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Abstract Objectives Stage 1: To evaluate the safety and efficacy of candidate agents as add-on therapies to standard of care (SoC) in patients hospitalised with COVID-19 in a screening stage. Stage 2: To confirm the efficacy of candidate agents selected on the basis of evidence from Stage 1 in patients hospitalised with COVID-19 in an expansion stage. Trial design ACCORD is a seamless, Phase 2, adaptive, randomised controlled platform study, designed to rapidly test candidate agents in the treatment of COVID-19. Designed as a master protocol with each candidate agent being included via its own sub-protocol, initially randomising equally between each candidate and a single contemporaneous SoC arm (which can adapt into 2:1). Candidate agents currently include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin. For each candidate a total of 60 patients will be recruited in Stage 1. If Stage 1 provides evidence of efficacy and acceptable safety the candidate will enter Stage 2 where a total of approximately 126 patients will be recruited into each study arm sub-protocol. Enrollees and outcomes will not be shared across the Stages; the endpoint, analysis and sample size for Stage 2 may be adjusted based on evidence from Stage 1. Additional arms may be added as new potential candidate agents are identified via candidate agent specific sub-protocols. Participants The study will include hospitalised adult patients (≥18 years) with confirmed SARS-CoV-2 infection, the virus that causes COVID-19, that clinically meet Grades 3 (hospitalised – mild disease, no oxygen therapy), Grades 4 (hospitalised, oxygen by mask or nasal prongs) and 5 (hospitalised, non-invasive ventilation or high flow oxygen) of the WHO Working Group on the Clinical Characteristics of COVID-19 9-point category ordinal scale. Participants will be recruited from England, Northern Ireland, Wales and Scotland. Intervention and comparator Comparator is current standard of care (SoC) for the treatment of COVID-19. Current candidate experimental arms include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin with others to be added over time. Bemcentinib could potentially reduce viral infection and blocks SARS-CoV-2 spike protein; MEDI3506 is a clinic-ready anti-IL-33 monoclonal antibody with the potential to treat respiratory failure caused by COVID; acalabrutinib is a BTK inhibitor which is anti-viral and anti-inflammatory; zilucoplan is a complement C5 inhibitor which may block the severe inflammatory response in COVID-19 and; nebulised heparin has been shown to bind with the spike protein. ACCORD is linked with the UK national COVID therapeutics task force to help prioritise candidate agents. Main outcomes Time to sustained clinical improvement of at least 2 points (from randomisation) on the WHO 9-point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the “responder” for the response rate analyses). Randomisation An electronic randomization will be performed by Cenduit using Interactive Response Technology (IRT). Randomisation will be stratified by baseline severity grade. Randomisation will proceed with an equal allocation to each arm and a contemporaneous SoC arm (e.g. 1:1 if control and 1 experimental arm; 1:1:1 if two experimental candidate arms etc) but will be reviewed as the trial progresses and may be changed to 2:1 in favour of the candidate agents. Blinding (masking) The trial is open label and no blinding is currently planned in the study. Numbers to be randomised (sample size) This will be in the order of 60 patients per candidate agent for Stage 1, and 126 patients for Stage 2. However, sample size re-estimation may be considered after Stage 1. It is estimated that up to 1800 patients will participate in the overall study. Trial Status Master protocol version ACCORD-2-001 - Master Protocol (Amendment 1) 22nd April 2020, the trial has full regulatory approval and recruitment is ongoing in the bemcentinib (first patient recruited 6/5/2020), MEDI3506 (first patient recruited 19/5/2020), acalabrutinib (first patient recruited 20/5/2020) and zilucoplan (first patient recruited 19/5/2020) candidates (and SoC). The recruitment dates of each arm will vary between candidate agents as they are added or dropped from the trial, but will have recruited and reported within a year. Trial registration EudraCT 2020-001736-95 , registered 28th April 2020. Full protocol The full protocol (Master Protocol with each of the candidate sub-protocols) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Most therapeutic monoclonal antibodies in biopharmaceutical processes are produced in Chinese hamster ovary (CHO) cells. Technological advances have rendered the selection procedure for higher producers a robust protocol. However, information on molecular mechanisms that impart the property of hyper-productivity in the final selected clones is currently lacking. In this study, an IgG-producing industrial cell line and its methotrexate (MTX)-amplified progeny cell line were analyzed using transcriptomic, proteomic, phosphoproteomic, and chromatin immunoprecipitation (ChIP) techniques. Computational prediction of transcription factor binding to the transgene cytomegalovirus (CMV) promoter by the Transcription Element Search System and upstream regulator analysis of the differential transcriptomic data suggested increased in vivo CMV promoter-cAMP response element binding protein (CREB1) interaction in the higher producing cell line. Differential nuclear proteomic analysis detected 1.3-fold less CREB1 in the nucleus of the high productivity cell line compared with the parental cell line. However, the differential abundance of multiple CREB1 phosphopeptides suggested an increase in CREB1 activity in the higher producing cell line, which was confirmed by increased association of the CMV promotor with CREB1 in the high producer cell line. Thus, we show here that the nuclear proteome and phosphoproteome have an important role in regulating final productivity of recombinant proteins from CHO cells, and that CREB1 may play a role in transcriptional enhancement. Moreover, CREB1 phosphosites may be potential targets for cell engineering for increased productivity.

Post-traumatic stress disorder (PTSD) is a common mental health problem. Here, the authors report a GWAS from the Psychiatric Genomics Consortium in which they identify two risk loci in European ancestry and one locus in African ancestry individuals and find that PTSD is genetically correlated with several other psychiatric traits.

Abstract Background To establish which major disorders are susceptible to increased mortality following acute admissions on weekends, compared with week days, and how this may be explained. Methods Cohorts based on national administrative inpatient and mortality data for 14,168,443 hospitalised patients in England and 913,068 in Wales who were admitted for 66 disorders that were associated with at least 200 deaths within 30 days of acute admission. The main outcome measure was the weekend mortality effect (defined as the conventional mortality odds ratio for admissions on weekends compared with week days). Results There were large, statistically significant weekend mortality effects (> 20%) in England for 22 of the 66 conditions and in both countries for 14. These 14 were 4 of 13 cancers (oesophageal, colorectal, lung and lymphomas); 4 of 13 circulatory disorders (angina, abdominal aortic aneurysm, peripheral vascular disease and arterial embolism & thrombosis); one of 8 respiratory disorders (pleural effusion); 2 of 12 gastrointestinal disorders (alcoholic and other liver disease); 2 of 3 ageing-related disorders (Alzheimer’s disease and dementia); none of 7 trauma conditions; and one of 10 other disorders (acute renal failure). Across the disorders, 64% of the variation in weekend mortality effects in England and Wales was explained by reductions in admission rates at weekends and the medical disease category. Conclusions The effect of weekend admission on 30 day mortality is seen mainly for cancers, some circulatory disorders, liver disease and a few other conditions which are mainly ageing- or cancer-related. Most of the increased mortality is associated with reduced admission rates at weekends and the medical disease category.

Abstract Background Calls for science education reform have been made for decades in the USA. The recent call to produce one million new science, technology, engineering, and math (STEM) graduates over 10 years highlights the need to employ evidence-based instructional practices (EBIPs) in undergraduate STEM classes to create engaging and effective learning environments. EBIPs are teaching strategies that have been empirically demonstrated to positively impact student learning, attitudes, and achievement in STEM disciplines. However, the mechanisms and processes by which faculty learn about and choose to implement EBIPs remain unclear. To explore this problem area, we used social network analysis to examine how an instructor’s knowledge and use of EBIPs may be influenced by their peers within a STEM department. We investigated teaching discussion networks in biology and chemistry departments at three public universities. Results We report that tie strength and tie diversity vary between departments, but that mean indegree is not correlated with organizational rank or tenure status. We also describe that teaching discussion ties can often be characterized as strong ties based on two measures of tie strength. Further, we compare peer influence models and find consistent evidence that peer influence in these departments follows a network disturbances model. Conclusions Our findings with respect to tie strength and tie diversity indicate that the social network structures in these departments vary in how conducive they might be to change. The correlation in teaching practice between discussion partner and peer influence models suggest that change agents should consider local social network characteristics when developing change strategies. In particular, change agents can expect that faculty may serve as opinion leaders regardless of their academic rank and that faculty can increase their use of EBIPs even if those they speak to about teaching use EBIPs comparatively less.

Abstract Neisseria gonorrhoeae causes the sexually transmitted disease gonorrhea exclusively in humans and uses multiple strategies to infect, including acquisition of host sialic acids that cap and mask lipooligosaccharide termini, while restricting complement activation. We hypothesized that gonococci selectively target human anti‐inflammatory sialic acid‐recognizing Siglec receptors on innate immune cells to blunt host responses and that pro‐inflammatory Siglecs and SIGLEC pseudogene polymorphisms represent host evolutionary adaptations to counteract this interaction. N. gonorrhoeae can indeed engage multiple human but not chimpanzee CD33rSiglecs expressed on innate immune cells and in the genitourinary tract––including Siglec‐11 (inhibitory) and Siglec‐16 (activating), which we detected for the first time on human cervical epithelium. Surprisingly, in addition to LOS sialic acid, we found that gonococcal porin (PorB) mediated binding to multiple Siglecs. PorB also bound preferentially to human Siglecs and not chimpanzee orthologs, modulating host immune reactions in a human‐specific manner. Lastly, we studied the distribution of null SIGLEC polymorphisms in a Namibian cohort with a high prevalence of gonorrhea and found that uninfected women preferentially harbor functional SIGLEC16 alleles encoding an activating immune receptor. These results contribute to the understanding of the human specificity of N. gonorrhoeae and how it evolved to evade the human immune defense.

Abstract Background The regulatory cyclin, Cyclin T1 (CycT1), is a host factor essential for HIV-1 replication in CD4 T cells and macrophages. The importance of CycT1 and the Positive Transcription Elongation Factor b (P-TEFb) complex for HIV replication is well-established, but regulation of CycT1 expression and protein levels during HIV replication and latency establishment in CD4 T cells is less characterized. Methods To better define the regulation of CycT1 levels during HIV replication in CD4 T cells, multiparameter flow cytometry was utilized to study the interaction between HIV replication (intracellular p24) and CycT1 of human peripheral blood memory CD4 T cells infected with HIV in vitro. CycT1 was further examined in CD4 T cells of human lymph nodes. Results In activated (CD3+CD28 costimulation) uninfected blood memory CD4 T cells, CycT1 was most significantly upregulated in maximally activated (CD69+CD25+ and HLA.DR+CD38+) cells. In memory CD4 T cells infected with HIV in vitro, two distinct infected populations of p24+CycT1+ and p24+CycT1- cells were observed during 7 days infection, suggestive of different phases of productive HIV replication and subsequent latency establishment. Intriguingly, p24+CycT1- cells were the predominant infected population in activated CD4 T cells, raising the possibility that productively infected cells may transition into latency subsequent to CycT1 downregulation. Additionally, when comparing infected p24+ cells to bystander uninfected p24- cells (after bulk HIV infections), HIV replication significantly increased T cell activation (CD69, CD25, HLA.DR, CD38, and Ki67) without concomitantly increasing CycT1 protein levels, possibly due to hijacking of P-TEFb by the viral Tat protein. Lastly, CycT1 was constitutively expressed at higher levels in lymph node CD4 T cells compared to blood T cells, potentially enhancing latency generation in lymphoid tissues. Conclusions CycT1 is most highly upregulated in maximally activated memory CD4 T cells as expected, but may become less associated with T cell activation during HIV replication. The progression into latency may further be predicated by substantial generation of p24+CycT1- cells during HIV replication.

GWAS have identified more than 500 genetic loci associated with blood lipid levels. Here, the authors report a genome-wide analysis of interactions between genetic markers and physical activity, and find that physical activity modifies the effects of four genetic loci on HDL or LDL cholesterol.

CD36 is a multifunctional scavenger receptor and lipid transporter implicated in metabolic and inflammatory pathologies, as well as cancer progression. CD36 is known to be expressed by adipocytes and monocytes/macrophages, but its expression by T cells is not clearly established. We found that CD4 and CD8 T cells in adipose tissue and liver of humans, monkeys, and mice upregulated CD36 expression (ranging from ~5–40% CD36+), whereas little to no CD36 was expressed by T cells in blood, spleen, and lymph nodes. CD36 was expressed predominantly by resting CD38-, HLA.DR-, and PD-1- adipose tissue T cells in monkeys, and increased during high-fat feeding in mice. Adipose tissue and liver promote a distinct phenotype in resident T cells characterized by CD36 upregulation.

Abstract Background Young adults (YA) are at high-risk for unhealthy dietary behaviors and weight gain. The Study of Novel Approaches to Weight Gain Prevention (SNAP) Trial demonstrated that two self-regulation approaches were effective in reducing weight gain over 2 years compared with control. The goal of this analysis was to examine effects of intervention on dietary outcomes and the association of diet changes with weight change. Methods Participants were 599 YA, age 18–35 years, BMI 21.0–30.0 kg/m2 (27.4 ± 4.4 years; 25.4 ± 2.6 kg/m2; 22% men; 73% non-Hispanic White), who were recruited in Providence, RI and Chapel Hill, NC and randomized to self-regulation with Small Changes (SC), self-regulation with Large Changes (LC) or Control (C). SC and LC emphasized frequent self-weighing to cue behavior changes (small daily changes vs. periodic large changes) and targeted high-risk dietary behaviors. Diet and weight were assessed at baseline, 4 months and 2 years. Results LC and SC had greater decreases in energy intake than C at 4 months but not 2 years. LC had the greatest changes in percent calories from fat at 4 months, but differences were attenuated at 2 years. No differences in diet quality were observed. Across conditions, increased total energy consumption, fast food, meals away from home, and binge drinking, and decreased dietary quality and breakfast consumption were all associated with weight gain at 2 years. Conclusions This study suggests the need to strengthen interventions to produce longer term changes in dietary intake and helps to identify specific behaviors associated with weight gain over time in young adults. Trial registration Clinicaltrials.gov #NCT01183689, registered August 18, 2010.

The objective was to examine bidirectional associations of accelerometer estimated sedentary time and physical activity with reported knee symptoms. Participants were 2,034 adults (mean age 45.3 ± 3.6 years, 58.7% female) from CARDIA. Generalized estimating equations for logistic regression and linear mixed regression models examined associations of accelerometer estimated sedentary time, light-intensity physical activity (LPA), and moderate-to-vigorous intensity physical activity (MVPA) at baseline (2005–06) with knee discomfort, pain, stiffness, and physical function (yes/no and continuous scores from short-form WOMAC function scale) at the 5- and 10-year follow-up exams. Linear regression models examined associations between knee symptoms at the 5-year follow-up with accelerometer estimates at the 10-year follow-up. Models were adjusted for confounders; individuals with comorbidities were excluded in sensitivity analyses. A 30 min/day increment in sedentary time at baseline was associated with lower odds of knee symptoms at the 5- and 10-year follow-up (OR: 0.95, 95% CI range: 0.92–0.98), while LPA and MVPA were associated with greater odds of knee symptoms (LPA OR range: 1.04–1.05, 95% CI range: 1.01–1.09; MVPA OR range: 1.17–1.19, 95% CI range: 1.06–1.32). Report of knee symptoms at the 5-year follow-up was associated with 13.52–17.51 (95% CI range: −29.90, −0.56) fewer minutes/day of sedentary time and 14.58–17.51 (95% CI range: 2.48, 29.38) more minutes/day of LPA at the 10-year follow-up, compared to those reporting no symptoms. Many associations were no longer statistically significant when excluding individuals with comorbidities. Findings support a bidirectional association of accelerometer estimated sedentary time and physical activity with knee symptoms across midlife.

Sheep are often used as a proxy for dairy cows when measuring the digestibility of a feed. In recent years grassland management guidelines for ruminant animals have been re-evaluated in accordance with the progression in animal genetics and the acknowledgement that genetic potential has an influence on both feed intake and digestibility. Recommended pre-grazing herbage mass (HM) targets are now much lower with improved perennial ryegrass varieties available for grazing swards. The objective of this study was to compare the in vivo digestibility of perennial ryegrass in wether sheep and lactating dairy cows. The experimental design was selected to measure the effect of animal species (cows, sheep), sward HM measured cutting herbage at 4 cm above ground level (low: 1 700 kg DM/ha and high: 4 000 kg DM/ha) and season (Spring: Apr–May, Summer: Jul–Aug) on the digestibility of perennial ryegrass. Each HM treatment was offered to each animal within species and season for 12 d using a 2 HM × 2 period changeover Latin square design. There were eight cows and eight sheep, so there were four 2 × 2 Latin squares for each animal species (two) at each season (two), giving 64 observations. During each 12 d experimental period, the first 6 d were used for adaptation (adaptation phase) and the final 6 d were used for measurement (measurement phase). In vivo organic matter digestibility (OMD) in spring did not differ between animal species but in summer sheep had higher in vivo OMD than cows. The results described herein highlight the suitability of wether sheep as an alternative to dairy cows for determining the digestibility of perennial ryegrass in spring but not in summer. Stage of growth of the plant, which is intrinsically linked to season, should be considered as results show that digestibility in the ruminant was affected by season but not differentially affected by changing sward HM.

The epithelial-to-mesenchymal transition (EMT) is considered a transcriptional process that induces a switch in cells from a polarized state to a migratory phenotype. Here, we show that KSR1 and ERK promote EMT-like phenotype through the preferential translation of Epithelial-Stromal Interaction 1 (EPSTI1), which is required to induce the switch from E- to N-cadherin and coordinate migratory and invasive behavior. EPSTI1 is overexpressed in human colorectal cancer (CRC) cells. Disruption of KSR1 or EPSTI1 significantly impairs cell migration and invasion in vitro, and reverses EMT-like phenotype, in part, by decreasing the expression of N-cadherin and the transcriptional repressors of E-cadherin expression, ZEB1 and Slug. In CRC cells lacking KSR1, ectopic EPSTI1 expression restored the E- to N-cadherin switch, migration, invasion, and anchorage-independent growth. KSR1-dependent induction of EMT-like phenotype via selective translation of mRNAs reveals its underappreciated role in remodeling the translational landscape of CRC cells to promote their migratory and invasive behavior.

Background The menopausal transition is characterized by increased cardiovascular risk, weight gain, and increased adiposity for many women. The adipose‐derived secretory proteins adiponectin and leptin are associated with insulin resistance, metabolic syndrome, and cardiovascular disease but their role in subclinical atherosclerotic disease is unclear. This cross‐sectional study evaluated the associations of adiponectin and leptin with carotid artery intima‐media thickness, adventitial diameter, presence of carotid plaques, and brachial‐ankle pulse wave velocity (baPWV) in women aged 54 to 65 years. Methods and Results Participants were 1399 women from SWAN (Study of Women's Health Across the Nation), a community‐based study of women transitioning through menopause. Carotid ultrasound and baPWV measures were obtained at SWAN follow‐up visits 12 or 13, when 97% of participants were post‐menopausal. Adipokines were assayed from serum specimens obtained concurrently at these visits. Linear and logistic regression models were used to evaluate adiponectin or leptin, both log‐transformed attributable to skewness, in relationship to carotid artery intima‐media thickness, adventitial diameter, baPWV, and presence of carotid plaque. Covariates included age, race, study site, smoking, alcohol use, obesity, cardiovascular disease risk factors, and menopausal status. Lower levels of adiponectin were related to greater carotid artery intima‐media thickness, wider adventitial diameter, and faster baPWV; associations were attenuated after adjusting for cardiovascular disease risk factors. Higher levels of leptin were associated with greater carotid artery intima‐media thickness and wider adventitial diameter in minimally and fully adjusted models, and contrary to expectation, with slower baPWV, particularly among women with diabetes mellitus or obesity. Conclusions Adiponectin and leptin are 2 important inflammatory pathways that may contribute to adverse subclinical cardiovascular disease risk profiles in women at midlife.

Increased participation in activities has been associated with improved positive mental health outcomes. However, there is much debate regarding the net effects of video games on individuals. Typified as a socially isolating activity, many games inherently contain socialization within the environment with game-generated characters or other players. Coinciding with the time of the initial pandemic/quarantine period was the release of a popular socializing and life simulation game, Animal Crossing: New Horizons. We investigated whether participation in this game was related to emotional outcomes associated with pandemics (e.g., loneliness and anxiety). The relationship between deleterious mental health and social gaming, amid a time of enforced reduction in socializing, would allow us to isolate the impact of the introduction of a social video game on improving the quality of life for players of this game. Participants (n = 1053) were asked about their time spent playing video games via an online survey, their socialization in game play, loneliness, and anxiety. We predicted that participants with higher levels of social interaction within the game would report less loneliness and anxiety. Utilizing multiple linear regression analyses, the research found that increased gaming and related activities were predictive of higher anxiety and somewhat related to increased loneliness. However, increased visits to another island were associated with lower levels of loneliness. As such, players may be utilizing gaming as a coping mechanism for anxiety. This research may inform generalized research regarding the influence that social games may have on feelings of loneliness and anxiety.

Prenatal alcohol exposure (PAE) is associated with physical anomalies, growth restriction, and a range of neurobehavioral deficits. Although declarative memory impairment has been documented extensively in individuals with fetal alcohol spectrum disorders (FASD), this cognitive process has been examined in only one functional magnetic resonance imaging (fMRI) study, and mechanisms underlying this impairment are not well understood. We used an event-related fMRI design to examine neural activations during visual scene encoding that predict subsequent scene memory in 51 right-handed children (age range = 10–14 years, M = 11.3, SD = 1.3) whose mothers had been recruited and interviewed prospectively about their alcohol use during pregnancy. Following examination by expert dysmorphologists, children were assigned to one of three FASD diagnostic groups: FAS/PFAS (nFAS = 7; nPFAS = 4), nonsyndromal heavily exposed (HE; n = 14), and Controls (n = 26). Subsequent memory was assessed in a post-scan recognition test, and subsequent memory activations were examined by contrasting activations during encoding of scenes that were subsequently remembered (hits) to those for incorrectly judged as ‘new’ (misses). Recognition accuracy did not differ between groups. Pooled across groups, we observed extensive bilateral subsequent memory effects in regions including the hippocampal formation, posterior parietal cortex, and occipital cortex—a pattern consistent with previous similar studies of typically developing children. Critically, in the group of children with FAS or PFAS, we observed activations in several additional regions compared to HE and Control groups. Given the absence of between-group differences in recognition accuracy, these data suggest that in achieving similar memory compared to children in the HE and Control groups, children with FAS and PFAS recruit more extensive neural resources to achieve successful memory formation.

ObjectivesThe development of a prognostic mortality risk model for hospitalized COVID-19 patients may facilitate patient treatment planning, comparisons of therapeutic strategies, and public health preparations.MethodsWe retrospectively reviewed the electronic health records of patients hospitalized within a 13-hospital New Jersey USA network between March 1, 2020 and April 22, 2020 with positive polymerase chain reaction results for SARS-CoV-2, with follow-up through May 29, 2020. With death or hospital discharge by day 40 as the primary endpoint, we used univariate followed by stepwise multivariate proportional hazard models to develop a risk score on one-half the data set, validated on the remainder, and converted the risk score into a patient-level predictive probability of 40-day mortality based on the combined dataset.ResultsThe study population consisted of 3123 hospitalized COVID-19 patients; median age 63 years; 60% were men; 42% had >3 coexisting conditions. 713 (23%) patients died within 40 days of hospitalization for COVID-19. From 22 potential candidate factors 6 were found to be independent predictors of mortality and were included in the risk score model: age, respiratory rate ≥25/minute upon hospital presentation, oxygenation ConclusionsA risk score using six variables is able to prognosticate mortality within 40-days of hospitalization for COVID-19.Trial registrationClinicaltrials.gov Identifier: NCT04347993.

BackgroundWe hypothesize that women undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis from appendiceal cancer will have a survival advantage compared to men.MethodsThe National Cancer Database (NCDB) public user file (2004-2014) was used to select patients with PC undergoing CRS and HIPEC from appendiceal cancer. Univariate and multivariable analyses were performed.Results1,190 patients with PC from appendiceal cancer underwent HIPEC and CRS. OS was significantly longer for women than for men, with mean and median OS being 73.8 months and 98.2 months for women vs 58.7 months and 82.5 months for men, respectively (p = 0.0032). On multivariable analysis, male sex (HR: 1.444, 95% CI: 1.141-1.827, p = 0.0022) and increasing age (HR: 1.017, 95% CI: 1.006-1.027, p = 0.0017) were both found to be independent risk factors for worse OS.ConclusionWomen undergoing CRS and HIPEC for PC from appendiceal origin live longer than men undergoing the same treatment. Increasing age was also found to be independent risk factors for worse survival.

Background: PTSD self-report measures are frequently used in mental health services but very few have been evaluated in clinical samples that include civilians. The PCL-5 was developed to assess for DSM-5 PTSD. Objective: The aim of this study was to evaluate the psychometric properties of the PCL-5 in a sample of trauma-exposed mental health service users who were evidencing symptoms of PTSD. Method: Reliability and validity of the PCL-5 were investigated in a sample of 273 participants who reported past diagnosis for PTSD or who had screened positively for traumatic stress symptoms. Diagnostic utility was evaluated in comparison to the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Results: The PCL-5 demonstrated high internal consistency, good convergent and divergent validity, acceptable stability and good diagnostic utility. However, operating characteristics differed from those found in other samples. Scores of 43–44 provided optimal efficiency for diagnosing PTSD. A post hoc regression analysis showed that depression explained more of the variance in PCL-5 total score than the CAPS-5. Conclusion: Whilst the PCL-5 is psychometrically sound it appears to have difficulty differentiating self-reported depression and anxiety symptoms from PTSD in trauma-exposed mental health service users and clinicians should take care to assess full symptomatology when individuals screen positively on the PCL-5. Clinicians and researchers should also take care not to assume that operating characteristics of self-report PTSD measures are valid for mental health service users, when these have been established in other populations.

Obesity is a global pandemic, but there is yet no effective measure to control it. Recent metabolomics studies have identified a signature of altered amino acid profiles to be associated with obesity, but it is unclear whether these findings have actionable clinical potential. The aims of this study were to reveal the metabolic alterations of obesity and to explore potential strategies to mitigate obesity. We performed targeted metabolomic profiling of the plasma/serum samples collected from six independent cohorts and conducted an individual data meta-analysis of metabolomics for body mass index (BMI) and obesity. Based on the findings, we hypothesized that restriction of branched-chain amino acids (BCAAs), phenylalanine, or tryptophan may prevent obesity and tested our hypothesis in a dietary restriction trial with eight groups of 4-week-old male C57BL/6J mice (n = 5/group) on eight different types of diets, respectively, for 16 weeks. A total of 3397 individuals were included in the meta-analysis. The mean BMI was 30.7 ± 6.1 kg/m2, and 49% of participants were obese. Fifty-eight metabolites were associated with BMI and obesity (all p ≤ 2.58 × 10−4), linked to alterations of the BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways. The restriction of BCAAs within a high-fat diet (HFD) maintained the mice’s weight, fat and lean volume, subcutaneous and visceral adipose tissue weight, and serum glucose and insulin at levels similar to those in the standard chow group, and prevented obesity, adipocyte hypertrophy, adipose inflammation, and insulin resistance induced by HFD. Our data suggest that four metabolic pathways, BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways, are altered in obesity and restriction of BCAAs within a HFD can prevent the development of obesity and insulin resistance in mice, providing a promising strategy to potentially mitigate diet-induced obesity.

Epigenetic dysregulation is implicated in the pathogenesis of lupus. We performed a longitudinal analysis to assess changes in DNA methylation in lupus neutrophils over 4 years of follow-up and across disease activity levels using 229 patient samples. We demonstrate that DNA methylation profiles in lupus are partly determined by ancestry-associated genetic variations and are highly stable over time. DNA methylation levels in 2 CpG sites correlated significantly with changes in lupus disease activity. Progressive demethylation in SNX18 was observed with increasing disease activity in African American patients. Importantly, demethylation of a CpG site located within GALNT18 was associated with the development of active lupus nephritis. Differentially methylated genes between African American and European American lupus patients include type I IFN–response genes such as IRF7 and IFI44, and genes related to the NF-κB pathway. TREML4, which plays a vital role in TLR signaling, was hypomethylated in African American patients and demonstrated a strong cis–methylation quantitative trait loci (cis-meQTL) effect among 8855 cis-meQTL associations identified in our study.

Head and Neck Squamous Cell Cancer (HNSCC) presents with multiple treatment challenges limiting overall survival rates and affecting patients' quality of life. Amongst these, resistance to radiation therapy constitutes a major clinical problem in HNSCC patients compounded by origin, location, and tumor grade that limit tumor control. While cisplatin is considered the standard radiosensitizing agent for definitive or adjuvant radiotherapy, in recurrent tumors or for palliative care other chemotherapeutics such as the antifolates methotrexate or pemetrexed are also being utilized as radiosensitizers. These drugs inhibit the enzyme dihydrofolate reductase, which is essential for DNA synthesis and connects the 1-C/folate metabolism to NAD(P)H and NAD(P)+ balance in cells. In previous studies, we identified MTHFD2, a mitochondrial enzyme involved in folate metabolism, as a key contributor to NAD(P)H levels in the radiation-resistant cells and HNSCC tumors. In the study presented here, we investigated the role of MTHFD2 in the response to radiation alone and in combination with β-lapachone, a NQO1 bioactivatable drug, which generates reactive oxygen species concomitant with NAD(P)H oxidation to NAD(P)+. These studies are performed in a matched HNSCC cell model of response to radiation: the radiation resistant rSCC-61 and radiation sensitive SCC-61 cells reported earlier by our group. Radiation resistant rSCC-61 cells had increased sensitivity to β-lapachone compared to SCC-61 and knockdown of MTHFD2 in rSCC-61 cells further potentiated the cytotoxicity of β-lapachone with radiation in a dose and time-dependent manner. rSCC-61 MTHFD2 knockdown cells irradiated and treated with β-lapachone showed increased PARP1 activation, inhibition of mitochondrial respiration, decreased respiration-linked ATP production, and increased mitochondrial superoxide and protein oxidation as compared to control rSCC-61 scrambled shRNA. Thus, these studies point to MTHFD2 as a potential target for development of radiosensitizing chemotherapeutics and potentiator of β-lapachone cytotoxicity.