Popular Musician Occupational Stress and Psychological Ill Health: An Exploratory Factor Analysis.

OBJECTIVE: Popular musicians are exposed to many occupational stressors, including unpredictable work schedules, touring and economic precarity, that have been associated in prior studies with psychological ill health. This study sought to identify occupational stressors most strongly associated with depression, anxiety, and alcohol misuse in popular musicians. METHODS: An online survey was completed by 317 popular musicians that included the Musician Occupational Stress Scale (MOSS), a validated measure of occupational stress in popular musicians. An exploratory principle-factor analysis (EFA) investigated the dimensions of response pat¬terns in the items comprising the MOSS. RESULTS: Four factors were identified that predicted 50% of musician occupational stress: Work Insecurity Stress, Tour Stress, Performance Stress, and Professional Relationship Stress. In addition to financial distress, each factor was significantly associated with depression and anxiety and Tour Stress also was associated with alcohol misuse. After adjusting for all other factors and financial distress, only Work Insecurity Stress remained associated with depression (odds ratio [OR]= 5.42; 95% confidence interval [CI] = 3.23-9.09) and anxiety (OR=5.95; 95% CI = 3.51-10.11). Tour Stress became inversely associated with depression (OR= 0.59; 95% CI = 0.40-0.89) and anxiety (OR=0.60; 95% CI = 0.40-0.89). After adjustment, alcohol misuse was associated with Professional Relationship Stress (OR=1.66; 95% CI = 1.04-2.65) but inversely correlated with Performance Stress (OR=0.60; 95% CI = 0.40-0.91). CONCLUSIONS: The four-factor model was shown to reliably simplify driving associations of occupational stressors that negatively impact psychological functioning in popular musicians. Dissemination of these findings could have practical implications in developing effective outreach messaging to promote psychological resilience and guide psychotherapeutic intervention strategies for this high-risk occupational group.

Intracellular complement and immunometabolism: The advantages of compartmentalization.

The complement system is a proteolytic cascade triggered by pathogen and danger-associated molecular patterns, with resultant outcomes of inflammation, cellular activation, and opsonization of material for removal by phagocytosis. While first discovered as an activity in serum, it is now recognized that complement components play important roles at local and individual cell-intrinsic levels. In particular, apart from the extracellular serum activities of complement, it is now believed that complement also acts intracellularly, as part of a cellular signal transduction cascade that can stimulate cellular survival and activation, and individual immune cell phenotypes, via effects on cellular metabolism. This review will describe what is currently known about how complement functions in intracellular signal transduction, and outline the functional advantages of a compartmentalized and intracellular complement system.

Vietnamese Americans' level of trust in sources of information and willingness to participate in COVID-19 clinical trials.

The survey investigates COVID-19 information source trust levels and Vietnamese Americans' willingness to participate in clinical trials. An analysis of 212 completed surveys revealed that trust in coronavirus disease 2019 (COVID-19) clinical trial information from university hospitals and drug companies was associated with willingness to participate in clinical trials. Trust in COVID-19 information from federal governments and state governments was also associated with willingness to participate in clinical trials. However, trust in local health facilities was linked to trial participation reluctance. The results suggest that Vietnamese Americans' participation in clinical trials can be increased by identifying and using trusted sources of information.

Addressing Housing Issues Among People With Kidney Disease: Importance, Challenges, and Recommendations.

Kidney disease disproportionately impacts people with low socioeconomic status, and low socioeconomic status is associated with worse outcomes for people with kidney disease. Unstable housing, which includes housing insecurity and homelessness, is increasing due to rising housing costs. There is mounting evidence that unstable housing and other health-related social needs are partially driving worse outcomes for people with low socioeconomic status. In this perspective, we consider the challenges to addressing housing for people with kidney disease, such as difficulty with identification of those with unstable housing, strict eligibility criteria for housing support, inadequate supply of affordable housing, and flaws in communities' prioritization of affordable housing. We discuss ways to tailor management for people experiencing unstable housing with kidney disease, and the importance of addressing safety, trauma, and emotional concerns as a part of care. We identify opportunities for the nephrology community to surmount challenges through increased screening, investment in workforce dedicated to community resource navigation, advocacy for investment in affordable housing, restructuring of communities' prioritization of affordable housing, and conducting needed research. Identifying and addressing housing needs among people with kidney disease is critical to eliminating kidney health disparities.

Intracellular C3 protects ß-cells from IL-1ß-driven cytotoxicity via interaction with Fyn-related kinase.

One of the hallmarks of type 1 but also type 2 diabetes is pancreatic islet inflammation, associated with altered pancreatic islet function and structure, if unresolved. IL-1ß is a proinflammatory cytokine which detrimentally affects ß-cell function. In the course of diabetes, complement components, including the central complement protein C3, are deregulated. Previously, we reported high C3 expression in human pancreatic islets, with upregulation after IL-1ß treatment. In the current investigation, using primary human and rodent material and CRISPR/Cas9 gene-edited ß-cells deficient in C3, or producing only cytosolic C3 from a noncanonical in-frame start codon, we report a protective effect of C3 against IL-1ß-induced ß-cell death, that is attributed to the cytosolic fraction of C3. Further investigation revealed that intracellular C3 alleviates IL-1ß-induced ß-cell death, by interaction with and inhibition of Fyn-related kinase (FRK), which is involved in the response of ß-cells to cytokines. Furthermore, these data were supported by increased ß-cell death in vivo in a ß-cell-specific C3 knockout mouse. Our data indicate that a functional, cytoprotective association exists between FRK and cytosolic C3.

Quantum Communications Feasibility Tests over a UK-Ireland 224 km Undersea Link.

The future quantum internet will leverage existing communication infrastructures, including deployed optical fibre networks, to enable novel applications that outperform current information technology. In this scenario, we perform a feasibility study of quantum communications over an industrial 224 km submarine optical fibre link deployed between Southport in the United Kingdom (UK) and Portrane in the Republic of Ireland (IE). With a characterisation of phase drift, polarisation stability and the arrival time of entangled photons, we demonstrate the suitability of the link to enable international UK-IE quantum communications for the first time.

The Effects of COVID-19 Lockdown on Social Connectedness and Psychological Distress in U.S. Adults with Chronic Diseases.

Lockdown measures enacted in 2020 to control the spread of COVID-19 led to increases in the prevalence of mental health problems. Due to their high-risk status, individuals with chronic diseases may be at increased risk and disproportionately adversely affected by the COVID-19 pandemic. The investigators examined associations between having a high-risk chronic condition, social connectedness, and general distress and COVID-19-specific distress among U.S. adults during the COVID-19 lockdown. Baseline measures of a longitudinal survey collected at the beginning of the pandemic (April to June 2020) were analyzed to identify factors associated with loss of social connectedness from pre- to post-lockdown. The associations between social connectedness and both general and COVID-19-specific psychological distress were adjusted for certain high-risk chronic illnesses and interaction effects. The sample available for analysis included 1354 subjects (262 high-risk chronic diseases and 1092 without chronic illness). Those reporting the loss of social connectedness were younger (median = 39 vs. 42) and more likely to be unemployed because of the pandemic (19.4% vs. 11.0%). Adjustment for interaction demonstrated a stronger negative association between social connectedness change and the psychosocial impact of COVID-19 for those with high-risk illness(es) (change in connectedness*chronic illness OR = 0.88, 95%CI: 0.79-0.98, p = 0.020). These findings inform our understanding of the distribution and intersection of responses to public health lockdown orders in the U.S. and build further evidence of the importance of social connectedness on psychological distress.

Emissions and energy impacts of the Inflation Reduction Act.

Economy-wide emissions drop 43 to 48% below 2005 levels by 2035 with accelerated clean energy deployment.

C4b-binding protein inhibits particulate- and crystalline-induced NLRP3 inflammasome activation.

Dysregulated NLRP3 inflammasome activation drives a wide variety of diseases, while endogenous inhibition of this pathway is poorly characterised. The serum protein C4b-binding protein (C4BP) is a well-established inhibitor of complement with emerging functions as an endogenously expressed inhibitor of the NLRP3 inflammasome signalling pathway. Here, we identified that C4BP purified from human plasma is an inhibitor of crystalline- (monosodium urate, MSU) and particulate-induced (silica) NLRP3 inflammasome activation. Using a C4BP mutant panel, we identified that C4BP bound these particles via specific protein domains located on the C4BP α-chain. Plasma-purified C4BP was internalised into MSU- or silica-stimulated human primary macrophages, and inhibited MSU- or silica-induced inflammasome complex assembly and IL-1ß cytokine secretion. While internalised C4BP in MSU or silica-stimulated human macrophages was in close proximity to the inflammasome adaptor protein ASC, C4BP had no direct effect on ASC polymerisation in in vitro assays. C4BP was also protective against MSU- and silica-induced lysosomal membrane damage. We further provide evidence for an anti-inflammatory function for C4BP in vivo, as C4bp-/- mice showed an elevated pro-inflammatory state following intraperitoneal delivery of MSU. Therefore, internalised C4BP is an inhibitor of crystal- or particle-induced inflammasome responses in human primary macrophages, while murine C4BP protects against an enhanced inflammatory state in vivo. Our data suggests C4BP has important functions in retaining tissue homeostasis in both human and mice as an endogenous serum inhibitor of particulate-stimulated inflammasome activation.

Conversion between B-type natriuretic peptide and N-terminal pro B-type natriuretic peptide in perioperative risk assessment: protocol for a prospective cohort study.

INTRODUCTION: Both B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP) are used to identify patients at risk of perioperative vascular events, but prognostic thresholds have been established in a large prospective cohort for NT-pro-BNP only. We designed this study to inform perioperative risk interpretation of BNP values. Our primary objective is to validate a formula to convert BNP to NT-pro-BNP concentrations before non-cardiac surgery. The secondary objective is to determine the association between BNP categories (established based on conversion from NT-pro-BNP categories) and a composite outcome of myocardial injury after non-cardiac surgery (MINS) and vascular death. METHODS AND ANALYSIS: This is a single-centre, prospective cohort study in patients undergoing non-cardiac surgery who are >65 years old, Revised Cardiac Risk Index ≥1 or >45 years old with significant cardiovascular disease. BNP and NT-pro-BNP will be measured preoperatively, and troponin measurements will be analysed on postoperative days 1, 2 and 3. MINS and vascular death will be ascertained up to 30 days after surgery. The primary analyses will compare measured NT-pro-BNP values to those predicted by an existing formula (from a non-surgical population) based on BNP concentrations and patient characteristics, and recalibrate and update the formula with additional variables. Secondary analyses will estimate the relationship between categories of measured BNP (corresponding to established NT-pro-BNP thresholds) and the composite of MINS and vascular death. The target sample size of 431 patients is based on our primary analysis (assessing the conversion formula). ETHICS AND DISSEMINATION: Ethics approval has been obtained by the Queen's University Health Sciences Research Ethics Board, and all participants will provide informed consent for participation in the study. The results will be submitted for publication in conferences and in a peer-reviewed journal, and will inform perioperative vascular risk interpretation of preoperative BNP. TRIAL REGISTRATION NUMBER: NCT05352698.

Examining Black and Hispanic physicians and other healthcare providers' attitudes toward the COVID-19 vaccine.

OBJECTIVES: Recognizing that the voice delivering the message is as important as the information being shared, we examined vaccine perceptions and willingness to encourage patients to obtain COVID-19 vaccinations among Black and Hispanic healthcare providers. METHODS: We conducted a cross-sectional, online survey of Black and Hispanic healthcare providers who were members of the National Medical Association (NMA), National Hispanic Medical Association (NHMA), and National Pharmaceutical Association (NPhA) between January 11 - March 3, 2021, shortly after emergency use authorization (EUA) for the Pfizer and Moderna COVID-19 vaccines. Three multivariable logistic regression models were used to determine factors associated with the willingness to encourage COVID-19 vaccination. RESULTS: The analytic sample consisted of 542 fully completed surveys. Pharmacists reported intent to take the vaccine (75.0% "as soon as you can" vs 91.4% for MD/DOs; p<0.001) and encouraged patients to get vaccinated (78.6% vs 91.0% for MD/DOs; p = 0.01). Providers in a suburban practice location were less likely to recommend vaccines to patients (OR=0.43, 95%CI: 0.22-0.87) and personal family (OR=0.45, 95%CI: 0.22-0.92) compared to those practicing in urban areas. Providers over age 45 were also more likely to report intent to take the vaccine themselves as soon as it was available (OR=3.72, 95%CI: 1.30-10.64). CONCLUSIONS: This is likely the first cross-sectional study in the United States demonstrating the substantial vaccine confidence among Black and Hispanic healthcare providers who serve minoritized communities that have borne the greatest risk of adverse COVID-related outcomes.

The complement receptor C3AR constitutes a novel therapeutic target in NPM1-mutated AML.

Mutated nucleophosmin 1 (NPM1) is the most common genetic alteration in acute myeloid leukemia (AML), found in ∼30% of cases. Although mutations in this gene are considered favorable according to current risk stratification guidelines, a large fraction of patients will experience relapse, demonstrating the urgent need for new treatment options. Therefore, we aimed to identify cell surface proteins specifically expressed on NPM1-mutated AML cells, allowing for potential targeting with antibody-based therapies. Herein, we report on an arrayed flow cytometry-based screen directed to 362 cell surface markers. In comparing the cell surface expression on NPM1-mutated AML cells with primitive (CD34+ CD38-) normal bone marrow cells, we identified the complement receptor C3AR as being specifically expressed in NPM1-mutated AML. By flow cytometry and single-cell RNA sequencing, we further show that normal hematopoietic stem and progenitor cells lack detectable C3AR gene and protein expression, making it particularly suitable as a target for antibody therapy. We also demonstrate that C3AR in combination with GPR56 distinguishes the leukemic stem cells (LSCs) in NPM1-mutated AML from the normal hematopoietic stem cells, defining the LSC population, as shown by transplantation into immunodeficient mice. Mechanistically, the stimulation of C3AR-expressing cells with C3a, the ligand of C3AR, leads to the activation of ERK1/2 and increased survival of AML cells, suggesting that this is an important signaling axis in this subtype of AML. Finally, we show that antibodies directed against C3AR efficiently elicit natural killer cell-mediated killing of primary AML cells ex vivo, highlighting C3AR as a candidate therapeutic target in NPM1-mutated AML.

Intracellular complement: Evidence, definitions, controversies, and solutions.

The term "intracellular complement" has been introduced recently as an umbrella term to distinguish functions of complement proteins that take place intracellularly, rather than in the extracellular environment. However, this rather undefined term leaves some confusion as to the classification of what intracellular complement really is, and as to which intracellular compartment(s) it should refer to. In this review, we will describe the evidence for both canonical and non-canonical functions of intracellular complement proteins, as well as the current controversies and unanswered questions as to the nature of the intracellular complement. We also suggest new terms to facilitate the accurate description and discussion of specific forms of intracellular complement and call for future experiments that will be required to provide more definitive evidence and a better understanding of the mechanisms of intracellular complement activity.

Alternative splicing encodes functional intracellular CD59 isoforms that mediate insulin secretion and are down-regulated in diabetic islets.

Human pancreatic islets highly express CD59, which is a glycosylphosphatidylinositol (GPI)-anchored cell-surface protein and is required for insulin secretion. How cell-surface CD59 could interact with intracellular exocytotic machinery has so far not been described. We now demonstrate the existence of CD59 splice variants in human pancreatic islets, which have unique C-terminal domains replacing the GPI-anchoring signal sequence. These isoforms are found in the cytosol of ß-cells, interact with SNARE proteins VAMP2 and SNAP25, colocalize with insulin granules, and rescue insulin secretion in CD59-knockout (KO) cells. We therefore named these isoforms IRIS-1 and IRIS-2 (Isoforms Rescuing Insulin Secretion 1 and 2). Antibodies raised against each isoform revealed that expression of both IRIS-1 and IRIS-2 is significantly lower in islets isolated from human type 2 diabetes (T2D) patients, as compared to healthy controls. Further, glucotoxicity induced in primary, healthy human islets led to a significant decrease of IRIS-1 expression, suggesting that hyperglycemia (raised glucose levels) and subsequent decreased IRIS-1 expression may contribute to relative insulin deficiency in T2D patients. Similar isoforms were also identified in the mouse CD59B gene, and targeted CRISPR/Cas9-mediated knockout showed that these intracellular isoforms, but not canonical CD59B, are involved in insulin secretion from mouse ß-cells. Mouse IRIS-2 is also down-regulated in diabetic db/db mouse islets. These findings establish the endogenous existence of previously undescribed non­GPI-anchored intracellular isoforms of human CD59 and mouse CD59B, which are required for normal insulin secretion.

Alternative translation and retrotranslocation of cytosolic C3 that detects cytoinvasive bacteria.

Complement C3 was originally regarded as a serum effector protein, although recent data has emerged suggesting that intracellular C3 can also regulate basic cellular processes. Despite the growing interest in intracellular C3 functions, the mechanism behind its generation has not been demonstrated. In this study we show that C3 can be expressed from an alternative translational start site, resulting in C3 lacking the signal peptide, which is therefore translated in the cytosol. In contrast to the secreted form, alternatively translated cytosolic C3 is not glycosylated, is present mainly in a reduced state, and is turned over by the ubiquitin-proteasome system. C3 can also be retrotranslocated from the endoplasmic reticulum into the cytosol, structurally resembling secreted C3. Finally, we demonstrate that intracellular cytosolic C3 can opsonize invasive Staphylococcus aureus within epithelial cell, slowing vacuolar escape as well as impacting bacterial survival on subsequent exposure to phagocytes. Our work therefore reveals the existence and origin of intracellular, cytosolic C3, and demonstrates functions for cytosolic C3 in intracellular detection of cytoinvasive pathogens.

The American Public Health Association Endorses Single-Payer Health System Reform.

Health care is a human right. Achieving universal health insurance coverage for all US residents requires significant system-wide reform. The most equitable and cost-effective health care system is a public, single-payer (SP) system. The rapid growth in national health expenditures can be addressed through a system that yields net savings over projected trends by eliminating profit and waste. With universal health insurance coverage through SP financing, providers can focus on optimizing delivery of services, rather than working within a system covered by payers who have incentives to limit costs regardless of benefit. Rather, with a SP, the people act as their own insurer through a partnership with provider organizations where tax dollars work for everyone. Consumer choice is then based on the best care to meet need with no out-of-pocket payments. SP financing is the best option to ensure equity, fairness, and public health priorities align with medical needs, providing incentives for wellness. Consumer choice will drive market forces, not provider network profits or insurer restrictions. This approach benefits public health, as everyone will have universal access to needed care, with treatment plans developed by providers based on what works best for the patient. In 2021, the American Public Health Association adopted a policy statement calling for comprehensive reforms to implement a SP system. The proposed action steps in this policy will help build a healthier nation, saving lives and reducing wasted health care expenditures while addressing inequities rooted in social, demographic, mental health, economic, and political determinants.

Leveraging Public-Private Partnerships During COVID-19: Providing Virtual Field Opportunities for Student Learners and Addressing Social Isolation in Older Adults.

While preventive and management measures are important to mitigate the spread of COVID-19, strategies like social distancing can have devastating effects on older adults who are already at risk for social isolation and loneliness. In response, two Colleges of Health Professions (Social Work and Nursing) at a large public University leveraged a partnership with a national health and wellbeing company to address social isolation and loneliness in Houston area older adults during the COVID-19 pandemic. This intergenerational linkage initiative involved 707 older adults and 177 graduate social work and nursing students. This study describes the process of developing a virtual educational opportunity for students while also meeting the needs of vulnerable older adults in Houston, the third largest, and one of the most diverse cities in the U.S. Findings include student/learner outcomes, as well as self-reported improvements in loneliness scores, and unhealthy physical and mental health days among enrolled older adults.

Predictors of COVID-19 perceived susceptibility: insights from population-based self-reported survey during lockdown in the United States.

BACKGROUND: The COVID-19 pandemic during lockdown has highlighted the importance of identifying individuals most at risk of infection with SARS-CoV-2, underscoring the need to assess factors contributing to susceptibility to disease. With the rapidly evolving nature of the pandemic and its new variants, there is an inadequate understanding on whether there are certain factors such as a specific symptom or collection of symptoms that combined with life-style behaviors may be useful to predict susceptibility. The study aims to explore such factors from pre-vaccination data to guide public health response to potential new waves. METHODS: An anonymous electronic survey was distributed through social media during the lockdown period in the United States from April to June 2020. Respondents were questioned regarding COVID testing, presenting symptoms, demographic information, comorbidities, and confirmation of COVID-19 test results. Stepwise logistic regression was used to identify predictors for COVID-19 perceived susceptibility. Selected classifiers were assessed for prediction performance using area under receiver operating characteristic (AUROC) curve analysis. RESULTS: A total of 130 participants deemed as susceptible because they self-reported their perception of having COVID-19 (but without the evidence of positive test) were compared with 130 individuals with documented negative test results. Participants had a mean age of 45 years, and 165 (63%) were female. Final multivariable model showed significant associations with perceived susceptibility for the following variables: fever (OR:33.5; 95%CI: 3.9,85.9), body ache (OR:3.0; 95%CI:1.1,6.4), contact history (OR:2.7; 95%CI:1.1,6.4), age> 50 (OR:2.7; 95%CI:1.1, 6.6) and smoking (OR:3.3; 95%CI: 1.2,9.1) after adjusting for other symptoms and presence of comorbid conditions. The AUROC ranged from poor to fair (0.65-0.76) for cluster of symptoms but improved to a good model (AUROC = 0.803) after inclusion of sociodemographic and lifestyle behaviors e.g., age and smoking tobacco. CONCLUSIONS: Fever and body aches suggest association with perceived COVID-19 susceptibility in the presence of demographic and lifestyle behaviors. Using other constitutional and respiratory symptoms with fever and body aches, the parsimonious classifier correctly predicts 80.3% of COVID-19 perceived susceptibility. A larger cohort of respondents will be needed to study and refine classifier performance in future lockdowns and with expected surge of new variants of COVID-19 pandemic.