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.

A Rare Occurrence of Bilateral Single-Rooted Mandibular First Molar.

It is essential to have an in-depth knowledge of root and root canal anatomy to prevent any iatrogenic errors. Many studies and case reports are present in the literature related to the anatomy of mandibular first molars, but most of them are on an extra number of roots and root canals. There are few studies related to a lower number of roots and root canals, but the occurrence of bilateral mandibular first and second molars with the presence of root fusion resulting in a single root is very rare. This case report presents the nonsurgical endodontic management of the left and right mandibular first molars with the presence of a single root confirmed using a CBCT and treated by placing an apical MTA plug followed by backfill using thermoplasticised gutta percha.

Outcomes of COVID-19 Patients Hospitalized at Acute Care Services: Real-World Experience in the New York Metropolitan Area During the Early Pandemic Before Initiation of Clinical Trials.

As New York became the epicenter of the COVID-19 pandemic early on, clinicians were challenged to provide optimal medical and pharmaceutical care, despite the paucity of supporting literature and guidance. We sought to describe prescribing patterns and outcomes of physician response to the urgent need to treat COVID-19 patients before initiation of randomized clinical trials. METHODS: This was a retrospective cohort study of adult patients with COVID-19 initially admitted to acute care services during March 2020. Critically ill patients requiring intensive care unit level of care on admission were excluded. RESULTS: A total of 639 consecutive patients (supportive care, n = 247; treatment n = 392) were included in the analysis. Overall, the 28-day mortality rate was 12.2%. The mortality was 8.7% higher in the treatment group (15.6% vs 6.9% in the supportive care group, P < 0.001). Treatment was not protective against progression to severe disease (18.4% vs 3.6% with supportive care, P < 0.0001). Time to defervescence, duration of oxygen support, and hospital and intensive care unit (ICU) length of stay were also higher in the treatment group. In multivariate analysis, 60 years or older, presence of severe disease, and need for ICU admission were identified as independent predictors of 28-day mortality. There were 41 (10.5%) adverse event in the treatment group, with the majority being QT prolongation and gastrointestinal effects. CONCLUSIONS: In this cohort of hospitalized patients admitted to acute care services, treatment with hydroxychloroquine, lopinavir/ritonavir or both could not be shown to improve mortality, progression to severe disease, or clinical response.

A quality assurance tool for daily checks of the gamma knife high definition motion management system.

PURPOSE: This note describes the performance of a quality assurance (QA) tool built for daily checks of the Gamma Knife's high definition motion management (HDMM) system. METHODS: The tool is a three-dimensional (3D)-printed platform with a raised corner in the center. A reflector post is placed at the corner and the HDMM tool is zeroed to this position. Gage blocks produce very accurate gaps between the post and corner and the HDMM system's readout is compared to the gage block thickness. The HDMM system and tool were tested for noise, stability, reproducibility, linearity, accuracy and overall setup times plus ease of use. RESULTS: The QA tool performed with accuracies better than 0.1 mm. The setup and use of this tool take less than two minutes making it a suitable tool for daily use. CONCLUSION: This QA tool is a cost-effective solution that provides a fast and easy confirmation of the HDMM accuracy, making it suitable for daily QA checks of the HDMM system.

To Assess the Success of Computerized Order Sets and Pharmacy Education Modules in Improving Antiretroviral Prescribing.

PURPOSE: To assess the success of order set and pharmacist training improvement (OSPTI) in improving prescription of antiretroviral therapy (ART) in a tertiary care, public, teaching hospital. METHODS: In this pre-OSPTI (January 2012 through June 2013) and post-OSPTI study (July 2013 through September 2014), an infectious disease pharmacist reviewed all patients on ART. A review of intervention data in July 2013 led to order-set changes in the hospital's computerized order entry system for frequently intervened on antiretrovirals: ritonavir, tenofovir, emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), and lamivudine. Concurrently, case-based education modules were conducted to help pharmacists identify ART errors. The number of patients on ART, number of interventions, and types of ritonavir interventions were compared between pre- and post-OSPTI periods. RESULTS: In the pre-OSPTI period, an average of 239 patients were reviewed per quarter compared to an average of 216 per quarter in the post-OSPTI period. After implementing enhanced order sets, the number of interventions decreased by approximately 34% ( P < .0001). The number of ritonavir interventions decreased on average by 45% ( P < .0001), although the types of ritonavir interventions were similar. CONCLUSION: Enhanced antiretroviral order sets and pharmacy education modules improved ART prescription by reducing the overall number of antiretroviral interventions required per quarter. This modality was effective in improving prescribing of ART and reducing the need for pharmacist interventions.

MCK1 is a novel regulator of myo-inositol phosphate synthase (MIPS) that is required for inhibition of inositol synthesis by the mood stabilizer valproate.

Myo-inositol, the precursor of all inositol compounds, is essential for the viability of eukaryotes. Identifying the factors that regulate inositol homeostasis is of obvious importance to understanding cell function and the pathologies underlying neurological and metabolic resulting from perturbation of inositol metabolism. The current study identifies Mck1, a GSK3 homolog, as a novel positive regulator of inositol de novo synthesis in yeast. Mck1 was required for normal activity of myo-inositol phosphate synthase (MIPS), which catalyzes the rate-limiting step of inositol synthesis. mck1Δ cells exhibited a 50% decrease in MIPS activity and a decreased rate of incorporation of [13C6]glucose into [13C6]-inositol-3-phosphate and [13C6]-inositol compared to WT cells. mck1Δ cells also exhibited decreased growth in the presence of the inositol depleting drug valproate (VPA), which was rescued by supplementation of inositol. However, in contrast to wild type cells, which exhibited more than a 40% decrease in MIPS activity in the presence of VPA, the drug did not significantly decrease MIPS activity in mck1Δ cells. These findings indicate that VPA-induced MIPS inhibition is Mck1-dependent, and suggest a model that unifies two current hypotheses of the mechanism of action of VPA-inositol depletion and GSK3 inhibition.

Yeast bioassay for identification of inositol depleting compounds.

Bipolar affective disorder is a chronic, severe, debilitating illness affecting 1-2% of the population. Valproate, along with lithium and carbamazepine, are the only drugs for which long-term efficacy has been established. However, these drugs are ineffective for, and not well tolerated by, a large number of patients and are also associated with teratogenicity and reproductive defects. Therefore, there is a substantial need to develop more effective anti-bipolar drugs. We have previously shown that valproate, like lithium, decreases intracellular inositol, which supports the inositol depletion hypothesis. We employed inositol depletion in yeast as a screening tool to identify potential new anti-bipolar medications. We show here that hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, ethylhexanoate, and methyloctanoate decrease intracellular inositol levels and increase the expression of INO1, the gene encoding myo-inositol-3-phosphate synthase (MIPS). Similar to valproate, these inositol-depleting carboxylic acids inhibited MIPS indirectly. A correlation was shown between cell growth inhibition and the increase in INO1 expression by the carboxylic acids, factors that were reversed in the presence of inositol. Inositol depletion in yeast may be exploited as an easy and inexpensive screening test for potential new inositol depleting anti-bipolar drugs.

Ethylbutyrate, a valproate-like compound, exhibits inositol-depleting effects--a potential mood-stabilizing drug.

AIMS: To screen for inositol-depleting valproate-like compounds as potential mood stabilizing drugs. MAIN METHODS: We exploited the yeast Saccharomyces cerevisiae, as a model in which inositol de novo synthesis has been extensively characterized, to test the effects of ethyl butyrate (EB), 2-ethyl-butyric acid, sodium butyrate, and n-propyl hexanoate on inositol biosynthesis. Cell growth was followed by measuring the optical density of the cultures (spectrophotometrically), RNA abundance was determined by Northern blot analysis, intracellular inositol was measured by a fluorometric assay, and 1-d-myo-inositol-3-phosphate synthase activity was examined using a chromatographic method. KEY FINDINGS: Of the tested compounds, only EB exhibited an inositol-depleting effect. The inositol-depleting effect of EB was achieved without significant adverse effect on cell growth, pointing to lesser toxicity compared to valproate. SIGNIFICANCE: These results indicate that EB is a potential candidate for mood-stabilizing therapy.

Tigecycline: a glycylcycline antimicrobial agent.

BACKGROUND: Tigecycline, the first glycylcycline to be approved by the US Food and Drug Administration, is a structural analogue of minocycline that was designed to avoid tetracycline resistance mediated by ribosomal protection and drug efflux. It is indicated for the treatment of complicated skin and skin-structure infections and complicated intra-abdominal infections and is available for intravenous administration only. OBJECTIVE: This article summarizes the in vitro and in vivo activities and pharmacologic and pharmacokinetic properties of tigecycline, and reviews its clinical efficacy and tolerability profile. METHODS: Relevant information was identified through a search of MEDLINE (1966-April 2006), Iowa Drug Information Service (1966-April 2006), and International Pharmaceutical Abstracts (1970-April 2006) using the terms tigecycline, GAR-936, and glycylcycline. Also consulted were abstracts and posters from meetings of the Infectious Diseases Society of America and the Interscience Conference on Antimicrobial Agents and Chemotherapy (1999-2006) and documents provided for formulary consideration by the US manufacturer of tigecycline. RESULTS: Like the tetracyclines, tigecycline binds to the 30S subunit of bacterial ribosomes and inhibits protein synthesis by preventing the incorporation of amino acid residues into elongating peptide chains. In vitro, tigecycline exhibits activity against a wide range of clinically significant gram-positive and gram-negative bacteria, including multidrug-resistant strains (eg, oxacillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Enterobacteriaceae), and anaerobes (eg, Bacteroides spp). In pharmacokinetic studies in human adults, tigecycline had a large Vd (7-9 L/kg), was moderately bound to plasma protein (71%-89%), had an elimination t(1/2) of 42.4 hours, and was eliminated primarily by biliary/fecal (59%) and renal (33%) excretion. Dose adjustment did not appear to be necessary based on age, sex, renal function, or mild to moderate hepatic impairment (Child-Pugh class A-B). In patients with severe hepatic impairment (Child-Pugh class C), the maintenance dose should be reduced by 50%. In 4 Phase III clinical trials in patients with complicated skin and skin-structure infections and complicated intra-abdominal infections, tigecycline was reported to be noninferior to its comparators (vancomycin + aztreonam in 2 studies and imipenem/cilastatin in 2 studies), with clinical cure rates among clinically evaluable patients of >80% (P < 0.001 for noninferiority). The most frequently reported (> or =5 %) adverse events with tigecycline were nausea (28.5%), vomiting (19.4%), diarrhea (11.6%), local IV-site reaction (8.2%), infection (6.7%), fever (6.3%), abdominal pain (6.0%), and headache (5.6%). The recommended dosage of tigecycline is 100 mg IV given as a loading dose, followed by 50 mg IV g12h for 5 to 14 days. CONCLUSIONS: In clinical trials, tigecycline was effective for the treatment of complicated skin and skin-structure infections and complicated intra-abdominal infections. With the exception of gastrointestinal adverse events, tigecycline was generally well tolerated. With a broad spectrum of activity that includes multidrug-resistant gram-positive and gram-negative pathogens, tigecycline may be useful in the treatment of conditions caused by these pathogens.