Favorable Antiviral Effect of Metformin on Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load in a Randomized, Placebo-Controlled Clinical Trial of Coronavirus Disease 2019.

BACKGROUND: Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. METHODS: COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. RESULTS: The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95% confidence interval [CI], -1.05 to -.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. CONCLUSIONS: In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. CLINICAL TRIALS REGISTRATION: NCT04510194.

Coordinated ARP2/3 and glycolytic activities regulate the morphological and functional fitness of human CD8+ T cells.

Actin cytoskeleton remodeling sustains the ability of cytotoxic T cells to search for target cells and eliminate them. We here investigated the relationship between energetic status, actin remodeling, and functional fitness in human CD8+ effector T cells. Cell spreading during migration or immunological synapse assembly mirrored cytotoxic activity. Morphological and functional fitness were boosted by interleukin-2 (IL-2), which also stimulated the transcription of glycolytic enzymes, actin isoforms, and actin-related protein (ARP)2/3 complex subunits. This molecular program scaled with F-actin content and cell spreading. Inhibiting glycolysis impaired F-actin remodeling at the lamellipodium, chemokine-driven motility, and adhesion, while mitochondrial oxidative phosphorylation blockade impacted cell elongation during confined migration. The severe morphological and functional defects of ARPC1B-deficient T cells were only partially corrected by IL-2, emphasizing ARP2/3-mediated actin polymerization as a crucial energy state integrator. The study therefore underscores the tight coordination between metabolic and actin remodeling programs to sustain the cytotoxic activity of CD8+ T cells.

Metformin reduces SARS-CoV-2 in a Phase 3 Randomized Placebo Controlled Clinical Trial.

Current antiviral treatment options for SARS-CoV-2 infections are not available globally, cannot be used with many medications, and are limited to virus-specific targets.1-3 Biophysical modeling of SARS-CoV-2 replication predicted that protein translation is an especially attractive target for antiviral therapy.4 Literature review identified metformin, widely known as a treatment for diabetes, as a potential suppressor of protein translation via targeting of the host mTor pathway.5 In vitro, metformin has antiviral activity against RNA viruses including SARS-CoV-2.6,7 In the COVID-OUT phase 3, randomized, placebo-controlled trial of outpatient treatment of COVID-19, metformin had a 42% reduction in ER visits/hospitalizations/death through 14 days; a 58% reduction in hospitalizations/death through 28 days, and a 42% reduction in Long COVID through 10 months.8,9 Here we show viral load analysis of specimens collected in the COVID-OUT trial that the mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95%CI, -1.05 to -0.06, p=0.027) while there was no virologic effect for ivermectin or fluvoxamine vs placebo. The metformin effect was consistent across subgroups and with emerging data.10,11 Our results demonstrate, consistent with model predictions, that a safe, widely available,12 well-tolerated, and inexpensive oral medication, metformin, can be repurposed to significantly reduce SARS-CoV-2 viral load.

Outpatient treatment of COVID-19 and incidence of post-COVID-19 condition over 10 months (COVID-OUT): a multicentre, randomised, quadruple-blind, parallel-group, phase 3 trial.

BACKGROUND: Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID. METHODS: We conducted a decentralised, randomised, quadruple-blind, parallel-group, phase 3 trial (COVID-OUT) at six sites in the USA. We included adults aged 30-85 years with overweight or obesity who had COVID-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before enrolment. Participants were randomly assigned via 2 × 3 parallel factorial randomisation (1:1:1:1:1:1) to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Participants, investigators, care providers, and outcomes assessors were masked to study group assignment. The primary outcome was severe COVID-19 by day 14, and those data have been published previously. Because the trial was delivered remotely nationwide, the a priori primary sample was a modified intention-to-treat sample, meaning that participants who did not receive any dose of study treatment were excluded. Long COVID diagnosis by a medical provider was a prespecified, long-term secondary outcome. This trial is complete and is registered with ClinicalTrials.gov, NCT04510194. FINDINGS: Between Dec 30, 2020, and Jan 28, 2022, 6602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long COVID at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37-54) and median BMI was 29·8 kg/m2 (IQR 27·0-34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2-8·2) in participants who received metformin and 10·4% (7·8-12·9) in those who received identical metformin placebo (hazard ratio [HR] 0·59, 95% CI 0·39-0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15-0·95). There was no effect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59-1·64) or fluvoxamine (1·36, 0·78-2·34) compared with placebo. INTERPRETATION: Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe. FUNDING: Parsemus Foundation; Rainwater Charitable Foundation; Fast Grants; UnitedHealth Group Foundation; National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; and National Center for Advancing Translational Sciences.

Implementing real-time prescription benefit tools: Early experiences from 5 academic medical centers.

BACKGROUND: Medication price transparency tools are increasingly available, but data on their use, and their potential effects on prescribing behavior, patient out of pocket (OOP) costs, and clinician workflow integration, is limited. OBJECTIVE: To describe the implementation experiences with real-time prescription benefit (RTPB) tools at 5 large academic medical centers and their early impact on prescription ordering. DESIGN: and Participants: In this cross-sectional study, we systematically collected information on the characteristics of RTPB tools through discussions with key stakeholders at each of the five organizations. Quantitative encounter data, prescriptions written, and RTPB alerts/estimates and prescription adjustment rates were obtained at each organization in the first three months after "go-live" of the RTPB system(s) between 2019 and 2020. MAIN MEASURES: Implementation characteristics, prescription orders, cost estimate retrieval rates, and prescription adjustment rates. KEY RESULTS: Differences were noted with respect to implementation characteristics related to RTPB tools. All of the organizations with the exception of one chose to display OOP cost estimates and suggested alternative prescriptions automatically. Differences were also noted with respect to a patient cost threshold for automatic display. In the first three months after "go-live," RTPB estimate retrieval rates varied greatly across the five organizations, ranging from 8% to 60% of outpatient prescriptions. The prescription adjustment rate was lower, ranging from 0.1% to 4.9% of all prescriptions ordered. CONCLUSIONS: In this study reporting on the early experiences with RTPB tools across five academic medical centers, we found variability in implementation characteristics and population coverage. In addition RTPB estimate retrieval rates were highly variable across the five organizations, while rates of prescription adjustment ranged from low to modest.

Where Do Real-Time Prescription Benefit Tools Fit in the Landscape of High US Prescription Medication Costs? A Narrative Review.

The problem of unaffordable prescription medications in the United States is complex and can result in poor patient adherence to therapy, worse clinical outcomes, and high costs to the healthcare system. While providers are aware of the financial burden of healthcare for patients, there is a lack of actionable price transparency at the point of prescribing. Real-time prescription benefit (RTPB) tools are new electronic clinical decision support tools that retrieve patient- and medication-specific out-of-pocket cost information and display it to clinicians at the point of prescribing. The rise in US healthcare costs has been a major driver for efforts to increase medication price transparency, and mandates from the Centers for Medicare & Medicaid Services for Medicare Part D sponsors to adopt RTPB tools may spur integration of such tools into electronic health records. Although multiple factors affect the implementation of RTPB tools, there is limited evidence on outcomes. Further research will be needed to understand the impact of RTPB tools on end results such as prescribing behavior, out-of-pocket medication costs for patients, and adherence to pharmacologic treatment. We review the terminology and concepts essential in understanding the landscape of RTPB tools, implementation considerations, barriers to adoption, and directions for future research that will be important to patients, prescribers, health systems, and insurers.

Using group testing in a two-phase epidemiologic design to identify the effects of a large number of antibody reactions on disease risk.

BACKGROUND: The role of immunological responses to exposed bacteria on disease incidence is increasingly under investigation. With many bacterial species, and many potential antibody reactions to a particular species, the large number of assays required for this type of discovery can make it prohibitively expensive. We propose a two-phase group testing design to more efficiently screen numerous antibody effects in a case-control setting. METHODS: Phase 1 uses group testing to select antibodies that are differentially expressed between cases and controls. The selected antibodies go on to Phase 2 individual testing. RESULTS: We evaluate the two-phase group testing design through simulations and example data and find that it substantially reduces the number of assays required relative to standard case-control and group testing designs, while maintaining similar statistical properties. CONCLUSION: The proposed two-phase group testing design can dramatically reduce the number of assays required, while providing comparable results to a case-control design.

Adolescent bariatric surgery: a systematic review of recommendation documents.

Bariatric surgery has been performed on adolescents since the 1970s, but little is known about the guidance offered to providers in recommendation documents published in the United States. A systematic review was conducted to generate a complete record of all US recommendation documents and describe variability across the documents. This study had 3 aims: to identify the developers, examine selection criteria, and document reasons why developers have recommended this intervention for adolescents. Four databases (MEDLINE, National Guidelines Clearinghouse, Trip, and Embase) ertr searched, followed by a hand search. Documents were eligible for inclusion if they satisfied 5 criteria: written in the English language; developed and published by a US organization; comprised a clinical practice guideline, position statement, or consensus statement; offered a minimum 1-sentence recommendation on bariatric surgery for the treatment of obesity or related co-morbidities; and offered a minimum 1-sentence recommendation on bariatric surgery for children, adolescents, or both. No date limits were applied. Sixteen recommendation documents published between 1991 and 2013 met our inclusion criteria: 10 clinical practice guidelines, 4 position statements, and 2 consensus statements. Nine were produced by medical organizations, 3 by surgical organizations, and 4 by public health/governmental bodies. One document recommended against bariatric surgery for minors, and 15 endorsed the intervention for this population. Body mass index (a measure of obesity calculated by dividing weight in kilograms by the square of height in meters) thresholds were the selection criteria most often provided. Minimum age varied widely. Of the 15 endorsing documents, 10 provided a reason for performing bariatric surgery on minors, most often to treat obesity-related co-morbidities that threaten the health of the adolescent. We make 3 suggestions to improve the quality of future recommendation documents.

A clinical study of efficacy of 4% articaine hydrochloride versus 2% lignocaine hydrochloride in dentistry.

BACKGROUND: Articaine in an anesthetic agent, which is used less frequently in dentistry. It differs from other agents due to the presence of a thiophene ring in its molecular structure. Few groups of researchers claim that it is superior to lignocaine. Hence, the purpose of this study was to compare the efficacy of 4% articaine hydrochloride and 2% lignocaine hydrochloride in the orthodontic extraction. MATERIALS AND METHODS: The study was carried out in 50 patients who needed the orthodontic extraction in the age group from 15 to 25 years. Experimental sites were injected with 0.5-1 ml of 4% articaine HCL containing 1:100000 adrenaline, incrementally in the buccal vestibule without palatal anaesthesia. Control sites were injected with 0.8-1 ml of 2% lignocaine HCL containing 1:100000 adrenaline, incrementally in the buccal vestibule. All the parameters, that is volume, duration, time of anesthesia and pain rating were noted and statistically compared. RESULT: When statistically compared mean volume of articaine (0.779 ± 0.1305) was less than lignocaine (1.337 ± 0.2369). Mean time of onset of articaine was 1.012 ± 0.2058 min, Whereas that of was 1.337 ± 0.2369. Pain rating showed not much difference, but in the lignocaine group palatal anesthesia was required in all the patients. Finally, the mean duration of anesthesia in articaine group was 69.08 ± 18.247, whereas in the lignocaine group was 55.66 ± 6.414. CONCLUSION: Articaine has proved its usefulness in all regards. Literatures have proved its usefulness. Like other anesthetic, it is safe and more effective. It surpasses the need of additional palatal anesthesia. Rapid inactivation in liver and plasma reduces the risk of the drug overdose. All the above factors make it an ideal anesthetic agent to be used in dentistry.

MiR-93 enhances angiogenesis and metastasis by targeting LATS2.

Here we report that miR-93, a miRNA in the miR-106B~25 cluster, a paralog of the miR-17-92 cluster, was significantly upregulated in human breast carcinoma tissues. We stably expressed miR-93 in the MT-1 human breast carcinoma cell line and found that tumors formed by the miR-93 cells contained more blood vessels than those formed by the control cells. Co-culture experiments indicated that the MT-1 cells displayed a high activity of adhesion with endothelial cells and could form larger and more tube-like structures with endothelial cells. Lung metastasis assays were performed in a mouse metastatic model, and it was found that expression of miR-93 promoted tumor cell metastasis to lung tissue. In cell culture, expression of miR-93 enhanced cell survival and invasion. We examined the potential target that mediated miR-93's effects and found that the large tumor suppressor, homology 2 (LATS2) was a target of miR-93. Higher levels of LATS2 were associated with cell death in the tumor mass. Silencing LATS2 expression promoted cell survival, tube formation and invasion, while ectopic expression of LATS2 decreased cell survival and invasion. These findings demonstrated that miR-93 promoted tumor angiogenesis and metastasis by suppressing LATS2 expression. Our results suggest that the inhibition of miR-93 function may be a feasible approach to repress tumor metastasis.