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Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 2019 (COVID-19) continues to have a devastating impact across the globe. However, little is known about the disease course in patients with autoimmune hepatitis (AIH). Methods Data for patients with AIH and SARS-CoV-2 infection were combined from three international reporting registries and outcomes were compared to those with chronic liver disease of other aetiology (non-AIH CLD) and to patients without liver disease (non-CLD). Results Between 25th March and 24th October 2020, data were collected for 932 patients with CLD and SARS-CoV-2 infection including 70 with autoimmune hepatitis (AIH). Fifty-eight (83%) of AIH patients were taking one or more immunosuppressive drug. There were no differences in rates of major outcomes between AIH and non-AIH CLD including hospitalization (76% vs 85%; p= 0.06), ICU admission (29% vs. 23%; p=0.240), and death (23% vs. 20%; p=0.643). Factors associated with death within the AIH cohort included age (OR 2.16/10 years; 1.07–3.81), Child-Turcotte-Pugh (CTP) class B (OR 42.48; 4.40–409.53), and CTP-C cirrhosis (OR 69.30; 2.83–1694.50), but not use of immunosuppression. Propensity score matched (PSM) analysis comparing AIH with non-AIH CLD demonstrated no increased risk adverse outcomes including death (+3.2%; -9.2%–15.7%). PSM analysis of AIH versus non-CLD patients (n=769) demonstrated increased risk of hospitalization with AIH (+18.4%; 5.6–31.2%), but equivalent risk of all other outcomes including death (+3.2%; -9.1%–15.6%). Conclusion AIH patients were not at increased risk of adverse outcomes despite immunosuppressive treatment compared to other causes of CLD and to matched cases without liver disease., Graphical abstract, Highlights • This is the largest cohort of patients with autoimmune hepatitis and laboratory proven SARS-COV-2 infection reported to date. • There were no differences in rates of major adverse COVID-19 outcomes including hospitalization, intensive care unit (ICU) admission, and death between AIH patients and those with other aetiologies of liver disease. • When compared to patients without liver disease in propensity score matched analysis, patients with AIH had higher rates of hospitalization but no increased risk of ICU admission or death despite potential reporting of AIH cases with more severe baseline liver disease. • Independent risk factors for death in AIH patients were age and baseline liver disease severity, but not the use of immunosuppression., Lay summary: Little is known about the outcomes of COVID-19 in patients with autoimmune hepatitis (AIH), a rare chronic inflammatory liver disease. This study combines data from three large registries to describe the course of COVID-19 in this patient group. We show that AIH patients do not appear to have an increased risk of death from COVID-19 compared to patients with other forms of liver disease and compared to patients without liver disease, despite the use of medications which suppress the immune system.

Many safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations dramatically reduce risks of coronavirus disease 2019 (COVID-19) complications and deaths. We aimed to describe cases of SARS-CoV-2 infection among patients with chronic liver disease (CLD) and liver transplant (LT) recipients with at least one prior COVID-19 vaccine dose. The SECURE-Liver and COVID-Hep international reporting registries were used to identify laboratory-confirmed COVID-19 in CLD and LT patients who received a COVID-19 vaccination. Of the 342 cases of lab-confirmed SARS-CoV-2 infections in the era after vaccine licensing, 40 patients (21 with CLD and 19 with LT) had at least one prior COVID-19 vaccination, including 12 who were fully vaccinated (���2 weeks after second dose). Of the 21 patients with CLD (90% with cirrhosis), 7 (33%) were hospitalized, 1 (5%) was admitted to the intensive care unit (ICU), and 0 died. In the LT cohort (n = 19), there were 6 hospitalizations (32%), including 3 (16%) resulting in mechanical ventilation and 2 (11%) resulting in death. All three cases of severe COVID-19 occurred in patients who had a single vaccine dose within the last 1-2 weeks. In contemporary patients with CLD, rates of symptomatic infection, hospitalization, ICU admission, invasive ventilation, and death were numerically higher in unvaccinated individuals. Conclusion: This case series demonstrates the potential for COVID-19 infections among patients with CLD and LT recipients who had received the COVID-19 vaccination. Vaccination against SARS-CoV-2 appears to result in favorable outcomes as attested by the absence of mechanical ventilation, ICU, or death among fully vaccinated patients.

Background and objectives In a randomized double-blind, placebo-controlled trial, treatment with spironolactone in early-stage CKD reduced left ventricular mass and arterial stiffness compared with placebo. It is not known if these effects were due to BP reduction or specific vascular and myocardial effects of spironolactone. Design, setting, participants, & measurements A prospective, randomized, open-label, blinded end point study conducted in four UK centers (Birmingham, Cambridge, Edinburgh, and London) comparing spironolactone 25 mg to chlorthalidone 25 mg once daily for 40 weeks in 154 participants with nondiabetic stage 2 and 3 CKD (eGFR 30–89 ml/min per 1.73 m2). The primary end point was change in left ventricular mass on cardiac magnetic resonance imaging. Participants were on treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and had controlled BP (target ≤130/80 mm Hg). Results There was no significant difference in left ventricular mass regression; at week 40, the adjusted mean difference for spironolactone compared with chlorthalidone was −3.8 g (95% confidence interval, −8.1 to 0.5 g, P=0.08). Office and 24-hour ambulatory BPs fell in response to both drugs with no significant differences between treatment. Pulse wave velocity was not significantly different between groups; at week 40, the adjusted mean difference for spironolactone compared with chlorthalidone was 0.04 m/s (−0.4 m/s, 0.5 m/s, P=0.90). Hyperkalemia (defined ≥5.4 mEq/L) occurred more frequently with spironolactone (12 versus two participants, adjusted relative risk was 5.5, 95% confidence interval, 1.4 to 22.1, P=0.02), but there were no patients with severe hyperkalemia (defined ≥6.5 mEq/L). A decline in eGFR >30% occurred in eight participants treated with chlorthalidone compared with two participants with spironolactone (adjusted relative risk was 0.2, 95% confidence interval, 0.05 to 1.1, P=0.07). Conclusions Spironolactone was not superior to chlorthalidone in reducing left ventricular mass, BP, or arterial stiffness in nondiabetic CKD.

Coronary microvascular disease (CMD), characterized by impaired coronary flow reserve (CFR), is a common finding in patients with stable angina. Impaired CFR, in the absence of obstructive coronary artery disease, is also present in up to 75% of patients with heart failure with preserved ejection fraction (HFpEF). Heart failure with preserved ejection fraction is a heterogeneous syndrome comprising distinct endotypes and it has been hypothesized that CMD lies at the centre of the pathogenesis of one such entity: the CMD–HFpEF endotype. This article provides a contemporary review of the pathophysiology underlying CMD, with a focus on the mechanistic link between CMD and HFpEF. We discuss the central role played by subendocardial ischaemia and impaired lusitropy in the development of CMD–HFpEF, as well as the clinical and research implications of the CMD–HFpEF mechanistic link. Future prospective follow-up studies detailing outcomes in patients with CMD and HFpEF are much needed to enhance our understanding of the pathological processes driving these conditions, which may lead to the development of physiology-stratified therapy to improve the quality of life and prognosis in these patients., Graphical Abstract The mechanistic link between coronary microvascular disease and heart failure with preserved ejection fraction.

Purpose of review To summarize new clinical findings of endothelin receptor antagonists (ERA) in various etiologies of kidney disease targeted in clinical trials. Recent findings Endothelin-1 is a multifunctional peptide with potential relevance to glomerular and tubulointerstitial kidney diseases. The phase 3 SONAR trial demonstrated a significant reduction in clinically relevant kidney outcomes for patients with diabetic kidney disease (DKD) after long-term treatment with the ERA, atrasentan, in addition to blockade of the renin-angiotensin-aldosterone system. Promising preclinical disease models and small clinical trials in non-DKD resulted in the initiation of phase 3 trials investigating the effects of long-term treatment with ERA in patients with immunoglobulin A (IgA) nephropathy and focal segmental glomeruloscelerosis (FSGS). The mechanisms by which ERA protects the kidneys have been extensively studied with evidence for the protection of tubule cells, podocytes, mesangial cells, the endothelial glycocalyx, and a reduction in glomerular perfusion pressure. The occurrence of fluid retention during ERA treatment, particularly in susceptible populations, necessitates strategies to support safe and effective treatment. Summary Treatment with ERA induces long-term kidney protection in DKD. Phase 3 trials are underway to investigate ERA effects in patients with IgA nephropathy and FSGS.

Determine the effectiveness and acceptability of a text message intervention (DTEXT) on HbA1c and self-management behaviors for Australian adults with type 2 diabetes.Using intention to treat analysis and generalized estimating equations, this randomized controlled trial of 395 adults determined change in HbA1c at 3 and 6 months between the intervention and control group. Secondary outcomes included change in nutrition, physical activity, blood lipid profile, body mass index, quality of life, self-efficacy, medication taking and program acceptability.No significant difference was observed between the intervention or control group for HbA1c at 3 months (P = 0.23) or 6 months (P = 0.22). Significant improvements were seen in consumption of vegetables at 3 months (P0.001) and 6 months (P = 0.04); fruit at 3 months (P = 0.046) and discretionary sweet foods at 3 months (P = 0.02). No other significant effects seen. The intervention demonstrated high rates of acceptability (94.0%) and minimal withdrawal (1.5%).DTEXT was an acceptable text message intervention that improved some nutritional behaviors in people with type 2 diabetes, but did not significantly improve HbA1c or other outcomes. Further research is required to optimize DTEXT.DTEXT provides an acceptable, feasible form of self-management support that may complement existing diabetes care.

Autistic individuals are at risk for developing depression though the risk and protective factors for co-occurring depression in autistic individuals are not yet fully characterized. In this retrospective medical chart review study, we explored factors associated with self-reported depressive symptoms (Patient Health Questionnaire-9) in autistic adults (N = 58). For autistic adults, engagement in one or more activities (recreational, educational and/or vocational) was associated with less severe depressive symptoms (Mann–Whitney U test, p = 0.006); and reported family history of depression/anxiety was associated with increased likelihood of suicidal ideation (Chi-square test, p = 0.027). Promotion of community-based activities and family support systems may be an integral part of creating effective treatment plans for depressive symptoms in autistic adults.

Purpose: To determine whether clinician-led immunization education with immediate onsite vaccination availability will increase pneumococcal immunizations during specialty care. Methods: We designed a controlled before and after QI project quasi-experimental design to retrospectively evaluate the QI effectiveness. The QI setting included two clinics. Clinic #1 was a part of the county hospital system and offered comprehensive care. Clinic #2 was a university clinic that hosted a private practice and a dermatology resident continuity clinic. 201 patients with planned or existing immunosuppressive medication regimens attending an initial or follow-up dermatology visit participated in the study. The intervention included clinician provided verbal immunization recommendations. Patients were then given the opportunity for immediate immunization. The main measure of outcome was pneumococcal immunization status after QI intervention. Results: Our analysis included 201 patients with planned or existing immunosuppressive medication regimens attending an initial or follow-up dermatology visit (aged 0-64 years [82.1%] ,aged ≥65 years [17.9%]; male [34.3%] female [65.6%%]). Of these, 146 [72.6%] were in the QI group and 55 [27.4%] in the comparison group. Our unadjusted analyses identified no significant group differences in immunization status at initial observation (p=0.329; Table 1). Of the 102 patients in the QI group with no pneumococcal immunizations at initial observation, 80.4% (95% CI: 71.4%, 87.1%) received at least one pneumonia vaccination by the final observation. For the 27 patients in the QI group with partial immunization at project initiation, 85.2% (95% CI: 65.9%, 94.5%) received at least one pneumonia vaccination. Overall, 81.4% (95% CI: 73.6, 87.3) of patients in the QI group without full immunization at initial observation received at least one vaccination by the final observation. Conclusion: These data demonstrate that immunization coverage in patients on immunosuppressive medications can be markedly improved by clinician recommendation with immediate availability of the pneumococcal vaccine during specialty care. Wider adoption of this model and its adaptation to other immunizations and settings is an important opportunity to reduce vaccine-preventable illness, including COVID-19, and improve population health.

Coagulopathy in traumatic brain injury (TBI) is associated with increased risk of poor outcomes, but accurate prediction of clinically significant progressive hemorrhagic injury (PHI) in patients with severe TBI remains a challenge. Thromboelastography (TEG) is a real-time test of whole blood coagulation that provides dynamic information about global hemostasis. This study aimed to identify differences in TEG values between patients with severe TBI who did or did not experience clinically significant PHI. This was a single-center retrospective cohort study of adult patients with severe TBI. Patients were eligible for inclusion if initial Glasgow coma scale (GCS) was ≤ 8 and baseline head computed tomography (CT) imaging and TEG were available. Exclusion criteria included receipt of hemostatic agents prior to TEG. PHI was defined as bleeding expansion on CT within 24 h associated with 2-point drop in GCS, neurosurgical intervention, or mortality within 24 h. The primary endpoint was TEG value differences between patients with and without PHI. Secondary endpoints included differences in conventional coagulation tests (CCTs) between groups. Of the 526 patients evaluated, 141 met inclusion criteria. The most common reason for exclusion was lack of baseline TEG and receipt of reversal product prior to TEG. Sixty-four patients experienced PHI in the first 24 h after presentation. K time (2.03 min vs. 1.33 min, P = 0.035) and alpha angle (65° vs. 69°, P = 0.015) were found to be significantly different in patients experiencing PHI. R time (5.25 min vs. 4.71 min), maximum amplitude (61 mm vs. 63 mm), and clot lysis at 30 min after maximum clot strength (3.5% vs. 1.7%) were not significantly different between groups. Of the CCTs, only activated partial thromboplastin time (30.3 s vs. 27.6 s, P = 0.014) was found to be different in patients with PHI. Prolonged K time and narrower alpha angle were found to be associated with developing clinically significant PHI in patients with severe TBI. Despite differences detected in alpha angle, median values in both groups were within normal reference ranges. These abnormalities may reflect pathologic hypoactivity of fibrinogen, and further study is warranted to evaluate TEG-guided cryoprecipitate administration in this patient population.

Adaptive functioning, or the suite of skills essential for real-world, day-to-day functioning, includes daily living, communication, and socialization abilities. Even in the absence of co-occurring intellectual disability (IQ 70) ASD (females = 75, males = 102), and 178 typically developing (TD) (females = 87, males = 91) youth, aged 8–17 years. We examined whether each group evidenced a gap between full-scale IQ and adaptive skills and its associations with age. ASD youth evinced significantly lower adaptive skills and a significantly greater IQ-adaptive functioning gap than their same-sex TD peers. In this cross-sectional sample, the increase in the IQ-adaptive functioning gap with age was of similar magnitude for ASD males and females, but only reached statistical significance in males. We discuss unique implications the profound IQ-socialization skills gap in particular may have for ASD females. Lay abstract Adaptive functioning refers to skills that are vital to success in day-to-day life, including daily living (e.g. grocery shopping, food preparation, transportation use), communication (e.g. verbal expression of needs), and socialization skills (e.g. interpersonal skills, including expressing and recognizing emotions, and understanding turn-taking in conversation). Among autistic individuals without intellectual disability, adaptive functioning is not commensurate with intellectual ability (IQ), and instead a gap exists between these individuals’ intellectual ability and their adaptive skills. Further, these autistic individuals show a widening of this gap with increasing age. Existing studies of the gap between IQ and adaptive functioning have studied predominantly male samples. Thus, we do not know if the gap also exists in autistic females. We therefore looked at adaptive functioning and the gap between IQ and adaptive functioning in a large sample of autistic girls and boys without intellectual disability. To disentangle effects of group (autistic vs typically developing) from effects of sex (girls vs boys), we compared autistic girls and boys to one another as well as to their same-sex typically developing peers. Analyses took into consideration differences in IQ between autistic and typically developing youth. We found autistic girls, like autistic boys, show lower adaptive functioning than their same-sex typically developing peers. Results underscore the need to evaluate adaptive functioning in autistic individuals without intellectual disability and to provide necessary supports. The large gap between intellectual ability and socialization skills, in particular, may be of critical importance in improving our understanding of outcomes and mental health difficulties among autistic females.

Introduction Sodium–glucose co-transporter 2 inhibitors (SGLT2is) are licensed for the treatment of type 2 diabetes (T2D) and more recently for heart failure with or without diabetes. They have been shown to be safe (from the cardiovascular (CV) perspective) and effective (in terms of glycaemia, and in some cases, in reducing CV events) in extensive randomised controlled trials (RCTs). However, there remain concerns regarding the generalisability of these findings (to those ineligible for RCT participation) and about non-CV safety. For effectiveness, population-based pharmacoepidemiology studies can confirm and extend the findings of RCTs to broader populations and explore safety, for which RCTs are not usually powered, in more detail. Methods A pre-planned and registered ((International PROSPEctive Register Of Systematic Reviews) PROSPERO registration CRD42019160792) systematic review of population-based studies investigating SGLT2i effectiveness and safety, following Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines was conducted. Results A total of 37 studies were identified (total n = 1,300,184 adults; total follow-up 910,577 person-years; exposures: SGLT2i class, canagliflozin, dapagliflozin and empagliflozin) exploring CV disease (CVD) outcomes, acute kidney injury (AKI), lower limb amputation (LLA), diabetic ketoacidosis (DKA), bone fracture, urinary tract infection (UTI), genital mycotic infection (GMI), hypoglycaemia, pancreatitis and venous thromboembolism. For CV and mortality outcomes, studies confirmed the associated safety of these drugs and correlated closely with the findings from RCTs, which may extend to primary CVD prevention (major adverse cardiovascular events point estimate range (PER) hazard ratio (HR) 0.78–0.94; hospitalised heart failure PER HR 0.48–0.79). For safety outcomes, SGLT2i exposure was not associated with an increased risk of AKI (PER HR 0.40–0.96), fractures (PER HR 0.87–1.11), hypoglycaemia (PER HR 0.76–2.49) or UTI (PER HR 0.72–0.98). There was a signal for increased association for GMIs (PER HR 2.08–3.15), and possibly for LLA (PER HR 0.74–2.79) and DKA (PER HR 0.96–2.14), but with considerable uncertainty. Conclusion In T2D, SGLT2is appear safe from the CV perspective and may have associated benefit in primary as well as secondary CVD prevention. For safety, they may be associated with an increased risk of GMI, LLA and DKA, although longer follow-up studies are needed. Supplementary Information The online version contains supplementary material available at 10.1007/s13300-021-01004-2.

Our understanding of the hepatic consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its resultant coronavirus disease 2019 (COVID-19) has evolved rapidly since the onset of the pandemic. In this Review, we discuss the hepatotropism of SARS-CoV-2, including the differential expression of viral receptors on liver cell types, and we describe the liver histology features present in patients with COVID-19. We also provide an overview of the pattern and relevance of abnormal liver biochemistry during COVID-19 and present the possible underlying direct and indirect mechanisms for liver injury. Furthermore, large international cohorts have been able to characterize the disease course of COVID-19 in patients with pre-existing chronic liver disease. Patients with cirrhosis have particularly high rates of hepatic decompensation and death following SARS-CoV-2 infection and we outline hypotheses to explain these findings, including the possible role of cirrhosis-associated immune dysfunction. This finding contrasts with outcome data in pharmacologically immunosuppressed patients after liver transplantation who seem to have comparatively better outcomes from COVID-19 than those with advanced liver disease. Finally, we discuss the approach to SARS-CoV-2 vaccination in patients with cirrhosis and after liver transplantation and predict how changes in social behaviours and clinical care pathways during the pandemic might lead to increased liver disease incidence and severity., This Review provides mechanistic and clinical insights into COVID-19 in the context of liver disease, discussing the potential underlying biology and clinical features of SARS-CoV-2 infection in patients with pre-existing liver conditions. The management of these patients is also discussed, including SARS-CoV-2 vaccination strategies., Key points Patients with cirrhosis have high rates of hepatic decompensation, acute-on-chronic liver failure and death from respiratory failure following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and should be prioritized for coronavirus disease 2019 (COVID-19) vaccination.The possible pathogenic mechanisms linking cirrhosis with severe COVID-19 lung disease include increased systemic inflammation, cirrhosis-associated immune dysfunction, coagulopathy and intestinal dysbiosis.Abnormal liver biochemistry values are common in patients with COVID-19; both the prognostic significance of these derangements and whether they are directly attributable to hepatic SARS-CoV-2 infection remain uncertain.Expression profiles of SARS-CoV-2 entry receptors vary across different in vitro and in vivo liver models; however, evidence of specific viral hepatotropism is limited.Liver transplant recipients do not appear to have an increased risk of mortality following SARS-CoV-2 infection compared with the matched general population.The pandemic has been associated with increased alcohol consumption, unhealthy eating habits, and interruptions to hepatology services, which might lead to an upward trend in liver disease incidence and severity.

Background Vasoplegic shock is a challenging complication of cardiac surgery and is often resistant to conventional therapies for shock. Norepinephrine and epinephrine are standards of care for vasoplegic shock, but vasopressin has increasingly been used as a primary pressor in vasoplegic shock because of its unique pharmacology and lack of inotropic activity. It remains unclear whether vasopressin has distinct benefits over standard of care for patients with vasoplegic shock. Aim To summarize the available literature evaluating vasopressin vs non-vasopressin alternatives on the clinical and patient-centered outcomes of vasoplegic shock in adult intensive care unit (ICU) patients. Methods This was a systematic review of vasopressin in adults (≥ 18 years) with vasoplegic shock after cardiac surgery. Randomized controlled trials, prospective cohorts, and retrospective cohorts comparing vasopressin to norepinephrine, epinephrine, methylene blue, hydroxocobalamin, or other pressors were included. The primary outcomes of interest were 30-d mortality, atrial/ventricular arrhythmias, stroke, ICU length of stay, duration of vasopressor therapy, incidence of acute kidney injury stage II-III, and mechanical ventilation for greater than 48 h. Results A total of 1161 studies were screened for inclusion with 3 meeting inclusion criteria with a total of 708 patients. Two studies were randomized controlled trials and one was a retrospective cohort study. Primary outcomes of 30-d mortality, stroke, ventricular arrhythmias, and duration of mechanical ventilation were similar between groups. Conflicting results were observed for acute kidney injury stage II-III, atrial arrhythmias, duration of vasopressors, and ICU length of stay with higher certainty of evidence in favor of vasopressin serving a protective role for these outcomes. Conclusion Vasopressin was not found to be superior to alternative pressor therapy for any of the included outcomes. Results are limited by mixed methodologies, small overall sample size, and heterogenous populations.

Despite advances in early detection, the average age of autism spectrum disorder (ASD) diagnosis exceeds 4 years and is often later in females. In typical development, biological sex predicts inter-individual variation across multiple developmental milestones, with females often exhibiting earlier progression. The goal of this study was to examine sex differences in caregiver-reported developmental milestones (first word, phrase, walking) and their contribution to timing of initial concerns expressed by caregivers and eventual age of diagnosis. 195 (105 males) children and adolescents aged 8 to 17 years with a clinical diagnosis of ASD were recruited to the study (mean IQ = 99.76). While developmental milestones did not predict timing of diagnosis or age parents first expressed concerns, females had earlier first words and phrases than males. There was a marginal difference in the age of diagnosis, with females receiving their diagnosis 1 year later than males. Despite sex differences in developmental milestones and diagnostic variables, IQ was the most significant predictor in the timing of initial concerns and eventual diagnosis, suggesting children with lower IQ, regardless of sex, are identified and diagnosed earlier. Overall, biological sex and developmental milestones did not account for a large proportion of variance for the eventual age of ASD diagnosis, suggesting other factors (such as IQ and the timing of initial concerns) are potentially more influential. LAY SUMMARY: In this study, a later age of diagnosis in females having ASD was confirmed; however, biological sex was not the stronger predictor of age of diagnosis. Parents reported that females learned language more quickly than males, and parents noted their first concerns when females were older than males. In this sample, the strongest predictor of age of diagnosis was the age of first concerns.

In 2019, the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) issued a substantial revision of the 2007 guideline on community-acquired pneumonia (CAP). Despite the fact that generalization of infectious disease guidelines is limited because of substantial geographic differences in microbiologic etiology and antimicrobial resistance, the ATS/IDSA guideline is frequently applied outside the United States. Therefore, this project aimed to give a perspective on the ATS/IDSA CAP recommendations related to the management of CAP outside the United States. For this, an expert panel composed of 14 international key opinion leaders in the field of CAP from 10 countries across five continents, who were not involved in producing the 2019 guideline, was asked to subjectively name the five most useful changes, the recommendation viewed most critically, and the recommendation that cannot be applied to their respective region. There was no formal consensus process, and the article reflects different opinions. Recommendations welcomed by most of the international pneumonia experts included the abandonment of the concept of “health-care-associated pneumonia,” the more restrictive indication for empiric macrolide treatment in outpatients, the increased emphasis on microbiologic diagnostics, and addressing the use of corticosteroids. Main criticisms included the somewhat arbitrary choice of a 25% resistance threshold for outpatient macrolide monotherapy. Experts from areas with elevated mycobacterial prevalence particularly opposed the recommendation of fluoroquinolones, even as an alternative.

Background Community-acquired pneumonia (CAP) guidelines have improved the treatment and outcomes of patients with CAP, primarily by standardization of initial empirical therapy. But current society-published guidelines exclude immunocompromised patients. Research Question There is no consensus regarding the initial treatment of immunocompromised patients with suspected CAP. Study Design and Methods This consensus document was created by a multidisciplinary panel of 45 physicians with experience in the treatment of CAP in immunocompromised patients. The Delphi survey methodology was used to reach consensus. Results The panel focused on 21 questions addressing initial management strategies. The panel achieved consensus in defining the population, site of care, likely pathogens, microbiologic workup, general principles of empirical therapy, and empirical therapy for specific pathogens. Interpretation This document offers general suggestions for the initial treatment of the immunocompromised patient who arrives at the hospital with pneumonia.

Background: COVID-19 was initially considered a respiratory disease but the SARS-CoV-2 virus can lead to serious systemic consequences affecting major organs including the digestive system. Summary: This review brings new clinically important information for the gastroenterologist. This includes: the mechanisms of tissue damage seen with the SARS-CoV-2 virus; the consequences of immunosuppression in patients with inflammatory bowel disease (IBD) and chronic liver disease with the additional risks of decompensation in patients with cirrhosis; the impact of COVID-19 on gastrointestinal emergencies, on gastrointestinal endoscopy, diagnosis and treatments. These highlight the need to understand the clinical pharmacology, toxicology and therapeutic implications of drugs commonly used by gastroenterologists and their links with COVID-19. Key Messages: Any part of the digestive system may be affected by the SARS-CoV-2 virus, and those with pre-existing disease are at greatest risk of adverse outcomes. The risk for drug-drug interactions is considerable in patients seriously ill with COVID-19 who often require mechanical ventilation and life support. Some repurposed drugs used against SARS-CoV-2 can cause or aggravate some of the COVID-19-related gastrointestinal symptoms and can also induce liver injury. Ongoing clinical studies will hopefully identify effective drugs with a more favourable risk-benefit ratio than many initially tried treatments.

Social motivation is a foundational construct with regard to the etiology, neurobiology, and phenotype of autism spectrum disorder (ASD). Multiple theories suggest that early emerging alterations to social motivation underlie a developmental cascade of social and communication deficits across the lifespan. Despite this significance, methods to measure social motivation vary widely, with little data to date as to how different measures might compare. In this study, we explore three existing caregiver-report measures that have been proposed to quantify social motivation among school-age children with ASD (n = 18; all male) and without ASD (n = 36; 50% female), with the broad goal of characterizing social motivation across measures and specific aims of investigating (a) diagnostic and sex differences in social motivation, (b) correspondence between measures, and (c) relationships between social motivation and broader social outcomes. Across all three measures, individuals with ASD had lower social motivation by caregiver-report. However, they did display individual differences in the degree of social motivation reported. There were no differences in social motivation between males and females without ASD on any of the three measures. For the full sample, measures of social motivation correlated with one another as anticipated, and stronger social motivation was associated with stronger social skills and fewer social difficulties. Our data suggest that social motivation among children with ASD may be best conceptualized as an individual difference that is diminished on average relative to peers but which varies among children and adolescents with ASD, rather than as an absolute absence or uniform deficit. LAY SUMMARY: Several theories suggest that children with autism spectrum disorder (ASD) experience less social motivation than their peers without ASD, contributing to difficulties in social skills. Based on multiple caregiver-report questionnaires, social motivation was reduced on average for school-age children with ASD but also varied among children with ASD. Stronger social motivation was related to stronger social skills and fewer social problems. Future work should include more girls with ASD, consider social motivation across age groups, and include first-hand perspectives from people with ASD.

Chronic kidney disease (CKD) is common, with hypertension and diabetes mellitus acting as major risk factors for its development. Cardiovascular disease is the leading cause of death worldwide and the most frequent end point of CKD. There is an urgent need for more precise methods to identify patients at risk of CKD and cardiovascular disease. Alterations in microvascular structure and function contribute to the development of hypertension, diabetes, CKD, and their associated cardiovascular disease. Homology between the eye and the kidney suggests that noninvasive imaging of the retinal vessels can detect these microvascular alterations to improve targeting of at-risk patients. Retinal vessel–derived metrics predict incident hypertension, diabetes, CKD, and cardiovascular disease and add to the current renal and cardiovascular risk stratification tools. The advent of optical coherence tomography (OCT) has transformed retinal imaging by capturing the chorioretinal microcirculation and its dependent tissue with near-histological resolution. In hypertension, diabetes, and CKD, OCT has revealed vessel remodeling and chorioretinal thinning. Clinical and preclinical OCT has linked retinal microvascular pathology to circulating and histological markers of injury in the kidney. The advent of OCT angiography allows contrast-free visualization of intraretinal capillary networks to potentially detect early incipient microvascular disease. Combining OCT’s deep imaging with the analytical power of deep learning represents the next frontier in defining what the eye can reveal about the kidney and broader cardiovascular health.

Adolescent dieting and disordered eating (DE) are risks for clinical eating disorders. In this five-wave longitudinal study, we tested gender-specific models linking early risk factors to temporal patterns of DE, considering appearance anxiety as a mediator. Participants were 384 Australian students (age 10 to 13; 45% boys) who reported their purging and skipping meals, experience with appearance-related teasing, media pressure, and appearance anxiety. Parents reported pubertal maturation and height/weight was measured. Gender differences in temporal patterns of DE were found and predictive models were tested using latent-variable growth curve and path models. Boys’ DE was generally stable over time; girls showed stability in purging but an average increase in skipping meals. Peer teasing, media pressure, and pubertal maturation were associated with more elevated initial DE in girls, and pubertal maturation was associated with a steeper increase in DE. For boys, body mass index had a direct positive association with DE. Appearance anxiety was associated with more DE, but there was only one significant indirect effect via anxiety, which was for boys’ pubertal maturation. Findings support the dominant role of social interactions and messages, as well as pubertal maturation, for girls’ DE and the prominence of physical risk factors for explaining boys’ DE.

PDE type 5 inhibitors (PDE5Is), such as sildenafil, tadalafil and vardenafil, are a class of drugs used to prolong the physiological effects of NO/cGMP signalling in tissues through the inhibition of cGMP degradation. Although these agents were originally developed for the treatment of hypertension and angina, unanticipated side effects led to advances in the treatment of erectile dysfunction and, later, pulmonary arterial hypertension. In the last decade, accumulating evidence suggests that PDE5Is may confer a wider range of clinical benefits than was previously recognised. This has led to a broader interest in the cardiovascular therapeutic potential of PDE5Is, in conditions such as hypertension, myocardial infarction, stroke, peripheral arterial disease, chronic kidney disease and diabetes mellitus. Here, we review the pharmacological properties and established licensed uses of this class of drug, along with emerging therapeutic developments and possible future indications.

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8–17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.

Haitian (HA) and African American (AA) men have the highest prostate cancer (PCa) and colorectal cancer (CRC) age-adjusted mortality rates compared with other racial/ethnic groups worldwide. One contributing factor to mortality differences is that a low percentage of age-eligible HA and AA men screen for PCa and CRC, even when healthcare access and insurance are available. Reasons for cancer screening disparities may be differences in knowledge, preferences and willingness in HA and AA men. However, limited information exists on whether HA and AA men are knowledgeable about and are willing to be screened for PCa and CRC. Moreover, understanding preferences and willingness of HA and AA men to use cancer screening tests completed at home is of paramount importance given the current pandemic. We used a cross-sectional study design to assess HA and AA men's knowledge, preferences and willingness to use at-home PCa and CRC screening tests. Survey items were developed from existing surveys assessing CRC knowledge and willingness to screen. Institutional Review Board approval was obtained to invite persons who identified as male, at least 18 years of age and Black (as either AA and/or HA) to complete the survey. A total of 36 Black men completed the survey; 42% self-identified as both 'African American' and 'Haitian' (AA/HA), 44% identified only as AA, and 14% identified only as HA. Regardless of race or ethnicity, 75% of all participants were 45 years or younger (range: 18-85). Although more than 80% of all participants heard about PCa and CRC, only 50% of participants aged at least 50 years old were screened for CRC. The majority of participants (AA/HA = 67%; HA = 80%; AA = 56%) were unaware of at-home CRC screening tests; however, 80% of AA/HA men and 60% of HA men were willing to use an at-home CRC screening test compared to 44% of AA men.

NK cell suppression of T cells is a key determinant of viral pathogenesis and vaccine efficacy. This process involves perforin-dependent elimination of activated CD4+ T cells during the first 3 days of infection. Although this mechanism requires cell-cell contact, NK cells and T cells typically reside in different compartments of lymphoid tissues at steady state. Here, we showed that NK cell suppression of T cells is associated with transient accumulation of NK cells within T cell-rich sites of the spleen during lymphocytic choriomeningitis virus infection. The chemokine receptor CXCR3 was required for this relocation and suppression of antiviral T cells. Accordingly, NK cell migration was mediated by type I IFN-dependent promotion of CXCR3 ligand expression. In contrast, adenoviral vectors that weakly induced type I IFN and did not stimulate NK cell inhibition of T cells also did not promote measurable redistribution of NK cells to T cell zones. Exogenous IFN rescued NK cell migration during adenoviral vector immunization. Thus, type I IFN and CXCR3 were critical for properly positioning NK cells to constrain antiviral T cell responses. Development of strategies to curtail migration of NK cells between lymphoid compartments may enhance vaccine-elicited immune responses.

Research Letter

ObjectiveThis study sought to compare disease recidivism rates between canal wall up mastoidectomy and a canal wall down with obliteration technique.MethodsPatients undergoing primary cholesteatoma surgery at our institution over a five-year period (2013–2017) using the aforementioned techniques were eligible for inclusion in the study. Rates of discharge and disease recidivism were analysed using chi-square statistics.ResultsA total of 104 ears (98 patients) were included. The mean follow-up period was 30 months (range, 12–52 months). A canal wall down with mastoid obliteration technique was performed in 55 cases and a canal wall up approach was performed in 49 cases. Disease recidivism rates were 7.3 per cent and 16.3 per cent in the canal wall down with mastoid obliteration and canal wall up groups respectively (p = 0.02), whilst discharge rates were similar (7.3 per cent and 10.2 per cent respectively).ConclusionOur direct comparative data suggest that canal wall down mastoidectomy with obliteration is superior to a canal wall up technique in primary cholesteatoma surgery, providing a lower recidivism rate combined with a low post-operative ear discharge rate.

Background & Aims Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammatory and fibrotic injury to the biliary tree. We sought to further delineate the contribution of macrophage lineages in PSC pathobiology. Methods Human liver tissues and/or blood samples from patients with PSC, primary biliary cholangitis, other non-cholestatic/non-autoimmune diseases, including alcohol-related liver disease and non-alcoholic steatohepatitis, as well as normal liver, were sourced from our liver transplantation program. Liver fibrosis was studied using Van Gieson staining, while the frequencies of infiltrating monocyte and macrophage lineages, both in the circulation and the liver, were investigated by flow cytometry, including the expression of TGR-5, a G protein-coupled receptor (GPBAR1/TGR-5). Results Significantly higher frequencies of CD68+CD206+ macrophages were detected in the livers of patients with PSC (median 19.17%; IQR 7.25–32.8%; n = 15) compared to those of patients with other liver diseases (median 12.05%; IQR 5.61–16.03%; n = 12; p = 0.0373). CD16+ monocytes, including both intermediate (CD14+CD16++) and non-classical (CD14dimCD16++) monocytes, were preferentially recruited into chronically diseased livers, with the highest recruitment ratios in PSC (median 15.83%; IQR 9.66–29.5%; n = 15), compared to other liver diseases (median 6.66%; IQR 2.88–11.64%, n = 14, p = 0.0152). The expression of TGR-5 on CD68+ intrahepatic macrophages was increased in chronic liver disease; TGR-5 expression on intrahepatic macrophages was highest in PSC (median 36.32%; IQR 17.71–63.61%; n = 6) and most TGR-5+ macrophages were CD68+CD206+ macrophages. Conclusions Underlying a potential role for macrophages in PSC pathobiology, we demonstrate, using patient-derived tissue, increased CD16+ monocyte recruitment and a higher frequency of CD68+CD206+ macrophages in the livers of patients with PSC; the CD68+CD206+ macrophage subset was associated with significantly higher TGR-5 expression in PSC. Lay summary Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease associated with progressive inflammation of the bile duct, leading to fibrosis and end-stage liver disease. In this study we explore the role of a type of immune cell, the macrophage, in contributing to PSC as a disease, hoping that our findings direct scientists towards new treatment targets. Our findings based on human liver and blood analyses demonstrate a greater frequency of a particular subset of immune cell, the CD68+CD206+ macrophage, with significantly higher TGR-5 expression on this subset in PSC., Graphical Abstract Unlabelled Image, Highlights • CD68+CD206+ macrophage populations predominate in the liver tissue of patients with primary sclerosing cholangitis. • Intrahepatic CD16+ monocytes preferentially accumulate in the livers of patients with primary sclerosing cholangitis. • The expression of TGR-5 is increased in chronic liver disease. • TGR-5 expression on CD68+CD206+ intrahepatic macrophages is higher in patients with primary sclerosing cholangitis.

PURPOSE: To validate an algorithm for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) episodes derived in an electronic health record (EHR) database, against AECOPD episodes collected in a randomized clinical trial using an electronic case report form (eCRF).METHODS: We analyzed two data sources from the Salford Lung Study in COPD: trial eCRF and the Salford Integrated Record, a linked primary-secondary routine care EHR database of all patients in Salford. For trial participants, AECOPD episodes reported in eCRF were compared with algorithmically derived moderate/severe AECOPD episodes identified in EHR. Episode characteristics (frequency, duration), sensitivity, and positive predictive value (PPV) were calculated. A match between eCRF and EHR episodes was defined as at least 1-day overlap.RESULTS: In the primary effectiveness analysis population (n = 2269), 3791 EHR episodes (mean [SD] length: 15.1 [3.59] days; range: 14-54) and 4403 moderate/severe AECOPD eCRF episodes (mean length: 13.8 [16.20] days; range: 1-372) were identified. eCRF episodes exceeding 28 days were usually broken up into shorter episodes in the EHR. Sensitivity was 63.6% and PPV 71.1%, where concordance was defined as at least 1-day overlap.CONCLUSIONS: The EHR algorithm performance was acceptable, indicating that EHR-derived AECOPD episodes may provide an efficient, valid method of data collection. Comparing EHR-derived AECOPD episodes with those collected by eCRF resulted in slightly fewer episodes, and eCRF episodes of extreme lengths were poorly captured in EHR. Analysis of routinely collected EHR data may be reasonable when relative, rather than absolute, rates of AECOPD are relevant for stakeholders' decision making.

Supplemental Digital Content is available in the text., Dyslipidemia is common in chronic kidney disease (CKD). Despite statins, many patients fail to adequately lower lipids and remain at increased risk of cardiovascular disease. Selective ETA (endothelin-A) receptor antagonists reduce cardiovascular disease risk factors. Preclinical data suggest that ETA antagonism has beneficial effects on circulating lipids. We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary analysis of a fully randomized, double-blind, 3-phase crossover study. Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ETA receptor antagonist, sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 weeks. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 weeks of ETA antagonism significantly reduced total (−11±1%) and low-density lipoprotein–associated (−20±3%) cholesterol, lipoprotein (a) (−16±2%) and triglycerides (−20±4%); high-density lipoprotein–associated cholesterol increased (+14±2%), P

Background: Diagnosis of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is challenging and new tools are needed for early diagnosis as well as to understand the biochemical events that underlie the pathology in TB-IRIS. Methods: Plasma samples were obtained from participants from a randomized HIV/TB treatment strategy study (AIDS Clinical Trials Group [ACTG] A5221) with (n = 26) and without TB-IRIS (n = 22) for an untargeted metabolomics pilot study by liquid-chromatography mass spectrometry. The metabolic profile of these participants was compared at the study entry and as close to the diagnosis of TB-IRIS as possible (TB-IRIS window). Molecular features with p

Background Mortality following lung cancer resection has been shown to double between 30 and 90 days and readmission following surgery is associated with an increased risk of mortality. The aim of this study was to describe the causes of readmission and mortality and enable the identification of potentially modifiable factors associated with these events. Methods Prospective cohort study at a United Kingdom tertiary referral centre conducted over 55 months. Binary logistic regression was used to identify factors associated with death within 90 days of surgery. Results The 30 day and 90 day mortality rates were 1.4% and 3.3% respectively. The most common causes of death were pneumonia, lung cancer and Acute Respiratory Distress Syndrome/Multi Organ Failure. Potentially modifiable risk factors for death identified were: Postoperative pulmonary complications (Odds ratio 6.1), preoperative lymphocyte count (OR 0.25), readmission within 30 days (OR 4.2) and type of postoperative analgesia (OR for intrathecal morphine 4.8). The most common causes of readmission were pneumonia, shortness of breath and pain. Conclusions Postoperative mortality is not simply due to fixed factors; the impacts of age, gender and surgical procedure on postoperative survival are reduced when the postoperative course of recovery is examined. Perioperative immune function, as portrayed by the occurrence of infection and lower lymphocyte count in the immediate perioperative period, and pain control method are strongly associated with 90 day mortality; further studies in these fields are indicated as are studies of psychological factors in recovery. Clinical registration number ISRCTN00061628.

Cardiovascular disease is a major contributor to global morbidity and mortality and is the common end point of many chronic diseases. The endothelins comprise three structurally similar peptides of 21 amino acids in length. Endothelin 1 (ET-1) and ET-2 activate two G protein-coupled receptors — endothelin receptor type A (ETA) and endothelin receptor type B (ETB) — with equal affinity, whereas ET-3 has a lower affinity for ETA. ET-1 is the most potent vasoconstrictor in the human cardiovascular system and has remarkably long-lasting actions. ET-1 contributes to vasoconstriction, vascular and cardiac hypertrophy, inflammation, and to the development and progression of cardiovascular disease. Endothelin receptor antagonists have revolutionized the treatment of pulmonary arterial hypertension. Clinical trials continue to explore new applications of endothelin receptor antagonists, particularly in treatment-resistant hypertension, chronic kidney disease and patients receiving antiangiogenic therapies. Translational studies have identified important roles for the endothelin isoforms and new therapeutic targets during development, in fluid-electrolyte homeostasis, and in cardiovascular and neuronal function. Novel pharmacological strategies are emerging in the form of small-molecule epigenetic modulators, biologics (such as monoclonal antibodies for ETB) and possibly signalling pathway-biased agonists and antagonists. Endothelin 1 is the most potent vasoconstrictor in the human cardiovascular system. In this Review, Dhaun and Webb discuss the biology of the endothelins and endothelin receptors and how these pathways can be therapeutically targeted in cardiovascular and renal diseases.

Background Diabetes prevalence is rapidly increasing, with type 2 diabetes predicted to be the leading contributor of non-communicable disease in Australia by 2020. It is anticipated that rates of type 2 diabetes will continue to increase if factors such as overweight and obesity, low physical activity and poor nutrition are not addressed. The majority of Australians with type 2 diabetes do not meet the guidelines for optimal diabetes management, and access to diabetes education is limited. This highlights the need for new interventions that can reduce existing barriers to diabetes education, attain greater population reach and support self-management strategies for people with type 2 diabetes. Mobile phone text messages have shown promising results as an intervention for people with chronic disease. They have the ability to achieve high levels of engagement and broad population reach, whilst requiring minimal resources. There is however, no evidence on the effect of text messaging to improve the health of people with type 2 diabetes in Australia. Methods/Design This randomised controlled trial aims to investigate if a 6 month text message intervention (DTEXT) can lead to improvements in glycated haemoglobin (HbA1c) and diabetes self-management among Australian residents in New South Wales (NSW) with type 2 diabetes. Community dwelling adults (n = 340) will be recruited with the primary outcome being change in HbA1c at 6 months. Secondary outcomes include behaviour change for diabetes self-management, self-efficacy, quality of life and intervention acceptability. An economic evaluation will be conducted using a funder plus patient perspective. Discussion This study will provide evidence on the effectiveness and cost effectiveness of a text message intervention to reduce HbA1c and enhance self-management of type 2 diabetes in the Australian population. If successful, this intervention could be used as a model to complement and extend existing diabetes care in the Australian health care system. Trial Registration The study has been registered with the Australian New Zealand Clinical Trials Registry, Trial ID: ACTRN12617000416392. Registered: 23 March 2017.

Background The 2012 American Society for Colposcopy and Cervical Pathology Consensus Guidelines provide information for managing abnormal cervical cancer screening tests and cancer precursors. According to these guidelines for Pap smear diagnosis of Atypical squamous cells of undetermined significance, reflex high risk (HR) human papilloma virus (HPV) genotyping is required among women 21 years of age or older. Whereas, in women of 30 to 65 years of age, HR-HPV can be ordered by the clinicians as part of co-testing with any diagnosis and every 5 years with a negative Cervico-Vaginal Pap test (CVPT). Methods A retrospective review of the CoPath database of the Pathology Department at the University of Florida, College of Medicine Jacksonville, FL, was performed to identify North Florida (NF) women who underwent CVPT and HR-HPV testing between 2006 and 2014. The women were stratified by race and age, respectively. Results The study included 19,933 CVPTs. Significant differences in the outcomes' distributions were found among age and race groups, respectively. Highest prevalence of HPV positivity was found in African American women, and in 14- to 20-year-old women, respectively. Twenty- to 30-year-old women had the highest percentage (59%) of epithelial abnormality. The most common HR-HPV genotypic distribution was other HR-HPV. Conclusions This study underscores the importance of using both HR-HPV and CVPT for screening for cervical cancer, and confirms the need for special focus on managing high-risk populations subgroups, such as African American women, and women of ages 14 to 20 years especially in high-risk populations.

Although the antimicrobial potential of nitric oxide (NO) is widely published, it is little used clinically. NO is a key signalling molecule modulating vascular, neuronal, inflammatory and immune responses. Endogenous antimicrobial activity is largely mediated by high local NO concentrations produced by cellular inducible nitric oxide synthase, and by derivative reactive nitrogen oxide species including peroxynitrite and S-nitrosothiols. NO may be taken as dietary substrate (inorganic nitrate, L-arginine), and therapeutically as gaseous NO, and transdermal, sublingual, oral, intranasal and intravenous nitrite or nitrate. Numerous preclinical studies have demonstrated that NO has generic static and cidal activities against viruses (including β-coronaviruses such as SARS-CoV-2), bacteria, protozoa and fungi/yeasts in vitro. Therapeutic effects have been seen in animal models in vivo, and phase II trials have demonstrated that NO donors can reduce microbial infection. Nevertheless, excess NO, as occurs in septic shock, is associated with increased morbidity and mortality. In view of the dose-dependent positive and negative effects of NO, safety and efficacy trials of NO and its donors are needed for assessing their role in the prevention and treatment of infections. Trials should test dietary inorganic nitrate for pre- or post-exposure prophylaxis and gaseous NO or oral, topical or intravenous nitrite and nitrate for treatment of mild-to-severe infections, including due to SARS-CoV-2 (COVID-19). This review summarises the evidence base from in vitro, in vivo and early phase clinical studies of NO activity in viral, bacterial, protozoal and fungal infections.

Francisella tularensis (Ft) is a Gram-negative, facultative intracellular bacterium that is a Tier 1 Select Agent of concern for biodefense for which there is no licensed vaccine. A subfamily of 9 Francisella phagosomal transporter (fpt) genes belonging to the Major Facilitator Superfamily of transporters was identified as critical to pathogenesis and potential targets for attenuation and vaccine development. We evaluated the attenuation and protective capacity of LVS derivatives with deletions of the fptA and fptF genes in the C57BL/6J mouse model of respiratory tularemia. LVSΔfptA and LVSΔfptF were highly attenuated with LD50 values of &gt, 20 times that of LVS when administered intranasally and conferred 100% protection against lethal challenge. Immune responses to the fpt mutant strains in mouse lungs on day 6 post-infection were substantially modified compared to LVS and were associated with reduced organ burdens and reduced pathology. The immune responses to LVSΔfptA and LVSΔfptF were characterized by decreased levels of IL-10 and IL-1β in the BALF versus LVS, and increased numbers of B cells, αβ and γδ T cells, NK cells, and DCs versus LVS. These results support a fundamental requirement for FptA and FptF in the pathogenesis of Ft and the modulation of the host immune response.

BackgroundCOVID-19, the clinical syndrome caused by infection with SARS-CoV-2, has been associated with deranged liver biochemistry in studies from China, Italy and the USA. However, the clinical utility of liver biochemistry as a prognostic marker of outcome for COVID-19 is currently debated.MethodsWe extracted routinely collected clinical data from a large teaching hospital in the UK, matching 585 hospitalised SARS-CoV-2 RT-PCR-positive patients to 1165 hospitalised SARS-CoV-2 RT-PCR-negative patients for age, gender, ethnicity and pre-existing comorbidities. Liver biochemistry was compared between groups over time to determine whether derangement was associated with outcome.Results26.8% (157/585) of COVID-19 patients died, compared to 11.9% (139/1165) in the non-COVID-19 group (pConclusionIn this UK population, liver biochemistry is commonly deranged in patients with COVID-19 but only baseline low albumin and a rising alkaline phosphatase over time are prognostic markers for death.Key PointsAge ≥ 75 years and low albumin at the time of a positive SARS-CoV-2 RT-PCR test can predict poor clinical outcome in COVID-19 patients.Liver biochemistry is more likely to be abnormal in patients with COVID-19 than in patients without COVID-19.Patients with COVID-19 who died showed a greater decline in albumin and a greater increase in alkaline phosphatase over time, compared to those who survived.Patients with pre-existing liver disease and COVID-19 had an increased mortality.Lay SummaryWe used routinely collected hospital data from a large UK teaching hospital to compare liver biochemistry (markers of liver inflammation or damage) between 585 patients with COVID-19 and 1165 patients of the same age and sex admitted to hospital but without COVID-19. Patients with COVID-19 were more likely to die than those without COVID-19, and deaths were significantly higher in those aged ≥75 years. We found that patients with COVID-19 were more likely to have abnormal liver biochemistry. Low albumin (a blood protein) at the time of being diagnosed with COVID-19 was associated with an increased chance of death.

Introduction Glucagon-like peptide 1 receptor agonists (GLP1RAs) are licensed for the treatment of type 2 diabetes (T2D). They have been shown to be safe (from the cardiovascular (CV) perspective) and effective (in terms of glycaemia, and in some cases, reducing CV events) in extensive randomised controlled trials (RCTs). However, there remain concerns regarding the generalisability of these findings (to those ineligible for RCT participation) and about non-CV safety. For effectiveness, population-based pharmacoepidemiology studies can confirm and extend the findings of RCTs findings to broader populations and explore safety, for which RCTs are not usually powered, in more detail. Method We did a pre-planned and registered (PROSPERO registration CRD42020165720) systematic review of population-based studies investigating GLP1RA effectiveness and safety, following Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines. Results A total of 22 studies were identified (including 200,148 participants and 396,457 person-years of follow-up) exploring exposure to GLP1RA class, exenatide and liraglutide (the only individual drugs with treatment effect estimates identified) on mortality, cardiovascular disease (CVD), acute pancreatitis (AP), pancreatic cancer (PC), thyroid cancer (TC), acute renal failure (ARF), diabetic retinopathy (DR), breast cancer (BC) and hypoglycaemia. For CV and mortality outcomes, studies confirmed the associated safety of these drugs. For liraglutide, point estimate (PE) range (PER) major adverse cardiovascular events (MACE) (0.53–0.95) and PER heart failure (0.34–1.22) were similar in direction to the beneficial effect observed in RCTs for MACE but varied widely for heart failure. For safety outcomes, exposure was not associated with AP (PER 0.50–1.17), PC (PER 0.40–1.54), BC (PER 0.90–1.51) or hypoglycaemia (PER 0.59–1.06). Only one study was identified exploring each of TC (no evidence of association, hazard ratio (HR) 1.46, 95% confidence interval (CI) 0.98–2.19), renal outcomes (no evidence of association, HR 0.77, 95% CI 0.42–1.41) and DR (no evidence of association, HR 0.67, 95% CI 0.51–0.90). Conclusion In T2D, GLP1RAs appear safe from the CV perspective and (for liraglutide) may have associated benefit in primary as well as secondary CVD prevention. For non-CV safety, GLP1RA exposure was not associated with an increased risk of AP, PC, BC or hypoglycaemia; the other outcomes had too few studies to draw firm conclusions and should be explored further. Supplementary Information The online version contains supplementary material available at 10.1007/s13300-021-01021-1.

Semaphorin 4D (Sema4D) is a glycoprotein that is expressed by several tumors and immune cells. It can function as a membrane bound protein or as a cleaved soluble protein (sSema4D). We sought to investigate the translational potential of plasma sSema4D as an immune marker in plasma of patients with head and neck squamous cell carcinoma (HNSCC). Paired peripheral blood and tumor tissue samples of 104 patients with HNSCC were collected at the same time point to allow for real time analysis. Scoring of the histological inflammatory subtype (HIS) was carried out using Sema4D immunohistochemistry on the tumor tissue. sSema4D was detected in plasma using direct ELISA assay. Defining elevated sSema4D as values above the 95th percentile in healthy controls, our data showed that sSema4D levels in plasma were elevated in 25.0% (95% CI, 16.7–34.9%) of the patients with HNSCC and showed significant association with HIS immune excluded (HIS-IE) (p = 0.007), Sema4D+ve tumor cells (TCs) (p = 0.018) and PD-L1+ve immune cells (ICs) (p = 0.038). A multi-variable logistic regression analysis showed that HIS was significantly (P = 0.004) associated with elevated sSema4D, an association not explained by available patient-level factors. Using the IO-360 nanoString platform, differential gene expression (DGE) analysis of 10 HNSCC tumor tissues showed that patients with high sSema4D in plasma (HsS4D) clustered as IFN-γ negative tumor immune signature and were mostly HIS-IE. The IC type in the HsS4D paired tumor tissue was predominantly myeloid, while the lymphoid compartment was higher in the low sSema4D (LsS4D). The Wnt signaling pathway was upregulated in the HsS4D group. Further analysis using the IO-360, 770 gene set, showed significant non-inflamed profile of the HsS4D tumors compared to the LsS4D. In conclusion, our data reveals an association between sSema4D and the histological inflammatory subtype.

BackgroundAccurate methods of identifying patients with COVID-19 who are at high risk of poor outcomes has become especially important with the advent of limited-availability therapies such as monoclonal antibodies. Here we describe development and validation of a simple but accurate scoring tool to classify risk of hospitalization and mortality.MethodsAll consecutive patients testing positive for SARS-CoV-2 from March 25-October 1, 2020 within the Intermountain Healthcare system were included. The cohort was randomly divided into 70% derivation and 30% validation cohorts. A multivariable logistic regression model was fitted for 14-day hospitalization. The optimal model was then adapted to a simple, probabilistic score and applied to the validation cohort and evaluated for prediction of hospitalization and 28-day mortality.Results22,816 patients were included; mean age was 40 years, 50.1% were female and 44% identified as non-white race or Hispanic/Latinx ethnicity. 6.2% required hospitalization and 0.4% died. Criteria in the simple model included: age (0.5 points per decade); high-risk comorbidities (2 points each): diabetes mellitus, severe immunocompromised status and obesity (body mass index≥30); non-white race/Hispanic or Latinx ethnicity (2 points), and 1 point each for: male sex, dyspnea, hypertension, coronary artery disease, cardiac arrythmia, congestive heart failure, chronic kidney disease, chronic pulmonary disease, chronic liver disease, cerebrovascular disease, and chronic neurologic disease. In the derivation cohort (n=16,030) area under the receiver-operator characteristic curve (AUROC) was 0.82 (95% CI 0.81-0.84) for hospitalization and 0.91 (0.83-0.94) for 28-day mortality; in the validation cohort (n=6,786) AUROC for hospitalization was 0.8 (CI 0.78-0.82) and for mortality 0.8 (CI 0.69-0.9).ConclusionA prediction score based on widely available patient attributes accurately risk stratifies patients with COVID-19 at the time of testing. Applications include patient selection for therapies targeted at preventing disease progression in non-hospitalized patients, including monoclonal antibodies. External validation in independent healthcare environments is needed.

Purpose This report describes our process of 4 health systems coming together to agree on standard use criteria for remdesivir as a coronavirus disease 2019 (COVID-19) treatment for patients in Utah. We hope our process provides a framework for remdesivir use in other states and insights on future use of other therapeutic agents that may also be in short supply, such as vaccines and monoclonal antibodies. Summary Emergency use authorization (EUA) criteria for COVID-19 treatments often allow for broad use of a treatment relative to limited supplies. Without national criteria, each health system must develop further rationing criteria. Health systems in Utah worked together as part of the state’s crisis standards of care workgroup to develop a framework for how to limit the EUA criteria for remdesivir to match available supplies. The 4 largest health systems were represented by infectious diseases specialists, chief medical officers, and pharmacists. The group met several times online and communicated via email over a 9-day period to develop the criteria. The clinicians agreed to use this framework to develop criteria for future therapeutics such as monoclonal antibodies. Conclusion The unique collaboration of the 4 health systems in Utah led to statewide criteria for use of remdesivir for patients with COVID-19, ensuring similar access to this limited resource for all patients in Utah.

Aim To test if 6 months' intervention with dietary nitrate and spironolactone could affect carotid subclinical atherosclerosis and stiffness, respectively, versus placebo/doxazosin, to control for blood pressure (BP). Methods A subgroup of participants in our double-blind, randomized-controlled, factorial VaSera trial had carotid imaging. Patients with hypertension and with/at risk of type 2 diabetes were randomized to active nitrate-containing beetroot juice or placebo nitrate-depleted juice, and spironolactone or doxazosin. Vascular ultrasound for carotid diameter (CD, mm) and intima-media thickness (CIMT, mm) was performed at baseline, 3- and 6-months. Carotid local stiffness (CS, m/s) was estimated from aortic pulse pressure (Arteriograph®) and carotid lumen area. Data was analysed by modified intention to treat and using mixed-model effect, adjusted for confounders. Results 93 subjects had a baseline evaluation and 86% had follow-up data. No statistical interactions occurred between the juice and drug arms and BP was similar between the juices and between the drugs. Nitrate-containing versus placebo juice significantly lowered CIMT [-0.06 (95% Confidence Interval -0.12, -0.01), p=0.034], an overall difference of ~8% relative to baseline; but had no effect on carotid diameter (CD) or carotid stiffness (CS). Doxazosin appeared to reduce CS from baseline [-0.34 (-0.62, -0.06)] however, no difference was detected versus spironolactone [-0.15 (-0.46, 0.16)]. No differences were detected between spironolactone or doxazosin on CIMT and CD. Conclusion Our results show that 6 months' intervention with dietary nitrate influences vascular remodelling, but not carotid stiffness or diameter. Neither spironolactone nor doxazosin had a BP-independent effect on carotid structure and function.

Background There is excess amenable mortality risk and evidence of healthcare quality deficits for persons with serious mental illness (SMI). We sought to identify sociodemographic and clinical characteristics associated with variations in two 2015 Healthcare Effectiveness Data and Information Set (HEDIS) measures, antipsychotic medication adherence and preventive diabetes screening, among Medicaid enrollees with serious mental illness (SMI). Methods We retrospectively analyzed claims data from September 2014 to December 2015 from enrollees in a Medicaid specialty health plan in Florida. All plan enrollees had SMI; analyses included continuously enrolled adults with antipsychotic medication prescriptions and schizophrenia or bipolar disorder. Associations were identified using mixed effects logistic regression models. Results Data for 5502 enrollees were analyzed. Substance use disorders, depression, and having both schizophrenia and bipolar disorder diagnoses were associated with both HEDIS measures but the direction of the associations differed; each was significantly associated with antipsychotic medication non-adherence (a marker of suboptimal care quality) but an increased likelihood of diabetes screening (a marker of quality care). Compared to whites, blacks and Hispanics had a significantly greater risk of medication non-adherence. Increasing age was significantly associated with increasing medication adherence, but the association between age and diabetes screening varied by sex. Other characteristics significantly associated with quality variations according to one or both measures were education (associated with antipsychotic medication adherence), urbanization (relative to urban locales, residing in suburban areas was associated with both adherence and diabetes screening), obesity (associated with both adherence and diabetes screening), language (non-English speakers had a greater likelihood of diabetes screening), and anxiety, asthma, and hypertension (each positively associated with diabetes screening). Conclusions The characteristics associated with variations in the quality of care provided to Medicaid enrollees with SMI as gauged by two HEDIS measures often differed, and at times associations were directionally opposite. The variations in the quality of healthcare received by persons with SMI that were identified in this study can guide quality improvement and delivery system reform efforts; however, given the sociodemographic and clinical characteristics’ differing associations with different measures of care quality, multidimensional approaches are warranted.

Aims: To evaluate how common radiation therapy techniques perform in the setting of the new European Society for Radiotherapy and Oncology-Advisory Committee in Radiation Oncology Practice (ESTRO-ACROP) delineation recommendations for immediate breast reconstruction (IBR). Materials and methods: Seven Danish radiation therapy centres and six international European centres participated in this project. Two breast cancer cases (one left-sided and one right-sided) with a retropectoral implant were chosen for radiation therapy planning using deep-inspiration breath-hold. Target volumes were delineated according to ESTRO-ACROP delineation recommendations. The centres were asked to plan the cases using any radiation therapy technique according to the Danish Breast Cancer Group plan objectives. Results: In total, 35 treatment plans were collected. Half of the submitted plans, for both the left-sided and the right-sided case, used the field-in-field (FiF) technique (nine for each), a quarter used volumetric arc radiation therapy (VMAT; five for right-sided, four for left-sided) and the remaining quarter was a mix of inverse intensity-modulated radiation therapy (IMRT), helicoidal therapy and hybrid (combined open fields and VMAT) techniques. Mean clinical target volume doses were in the range 99-102% of the prescribed dose. The median FiF mean heart dose (MHD) for right-sided radiation therapy was 1 Gy (range 0.8-3.7) and 5.2 Gy for left-sided radiation therapy (range 2.2-6.5). For right-sided radiation therapy, the median VMAT MHD was 3.42 Gy, for IMRT was 2.3 Gy and for helicoidal therapy was 5.1 Gy. For left-sided radiation therapy, the median VMAT MHD was 6.3 Gy, for IMRT was 7.8 Gy and for helicoidal therapy was 7.3 Gy. Conclusions: Different radiation therapy techniques could be used to plan radiation therapy in the setting of IBR. FiF provided good coverage with acceptable organ at risk doses. The best dose distribution results as a trade-off between the objectives of target volume coverage and high-dose organ at risk inclusion. The radiation therapy technique affects the interplay between these objectives. (C) 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.