Exebacase for Staphylococcus aureus bloodstream infection and endocarditis

BACKGROUND: Novel therapeutic approaches are critically needed for Staphylococcus aureus bloodstream infections (BSI), particularly for methicillin-resistant S. aureus (MRSA). Exebacase, a first-in-class antistaphylococcal lysin, is a direct lytic agent that is rapidly bacteriolytic, eradicates biofilms, and synergizes with antibiotics. METHODS: In this superiority-design study, we randomly assigned 121 patients with S. aureus BSI/endocarditis to receive a single dose of exebacase or placebo. All patients received standard-of-care antibiotics. The primary efficacy endpoint was clinical outcome (responder rate) at Day 14. RESULTS: Clinical responder rates at Day 14 were 70.4% and 60.0% in the exebacase + antibiotics and antibiotics alone groups, respectively (difference=10.4, 90% CI [-6.3, 27.2], p-value=0.31), and were 42.8 percentage points higher in the pre-specified exploratory MRSA subgroup (74.1% vs. 31.3%, difference=42.8, 90% CI [14.3, 71.4], ad hoc p value=0.01). Rates of adverse events (AEs) were similar in both groups. No AEs of hypersensitivity to exebacase were reported. Thirty-day all-cause mortality rates were 9.7% and 12.8% in the exebacase + antibiotics and antibiotics alone groups, respectively, with a notable difference in MRSA (3.7% vs. 25.0%, difference= -21.3, 90% CI [-45.1, 2.5], ad hoc p-value=0.06). Among MRSA patients in the United States, median length-of-stay was 4-days shorter and 30-day hospital readmission rates were 48 percentage points lower in the exebacase-treated group compared with antibiotics alone. CONCLUSIONS: This study establishes proof-of-concept for exebacase and direct lytic agents as potential therapeutics and supports conduct of a confirmatory study focused on exebacase to treat MRSA BSI

Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load

Objective A hallmark of chronic HBV (cHBV) infection is the presence of impaired HBV-specific CD8+ T cell responses. Functional T cell exhaustion induced by persistent antigen stimulation is considered a major mechanism underlying this impairment. However, due to their low frequencies in chronic infection, it is currently unknown whether HBV-specific CD8+ T cells targeting different epitopes are similarly impaired and share molecular profiles indicative of T cell exhaustion. Design By applying peptide-loaded MHC I tetramer-based enrichment, we could detect HBV-specific CD8+ T cells targeting epitopes in the HBV core and the polymerase proteins in the majority of 85 tested cHBV patients with low viral loads. Lower detection rates were obtained for envelope-specific CD8+ T cells. Subsequently, we performed phenotypic and functional in-depth analyses. Results HBV-specific CD8+ T cells are not terminally exhausted but rather exhibit a memory-like phenotype in patients with low viral load possibly reflecting weak ongoing cognate antigen recognition. Moreover, HBV-specific CD8+ T cells targeting core versus polymerase epitopes significantly differed in frequency, phenotype and function. In particular, in comparison with core-specific CD8+ T cells, a higher frequency of polymerase-specific CD8+ T cells expressed CD38, KLRG1 and Eomes accompanied by low T-bet expression and downregulated CD127 indicative of a more severe T cell exhaustion. In addition, polymerase-specific CD8+ T cells exhibited a reduced expansion capacity that was linked to a dysbalanced TCF1/BCL2 expression. Conclusions Overall, the molecular mechanisms underlying impaired T cell responses differ with respect to the targeted HBV antigens. These results have potential implications for immunotherapeutic approaches in HBV cure

Leafhopper diversity in home gardens – results of a survey in four countries across Europe (Hemiptera, Auchenorrhyncha)

Despite urbanisation being one of the main drivers of habitat destruction and biodiversity loss, home gardens can provide habitat for a wide range of species. Here we report the results of a leafhopper survey in 12 gardens in four European countries (Germany, Serbia, Austria and Bulgaria). Sampling was conducted in a semi-standardised way across the summer 2020. In total, 143 Auchenorrhyncha species with 2,361 adult specimens were recorded, including several red-listed species. The number of species per garden varied between 9 and 58. On average, around 26 species were found. Leafhopper diversity was positively influenced by garden area, age, plant diversity, extensive management and the cover of forests and parks in the surroundings, but also by the number of sampling dates. We conclude that extensively managed home gardens across Europe can support diverse communities of leafhoppers which is crucial in times of severe insect declines

Changes in health-related behaviours and mental health in a UK public sample during the first set of COVID-19 public health restrictions

Public health restrictions, in response to the COVID-19 pandemic, have had potentially wide-ranging, unintended effects on health-related behaviours such as diet and physical activity and also affected mental health due to reduced social interactions. This study explored how health-related behaviours and mental health were impacted in a sample of the UK public during the first set of COVID-19 public health restrictions. Two online surveys were administered in the UK, one within the first three months of the restrictions (Timepoints 1 (T1—involving pre-pandemic recall) and 2/T2) and another ten weeks later (Timepoint 3/T3). Moderate–vigorous physical activity (MVPA), outdoor time, sitting time, screen time and sexual activity were self-reported. Diet was assessed using the Dietary Instrument for Nutrition Education questionnaire. Mental health was measured using the short-form Warwick–Edinburgh Mental Wellbeing Scale and Becks’ Anxiety and Depression Inventories. Differences between timepoints were explored using the Friedman, Wilcoxon signed-rank, McNemar and McNemar–Bowker tests. Two hundred and ninety-six adults (74% under 65 years old; 65% female) provided data across all timepoints. Between T1 and T2, MVPA, time outdoors and sexual activity decreased while sitting, and screen time increased (p < 0.05). Between T2 and T3, saturated fat intake, MVPA, time outdoors, and mental wellbeing increased while sitting, screen time and anxiety symptoms decreased (p < 0.05). This study found that depending on the level of COVID-19 public health restrictions in place, there appeared to be a varying impact on different health-related behaviours and mental health. As countries emerge from restrictions, it is prudent to direct necessary resources to address these important public health issues

Associations between Physical Activity, Sitting Time, and Time Spent Outdoors with Mental Health during the First COVID-19 Lock Down in Austria.

Measures implemented to reduce the spread of SARS-CoV-2 have resulted in a decrease in physical activity (PA) while sedentary behaviour increased. The aim of the present study was to explore associations between PA and mental health in Austria during COVID-19 social restrictions. In this web-based cross-sectional study (April-May 2020) moderate-to-vigorous physical activity (MVPA), sitting time, and time spent outdoors were self-reported before and during self-isolation. Mental well-being was assessed with the Warwick-Edinburgh Mental Well-being Scale, and the Beck depression and anxiety inventories. The majority of the participants (n = 652) were female (72.4%), with a mean age of 36.0 years and a standard deviation (SD) of 14.4. Moreover, 76.5% took part in ≥30 min/day of MVPA, 53.5% sat ≥10 h/day, and 66.1% spent ≥60 min/day outdoors during self-isolation. Thirty-eight point five percent reported high mental well-being, 40.5% reported depressive symptoms, and 33.9% anxiety symptoms. Participating in higher levels of MVPA was associated with higher mental well-being (odds ratio = OR: 3.92; 95% confidence interval = 95%CI: 1.51-10.15), less depressive symptoms (OR: 0.44; 95%CI: 0.29-0.66) and anxiety symptoms (OR = 0.62; 95%CI: 0.41-0.94), and less loneliness (OR: 0.46; 95%CI: 0.31-0.69). Participants sitting <10 h/day had higher odds of mental well-being (OR: 3.58; 95%CI: 1.13-11.35). Comparable results were found for spending ≥60 min/day outdoors. Maintaining one's MVPA levels was associated with higher mental well-being (OR = 8.61, 95%CI: 2.68-27.62). In conclusion, results show a positive association between PA, time spent outdoors and mental well-being during COVID-19 social restrictions. Interventions aiming to increase PA might mitigate negative effects of such restrictions

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Unique and common features of innate-like human Vδ2+ γδT cells and mucosal-associated invariant T cells

Mucosal-associated invariant T (MAIT) cells are innate-like T cells abundant in humans that can be activated in a TCR-independent manner by inflammatory and anti-viral cytokines. In humans, the capacity for TCR-independent activation is functionally linked to a transcriptional program that can be identified by the expression of the C-type lectin receptor, CD161. In addition to MAIT cells, it has been demonstrated that a subset of [gamma][delta]T cells expresses CD161 and can be activated by TCR-independent cytokine stimulation. In this study, we sought to clarify the nature of cytokine-responsive human [gamma][delta]T cells. We could link CD161 expression on V[delta]2+ versus V[delta]1+ [gamma][delta]T cells to the observation that V[delta]2+ [gamma][delta]T cells, but not V[delta]1+ [gamma][delta]T cells, robustly produced IFN-[gamma] upon stimulation with a variety of cytokine combinations. Interestingly, both CD161+ and CD161- V[delta]2+ [gamma][delta]T cells responded to these stimuli, with increased functionality within the CD161+ subset. This innate-like responsiveness corresponded to high expression of PLZF and IL-18R[alpha], analogous to MAIT cells. V[delta]2+ [gamma][delta]T cells in human duodenum and liver maintained a CD161+ IL-18R[alpha]+ phenotype and produced IFN-[gamma] in response to IL-12 and IL-18 stimulation. In contrast to MAIT cells, we could not detect IL-17A production but observed higher steady state expression of Granzyme B by V[delta]2+ [gamma][delta]T cells. Finally, we investigated the frequency and functionality of [gamma][delta]T cells in the context of chronic hepatitis C virus infection, as MAIT cells are reduced in frequency in this disease. In contrast, V[delta]2+ [gamma][delta]T cells were maintained in frequency and displayed unimpaired IFN-[gamma] production in response to cytokine stimulation. In sum, human V[delta]2+ [gamma][delta]T cells are a functionally distinct population of cytokine-responsive innate-like T cells that is abundant in blood and tissues with similarities to human MAIT cells

Unique and Common Features of Innate-Like Human Vδ2+ γδT Cells and Mucosal-Associated Invariant T Cells

Mucosal-associated invariant T (MAIT) cells are innate-like T cells abundant in humans that can be activated in a TCR-independent manner by inflammatory and antiviral cytokines. In humans, the capacity for TCR-independent activation is functionally linked to a transcriptional program that can be identified by the expression of the C-type lectin receptor, CD161. In addition to MAIT cells, it has been demonstrated that a subset of γδT cells expresses CD161 and can be activated by TCR-independent cytokine stimulation. In this study, we sought to clarify the nature of cytokine-responsive human γδT cells. We could link CD161 expression on Vδ2+ versus Vδ1+ γδT cells to the observation that Vδ2+ γδT cells, but not Vδ1+ γδT cells, robustly produced IFN-γ upon stimulation with a variety of cytokine combinations. Interestingly, both CD161+ and CD161− Vδ2+ γδT cells responded to these stimuli, with increased functionality within the CD161+ subset. This innate-like responsiveness corresponded to high expression of PLZF and IL-18Rα, analogous to MAIT cells. Vδ2+ γδT cells in human duodenum and liver maintained a CD161+ IL-18Rα+ phenotype and produced IFN-γ in response to IL-12 and IL-18 stimulation. In contrast to MAIT cells, we could not detect IL-17A production but observed higher steady-state expression of Granzyme B by Vδ2+ γδT cells. Finally, we investigated the frequency and functionality of γδT cells in the context of chronic hepatitis C virus infection, as MAIT cells are reduced in frequency in this disease. By contrast, Vδ2+ γδT cells were maintained in frequency and displayed unimpaired IFN-γ production in response to cytokine stimulation. In sum, human Vδ2+ γδT cells are a functionally distinct population of cytokine-responsive innate-like T cells that is abundant in blood and tissues with similarities to human MAIT cells

Leafhopper diversity in home gardens – results of a survey in four countries across Europe (Hemiptera, Auchenorrhyncha)

Despite urbanisation being one of the main drivers of habitat destruction and biodiversity loss, home gardens can provide habitat for a wide range of species. Here we report the results of a leafhopper survey in 12 gardens in four European countries (Germany, Serbia, Austria and Bulgaria). Sampling was conducted in a semi-standardised way across the summer 2020. In total, 143 Auchenorrhyncha species with 2,361 adult specimens were recorded, including several red-listed species. The number of species per garden varied between 9 and 58. On average, around 26 species were found. Leafhopper diversity was positively influenced by garden area, age, plant diversity, extensive management and the cover of forests and parks in the surroundings, but also by the number of sampling dates. We conclude that extensively managed home gardens across Europe can support diverse communities of leafhoppers which is crucial in times of severe insect declines.Despite urbanisation being one of the main drivers of habitat destruction and&nbsp;biodiversity loss, home gardens can provide habitat for a wide range of species. Here we&nbsp;report the results of a leafhopper survey in 12 gardens in four European countries (Germany,&nbsp;Serbia, Austria and Bulgaria). Sampling was conducted in a semi-standardised way across the summer 2020. In total, 143 Auchenorrhyncha species with 2,361 adult specimens were&nbsp;recorded, including several red-listed species. The number of species per garden varied between&nbsp;9 and 58. On average, around 26 species were found. Leafhopper diversity was positively influenced by garden area, age, plant diversity, extensive management and the cover&nbsp;of forests and parks in the surroundings, but also by the number of sampling dates. We conclude&nbsp;that extensively managed home gardens across Europe can support diverse communities&nbsp;of leafhoppers which is crucial in times of severe insect declines