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Congenital heart defects can be caused by mutations in genes that guide cardiac lineage formation. Here, we show deletion of NKX2-5 , a critical component of the cardiac gene regulatory network, in human embryonic stem cells (hESCs), results in impaired cardiomyogenesis, failure to activate VCAM1 and to downregulate the progenitor marker PDGFRα. Furthermore, NKX2-5 null cardiomyocytes have abnormal physiology, with asynchronous contractions and altered action potentials. Molecular profiling and genetic rescue experiments demonstrate that the bHLH protein HEY2 is a key mediator of NKX2-5 function during human cardiomyogenesis. These findings identify HEY2 as a novel component of the NKX2-5 cardiac transcriptional network, providing tangible evidence that hESC models can decipher the complex pathways that regulate early stage human heart development. These data provide a human context for the evaluation of pathogenic mutations in congenital heart disease. A gene regulatory network, including the transcription factor Nkx2-5 , regulates cardiac development. Here, the authors show that on deletion of NKX2-5 from human embryonic stem cells, there is impaired cardiomyogenesis and changes in action potentials, and that this is regulated via HEY2 .

Data on the utility of coagulation factor testing (INR, aPTT) in non-anticoagulated patients with low-risk trauma is limited. In this study, we describe the rate in which coagulation studies are ordered this population and report the frequency in which these tests were abnormal and resulted in intervention. This was a multi-center retrospective observational study evaluating patients aged 65 years and older with low-risk mechanical falls not on chronic oral anticoagulation. If blood work was obtained, we documented the initial/highest INR and the initial/highest aPTT. Our primary outcome was the frequency of intervention due to abnormal coagulation studies, defined as (1) administration of vitamin K, FFP, PCC, or protamine and/or (2) admission/observation due to the abnormal coagulation study. A total of 1208 patients were included. The frequency in which an INR was obtained was 559 (46.3 %). The median value of the INR was 1.1 (range 0.9–1.6). There were 536 patients (44.4 %) who had aPTT drawn. The median value was 26.2 (range 20.1–43.4). There were no instances of our primary outcome (abnormal INR or aPTT that required intervention). In this cohort of 1208 patients, approximately 45 % percent had coagulation studies ordered and nearly 95 % of these studies were normal. None of them were critically elevated, necessitating intervention. Our findings suggest that for patients similar to those in our study cohort, routine coagulation studies may have limited utility and are unlikely to result in changes in ED management.

Psoriasis is a chronic inflammatory systemic disease characterized by a wide range of comorbidities. Respiratory comorbidities are currently poorly characterized and with discordant results. The systemic state of inflammation caused by psoriasis acts de novo on respiratory tissues and amplifies preexisting inflammation from asthma or chronic obstructive pulmonary disease. Because the lungs act as a gas exchanger between the internal and external environment, the impact of chronic psoriasis inflammation may be easily assessed through the analysis of exhaled breath. The fraction of exhaled nitric oxide test (FeNO) is a potential noninvasive solution that can provide quantitative and qualitative indices of respiratory airway inflammation. FeNO is routinely used to screen and manage asthmatic patients. Recent pilot studies contain encouraging data that underscore its possible use with systemic inflammatory nonpulmonary diseases, such as psoriasis. FeNO may therefore be a useful tool to evaluate underestimated airway inflammation and at the same time globally evaluate the impact of systemically antipsoriatic therapies.

Neutrophilic dermatoses (ND) are a polymorphous group of noncontagious dermatological disorders that share the common histological feature of a sterile cutaneous infiltration of mature neutrophils. Clinical manifestations can vary from nodules, pustules, and bulla to erosions and ulcerations. The etiopathogenesis of neutrophilic dermatoses has continuously evolved. Accumulating genetic, clinical, and histological evidence point to NDs being classified in the spectrum of autoinflammatory conditions. However, unlike the monogenic autoinflammatory syndromes where a clear multiple change in the inflammasome structure/function is demonstrated, NDs display several proinflammatory abnormalities, mainly driven by IL-1, IL-17, and tumor necrosis factor-alpha (TNF-a). Additionally, because of the frequent association with extracutaneous manifestations where neutrophils seem to play a crucial role, it was plausible also to consider NDs as a cutaneous presentation of a systemic neutrophilic condition. Neutrophilic dermatoses are more frequently recognized in association with respiratory disorders than by chance alone. The combination of the two, particularly in the context of their overlapping immune responses mediated primarily by neutrophils, raises the likelihood of a common neutrophilic systemic disease or an aberrant innate immunity disorder. Associated respiratory conditions can serve as a trigger or may develop or be exacerbated secondary to the uncontrolled skin disorder. Physicians should be aware of the possible pulmonary comorbidities and apply this knowledge in the three steps of patients’ management, work-up, diagnosis, and treatment. In this review, we attempt to unravel the pathophysiological mechanisms of this association and also present some evidence for the role of targeted therapy in the treatment of both conditions.

BackgroundSystemic lupus erythematosus (SLE) is a chronic, auto-immune, multi-organ disease that can affect both the skin and the lungs. Malar rash is a common skin manifestation of SLE and is linked to SLE disease activity, whereas lung involvement is a generally negative prognostic factor for these patients. However, a sensitive and non-invasive screening tool for potential lung involvement in SLE patients is still not available.MethodsThis study aimed to investigate the relationship between malar rash and airway inflammation in adult SLE patients who were not known to have any lung involvement (clinical or radiologic). The study comprised of the measurement of the concentration of NO in exhaled breath or fraction of exhaled nitric oxide (FeNO) and levels were compared between those with and without malar rash. This tool is considered as a sensitive and non-invasive method that is routinely used in patients with asthma or other respiratory diseases to identify airway inflammation.ResultsA total of 125 patients (100 females, 25 males) were enrolled during the study period from January 2011 to December 2014. Patients with malar rash (N = 35) had a significant decrease in serum levels of C4 (p < 0.05) compared to patients without malar rash (N = 90). The mean levels of FeNO in overall patients were 36.44 ± 8.87 ppb. A statistically significant difference in FeNO50 values between patients with malar rash (43.46 ± 6.72 ppb) and without (29.43 ± 3.64 ppb) was found (p < 0.001). FeNO50 values were inversely correlated only with serum C4 (p < 0.01). However, no correlation between FeNO50 values and SLE clinical disease activity scores was found.ConclusionsThe presence of a malar rash may predict sub-clinical airway inflammation in SLE patients. Further prospective studies are needed to confirm the usefulness of FeNO measurements in monitoring SLE-associated airway inflammation.

Progesterone administration has been shown to reduce the risk of preterm birth and neonatal morbidity in women at high risk, but there is uncertainty about longer term effects on the child. We did a double-blind, randomised, placebo-controlled trial of vaginal progesterone, 200 mg daily taken from 22–24 to 34 weeks of gestation, on pregnancy and infant outcomes in women at risk of preterm birth (because of previous spontaneous birth at ≤34 weeks and 0 days of gestation, or a cervical length ≤25 mm, or because of a positive fetal fibronectin test combined with other clinical risk factors for preterm birth [any one of a history in a previous pregnancy of preterm birth, second trimester loss, preterm premature fetal membrane rupture, or a history of a cervical procedure to treat abnormal smears]). The objective of the study was to determine whether vaginal progesterone prophylaxis given to reduce the risk of preterm birth affects neonatal and childhood outcomes. We defined three primary outcomes: fetal death or birth before 34 weeks and 0 days gestation (obstetric), a composite of death, brain injury, or bronchopulmonary dysplasia (neonatal), and a standardised cognitive score at 2 years of age (childhood), imputing values for deaths. Randomisation was done through a web portal, with participants, investigators, and others involved in giving the intervention, assessing outcomes, or analysing data masked to treatment allocation until the end of the study. Analysis was by intention to treat. This trial is registered at ISRCTN.com, number ISRCTN14568373. Between Feb 2, 2009, and April 12, 2013, we randomly assigned 1228 women to the placebo group (n=610) and the progesterone group (n=618). In the placebo group, data from 597, 587, and 439 women or babies were available for analysis of obstetric, neonatal, and childhood outcomes, respectively; in the progesterone group the corresponding numbers were 600, 589, and 430. After correction for multiple outcomes, progesterone had no significant effect on the primary obstetric outcome (odds ratio adjusted for multiple comparisons [OR] 0·86, 95% CI 0·61–1·22) or neonatal outcome (OR 0·72, 0·44–1·17), nor on the childhood outcome (cognitive score, progesterone group vs placebo group, 97·3 [SD 17·9] vs 97·7 [17·5]; difference in means –0·48, 95% CI –2·77 to 1·81). Maternal or child serious adverse events were reported in 70 (11%) of 610 patients in the placebo group and 59 (10%) of 616 patients in the progesterone group (p=0·27). Vaginal progesterone was not associated with reduced risk of preterm birth or composite neonatal adverse outcomes, and had no long-term benefit or harm on outcomes in children at 2 years of age. Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales.

Polymyxins are antibiotics used in the last line of defense to combat multidrug-resistant infections by Gram-negative bacteria. Polymyxin resistance arises through charge modification of the bacterial outer membrane with the attachment of the cationic sugar 4-amino-4-deoxy-L-arabinose to lipid A, a reaction catalyzed by the integral membrane lipid-to-lipid glycosyltransferase 4-amino-4-deoxy-L-arabinose transferase (ArnT). Here, we report crystal structures of ArnT from Cupriavidus metallidurans, alone and in complex with the lipid carrier undecaprenyl phosphate, at 2.8 and 3.2 angstrom resolution, respectively. The structures show cavities for both lipidic substrates, which converge at the active site. A structural rearrangement occurs on undecaprenyl phosphate binding, which stabilizes the active site and likely allows lipid A binding. Functional mutagenesis experiments based on these structures suggest a mechanistic model for ArnT family enzymes.

The outer membrane of Gram-negative bacteria has an external leaflet that is largely composed of lipopolysaccharide, which provides a selective permeation barrier, particularly against antimicrobials 1 . The final and crucial step in the biosynthesis of lipopolysaccharide is the addition of a species-dependent O-antigen to the lipid A core oligosaccharide, which is catalysed by the O-antigen ligase WaaL 2 . Here we present structures of WaaL from Cupriavidus metallidurans , both in the apo state and in complex with its lipid carrier undecaprenyl pyrophosphate, determined by single-particle cryo-electron microscopy. The structures reveal that WaaL comprises 12 transmembrane helices and a predominantly α-helical periplasmic region, which we show contains many of the conserved residues that are required for catalysis. We observe a conserved fold within the GT-C family of glycosyltransferases and hypothesize that they have a common mechanism for shuttling the undecaprenyl-based carrier to and from the active site. The structures, combined with genetic, biochemical, bioinformatics and molecular dynamics simulation experiments, offer molecular details on how the ligands come in apposition, and allows us to propose a mechanistic model for catalysis. Together, our work provides a structural basis for lipopolysaccharide maturation in a member of the GT-C superfamily of glycosyltransferases. Cryo-electron microscopy structures of the bacterial O-antigen ligase WaaL, combined with genetics, biochemistry and molecular dynamics simulations, provide insight into the mechanism by which WaaL catalyses the biosynthesis of lipopolysaccharide.

IntroductionLong COVID, a new condition whose origins and natural history are not yet fully established, currently affects 1.5 million people in the UK. Most do not have access to specialist long COVID services. We seek to optimise long COVID care both within and outside specialist clinics, including improving access, reducing inequalities, helping self-management and providing guidance and decision support for primary care. We aim to establish a ‘gold standard’ of care by systematically analysing current practices, iteratively improving pathways and systems of care.Methods and analysisThis mixed-methods, multisite study is informed by the principles of applied health services research, quality improvement, co-design, outcome measurement and learning health systems. It was developed in close partnership with patients (whose stated priorities are prompt clinical assessment; evidence-based advice and treatment and help with returning to work and other roles) and with front-line clinicians. Workstreams and tasks to optimise assessment, treatment and monitoring are based in three contrasting settings: workstream 1 (qualitative research, up to 100 participants), specialist management in 10 long COVID clinics across the UK, via a quality improvement collaborative, experience-based co-design and targeted efforts to reduce inequalities of access, return to work and peer support; workstream 2 (quantitative research, up to 5000 participants), patient self-management at home, technology-supported monitoring and validation of condition-specific outcome measures and workstream 3 (quantitative research, up to 5000 participants), generalist management in primary care, harnessing electronic record data to study population phenotypes and develop evidence-based decision support, referral pathways and analysis of costs. Study governance includes an active patient advisory group.Ethics and disseminationLOng COvid Multidisciplinary consortium Optimising Treatments and servIces acrOss the NHS study is sponsored by the University of Leeds and approved by Yorkshire & The Humber—Bradford Leeds Research Ethics Committee (ref: 21/YH/0276). Participants will provide informed consent. Dissemination plans include academic and lay publications, and partnerships with national and regional policymakers.Trial registration number NCT05057260, ISRCTN15022307.

Purpose The Pediatric Quality of Life Inventory™ (PedsQL™) General Core Scales (GCS) were designed to provide a modular approach to measuring health-related quality of life in healthy children, as well as those with acute and chronic health conditions, across the broadest, empirically feasible, age groups (2–18 years). Currently, it is not possible to estimate health utilities based on the PedsQL™ GCS, either directly or indirectly. This paper assesses different mapping methods for estimating EQ-5D health utilities from PedsQL™ GCS responses. Methods This study is based on data from a cross-sectional survey conducted in four secondary schools in England amongst children aged 11–15 years. We estimate models using both direct and response mapping approaches to predict EQ-5D health utilities and responses. The mean squared error (MSE) and mean absolute error (MAE) were used to assess the predictive accuracy of the models. The models were internally validated on an estimation dataset that included complete PedsQL™ GCS and EQ-5D scores for 559 respondents. Validation was also performed making use of separate data for 337 respondents. Results Ordinary least squares (OLS) models that used the PedsQL™ GCS subscale scores, their squared terms and interactions (with and without age and gender) to predict EQ-5D health utilities had the best prediction accuracy. In the external validation sample, the OLS model with age and gender had a MSE (MAE) of 0.036 (0.115) compared with a MSE (MAE) of 0.036 (0.114) for the OLS model without age and gender. However, both models generated higher prediction errors for children in poorer health states (EQ-5D utility score <0.6). The response mapping models encountered some estimation problems because of insufficient data for some of the response levels. Conclusion Our mapping algorithms provide an empirical basis for estimating health utilities in childhood when EQ-5D data are not available; they can be used to inform future economic evaluations of paediatric interventions. They are likely to be robust for populations comparable to our own (children aged 11–15 years in attendance at secondary school). The performance of these algorithms in childhood populations, which differ according to age or clinical characteristics to our own, remains to be evaluated.