The effect of an antenatal lifestyle intervention in overweight and obese women on circulating cardiometabolic and inflammatory biomarkers: secondary analyses from the LIMIT randomised trial

Background: Maternal overweight and obesity during pregnancy is associated with insulin resistance, hyperglycaemia, hyperlipidaemia and a low-grade state of chronic inflammation. The aim of this pre-specified analysis of secondary outcome measures was to evaluate the effect of providing antenatal dietary and lifestyle advice on cardiometabolic and inflammatory biomarkers. Methods: We conducted a multicentre trial in which pregnant women who were overweight or obese were randomised to receive either Lifestyle Advice or Standard Care. We report a range of pre-specified secondary maternal and newborn cardiometabolic and inflammatory biomarker outcomes. Maternal whole venous blood was collected at trial entry (mean 14 weeks gestation; non-fasting), at 28 weeks gestation (fasting), and at 36 weeks gestation (non-fasting). Cord blood was collected after birth and prior to the delivery of the placenta. A range of cardiometabolic and inflammatory markers were analysed (total cholesterol, triglycerides, non-esterified fatty acids, high-density lipoprotein cholesterol, insulin, glucose, leptin, adiponectin, C-reactive protein, granulocyte macrophage-colony stimulating factor, interferon gamma, TNF-α, and interleukins 1β, 2, 4, 5, 6, 8, and 10). Participants were analysed in the groups to which they were randomised, and were included in the analyses if they had a measure at any time point. results: One or more biological specimens were available from 1951 women (989 Lifestyle Advice and 962 Standard Care), with cord blood from 1174 infants (596 Lifestyle Advice and 578 Standard Care). There were no statistically significant differences in mean cardiometabolic and inflammatory marker concentrations across pregnancy and in infant cord blood between treatment groups. Estimated treatment group differences were close to zero, with 95% confidence intervals spanning a range of differences that were short of clinical relevance. There was no evidence to suggest that the intervention effect was modified by maternal BMI category. Conclusions: Despite our findings, it will be worth considering potential relationships between cardiometabolic and inflammatory markers and clinical outcomes, including longer-term infant health and adiposity. Trial Registration: Australian and New Zealand Clinical Trials Registry ( ACTRN12607000161426 ; Date Registered 09/03/2007).Lisa J. Moran, Louise M. Fraser, Tulika Sundernathan, Andrea R. Deussen, Jennie Louise, Lisa N. Yelland, Rosalie M. Grivell, Anne Macpherson, Matthew W. Gillman, Jeffrey S. Robinson, Julie A. Owens and Jodie M. Dod

ARK: Aggregation of Reads by K-Means for Estimation of Bacterial Community Composition.

MOTIVATION: Estimation of bacterial community composition from high-throughput sequenced 16S rRNA gene amplicons is a key task in microbial ecology. Since the sequence data from each sample typically consist of a large number of reads and are adversely impacted by different levels of biological and technical noise, accurate analysis of such large datasets is challenging. RESULTS: There has been a recent surge of interest in using compressed sensing inspired and convex-optimization based methods to solve the estimation problem for bacterial community composition. These methods typically rely on summarizing the sequence data by frequencies of low-order k-mers and matching this information statistically with a taxonomically structured database. Here we show that the accuracy of the resulting community composition estimates can be substantially improved by aggregating the reads from a sample with an unsupervised machine learning approach prior to the estimation phase. The aggregation of reads is a pre-processing approach where we use a standard K-means clustering algorithm that partitions a large set of reads into subsets with reasonable computational cost to provide several vectors of first order statistics instead of only single statistical summarization in terms of k-mer frequencies. The output of the clustering is then processed further to obtain the final estimate for each sample. The resulting method is called Aggregation of Reads by K-means (ARK), and it is based on a statistical argument via mixture density formulation. ARK is found to improve the fidelity and robustness of several recently introduced methods, with only a modest increase in computational complexity. AVAILABILITY: An open source, platform-independent implementation of the method in the Julia programming language is freely available at https://github.com/dkoslicki/ARK. A Matlab implementation is available at http://www.ee.kth.se/ctsoftware

Substrate recognition by the cell surface palmitoyl transferase DHHC5

The cardiac phosphoprotein phospholemman (PLM) regulates the cardiac sodium pump, activating the pump when phosphorylated and inhibiting it when palmitoylated. Protein palmitoylation, the reversible attachment of a 16 carbon fatty acid to a cysteine thiol, is catalyzed by the Asp-His-His-Cys (DHHC) motif-containing palmitoyl acyltransferases. The cell surface palmitoyl acyltransferase DHHC5 regulates a growing number of cellular processes, but relatively few DHHC5 substrates have been identified to date. We examined the expression of DHHC isoforms in ventricular muscle and report that DHHC5 is among the most abundantly expressed DHHCs in the heart and localizes to caveolin-enriched cell surface microdomains. DHHC5 coimmunoprecipitates with PLM in ventricular myocytes and transiently transfected cells. Overexpression and silencing experiments indicate that DHHC5 palmitoylates PLM at two juxtamembrane cysteines, C40 and C42, although C40 is the principal palmitoylation site. PLM interaction with and palmitoylation by DHHC5 is independent of the DHHC5 PSD-95/Discs-large/ZO-1 homology (PDZ) binding motif, but requires a ∼120 amino acid region of the DHHC5 intracellular C-tail immediately after the fourth transmembrane domain. PLM C42A but not PLM C40A inhibits the Na pump, indicating PLM palmitoylation at C40 but not C42 is required for PLM-mediated inhibition of pump activity. In conclusion, we demonstrate an enzyme–substrate relationship for DHHC5 and PLM and describe a means of substrate recruitment not hitherto described for this acyltransferase. We propose that PLM palmitoylation by DHHC5 promotes phospholipid interactions that inhibit the Na pump

Thrombotic and hemorrhagic complications of COVID-19 in adults hospitalized in high-income countries compared with those in adults hospitalized in low-and middle-income countries in an international registry

Background: COVID-19 has been associated with a broad range of thromboembolic, ischemic, and hemorrhagic complications (coagulopathy complications). Most studies have focused on patients with severe disease from high-income countries (HICs). Objectives: The main aims were to compare the frequency of coagulopathy complications in developing countries (low- and middle-income countries [LMICs]) with those in HICs, delineate the frequency across a range of treatment levels, and determine associations with in-hospital mortality. Methods: Adult patients enrolled in an observational, multinational registry, the International Severe Acute Respiratory and Emerging Infections COVID-19 study, between January 1, 2020, and September 15, 2021, met inclusion criteria, including admission to a hospital for laboratory-confirmed, acute COVID-19 and data on complications and survival. The advanced-treatment cohort received care, such as admission to the intensive care unit, mechanical ventilation, or inotropes or vasopressors; the basic-treatment cohort did not receive any of these interventions. Results: The study population included 495,682 patients from 52 countries, with 63% from LMICs and 85% in the basic treatment cohort. The frequency of coagulopathy complications was higher in HICs (0.76%-3.4%) than in LMICs (0.09%-1.22%). Complications were more frequent in the advanced-treatment cohort than in the basic-treatment cohort. Coagulopathy complications were associated with increased in-hospital mortality (odds ratio, 1.58; 95% CI, 1.52-1.64). The increased mortality associated with these complications was higher in LMICs (58.5%) than in HICs (35.4%). After controlling for coagulopathy complications, treatment intensity, and multiple other factors, the mortality was higher among patients in LMICs than among patients in HICs (odds ratio, 1.45; 95% CI, 1.39-1.51). Conclusion: In a large, international registry of patients hospitalized for COVID-19, coagulopathy complications were more frequent in HICs than in LMICs (developing countries). Increased mortality associated with coagulopathy complications was of a greater magnitude among patients in LMICs. Additional research is needed regarding timely diagnosis of and intervention for coagulation derangements associated with COVID-19, particularly for limited-resource settings

Yield of colorectal cancer at colonoscopy according to faecal haemoglobin concentration in symptomatic patients referred from primary care

Background: Lower gastrointestinal (GI) symptoms are poor predictors of colorectal cancer (CRC). This study examined the diagnostic yield of colonoscopy by faecal haemoglobin concentration (f‐Hb) in symptomatic patients assessed in primary care by faecal immunochemical testing (FIT). Methods: In three Scottish NHS Boards, FIT kits (HM‐JACKarc, Hitachi Chemical Diagnostics Systems Co., Ltd, Tokyo, Japan) were used by GPs to guide referrals for patients with lower GI symptoms (lab data studied for 12 months from December 2015 onward in Tayside, 18 months from June 2018 onward in Fife, and 5 months from September 2018 onward in Greater Glasgow and Clyde). CRC cases diagnosed at colonoscopy were ascertained from colonoscopy and pathology records. Results: 4841 symptomatic patients who underwent colonoscopy after FIT submission were included. Of 2166 patients (44.7%) with f‐Hb <10 µg Hb/g faeces (µg/g), 14 (0.6%) were diagnosed with CRC, with a number needed to scope (NNS) of 155. Of 2675 patients (55.3%) with f‐Hb ≥10 µg/g, 252 were diagnosed with CRC (9.4%) with a NNS of 11. Of 705 patients with f‐Hb ≥400 µg/g, 158 (22.4%) were diagnosed with CRC with a NNS of 5. Over half of those diagnosed with CRC with f‐Hb <10 µg/g had co‐existing anaemia. Conclusions: Symptomatic patients with f‐Hb ≥10 µg/g should undergo further investigation for CRC, while higher f‐Hb could be used to triage its urgency during the COVID‐19 recovery phase. Patients with f‐Hb <10 µg/g, without anaemia, are very unlikely to be diagnosed with CRC and the majority need no further investigation

Effects of expectation on face perception and its association with expertise

Perceptual decisions are derived from the combination of priors and sensorial input. While priors are broadly understood to reflect experience/expertise developed over one’s lifetime, the role of perceptual expertise at the individual level has seldom been directly explored. Here, we manipulate probabilistic information associated with a high and low expertise category (faces and cars respectively), while assessing individual level of expertise with each category. 67 participants learned the probabilistic association between a color cue and each target category (face/car) in a behavioural categorization task. Neural activity (EEG) was then recorded in a similar paradigm in the same participants featuring the previously learned contingencies without the explicit task. Behaviourally, perception of the higher expertise category (faces) was modulated by expectation. Specifically, we observed facilitatory and interference effects when targets were correctly or incorrectly expected, which were also associated with independently measured individual levels of face expertise. Multivariate pattern analysis of the EEG signal revealed clear effects of expectation from 100 ms post stimulus, with significant decoding of the neural response to expected vs. not stimuli, when viewing identical images. Latency of peak decoding when participants saw faces was directly associated with individual level facilitation effects in the behavioural task. The current results not only provide time sensitive evidence of expectation effects on early perception but highlight the role of higher-level expertise on forming priors

Nuclear receptor binding protein 1 regulates intestinal progenitor cell homeostasis and tumour formation.

Genetic screens in simple model organisms have identified many of the key components of the conserved signal transduction pathways that are oncogenic when misregulated. Here, we identify H37N21.1 as a gene that regulates vulval induction in let-60(n1046gf), a strain with a gain-of-function mutation in the Caenorhabditis elegans Ras orthologue, and show that somatic deletion of Nrbp1, the mouse orthologue of this gene, results in an intestinal progenitor cell phenotype that leads to profound changes in the proliferation and differentiation of all intestinal cell lineages. We show that Nrbp1 interacts with key components of the ubiquitination machinery and that loss of Nrbp1 in the intestine results in the accumulation of Sall4, a key mediator of stem cell fate, and of Tsc22d2. We also reveal that somatic loss of Nrbp1 results in tumourigenesis, with haematological and intestinal tumours predominating, and that nuclear receptor binding protein 1 (NRBP1) is downregulated in a range of human tumours, where low expression correlates with a poor prognosis. Thus NRBP1 is a conserved regulator of cell fate, that plays an important role in tumour suppression

The life cycle and field epidemiology of Uromycladium acaciae (Pucciniales) on Acacia mearnsii in South Africa

Uromycladium acaciae has damaged plantations of Acacia mearnsii in southern Africa since 2013. Uredinia of a species of Uromycladium have been known on A. mearnsii in South Africa since the 1980s. However, the recent damage is associated with telia and spermogonia. Uredinia and telia were previously treated as conspecific with a phylogenetic species concept. However, uredinia did not form after previous artificial inoculation experiments with teliospores. Controlled studies identified the optimum conditions for basidiospore infection, but the optimum conditions for sporulation and dispersal have not been identified. To investigate the life cycle and field epidemiology of Uromycladium on A. mearnsii, spores were trapped weekly and development of disease symptoms and plant phenology were monitored monthly at three plantations. Telia and spermogonia developed independently from uredinia, and nucleotide polymorphisms between rDNA of uredinia and telia were fixed based on high throughput sequencing and PCRs. All three weather variables measured had a significant effect on teliospore abundance at two of the three sites. Teliospore abundance was greatest during trapping periods when mean relative humidity was high, mean rainfall was 4–5 mm day−1 and mean temperature was 15–16°C. Teliospore counts peaked at the end of summer, potentially the result of epidemic build-up. Results support the hypothesis that despite sharing a most recent common ancestor, uredinia on A. mearnsii in southern Africa are independent to the life cycle of the telial rust, which likely constitutes a new introduction. Furthermore, teliospores of U. acaciae disperse under wet conditions, and the wet season between October and March is the optimal period for wattle rust development.Members of the Tree Protection Co-operative Programme (TPCP), the Department of Science and Technology (DST)/National Research Foundation (NRF) Centre of Excellence in Tree Health Biotechnology (CTHB) and the Wattle Rust Steering Committee funded by the Sector Innovation Fund (SIF) of the Department of Science and Technology (DST). The Genomics Research Institute of the University of Pretoria provided funding for high-throughput sequencing of Uromycladium acaciae. Stuart Fraser acknowledges Postdoctoral Fellowship funding from the University of Pretoria and New Zealand Ministry for Business Innovation and Employment through the Science Strategic Investment Fund.http://wileyonlinelibrary.com/journal/aabhj2022Forestry and Agricultural Biotechnology Institute (FABI)Plant Production and Soil Scienc

Research priorities in children and adults with congenital heart disease: a James Lind Alliance Priority Setting Partnership

Objective To bring together patients, parents, charities and clinicians in a Priority Setting Partnership to establish national clinical priorities for research in children and adults with congenital heart disease. Methods The established James Lind Alliance methodology was used to identify and prioritise research on the management of congenital heart disease, focusing on diagnosis, treatment and outcomes. An initial open survey was used to gather potential uncertainties which were filtered, categorised, converted into summary questions and checked against current evidence. In a second survey, respondents identified the unanswered questions most important to them. At two final workshops, patients, parents, charities and healthcare professionals agreed the top 10 lists of priorities for child/antenatal and adult congenital heart disease research. Results 524 respondents submitted 1373 individual questions, from which 313 out of scope or duplicate questions were removed. The remaining 1060 questions were distilled into summary questions and checked against existing literature, with only three questions deemed entirely answered and removed. 250 respondents completed the child/antenatal survey (56 uncertainties) and 252 completed the adult survey (47 uncertainties). The questions ranked the highest by clinicians and non-clinicians were taken forward to consensus workshops, where two sets of top 10 research priorities were agreed. Conclusions Through an established and equitable process, we determined national clinical priorities for congenital heart disease research. These will be taken forward by specific working groups, a national patient and public involvement group, and through the establishment of a UK and Ireland network for collaborative, multicentre clinical trials in congenital heart disease