Guidelines for Diagnosis and Management of Infective Endocarditis in Adults: A WikiGuidelines Group Consensus Statement.

Importance: Practice guidelines often provide recommendations in which the strength of the recommendation is dissociated from the quality of the evidence. Objective: To create a clinical guideline for the diagnosis and management of adult bacterial infective endocarditis (IE) that addresses the gap between the evidence and recommendation strength. Evidence Review: This consensus statement and systematic review applied an approach previously established by the WikiGuidelines Group to construct collaborative clinical guidelines. In April 2022 a call to new and existing members was released electronically (social media and email) for the next WikiGuidelines topic, and subsequently, topics and questions related to the diagnosis and management of adult bacterial IE were crowdsourced and prioritized by vote. For each topic, PubMed literature searches were conducted including all years and languages. Evidence was reported according to the WikiGuidelines charter: clear recommendations were established only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were crafted discussing the risks and benefits of different approaches. Findings: A total of 51 members from 10 countries reviewed 587 articles and submitted information relevant to 4 sections: establishing the diagnosis of IE (9 questions); multidisciplinary IE teams (1 question); prophylaxis (2 questions); and treatment (5 questions). Of 17 unique questions, a clear recommendation could only be provided for 1 question: 3 randomized clinical trials have established that oral transitional therapy is at least as effective as intravenous (IV)-only therapy for the treatment of IE. Clinical reviews were generated for the remaining questions. Conclusions and Relevance: In this consensus statement that applied the WikiGuideline method for clinical guideline development, oral transitional therapy was at least as effective as IV-only therapy for the treatment of IE. Several randomized clinical trials are underway to inform other areas of practice, and further research is needed.

Use of Baricitinib in Combination With Remdesivir and Steroid in COVID-19 Treatment: A Multicenter Retrospective Study.

Introduction Hospitalized patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can develop severe complications. Baricitinib, a Janus kinase (JAK) JAK1/JAK2 inhibitor used to treat rheumatoid arthritis, has been proposed to prevent intracellular uptake of SARS-CoV-2 by targeting the angiotensin-converting enzyme 2 (ACE2) receptor, suppressing cytokine storm. We evaluated the effects of baricitinib on coronavirus disease 2019 (COVID-19) patient survival. Methods We conducted a retrospective study of 100 COVID-19 patients hospitalized in Southern California, United States, throughout September 2021. Univariate analysis of study variables was conducted with bivariate analysis of their relationships using chi-square and t-test with p-value <0.05 considered significant. Kaplan-Meier survival analysis was performed to compare outcomes of COVID-19 patients treated with baricitinib and those that were not. Results Our study included a patient population with a mean age of 62 years. Twenty-four percent of our patients were admitted to the intensive care unit (ICU), 16% were placed on mechanical ventilation, and 27% were expired. Patients receiving baricitinib were more likely to be admitted to the ICU and receive concomitant remdesivir therapy. Use of baricitinib increased median survival (p = 0.045). Conclusion Baricitinib administered with remdesivir and dexamethasone was shown to increase the survival of hospitalized patients with COVID-19. More studies are required to evaluate the benefits of conjunctive therapy with baricitinib, remdesivir, and dexamethasone. Though our study shows increased survival in patients receiving therapy, our study is limited by small sample size and there was not enough data to confirm whether baricitinib therapy decreased disease progression. Further studies are required.

Functional adult myocardium in the absence of Na+-Ca2+ exchange: cardiac-specific knockout of NCX1.

The excitation-contraction coupling cycle in cardiac muscle is initiated by an influx of Ca2+ through voltage-dependent Ca2+ channels. Ca2+ influx induces a release of Ca2+ from the sarcoplasmic reticulum and myocyte contraction. To maintain Ca2+ homeostasis, Ca2+ entry is balanced by efflux mediated by the sarcolemmal Na+-Ca2+ exchanger. In the absence of Na+-Ca2+ exchange, it would be expected that cardiac myocytes would overload with Ca2+. Using Cre/loxP technology, we generated mice with a cardiac-specific knockout of the Na+-Ca2+ exchanger, NCX1. The exchanger is completely ablated in 80% to 90% of the cardiomyocytes as determined by immunoblot, immunofluorescence, and exchange function. Surprisingly, the NCX1 knockout mice live to adulthood with only modestly reduced cardiac function as assessed by echocardiography. At 7.5 weeks of age, measures of contractility are decreased by 20% to 30%. We detect no adaptation of the myocardium to the absence of the Na+-Ca2+ exchanger as measured by both immunoblots and microarray analysis. Ca2+ transients of isolated myocytes from knockout mice display normal magnitudes and relaxation kinetics and normal responses to isoproterenol. Under voltage clamp conditions, the current through L-type Ca2+ channels is reduced by 50%, although the number of channels is unchanged. An abbreviated action potential may further reduce Ca2+ influx. Rather than upregulate other Ca2+ efflux mechanisms, the myocardium appears to functionally adapt to the absence of the Na+-Ca2+ exchanger by limiting Ca2+ influx. The magnitude of Ca2+ transients appears to be maintained by an increased gain of sarcoplasmic reticular Ca2+ release. The myocardium of the NCX1 knockout mice undergoes a remarkable adaptation to maintain near normal cardiac function.