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.

Are fewer cases of diabetes mellitus diagnosed in the months after SARS-CoV-2 infection? A population-level view in the EHR-based RECOVER program.

Long-term sequelae of severe acute respiratory coronavirus-2 (SARS-CoV-2) infection may include increased incidence of diabetes. Here we describe the temporal relationship between new type 2 diabetes and SARS-CoV-2 infection in a nationwide database. We found that while the proportion of newly diagnosed type 2 diabetes increased during the acute period of SARS-CoV-2 infection, the mean proportion of new diabetes cases in the 6 months post-infection was about 83% lower than the 6 months preinfection. These results underscore the need for further investigation to understand the timing of new diabetes after COVID-19, etiology, screening, and treatment strategies.

Impact of SARS-CoV-2 vaccination and booster on COVID-19 symptom severity over time in the COVID-OUT trial.

BACKGROUND: SARS-CoV-2 vaccination has decreasing protection from acquiring any infection with emergence of new variants; however, vaccination continues to protect against progression to severe COVID-19. The impact of vaccination status on symptoms over time is less clear. METHODS: Within a randomized trial on early outpatient COVID-19 therapy testing metformin, ivermectin, and/or fluvoxamine, participants recorded symptoms daily for 14 days. Participants were given a paper symptom diary allowing them to circle the severity of 14 symptoms as none (0), mild (1), moderate (2), or severe (3). This is a secondary analysis of clinical trial data on symptom severity over time using generalized estimating equations comparing those unvaccinated, SARS-CoV-2 vaccinated with primary vaccine series only, or vaccine-boosted. RESULTS: The parent clinical trial prospectively enrolled 1323 participants, of whom 1062 (80%) prospectively recorded some daily symptom data. Of these, 480 (45%) were unvaccinated, 530 (50%) were vaccinated with primary series only, and 52 (5%) vaccine-boosted. Overall symptom severity was least for the vaccine-boosted group and most severe for unvaccinated at baseline and over the 14 days (P < 0.001). Individual symptoms were least severe in the vaccine-boosted group including: cough, chills, fever, nausea, fatigue, myalgia, headache, and diarrhea, as well as smell and taste abnormalities. Results were consistent over delta and omicron variant time periods. CONCLUSIONS: SARS-CoV-2 vaccine-boosted participants had the least severe symptoms during COVID-19 which abated the quickest over time.

A method for comparing multiple imputation techniques: A case study on the U.S. national COVID cohort collaborative.

Healthcare datasets obtained from Electronic Health Records have proven to be extremely useful for assessing associations between patients' predictors and outcomes of interest. However, these datasets often suffer from missing values in a high proportion of cases, whose removal may introduce severe bias. Several multiple imputation algorithms have been proposed to attempt to recover the missing information under an assumed missingness mechanism. Each algorithm presents strengths and weaknesses, and there is currently no consensus on which multiple imputation algorithm works best in a given scenario. Furthermore, the selection of each algorithm's parameters and data-related modeling choices are also both crucial and challenging. In this paper we propose a novel framework to numerically evaluate strategies for handling missing data in the context of statistical analysis, with a particular focus on multiple imputation techniques. We demonstrate the feasibility of our approach on a large cohort of type-2 diabetes patients provided by the National COVID Cohort Collaborative (N3C) Enclave, where we explored the influence of various patient characteristics on outcomes related to COVID-19. Our analysis included classic multiple imputation techniques as well as simple complete-case Inverse Probability Weighted models. Extensive experiments show that our approach can effectively highlight the most promising and performant missing-data handling strategy for our case study. Moreover, our methodology allowed a better understanding of the behavior of the different models and of how it changed as we modified their parameters. Our method is general and can be applied to different research fields and on datasets containing heterogeneous types.

Diabetes medications and associations with Covid-19 outcomes in the N3C database: A national retrospective cohort study.

BACKGROUND: While vaccination is the most important way to combat the SARS-CoV-2 pandemic, there may still be a need for early outpatient treatment that is safe, inexpensive, and currently widely available in parts of the world that do not have access to the vaccine. There are in-silico, in-vitro, and in-tissue data suggesting that metformin inhibits the viral life cycle, as well as observational data suggesting that metformin use before infection with SARS-CoV2 is associated with less severe COVID-19. Previous observational analyses from single-center cohorts have been limited by size. METHODS: Conducted a retrospective cohort analysis in adults with type 2 diabetes (T2DM) for associations between metformin use and COVID-19 outcomes with an active comparator design of prevalent users of therapeutically equivalent diabetes monotherapy: metformin versus dipeptidyl-peptidase-4-inhibitors (DPP4i) and sulfonylureas (SU). This took place in the National COVID Cohort Collaborative (N3C) longitudinal U.S. cohort of adults with +SARS-CoV-2 result between January 1 2020 to June 1 2021. Findings included hospitalization or ventilation or mortality from COVID-19. Back pain was assessed as a negative control outcome. RESULTS: 6,626 adults with T2DM and +SARS-CoV-2 from 36 sites. Mean age was 60.7 +/- 12.0 years; 48.7% male; 56.7% White, 21.9% Black, 3.5% Asian, and 16.7% Latinx. Mean BMI was 34.1 +/- 7.8kg/m2. Overall 14.5% of the sample was hospitalized; 1.5% received mechanical ventilation; and 1.8% died. In adjusted outcomes, compared to DPP4i, metformin had non-significant associations with reduced need for ventilation (RR 0.68, 0.32-1.44), and mortality (RR 0.82, 0.41-1.64). Compared to SU, metformin was associated with a lower risk of ventilation (RR 0.5, 95% CI 0.28-0.98, p = 0.044) and mortality (RR 0.56, 95%CI 0.33-0.97, p = 0.037). There was no difference in unadjusted or adjusted results of the negative control. CONCLUSIONS: There were clinically significant associations between metformin use and less severe COVID-19 compared to SU, but not compared to DPP4i. New-user studies and randomized trials are needed to assess early outpatient treatment and post-exposure prophylaxis with therapeutics that are safe in adults, children, pregnancy and available worldwide.

Effect of SARS-CoV-2 Infection and Infection Severity on Longer-Term Glycemic Control and Weight in People With Type 2 Diabetes.

OBJECTIVE: To evaluate the association of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severity of infection with longer-term glycemic control and weight in people with type 2 diabetes (T2D) in the U.S. RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study using longitudinal electronic health record data of patients with SARS-CoV-2 infection from the National COVID Cohort Collaborative (N3C). Patients were ≥18 years old with an ICD-10 diagnosis of T2D and at least one HbA1c and weight measurement prior to and after an index date of their first coronavirus disease 2019 (COVID-19) diagnosis or negative SARS-CoV-2 test. We used propensity scores to identify a matched cohort balanced on demographic characteristics, comorbidities, and medications used to treat diabetes. The primary outcome was the postindex average HbA1c and postindex average weight over a 1 year time period beginning 90 days after the index date among patients who did and did not have SARS-CoV-2 infection. Secondary outcomes were postindex average HbA1c and weight in patients who required hospitalization or mechanical ventilation. RESULTS: There was no significant difference in the postindex average HbA1c or weight in patients who had SARS-CoV-2 infection compared with control subjects. Mechanical ventilation was associated with a decrease in average HbA1c after COVID-19. CONCLUSIONS: In a multicenter cohort of patients in the U.S. with preexisting T2D, there was no significant change in longer-term average HbA1c or weight among patients who had COVID-19. Mechanical ventilation was associated with a decrease in HbA1c after COVID-19.

Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19.

BACKGROUND: Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. METHODS: In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs - metformin, ivermectin, and fluvoxamine - in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications. RESULTS: A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P = 0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P = 0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P = 0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine. CONCLUSIONS: None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials.gov number, NCT04510194.).

Re-examining the widespread policy of stopping sodium-glucose cotransporter-2 inhibitors during acute illness: A perspective based on the updated evidence.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are now seen as an integral part of therapy in type 2 diabetes to control not only blood glucose but to improve cardiovascular and kidney outcomes. Diabetic ketoacidosis (DKA) is an uncommon but serious complication of type 2 diabetes, which has a high case fatality rate. The absolute risk of DKA in large, prospective randomized clinical trials in people with type 2 diabetes using SGLT2 inhibitors has been low, although the relative risk is higher in those assigned to SGLT2 inhibitors compared with placebo. In those without diabetes but prescribed SGLT2 inhibitors for heart failure or chronic kidney disease, the risk of DKA is similar to placebo. Over the course of the COVID-19 pandemic, cases of DKA have also been reported in cases of COVID-19 hospitalizations. Consensus guidelines have recommended that SGLT2 inhibitors should be avoided in cases of serious illness and suggest they are not recommended for routine in-hospital use. However, recent data suggest potential beneficial effects of SGLT2 inhibitors in the setting of acute illness with COVID-19 with no increase in adverse events and low rates of DKA, which were non-severe. Given the low rates of DKA in cardiovascular outcome trials and in hospitalized patients with type 2 diabetes, the potential for SGLT2 inhibitors not being re-initiated following discharge and their cardiovascular and kidney benefits, we believe the practice of routine 'sick day' guidance should be re-examined based on current evidence with a call for further research in this area. Furthermore, high-quality trials of initiation of SGLT2 inhibitors in people admitted to hospital with cardiovascular disease or kidney disease, and trials of continuation of SGLT2 inhibitors in people, with careful monitoring of DKA should be conducted. These should be further supplemented with large observational studies.

Vaccination Against SARS-CoV-2 Is Associated With a Lower Viral Load and Likelihood of Systemic Symptoms.

Background: Data conflict on whether vaccination decreases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load. The objective of this analysis was to compare baseline viral load and symptoms between vaccinated and unvaccinated adults enrolled in a randomized trial of outpatient coronavirus disease 2019 (COVID-19) treatment. Methods: Baseline data from the first 433 sequential participants enrolling into the COVID-OUT trial were analyzed. Adults aged 30-85 with a body mass index (BMI) ≥25 kg/m2 were eligible within 3 days of a positive SARS-CoV-2 test and <7 days of symptoms. Log10 polymerase chain reaction viral loads were normalized to human RNase P by vaccination status, by time from vaccination, and by symptoms. Results: Two hundred seventy-four participants with known vaccination status contributed optional nasal swabs for viral load measurement: median age, 46 years; median (interquartile range) BMI 31.2 (27.4-36.4) kg/m2. Overall, 159 (58%) were women, and 217 (80%) were White. The mean relative log10 viral load for those vaccinated <6 months from the date of enrollment was 0.11 (95% CI, -0.48 to 0.71), which was significantly lower than the unvaccinated group (P = .01). Those vaccinated ≥6 months before enrollment did not differ from the unvaccinated with respect to viral load (mean, 0.99; 95% CI, -0.41 to 2.40; P = .85). The vaccinated group had fewer moderate/severe symptoms of subjective fever, chills, myalgias, nausea, and diarrhea (all P < .05). Conclusions: These data suggest that vaccination within 6 months of infection is associated with a lower viral load, and vaccination was associated with a lower likelihood of having systemic symptoms.

Serious Cardiovascular Adverse Events Associated with Hydroxychloroquine/Chloroquine Alone or with Azithromycin in Patients with COVID-19: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (FAERS).

BACKGROUND: The use of hydroxychloroquine or chloroquine (HCQ/CQ) as monotherapy or combined with azithromycin for the treatment of coronavirus disease 2019 (COVID-19) may increase the risk of serious cardiovascular adverse events (SCAEs). OBJECTIVE: Our objective was to describe and evaluate the risk of SCAEs with HCQ/CQ as monotherapy or combined with azithromycin compared with that for therapeutic alternatives. METHODS: We performed a disproportionality analysis and descriptive case series using the US FDA Adverse Event Reporting System. RESULTS: Compared with remdesivir, HCQ/CQ was associated with increased reporting of SCAEs (reporting odds ratio [ROR] 2.1; 95% confidence interval [CI] 1.8-2.5), torsade de pointes (TdP)/QTc prolongation (ROR 35.4; 95% CI 19.4-64.5), and ventricular arrhythmia (ROR 2.5; 95% CI 1.6-3.9); similar results were found in comparison with other therapeutic alternatives. Compared with lopinavir/ritonavir, HCQ/CQ was associated with increased reporting of ventricular arrhythmia (ROR 10.5; 95% CI 3.3-33.4); RORs were larger when HCQ/CQ was used in combination with azithromycin. In 2020, 312 of the 575 reports of SCAEs listed concomitant use of HCQ/CQ and azithromycin, including QTc prolongation (61.4%), ventricular arrhythmia (12.0%), atrial fibrillation (8.2%), TdP (4.9%), and cardiac arrest (4.4%); 88 (15.3%) cases resulted in hospitalization and 79 (13.7%) resulted in death. In total, 122 fatal QTc prolongation-related cardiovascular reports were associated with 1.4 times higher odds of reported death than those induced by SCAEs; 87 patients received more than one QTc-prolonging agent. CONCLUSIONS: Patients treated with HCQ/CQ monotherapy or HCQ/CQ + azithromycin may be at increased risk of SCAEs, TdP/QTc prolongation, and ventricular arrhythmia. Cardiovascular risks need to be considered when evaluating the benefit/harm balance of treatment with HCQ/CQ, especially with the concurrent use of QTc-prolonging agents and cytochrome P450 3A4 inhibitors when treating COVID-19.

Glycemic Control and Clinical Outcomes in U.S. Patients With COVID-19: Data From the National COVID Cohort Collaborative (N3C) Database.

OBJECTIVE: The purpose of the study is to evaluate the relationship between HbA1c and severity of coronavirus disease 2019 (COVID-19) outcomes in patients with type 2 diabetes (T2D) with acute COVID-19 infection. RESEARCH DESIGN AND METHODS: We conducted a retrospective study using observational data from the National COVID Cohort Collaborative (N3C), a longitudinal, multicenter U.S. cohort of patients with COVID-19 infection. Patients were ≥18 years old with T2D and confirmed COVID-19 infection by laboratory testing or diagnosis code. The primary outcome was 30-day mortality following the date of COVID-19 diagnosis. Secondary outcomes included need for invasive ventilation or extracorporeal membrane oxygenation (ECMO), hospitalization within 7 days before or 30 days after COVID-19 diagnosis, and length of stay (LOS) for patients who were hospitalized. RESULTS: The study included 39,616 patients (50.9% female, 55.4% White, 26.4% Black or African American, and 16.1% Hispanic or Latino, with mean ± SD age 62.1 ± 13.9 years and mean ± SD HbA1c 7.6% ± 2.0). There was an increasing risk of hospitalization with incrementally higher HbA1c levels, but risk of death plateaued at HbA1c >8%, and risk of invasive ventilation or ECMO plateaued >9%. There was no significant difference in LOS across HbA1c levels. CONCLUSIONS: In a large, multicenter cohort of patients in the U.S. with T2D and COVID-19 infection, risk of hospitalization increased with incrementally higher HbA1c levels. Risk of death and invasive ventilation also increased but plateaued at different levels of glycemic control.

COVID-19, Hyperglycemia, and New-Onset Diabetes.

Certain chronic comorbidities, including diabetes, are highly prevalent in people with coronavirus disease 2019 (COVID-19) and are associated with an increased risk of severe COVID-19 and mortality. Mild glucose elevations are also common in COVID-19 patients and associated with worse outcomes even in people without diabetes. Several studies have recently reported new-onset diabetes associated with COVID-19. The phenomenon of new-onset diabetes following admission to the hospital has been observed previously with other viral infections and acute illnesses. The precise mechanisms for new-onset diabetes in people with COVID-19 are not known, but it is likely that a number of complex interrelated processes are involved, including previously undiagnosed diabetes, stress hyperglycemia, steroid-induced hyperglycemia, and direct or indirect effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the ß-cell. There is an urgent need for research to help guide management pathways for these patients. In view of increased mortality in people with new-onset diabetes, hospital protocols should include efforts to recognize and manage acute hyperglycemia, including diabetic ketoacidosis, in people admitted to the hospital. Whether new-onset diabetes is likely to remain permanent is not known, as the long-term follow-up of these patients is limited. Prospective studies of metabolism in the setting of postacute COVID-19 will be required to understand the etiology, prognosis, and treatment opportunities.

Association Between Glucagon-Like Peptide 1 Receptor Agonist and Sodium-Glucose Cotransporter 2 Inhibitor Use and COVID-19 Outcomes.

OBJECTIVE: To determine the respective associations of premorbid glucagon-like peptide-1 receptor agonist (GLP1-RA) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) use, compared with premorbid dipeptidyl peptidase 4 inhibitor (DPP4i) use, with severity of outcomes in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. RESEARCH DESIGN AND METHODS: We analyzed observational data from SARS-CoV-2-positive adults in the National COVID Cohort Collaborative (N3C), a multicenter, longitudinal U.S. cohort (January 2018-February 2021), with a prescription for GLP1-RA, SGLT2i, or DPP4i within 24 months of positive SARS-CoV-2 PCR test. The primary outcome was 60-day mortality, measured from positive SARS-CoV-2 test date. Secondary outcomes were total mortality during the observation period and emergency room visits, hospitalization, and mechanical ventilation within 14 days. Associations were quantified with odds ratios (ORs) estimated with targeted maximum likelihood estimation using a super learner approach, accounting for baseline characteristics. RESULTS: The study included 12,446 individuals (53.4% female, 62.5% White, mean ± SD age 58.6 ± 13.1 years). The 60-day mortality was 3.11% (387 of 12,446), with 2.06% (138 of 6,692) for GLP1-RA use, 2.32% (85 of 3,665) for SGLT2i use, and 5.67% (199 of 3,511) for DPP4i use. Both GLP1-RA and SGLT2i use were associated with lower 60-day mortality compared with DPP4i use (OR 0.54 [95% CI 0.37-0.80] and 0.66 [0.50-0.86], respectively). Use of both medications was also associated with decreased total mortality, emergency room visits, and hospitalizations. CONCLUSIONS: Among SARS-CoV-2-positive adults, premorbid GLP1-RA and SGLT2i use, compared with DPP4i use, was associated with lower odds of mortality and other adverse outcomes, although DPP4i users were older and generally sicker.

Causal role of frontal-midline theta in cognitive effort: a pilot study.

Frontal-midline theta (FMT) oscillations are increased in amplitude during cognitive control tasks. Since these tasks often conflate cognitive control and cognitive effort, it remains unknown if FMT amplitude maps onto cognitive control or effort. To address this gap, we utilized the glucose facilitation effect to manipulate cognitive effort without changing cognitive control demands. We performed a single-blind, crossover human study in which we provided participants with a glucose drink (control session: volume-matched water) to reduce cognitive effort and improve performance on a visuospatial working memory task. Following glucose consumption, participants performed the working memory task at multiple time points of a 3-h window to sample across the rise and fall of blood glucose. Using high-density electroencephalography (EEG), we calculated FMT amplitude during the delay period of the working memory task. Source localization analysis revealed that FMT oscillations originated from bilateral prefrontal cortex. We found that glucose increased working memory accuracy during the high working memory load condition but decreased FMT amplitude. The decrease in FMT amplitude coincided with both peak blood glucose elevation and peak performance enhancement for glucose relative to water. Therefore, the positive association between glucose consumption and task performance provided causal evidence that the amplitude of FMT oscillations may correspond to cognitive effort, rather than cognitive control. Due to the COVID-19 pandemic, data collection was terminated prematurely; the preliminary nature of these findings due to small sample size should be contextualized by rigorous experimental design and use of a novel causal perturbation to dissociate cognitive effort and cognitive control.NEW & NOTEWORTHY We investigated whether frontal-midline theta (FMT) oscillations tracked with cognitive control or cognitive effort by simultaneous manipulation of cognitive control demands in a working memory task and causal perturbation of cognitive effort using glucose consumption. Facilitation of performance from glucose consumption corresponded with decreased FMT amplitude, which provided preliminary causal evidence for a relationship between FMT amplitude with cognitive effort.

Managing the risks and benefits of clinical research in response to a pandemic.

Introduction: The coronavirus disease 2019 (COVID-19) created major disruptions at academic centers and healthcare systems globally. Clinical and Translational Science Awards (CTSA) fund hubs supported by the National Center for Advancing Translational Sciences provideinfrastructure and leadership for clinical and translational research at manysuch institutions. Methods: We surveyed CTSA hubs and received responses from 94% of them regarding the impact of the pandemic and the processes employed for the protection of research personnel and participants with respect to the conduct of research, specifically for studies unrelated to COVID-19. Results: In this report, we describe the results of the survey findings in the context of the current understanding of disease transmission and mitigation techniques. Conclusions: We reflect on common practices and provide recommendations regarding lessons learned that will be relevant to future pandemics, particularly with regards to staging the cessation and resumption of research activities with an aim to keep the workforce, research participants, and our communities safe in future pandemics.

Re-engineering The Clinical Research Enterprise in Response to COVID-19: The Clinical Translational Science Award (CTSA) experience and proposed playbook for future pandemics.

The 2020 COVID-19 pandemic has had a profound impact on the clinical research enterprises at the 60 Clinical and Translational Science Award (CTSA) Hubs throughout the nation. There was simultaneously a need to expand research to obtain crucial data about disease prognosis and therapy and enormous limitations on conducting research as localities and institutions limited travel and person-to-person contact. These imperatives resulted in major changes in the way research was conducted, including expediting Institutional Review Board review, shifting to remote interactions with participants, centralizing decision-making in prioritizing research protocols, establishing biobanks, adopting novel informatics platforms, and distributing study drugs in unconventional ways. National CTSA Steering Committee meetings provided an opportunity to share best practices and develop the idea of capturing the CTSA program experiences in a series of papers. Here we bring together the recommendations from those papers in a list of specific actions that research sites can take to strengthen operations and prepare for similar future public health emergencies. Most importantly, creative innovations developed in response to the COVID-19 pandemic deserve serious consideration for adoption as new standards, thus converting the painful trauma of the pandemic into "post-traumatic growth" that makes the clinical research enterprise stronger, more resilient, and more effective.

Diabetes and COVID-19: Risks, Management, and Learnings From Other National Disasters.

Evidence relating to the impact of COVID-19 in people with diabetes (PWD) is limited but continuing to emerge. PWD appear to be at increased risk of more severe COVID-19 infection, though evidence quantifying the risk is highly uncertain. The extent to which clinical and demographic factors moderate this relationship is unclear, though signals are emerging that link higher BMI and higher HbA1c to worse outcomes in PWD with COVID-19. As well as posing direct immediate risks to PWD, COVID-19 also risks contributing to worse diabetes outcomes due to disruptions caused by the pandemic, including stress and changes to routine care, diet, and physical activity. Countries have used various strategies to support PWD during this pandemic. There is a high potential for COVID-19 to exacerbate existing health disparities, and research and practice guidelines need to take this into account. Evidence on the management of long-term conditions during national emergencies suggests various ways to mitigate the risks presented by these events.

Inpatient Transition to Virtual Care During COVID-19 Pandemic.

Introduction: During the coronavirus disease 2019 (COVID-19) outbreak, novel approaches to diabetes care have been employed. Care in both the inpatient and outpatient setting has transformed considerably. Driven by the need to reduce the use of personal protective equipment and exposure for patients and providers alike, we transitioned inpatient diabetes management services to largely "virtual" or remotely provided care at our hospital. Methods: Implementation of a diabetes co-management service under the direction of the University of North Carolina division of endocrinology was initiated in July 2019. In response to the COVID-19 pandemic, the diabetes service was largely transitioned to a virtual care model in March 2020. Automatic consults for COVID-19 patients were implemented. Glycemic outcomes from before and after transition to virtual care were evaluated. Results: Data over a 15-week period suggest that using virtual care for diabetes management in the hospital is feasible and can provide similar outcomes to traditional face-to-face care. Conclusion: Automatic consults for COVID-19 patients ensure that patients with serious illness receive specialized diabetes care. Transitioning to virtual care models does not limit the glycemic outcomes of inpatient diabetes care and should be employed to reduce patient and provider exposure in the setting of COVID-19. These findings may have implications for reducing nosocomial infection in less challenging times and might address shortage of health care providers, especially in the remote areas.