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.).

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.

N-glycosylation of the SARS-CoV-2 spike protein at Asn331 and Asn343 is involved in spike-ACE2 binding, virus entry, and regulation of IL-6.

The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global public health crisis. The causative agent, the SARS-CoV-2 virus, enters host cells via molecular interactions between the viral spike protein and the host cell ACE2 surface protein. The SARS-CoV-2 spike protein is extensively decorated with up to 66 N-linked glycans. Glycosylation of viral proteins is known to function in immune evasion strategies but may also function in the molecular events of viral entry into host cells. Here, we show that N-glycosylation at Asn331 and Asn343 of SARS-CoV-2 spike protein is required for it to bind to ACE2 and for the entry of pseudovirus harboring the SARS-CoV-2 spike protein into cells. Interestingly, high-content glycan binding screening data have shown that N-glycosylation of Asn331 and Asn343 of the RBD is important for binding to the specific glycan molecule G4GN (Galß-1,4 GlcNAc), which is critical for spike-RBD-ACE2 binding. Furthermore, IL-6 was identified through antibody array analysis of conditioned media of the corresponding pseudovirus assay. Mutation of N-glycosylation of Asn331 and Asn343 sites of the spike receptor-binding domain (RBD) significantly reduced the transcriptional upregulation of pro-inflammatory signaling molecule IL-6. In addition, IL-6 levels correlated with spike protein levels in COVID-19 patients' serum. These findings establish the importance of RBD glycosylation in SARS-CoV-2 pathogenesis, which can be exploited for the development of novel therapeutics for COVID-19.

Photochemically Aided Arteriovenous Fistula Creation to Accelerate Fistula Maturation.

Rates of arteriovenous fistula maturation failure are still high, especially when suboptimal size veins are used. During successful maturation, the vein undergoes lumen dilatation and medial thickening, adapting to the increased hemodynamic forces. The vascular extracellular matrix plays an important role in regulating these adaptive changes and may be a target for promoting fistula maturation. In this study, we tested whether a device-enabled photochemical treatment of the vein prior to fistula creation facilitates maturation. Sheep cephalic veins were treated using a balloon catheter coated by a photoactivatable molecule (10-8-10 Dimer) and carrying an internal light fiber. As a result of the photochemical reaction, new covalent bonds were created during light activation among oxidizable amino acids of the vein wall matrix proteins. The treated vein lumen diameter and media area became significantly larger than the contralateral control fistula vein at 1 week (p = 0.035 and p = 0.034, respectively). There was also a higher percentage of proliferating smooth muscle cells in the treated veins than in the control veins (p = 0.029), without noticeable intimal hyperplasia. To prepare for the clinical testing of this treatment, we performed balloon over-dilatation of isolated human veins and found that veins can tolerate up to 66% overstretch without notable histological damage.

Creating a Natural Vascular Scaffold by Photochemical Treatment of the Extracellular Matrix for Vascular Applications.

The development of bioscaffolds for cardiovascular medical applications, such as peripheral artery disease (PAD), remains to be a challenge for tissue engineering. PAD is an increasingly common and serious cardiovascular illness characterized by progressive atherosclerotic stenosis, resulting in decreased blood perfusion to the lower extremities. Percutaneous transluminal angioplasty and stent placement are routinely performed on these patients with suboptimal outcomes. Natural Vascular Scaffolding (NVS) is a novel treatment in the development for PAD, which offers an alternative to stenting by building on the natural structural constituents in the extracellular matrix (ECM) of the blood vessel wall. During NVS treatment, blood vessels are exposed to a photoactivatable small molecule (10-8-10 Dimer) delivered locally to the vessel wall via an angioplasty balloon. When activated with 450 nm wavelength light, this therapy induces the formation of covalent protein-protein crosslinks of the ECM proteins by a photochemical mechanism, creating a natural scaffold. This therapy has the potential to reduce the need for stent placement by maintaining a larger diameter post-angioplasty and minimizing elastic recoil. Experiments were conducted to elucidate the mechanism of action of NVS, including the molecular mechanism of light activation and the impact of NVS on the ECM.

Extended Duration Enoxaparin Decreases the Rate of Venous Thromboembolic Events after Radical Cystectomy Compared to Inpatient Only Subcutaneous Heparin.

PURPOSE: Venous thromboembolic events are a significant source of morbidity after radical cystectomy. At our institution subcutaneous heparin was historically given to patients undergoing radical cystectomy immediately before incision and throughout the inpatient stay. In an effort to decrease the overall rate of venous thromboembolism and post-discharge venous thromboembolism, a regimen including extended duration enoxaparin was initiated for patients undergoing radical cystectomy. MATERIALS AND METHODS: In January 2013 thromboprophylaxis was modified for patients undergoing radical cystectomy by replacing a regimen of subcutaneous heparin before induction and then every 8 hours until discharge home with enoxaparin daily for postoperative prophylaxis continued until 28 days after discharge. Data from our institutional radical cystectomy database for patients undergoing surgery from January 2011 to May 2014 were reviewed. The primary outcome was clinically symptomatic postoperative venous thromboembolism. Secondary outcomes included timing of venous thromboembolism and blood transfusions. Multivariate logistic regression was used to control for differences between cohorts. RESULTS: Of the 402 patients 234 underwent radical cystectomy before the change and 168 after. The enoxaparin regimen decreased the rate of venous thromboembolism (12% vs 5%, p=0.024) with the main benefit on post-discharge venous thromboembolism (6% vs 2%, p=0.039). Overall 17 of 37 (46%) venous thromboembolisms occurred after discharge home. Multivariate analysis confirmed that the enoxaparin regimen was independently associated with reduced odds of venous thromboembolism (OR 0.33, 95% CI 0.14-0.76, p=0.009). Intraoperative and postoperative transfusion rates were similar between cohorts. CONCLUSIONS: Thromboprophylaxis with extended duration enoxaparin decreased the rate of venous thromboembolism after radical cystectomy compared to inpatient only subcutaneous heparin with no increased risk of bleeding.

Hounsfield Units for nephrolithiasis: predictive power for the clinical urologist.

INTRODUCTION: We aim to determine the optimal method for measuring Hounsfield Units (HU) of calculi for the clinical urologist. MATERIALS AND METHODS: We present a single institution prospective study from 2014-2015 for 125 consecutive patients. Demographics, baseline characteristics, imaging, and stone analysis were collected. CT scanners and settings were heterogeneous. Hounsfield units were measured by use of ellipsoid tool and free hand outline by two independent urology graders using Philips iSite PACs. RESULTS: Stone analysis demonstrated 26 pure calcium oxalate (CaOx) stones, 15 pure calcium phosphate (CaP) stones, and 7 uric acid stones, among other mixed types. Excellent agreement was notable amongst the two graders for ellipsoid and free hand grading, and values were consistent with those previously published with other methods. Mean grades for free-hand versus ellipse differed overall (p = 0.006) as ellipsoid HU measurement was consistently higher than free-hand measurement by an average of 107 units. Either method could differentiate between uric acid stones and any calcium containing stone (p ≤ 0.05). The free-hand method demonstrated statistical difference between pure calcium oxalate and calcium phosphate stones (p = 0.03). Applying either method took less than 6 seconds. CONCLUSIONS: For urologists lacking HU on their radiology reports, free hand or ellipsoid measurement may quickly provide an additional tool to guide management. Both methods differentiate between any calcium containing stone and uric acid stones.

The impact of days off between cases on perioperative outcomes for robotic-assisted laparoscopic prostatectomy.

PURPOSE: To examine the effect of days off between cases on perioperative outcomes for robotic-assisted laparoscopic prostatectomy (RALP). METHODS: We analyzed a single-surgeon series of 2036 RALP cases between 2003 and 2014. Days between cases (DBC) was calculated as the number of days elapsed since the surgeon's previous RALP with the second start cases assigned 0 DBC. Surgeon experience was assessed by dividing sequential case experience into cases 0-99, cases 100-249, cases 250-999, and cases 1000+ based on previously reported learning curve data for RALP. Outcomes included estimated blood loss (EBL), operative time (OT), and positive surgical margins (PSMs). Multiple linear regression was used to assess the impact of the DBC and surgeon experience on EBL, OT, and PSM, while controlling for patient characteristics, surgical technique, and pathologic variables. RESULTS: Overall median DBC was 1 day (0-3) and declined with increasing surgeon case experience. Multiple linear regression demonstrated that each additional DBC was independently associated with increased EBL [ß = 3.7, 95% CI (1.3-6.2), p < 0.01] and OT [ß = 2.3 (1.4-3.2), p < 0.01], but was not associated with rate of PSM [ß = 0.004 (-0.003-0.010), p = 0.2]. Increased experience was also associated with reductions in EBL and OT (p < 0.01). Surgeon experience of 1000+ cases was associated with a 10% reduction in PSM rate (p = 0.03) compared to cases 0-99. CONCLUSIONS: In a large single-surgeon RALP series, DBC was associated with increased blood loss and operative time, but not associated with positive surgical margins, when controlling for surgeon experience.

Comparison of Patients Undergoing PVP Versus TURP for LUTS/BPH.

Transurethral resection of the prostate (TURP) and photoselective vaporization of the prostate (PVP) are currently the two most commonly performed procedures for the treatment of benign prostatic hyperplasia (BPH). While each procedure has been shown to be efficacious, TURP or PVP may be preferred in certain clinical scenarios. A number of factors may influence the choice of which patients undergo PVP or TURP. This decision may take into account patient characteristics, such as age, co-morbidities, predominance of irritative symptoms, and/or ongoing anticoagulation. Additionally, balancing desired outcomes with possible risks is critical. Considerations should include possible effects on sexual function, rates of reoperation, cost, and need for tissue specimen in those at risk for prostate cancer. The primary objective of this article is to summarize the comparative research of PVP and TURP and the implications on differences between patients who undergo either procedure.

Prehospital recognition of severe sepsis: development and validation of a novel EMS screening tool.

OBJECTIVE: To derive and validate a predictive model and novel emergency medical services (EMS) screening tool for severe sepsis (SS). DESIGN: Retrospective cohort study. SETTING: A single EMS system and an urban, public hospital. PATIENTS: Sequential adult, nontrauma, nonarrest, at-risk, EMS-transported patients between January 1, 2011, and December 31, 2012 were included in the study. At-risk patients were defined as having all 3 of the following criteria present in the EMS setting: (1) heart rate greater than 90 beats/min, (2) respiratory rate greater than 20 beats/min, and (3) systolic blood pressure less than 110 mm Hg. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 66,439 EMS encounters, 555 met the criteria for analysis. Fourteen percent (n = 75) of patients had SS, of which 19% (n = 14) were identified by EMS clinical judgment. In-hospital mortality for patients with SS was 31% (n = 23). Six EMS characteristics were found to be predictors of SS: older age, transport from nursing home, Emergency Medical Dispatch (EMD) 9-1-1 chief concern category of "sick person," hot tactile temperature assessment, low systolic blood pressure, and low oxygen saturation. The final predictive model showed good discrimination in derivation and validation subgroups (areas under curves, 0.843 and 0.820, respectively). Sensitivity of the final model was 91% in the derivation group and 78% in the validation group. At a predefined threshold of 2 or more points, prehospital severe sepsis (PRESS) score sensitivity was 86%. CONCLUSIONS: The PRESS score is a novel EMS screening tool for SS that demonstrates a sensitivity of 86% and a specificity of 47%. Additional validation is needed before this tool can be recommended for widespread clinical use.

Adult fruit fly attraction to larvae biases experience and mediates social learning.

We investigated whether adult fruit flies (Drosophila melanogaster) use cues of larvae as social information in their food patch choice decisions. Adult male and female fruit flies showed attraction to odours emanating from foraging larvae, and females preferred to lay eggs on food patches occupied by larvae over similar unoccupied patches. Females learned and subsequently preferred to lay eggs at patches with novel flavours previously associated with feeding larvae over patches with novel flavours previously associated with no larvae. However, when we controlled for the duration of exposure to each flavoured patch, females no longer preferred the flavour previously associated with feeding larvae. This suggests that social learning in this context is indirect, as a result of strong social attraction biasing experience.

Brachial plexus injury: a descriptive study of American football.

A stinger is a common, yet understudied, injury that involves stretching or compression of the brachial plexus, often occurring during contact sports. Five football teams, including high school, collegiate, and professional teams, completed questionnaires. Questions were designed to obtain descriptive information regarding the nature and consequence of this injury and assess effectiveness of current preventive measures. Three hundred and four surveys were returned with 153 players reporting a stinger in their career (50.3%). The prevalence increased with years played and was most common in running backs (69%), defensive linemen (60%), linebackers (55%), and defensive secondary (54%). Current protective equipment and neck-strengthening programs did not provide protective benefits. Players at greatest risk of developing a stinger include those having played 3 or more years and players whose primary position is running back, defensive back, or defensive lineman. Further study is needed to better evaluate the effectiveness of current preventive measures.

Outcomes of infants undergoing robot-assisted laparoscopic pyeloplasty compared to open repair.

PURPOSE: Robotic surgery has evolved from simple extirpative surgery to complex reconstructions even in infants. Data are lacking comparing surgical and direct costs to open approaches. We describe the feasibility, salient tips and outcomes of robot-assisted laparoscopic pyeloplasty compared to an open approach. MATERIALS AND METHODS: We evaluated patients undergoing open pyeloplasty or robot-assisted laparoscopic pyeloplasty. Ten patients in each group met inclusion criteria. RESULTS: Mean patient age was 3.31 months in the open group and 7.3 months in the robotic group (p=0.02). Postoperative outcomes including length of stay (2.2 vs 2.1 days), estimated blood loss (6.5 vs 7.6 ml), days to regular diet (1 vs 1.1) and days to Foley catheter removal (1.3 vs 1.3) were similar between the open and robotic groups. Total operating time (199 vs 242 minutes) was significantly longer in the robotic group. Postoperative improvement in hydronephrosis was identical in both groups. Direct costs, excluding amortization, robotic cost, maintenance and depreciation, were $4,410 in the open group and $4,979 in the robotic group (p=0.10). CONCLUSIONS: In our preliminary experience robotic pyeloplasty in infants is feasible and safe. The immediate outcomes are similar to those of an open approach. The robotic technique in infants currently has the benefits of improved esthetic appearance, improved pain control and similar direct costs compared to the traditional open approach.

Interleukin-11 (IL11) inhibits myogenic differentiation of C2C12 cells through activation of extracellular signal-regulated kinase (ERK).

Cancer-associated cachexia (CAC) is a multifactorial wasting syndrome characterized by loss of skeletal muscle. Interleukin-11 (IL11), one of the IL6 family cytokines, is highly expressed in various types of cancer including cancers frequently associated with cachexia. However, the impact of IL11 on muscle metabolism remains to be determined. Since one of the mechanisms of muscle wasting in cachexia is defective muscle regeneration due to impaired myogenic differentiation, we examined the effect of IL11 on the differentiation of C2C12 mouse myoblasts. Treatment of C2C12 cells with recombinant mouse IL11 resulted in decreased myotube formation. In addition, IL11 treatment reduced the protein and mRNA levels of myosin heavy chain (MHC), a marker of myogenic differentiation. Moreover, the levels of myogenic regulatory factors including myogenin and Mrf4 were significantly reduced by IL11 treatment. IL11 treatment increased the number of BrdU-positive cells and the level of phosphorylated retinoblastoma (Rb) protein, while the levels of p21Waf1 and p27Kip1 were reduced by IL11 treatment in differentiating C2C12 cells, suggesting that IL11 interferes with cell cycle exit during the early stages of myogenic differentiation. Consistent with this, IL11 treatment at the late stage of differentiation did not affect myotube formation and MHC expression. IL11 treatment resulted in an activation of ERK, STAT3, and AKT in differentiating C2C12 cells. However, only ERK inhibitors including PD98059 and U0126 were able to ameliorate the suppressive effect of IL11 on the expression of MHC and myogenin. Additionally, pretreatment with PD98059 and U0126 resulted in improved myotube formation and reduced BrdU staining in IL11-treated cells. Together, our results suggest that IL11 inhibits myogenic differentiation through delayed cell cycle exit in an ERK-dependent manner. To our knowledge, this study is the first to demonstrate an inhibitory role of IL11 in myogenic differentiation and identifies the previously unrecognized role of IL11 as a possible mediator of CAC.

Photochemical Modification of the Extracellular Matrix to Alter the Vascular Remodeling Process.

Therapeutic interventions for vascular diseases aim at achieving long-term patency by controlling vascular remodeling. The extracellular matrix (ECM) of the vessel wall plays a crucial role in regulating this process. This study introduces a novel photochemical treatment known as Natural Vascular Scaffolding, utilizing a 4-amino substituted 1,8-naphthimide (10-8-10 Dimer) and 450 nm light. This treatment induces structural changes in the ECM by forming covalent bonds between amino acids in ECM fibers without harming vascular cell survival, as evidenced by our results. To further investigate the mechanism of this treatment, porcine carotid artery segments were exposed to 10-8-10 Dimer and light activation. Subsequent experiments subjected these segments to enzymatic degradation through elastase or collagenase treatment and were analyzed using digital image analysis software (MIPAR) after histological processing. The results demonstrated significant preservation of collagen and elastin structures in the photochemically treated vascular wall, compared to controls. This suggests that photochemical treatment can effectively modulate vascular remodeling by enhancing the resistance of the ECM scaffold to degradation. This approach shows promise in scenarios where vascular segments experience significant hemodynamic fluctuations as it reinforces vascular wall integrity and preserves lumen patency. This can be valuable in treating veins prior to fistula creation and grafting or managing arterial aneurysm expansion.

Early and fair COVID-19 outcome risk assessment using robust feature selection.

Personalized medicine plays an important role in treatment optimization for COVID-19 patient management. Early treatment in patients at high risk of severe complications is vital to prevent death and ventilator use. Predicting COVID-19 clinical outcomes using machine learning may provide a fast and data-driven solution for optimizing patient care by estimating the need for early treatment. In addition, it is essential to accurately predict risk across demographic groups, particularly those underrepresented in existing models. Unfortunately, there is a lack of studies demonstrating the equitable performance of machine learning models across patient demographics. To overcome this existing limitation, we generate a robust machine learning model to predict patient-specific risk of death or ventilator use in COVID-19 positive patients using features available at the time of diagnosis. We establish the value of our solution across patient demographics, including gender and race. In addition, we improve clinical trust in our automated predictions by generating interpretable patient clustering, patient-level clinical feature importance, and global clinical feature importance within our large real-world COVID-19 positive patient dataset. We achieved 89.38% area under receiver operating curve (AUROC) performance for severe outcomes prediction and our robust feature ranking approach identified the presence of dementia as a key indicator for worse patient outcomes. We also demonstrated that our deep-learning clustering approach outperforms traditional clustering in separating patients by severity of outcome based on mutual information performance. Finally, we developed an application for automated and fair patient risk assessment with minimal manual data entry using existing data exchange standards.

Effects of face masks on oxygen saturation at graded exercise intensities.

CONTEXT: Mask wearing to mitigate the spread of COVID-19 and other viral infections may raise concerns on the effects of face masks on breathing and cardiopulmonary health. Non-evidence-based apprehensions may limit the use of masks in public. OBJECTIVES: We will assess the parameters related to heart and lung physiology between healthy male and female adults exposed to wearing face masks (or not) under conditions of rest and graded exercise. METHODS: We performed a cross-sectional study including 20 male and 20 female adults who met our inclusion criteria. Adults with underlying respiratory and cardiac conditions were excluded. Physiologic parameters were measured while the participants underwent three activity levels (10 min each) in a randomly assigned order: rest, walking, and stair climbing. Each activity level was conducted under three mask conditions: no mask, surgical mask, and N95 respirator. Heart rate (HR) and blood oxygen saturation (SpO2) were recorded via pulse oximeter after each activity. Perceived exertion was recorded utilizing a Borg 15-point scale. A mixed-effects analysis of variance (ANOVA) was utilized to interpret the results. RESULTS: A significant increase in perceived exertion was reported for N95 users (p<0.0001). There was also a significant increase in mean HR for N95 users in comparison to no-mask users (p=0.0031). The mean SpO2 in females was higher than males under rest and walking conditions (p=0.0055). There was no change in SpO2 between mask type overall, nor between mask type vs. exercise intensity, nor between mask type and sex. CONCLUSIONS: Our findings provide evidence that surgical masks and N95 respirators do not influence SpO2 at rest or during exercise.

Use of Natural Language Processing of Patient-Initiated Electronic Health Record Messages to Identify Patients With COVID-19 Infection.

Importance: Natural language processing (NLP) has the potential to enable faster treatment access by reducing clinician response time and improving electronic health record (EHR) efficiency. Objective: To develop an NLP model that can accurately classify patient-initiated EHR messages and triage COVID-19 cases to reduce clinician response time and improve access to antiviral treatment. Design, Setting, and Participants: This retrospective cohort study assessed development of a novel NLP framework to classify patient-initiated EHR messages and subsequently evaluate the model's accuracy. Included patients sent messages via the EHR patient portal from 5 Atlanta, Georgia, hospitals between March 30 and September 1, 2022. Assessment of the model's accuracy consisted of manual review of message contents to confirm the classification label by a team of physicians, nurses, and medical students, followed by retrospective propensity score-matched clinical outcomes analysis. Exposure: Prescription of antiviral treatment for COVID-19. Main Outcomes and Measures: The 2 primary outcomes were (1) physician-validated evaluation of the NLP model's message classification accuracy and (2) analysis of the model's potential clinical effect via increased patient access to treatment. The model classified messages into COVID-19-other (pertaining to COVID-19 but not reporting a positive test), COVID-19-positive (reporting a positive at-home COVID-19 test result), and non-COVID-19 (not pertaining to COVID-19). Results: Among 10 172 patients whose messages were included in analyses, the mean (SD) age was 58 (17) years; 6509 patients (64.0%) were women and 3663 (36.0%) were men. In terms of race and ethnicity, 2544 patients (25.0%) were African American or Black, 20 (0.2%) were American Indian or Alaska Native, 1508 (14.8%) were Asian, 28 (0.3%) were Native Hawaiian or other Pacific Islander, 5980 (58.8%) were White, 91 (0.9%) were more than 1 race or ethnicity, and 1 (0.01%) chose not to answer. The NLP model had high accuracy and sensitivity, with a macro F1 score of 94% and sensitivity of 85% for COVID-19-other, 96% for COVID-19-positive, and 100% for non-COVID-19 messages. Among the 3048 patient-generated messages reporting positive SARS-CoV-2 test results, 2982 (97.8%) were not documented in structured EHR data. Mean (SD) message response time for COVID-19-positive patients who received treatment (364.10 [784.47] minutes) was faster than for those who did not (490.38 [1132.14] minutes; P = .03). Likelihood of antiviral prescription was inversely correlated with message response time (odds ratio, 0.99 [95% CI, 0.98-1.00]; P = .003). Conclusions and Relevance: In this cohort study of 2982 COVID-19-positive patients, a novel NLP model classified patient-initiated EHR messages reporting positive COVID-19 test results with high sensitivity. Furthermore, when responses to patient messages occurred faster, patients were more likely to receive antiviral medical prescription within the 5-day treatment window. Although additional analysis on the effect on clinical outcomes is needed, these findings represent a possible use case for integration of NLP algorithms into clinical care.

Strategies used for the COVID-OUT decentralized trial of outpatient treatment of SARS-CoV-2.

The COVID-19 pandemic accelerated the development of decentralized clinical trials (DCT). DCT's are an important and pragmatic method for assessing health outcomes yet comprise only a minority of clinical trials, and few published methodologies exist. In this report, we detail the operational components of COVID-OUT, a decentralized, multicenter, quadruple-blinded, randomized trial that rapidly delivered study drugs nation-wide. The trial examined three medications (metformin, ivermectin, and fluvoxamine) as outpatient treatment of SARS-CoV-2 for their effectiveness in preventing severe or long COVID-19. Decentralized strategies included HIPAA-compliant electronic screening and consenting, prepacking investigational product to accelerate delivery after randomization, and remotely confirming participant-reported outcomes. Of the 1417 individuals with the intention-to-treat sample, the remote nature of the study caused an additional 94 participants to not take any doses of study drug. Therefore, 1323 participants were in the modified intention-to-treat sample, which was the a priori primary study sample. Only 1.4% of participants were lost to follow-up. Decentralized strategies facilitated the successful completion of the COVID-OUT trial without any in-person contact by expediting intervention delivery, expanding trial access geographically, limiting contagion exposure, and making it easy for participants to complete follow-up visits. Remotely completed consent and follow-up facilitated enrollment.

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.