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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.
Radiocarbon (14C) ages cannot provide absolutely dated chronologies for archaeological or paleoenvironmental studies directly but must be converted to calendar age equivalents using a calibration curve compensating for fluctuations in atmospheric 14C concentration. Although calibration curves are constructed from independently dated archives, they invariably require revision as new data become available and our understanding of the Earth system improves. In this volume the international 14C calibration curves for both the Northern and Southern Hemispheres, as well as for the ocean surface layer, have been updated to include a wealth of new data and extended to 55,000 cal BP. Based on tree rings, IntCal20 now extends as a fully atmospheric record to ca. 13,900 cal BP. For the older part of the timescale, IntCal20 comprises statistically integrated evidence from floating tree-ring chronologies, lacustrine and marine sediments, speleothems, and corals. We utilized improved evaluation of the timescales and location variable 14C offsets from the atmosphere (reservoir age, dead carbon fraction) for each dataset. New statistical methods have refined the structure of the calibration curves while maintaining a robust treatment of uncertainties in the 14C ages, the calendar ages and other corrections. The inclusion of modeled marine reservoir ages derived from a three-dimensional ocean circulation model has allowed us to apply more appropriate reservoir corrections to the marine 14C data rather than the previous use of constant regional offsets from the atmosphere. Here we provide an overview of the new and revised datasets and the associated methods used for the construction of the IntCal20 curve and explore potential regional offsets for tree-ring data. We discuss the main differences with respect to the previous calibration curve, IntCal13, and some of the implications for archaeology and geosciences ranging from the recent past to the time of the extinction of the Neanderthals.
While policy attention is understandably diverted to COVID-19, the end of the UK's post-Brexit ‘transition period’ remains 31 December 2020. All forms of future EU−UK relationship are worse for health than EU membership, but analysis of the negotiating texts shows some forms are better than others. The likely outcomes involve major negative effects for NHS staffing, funding for health and social care, and capital financing for the NHS; and for UK global leadership and influence. We expect minor negative effects for cross border healthcare (except in Northern Ireland); research collaboration; and data sharing, such as the Early Warning and Response System for health threats. Despite political narratives, the legal texts show that the UK seeks de facto continuity in selected key areas for pharmaceuticals, medical devices, and equipment [including personal protective equipment (PPE)], especially clinical trials, pharmacovigilance, and batch-testing. The UK will be excluded from economies of scale of EU membership, e.g. joint procurement programmes as used recently for PPE. Above all, there is a major risk of reaching an agreement with significant adverse effects for health, without meaningful oversight by or input from the UK Parliament, or other health policy stakeholders.
Lichens of the Ramalina siliquosa complex dominate seashore cliffs in Europe and South-East Asia, but their taxonomy has been vigorously debated for over a century. On many cliffs, they exhibit a bewildering zonation of chemotypes that resembles the classic zonation of organisms that occupy the littoral zone below. Do the chemotypes represent separate species, or infraspecific variation? To better understand the systematics of this group, sequences from four genetic loci (ITS, IGS, RPB1 and RPB2) were obtained for 59 samples from Denmark, France, Iceland, Norway, UK, Japan and Korea, including all major chemotypes. Maximum likelihood analysis of these sequences, together with sequences from 36 other Ramalina species, reveals that the complex comprises two distinct phylogenetic lineages, each including multiple chemotypes. These two putative species-level lineages correspond to the currently accepted taxa R. cuspidata and R. siliquosa. There is no evidence that these two taxa are phylogenetic sister species. Consequently, the explanation of this chemotype complex as an example of ‘sibling speciation’ is rejected. Specimens traditionally called ‘R. siliquosa’ from South-East Asia form a third clade, identified here as R. semicuspidata, with an additional, divaricatic acid chemotype. Other results include a robustly supported clade of Ramalina species that produce medullary depsides and depsidones; this clade includes another well-supported clade of south-eastern United States coastal plain and tropical Ramalina species. By contrast, large, strap-shaped Ramalina species that lack medullary depsides and depsidones occur in separate lineages. In addition, close relationships between the following groups of species are indicated: R. farinacea with R. subfarinacea; R. fraxinea with R. leptocarpha, R. menziesii and R. subleptocarpha; R. sinensis with R. unifolia. Furthermore, a new, variolaric acid-only chemotype is reported for R. farinacea, and a new, acid-deficient chemotype is reported for a more broadly circumscribed R. culbersoniorum.
Reading and language abilities are critical for educational achievement and success in adulthood. Variation in these traits is highly heritable, but the underlying genetic architecture is largely undiscovered. Genetic studies of reading and language skills traditionally focus on children with developmental disorders; however, much larger unselected adult samples are available, increasing power to identify associations with specific genetic variants of small effect size. We introduce an Australian adult population cohort (41.7–73.2 years of age, N = 1505) in which we obtained data using validated measures of several aspects of reading and language abilities. We performed genetic association analysis for a reading and spelling composite score, nonword reading (assessing phonological processing: a core component in learning to read), phonetic spelling, self-reported reading impairment and nonword repetition (a marker of language ability). Given the limited power in a sample of this size (~80% power to find a minimum effect size of 0.005), we focused on analyzing candidate genes that have been associated with dyslexia and developmental speech and language disorders in prior studies. In gene-based tests, FOXP2, a gene implicated in speech/language disorders, was associated with nonword repetition (p < .001), phonetic spelling (p = .002) and the reading and spelling composite score (p < .001). Gene-set analyses of candidate dyslexia and speech/language disorder genes were not significant. These findings contribute to the assessment of genetic associations in reading and language disorders, crucial for understanding their etiology and informing intervention strategies, and validate the approach of using unselected adult samples for gene discovery in language and reading.
Lightweighting of vehicles and portable structures is an important undertaking. Multimaterial design is required to achieve conflicting design targets such as cost, stiffness, and weight. Friction stir welding (FSW) variants, such as friction stir dovetailing and friction stir scribe, are enabling technologies for joining of dissimilar metals. This article discusses how FSW variants are capable of joining aluminum to steel in particular. The characteristics of metallurgical bonding at the dissimilar materials interface are strongly affected by weld temperature. Control of FSW process temperature enables metallurgical bonding with suppressed formation of intermetallics at the dissimilar materials interface, resulting in improved mechanical properties relative to competing techniques. Temperature control is thus a powerful tool for process development and ensuring weld quality of dissimilar materials welds.
Item 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total score correlations and the diagnostic accuracy to detect major depression of the PHQ-8 and PHQ-9.
We conducted an individual patient data meta-analysis. We fit bivariate random-effects models to assess diagnostic accuracy.
16 742 participants (2097 major depression cases) from 54 studies were included. The correlation between PHQ-8 and PHQ-9 scores was 0.996 (95% confidence interval 0.996 to 0.996). The standard cutoff score of 10 for the PHQ-9 maximized sensitivity + specificity for the PHQ-8 among studies that used a semi-structured diagnostic interview reference standard (N = 27). At cutoff 10, the PHQ-8 was less sensitive by 0.02 (−0.06 to 0.00) and more specific by 0.01 (0.00 to 0.01) among those studies (N = 27), with similar results for studies that used other types of interviews (N = 27). For all 54 primary studies combined, across all cutoffs, the PHQ-8 was less sensitive than the PHQ-9 by 0.00 to 0.05 (0.03 at cutoff 10), and specificity was within 0.01 for all cutoffs (0.00 to 0.01).
PHQ-8 and PHQ-9 total scores were similar. Sensitivity may be minimally reduced with the PHQ-8, but specificity is similar.
The objectives of this paper are to: (1) identify contextual factors such as policy that impacted the implementation of community-based primary health care (CBPHC) innovations among 12 Canadian research teams and (2) describe strategies used by the teams to address contextual factors influencing implementation of CBPHC innovations. In primary care settings, consideration of contextual factors when implementing change has been recognized as critically important to success. However, contextual factors are rarely recorded, analyzed or considered when implementing change. The lack of consideration of contextual factors has negative implications not only for successfully implementing primary health care (PHC) innovations, but also for their sustainability and scalability. For this evaluation, data collection was conducted using self-administered questionnaires and follow-up telephone interviews with team representatives. We used a combination of directed and conventional content analysis approaches to analyze the questionnaire and interview data. Representatives from all 12 teams completed the questionnaire and 11 teams participated in the interviews; 40 individuals participated in this evaluation. Four themes representing contextual factors that impacted the implementation of CBPHC innovations were identified: (I) diversity of jurisdictions (II) complexity of interactions and collaborations (III) policy, and (IV) the multifaceted nature of PHC. The teams used six strategies to address these contextual factors including: (1) conduct an environmental scan at the beginning (2) maintaining engagement among partners and stakeholders by encouraging open and inclusive communication; (3) contextualizing the innovation for different settings; (4) anticipating and addressing changes, delays, and the need for additional resources; (5) fostering a culture of research and innovation among partners and stakeholders; and (6) ensuring information about the innovation is widely available. Implementing CBPHC innovations across jurisdictions is complex and involves navigating through multiple contextual factors. Awareness of the dynamic nature of context should be considered when implementing innovations.
The aim of the 25 and Up (25Up) study was to assess a wide range of psychological and behavioral risk factors behind mental illness in a large cohort of Australian twins and their non-twin siblings. Participants had already been studied longitudinally from the age of 12 and most recently in the 19Up study (mean age = 26.1 years, SD = 4.1, range = 20–39). This subsequent wave follows up these twins several years later in life (mean age = 29.7 years, SD = 2.2, range = 22–44). The resulting data set enables additional detailed investigations of genetic pathways underlying psychiatric illnesses in the Brisbane Longitudinal Twin Study (BLTS). Data were collected between 2016 and 2018 from 2540 twins and their non-twin siblings (59% female, including 341 monozygotic complete twin-pairs, 415 dizygotic complete pairs and 1028 non-twin siblings and singletons). Participants were from South-East Queensland, Australia, and the sample was of predominantly European ancestry. The 25Up study collected information on 20 different mental disorders, including depression, anxiety, substance use, psychosis, bipolar and attention-deficit hyper-activity disorder, as well as general demographic information such as occupation, education level, number of children, self-perceived IQ and household environment. In this article, we describe the prevalence, comorbidities and age of onset for all 20 examined disorders. The 25Up study also assessed general and physical health, including physical activity, sleep patterns, eating behaviors, baldness, acne, migraines and allergies, as well as psychosocial items such as suicidality, perceived stress, loneliness, aggression, sleep–wake cycle, sexual identity and preferences, technology and internet use, traumatic life events, gambling and cyberbullying. In addition, 25Up assessed female health traits such as morning sickness, breastfeeding and endometriosis. Furthermore, given that the 25Up study is an extension of previous BLTS studies, 86% of participants have already been genotyped. This rich resource will enable the assessment of epidemiological risk factors, as well as the heritability and genetic correlations of mental conditions.
To evaluate the feasibility and acceptability of the Takeaway Masterclass, a three-hour training session delivered to staff of independent takeaway food outlets that promoted healthy cooking practices and menu options.
A mixed-methods study design. All participating food outlets provided progress feedback at 6 weeks post-intervention. Baseline and 6-week post-intervention observational and self-reported data were collected in half of participating takeaway food outlets.
North East England.
Independent takeaway food outlet owners and managers.
Staff from eighteen (10 % of invited) takeaway food outlets attended the training; attendance did not appear to be associated with the level of deprivation of food outlet location. Changes made by staff that required minimal effort or cost to the business were the most likely to be implemented and sustained. Less popular changes included using products that are difficult (or expensive) to source from suppliers, or changes perceived to be unpopular with customers.
The Takeaway Masterclass appears to be a feasible and acceptable intervention for improving cooking practices and menu options in takeaway food outlets for those who attended the training. Further work is required to increase participation and retention and explore effectiveness, paying particular attention to minimising adverse inequality effects.
The increased use of insecticide seed treatments in rice has raised many questions about the potential benefits of these products. In 2014 and 2015, a field experiment was conducted near Stuttgart and Lonoke, AR, to evaluate whether an insecticide seed treatment could possibly lessen injury from acetolactate synthase (ALS)–inhibiting herbicides in imidazolinone-resistant (IR) rice. Two IR cultivars were tested (a hybrid, ‘CLXL745’, and an inbred, ‘CL152’), with and without an insecticide seed treatment (thiamethoxam). Four different herbicide combinations were evaluated: a nontreated control, two applications of bispyribac-sodium (hereafter bispyribac), two applications of imazethapyr, and two applications of imazethapyr plus bispyribac. The first herbicide application was to two- to three-leaf rice, and the second immediately prior to flooding (one- to two-tiller). At both 2 and 4 wk after final treatment (WAFT), the sequential applications of imazethapyr or bispyribac plus imazethapyr were more injurious to CLXL745 than CL152. This increased injury led to decreased groundcover 3 WAFT. Rice treated with thiamethoxam was less injured than nontreated rice and had improved groundcover and greater canopy heights. Even with up to 32% injury, the rice plants recovered by the end of the growing season, and yields within a cultivar were similar with and without a thiamethoxam seed treatment across all herbicide treatments. Based on these results, thiamethoxam can partially protect rice from injury caused by ALS-inhibiting herbicides as well as increase groundcover and canopy height; that is, the injury to rice never negatively affected yield.
OBJECTIVES/SPECIFIC AIMS: Our objective was to compare the proteomics of HDL between youth with T1DM and healthy controls (HC). METHODS/STUDY POPULATION: We did chromatography-based HDL purification and SWATH-MS-based proteomic quantitation. Proteomic alterations of HDL fractions and their association with glycemic control was examined. Study population: 26 patients with T1DM and 13 HC. RESULTS/ANTICIPATED RESULTS: We quantified 78 proteins in isolated HDL, using mass spectrometry and label-free SWATH quantification. Youth with T1DM had significantly higher protein levels of A1BG (P = 0.008), A2AP (P = 0.0448), APOA4 (P = 0.0366), CFAH (P = 0.0476), FHR2 (P = 0.0005), ITIH4(P = 0.01), PGRP2 (P = 0.0167) and lower levels of ALBU (P = 0.0164) and CO3 (P = 0.019) compared to HC. A1BG (r=0.541, P<0.001) and ITIH4 (r=0.357, P = 0.026) were significantly positively correlated with HbA1c. DISCUSSION/SIGNIFICANCE OF IMPACT: Youth with T1DM have proteomic alterations of their HDL compared to HC, despite similar concentration of HDL cholesterol, that might affect the cardioprotective mechanisms of HDL. Future efforts should focus on investigating the role of these HDL associated proteins in regard to HDL function and their role in CVD risk in patients with T1DM.
Matching adjusted indirect comparison (MAIC) methods are extremely useful when conducting ITCs, as they reduce baseline imbalances between studies, particularly upon patient characteristics that are confounded with treatment. The standard approach when conducting MAIC is that proposed by Signorovitch et al. (2010). However, there are newer, and potentially better, methods available.
Three different MAIC methods (Signorovitch, Entropy Balancing, Polynomial Weighting) were compared using multiple phase 3 RCTs conducted in Diabetic Retinal Edema. The matching ability of each method was assessed, alongside its ability to avoid large weights (i.e. avoiding high leverage), and maximise effective same size (ESS). Each method's overall ease of use and impact upon estimates of treatment effectiveness were also evaluated.
All methods were able to precisely match the aggregate level data. However, the Entropy Balancing and Polynomial Weighting both outperformed the Signorovitch method in terms of having the lowest maximum weights. The Polynomial Weighting provided the highest ESS. The Entropy Balancing method was arguably the most challenging to implement, whilst the Signorovitch method the least. The Polynomial Weighting method appears to provide the greatest flexibility to the user.
Whilst the Signorovitch method has become almost synonymous with MAIC, the Entropy Balancing and Polynomial Weighting methods offer potentially superior performance. In the absence of head-to-head trial data, these new MAIC approaches should provide less biased and more precise estimates of comparative effectiveness – ultimately leading to better decision making by regulators and payers.
Radiocarbon (14C) dating is widely used to determine the age of organic material in palaeoenvironmental research. Here we compare 14C dates (n=17) resulting from macro-charcoal (>250 μm), short-lived plant macrofossils and pollen-rich residues isolated from two mire environments in eastern Australia. In most samples we found that short-lived plant macrofossils were the youngest organic component, the charcoal samples most often fell into the middle and the pollen-rich residues consistently returned older dates than the other samples. Although pollen-rich residues have been widely used for 14C dating in Australasia we suggest some caution in their use, perhaps because in our fire-prone environments these samples often also contain fine charcoal and other oxidative resistant organic matter that is older than the surrounding sediment matrix. The macro-charcoal samples also often returned older calibrated ages compared to short-lived plant macrofossils from the same depth, although this difference was relatively small (<245 years). Our results demonstrate that 14C dating of short-lived plant macrofossils are likely to yield more accurate chronologies and we advocate their routine use in palaeoenvironmental research when they are available.
Each year there are multiple reports of drift occurrences, and the majority of drift complaints in rice are from imazethapyr or glyphosate. In 2014 and 2015, multiple field experiments were conducted near Stuttgart, AR, and near Lonoke, AR, to evaluate whether insecticide seed treatments would reduce injury from glyphosate or imazethapyr drift or decrease the recovery time following exposure to a low rate of these herbicides. Study I was referred to as the “seed treatment study,” and Study II was the “drift timing study.” In the seed treatment study the conventional rice cultivar ‘Roy J’ was planted, and herbicide treatments included imazethapyr at 10.5 g ai ha–1, glyphosate at 126 g ae ha–1, or no herbicide. Each plot had either a seed treatment of thiamethoxam, clothianidin, chlorantraniliprole, or no insecticide seed treatment. The herbicides were applied at the two- to three-leaf growth stage. Crop injury was assessed 1, 3, and 5 wk after application. Averaged over site-years, thiamethoxam-treated rice had less injury than rice with no insecticide seed treatment at each rating, along with an increased yield. Clothianidin-treated rice had an increased yield over no insecticide seed treatment, but the reduction in injury for both herbicides was less pronounced than in the thiamethoxam-treated plots. Overall, chlorantraniliprole was generally the least effective of the three insecticides in reducing injury from either herbicide and in protecting rice yield potential. A second experiment conducted at Stuttgart, AR, was meant to determine whether damage to rice from glyphosate and imazethapyr was influenced by the timing (15, 30, and 45 d after planting) of exposure to herbicides for thiamethoxam-treated and nontreated rice. There was an overall reduction in injury with the use of thiamethoxam, but the reduction in injury was not dependent on the timing of the drift event. Reduction in damage from physical drift of glyphosate and imazethapyr as well as increased yields over the absence of an insecticide seed treatment appear to be an added benefit.
The X-Shooter Spectral Library (XSL) contains more than 800 spectra of stars across the color-magnitude diagram, that extend from near-UV to near-IR wavelengths (320-2450 nm). We summarize properties of the spectra of O-rich Long Period Variables in the XSL, such as phase-related features, and we confront the data with synthetic spectra based on static and dynamical stellar atmosphere models. We discuss successes and remaining discrepancies, keeping in mind the applications to population synthesis modeling that XSL is designed for.