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Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10–10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10–6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10–3; p = 2.29 × 10–3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10–3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.
Currently, there are seven herbicides labeled for U.S. tobacco production; however, additional modes of action are greatly needed in order to reduce the risk of herbicide resistance. Field experiments were conducted at five locations during the 2017 and 2018 growing seasons to evaluate flue-cured tobacco tolerance to S-metolachlor applied pretransplanting incorporated (PTI) and pretransplanting (PRETR) at 1.07 (1×) and 2.14 (2×) kg ai ha−1. Severe injury was observed 6 wk after transplanting at the Whiteville environment in 2017 when S-metolachlor was applied PTI. End-of-season plant heights from PTI treatments at Whiteville were likewise reduced by 9% to 29% compared with nontreated controls, although cured leaf yield and value were reduced only when S-metolachlor was applied PTI at the 2× rate. Severe growth reduction was also observed at the Kinston location in 2018 where S-metolachlor was applied at the 2× rate. End-of-season plant heights were reduced 11% (PTI, 2×) and 20% (PRETR, 2×) compared with nontreated control plants. Cured leaf yield was reduced in Kinston when S-metolachlor was applied PRETR at the 2× rate; however, treatments did not impact cured leaf quality or value. Visual injury and reductions in stalk height, yield, quality, and value were not observed at the other three locations. Ultimately, it appears that injury potential from S-metolachlor is promoted by coarse soil texture and high early-season precipitation close to transplanting, both of which were documented at the Whiteville and Kinston locations. To reduce plant injury and the negative impacts to leaf yield and value, application rates lower than 1.07 kg ha−1 may be required in these scenarios.
This study provides a morphological and phylogenetic characterization of two novel species of the order Haplosporida (Haplosporidium carcini n. sp., and H. cranc n. sp.) infecting the common shore crab Carcinus maenas collected at one location in Swansea Bay, South Wales, UK. Both parasites were observed in the haemolymph, gills and hepatopancreas. The prevalence of clinical infections (i.e. parasites seen directly in fresh haemolymph preparations) was low, at ~1%, whereas subclinical levels, detected by polymerase chain reaction, were slightly higher at ~2%. Although no spores were found in any of the infected crabs examined histologically (n = 334), the morphology of monokaryotic and dikaryotic unicellular stages of the parasites enabled differentiation between the two new species. Phylogenetic analyses of the new species based on the small subunit (SSU) rDNA gene placed H. cranc in a clade of otherwise uncharacterized environmental sequences from marine samples, and H. carcini in a clade with other crustacean-associated lineages.
We present a calibration component for the Murchison Widefield Array All-Sky Virtual Observatory (MWA ASVO) utilising a newly developed PostgreSQL database of calibration solutions. Since its inauguration in 2013, the MWA has recorded over 34 petabytes of data archived at the Pawsey Supercomputing Centre. According to the MWA Data Access policy, data become publicly available 18 months after collection. Therefore, most of the archival data are now available to the public. Access to public data was provided in 2017 via the MWA ASVO interface, which allowed researchers worldwide to download MWA uncalibrated data in standard radio astronomy data formats (CASA measurement sets or UV FITS files). The addition of the MWA ASVO calibration feature opens a new, powerful avenue for researchers without a detailed knowledge of the MWA telescope and data processing to download calibrated visibility data and create images using standard radio astronomy software packages. In order to populate the database with calibration solutions from the last 6 yr we developed fully automated pipelines. A near-real-time pipeline has been used to process new calibration observations as soon as they are collected and upload calibration solutions to the database, which enables monitoring of the interferometric performance of the telescope. Based on this database, we present an analysis of the stability of the MWA calibration solutions over long time intervals.
Many institutions are attempting to implement patient-reported outcome (PRO) measures. Because PROs often change clinical workflows significantly for patients and providers, implementation choices can have major impact. While various implementation guides exist, a stepwise list of decision points covering the full implementation process and drawing explicitly on a sociotechnical conceptual framework does not exist.
To facilitate real-world implementation of PROs in electronic health records (EHRs) for use in clinical practice, members of the EHR Access to Seamless Integration of Patient-Reported Outcomes Measurement Information System (PROMIS) Consortium developed structured PRO implementation planning tools. Each institution pilot tested the tools. Joint meetings led to the identification of critical sociotechnical success factors.
Three tools were developed and tested: (1) a PRO Planning Guide summarizes the empirical knowledge and guidance about PRO implementation in routine clinical care; (2) a Decision Log allows decision tracking; and (3) an Implementation Plan Template simplifies creation of a sharable implementation plan. Seven lessons learned during implementation underscore the iterative nature of planning and the importance of the clinician champion, as well as the need to understand aims, manage implementation barriers, minimize disruption, provide ample discussion time, and continuously engage key stakeholders.
Highly structured planning tools, informed by a sociotechnical perspective, enabled the construction of clear, clinic-specific plans. By developing and testing three reusable tools (freely available for immediate use), our project addressed the need for consolidated guidance and created new materials for PRO implementation planning. We identified seven important lessons that, while common to technology implementation, are especially critical in PRO implementation.
While previous studies have described career outcomes of physician-scientist trainees after graduation, trainee perceptions of research-intensive career pathways remain unclear. This study sought to identify the perceived interests, factors, and challenges associated with academic and research careers among predoctoral MD trainees, MD trainees with research-intense (>50%) career intentions (MD-RI), and MD-PhD trainees.
A 70-question survey was administered to 16,418 trainees at 32 academic medical centers from September 2012 to December 2014. MD vs. MD-RI (>50% research intentions) vs. MD-PhD trainee responses were compared by chi-square tests. Multivariate logistic regression analyses were performed to identify variables associated with academic and research career intentions.
There were 4433 respondents (27% response rate), including 2625 MD (64%), 653 MD-RI (15%), and 856 MD-PhD (21%) trainees. MD-PhDs were most interested in pursuing academia (85.8%), followed by MD-RIs (57.3%) and MDs (31.2%). Translational research was the primary career intention for MD-PhD trainees (42.9%). Clinical duties were the primary career intention for MD-RIs (51.9%) and MDs (84.2%). While 39.8% of MD-PhD respondents identified opportunities for research as the most important career selection factor, only 12.9% of MD-RI and 0.5% of MD respondents shared this perspective. Interest in basic research, translational research, clinical research, education, and the ability to identify a mentor were each independently associated with academic career intentions by multivariate regression.
Predoctoral MD, MD-RI, and MD-PhD trainees are unique cohorts with different perceptions and interests toward academic and research careers. Understanding these differences may help to guide efforts to mentor the next generation of physician-scientists.
Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds.
We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes.
In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47–0.68%, p = 2.0 × 10−8–1.0 × 10−10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10−8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10−6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10−11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10−7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10−16).
AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.
In the broad literature on the effects of ingredients, foods and diets on appetite and energy intake (EI), most trials involve a single acute intervention. It is unclear whether these acute results are generally sustained over longer periods. Researchers and regulators therefore lack an objective basis to judge the appropriate duration of efficacy trials in appetite control, to have confidence that acute effects are likely to be maintained. This gap creates uncertainty in requirements and study designs for the substantiation of satiety-enhancing approaches to help in controlling eating behaviour.
Materials and Methods:
A systematic search of literature (Prospero registration number CRD42015023686) identified studies testing both the acute and chronic effects of food-based interventions aimed at reducing appetite or EI. From 9680 unique records identified from titles and abstracts, 178 papers were selected for full screening. Twenty-six trials met the inclusion criteria and provided data sufficient for use in this analysis, and were also scored for risk of bias (RoB) indicators.
Most of these trials (21/26) measured appetite outcomes and over half (14/26) had objective measures of EI. A significant acute effect of the intervention was retained in 10 of 12 trials for appetite outcomes, and six of nine studies for EI. Initial effects were most likely retained where these were more robust and studies adequately powered. Where the initial, acute effect was not statistically significant, a significant effect was later observed in only two of nine studies for appetite and none of five studies for EI. The main sources of RoB were lack of a priori power calculations and failure to report analyses based on intention-to-treat. Furthermore, 12/26 studies were not adequately powered to detect a meaningful reduction in appetite (~10%).
Maintenance of acute intervention effects on appetite or EI need to be confirmed, but seems likely where the initially observed effects are robust and replicable in adequately powered studies.
The present study explored relationships among personality, Alzheimer’s disease (AD) biomarkers, and dementia by addressing the following questions: (1) Does personality discriminate healthy aging and earliest detectable stage of AD? (2) Does personality predict conversion from healthy aging to early-stage AD? (3) Do AD biomarkers mediate any observed relationships between personality and dementia status/conversion?
Both self- and informant ratings of personality were obtained in a large well-characterized longitudinal sample of cognitively normal older adults (N = 436) and individuals with early-stage dementia (N = 74). Biomarkers included amyloid imaging, hippocampal volume, cerebral spinal fluid (CSF) Aβ42, and CSF tau.
Higher neuroticism, lower conscientiousness, along with all four biomarkers strongly discriminated cognitively normal controls from early-stage AD individuals. The direct effects of neuroticism and conscientiousness were only mediated by hippocampal volume. Conscientiousness along with all biomarkers predicted conversion from healthy aging to early-stage AD; however, none of the biomarkers mediated the relationship between conscientiousness and conversion. Conscientiousness predicted conversion as strongly as the biomarkers, with the exception of hippocampal volume.
Conscientiousness and to a lesser extent neuroticism serve as important independent behavioral markers for AD risk.
Electron microscopy is uniquely suited for atomic-resolution imaging of heterogeneous and complex materials, where composition, physical, and electronic structure need to be analyzed simultaneously. Historically, the technique has demonstrated optimal performance at room temperature, since practical aspects such as vibration, drift, and contamination limit exploration at extreme temperature regimes. Conversely, quantum materials that exhibit exotic physical properties directly tied to the quantum mechanical nature of electrons are best studied (and often only exist) at extremely low temperatures. As a result, emergent phenomena, such as superconductivity, are typically studied using scanning probe-based techniques that can provide exquisite structural and electronic characterization, but are necessarily limited to surfaces. In this article, we focus not on the various methods that have been used to examine quantum materials at extremely low temperatures, but on what could be accomplished in the field of quantum materials if the power of electron microscopy to provide structural analysis at the atomic scale was extended to extremely low temperatures.
Englacial layers in Antarctica and Greenland are indicators of the dynamic, rheological and subglacial configuration of the ice sheets. Airborne radar sounder data is the primary remote sensing solution for directly observing englacial layers and structures at the glacier-catchment to ice-sheet scale. However, when traditional along-track synthetic aperture radar (SAR) processing is applied, steep layers can disappear, limiting the detectability and interpretability of englacial layer geometry. This study provides a reconstruction algorithm to address the problem of destructive phase interference during the radargram formation. We develop and apply a novel SAR processor optimized for layer detection that enhances the Signal-to-Noise ratio (SNR) of specular reflectors. The algorithm also enables the automatic estimation of layer slope. We demonstrate the algorithm using data acquired at the Institute Ice Stream, West Antarctica.
Major depressive disorder and neuroticism (Neu) share a large genetic basis. We sought to determine whether this shared basis could be decomposed to identify genetic factors that are specific to depression.
We analysed summary statistics from genome-wide association studies (GWAS) of depression (from the Psychiatric Genomics Consortium, 23andMe and UK Biobank) and compared them with GWAS of Neu (from UK Biobank). First, we used a pairwise GWAS analysis to classify variants as associated with only depression, with only Neu or with both. Second, we estimated partial genetic correlations to test whether the depression's genetic link with other phenotypes was explained by shared overlap with Neu.
We found evidence that most genomic regions (25/37) associated with depression are likely to be shared with Neu. The overlapping common genetic variance of depression and Neu was genetically correlated primarily with psychiatric disorders. We found that the genetic contributions to depression, that were not shared with Neu, were positively correlated with metabolic phenotypes and cardiovascular disease, and negatively correlated with the personality trait conscientiousness. After removing shared genetic overlap with Neu, depression still had a specific association with schizophrenia, bipolar disorder, coronary artery disease and age of first birth. Independent of depression, Neu had specific genetic correlates in ulcerative colitis, pubertal growth, anorexia and education.
Our findings demonstrate that, while genetic risk factors for depression are largely shared with Neu, there are also non-Neu-related features of depression that may be useful for further patient or phenotypic stratification.
Sleep disturbance is a symptom of and a well-known risk factor for depression. Further, atypical functioning of the HPA axis has been linked to the pathogenesis of depression. The purpose of this study was to examine the role of adolescent HPA axis functioning in the link between adolescent sleep problems and later depressive symptoms. Methods: A sample of 157 17–18 year old adolescents (61.8% female) completed the Pittsburgh Sleep Quality Inventory (PSQI) and provided salivary cortisol samples throughout the day for three consecutive days. Two years later, adolescents reported their depressive symptoms via the Center for Epidemiological Studies Depression Scale (CES-D). Results: Individuals (age 17–18) with greater sleep disturbance reported greater depressive symptoms two years later (age 19–20). This association occurred through the indirect effect of sleep disturbance on the cortisol awakening response (CAR) (indirect effect = 0.14, 95%CI [.02 -.39]). Conclusions: One pathway through which sleep problems may lead to depressive symptoms is by up-regulating components of the body’s physiological stress response system that can be measured through the cortisol awakening response. Behavioral interventions that target sleep disturbance in adolescents may mitigate this neurobiological pathway to depression during this high-risk developmental phase.
A national need is to prepare for and respond to accidental or intentional disasters categorized as chemical, biological, radiological, nuclear, or explosive (CBRNE). These incidents require specific subject-matter expertise, yet have commonalities. We identify 7 core elements comprising CBRNE science that require integration for effective preparedness planning and public health and medical response and recovery. These core elements are (1) basic and clinical sciences, (2) modeling and systems management, (3) planning, (4) response and incident management, (5) recovery and resilience, (6) lessons learned, and (7) continuous improvement. A key feature is the ability of relevant subject matter experts to integrate information into response operations. We propose the CBRNE medical operations science support expert as a professional who (1) understands that CBRNE incidents require an integrated systems approach, (2) understands the key functions and contributions of CBRNE science practitioners, (3) helps direct strategic and tactical CBRNE planning and responses through first-hand experience, and (4) provides advice to senior decision-makers managing response activities. Recognition of both CBRNE science as a distinct competency and the establishment of the CBRNE medical operations science support expert informs the public of the enormous progress made, broadcasts opportunities for new talent, and enhances the sophistication and analytic expertise of senior managers planning for and responding to CBRNE incidents.
Psychotic symptoms and psychotic disorders occur at increased rates in adults with intellectual disability, including borderline intellectual functioning, compared with the general population. Little is known about the development of such symptoms in this population.
To examine whether clinical factors predictive of psychotic disorder in a familial study of schizophrenia also apply to those with intellectual disability.
Adolescents with special educational needs (SEN) were assessed with the Structured Interview for Schizotypy (SIS) and Childhood Behavioural Checklist (CBCL). These scores were used to prospectively divide participants based on their anticipated risk for psychotic disorder. A subsample were reassessed three times over 6 years, using the Positive and Negative Syndrome Scale (PANSS).
The SEN group were more symptomatic than controls throughout (Cohen's d range for PANSS subscale scores: 0.54–1.4, all P < 0.007). Over 6 years of follow-up, those above the SIS and CBCL cut-off values at baseline were more likely than those below to display morbid positive psychotic symptoms (odds ratio, 3.5; 95% CI 1.3–9.0) and develop psychotic disorder (odds ratio, 11.4; 95% CI 2.6–50.1). Baseline SIS and CBCL cut-off values predicted psychotic disorder with sensitivity of 0.67, specificity of 0.85, positive predictive value of 0.26 and negative predictive value of 0.97.
Adolescents with SEN have increased psychotic and non-psychotic symptoms. The personality and behavioural features associated with later psychotic disorder in this group are similar to those in people with familial loading. Relatively simple screening measures may help identify those in this vulnerable group who do and do not require monitoring for psychotic symptoms.