Dietary patterns and risk of systemic lupus erythematosus in women.

OBJECTIVE: Dietary intake is a complex exposure and a potential risk factor for systemic lupus erythematosus (SLE) due to its impact on lipid and glucose metabolism, oxidative stress, and the intestinal microbiome. We aimed to test whether a prudent dietary pattern is associated with a lower risk of SLE, and whether a Western dietary pattern is associated with a higher risk of SLE. METHODS: We prospectively investigated two dietary patterns and SLE risk among women in the Nurses' Health Study (NHS, 1984-2014) and Nurses' Health Study II (NHSII, 1991-2015). Food frequency questionnaires were completed every four years. Congruent with prior work in NHS and NHSII, we derived two separate dietary patterns (prudent and Western) using principal component analysis within each cohort. Incident SLE was confirmed by the American College of Rheumatology's 1997 criteria. We estimated hazard ratios (HR) and 95% confidence intervals (CI) for SLE by dietary pattern quartiles using Cox models adjusted for time-varying covariates. Models were performed separately in each cohort and results were meta-analyzed. Stratified analyses tested the association of dietary patterns with anti-dsDNA positive SLE and anti-dsDNA negative SLE. RESULTS: We confirmed 82 NHS incident SLE cases and 98 NHSII SLE cases during 3,833,054 person-years of follow-up. A higher (healthier) prudent dietary pattern score was not associated with SLE risk (meta-analyzed HRQ4 versus Q1 0.84 [95% CI 0.51, 1.38]). Women with higher (less healthy) Western dietary pattern scores did not have a significantly increased risk for SLE (meta-analyzed HRQ4 versus Q1 1.35 [95% CI 0.77, 2.35]). Results were similar after further adjustment for body mass index. Incident anti-dsDNA positive SLE and anti-dsDNA negative SLE were not associated with either dietary pattern. CONCLUSION: We did not observe a relationship between prudent or Western dietary pattern score and risk of SLE.

Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability.

The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case-control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European-American females of 29% that is similar to h2SNP for schizophrenia and is substantially higher than h2SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD-for both European- and African-American individuals-and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.

Post-traumatic stress disorder symptom duration and remission in relation to cardiovascular disease risk among a large cohort of women.

BACKGROUND: Prior studies suggest that post-traumatic stress disorder (PTSD) is associated with elevated cardiovascular disease (CVD) risk, but effects of duration and remission of PTSD symptoms have rarely been evaluated. METHOD: We examined the association of time-updated PTSD symptom severity, remission and duration with incident CVD risk (552 confirmed myocardial infarctions or strokes) over 20 years in 49 859 women in the Nurses' Health Study II. Among women who reported trauma on the Brief Trauma Questionnaire, PTSD symptoms, assessed by a screener, were classified by symptom severity and chronicity: (a) no symptoms, (b) 1-3 ongoing, (c) 4-5 ongoing, (d) 6-7 ongoing, (e) 1-3 remitted, (f) 4-7 remitted symptoms. Inverse probability weighting was used to estimate marginal structural logistic regression models, adjusting for time-varying and time-invariant confounders. RESULTS: Compared with women with no trauma exposure, women with trauma/no PTSD [odds ratio (OR) 1.30, 95% confidence interval (CI) 1.03-1.65] and women with trauma/6-7 symptoms (OR 1.69, 95% CI 1.08-2.63) had elevated risk of CVD; women with remitted symptoms did not have elevated CVD risk. Among women exposed to trauma, every 5 additional years of PTSD symptomology was associated with 9% higher CVD incidence compared with women with trauma/no PTSD. CONCLUSIONS: The findings suggest that alleviating PTSD symptoms shortly after onset may attenuate CVD risk.

Post-traumatic stress disorder and cardiometabolic disease: improving causal inference to inform practice.

Post-traumatic stress disorder (PTSD) has been declared 'a life sentence' based on evidence that the disorder leads to a host of physical health problems. Some of the strongest empirical research - in terms of methodology and findings - has shown that PTSD predicts higher risk of cardiometabolic diseases, specifically cardiovascular disease (CVD) and type 2 diabetes (T2D). Despite mounting evidence, PTSD is not currently acknowledged as a risk factor by cardiovascular or endocrinological medicine. This view is unlikely to change absent compelling evidence that PTSD causally contributes to cardiometabolic disease. This review suggests that with developments in methods for epidemiological research and the rapidly expanding knowledge of the behavioral and biological effects of PTSD the field is poised to provide more definitive answers to questions of causality. First, we discuss methods to improve causal inference using the observational data most often used in studies of PTSD and health, with particular reference to issues of temporality and confounding. Second, we consider recent work linking PTSD with specific behaviors and biological processes, and evaluate whether these may plausibly serve as mechanisms by which PTSD leads to cardiometabolic disease. Third, we evaluate how looking more comprehensively into the PTSD phenotype provides insight into whether specific aspects of PTSD phenomenology are particularly relevant to cardiometabolic disease. Finally, we discuss new areas of research that are feasible and could enhance understanding of the PTSD-cardiometabolic relationship, such as testing whether treatment of PTSD can halt or even reverse the cardiometabolic risk factors causally related to CVD and T2D.

The complement receptor 3 (CD11b/CD18) agonist Leukadherin-1 suppresses human innate inflammatory signalling.

Complement receptor 3 (CR3, CD11b/CD18) is a multi-functional receptor expressed predominantly on myeloid and natural killer (NK) cells. The R77H variant of CD11b, encoded by the ITGAM rs1143679 polymorphism, is associated robustly with development of the autoimmune disease systemic lupus erythematosus (SLE) and impairs CR3 function, including its regulatory role on monocyte immune signalling. The role of CR3 in NK cell function is unknown. Leukadherin-1 is a specific small-molecule CR3 agonist that has shown therapeutic promise in animal models of vascular injury and inflammation. We show that Leukadherin-1 pretreatment reduces secretion of interferon (IFN)-γ, tumour necrosis factor (TNF) and macrophage inflammatory protein (MIP)-1ß by monokine-stimulated NK cells. It was associated with a reduction in phosphorylated signal transducer and activator of transcription (pSTAT)-5 following interleukin (IL)-12 + IL-15 stimulation (P < 0·02) and increased IL-10 secretion following IL-12 + IL-18 stimulation (P < 0·001). Leukadherin-1 pretreatment also reduces secretion of IL-1ß, IL-6 and TNF by Toll-like receptor (TLR)-2 and TLR-7/8-stimulated monocytes (P < 0·01 for all). The R77H variant did not affect NK cell response to Leukadherin-1 using ex-vivo cells from homozygous donors; nor did the variant influence CR3 expression by these cell types, in contrast to a recent report. These data extend our understanding of CR3 biology by demonstrating that activation potently modifies innate immune inflammatory signalling, including a previously undocumented role in NK cell function. We discuss the potential relevance of this to the pathogenesis of SLE. Leukadherin-1 appears to mediate its anti-inflammatory effect irrespective of the SLE-risk genotype of CR3, providing further evidence to support its evaluation of Leukadherin-1 as a potential therapeutic for autoimmune disease.

Post-traumatic stress disorder symptoms and risk of hypertension over 22 years in a large cohort of younger and middle-aged women.

BACKGROUND: Post-traumatic stress disorder (PTSD) has been linked to hypertension, but most research on PTSD and hypertension is cross-sectional, and potential mediators have not been clearly identified. Moreover, PTSD is twice as common in women as in men, but understanding of the PTSD-hypertension relationship in women is limited. We examined trauma exposure and PTSD symptoms in relation to incident hypertension over 22 years in 47 514 civilian women in the Nurses' Health Study II. METHOD: We used proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for new-onset hypertension (N = 15 837). RESULTS: PTSD symptoms assessed with a screen were modestly associated with incident hypertension in a dose-response fashion after adjusting for potential confounders. Compared to women with no trauma exposure, women with 6-7 PTSD symptoms had the highest risk of developing hypertension (HR 1.20, 95% CI 1.12-1.30), followed by women with 4-5 symptoms (HR 1.17, 95% CI 1.10-1.25), women with 1-3 symptoms (HR 1.12, 95% CI 1.06-1.18), and trauma-exposed women with no symptoms (HR 1.04, 95% CI 1.00-1.09). Findings were maintained, although attenuated, adjusting for hypertension-relevant medications, medical risk factors, and health behaviors. Higher body mass index and antidepressant use accounted for 30% and 21% of the PTSD symptom-hypertension association, respectively. CONCLUSIONS: Screening for hypertension and reducing unhealthy lifestyle factors, particularly obesity, in women with PTSD may hold promise for offsetting cardiovascular risk.

Habitat complexity reduces parasitoid foraging efficiency, but does not prevent orientation towards learned host plant odours.

It is well known that many parasitic wasps use herbivore-induced plant odours (HIPVs) to locate their inconspicuous host insects, and are often able to distinguish between slight differences in plant odour composition. However, few studies have examined parasitoid foraging behaviour under (semi-)field conditions. In nature, food plants of parasitoid hosts are often embedded in non-host-plant assemblages that confer both structural and chemical complexity. By releasing both naïve and experienced Cotesia glomerata females in outdoor tents, we studied how natural vegetation surrounding Pieris brassicae-infested Sinapis arvensis and Barbarea vulgaris plants influences their foraging efficiency as well as their ability to specifically orient towards the HIPVs of the host plant species on which they previously had a positive oviposition experience. Natural background vegetation reduced the host-encounter rate of naïve C. glomerata females by 47 %. While associative learning of host plant HIPVs 1 day prior to foraging caused a 28 % increase in the overall foraging efficiency of C. glomerata, it did not reduce the negative influence of natural background vegetation. At the same time, however, females foraging in natural vegetation attacked more host patches on host-plant species on which they previously had a positive oviposition experience. We conclude that, even though the presence of natural vegetation reduces the foraging efficiency of C. glomerata, it does not prevent experienced female wasps from specifically orienting towards the host-plant species from which they had learned the HIPVs.

The role of allelic variation in estrogen receptor genes and major depression in the Nurses Health Study.

PURPOSE: The role of exogenous and endogenous sex hormones in the etiology of depression remains elusive, in part because sex hormone variation is often correlated with behaviors, life stage changes, and other factors that may influence depression. Estrogen receptor alpha (ESR1) and beta (ESR2) are known to regulate gene expression and estrogen response in areas of the brain associated with major depression and are unlikely to be correlated with exogenous factors that may influence depression. METHODS: We examined whether functional polymorphisms in these genes are associated with lifetime major depression and chronic major depression among a sample of women from the Nurses' Health Study II (N = 2527). DSM-IV depressive disorder symptoms were assessed by structured interview in 2007. Genotyping was performed on DNA extracted from blood using Taq-man. RESULTS: Women with the AA alleles of ESR2 RS4986938 had the higher prevalence of lifetime major depression than women with other allele frequencies (36.7 % for those with AA versus 28.5 % with GA and 29.1 % with GG, p = 0.02) and chronic major depression (14.7 % for those with AA versus 9.3 % with GA and 9.1 % with GG, p = 0.01). History of post-menopausal hormone (PMH) use modified the association of ESR1 polymorphism RS2234693 with any lifetime depression; specifically, those with the TT allele had the highest risk of lifetime depression among PMH users, and the lowest risk of depression among non-PMH users (p value for interaction = 0.02). Further, carriers of the AA alleles in ESR1 polymorphism RS9340799 had increased prevalence of lifetime major depression only among lifetime PMH users (p = 0.007). CONCLUSIONS: Our findings support the hypothesis that estrogen receptor polymorphisms influence risk for major depression; the role of estrogen receptors and other sex steroid-related genetic factors may provide unique insights into etiology.

Translating obstetrics and gynaecology undergraduate experience into career aspiration: an audit of Royal College of Obstetricians and Gynaecologists (RCOG) medical student placement standards.

In 2006, the Royal College of Obstetricians and Gynaecologists (RCOG) published a list of undergraduate placement standards in an effort to improve the obstetrics and gynaecology (O&G) undergraduate experience and reverse declining interest in the specialty among UK graduates. We surveyed 3rd-year medical students undertaking O&G placements to investigate how appropriate they felt the RCOG placement standards were. We present the first evaluation of these standards and discuss their potential role in improving the undergraduate O&G experience. We also sought to examine the influence of undergraduate O&G exposure on interest in entering the specialty and the effect of gender on perceived learning experience. Students rated the RCOG standards as highly appropriate, and significant differences in clinical exposure and career intentions were seen between genders. Overall, students demonstrated greater interest in pursuing O&G than has previously been documented, which may represent a wider upturn in interest in the speciality.

Race/ethnic differences in exposure to traumatic events, development of post-traumatic stress disorder, and treatment-seeking for post-traumatic stress disorder in the United States.

BACKGROUND: To identify sources of race/ethnic differences related to post-traumatic stress disorder (PTSD), we compared trauma exposure, risk for PTSD among those exposed to trauma, and treatment-seeking among Whites, Blacks, Hispanics and Asians in the US general population. METHOD: Data from structured diagnostic interviews with 34 653 adult respondents to the 2004-2005 wave of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) were analysed. RESULTS: The lifetime prevalence of PTSD was highest among Blacks (8.7%), intermediate among Hispanics and Whites (7.0% and 7.4%) and lowest among Asians (4.0%). Differences in risk for trauma varied by type of event. Whites were more likely than the other groups to have any trauma, to learn of a trauma to someone close, and to learn of an unexpected death, but Blacks and Hispanics had higher risk of child maltreatment, chiefly witnessing domestic violence, and Asians, Black men, and Hispanic women had higher risk of war-related events than Whites. Among those exposed to trauma, PTSD risk was slightly higher among Blacks [adjusted odds ratio (aOR) 1.22] and lower among Asians (aOR 0.67) compared with Whites, after adjustment for characteristics of trauma exposure. All minority groups were less likely to seek treatment for PTSD than Whites (aOR range: 0.39-0.61), and fewer than half of minorities with PTSD sought treatment (range: 32.7-42.0%). CONCLUSIONS: When PTSD affects US race/ethnic minorities, it is usually untreated. Large disparities in treatment indicate a need for investment in accessible and culturally sensitive treatment options.

Seroprevalence of SARS-CoV-2 antibodies, associated epidemiological factors and antibody kinetics among healthcare workers in Connecticut.

BACKGROUND: Healthcare workers (HCWs) are at the front line of the ongoing coronavirus 2019 (COVID-19) pandemic. Comprehensive evaluation of the seroprevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) among HCWs in a large healthcare system could help to identify the impact of epidemiological factors and the presence of symptoms on the immune response to the infection over time. AIM: To determine the seroprevalence of SARS-CoV-2-specific antibodies among HCWs, identify associated epidemiological factors and study antibody kinetics. METHODS: A longitudinal evaluation of the seroprevalence and epidemiology of SARS-CoV-2-specific antibodies was undertaken in approximately 30,000 HCWs in the largest healthcare system in Connecticut, USA. FINDINGS: At baseline, the prevalence of SARS-CoV-2 antibody among 6863 HCWs was 6.3% [95% confidence interval (CI) 5.7-6.9%], and was highest among patient care support (16.7%), medical assistants (9.1%) and nurses (8.2%), and lower for physicians (3.8%) and advanced practice providers (4.5%). Seroprevalence was significantly higher among African Americans [odds ratio (OR) 3.26 compared with Caucasians, 95% CI 1.77-5.99], in participants with at least one symptom of COVID-19 (OR 3.00, 95% CI 1.92-4.68), and in those reporting prior quarantine (OR 3.83, 95% CI 2.57-5.70). No symptoms were reported in 24% of seropositive participants. Among the 47% of participants who returned for a follow-up serological test, the seroreversion rate was 39.5% and the seroconversion rate was 2.2%. The incidence of re-infection in the seropositive group was zero. CONCLUSION: Although there is a decline in the immunoglobulin G antibody signal over time, 60.5% of seropositive HCWs had maintained their seroconversion status after a median of 5.5 months.

Percent body fat prediction equations for 8- to 17-year-old American children.

BACKGROUND: Percent body fat equations are usually developed in specific populations and have low generalizability. OBJECTIVES: To use a nationally representative sample of the American youth population (8-17 years old) from the 1999-2004 National Health and Nutrition Examination Survey data to develop gender-specific percent body fat equations. METHODS: Percent body fat equations were developed for girls and boys using information on weight, height, waist circumference, triceps skin-folds, age, race/ethnicity and menses status compared to dual-emission X-ray absorptiometry. Terms were selected using forward and backward selection in regression models in a 2/3 development sample and were cross-validated in the remaining sample. Final coefficients were estimated in the full sample. RESULTS: Final equations included ten terms in girls and eight terms in boys including interactions with age and race/ethnicity. In the cross-validation sample, the adjusted R2 was 0.818 and the root mean squared error was 2.758 in girls. Comparable estimates in boys were 0.893 and 2.525. Systematic bias was not detected in the estimates by race/ethnicity or by body mass index categories. CONCLUSION: Gender-specific percent body fat equations were developed in youth with a strong potential for generalizability and utilization by other investigators studying adiposity-related issues in youth.

Family ties: maternal-offspring attachment and young adult nonmedical prescription opioid use.

BACKGROUND: Nonmedical prescription drug use is prevalent among young adults, yet little is known about modifiable determinants of use. We examined whether maternal-offspring attachment reported at mean age 21 was associated with nonmedical prescription opioid use at mean age 26, and investigated whether a history of depressive symptoms and substance use played a role in associations between maternal-offspring attachment and nonmedical prescription opioid use. METHODS: We used data from the Growing Up Today Study, a longitudinal cohort of United States adolescents followed into young adulthood. Maternal-offspring attachment was reported by young adults and their mothers, and defined as mutual low, mutual medium or high, and dissonant. Analyses were carried out in the full sample using generalized estimating equation models, and in a sibling subsample, using conditional fixed effects models to control for stable aspects of the family environment. RESULTS: Analyses with the full sample and the sibling subsample both showed that mutual medium/high maternal-offspring attachment at age 21 was associated with lower odds of nonmedical prescription opioid use at age 26 (RR=0.74; 95% CI=0.57-0.97 in full sample). The association was partly mediated by mean age 23 offspring smoking, heavy episodic drinking, and illicit drug use. CONCLUSIONS: Promoting reciprocal attachment in the maternal-offspring dyad should be investigated as a strategy to prevent nonmedical prescription opioid use by young adulthood. Even in young adulthood, programs that target both parents and offspring may have greater impact on offspring substance use than programs that target offspring alone.

Phase improvement by cross-validated density modification.

Solvent flattening is a useful constraint for the early stages of crystallographic structure determination. However, sometimes it fails to produce significant improvement of poor experimental or molecular-replacement phases. This often occurs as a result of incorrect parameterization. In addition, the potential of overfitting or misinterpretation of the data exists. We have implemented a cross-validated (or free) R value in order to reduce this risk. The free R value was calculated between the experimental F(obs)(h) and the calculated structure factors, F(sf)(h), obtained by inverse Fourier transformation of the solvent-flattened electron density. Because of the sensitivity of the free R value to the test set selection at low resolution complete cross-validation may be required. The reliability of this approach was assessed by examining the correlation between the free R value and the known phase errors for two test cases. A high correlation was found upon variation of the extent of negative density elimination, figure of merit estimation, and the relative weighting in the phase combination procedure. The free R value can be used to optimize parameters of density-modification procedures when independent phase error estimates are unavailable.

Nucleophilic aromatic substitution reactions of chloroazines with bisulfide (HS-) and polysulfides (Sn2-).

Reactions of bisulfide and polysulfides with chloroazines (important constituents of agrochemicals and textile dyes) were examined in aqueous solution at 25 degrees C. For atrazine, rates are first-order in polysulfide concentration, and polysulfide dianions are the principal reactive nucleophiles; no measurable reaction occurs with HS-. Second-order rate constants for reactions of an array of chloroazines with polysulfides are several orders of magnitude greater than for reactions with HS-. Transformation products indicate the substitution of halogen(s) by sulfur. Ring aza nitrogens substantially enhance reactivity through a combination of inductive and mesomeric effects, and electron-withdrawing or electron-donating substituents markedly enhance or diminish reactivity, respectively. The overall second-order nature of the reaction, the products observed, and reactivity trends are all consistent with a nucleophilic aromatic substitution (S(N)Ar) mechanism. Rate constants for reactions with HS- and Sn2- (n = 2-5) correlate only weakly with lowest unoccupied molecular orbital energies, suggesting that the electrophilicity of a chloroazine is not the sole determinant of its reactivity. When second-order rate constants are extrapolated to HS- and Sn2- concentrations reported in salt marsh pore waters, half-lives of minutes to years are obtained. Polysulfides in particular could play an important role in effecting abiotic transformations of chloroazines in hypoxic marine waters.

Alkyl bromides as mechanistic probes of reductive dehalogenation: reactions of vicinal dibromide stereoisomers with zerovalent metals.

Whether reductive dehalogenation proceeds via a one- or a two-electron mechanism has been suggested to affect product distributions, hence potentially influencing the success of engineered treatment systems. In this work, we explore vicinal dibromide stereoisomers as "probes" of the concertedness of electron transfer in reduction by aqueous suspensions of iron and zinc metal. Dibromides consisted of 2,3-dibromopentane (diBP) stereoisomers and (+/-)-1,2-dibromo-1,2-diphenylethane. All dibromides reacted with metals to give the same E:Z ratio of olefins observed during dehalogenation by iodide (a two-electron reductant). Reduction by Cr(II) (a one-electron reductant) yielded distinctly different proportions of E and Z olefins. Although this might be construed as evidence that metals function as two-electron reductants, high stereo-specificity was also obtained for reduction of diBPs by Fe(II) adsorbed to goethite, a presumed one-electron reductant; this can be explained by two single-electron transfers in rapid succession, facilitated by the locally elevated concentration of reducing equivalents at the oxide-water interface. The results suggest that reduction of alkyl halides by metals is not likely to produce free radicals that persist long enough to undergo radical-radical coupling or hydrogen-atom abstraction from minor dissolved constituents. Apparent free-radical coupling products are more likely to result from (possibly surface-bound) organometallic intermediates.