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Human metapneumovirus (HMPV) is an important cause of acute respiratory tract infection and causes significant morbidity and mortality. There is no specific antiviral drug to treat HMPV or vaccine to prevent HMPV. This study determined if probenecid, a host-targeting antiviral drug, had prophylactic (pre-virus) or therapeutic (post-virus) efficacy to inhibit HMPV replication in LLC-MK2 cells in vitro and in the lungs of BALB/c mice. This study showed that ≥0.5 μM probenecid significantly inhibited HMPV replication in vitro, and 2–200 mg/kg probenecid prophylaxis or treatment reduced HMPV replication in BALB/c mice. [ABSTRACT FROM AUTHOR]

Effective vaccines are slowing the COVID-19 pandemic, but SARS-CoV-2 will likely remain an issue in the future making it important to have therapeutics to treat patients. There are few options for treating patients with COVID-19. We show probenecid potently blocks SARS-CoV-2 replication in mammalian cells and virus replication in a hamster model. Furthermore, we demonstrate that plasma concentrations up to 50-fold higher than the protein binding adjusted IC90 value are achievable for 24 h following a single oral dose. These data support the potential clinical utility of probenecid to control SARS-CoV-2 infection in humans. [ABSTRACT FROM AUTHOR]

RNA viruses like SARS-CoV-2, influenza virus, and respiratory syncytial virus (RSV) are dependent on host genes for replication. We investigated if probenecid, an FDA-approved and safe urate-lowering drug that inhibits organic anion transporters (OATs) has prophylactic or therapeutic efficacy to inhibit RSV replication in three epithelial cell lines used in RSV studies, i.e., Vero E6 cells, HEp-2 cells, and in primary normal human bronchoepithelial (NHBE) cells, and in BALB/c mice. The studies showed that nanomolar concentrations of all probenecid regimens prevent RSV strain A and B replication in vitro and RSV strain A in vivo, representing a potential prophylactic and chemotherapeutic for RSV. [ABSTRACT FROM AUTHOR]

Bevirimat is a first in class, orally active, potent and selective inhibitor of HIV-1. It may have utility for the treatment of HIV-1-infected patients who are failing current regimens because of the development of drug resistance. In earlier studies in HIV-1-infected patients, an immediaterelease tablet formulation exhibited a relative bioavailability (Frel) of 50% or greater and a higher intersubject variability than an oral solution. The purpose of this study was to determine whether this pharmacokinetic profile is attributable to a narrow permeability-dependent absorption window within the gastrointestinal tract. Three groups of subjects completed an open-label, 2-way crossover, randomized pharmacoscintigraphic study. Subjects received a 25-mg bevirimat oral immediate-release solution plus 25 mg bevirimat solution delivered to the proximal small bowel, distal small bowel, or colon via the Enterion™ capsule. The results indicate that the permeability of bevirimat throughout the small intestine was excellent and suggest that the variability observed for the immediate release tablet was not related to the presence of an absorption window in the small intestine. [ABSTRACT FROM AUTHOR]

Abstract: 3-O-(3′,3′-dimethylsuccinyl) betulinic acid, also termed PA-457 or DSB, is a novel HIV-1 inhibitor that blocks virus maturation by disrupting cleavage of the capsid precursor, CA-SP1. To better define the molecular target for PA-457, we prepared a panel of mutant viruses with point deletions spanning the CA-SP1 cleavage domain and characterized each of these viruses for PA-457 sensitivity. Our results indicate that amino acid residues in the N-terminal half of SP1 serve as determinants of PA-457 activity, while residues in the C-terminal half of SP1 were not involved in compound activity. These findings support and extend previous observations that PA-457 is a specific inhibitor of CA-SP1 cleavage and identify the CA-SP1 domain as the primary viral determinant for this novel inhibitor of HIV-1 replication. [Copyright &y& Elsevier]

We examined the effect of probenecid in regulating the ERK and JNK downstream MAPK pathways affecting respiratory syncytial virus replication., Background: We have previously shown that probenecid inhibits RSV, influenza virus, and SARS-CoV-2 replication in vitro in preclinical animal models and in humans. In a Phase two randomized, placebo-controlled, single-blind, dose range-finding study using probenecid to treat non-hospitalized patients with symptomatic, mild-to-moderate COVID-19, we previously showed that a 1000 mg twice daily treatment for 5 days reduced the median time to viral clearance from 11 to 7 days, and a 500 mg twice daily treatment for 5 days reduced the time to viral clearance from 11 to 9 days more than the placebo., Methods: In this study, we sought to determine the mechanism of action of the probenecid inhibition of RSV replication in human respiratory epithelial (A549) cells., Results: We show that probenecid inhibits the RSV-induced phosphorylation of JNKs and ERKs and the downstream phosphorylation of c-jun, a component of the AP-1 transcription complex needed for virus replication. The inhibition of JNKs by probenecid reversed the repression of transcription factor HNF-4., Conclusion: The probenecid inhibition of JNK and ERK phosphorylation involves the MAPK pathway that precludes virus replication.

Introduction: Respiratory viruses are responsible for significant worldwide morbidity and mortality. While vaccines are highly effective at reducing the morbidity and mortality associated with viral infections, this protection is incomplete. It requires a high degree of compliance, which is hindered by vaccine hesitancy. To address these gaps, antiviral agents and therapeutics are crucial in combating diseases caused by respiratory viruses. Antiviral agents are broadly classified into two groups: 1) direct-acting antivirals (DAA) and 2) host-directed antivirals (HDA)., Areas Covered: This review comprehensively examines Phase II FDA-approved antiviral drugs for influenza virus, SARS-CoV-2, and RSV as published in clinicaltrials.gov. It focuses on DAAs and various monoclonal antibodies (mAbs) that have been approved for the prevention and treatment of viral respiratory tract infections., Expert Opinion: Antiviral drugs being developed assess different mechanisms of action to combat viruses and other delivery routes (i.e. oral, inhalation, or parenteral). The associated clinical trials address the impact on disease while determining the appropriate dosage levels for further investigation in Phase III. A robust pipeline of agents is necessary to meet the global need for effective antiviral therapeutics.

Infective endocarditis (IE) can present with a variety of signs and symptoms, including skin lesions. The few papers describing a relationship between IE and vasculitis are split between IE being able to mimic vasculitis and between IE indeed being associated with a vasculitis involving the skin, kidney, gastrointestinal tract, or peripheral nerves. It is important for clinicians to distinguish between an isolated vasculitis, infective endocarditis, and IE-associated vasculitis because the treatments and outcomes are different. We report a case of a patient with a history of intravenous (IV) drug use who initially presented with chest pain, was started on vancomycin following diagnosis of methicillin-resistant  Staphylococcus aureus  (MRSA) IE, left against medical advice (AMA), and then returned to the hospital due to development of a purpuric rash. We contend that while he did not have a skin biopsy due to time delay, his symmetrically distributed purpura was consistent with cutaneous vasculitis. His symptoms, including his rash and an acute kidney injury (AKI), improved with antibiotics to treat the endocarditis., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Lane et al.)

Background  Individuals with mental illness are stigmatized by peers in societal, workplace, and healthcare settings. The stigmatization individuals experience from healthcare providers is well documented and pervasive, often being a detriment to the quality of healthcare these individuals receive. Objective Recognizing and addressing stigmatization toward individuals with mental illnesses is imperative during residency training in Graduate Medical Education (GME) programs and throughout professional practice. We hope that this cross-sectional study will cultivate mindfulness and improve the healthcare outcomes of stigmatized individuals. Methodology A cross-sectional study using a web-based Attitude to Mental Illness Questionnaire (AMIQ) with additional scenarios was utilized to assess stigma among resident physicians in differing specialties in a hospital training system. The research investigators collected anonymous data on demographics, characteristics, specialties, and the AMIQ. In eight vignettes, participants responded to five items using a five-point Likert scale assessing attitudes toward individuals. Results Of the 104 resident physicians enrolled in the hospital training system where the study was conducted, 58 (56%) volunteered to participate. The participating residents markedly exhibited negative attitudes toward the individual in the vignette with multiple inpatient psychiatric admissions. Residents also exhibited more negative attitudes toward individuals with schizophrenia, self-harm by way of overdose, psychedelic users, cannabis users, and alcohol problems compared to diabetic and Christian individuals. Conclusions Residents exhibited negative attitudes toward individuals with mental illness. Additional research would further our understanding of the reasons for physician bias. Moreover, GME programs and medical educators can play a crucial role in mitigating stigma among future physicians, thereby enhancing care for individuals with mental illness., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Harding University Institutional Review Board (IRB) issued approval Proposal number: 2021-09 (research exempted). Proposal number: 2021-09 The proposal referenced above has been reviewed and the decision rendered is noted below: This study has been found to fall under the following exemption: Research exempted from IRB Review. In the event that, after this exemption is granted, this research proposal is changed, it may require a review by the full IRB. In such case, a Request for Amendment to Approved Research form must be completed and submitted. The IRB reserves the right to observe, review and evaluate this study and its procedures during the course of the study. Dr. Cody Sipe, Chair Harding University Institutional Review Board. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Hemingway et al.)

Vitamin B12 deficiency is a common condition that is often asymptomatic, though in severe cases may cause megaloblastic anemia and even neurologic symptoms. Occasionally, the clinical presentation can include pancytopenia and thus mimic a more concerning myelodysplastic syndrome (MDS) until corrected by B12 supplementation. In this unusual case, we present a patient with B12 deficiency who presents with severe macrocytic anemia, neutropenia, lymphocytosis, and a bone marrow morphology consistent with MDS., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Mecham et al.)

Avian influenza (AI) viruses cause infection in birds and humans. Several H5N1 and H7N9 variants are highly pathogenic avian influenza (HPAI) viruses. H5N1 is a highly infectious bird virus infecting primarily poultry, but unlike other AIs, H5N1 also infects mammals and transmits to humans with a case fatality rate above 40%. Similarly, H7N9 can infect humans, with a case fatality rate of over 40%. Since 1996, there have been several HPAI outbreaks affecting humans, emphasizing the need for safe and effective antivirals. We show that probenecid potently inhibits H5N1 and H7N9 replication in prophylactically or therapeutically treated A549 cells and normal human broncho-epithelial (NHBE) cells, and H5N1 replication in VeroE6 cells and mice.