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Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92–1.16]; I 2 =28%; P -heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.

Receiving regular HIV care is crucial for maintaining good health among persons with HIV. However, racial and gender disparities in HIV care receipt exist. Discrimination and its impact may vary by race/ethnicity and gender, contributing to disparities. Data from 1578 women in the Women’s Interagency HIV Study ascertained from 10/1/2012 to 9/30/2016 were used to: (1) estimate the relationship between discrimination and missing any scheduled HIV care appointments and (2) assess whether this relationship is effect measure modified by race/ethnicity. Self-reported measures captured discrimination and the primary outcome of missing any HIV care appointments in the last 6 months. Log-binomial models accounting for measured sources of confounding and selection bias were fit. For the primary outcome analyses, women experiencing discrimination typically had a higher prevalence of missing an HIV care appointment. Moreover, there was no statistically significant evidence for effect measure modification by race/ethnicity. Interventions to minimize discrimination or its impact may improve HIV care engagement among women.

Diverse microbial ecosystems underpin life in the sea. Among these microbes are many unicellular eukaryotes that span the diversity of the eukaryotic tree of life. However, genetic tractability has been limited to a few species, which do not represent eukaryotic diversity or environmentally relevant taxa. Here, we report on the development of genetic tools in a range of protists primarily from marine environments. We present evidence for foreign DNA delivery and expression in 13 species never before transformed and for advancement of tools for eight other species, as well as potential reasons for why transformation of yet another 17 species tested was not achieved. Our resource in genetic manipulation will provide insights into the ancestral eukaryotic lifeforms, general eukaryote cell biology, protein diversification and the evolution of cellular pathways., This collaborative effort was supported by the Gordon and Betty Moore Foundation EMS Program of the Marine Microbiology Initiative (grant nos. GBMF4972 and 4972.01 to F.-Y.B.; GBMF4970 and 4970.01 to M.A. and A.Z.W.; GBMF3788 to A.Z.W.; GBMF 4968 and 4968.01 to H.C.; GBMF4984 to V.H.; GBMF4974 and 4974.01 to C. Brownlee; GBMF4964 to Y. Hirakawa; GBMF4961 to T. Mock; GBMF4958 to P.S.; GBMF4957 to A.T.; GBMF4960 to G.J.S.; GBMF4979 to K.C.; GBMF4982 and 4982.01 to J.L.C.; GBMF4964 to P.J.K.; GBMF4981 to P.v.D.; GBMF5006 to A.E.A.; GBMF4986 to C.M.; GBMF4962 to J.A.F.R.; GBMF4980 and 4980.01 to S.L.; GBMF 4977 and 4977.01 to R.F.W.; GBMF4962.01 to C.H.S.; GBMF4985 to J.M.; GBMF4976 and 4976.01 to C.H.; GBMF4963 and 4963.01 to V.E.; GBMF5007 to C.L.D.; GBMF4983 and 4983.01 to J.L.; GBMF4975 and 4975.01 to A.D.T.; GBMF4973 and 4973.01 to I.R.-T. and GBMF4965 to N.K.), by The Leverhulme Trust (RPG-2017-364) to T. Mock and A. Hopes, and by ERD funds (16_019/0000759) from the Czech Ministry of Education to J.L.

Potable water reuse is a viable option for communities with extreme water scarcity. Improvements in measurement capabilities and greater occurrence of contaminants of emerging concern (CECs) have made the investigation of the removal of CECs through advanced treatment facilities essential for further reuse considerations. Reverse osmosis (RO) has been demonstrated to remove many CECs, but poor removal has been observed for many low molecular weight (MW), neutral organic compounds. With the availability of many RO membrane products on the market, it is increasingly important to be able to predict organics rejection through different products without detailed information about the RO membrane's properties or structure. This laboratory-scale study investigated the rejection of low-MW, neutral organics, boron, and sodium chloride by six RO membrane products. The experimental results were used to develop a correlation between the removal of organics and boron. If the rejection of boron and a neutral organic through one reference membrane is available, then the rejection of that organic through any other membrane product can be estimated using the rejection of boron through that membrane.

We thank the Robert Bosch Foundation, the Max Planck Society and the University of St Andrews for funding. 1. Distance sampling (DS) is a widely used framework for estimating animal abundance. DS models assume that observations of distances to animals are independent. Non‐independent observations introduce overdispersion, causing model selection criteria such as AIC or AICc to favour overly complex models, with adverse effects on accuracy and precision. 2. We describe, and evaluate via simulation and with real data, estimators of an overdispersion factor (ĉ), and associated adjusted model selection criteria (QAIC) for use with overdispersed DS data. In other contexts, a single value of ĉ is calculated from the “global” model, that is the most highly parameterised model in the candidate set, and used to calculate QAIC for all models in the set; the resulting QAIC values, and associated ΔQAIC values and QAIC weights, are comparable across the entire set. Candidate models of the DS detection function include models with different general forms (e.g. half‐normal, hazard rate, uniform), so it may not be possible to identify a single global model. We therefore propose a two‐step model selection procedure by which QAIC is used to select among models with the same general form, and then a goodness‐of‐fit statistic is used to select among models with different forms. A drawback of thi approach is that QAIC values are not comparable across all models in the candidate set. 3. Relative to AIC, QAIC and the two‐step model selection procedure avoided overfitting and improved the accuracy and precision of densities estimated from simulated data. When applied to six real datasets, adjusted criteria and procedures selected either the same model as AIC or a model that yielded a more accurate density estimate in five cases, and a model that yielded a less accurate estimate in one case. 4. Many DS surveys yield overdispersed data, including cue counting surveys of songbirds and cetaceans, surveys of social species including primates, and camera‐trapping surveys. Methods that adjust for overdispersion during the model selection stage of DS analyses therefore address a conspicuous gap in the DS analytical framework as applied to species of conservation concern. Postprint

People living with Human Immunodeficiency Virus (PLWH) face numerous adversities at the individual, interpersonal, and neighborhood levels, which have been linked to negative health behaviors and outcomes. Therefore, there is a growing interest in studying resilience among PLWH to inform future research and intervention efforts. We use a socioecological model of health to define resilience, review the definition and study of resilience among PLWH in the existing peer-reviewed literature, and discuss the strengths and limitations of how resilience is defined and studied in HIV research. We conducted a review of resilience research among for HIV-related behaviors/outcomes of antiretroviral therapy (ART) adherence, clinic attendance, CD4 cell count, viral load, viral suppression, and/or immune functioning among PLWH. We performed searches using PubMed, PsycINFO and Google Scholar databases. The initial search generated 14,296 articles across the three databases, but based on our screening of these articles and inclusion criteria, n = 54 articles were included for review. The majority of HIV resilience research defines resilience only at the individual (i.e., psychological) level or studies individual and limited interpersonal resilience (e.g., social support). The exclusion of neighborhood resilience and more interpersonal factors contrasts with qualitative and quantitative evidence that describes these factors as resilience resources for PLWH. Furthermore, the preponderance of HIV resilience research uses general measures of psychological or interpersonal resilience; these measures have not been developed with or tailored to the needs of PLWH. Our review suggests that a socioecological model of health approach can more fully represent the construct of resilience. Furthermore, measures specific to PLWH that capture individual, interpersonal, and neighborhood resilience are needed. Future research should develop and test multilevel resilience measures for PLWH.

Viral vectors are rapidly being developed for a range of applications in research and gene therapy. Prototype foamy virus (PFV) vectors have been described for gene therapy, although their use has mainly been restricted to ex vivo stem cell modification. Here we report direct in vivo transgene delivery with PFV vectors carrying reporter gene constructs. In our investigations, systemic PFV vector delivery to neonatal mice gave transgene expression in the heart, xiphisternum, liver, pancreas, and gut, whereas intracranial administration produced brain expression until animals were euthanized 49 days post-transduction. Immunostaining and confocal microscopy analysis of injected brains showed that transgene expression was highly localized to hippocampal architecture despite vector delivery being administered to the lateral ventricle. This was compared with intracranial biodistribution of lentiviral vectors and adeno-associated virus vectors, which gave a broad, non-specific spread through the neonatal mouse brain without regional localization, even when administered at lower copy numbers. Our work demonstrates that PFV can be used for neonatal gene delivery with an intracranial expression profile that localizes to hippocampal neurons, potentially because of the mitotic status of the targeted cells, which could be of use for research applications and gene therapy of neurological disorders. Keywords: foamy virus, spumavirus, viral vector, gene therapy, vector tropism, bioimaging, hippocampus

A series of experiments on vertical head loss modules or columns to measure conventional and chemical head loss was carried out to support the resolution of Generic Safety Issue 191 for the Vogtle nuclear power plant (NPP). The head loss (conventional and chemical) was measured on multi-constituent fibrous debris beds of different particulate-to-fiber ratios (η). The debris beds were generated on a horizontal screen following the new procedure developed at the University of New Mexico and are summarized herein. The generated debris beds have been shown to produce repeatable and stable conventional head loss (CHL) and have the ability to detect chemical surrogates. Prototypical Vogtle NPP containment debris materials were used to form three different particulate-to-fiber–ratio (η) debris beds: 6.89 (thin bed), 2 (intermediate bed), and 1.15 (thick bed). The particulates were presented as 90% epoxy paint, 5% inorganic zinc, and 5% latent debris dirt by mass. The obtained results show that the measur...

The impact of survival-related selection bias has not always been discussed in relevant studies of racial health disparities. Moreover, the analytic approaches most frequently employed in the epidemiologic literature to minimize selection bias are difficult to implement appropriately in racial disparities research. This difficulty stems from the fact that frequently employed analytic techniques require that common causes of survival and the outcome are accurately measured. Unfortunately, such common causes are often unmeasured or poorly measured in racial health disparities studies. In the absence of accurate measures of the aforementioned common causes, redefining the target population or changing the study design represent useful approaches for reducing the extent of survival-related selection bias. To help researchers recognize and minimize survival-related selection bias in racial health disparities studies, we illustrate the aforementioned selection bias as well as how redefining the target population or changing the study design can be useful.

Retention in care and viral suppression are critical to delaying HIV progression and reducing transmission. Neighborhood socioeconomic context (NSEC) may affect HIV care receipt. We therefore assessed NSEC's impact on retention and viral suppression in a diverse HIV clinical cohort. HIV-positive adults with ≥1 visit at the Vanderbilt Comprehensive Care Clinic and 5-digit ZIP code tabulation area (ZCTA) information between 2008 and 2012 contributed. NSEC z-score indices used neighborhood-level socioeconomic indicators for poverty, education, labor-force participation, proportion of males, median age, and proportion of residents of black race by ZCTA. Retention was defined as ≥2 HIV care visits per calendar year,90 days apart. Viral suppression was defined as an HIV-1 RNA200 copies/mL at last measurement per calendar year. Modified Poisson regression was used to estimate risk ratios (RR) and 95% confidence intervals (CI). Among 2272 and 2541 adults included for retention and viral suppression analyses, respectively, median age and CD4 count at enrollment were approximately 38 (1st and 3rd quartile: 30, 44) years and 351 (176, 540) cells/μL, respectively, while 24% were female, and 39% were black. Across 243 ZCTAs, median NSEC z-score was 0.09 (-0.66, 0.48). Overall, 79% of person-time contributed was retained and 74% was virally suppressed. In adjusted models, NSEC was not associated with retention, though being in the 4th vs. 1st NSEC quartile was associated with lack of viral suppression (RR = 0.88; 95% CI: 0.80-0.97). Residing in the most adverse NSEC was associated with lack of viral suppression. Future studies are needed to confirm this finding.

This article explores how a selection of films produced in Germany during the period of the Weimar Republic represent and critique the criminal justice system. Its starting premise is that the cinema of the era emerges as an important site for the negotiation of the contemporary crisis of law and justice outside the parameters of official legal procedure and politics. Focusing on a set of key legal and ethical dilemmas surrounding particular paragraphs of the German Criminal Code (§ 218 on abortion, § 175 on homosexuality, § 51 on criminal responsibility attribution), the aim is to exemplify how certain representative films contain and disseminate a popular jurisprudence that both reflects and contributes to contemporary legal-political debate.

‘Candidatus Profftella armatura’ a bacterial endosymbiont of D. citri, biosynthesizes diaphorin, which is a hybrid polyketide–nonribosomal peptide comprising two highly substituted tetra­hydro­pyran rings joined by an N-acyl aminal bridge. The relative configurations of three out of its nine stereogenic centers, which could not be determined by NMR, were assigned based on the crystal structure., The title compound C22H39NO9·CH3OH [systematic name: (S)-N-((S)-{(2S,4R,6R)-6-[(S)-2,3-di­hydroxy­prop­yl]-4-hy­droxy-5,5-di­methyl­tetra­hydro-2H-pyran-2-yl}(hy­droxy)meth­yl)-2-hy­droxy-2-[(2R,5R,6R)-2-meth­oxy-5,6-dimeth­yl-4-methyl­ene­tetra­hydro-2H-pyran-2-yl]acetamide methanol monosolvate], was isolated from the Asian citrus psyllid, Diaphorina citri Kuwayama, and crystallizes in the space group P21. ‘Candidatus Profftella armatura’ a bacterial endosymbiont of D. citri, biosynthesizes diaphorin, which is a hybrid polyketide–nonribosomal peptide comprising two highly substituted tetra­hydro­pyran rings joined by an N-acyl aminal bridge [Nakabachi et al. (2013 ▸). Curr. Biol. 23, 1478–1484]. The crystal structure of the title compound establishes the complete relative configuration of diaphorin, which agrees at all nine chiral centers with the structure of the methanol monosolvate of the di-p-bromo­benzoate derivative of pederin, a biogenically related compound whose crystal structure was reported previously [Furusaki et al. (1968 ▸). Tetra­hedron Lett. 9, 6301–6304]. Thus, the absolute configuration of diaphorin is proposed by analogy to that of pederin.

This article presents an overview of Peace Engineering activities at the University of New Mexico (UNM) School of Engineering (SOE) and Health Sciences Center (HSC). In 2018, UNM's SOE hosted the joint summit of the World Engineering Education Forum and Global Engineering Deans Council. The theme, “Peace Engineering,” focused on science and engineering-based solutions to the world's grand challenges. Outcomes of this first global conference on Peace Engineering include creating new academic programs and opening a wide new area for education, research and innovation addressing climate change, water, health care, food security, ethics, transparency, infrastructure resilience, sustainability, social equity and diversity. UNM Peace Engineering-related activities include the Ibero–American Science and Technology Education Consortium (ISTEC), the Sustainable Water Resources Grand Challenge associated with the Center for Water and the Environment (CWE), the Microgrid Systems Laboratory and Smart City Initiative, the Center for Engineered Resilience and Ecological Sustainability, Project ECHO, the WHY (What do engineers do? How the heck do you do that? WhY am I taking this course?) Lab the Global Peace Laboratories Network, Peace Engineering minor, webinars and case studies. UNM is collaborating with national laboratories, industry, and academia globally. Engineers must understand, measure, and predict the intended and unintended consequences of their work and products. We summarize a complex systems approach to measure positive and negative peace interactions and provide a path to analytic and predictive tools that link engineering abstraction to real-life world experiences.

Photosynthetic microorganisms can export electrons outside their cells, a phenomenon called exoelectrogenesis, which can be harnessed for solar energy conversion. However, the route electrons take from thylakoid membranes to the cell exterior is not understood. Electrochemistry is a powerful analytical technique for studying electron transfer pathways. Here, we show how photoelectrochemistry can be used to compare electron flux from cyanobacterial cells of different growth stages, species and with the outer layers systematically removed. We show that the periplasmic space contributes significantly to the photocurrent profile complexity of whole cells, indicating that it gates electron transfer in exoelectrogenesis. We found that although components of the type IV pili machinery do not have a role in exoelectrogenesis, they contribute significantly to cell-electrode adherence. This study establishes that analytical photoelectrochemistry and molecular microbiology provide a powerful combination to study exoelectrogenesis, enabling future studies to answer biological questions and advance solar energy conversion applications.

This study examined the validity and reliability of a 30-second running sprint test using two non-motorized treadmills compared to the established Wingate Anaerobic Test. Twenty-four participants completed three sessions in a randomized order on a: (1) manual mode treadmill (Woodway); (2) specialized interval training treadmill (HiTrainer); and (3) Wingate cycle ergometer. In a subset of 15 participants, 2 additional sessions were completed on both treadmills to establish the test–retest reliability. Peak (Woodway: r = .68; HiTrainer: r = .58; p .75). Fatigue index during the Wingate Anaerobic Test (51.20 ± 7.14%) was moderately correlated with the Woodway (32.9 ± 10.9%, r = .55, p ...

Introduction Stroke-associated pneumonia (SAP) is common, however, data on the economic impact of SAP are scarce. This study aimed to prospectively evaluate the impact of SAP on acute stroke care costs in a UK setting. Methods Prospective cohort study of 213 consecutive patients with stroke (196 ischemic, 17 hemorrhagic) was admitted to a UK hospital over 1 year. Socio demographic and clinical characteristics were recorded along with all treatments and rehabilitation activity. Patients were classified as having SAP if they fulfilled criteria for "probable" or "definite" respiratory tract infection according to the Centres for Disease Control and Prevention definition, within the first seven days following stroke. Resource use was calculated using a "bottom up" approach of cumulative unit costs. Univariate and multivariate regression analyses were used to establish independent predictors of direct costs. Results Probable or definite SAP occurred in 13.2% (28/213) of patients. Patients with SAP experienced greater inpatient stays (31 days vs. 9 days, p ≤ 0.001) and higher in-hospital mortality (29.2% vs. 10.2%, p = 0.007). Mean (SD) acute care costs per patient was £7035 (6767), but costs were significantly greater for patients with SAP than without [£14,371 (9484) versus £6,103 (5,735); p ≤ 0.001]. SAP was an independent predictor of costs along with increasing stroke severity (NIHSS) and age. Occurrence of SAP resulted in an adjusted incremental additional cost of £5817 (95% CI 4945-6689; p = 0.001) per patient. Conclusions SAP increased acute care costs for stroke by approximately 80%. This provides further impetus for research aimed at reducing SAP, and will inform cost-effectiveness analyses of potential therapeutic strategies.

Purpose Obesity prevention efforts may be ineffective if parents lack awareness of their children's overweight status. This study examined the factors that predicted parents' underestimation of child weight status. Design and Methods Using a cross sectional design, researchers recruited children and parents in a local children's museum. Parents completed a demographic questionnaire, the Newest Vital Sign, and the Child Body Image Scale. Children's height and weight were measured to calculate child BMI. Random effects modeling examined the association between predictor variables (parent race/ethnicity, income, education, and health literacy, and child BMI percentile, gender, and age) and the dependent variable, parent underestimation of child weight status. Results Participants included 160 parents (213 children aged 7–12 years) representing a racially and ethnically diverse sample who were affluent, educated, and with 36.6% of parents assessed with limited health literacy. Although 45.1% of children were overweight/obese, only 7.5% of parents chose this weight status; 80% of parents underestimated the weight of their normal weight children, 96% underestimated their overweight children, and 72% underestimated their obese children. Parents were more likely to underestimate weight of older children and those under 81st percentile of BMI. No other predictors were significant. Conclusions Parent underestimation of child weight status appears to be a widespread phenomenon in this sample, regardless of race, ethnicity, income, education, and health literacy. Practice Implications The consistent underestimation of child weight suggests that parents' misperception of weight status represents a critical pathway for intervention. Methods to improve parents' perception of child weight need be developed and tested.

Microbial biophotovoltaic cells exploit the ability of cyanobacteria and microalgae to convert light energy into electrical current using water as the source of electrons. Such bioelectrochemical systems have a clear advantage over more conventional microbial fuel cells which require the input of organic carbon for microbial growth. However, innovative approaches are needed to address scale-up issues associated with the fabrication of the inorganic (electrodes) and biological (microbe) parts of the biophotovoltaic device. Here we demonstrate the feasibility of using a simple commercial inkjet printer to fabricate a thin-film paper-based biophotovoltaic cell consisting of a layer of cyanobacterial cells on top of a carbon nanotube conducting surface. We show that these printed cyanobacteria are capable of generating a sustained electrical current both in the dark (as a ‘solar bio-battery’) and in response to light (as a ‘bio-solar-panel’) with potential applications in low-power devices., Cyanobacteria can be exploited to convert light energy into electrical current, however utilising them efficiently for power generation is a challenge. Here, the authors use a simple commercial inkjet printer to fabricate a thin-film paper-based biophotovoltaic cell capable of driving low-power devices.

Highlights • Smoking has been shown to affect body weight but evidence for the converse is limited. • Higher body mass index (BMI) was associated with smoking initiation in adolescent females but not males. • Body dissatisfaction was associated with smoking initiation in both sexes. • BMI genetic risk score did not predict smoking, but estimates were imprecise. • BMI and body dissatisfaction may be important considerations for smoking prevention., Background Smoking influences body weight, but there is little evidence as to whether body mass index (BMI) and body dissatisfaction increase smoking initiation in adolescents. Methods We evaluated the association between measured BMI, body dissatisfaction and latent classes of smoking initiation (never smokers, experimenters, late onset regular smokers, early onset regular smokers) in the Avon Longitudinal Study of Parents and Children. In observational analyses we used BMI (N = 3754) and body dissatisfaction at age 10.5 years (N = 3349). In Mendelian randomisation (MR) analysis, we used a BMI genetic risk score of 76 single nucleotide polymorphisms (N = 4017). Results In females, higher BMI was associated with increased odds of early onset regular smoking (OR: 1.11, 95% CI: 1.04, 1.18) compared to being a never smoker, but not clearly associated with experimenting with smoking (OR: 1.04, 95% CI: 0.99, 1.10) or late onset regular smoking (OR: 1.01, 95% CI: 0.94, 1.09). No clear evidence was found for associations between BMI and smoking initiation classes in males (p-value for sex interaction ≤ 0.001). Body dissatisfaction was associated with increased odds of late-onset regular smoking (OR: 1.71, 95% CI: 1.32, 1.99) in males and females combined (P-value for sex interaction = 0.32). There was no clear evidence for an association between the BMI genetic risk score and smoking latent classes in males or females but estimates were imprecise. Conclusions BMI in females and body dissatisfaction in males and females are associated with increased odds of smoking initiation, highlighting these as potentially important factors for consideration in smoking prevention strategies.

Fatty acids (FAs) are essential components of cell membranes and play an integral role in membrane fluidity. The lipophilic index [LI, defined as the sum of the products between FA levels and melting points (°C), divided by the total amount of FA: $${\text{LI}} = \frac{{\mathop \sum \nolimits_{k} [{\text{fatty acid}} \times {\text{melting point}}]}}{{\mathop \sum \nolimits_{k} {\text{fatty acid}} }}$$ ] is thought to reflect membrane and lipoprotein fluidity and may be associated with the risk of coronary heart disease (CHD). Therefore, we examined the associations of dietary and plasma phospholipid (PL) LI with CHD risk among postmenopausal women. We determined dietary LI for the cohort with completed baseline food frequency questionnaires and free of prevalent cardiovascular diseases in the Women’s Health Initiative (WHI) observational study (N = 85,563). We additionally determined plasma PL LI in a matched case-control study (N = 2428) nested within the WHI observational cohort study. Cox proportional hazard regression and multivariable conditional logistic regression were used to calculate HRs/ORs for CHD risk between quartiles of LI after adjusting for potential sources of confounding and selection bias. Higher dietary LI in the cohort study and plasma PL LI in the case-control study were significantly associated with increased risk of CHD: HR = 1.18 (95% CI 1.07–1.31, P for trend

Play analysis is used to delineate areas containing geologically similar discoveries and prospects. The yet-to-find (YTF) recoverable resource for a conventional play can be predicted using deterministic scenarios utilizing the fact that discoveries within a part play (or common risk segment) can be fitted to a lognormal distribution. Assuming the part play works, a YTF scenario can be made with estimates of (i) the number of drillable prospects, (ii) the average prospect risk, (iii) the resource size of an upside discovery (based on the evaluation of a favoured prospect), and (iv) a downside resource from an implied P99 volume (based on historical data or calculation). A range of YTF is then developed using low, median and high case scenarios. The value of the different scenarios can be estimated provided a minimum economic field size for a generic prospect is available plus a pre-drill net present value for an average economic discovery. Useful reality checks of YTF estimations include the historical discovery rate, the areal density of traps in analogue settings, the historical average discovery size and the total estimated recoverable resource per unit area. YTF from prospect inventories using Monte Carlo simulations tend to focus on mature areas and are biased to outcomes where all pre-drill models are correct, unless the prospect sizes are adjusted to account for discoveries which are smaller than predicted by seismic interpretation. YTF estimates will change as information about the play evolves, meaning that it is important that the calculations are kept relatively simple and easy to adjust as new well and seismic data becomes available.

Empirical evidence indicates that aspects of the neighborhood environment may affect HIV prevention efforts. Therefore, the neighborhood environment should be considered when implementing prevention interventions. However, much of the empirical evidence is derived from studies conducted among drug users, men, or adolescents. Such evidence may not be as applicable to adult women whose primary risk for HIV infection is via heterosexual sexual behavior. Therefore, a systematic review examining the relationship between neighborhood environments and HIV sexual risk behaviors among adult U.S. women was conducted. Three databases were searched for articles published in English in peer-reviewed journals between 1/1/1980 and 12/31/2016 meeting relevant criteria. Seven articles identified from the three databases or additional hand searches met inclusion criteria and were summarized. Findings were mixed with several studies indicating associations between neighborhood environments and HIV sexual risk behaviors. However, all summarized studies were cross-sectional. Longitudinal studies conducted among women are needed.

Histone post-translational modifications (PTMs) alter chromatin structure by promoting the interaction of chromatin-modifying complexes with nucleosomes. The majority of chromatin-modifying complexes contain multiple domains that preferentially interact with modified histones, leading to speculation that these domains function in concert to target nucleosomes with distinct combinations of histone PTMs. In Saccharomyces cerevisiae, the NuA3 histone acetyltransferase complex contains three domains, the PHD finger in Yng1, the PWWP domain in Pdp3, and the YEATS domain in Taf14; which in vitro bind to H3K4 methylation, H3K36 methylation, and acetylated and crotonylated H3K9, respectively. While the in vitro binding has been well characterized, the relative in vivo contributions of these histone PTMs in targeting NuA3 is unknown. Here, through genome-wide colocalization and by mutational interrogation, we demonstrate that the PHD finger of Yng1, and the PWWP domain of Pdp3 independently target NuA3 to H3K4 and H3K36 methylated chromatin, respectively. In contrast, we find no evidence to support the YEATS domain of Taf14 functioning in NuA3 recruitment. Collectively our results suggest that the presence of multiple histone PTM binding domains within NuA3, rather than restricting it to nucleosomes containing distinct combinations of histone PTMs, can serve to increase the range of nucleosomes bound by the complex. Interestingly, however, the simple presence of NuA3 is insufficient to ensure acetylation of the associated nucleosomes, suggesting a secondary level of acetylation regulation that does not involve control of HAT-nucleosome interactions.

Photomixotrophy is a metabolic state, which enables photosynthetic microorganisms to simultaneously perform photosynthesis and metabolism of imported organic carbon substrates. This process is complicated in cyanobacteria, since many, including Synechocystis sp. PCC 6803, conduct photosynthesis and respiration in an interlinked thylakoid membrane electron transport chain. Under photomixotrophy, the cell must therefore tightly regulate electron fluxes from photosynthetic and respiratory complexes. In this study, we show via characterization of photosynthetic apparatus and the proteome, that photomixotrophic growth results in a gradual reduction of the plastoquinone pool in wild-type Synechocystis, which fully downscales photosynthesis over three days of growth. This process is circumvented by deleting the gene encoding cytochrome cM (CytM), a cryptic c-type heme protein widespread in cyanobacteria. ΔCytM maintained active photosynthesis over the three day period, demonstrated by high photosynthetic O2 and CO2 fluxes and effective yields of Photosystem II and Photosystem I. Overall, this resulted in a higher growth rate than wild-type, which was maintained by accumulation of proteins involved in phosphate and metal uptake, and cofactor biosynthetic enzymes. While the exact role of CytM has not been determined, a mutant deficient in the thylakoid-localised respiratory terminal oxidases and CytM (ΔCox/Cyd/CytM) displayed a similar phenotype under photomixotrophy to ΔCytM, demonstrating that CytM is not transferring electrons to these complexes, which has previously been suggested. In summary, the obtained data suggests that CytM may have a regulatory role in photomixotrophy by reducing the photosynthetic capacity of cells.One sentence summaryThe cryptic, highly conserved cytochrome cM completely blocks photosynthesis in Synechocystis under three days of photomixotrophy, possibly by suppressing CO2 assimilation.

Alcohol use is correlated within spouse-pairs, but it is difficult to disentangle effects of alcohol consumption on mate-selection from social factors or the shared spousal environment. We hypothesised that genetic variants related to alcohol consumption may, via their effect on alcohol behaviour, influence mate selection. Here, we find strong evidence that an individual’s self-reported alcohol consumption and their genotype at rs1229984, a missense variant in ADH1B, are associated with their partner’s self-reported alcohol use. Applying Mendelian randomization, we estimate that a unit increase in an individual’s weekly alcohol consumption increases partner’s alcohol consumption by 0.26 units (95% C.I. 0.15, 0.38; P = 8.20 × 10−6). Furthermore, we find evidence of spousal genotypic concordance for rs1229984, suggesting that spousal concordance for alcohol consumption existed prior to cohabitation. Although the SNP is strongly associated with ancestry, our results suggest some concordance independent of population stratification. Our findings suggest that alcohol behaviour directly influences mate selection.

A novel mediatorless photo-bioelectrochemical sensor operated with a biofilm of the cyanobacterium Synechocystis PCC6803 wt. for herbicide detection with long term stability (&gt, 20 days) was successfully developed and tested. Photoanodic current generation was obtained in the absence of artificial mediators. The inhibitory effect on photocurrent of three commonly used herbicides (i.e., atrazine, diuron, and paraquat) was used as a means of measuring their concentrations in aqueous solution. The injection of atrazine and diuron into the algal medium caused an immediate photocurrent drop due to the inhibition of photosynthetic electron transport. The detected concentrations were suitable for environmental analysis, as revealed by a comparison with the freshwater quality benchmarks set by the Environmental Protection Agency of the United States (US EPA). In contrast, paraquat caused an initial increase (~2 h) of the photocurrent effect of about 200%, as this compound can act as a redox mediator between the cells and the anode. A relatively long-term stability of the biosensor was demonstrated, by keeping anodes colonized with cyanobacterial biofilm in the dark at 4 &deg, C. After 22 days of storage, the performance in terms of the photocurrent was comparable with the freshly prepared biosensor. This result was confirmed by the measurement of chlorophyll content, which demonstrated preservation of the cyanobacterial biofilm. The capacity of this biosensor to recover after a cold season or other prolonged environmental stresses could be a key advantage in field applications, such as in water bodies and agriculture. This study is a step forward in the biotechnological development and implementation of storable mediatorless electrochemical biosensors for herbicide detection.

BackgroundThere is growing evidence that polygenic risk scores (PRS) can be used to identify individuals at high lifetime risk of coronary artery disease (CAD). Whether they can also be used to stratify risk of subsequent events among those surviving a first CAD event remains uncertain.MethodsUsing two subsamples of UK Biobank, defined at baseline as prevalent CAD (N=10,287) and without CAD (N=393,108), we evaluated associations between a CAD PRS and incident cardiovascular and fatal outcomes, during a median follow up of 7.8 years.ResultsA 1 S.D. higher PRS was associated with increased risk of incident MI in participants without CAD (OR 1.33; 95% C.I. 1.29, 1.38), but the effect estimate was markedly attenuated in those with prevalent CAD (OR 1.15; 95% C.I. 1.06, 1.25); heterogeneity P =0.0012. Additionally, among prevalent CAD cases, we found evidence of an inverse association between the CAD PRS and risk of all-cause death (OR 0.91; 95% C.I. 0.85, 0.98) compared to those without CAD (OR 1.01; 95% C.I. 0.99, 1.03); heterogeneity P =0.0041. A similar inverse association was found for ischaemic stroke (Prevalent CAD (OR 0.78; 95% C.I. 0.67, 0.90); without CAD (OR 1.09; 95% C.I. 1.04, 1.15), heterogeneity P ConclusionsBias induced by case stratification and survival into UK Biobank may attenuate, or reverse, associations of polygenic risk scores derived from case-control studies or populations initially free of disease. Polygenic risk scores for subsequent events should be derived from new genome wide association studies conducted in patients with established disease.Key messagesCAD PRS are positively associated with incident myocardial infarction risk amongst established CAD cases.However, the effect size is attenuated compared to estimates from CAD-free populations.CAD PRS are inversely associated with mortality and stroke risk amongst established CAD cases.These associations may reflect index event bias induced by stratifying on case status.Dedicated GWAS of coronary disease progression are required to improve prediction of subsequent event risk.

Background This article intended to identify and describe areas in need of services and interventions for individuals with autism spectrum disorder (ASD) and their families in Seoul, Korea. Methods A descriptive comparison was made between available services and interventions in Seoul, Korea and Massachusetts, USA. Relevant information was obtained through sending phone/email inquiries to the governments and organizations, visiting their official websites, and searching for published articles or reports. Results In a few areas such as level of education, economy, and general quality of healthcare, Seoul was found to be similar to Massachusetts. However, in terms of services and interventions for individuals with ASD and their families, especially early identification and intervention, special education, care coordination, school-based programs, and transition to adulthood, Massachusetts was shown to have far more availability. Conclusion The limited availability of services and interventions for individuals with ASD and their families in Seoul in comparison to Massachusetts, underlines target areas for further investment and development., Graphical Abstract

Histone acetylation is a ubiquitous hallmark of transcriptional activity, but whether the link is of a causal or consequential nature is still a matter of debate. In this study we resolve this question. Using both immunoblot analysis and chromatin immunoprecipitation-sequencing (ChIP-seq) in S. cerevisiae, we show that the majority of histone acetylation is dependent on transcription. Loss of histone H4 acetylation upon transcription inhibition is partially explained by depletion of histone acetyltransferases (HATs) from gene bodies, implicating transcription in HAT targeting. Despite this, HAT occupancy alone poorly predicts histone acetylation, suggesting that HAT activity is regulated at a step post-recruitment. Collectively, these data show that the majority of histone acetylation is a consequence of RNAPII promoting both the recruitment and activity of histone acetyltransferases.

Biophotovoltaic systems (BPVs) resemble microbial fuel cells, but utilise oxygenic photosynthetic microorganisms associated with an anode to generate an extracellular electrical current, which is stimulated by illumination. Study and exploitation of BPVs have come a long way over the last few decades, having benefited from several generations of electrode development and improvements in wiring schemes. Power densities of up to 0.5 W m−2 and the powering of small electrical devices such as a digital clock have been reported. Improvements in standardisation have meant that this biophotoelectrochemical phenomenon can be further exploited to address biological questions relating to the organisms. Here, we aim to provide both biologists and electrochemists with a review of the progress of BPV development with a focus on biological materials, electrode design and interfacial wiring considerations, and propose steps for driving the field forward., Forward thinking: Biophotovoltaic (BPV) systems utilise oxygenic photosynthetic microorganisms associated with an anode to generate an extracellular electrical current, which is stimulated by illumination. The aim of this Minireview is to provide both biologists and electrochemists with an overview of the progress of BPV development with a focus on biological materials, electrode design and interfacial wiring considerations, and propose steps for driving the field forward.

Potable reuse facilities must be designed and operated to minimize the presence of contaminants of emerging concern (CECs) and other trace organics in the product water. Reverse osmosis (RO) is incorporated into the process train of many potable reuse facilities and has been demonstrated to achieve excellent removal of many, but not all, organic compounds. Organics that may be poorly removed by RO include low-molecular weight (MW) neutral compounds. This laboratory study examined the rejection of 73 low-MW neutral organics through a commercial RO membrane that is commonly used in potable reuse applications. The organics were selected using a reductionist approach so that the effect of individual functional groups on rejection could be ascertained. The research demonstrated that halogens, carbonyl functional groups, C═C double bonds, and aromaticity decrease rejection, that methyl and hydroxyl functional groups increase rejection, and that the position of functional groups in structural isomers has a significant effect on rejection. The results help explain the discrepancies and inconsistencies in RO rejection of neutral organics that are observed when considered from the conventional perspective of molecular size and hydrophobicity.

The field of cell and gene therapy (GT) is expanding rapidly and there is undoubtedly a wave of enthusiasm and anticipation for what these treatments could achieve next. Here we assessed the worldwide landscape of GT assets currently in early clinical development (clinical trial phase 1/2 or about to enter clinical trial). We included all gene therapies, i.e., strategies that modify an individual's protein make-up by introducing exogenous nucleic acid or nucleic acid modifiers, regardless of delivery. Unmodified cell therapies, oncology therapies (reviewed elsewhere), and vaccine programs (distinct therapeutic strategy) were not included. Using a December 31, 2018 cutoff date, we identified 336 gene therapies being developed for 138 different indications covering 165 genetic targets. In all, we found that the early clinical GT landscape comprises a very disparate group of drug candidates in terms of indications, organizations, and delivery methods. We also highlight interesting trends, revealing the evolution of the field toward in vivo therapies and adeno-associated virus vector-based delivery systems. It will be interesting to witness what proportion of this current list effectively translates into new medicines.

Fabry disease (FD) is caused by mutations in the GLA gene that encodes lysosomal α-galactosidase-A (α-gal-A). A number of pathogenic mechanisms have been proposed and these include loss of mitochondrial respiratory chain activity. For FD, gene therapy is beginning to be applied as a treatment. In view of the loss of mitochondrial function reported in FD, we have considered here the impact of loss of mitochondrial respiratory chain activity on the ability of a GLA lentiviral vector to increase cellular α-gal-A activity and participate in cross correction. Jurkat cells were used in this study and were exposed to increasing viral copies. Intracellular and extracellular enzyme activities were then determined, this in the presence or absence of the mitochondrial complex I inhibitor, rotenone. The ability of cells to take up released enzyme was also evaluated. Increasing transgene copies was associated with increasing intracellular α-gal-A activity but this was associated with an increase in Km. Release of enzyme and cellular uptake was also demonstrated. However, in the presence of rotenone, enzyme release was inhibited by 37%. Excessive enzyme generation may result in a protein with inferior kinetic properties and a background of compromised mitochondrial function may impair the cross correction process.

Mendelian randomization (MR) is increasingly used to make causal inferences in a wide range of fields, from drug development to etiologic studies. Causal inference in MR is possible because of the process of genetic inheritance from parents to offspring. Specifically, at gamete formation and conception, meiosis ensures random allocation to the offspring of one allele from each parent at each locus, and these are unrelated to most of the other inherited genetic variants. To date, most MR studies have used data from unrelated individuals. These studies assume that genotypes are independent of the environment across a sample of unrelated individuals, conditional on covariates. Here we describe potential sources of bias, such as transmission ratio distortion, selection bias, population stratification, dynastic effects and assortative mating that can induce spurious or biased SNP–phenotype associations. We explain how studies of related individuals such as sibling pairs or parent–offspring trios can be used to overcome some of these sources of bias, to provide potentially more reliable evidence regarding causal processes. The increasing availability of data from related individuals in large cohort studies presents an opportunity to both overcome some of these biases and also to evaluate familial environmental effects. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Background Early identification and treatment of individuals with autism spectrum disorder (ASD) improves outcomes, but specific evidence needed to individualize treatment recommendations is lacking. Biomarkers that could be routinely measured within the clinical setting could potentially transform clinical care for patients with ASD. This demonstration project employed collection of biomarker data during regular autism specialty clinical visits and explored the relationship of biomarkers with clinical ASD symptoms. Methods Eighty-three children with ASD, aged 5–10 years, completed a multi-site feasibility study integrating the collection of biochemical (blood serotonin, urine melatonin sulfate excretion) and clinical (head circumference, dysmorphology exam, digit ratio, cognitive and behavioral function) biomarkers during routine ASD clinic visits. Parents completed a demographic survey and the Aberrant Behavior Checklist-Community. Cognitive function was determined by record review. Data analysis utilized Wilcoxon two-sample tests and Spearman correlations. Results Participants were 82% male, 63% White, 19% Hispanic, with a broad range of functioning. Group means indicated hyperserotonemia. In a single regression analysis adjusting for race and median household income, higher income was associated with higher levels of blood serotonin and urine melatonin sulfate excretion levels (p = 0.004 and p = 0.04, respectively). Melatonin correlated negatively with age (p = 0.048) and reported neurologic problems (p = 0.02). Dysmorphic status correlated with higher reported stereotyped behavior (p = 0.02) and inappropriate speech (p = 0.04). Conclusion This demonstration project employed collection of multiple biomarkers, allowed for examination of associations between biochemical and clinical measures, and identified several findings that suggest direction for future studies. This clinical research model has promise for integrative biomarker research in individuals with complex, heterogeneous neurodevelopmental disorders such as ASD.

We thank Dr. Barry Weiss for his comments about our study on the use of the NVS in children. We certainly have consensus that the NVS is not an appropriate instrument to measure children's health literacy. However, we assert that it is vital for clinicians and researchers alike to assess the health literacy of all patients, including children—particularly those who are school-aged and making decisions about their nutrition independently of their parents. Adoption of healthy or unhealthy behaviors begins in childhood and continues into adulthood. Given the high rate of overweight and obesity among children in the United States, the importance of child health literacy cannot be overstated.

Dinoflagellates are a diverse and widely distributed protist group, of major environmental and economic importance. Many, but not all, are photosynthetic. Many of the photosynthetic species contain a secondary chloroplast of red algal origin with peridinin as an accessory pigment. These organisms have a highly anomalous chloroplast genome that is fragmented into plasmid-like molecules and highly reduced, encoding 12 proteins involved in photosynthetic light reactions as well as rRNA and some tRNAs. Chloroplast transcripts receive 3’ polyU tails, and many undergo RNA editing. Some lineages have replaced chloroplasts with others from non-dinoflagellate taxa, and in some instances the unusual processing pathways are applied to the newly acquired chloroplasts. Some non-photosynthetic lineages have lost chloroplast genomes, and others may have lost chloroplasts altogether.

Mendelian randomization (MR) is a widely-used method for causal inference using genetic data. Mendelian randomization studies of unrelated individuals may be susceptible to bias from family structure, for example, through dynastic effects which occur when parental genotypes directly affect offspring phenotypes. Here we describe methods for within-family Mendelian randomization and through simulations show that family-based methods can overcome bias due to dynastic effects. We illustrate these issues empirically using data from 61,008 siblings from the UK Biobank and Nord-Trøndelag Health Study. Both within-family and population-based Mendelian randomization analyses reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while MR estimates from population-based samples of unrelated individuals suggested that taller height and lower BMI increase educational attainment, these effects largely disappeared in within-family MR analyses. We found differences between population-based and within-family based estimates, indicating the importance of controlling for family effects and population structure in Mendelian randomization studies.

High levels of prenatal alcohol exposure are known to cause an array of adverse outcomes including foetal alcohol syndrome (FAS); however, the effects of low to moderate exposure are less-well characterised. Previous findings suggest that differences in normal-range facial morphology may be a marker for alcohol exposure and related adverse effects. Therefore, in the Avon Longitudinal Study of Parents and Children, we tested for an association between maternal alcohol consumption and six FAS-related facial phenotypes in their offspring, using both self-report questionnaires and the maternal genotype at rs1229984 inADH1Bas measures of maternal alcohol consumption. In both self-reported alcohol consumption (N=4,233) and rs1229984 genotype (N=3,139) analyses, we found no strong statistical evidence for an association between maternal alcohol consumption and facial phenotypes tested. The directions of effect estimates were compatible with the known effects of heavy alcohol exposure, but confidence intervals were largely centred around zero. We conclude that, in a sample representative of the general population, there is no strong evidence for an effect of prenatal alcohol exposure on normal-range variation in facial morphology.