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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.).
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Tratamiento Farmacológico de COVID-19 , COVID-19 , Fluvoxamina , Ivermectina , Metformina , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/complicaciones , Vacunas contra la COVID-19 , Método Doble Ciego , Femenino , Fluvoxamina/uso terapéutico , Humanos , Hipoxia/etiología , Ivermectina/uso terapéutico , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Obesidad/complicaciones , Sobrepeso/complicaciones , Embarazo , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , SARS-CoV-2RESUMEN
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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Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Metformina , SARS-CoV-2 , Carga Viral , Humanos , Metformina/uso terapéutico , Metformina/farmacología , Carga Viral/efectos de los fármacos , Masculino , SARS-CoV-2/efectos de los fármacos , Femenino , Persona de Mediana Edad , Método Doble Ciego , Antivirales/uso terapéutico , Antivirales/farmacología , Adulto , COVID-19/virología , Ivermectina/uso terapéutico , Ivermectina/farmacología , Fluvoxamina/uso terapéutico , Fluvoxamina/farmacología , AncianoRESUMEN
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (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 coronavirus disease 2019 (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 < .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. Clinical Trial Registration. NCT04510194.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/prevención & control , Vacunas contra la COVID-19 , VacunaciónRESUMEN
Heart failure management requires intensive care coordination. Guideline-directed medical therapies have been shown to save lives but are practically challenging to implement because of the fragmented care that heart failure patients experience. Electronic health record adoption has transformed the collection and storage of clinical data, but accessing these data often remains prohibitively difficult. Current legislation aims to increase the interoperability of software systems so that providers and patients can easily access the clinical information they desire. Novel heart failure devices and technologies leverage patient-generated data to manage heart failure patients, whereas new data standards make it possible for this information to guide clinical decision-making.
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Registros Electrónicos de Salud/normas , Insuficiencia Cardíaca/terapia , Humanos , Programas InformáticosRESUMEN
One challenge of contemporary medical education is that shorter lengths of stay and time-limited clerkships often interrupt a student's relationship with a patient before a diagnosis is made or treatment is completed, limiting the learning experience. Medical students sometimes use electronic health records (EHRs) to overcome these limitations. EHRs provide access to patients' future medical records, enabling students to track former patients across care venues to audit their diagnostic impressions and observe outcomes. While this activity has potential to improve clinical training, there is a risk of unintended harm to patients through loss of privacy. Students need guidance on how to perform this activity appropriately. This article describes an ethical framework for tracking using an "educational registry," a list of former patients housed within the EHR that one follows longitudinally for educational purposes. Guiding principles include obtaining permission from patients, having legitimate educational intent, and restricting review of records to those essential for training. This framework could serve as a foundation for institutions seeking to develop a policy on tracking former patients, and may facilitate research on the use of EHRs to improve medical education, such as reducing diagnostic error and promoting self-directed learning.
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Confidencialidad , Educación Médica/normas , Registros Electrónicos de Salud/normas , Sistema de Registros , Registros Electrónicos de Salud/ética , Humanos , Estudiantes de MedicinaRESUMEN
BACKGROUND: Hospital-based patient portals have the potential to better inform and engage patients in their care. We sought to assess patients' and healthcare providers' perceptions of a hospital-based portal and identify opportunities for design enhancements. METHODS: We developed a mobile patient portal application including information about the care team, scheduled tests and procedures, and a list of active medications. Patients were offered use of tablet computers, with the portal application, during their hospitalization. We conducted semi-structured interviews of patients and provider focus groups. Text from transcribed interviews and focus groups was independently coded by two investigators using a constant comparative approach. Codes were reviewed by a third investigator and discrepancies resolved via consensus. RESULTS: Overall, 18 patients completed semi-structured interviews and 21 providers participated in three focus groups. Patients found information provided by the portal to be useful, especially regarding team members and medications. Many patients described frequent use of games and non-clinical applications and felt the tablet helped them cope with their acute illness. Patients expressed a desire for additional detail about medications, test results, and the ability to record questions. Providers felt the portal improved patient engagement, but worried that additional features might result in a volume and complexity of information that could be overwhelming for patients. Providers also expressed concern over an enhanced portal's impact on patient-provider communication and workflow. CONCLUSIONS: Optimizing a hospital-based patient portal will require attention to type, timing and format of information provided, as well as the impact on patient-provider communication and workflow.
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Importance: Disparities in patient access and use of health care portals have been documented. Limited research has evaluated disparities in portal use during and after the COVID-19 pandemic. Objective: To assess prevalence of health care portal use before, during, and after the most restrictive phase of the pandemic (2019-2022) among the COVID-19 & Chronic Conditions (C3) cohort and to investigate any disparities in use by sociodemographic factors. Design, Setting, and Participants: This cohort study uses data from the C3 study, an ongoing, longitudinal, telephone-based survey of participants with multiple chronic conditions. Participants were middle aged and older-adult primary care patients who had an active portal account, recruited from a single academic medical center in Chicago, Illinois, between 2019 and 2022. Data were analyzed between March and June 2022. Main Outcomes and Measures: Outcomes of portal use (ie, number of days of portal login by year) were recorded for all study participants by the electronic data warehouse. All parent studies had uniform sociodemographic data and measures of social support, self-efficacy, health literacy, and health activation. Results: Of 536 participants (mean [SD] age, 66.7 [12.0] years; 336 [62.7%] female), 44 (8.2%) were Hispanic or Latinx, 142 (26.5%) were non-Hispanic Black, 322 (60.1%) were non-Hispanic White, and 20 individuals (3.7%) identified as other race, including Asian, Native American or Alaskan Native, and self-reported other race. In multivariable analyses, portal login activity was higher during the 3 years of the COVID-19 pandemic compared with the 2019 baseline. Higher portal login activity was associated with adequate health literacy (incidence rate ratio [IRR], 1.51; 95% CI, 1.18-1.94) and multimorbidity (IRR, 1.38; 95% CI, 1.17-1.64). Lower portal activity was associated with older age (≥70 years: IRR, 0.69; 95% CI, 0.55-0.85) and female sex (IRR, 0.77; 95% CI, 0.66-0.91). Compared with non-Hispanic White patients, lower portal activity was observed among Hispanic or Latinx patients (IRR, 0.66; 95% CI, 0.49-0.89), non-Hispanic Black patients (IRR, 0.68; 95% CI, 0.56-0.83), and patients who identified as other race (IRR, 0.42; 95% CI, 0.28-0.64). Conclusions and Relevance: This cohort study using data from the C3 study identified changes in portal use over time and highlighted populations that had lower access to health information. The COVID-19 pandemic was associated with an increase in portal use. Sociodemographic disparities by sex and age were reduced, although disparities by health literacy widened. A brief validated health literacy measure may serve as a useful digital literacy screening tool to identify patients who need further support.
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COVID-19 , Portales del Paciente , Adulto , Persona de Mediana Edad , Humanos , Femenino , Anciano , Masculino , Estudios de Cohortes , Pandemias , Enfermedad Crónica , COVID-19/epidemiologíaRESUMEN
This study describes decentralized recruitment and enrollment for a COVID-19 treatment trial, while comparing 5 primary recruitment methods: search engine ads, paid advertising within a national testing company, paid advertising within a regional testing company, electronic health record messages, and word of mouth. These are compared across patient demographics, efficiency, and cost. Clinical Trials Registration: NCT04510194.
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Importance: The profile of gastrointestinal (GI) outcomes that may affect children in post-acute and chronic phases of COVID-19 remains unclear. Objective: To investigate the risks of GI symptoms and disorders during the post-acute phase (28 days to 179 days after SARS-CoV-2 infection) and the chronic phase (180 days to 729 days after SARS-CoV-2 infection) in the pediatric population. Design: We used a retrospective cohort design from March 2020 to Sept 2023. Setting: twenty-nine healthcare institutions. Participants: A total of 413,455 patients aged not above 18 with SARS-CoV-2 infection and 1,163,478 patients without SARS-CoV-2 infection. Exposures: Documented SARS-CoV-2 infection, including positive polymerase chain reaction (PCR), serology, or antigen tests for SARS-CoV-2, or diagnoses of COVID-19 and COVID-related conditions. Main Outcomes and Measures: Prespecified GI symptoms and disorders during two intervals: post-acute phase and chronic phase following the documented SARS-CoV-2 infection. The adjusted risk ratio (aRR) was determined using a stratified Poisson regression model, with strata computed based on the propensity score. Results: Our cohort comprised 1,576,933 patients, with females representing 48.0% of the sample. The analysis revealed that children with SARS-CoV-2 infection had an increased risk of developing at least one GI symptom or disorder in both the post-acute (8.64% vs. 6.85%; aRR 1.25, 95% CI 1.24-1.27) and chronic phases (12.60% vs. 9.47%; aRR 1.28, 95% CI 1.26-1.30) compared to uninfected peers. Specifically, the risk of abdominal pain was higher in COVID-19 positive patients during the post-acute phase (2.54% vs. 2.06%; aRR 1.14, 95% CI 1.11-1.17) and chronic phase (4.57% vs. 3.40%; aRR 1.24, 95% CI 1.22-1.27). Conclusions and Relevance: In the post-acute phase or chronic phase of COVID-19, the risk of GI symptoms and disorders was increased for COVID-positive patients in the pediatric population.
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Introduction: The rapid development of artificial intelligence (AI) in healthcare has exposed the unmet need for growing a multidisciplinary workforce that can collaborate effectively in the learning health systems. Maximizing the synergy among multiple teams is critical for Collaborative AI in Healthcare. Methods: We have developed a series of data, tools, and educational resources for cultivating the next generation of multidisciplinary workforce for Collaborative AI in Healthcare. We built bulk-natural language processing pipelines to extract structured information from clinical notes and stored them in common data models. We developed multimodal AI/machine learning (ML) tools and tutorials to enrich the toolbox of the multidisciplinary workforce to analyze multimodal healthcare data. We have created a fertile ground to cross-pollinate clinicians and AI scientists and train the next generation of AI health workforce to collaborate effectively. Results: Our work has democratized access to unstructured health information, AI/ML tools and resources for healthcare, and collaborative education resources. From 2017 to 2022, this has enabled studies in multiple clinical specialties resulting in 68 peer-reviewed publications. In 2022, our cross-discipline efforts converged and institutionalized into the Center for Collaborative AI in Healthcare. Conclusions: Our Collaborative AI in Healthcare initiatives has created valuable educational and practical resources. They have enabled more clinicians, scientists, and hospital administrators to successfully apply AI methods in their daily research and practice, develop closer collaborations, and advanced the institution-level learning health system.
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BACKGROUND: Cutaneous melanoma is a cancer arising in melanocyte skin cells and is the deadliest form of skin cancer worldwide. Although some risk factors are known, accurate prediction of disease progression and probability for metastasis are difficult to ascertain, given the complexity of the disease and the absence of reliable predictive markers. Since early detection and treatment are essential to enhance survival, this study utilizing machine learning (ML) aims to further delineate additional risk factors associated with cutaneous melanoma. METHODS: A Bayesian Gaussian Mixture ML model was created with data from 2056 patients diagnosed with cutaneous melanoma and then used to group the patients into six Clusters based on a Silhouette Score analysis. A t-distributed stochastic neighbor embedding (t-SNE) model was used to visualize the six Clusters. RESULTS: Statistical analysis revealed that Cluster 4 showed a significantly higher rate of metastatic disease, as well as higher Breslow depth at diagnosis, compared to the other five Clusters. Compared to the other five Clusters, patients represented in Cluster 4 also had lower healthcare utilization, fewer dermatology clinic visits, fewer primary care providers, and less frequent colonoscopies and mammograms, and were more likely to smoke and less likely to have a prior diagnosis of basal cell carcinoma. CONCLUSIONS: This study uncovers gaps in healthcare utilization of services among patient groups with cutaneous melanoma as well as possible implications for management of disease progression. Data-driven analyses emphasize the importance of routine clinic visits to dermatologists and/or primary care physicians (PCPs) for early detection and management of cutaneous melanoma. The findings from this study demonstrate that unsupervised ML methodology may serve to define the best candidate patients to benefit from enhanced dermatology/primary care which, in turn, is expected to improve outcomes for cutaneous melanoma.
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Melanoma , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/terapia , Melanoma/diagnóstico , Melanoma/terapia , Teorema de Bayes , Aprendizaje Automático , Progresión de la Enfermedad , Melanoma Cutáneo MalignoRESUMEN
OBJECTIVE: ChatGPT is the first large language model (LLM) to reach a large, mainstream audience. Its rapid adoption and exploration by the population at large has sparked a wide range of discussions regarding its acceptable and optimal integration in different areas. In a hybrid (virtual and in-person) panel discussion event, we examined various perspectives regarding the use of ChatGPT in education, research, and healthcare. MATERIALS AND METHODS: We surveyed in-person and online attendees using an audience interaction platform (Slido). We quantitatively analyzed received responses on questions about the use of ChatGPT in various contexts. We compared pairwise categorical groups with a Fisher's Exact. Furthermore, we used qualitative methods to analyze and code discussions. RESULTS: We received 420 responses from an estimated 844 participants (response rate 49.7%). Only 40% of the audience had tried ChatGPT. More trainees had tried ChatGPT compared with faculty. Those who had used ChatGPT were more interested in using it in a wider range of contexts going forwards. Of the three discussed contexts, the greatest uncertainty was shown about using ChatGPT in education. Pros and cons were raised during discussion for the use of this technology in education, research, and healthcare. DISCUSSION: There was a range of perspectives around the uses of ChatGPT in education, research, and healthcare, with still much uncertainty around its acceptability and optimal uses. There were different perspectives from respondents of different roles (trainee vs faculty vs staff). More discussion is needed to explore perceptions around the use of LLMs such as ChatGPT in vital sectors such as education, healthcare and research. Given involved risks and unforeseen challenges, taking a thoughtful and measured approach in adoption would reduce the likelihood of harm.
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Docentes , Integración Escolar , Humanos , Escolaridad , Instituciones de Salud , ProbabilidadRESUMEN
INTRODUCTION: Women with type 2 diabetes (T2DM) are more likely to experience adverse reproductive outcomes, yet preconception care can significantly reduce these risks. For women with T2DM, preconception care includes reproductive planning and patient education on: (1) the importance of achieving glycaemic control before pregnancy, (2) using effective contraception until pregnancy is desired, (3) discontinuing teratogenic medications if pregnancy could occur, (4) taking folic acid, and (5) managing cardiovascular and other risks. Despite its importance, few women with T2DM receive recommended preconception care. METHODS AND ANALYSIS: We are conducting a two-arm, clinic-randomised trial at 51 primary care practices in Chicago, Illinois to evaluate a technology-based strategy to 'hardwire' preconception care for women of reproductive age with T2DM (the PREPARED (Promoting REproductive Planning And REadiness in Diabetes) strategy) versus usual care. PREPARED leverages electronic health record (EHR) technology before and during primary care visits to: (1) promote medication safety, (2) prompt preconception counselling and reproductive planning, and (3) deliver patient-friendly educational tools to reinforce counselling. Post-visit, text messaging is used to: (4) encourage healthy lifestyle behaviours. English and Spanish-speaking women, aged 18-44 years, with T2DM will be enrolled (N=840; n=420 per arm) and will receive either PREPARED or usual care based on their clinic's assignment. Data will be collected from patient interviews and the EHR. Outcomes include haemoglobin A1c (primary), reproductive knowledge and self-management behaviours. We will use generalised linear mixed-effects models (GLMMs) to evaluate the impact of PREPARED on these outcomes. GLMMs will include a fixed effect for treatment assignment (PREPARED vs usual care) and random clinic effects. ETHICS AND DISSEMINATION: This study was approved by the Northwestern University Institutional Review Board (STU00214604). Study results will be published in journals with summaries shared online and with participants upon request. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04976881).
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Diabetes Mellitus Tipo 2 , Embarazo , Humanos , Femenino , Diabetes Mellitus Tipo 2/terapia , Atención Preconceptiva/métodos , Reproducción , Anticoncepción , Ácido Fólico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Peripheral artery disease (PAD) is underdiagnosed due to poor patient and clinician awareness. Despite this, no widely accepted PAD screening is recommended. OBJECTIVES: The authors used machine learning to develop an automated risk stratification tool for identifying patients with a high likelihood of PAD. METHODS: Using data from the electronic health record (EHR), ankle-brachial indices (ABIs) were extracted for 3,298 patients. In addition to ABI, we extracted 60 other patient characteristics and used a random forest model to rank the features by association with ABI. The model identified several features independently correlated with PAD. We then built a logistic regression model to predict PAD status on a validation set of patients (n = 1,089), an external cohort of patients (n = 2,922), and a national database (n = 2,488). The model was compared to an age-based and random forest model. RESULTS: The model had an area under the curve (AUC) of 0.68 in the validation set. When evaluated on an external population using EHR data, it performed similarly with an AUC of 0.68. When evaluated on a national database, it had an AUC of 0.72. The model outperformed an age-based model (AUC: 0.62; P < 0.001). A random forest model with inclusion of all 60 features did not perform significantly better (AUC: 0.71; P = 0.31). CONCLUSIONS: Statistical techniques can be used to build models which identify individuals at high risk for PAD using information accessible from the EHR. Models such as this may allow large health care systems to efficiently identify patients that would benefit from aggressive preventive strategies or targeted-ABI screening.
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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.
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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 2â×â3 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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COVID-19 , Metformina , Adulto , Embarazo , Humanos , Masculino , Femenino , Persona de Mediana Edad , Incidencia , Ivermectina/uso terapéutico , Síndrome Post Agudo de COVID-19 , Tratamiento Farmacológico de COVID-19 , Fluvoxamina , Pacientes Ambulatorios , SARS-CoV-2 , Metformina/uso terapéutico , Método Doble Ciego , Resultado del TratamientoRESUMEN
Current antiviral treatment options for SARS-CoV-2 infections are not available globally, cannot be used with many medications, and are limited to virus-specific targets.1-3 Biophysical modeling of SARS-CoV-2 replication predicted that protein translation is an especially attractive target for antiviral therapy.4 Literature review identified metformin, widely known as a treatment for diabetes, as a potential suppressor of protein translation via targeting of the host mTor pathway.5 In vitro, metformin has antiviral activity against RNA viruses including SARS-CoV-2.6,7 In the COVID-OUT phase 3, randomized, placebo-controlled trial of outpatient treatment of COVID-19, metformin had a 42% reduction in ER visits/hospitalizations/death through 14 days; a 58% reduction in hospitalizations/death through 28 days, and a 42% reduction in Long COVID through 10 months.8,9 Here we show viral load analysis of specimens collected in the COVID-OUT trial that the mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95%CI, -1.05 to -0.06, p=0.027) while there was no virologic effect for ivermectin or fluvoxamine vs placebo. The metformin effect was consistent across subgroups and with emerging data.10,11 Our results demonstrate, consistent with model predictions, that a safe, widely available,12 well-tolerated, and inexpensive oral medication, metformin, can be repurposed to significantly reduce SARS-CoV-2 viral load.
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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 (Pâ =â .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; Pâ =â .85). The vaccinated group had fewer moderate/severe symptoms of subjective fever, chills, myalgias, nausea, and diarrhea (all Pâ <â .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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Allergy mention normalization is challenging because of the wide range of possible allergens including medications, foods, plants, animals, and consumer products. This paper describes the process of mapping free-text allergy information from an electronic health record (EHR) system in a university hospital to standard terminologies and migration of those data into an enterprise EHR system. The review, mapping, and migration revealed interesting issues and challenges with the free-text allergy information and the mapping in preparation for implementation in the new EHR system. These findings provide insights that can form the basis of guidelines for future mapping and migration efforts involving free-text allergy data. As part of this process, we generate and make freely available AllergyMap, a mapping between free-text entered allergy medication to standard non-proprietary ontologies. To our knowledge, this is the first such mapping available and could serve as a public resource for allergy mention normalization and system evaluation.
Asunto(s)
Alérgenos , Minería de Datos , Registros Electrónicos de Salud/normas , Hipersensibilidad , Procesamiento de Lenguaje Natural , Humanos , Sistemas de Registros Médicos Computarizados , Sistemas de Medicación en Hospital , RxNorm , Integración de SistemasRESUMEN
PURPOSE: To examine the extent to which outpatient clinicians currently document drug indications in prescription instructions. METHODS: Free-text sigs were extracted from all outpatient prescriptions generated by the computerized prescriber order entry system of a major academic institution during a 5-year period. Natural language processing was used to identify drug indications. The data set was analyzed to determine the rates at which prescribers included indications. It was stratified by provider specialty, drug class, and specific medications, to determine how often these indications were in prescriptions for as-needed (PRN) versus non-PRN medications. RESULTS: During the study period, 4,356,086 prescriptions were ordered. Indications were included in 322,961 orders (7.41%). From these orders, 249,262 indications (77.18%) were written for PRN orders. Although internal medicine prescribers generated the highest number of medication orders, they included indications in only 6.26% of their prescriptions, whereas orthopedic surgery providers had the highest rate of documenting indications (33.41%). Pain was the most common indication, accounting for 30.35% of all documented indications. The drug class with the highest number of sigs-containing indications was narcotic analgesics. Non-PRN chronic medication prescriptions rarely included the indication. CONCLUSION: Prescribers rarely included drug indications in electronic free-text prescription instructions, and, when they did, it was mostly for PRN uses such as pain.