy analytic hierarchy process (FAHP) is adopted to explore the weights of indices, and the VlseKriterijumska Optimizacija I Kompromisno Resenje (VIKOR), grey relation analysis (GRA), and the technique for order preference by similarity to ideal solution (TOPSIS) are utilized to rank the three alternatives. The results show that a single brand is the best e-book firms' business strategy that is simultaneously integrated by content, platforms, and devices, while the top two weights of the evaluation criteria are the business strategy and market characteristics to enable firms to develop an appropriate e-book business model.

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 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.

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 13C-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 13C-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.

The study attempts to investigate the features and determinants of China's outward foreign direct investment (OFDI) into 138 countries and Chinese firms' investment strategies over the 2003–2009 period using an augmented gravity model with spatial linkages. The respective evaluations of China's OFDI are indicative of the important role played by non-financial OFDI. At the same time, Chinese firms prefer to invest in high-tech industries in developed countries while also focusing on the extraction of natural resources around the world. The empirical findings show that the host country's economic size has a significantly positive effect in terms of promoting Chinese OFDI. Chinese firms favour a complex-vertical platform in the developed countries while they prefer a market potential foreign direct investment (FDI) surrounding the host developing countries and an export-platform FDI in the petroleum exporting countries based on the surrounding market potential effect and spatial effect. The fuel extr...

BackgroundObesity and anxiety are often linked but the direction of effects is not clear.MethodUsing genetic instrumental variable (IV) analyses in 5911 female participants from the Nurses' Health Study (NHS, initiated 1976) and 3697 male participants from the Health Professional Follow-up Study (HPFS, initiated 1986), we aimed to determine whether obesity increases symptoms of phobic anxiety. As instrumental variables we used the fat mass and obesity-associated (FTO) gene, the melanocortin 4 receptor (MC4R) gene and a genetic risk score (GRS) based on 32 single nucleotide polymorphisms (SNPs) that significantly predict body mass index (BMI). ‘Functional’ GRSs corresponding with specific biological pathways that shape BMI (adipogenesis, appetite and cardiopulmonary) were considered. The main outcome was phobic anxiety measured by the Crown Crisp Index (CCI) in 2004 in the NHS and in 2000 in the HPFS.ResultsIn observational analysis, a 1-unit higher BMI was associated with higher phobic anxiety symptoms [women:β = 0.05, 95% confidence interval (CI) 0.030–0.068; men:β = 0.04, 95% CI 0.016–0.071). IV analyses showed that BMI was associated with higher phobic anxiety symptoms in theFTO-instrumented analysis (p = 0.005) but not in the GRS-instrumented analysis (p = 0.256). Functional GRSs showed heterogeneous, non-significant effects of BMI on phobic anxiety symptoms.ConclusionsOur findings do not provide conclusive evidence in favor of the hypothesis that higher BMI leads to higher levels of phobic anxiety, but rather suggest that genes that influence obesity, in particularFTO, may have direct effects on phobic anxiety, and hence that obesity and phobic anxiety may share common genetic determinants.

Background Despite moderate heritability estimates for depression-related phenotypes, few robust genetic predictors have been identified. Potential explanations for this discrepancy include the use of phenotypic measures taken from a single time point, rather than integrating information over longer time periods via multiple assessments, and the possibility that genetic risk is shaped by multiple loci with small effects. Methods We developed a 14-year long-term average depression measure based on 14 years of follow-up in the Nurses' Health Study (NHS; N = 6989 women). We estimated polygenic scores (PS) with internal whole-genome scoring (NHS-GWAS-PS). We also constructed PS by applying two external PS weighting algorithms from independent samples, one previously shown to predict depression (GAIN-MDD-PS) and another from the largest genome-wide analysis currently available (PGC-MDD-PS). We assessed the association of all three PS with our long-term average depression phenotype using linear, logistic, and quantile regressions. Results In this study, the three PS approaches explained at most 0.2% of variance in the long-term average phenotype. Quantile regressions indicated PS had larger impacts at higher quantiles of depressive symptoms. Quantile regression coefficients at the 75th percentile were at least 40% larger than at the 25th percentile in all three polygenic scoring algorithms. The interquartile range comparison suggested the effects of PS significantly differed at the 25th and 75th percentiles of the long-term depressive phenotype for the PGC-MDD-PS (P = 0.03), and this difference also reached borderline statistical significance for the GAIN-MDD-PS (P = 0.05). Conclusions Integrating multiple phenotype assessments spanning 14 years and applying different polygenic scoring approaches did not substantially improve genetic prediction of depression. Quantile regressions suggested the effects of PS may be largest at high quantiles of depressive symptom scores, presumably among people with additional, unobserved sources of vulnerability to depression.

Some evidence suggests that genetic polymorphisms in oxytocin pathway genes influence various social behaviors, but findings thus far have been mixed. Many studies have been based in small samples and there is possibility of publication bias. Using data from 2 large U.S. prospective cohorts with over 11,000 individuals, we investigated 88 SNPs in OXTR, AVPR1A, and CD38, in relation to social integration (measured as social connectedness in both binary and continuous forms and being continuously married). After correction for multiple testing only one SNP in CD38 (rs12644506) was significantly associated with social integration and that SNP predicted when using a dichotomized indicator of social connectedness (adjusted p=0.02), but not a continuous measure of social connectedness or the continuously married outcome. A significant gender-heterogeneous effect was identified in one OXTR SNP on dichotomized social connectedness; specifically, rs4686302 T allele was nominally associated with social connectedness in men, whereas the association direction was opposite in women (adjusted gender heterogeneity p=0.02). Furthermore, the rs53576 A allele was significantly associated with social connectedness only in women, and the effect magnitude was stronger in a dominant genetic model (adjusted p=0.003). In summary, our findings suggested that common genetic variants of OXTR, CD38, and AVPR1A are not associated with social integration as measured in this study using the simplified Berkman-Syme Social Network Index, but these findings and other work hint that effects may be modified by gender or other social experiences. Further work considering genetic pathways in relation to social integration may be more fruitful if these additional factors can be more comprehensively evaluated.

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. © 2013 Wiley Periodicals, Inc.

The right decision policy for selecting a business strategy at the business development stage can maximize the benefits realized by firms. By means of the analytic network process (ANP) methodology infrastructure, and the sensitivity test, we evaluate the best alternative business strategies for one of medium-firms in the Taiwanese communications and networking industry. The findings show that the firm would be well advised to adopt the customer-driven demand to strategic project demand upon the limitation in its capability for solution designs, reliability in production management, and flexibility in financial leverage. This research and analysis can be deployed on the assessment and measurement of enterprise management and business strategy selection.

Low socioeconomic position (SEP) has previously been linked to a number of negative health indicators, including poor mental health. The biologic mechanisms linking SEP and mental health remain poorly understood. Recent work suggests that social exposures influence DNA methylation in a manner salient to mental health. We conducted a pilot investigation to assess whether SEP, measured as educational attainment, modifies the association between genomic methylation profiles and traumatic stress in a trauma-exposed sample. Results show that methylation × SEP interactions occur preferentially in genes pertaining to nervous system function, suggesting a plausible biological pathway by which SEP may enhance sensitivity to stress and, in turn, risk of posttraumatic stress disorder.[Supplementary materials are available for this article. Go to the publisher's online edition of Biodemography and Social Biology for the following free supplemental resource: Supplementary tables of full model and functional annotation clustering results.].

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. Language: en

Objective: We investigated 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 four years of RA/index date. We used Cox regression to obtain HRs for mortality, comparing sustained smoking cessation to continued smoking. Results: Among 121,701 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 (OR for sustained cessation 1.18, 95%CI 0.88-1.58). There were 313 (33.4%) deaths 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; pinteraction5 pack-years after RA diagnosis significantly increased mortality beyond the risk of non-RA comparators. This article is protected by copyright. All rights reserved.

We conducted genome-wide association studies of three phenotypes: subjective well-being (N = 298,420), depressive symptoms (N = 161,460), and neuroticism (N = 170,910). We identified three variants associated with subjective well-being, two with depressive symptoms, and eleven with neuroticism, including two inversion polymorphisms. The two depressive symptoms loci replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ̂| ≈ 0.8) strengthen the overall credibility of the findings, and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal/pancreas tissues are strongly enriched for association.

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. 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. 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). 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.

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.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.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.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 WileySons, Ltd.

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.

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (vertical bar(p) over cap vertical bar approximate to 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.

This study attempts to investigate market power in the U.S. commercial banking industry since the U.S. government began to deregulate the banking sector in the early 1990s using the static Bresnahan–Lau model (SBLM) and dynamic Bresnahan–Lau model with error corrections (DBLEC). In particular, panel unit root and panel cointegration techniques are utilized to examine the dynamic model. The empirical results of the SBLM show that the banking industry is highly competitive. The empirical results of DBLEC also suggest that the commercial banking industry is close to being perfectly competitive in the short run. By contrast, the adjustment speeds of the supply and demand sides towards the long-run equilibrium are quite slow in that market, which implies that the U.S. commercial banks enjoy a certain degree of long-run market power.