Ferredoxin reduction by hydrogen with iron functions as an evolutionary precursor of flavin-based electron bifurcation.

Autotrophic theories for the origin of metabolism posit that the first cells satisfied their carbon needs from CO and were chemolithoautotrophs that obtained their energy and electrons from H. The acetyl-CoA pathway of CO fixation is central to that view because of its antiquity: Among known CO fixing pathways it is the only one that is i) exergonic, ii) occurs in both bacteria and archaea, and iii) can be functionally replaced in full by single transition metal catalysts in vitro. In order to operate in cells at a pH close to 7, however, the acetyl-CoA pathway requires complex multi-enzyme systems capable of flavin-based electron bifurcation that reduce low potential ferredoxin-the physiological donor of electrons in the acetyl-CoA pathway-with electrons from H.

Oral β-Lactams, Fluoroquinolones, or Trimethoprim-Sulfamethoxazole for Definitive Treatment of Uncomplicated or Species Bacteremia From a Urinary Tract Source.

Background: Fluoroquinolones (FQs) are effective for oral step-down therapy for gram-negative bloodstream infections but are associated with unfavorable toxic effects. Robust data are lacking for trimethoprim-sulfamethoxazole (TMP-SMX) and high-bioavailability β-lactams (HBBLs).

Methods: In this multicenter observational cohort study, we simulated a 3-arm registry trial using causal inference methods to compare the effectiveness of FQs, TMP-SMX, or HBBLs for gram-negative bloodstream infections oral step-down therapy.

Excellence in Antibiotic Stewardship: A Mixed-Methods Study Comparing High-, Medium-, and Low-Performing Hospitals.

Background: Despite antibiotic stewardship programs existing in most acute care hospitals, there continues to be variation in appropriate antibiotic use. While existing research examines individual prescriber behavior, contextual reasons for variation are poorly understood.

Methods: We conducted an explanatory, sequential mixed-methods study of a purposeful sample of 7 hospitals with varying discharge antibiotic overuse.

Antibiotic prescribing for adults with group A streptococcal bacteremia in a large healthcare system.

Purpose: Limited data exist regarding treatment of invasive group A streptococcal (GAS) infections, including safety and efficacy of oral (PO) step-down therapy. We sought to describe current prescribing practices and clinical outcomes for patients with GAS bacteremia across a large health system, including a prespecified subset of patients who stepped down to PO antibiotics.

Methods: This retrospective cohort study included adult patients with a positive blood culture for GAS between July 2018 and July 2021.

Impact of a Multifaceted Intervention on Antibiotic Prescribing for Cystitis and Asymptomatic Bacteriuria in 23 Community Hospital Emergency Departments.

Urinary tract infections (UTIs) are over-diagnosed and over-treated in the emergency department (ED) leading to unnecessary antibiotic exposure and avoidable side effects. However, data describing effective large-scale antimicrobial stewardship program (ASP) interventions to improve UTI and asymptomatic bacteriuria (ASB) management in the ED are lacking. We implemented a multifaceted intervention across 23 community hospital EDs in Utah and Idaho consisting of in-person education for ED prescribers, updated electronic order sets, and implementation/dissemination of UTI guidelines for our healthcare system.

Implementation of an Antibiotic Stewardship Initiative in a Large Urgent Care Network.

Importance: Urgent Care (UC) encounters result in more inappropriate antibiotic prescriptions than other outpatient setting. Few stewardship interventions have focused on UC.

Objective: To evaluate the effectiveness of an antibiotic stewardship initiative to reduce antibiotic prescribing for respiratory conditions in a UC network.

Care of the Seriously Ill Patient with SARS-CoV-2.

In late 2019, SARS-CoV-2 caused the greatest global health crisis in a century, impacting all aspects of society. As the COVID-19 pandemic evolved throughout 2020 and 2021, multiple variants emerged, contributing to multiple surges in cases of COVID-19 worldwide. In 2021, highly effective vaccines became available, although the pandemic continues into 2022.

Purification and structural characterization of the Na-translocating ferredoxin: NAD reductase (Rnf) complex of Clostridium tetanomorphum.

Various microbial metabolisms use H/Na-translocating ferredoxin:NAD reductase (Rnf) either to exergonically oxidize reduced ferredoxin by NAD for generating a transmembrane electrochemical potential or reversely to exploit the latter for producing reduced ferredoxin. For cryo-EM structural analysis, we elaborated a quick four-step purification protocol for the Rnf complex from Clostridium tetanomorphum and integrated the homogeneous and active enzyme into a nanodisc. The obtained 4.

Hydroxychloroquine/chloroquine for the treatment of hospitalized patients with COVID-19: An individual participant data meta-analysis.

Background: Results from observational studies and randomized clinical trials (RCTs) have led to the consensus that hydroxychloroquine (HCQ) and chloroquine (CQ) are not effective for COVID-19 prevention or treatment. Pooling individual participant data, including unanalyzed data from trials terminated early, enables more detailed investigation of the efficacy and safety of HCQ/CQ among subgroups of hospitalized patients.

Methods: We searched ClinicalTrials.

Harnessing the Power of Health Systems and Networks for Antimicrobial Stewardship.

Twenty of 21 health systems and network-based antimicrobial stewardship programs (ASPs) who were invited participated in a questionnaire, a webinar, and focus groups to understand implementation strategies for system-wide antimicrobial stewardship. Four centralized ASPs structures emerged. Of participating organizations, 3 (15%) confirmed classification as collaborative, 3 (15%) as centrally coordinated, 3 (15%) as in between or in transition between centrally coordinated and centrally led, 8 (40%) as centrally led, 2 (10%) as collaborative, consultative network.

Hydroxychloroquine/chloroquine for the treatment of hospitalized patients with COVID-19: An individual participant data meta-analysis.

Background: Results from observational studies and randomized clinical trials (RCTs) have led to the consensus that hydroxychloroquine (HCQ) and chloroquine (CQ) are not effective for COVID-19 prevention or treatment. Pooling individual participant data, including unanalyzed data from trials terminated early, enables more detailed investigation of the efficacy and safety of HCQ/CQ among subgroups of hospitalized patients.

Methods: We searched ClinicalTrials.

Energy Conservation in Fermentations of Anaerobic Bacteria.

Anaerobic bacteria ferment carbohydrates and amino acids to obtain energy for growth. Due to the absence of oxygen and other inorganic electron acceptors, the substrate of a fermentation has to serve as electron donor as well as acceptor, which results in low free energies as compared to that of aerobic oxidations. Until about 10 years ago, anaerobes were thought to exclusively use substrate level phosphorylation (SLP), by which only part of the available energy could be conserved.

Real-world Effectiveness and Tolerability of Monoclonal Antibody Therapy for Ambulatory Patients With Early COVID-19.

Background: Neutralizing monoclonal antibodies (MAbs) are a promising therapy for early coronavirus disease 2019 (COVID-19), but their effectiveness has not been confirmed in a real-world setting.

Methods: In this quasi-experimental pre-/postimplementation study, we estimated the effectiveness of MAb treatment within 7 days of symptom onset in high-risk ambulatory adults with COVID-19. The primary outcome was a composite of emergency department visits or hospitalizations within 14 days of positive test.

Flavins in the electron bifurcation process.

The discovery of a new energy-coupling mechanism termed flavin-based electron bifurcation (FBEB) in 2008 revealed a novel field of application for flavins in biology. The key component is the bifurcating flavin endowed with strongly inverted one-electron reduction potentials (FAD/FAD• ≪ FAD•/FADH) that cooperatively transfers in its reduced state one low and one high-energy electron into different directions and thereby drives an endergonic with an exergonic reduction reaction. As energy splitting at the bifurcating flavin apparently implicates one-electron chemistry, the FBEB machinery has to incorporate prior to and behind the central bifurcating flavin 2e-to-1e and 1e-to-2e switches, frequently also flavins, for oxidizing variable medium-potential two-electron donating substrates and for reducing high-potential two-electron accepting substrates.

Spectral deconvolution of redox species in the crotonyl-CoA-dependent NADH:ferredoxin oxidoreductase from Megasphaera elsdenii. A flavin-dependent bifurcating enzyme.

We have undertaken a spectral deconvolution of the three FADs of EtfAB/bcd to the spectral changes seen in the course of reduction, including the spectrally distinct anionic and neutral semiquinone states of electron-transferring and bcd flavins. We also demonstrate that, unlike similar systems, no charge-transfer complex is observed on titration of the reduced M. elsdenii EtfAB with NAD.

Developing statewide remdesivir use criteria.

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.

Rapid kinetics reveal surprising flavin chemistry in bifurcating electron transfer flavoprotein from Acidaminococcus fermentans.

Electron bifurcation uses free energy from exergonic redox reactions to power endergonic reactions. β-FAD of the electron transfer flavoprotein (EtfAB) from the anaerobic bacterium Acidaminococcus fermentans bifurcates the electrons of NADH, sending one to the low-potential ferredoxin and the other to the high-potential α-FAD semiquinone (α-FAD). The resultant α-FAD hydroquinone (α-FADH) transfers one electron further to butyryl-CoA dehydrogenase (Bcd); two such transfers enable Bcd to reduce crotonyl-CoA to butyryl-CoA.

Hydroxychloroquine vs. Azithromycin for Hospitalized Patients with COVID-19 (HAHPS): Results of a Randomized, Active Comparator Trial.

Rationale: The COVID-19 pandemic struck an immunologically naïve, globally interconnected population. In the face of a new infectious agent causing acute respiratory failure for which there were no known effective therapies, rapid, often pragmatic trials were necessary to evaluate potential treatments, frequently starting with medications that are already marketed for other indications. Early in the pandemic, hydroxychloroquine and azithromycin were two such candidates.

Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study.

Background: A subset of patients with COVID-19 develops a hyperinflammatory syndrome that has similarities with other hyperinflammatory disorders. However, clinical criteria specifically to define COVID-19-associated hyperinflammatory syndrome (cHIS) have not been established. We aimed to develop and validate diagnostic criteria for cHIS in a cohort of inpatients with COVID-19.

Hydroxychloroquine versus Azithromycin for Hospitalized Patients with Suspected or Confirmed COVID-19 (HAHPS). Protocol for a Pragmatic, Open-Label, Active Comparator Trial.

Coronavirus disease (COVID-19) is a potentially fatal illness with no proven therapy beyond excellent supportive care. Treatments are urgently sought. Adaptations to traditional trial logistics and design to allow rapid implementation, evaluation of trials within a global trials context, flexible interim monitoring, and access outside traditional research hospitals (even in settings where formal placebos are unavailable) may be helpful.

Modulations of the reduction potentials of flavin-based electron bifurcation complexes and semiquinone stabilities are key to control directional electron flow.

The flavin-based electron bifurcation (FBEB) system from Acidaminococcus fermentans is composed of the electron transfer flavoprotein (EtfAB) and butyryl-CoA dehydrogenase (Bcd). α-FAD binds to domain II of the A-subunit of EtfAB, β-FAD to the B-subunit of EtfAB and δ-FAD to Bcd. NADH reduces β-FAD to β-FADH , which bifurcates one electron to the high potential α-FAD semiquinone followed by the other to the low potential ferredoxin (Fd).