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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.

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OBJECTIVE: Implantable loop recorders (ILRs) are increasingly used for long-term rhythm monitoring after ischaemic and cryptogenic stroke, with the goal of detecting atrial fibrillation (AF) and subsequent initiation of oral anticoagulation to reduce risk of adverse clinical outcomes. There is a need to determine the effectiveness of different rhythm monitoring strategies in this context. METHODS: We conducted a retrospective cohort analysis of individuals with commercial and Medicare Advantage insurance in Optum Labs Data Warehouse who had incident ischaemic or cryptogenic stroke and no prior cardiovascular implantable electronic device from 1 January 2016 to 30 June 2021. Patients were stratified by rhythm monitoring strategy: ILR, long-term continuous external cardiac monitor (>48 hours to 30 days) or Holter monitor (≤48 hours). The primary outcome was risk-adjusted all-cause mortality at 12 months. Secondary outcomes included new diagnosis of AF and oral anticoagulation, bleeding, and costs. RESULTS: Among 48 901 patients with ischaemic or cryptogenic stroke, 9235 received an ILR, 29 103 long-term continuous external monitor and 10 563 Holter monitor only. Mean age was 69.9 (SD 11.9) years and 53.5% were female. During the 12-month follow-up period, patients who received ILRs compared with those who received long-term continuous external monitors had a higher odds of new diagnosis of AF and oral anticoagulant initiation (adjusted OR 2.27, 95% CI 2.09 to 2.48). Compared with patients who received long-term continuous external monitors, those who received ILRs had similar 12-month mortality (HR 1.00; 95% CI 0.89 to 1.12), with approximately $13 000 higher costs at baseline (including monitor cost) and $2500 higher costs during 12-month follow-up. CONCLUSIONS: In this large real-world study of patients with ischaemic or cryptogenic stroke, ILR placement resulted in more diagnosis of AF and initiation of oral anticoagulation, but no difference in mortality compared with long-term continuous external monitors.

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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.

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There is a need to reassess contemporary oral anticoagulation (OAC) trends and barriers against guideline directed therapy in the United States. Most previous studies were performed before major guideline changes recommended direct oral anticoagulant (DOAC) use over warfarin or have otherwise lacked patient level data. Data on overuse of OAC in low-risk group is also limited. To address these knowledge gaps, we performed a nationwide analysis to analyze current trends. This is a retrospective cohort study assessing non-valvular AF identified using a large United States de-identified administrative claims database, including commercial and Medicare Advantage enrollees. Prescription fills were assessed within a 90-day follow-up from the patient's index AF encounter between January 1, 2016, and December 31, 2020. Among the 339,197 AF patients, 4.4%, 8.0%, and 87.6% were in the low-, moderate-, and high-risk groups (according to CHA2DS2-VASc score). An over (29.6%) and under (52.2%) utilization of OAC was reported in low- and high-risk AF patients. A considerably high frequency for warfarin use was also noted among high-risk group patients taking OAC (33.1%). The results suggest that anticoagulation use for stroke prevention in the United States is still comparable to the pre-DOAC era studies. About half of newly diagnosed high-risk non-valvular AF patients remain unprotected against stroke risk. Several predictors of OAC and DOAC use were also identified. Our findings may identify a population at risk of complications due to under- or over-treatment and highlight the need for future quality improvement efforts.

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Emerging research suggests suicidality may have increased during the COVID-19 pandemic. This cross-sectional study aimed to advance understanding of suicide risk during the pandemic through novel use of a large insurance database. Using logistic regression across time-points, we estimated the effect of exposure to SARS-CoV-2 infection on rates of suicidal ideation and suicide attempts in infected individuals versus uninfected controls during the pandemic (March 2020 - September 2021). In uninfected individuals, we estimated the effect of exposure to the pandemic period versus the pre-pandemic control period (January 2017 to February 2020) on suicidality rates. We also investigated within-pandemic temporal patterns of suicidality. All patients with data in the UnitedHealth Group claims during those intervals were included. ICD-10 codes defined suicidality measures. There were 525,312,717 (62.3% over age 45, 57.7% female) included encounters. From the pandemic subsample (32.8%), 1.7% were COVID+. Adjusted odds ratios showed that COVID+ patients were significantly more likely to have suicidal ideation and suicide attempts than COVID- patients. Among COVID- patients, adjusted odds of suicidality were significantly lower during versus prior to the pandemic. Results were unfortunately limited by the absence of data on deaths by suicide. Further research should examine how SARS-CoV-2 infection may influence suicidality.

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Importance: Spinal cord stimulators (SCSs) are increasingly used for the treatment of chronic pain. There is a need for studies with long-term follow-up. Objective: To determine the comparative effectiveness and costs of SCSs compared with conventional medical management (CMM) in a large cohort of patients with chronic pain. Design, Setting, and Participants: This was a 1:5 propensity-matched retrospective comparative effectiveness research analysis of insured individuals from April 1, 2016, to August 31, 2018. This study used administrative claims data, including longitudinal medical and pharmacy claims, from US commercial and Medicare Advantage enrollees 18 years or older in Optum Labs Data Warehouse. Patients with incident diagnosis codes for failed back surgery syndrome, complex regional pain syndrome, chronic pain syndrome, and other chronic postsurgical back and extremity pain were included in this study. Data were analyzed from February 1, 2021, to August 31, 2022. Exposures: SCSs or CMM. Main Outcomes and Measures: Surrogate measures for primary chronic pain treatment modalities, including pharmacologic and nonpharmacologic pain interventions (epidural and facet corticosteroid injections, radiofrequency ablation, and spine surgery), as well as total costs. Results: In the propensity-matched population of 7560 patients, mean (SD) age was 63.5 (12.5) years, 3080 (40.7%) were male, and 4480 (59.3%) were female. Among matched patients, during the first 12 months, patients treated with SCSs had higher odds of chronic opioid use (adjusted odds ratio [aOR], 1.14; 95% CI, 1.01-1.29) compared with patients treated with CMM but lower odds of epidural and facet corticosteroid injections (aOR, 0.44; 95% CI, 0.39-0.51), radiofrequency ablation (aOR, 0.57; 95% CI, 0.44-0.72), and spine surgery (aOR, 0.72; 95% CI, 0.61-0.85). During months 13 to 24, there was no significant difference in chronic opioid use (aOR, 1.06; 95% CI, 0.94-1.20), epidural and facet corticosteroid injections (aOR, 1.00; 95% CI, 0.87-1.14), radiofrequency ablation (aOR, 0.84; 95% CI, 0.66-1.09), or spine surgery (aOR, 0.91; 95% CI, 0.75-1.09) with SCS use compared with CMM. Overall, 226 of 1260 patients (17.9%) treated with SCS experienced SCS-related complications within 2 years, and 279 of 1260 patients (22.1%) had device revisions and/or removals, which were not always for complications. Total costs of care in the first year were $39 000 higher with SCS than CMM and similar between SCS and CMM in the second year. Conclusions and Relevance: In this large, real-world, comparative effectiveness research study comparing SCS and CMM for chronic pain, SCS placement was not associated with a reduction in opioid use or nonpharmacologic pain interventions at 2 years. SCS was associated with higher costs, and SCS-related complications were common.

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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.

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OBJECTIVE: To characterize the risk of persistent and new clinical sequelae in adults aged ≥65 years after the acute phase of SARS-CoV-2 infection. DESIGN: Retrospective cohort study. SETTING: UnitedHealth Group Clinical Research Database: deidentified administrative claims and outpatient laboratory test results. PARTICIPANTS: Individuals aged ≥65 years who were continuously enrolled in a Medicare Advantage plan with coverage of prescription drugs from January 2019 to the date of diagnosis of SARS-CoV-2 infection, matched by propensity score to three comparison groups that did not have covid-19: 2020 comparison group (n=87 337), historical 2019 comparison group (n=88 070), and historical comparison group with viral lower respiratory tract illness (n=73 490). MAIN OUTCOME MEASURES: The presence of persistent and new sequelae at 21 or more days after a diagnosis of covid-19 was determined with ICD-10 (international classification of diseases, 10th revision) codes. Excess risk for sequelae caused by infection with SARS-CoV-2 was estimated for the 120 days after the acute phase of the illness with risk difference and hazard ratios, calculated with 95% Bonferroni corrected confidence intervals. The incidence of sequelae after the acute infection was analyzed by age, race, sex, and whether patients were admitted to hospital for covid-19. RESULTS: Among individuals who were diagnosed with SARS-CoV-2, 32% (27 698 of 87 337) sought medical attention in the post-acute period for one or more new or persistent clinical sequelae, which was 11% higher than the 2020 comparison group. Respiratory failure (risk difference 7.55, 95% confidence interval 7.18 to 8.01), fatigue (5.66, 5.03 to 6.27), hypertension (4.43, 2.27 to 6.37), memory difficulties (2.63, 2.23 to 3.13), kidney injury (2.59, 2.03 to 3.12), mental health diagnoses (2.50, 2.04 to 3.04), hypercoagulability 1.47 (1.2 to 1.73), and cardiac rhythm disorders (2.19, 1.76 to 2.57) had the greatest risk differences compared with the 2020 comparison group, with similar findings to the 2019 comparison group. Compared with the group with viral lower respiratory tract illness, however, only respiratory failure, dementia, and post-viral fatigue had increased risk differences of 2.39 (95% confidence interval 1.79 to 2.94), 0.71 (0.3 to 1.08), and 0.18 (0.11 to 0.26) per 100 patients, respectively. Individuals with severe covid-19 disease requiring admission to hospital had a markedly increased risk for most but not all clinical sequelae. CONCLUSIONS: The results confirm an excess risk for persistent and new sequelae in adults aged ≥65 years after acute infection with SARS-CoV-2. Other than respiratory failure, dementia, and post-viral fatigue, the sequelae resembled those of viral lower respiratory tract illness in older adults. These findings further highlight the wide range of important sequelae after acute infection with the SARS-CoV-2 virus.

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Background: Long Covid is an emerging chronic illness potentially affecting millions, sometimes preventing the ability to work or participate in normal daily activities. COVID-OUT was an investigator-initiated, multi-site, phase 3, randomized, quadruple-blinded placebo-controlled clinical trial (NCT04510194). The design simultaneously assessed three oral medications (metformin, ivermectin, fluvoxamine) using two by three parallel treatment factorial assignment to efficiently share placebo controls and assessed Long Covid outcomes for 10 months to understand whether early outpatient treatment of SARS-CoV-2 with metformin, ivermectin, or fluvoxamine prevents Long Covid. Methods: This was a decentralized, remotely delivered trial in the US of 1,125 adults age 30 to 85 with overweight or obesity, fewer than 7 days of symptoms, and enrolled within three days of a documented SARS-CoV-2 infection. Immediate release metformin titrated over 6 days to 1,500mg per day 14 days total; ivermectin 430mcg/kg/day for 3 days; fluvoxamine, 50mg on day one then 50mg twice daily through 14 days. Medical-provider diagnosis of Long Covid, reported by participant by day 300 after randomization was a pre-specified secondary outcome; the primary outcome of the trial was severe Covid by day 14. Result: The median age was 45 years (IQR 37 to 54), 56% female of whom 7% were pregnant. Two percent identified as Native American; 3.7% as Asian; 7.4% as Black/African American; 82.8% as white; and 12.7% as Hispanic/Latino. The median BMI was 29.8 kg/m2 (IQR 27 to 34); 51% had a BMI >30kg/m2. Overall, 8.4% reported having received a diagnosis of Long Covid from a medical provider: 6.3% in the metformin group and 10.6% in the metformin control; 8.0% in the ivermectin group and 8.1% in the ivermectin control; and 10.1% in the fluvoxamine group and 7.5% in the fluvoxamine control. The Hazard Ratio (HR) for Long Covid in the metformin group versus control was 0.58 (95% CI 0.38 to 0.88); 0.99 (95% CI 0.592 to 1.643) in the ivermectin group; and 1.36 in the fluvoxamine group (95% CI 0.785 to 2.385). Conclusions: There was a 42% relative decrease in the incidence of Long Covid in the metformin group compared to its blinded control in a secondary outcome of this randomized phase 3 trial.

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OBJECTIVE: To evaluate the excess risk and relative hazards for developing incident clinical sequelae after the acute phase of SARS-CoV-2 infection in adults aged 18-65. DESIGN: Retrospective cohort study. SETTING: Three merged data sources from a large United States health plan: a large national administrative claims database, an outpatient laboratory testing database, and an inpatient hospital admissions database. PARTICIPANTS: Individuals aged 18-65 with continuous enrollment in the health plan from January 2019 to the date of a diagnosis of SARS-CoV-2 infection. Three comparator groups, matched by propensity score, to individuals infected with SARS-CoV-2: a 2020 comparator group, an historical 2019 comparator group, and an historical comparator group with viral lower respiratory tract illness. MAIN OUTCOME MEASURES: More than 50 clinical sequelae after the acute phase of SARS-CoV-2 infection (defined as the date of first SARS-CoV-2 diagnosis (index date) plus 21 days) were identified using ICD-10 (international classification of diseases, 10th revision) codes. Excess risk in the four months after acute infection and hazard ratios with Bonferroni corrected 95% confidence intervals were calculated. RESULTS: 14% of adults aged ≤65 who were infected with SARS-CoV-2 (27 074 of 193 113) had at least one new type of clinical sequelae that required medical care after the acute phase of the illness, which was 4.95% higher than in the 2020 comparator group. The risk for specific new sequelae attributable to SARS-Cov-2 infection after the acute phase, including chronic respiratory failure, cardiac arrythmia, hypercoagulability, encephalopathy, peripheral neuropathy, amnesia (memory difficulty), diabetes, liver test abnormalities, myocarditis, anxiety, and fatigue, was significantly greater than in the three comparator groups (2020, 2019, and viral lower respiratory tract illness groups) (all P<0.001). Significant risk differences because of SARS-CoV-2 infection ranged from 0.02 to 2.26 per 100 people (all P<0.001), and hazard ratios ranged from 1.24 to 25.65 compared with the 2020 comparator group. CONCLUSIONS: The results indicate the excess risk of developing new clinical sequelae after the acute phase of SARS-CoV-2 infection, including specific types of sequelae less commonly seen in other viral illnesses. Although individuals who were older, had pre-existing conditions, and were admitted to hospital because of covid-19 were at greatest excess risk, younger adults (aged ≤50), those with no pre-existing conditions, or those not admitted to hospital for covid-19 also had an increased risk of developing new clinical sequelae. The greater risk for incident sequelae after the acute phase of SARS-CoV-2 infection is relevant for healthcare planning.

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Observational studies suggest outpatient metformin use is associated with reduced mortality from coronavirus disease-2019 (COVID-19). Metformin is known to decrease interleukin-6 and tumor-necrosis factor-α, which appear to contribute to morbidity in COVID-19. We sought to understand whether outpatient metformin use was associated with reduced odds of severe COVID-19 disease in a large US healthcare data set. Retrospective cohort analysis of electronic health record (EHR) data that was pooled across multiple EHR systems from 12 hospitals and 60 primary care clinics in the Midwest between March 4, 2020 and December 4, 2020. Inclusion criteria: data for body mass index (BMI) > 25 kg/m2 and a positive SARS-CoV-2 polymerase chain reaction test; age ≥ 30 and ≤85 years. Exclusion criteria: patient opt-out of research. Metformin is the exposure of interest, and death, admission, and intensive care unit admission are the outcomes of interest. Metformin was associated with a decrease in mortality from COVID-19, OR 0.32 (0.15, 0.66; p = .002), and in the propensity-matched cohorts, OR 0.38 (0.16, 0.91; p = .030). Metformin was associated with a nonsignificant decrease in hospital admission for COVID-19 in the overall cohort, OR 0.78 (0.58-1.04, p = .087). Among the subgroup with a hemoglobin HbA1c available (n = 1193), the adjusted odds of hospitalization (including adjustment for HbA1c) for metformin users was OR 0.75 (0.53-1.06, p = .105). Outpatient metformin use was associated with lower mortality and a trend towards decreased admission for COVID-19. Given metformin's low cost, established safety, and the mounting evidence of reduced severity of COVID-19 disease, metformin should be prospectively assessed for outpatient treatment of COVID-19.

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Over the past two decades, there have been a lot of advances in the field of pattern analyses for biomedical signals, which have helped in both medical diagnoses and in furthering our understanding of the human body. A relatively recent area of interest is the utility of biomedical signals in the field of biometrics, i.e., for user identification. Seminal work in this domain has already been done using electrocardiograph (ECG) signals. In this paper, we discuss our ongoing work in using a relatively recent modality of biomedical signals-a cardio-synchronous waveform measured using a Radio-Frequency Impedance-Interrogation (RFII) device for the purpose of user identification. Compared to an ECG setup, this device is noninvasive and measurements can be obtained easily and quickly. Here, we discuss the feasibility of reducing the dimensions of these signals by projecting onto various subspaces while still preserving interuser discriminating information. We compare the classification performance using classical dimensionality reduction methods such as principal component analysis (PCA), independent component analysis (ICA), random projections, with more recent techniques such as K-SVD-based dictionary learning. We also report the reconstruction accuracies in these subspaces. Our results show that the dimensionality of the measured signals can be reduced by 60 fold while maintaining high user identification rates.

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Four patients with brain tumors were diagnosed with atypical teratoid/rhabdoid tumors and underwent CT and MR imaging. For all tumors, aggressive features were shown by imaging studies and included hydrocephalus, apparent invasion of the adjacent brain and dura, and marked mass effect. The striking heterogeneity of the atypical teratoid/rhabdoid tumor shown by imaging studies reflects the histopathologic complexity of these tumors, and awareness of atypical teratoid/rhabdoid tumor is important in making the correct diagnosis of this uncommon but probably underdiagnosed entity.

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