The Role of Soluble Guanylyl Cyclase Signaling in Mitochondrial Biogenesis and Renal Injury

Soluble Guanylyl Cyclase (sGC) is responsible for converting GTP to cyclic GMP (cGMP). sGC function and regulation is complex and cell -type dependent. An increase in cGMP production can target phosphodiesterases (PDEs), cGMP gated ion channels, and protein kinase G (PKG). Increasing sGC activity and inhibiting the degradation of cGMP by targeting PDEs are two approaches to maintaining cGMP levels in a given system. Interestingly, cGMP can also regulate mitochondrial biogenesis (MB), the generation of new and functional mitochondria. Previously in our laboratory, we have shown that MB is suppressed after ischemia and reperfusion (I/R) injury and certain mitochondrial biogenic compounds can accelerate recovery and attenuate the decrease in MB. In particular, we have shown that administration of an inhibitor of PDE5, sildenafil, can restore MB and renal function after I/R. However, the role of sGC in I/R is still under investigation. Here, we have elucidated a potential signaling pathway for the involvement of sGC in the suppression of MB. We performed I/R on mice and focused on the events that occur within the first 24 h of I/R injury. We optimized an sGC enzyme assay for the kidney to better understand the redox state of sGC. We proposed that the suppression of MB is cGMP-dependent and that PKG is a mediator of these effects. Moreover, we have proposed a role for ERK1/2 in the sGC/cGMP/PKG induced suppression of MB. Alternatively, we have shown that cGMP can induce MB in renal proximal tubule cells by 24 h with exposure to a cGMP analog, 8 -Br-cGMP. However, the mechanism behind this finding is unknown. Therefore, we treated renal proximal tubule cells with a 8 -Br- cGMP, for an 1 h to elucidate the mechanism behind this event. We measured the phosphorylation of serine and threonine residues on PGC-1α, the master regulator of MB, since phosphorylation can prolong the half -life of PGC-1α and induce MB. We found that the induction of MB is PKG dependent and that p38 MAPK plays a prominent role in the phosphorylation of PGC-1α. Here, we present sufficient evidence for the role of sGC signaling in regulating MB in the kidney

Cardiac Tamponade Secondary to COVID-19

A 67-year-old female presented with upper respiratory symptoms and was diagnosed with COVID-19. She was found to have a large hemorrhagic pericardial effusion with echocardiographic signs of tamponade and mild left ventricular impairment. Clinical course was complicated by development of Takotsubo cardiomyopathy. She was treated with pericardiocentesis, colchicine, corticosteroids and hydroxychloroquine with improvement in symptoms

Comparison of bacterial maxillary sinus cultures between odontogenic sinusitis and chronic rhinosinusitis

BACKGROUND: Bacterial odontogenic sinusitis (ODS) is distinct from other forms of rhinosinusitis. Diagnosing ODS can be challenging because of nonspecific clinical presentations and underrepresentation in the literature. The purpose of this study was to compare maxillary sinus bacterial cultures between patients with ODS and chronic rhinosinusitis (CRS), to determine whether certain bacteria are associated with ODS. METHODS: This was a retrospective case-control study of 276 consecutive patients from August 2015 to August 2019 who underwent endoscopic sinus surgery (ESS) for bacterial ODS, CRS without nasal polyps (CRSsNP), or CRS with nasal polyps (CRSwNP). When present, pus was sterilely cultured from maxillary sinuses after maxillary antrostomy, and aerobic and anaerobic cultures were immediately sent for processing. Demographics and culture results were compared between ODS and CRS patients, and then separately between ODS and CRSsNP, and ODS and CRSwNP. ODS culture results were also compared between different dental pathologies (endodontic vs oroantral fistula). RESULTS: The following bacteria were significantly more likely in ODS compared to CRS: mixed anaerobes, Fusobacterium spp., Eikenella corrodens, Streptococcus intermedius, Streptococcus anginosus, and Streptococcus constellatus. Staphylococcus aureus and Pseudomonas aeruginosa were inversely related to ODS. There were no significant differences in cultures between the different dental pathologies. CONCLUSION: Certain bacteria were more likely to be associated with ODS compared to CRS when purulence was cultured from the maxillary sinus. Physicians should evaluate for an odontogenic source of sinusitis when these ODS-associated bacteria are identified in maxillary sinus cultures

Early Short Course Corticosteroids in Hospitalized Patients with COVID-19

BACKGROUND: There is no proven antiviral or immunomodulatory therapy for COVID-19. The disease progression associated with the pro-inflammatory host response prompted us to examine the role of early corticosteroid therapy in patients with moderate to severe COVID-19. METHODS: We conducted a single pre-test, single post-test quasi-experiment in a multi-center health system in Michigan from March 12 to March 27, 2020. Adult patients with confirmed moderate to severe COVID were included. A protocol was implemented on March 20, 2020 using early, short-course, methylprednisolone 0.5 to 1 mg/kg/day divided in 2 intravenous doses for 3 days. Outcomes of standard of care (SOC) and early corticosteroid groups were evaluated, with a primary composite endpoint of escalation of care from ward to ICU, new requirement for mechanical ventilation, and mortality. All patients had at least 14 days of follow-up. RESULTS: We analyzed 213 eligible subjects, 81 (38%) and 132 (62%) in SOC and early corticosteroid groups, respectively.The composite endpoint occurred at a significantly lower rate in the early corticosteroid group (34.9% vs. 54.3%, p=0.005). This treatment effect was observed within each individual component of the composite endpoint. Significant reduction in median hospital length of stay was also observed in the early corticosteroid group (8 vs. 5 days, p \u3c 0.001). Multivariate regression analysis demonstrated an independent reduction in the composite endpoint at 14-days controlling for other factors (aOR: 0.41; 95% CI [0.22 - 0.77]). CONCLUSION: An early short course of methylprednisolone in patients with moderate to severe COVID-19 reduced escalation of care and improved clinical outcomes

Characteristics and comparative clinical outcomes of prisoner versus non-prisoner populations hospitalized with COVID-19

Prisons in the United States have become a hotbed for spreading COVID-19 among incarcerated individuals. COVID-19 cases among prisoners are on the rise, with more than 143,000 confirmed cases to date. However, there is paucity of data addressing clinical outcomes and mortality in prisoners hospitalized with COVID-19. An observational study of all patients hospitalized with COVID-19 between March 10 and May 10, 2020 at two Henry Ford Health System hospitals in Michigan. Clinical outcomes were compared amongst hospitalized prisoners and non-prisoner patients. The primary outcomes were intubation rates, in-hospital mortality, and 30-day mortality. Multivariable logistic regression and Cox-regression models were used to investigate primary outcomes. Of the 706 hospitalized COVID-19 patients (mean age 66.7 ± 16.1 years, 57% males, and 44% black), 108 were prisoners and 598 were non-prisoners. Compared to non-prisoners, prisoners were more likely to present with fever, tachypnea, hypoxemia, and markedly elevated inflammatory markers. Prisoners were more commonly admitted to the intensive care unit (ICU) (26.9% vs. 18.7%), required vasopressors (24.1% vs. 9.9%), and intubated (25.0% vs. 15.2%). Prisoners had higher unadjusted inpatient mortality (29.6% vs. 20.1%) and 30-day mortality (34.3% vs. 24.6%). In the adjusted models, prisoner status was associated with higher in-hospital death (odds ratio, 2.32; 95% confidence interval (CI), 1.33 to 4.05) and 30-day mortality (hazard ratio, 2.00; 95% CI, 1.33 to 3.00). In this cohort of hospitalized COVID-19 patients, prisoner status was associated with more severe clinical presentation, higher rates of ICU admissions, vasopressors requirement, intubation, in-hospital mortality, and 30-day mortality

Multinational Comparative Cross-Sectional Survey of Views of medical students about Acceptable Terminology and Subgroups in Schizophrenia

AIM: The aim of this study was to inform thinking around the terminology for \u27schizophrenia\u27 in different countries. OBJECTIVES: The objective of this study was to investigate: (1) whether medical students view alternative terminology (psychosis subgroups), derived from vulnerability-stress models of schizophrenia, as acceptable and less stigmatising than the term schizophrenia; (2) if there are differences in attitudes to the different terminology across countries with different cultures and (3) whether clinical training has an impact in reducing stigma. DESIGN: This is a cross-sectional survey that examined the attitudes of medical students towards schizophrenia and the alternative subgroups. SETTING: The study was conducted across eight sites: (1) University of Southampton, UK; (2) All India Institute of Medical Science, India; (3) Rowan University, USA; (4) Peshawar Medical College, Pakistan; (5) Capital Medical University, China; (6) College of Medicine and Medical sciences, Bahrain; (7) Queens University, Kingston, Canada and (8) University of Cape Town, South Africa. METHOD: This study extended an initial pilot conducted by the Royal College of Psychiatrists on the term schizophrenia and psychosis subgroups to assess whether the subgroup terminology might have an effect on the attitudes of a convenience sample of medical students from eight different countries and potentially play a role in reducing stigmatisation. RESULTS: 1873 medical students completed a questionnaire recording their attitudes to schizophrenia and the psychosis subgroups. A reduction in negative perceptions were found for the psychosis subgroups, especially for the stress sensitivity psychosis and anxiety psychosis subgroups. Negative perceptions were found for drug-related psychosis. Participants who had undergone clinical training had overall positive attitudes. Differences across different countries were found. CONCLUSION: The attitudes towards psychosis subgroups used in this study have shown mixed results and variation across countries. Further research is warranted to investigate acceptability of terminology. Methods of reducing stigma are discussed in line with the findings. ETHICS: The study received ethical approval from ERGO (Ethics and Research Governance Online; ID: 15972) and subsequently from the ethics committee at each site

Project #37: Management Guidelines for Patients with COVID-19: Rapid Cycle Improvement

Project’s purpose is to rapidly devise, continually improve, educate, and implement a live and changing COVID-19 management guideline based upon emerging best available evidence. This project also aims to optimize the care of patients with COVID-19 and improve patient outcomes.https://scholarlycommons.henryford.com/qualityexpo2022/1004/thumbnail.jp

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Nations within a nation: variations in epidemiological transition across the states of India, 1990–2016 in the Global Burden of Disease Study

18% of the world's population lives in India, and many states of India have populations similar to those of large countries. Action to effectively improve population health in India requires availability of reliable and comprehensive state-level estimates of disease burden and risk factors over time. Such comprehensive estimates have not been available so far for all major diseases and risk factors. Thus, we aimed to estimate the disease burden and risk factors in every state of India as part of the Global Burden of Disease (GBD) Study 2016