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.

Preliminary Validity of a Telephone-Based Neuropsychological Battery in a Consecutive Series of Persons with HIV Disease Referred for Clinical Evaluation.

OBJECTIVE: The COVID-19 pandemic necessitated use of remote assessments by clinical neuropsychologists. Telehealth was particularly important for vulnerable groups, including persons living with HIV (PLWH); however, limited internet access can be a serious barrier to care. This study examined the preliminary validity of a telephone-based neuropsychological assessment in a clinical sample of PLWH. METHOD: A consecutive series of 59 PLWH were assessed via telephone at an HIV clinic in the southern U.S. between April 2020 and July 2022. The battery included auditory-verbal neuropsychological tests of memory, attention, and executive functions, and questionnaires assessing self-reported mood and activities of daily living (ADL). RESULTS: Study measures demonstrated acceptable internal consistency. PLWH demonstrated worse neuropsychological performance compared with expectations derived from the normal curve and an HIV-seronegative adult sample (N = 44). PLWH assessed via telephone demonstrated similar impairment rates to that of a consecutive series of PLWH (N = 41) assessed in-person immediately prior to the pandemic. Higher telephone-based global neuropsychological scores were related to younger age, more education, better fund of knowledge, White race/ethnicity, fewer medical conditions, and fewer depression symptoms. Global neuropsychological impairment was strongly and independently associated with greater dependence in ADL domains, particularly for instrumental activities. CONCLUSIONS: Although telephone-based approaches to neuropsychological assessment are not ideal, these data provide support for the feasibility, internal consistency, and preliminary validity of this method in a consecutive clinical series of PLWH. The direct comparability of telephone-based and in-person neuropsychological assessments remains to be determined by prospective, counterbalanced study designs examining both PLWH and seronegative individuals.

Are accuracy discernment and sharing of COVID-19 misinformation associated with older age and lower neurocognitive functioning?

The online proliferation of COVID-19 misinformation led to adverse health and societal consequences. This study investigated possible differences in COVID-19 headline accuracy discernment and online sharing of COVID-19 misinformation between older and younger adults, as well as the role of individual differences in global cognition, health literacy and verbal IQ. Fifty-two younger (18–35 years old) and fifty older adults (age 50 and older) completed a neurocognitive battery, health literacy and numeracy measures, and self-report questionnaires via telephone. Participants also completed a social media headline-sharing experiment (Pennycook et al., Psychological science, 31(7), 770–780, 2020) in which they were presented with true and false COVID-19 headlines about which they indicated: 1) the likelihood that they would share the story on social media;and 2) the factual accuracy of the story. A repeated measures multivariate analysis of variance controlling for gender and race/ethnicity showed no effects of age (p = .099) but a significant interaction between actual COVID-19 headline accuracy and the likelihood of sharing (p < .001), such that accuracy was more strongly related to sharing false headlines (r = −.64) versus true headlines (r = −.43). Moreover, a higher likelihood of sharing false COVID-19 headlines was associated with lower verbal IQ and numeracy skills in older adults (rs = −.51--.40) and with lower verbal IQ, numeracy, and global cognition in younger adults (rs = −.66--.60). Findings indicate that headline accuracy judgements, numeracy, and verbal IQ are important contributors to sharing COVID-19 misinformation in both older and younger adults. Future work might examine the benefits of psychoeducation for improving health and science literacy for COVID-19. Supplementary Information The online version contains supplementary material available at 10.1007/s12144-023-04464-w.

Are accuracy discernment and sharing of COVID-19 misinformation associated with older age and lower neurocognitive functioning?

The online proliferation of COVID-19 misinformation led to adverse health and societal consequences. This study investigated possible differences in COVID-19 headline accuracy discernment and online sharing of COVID-19 misinformation between older and younger adults, as well as the role of individual differences in global cognition, health literacy and verbal IQ. Fifty-two younger (18-35 years old) and fifty older adults (age 50 and older) completed a neurocognitive battery, health literacy and numeracy measures, and self-report questionnaires via telephone. Participants also completed a social media headline-sharing experiment (Pennycook et al., Psychological science, 31(7), 770-780, 2020) in which they were presented with true and false COVID-19 headlines about which they indicated: 1) the likelihood that they would share the story on social media; and 2) the factual accuracy of the story. A repeated measures multivariate analysis of variance controlling for gender and race/ethnicity showed no effects of age (p = .099) but a significant interaction between actual COVID-19 headline accuracy and the likelihood of sharing (p < .001), such that accuracy was more strongly related to sharing false headlines (r = -.64) versus true headlines (r = -.43). Moreover, a higher likelihood of sharing false COVID-19 headlines was associated with lower verbal IQ and numeracy skills in older adults (rs = -.51--.40) and with lower verbal IQ, numeracy, and global cognition in younger adults (rs = -.66--.60). Findings indicate that headline accuracy judgements, numeracy, and verbal IQ are important contributors to sharing COVID-19 misinformation in both older and younger adults. Future work might examine the benefits of psychoeducation for improving health and science literacy for COVID-19. Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-023-04464-w.

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.).

How did individual differences in neurocognition and health literacy influence the initial uptake and use of health-related information about COVID-19?

Introduction: The rapid development of coronavirus disease 2019 (COVID-19) into a pandemic required people to quickly acquire, evaluate, and apply novel complex health-related information about the virus and transmission risks. This study examined the potentially unique and synergistic roles of individual differences in neurocognition and health literacy in the early uptake and use of COVID-19 public health information.Method: Data were collected between April 23 and 21 May 2020, a period during which 42 out of 50 states were under a stay-at-home order. Participants were 217 healthy adults who completed a telephone-based battery that included standard tests of neurocognition, health literacy, verbal IQ, personality, and anxiety. Participants also completed measures of COVID-19 information-seeking skills, knowledge, prevention intentions, and prevention behaviors.Results: A series of hierarchical multiple regressions with data-driven covariates showed that neurocognition (viz, episodic verbal memory and executive functions) was independently related to COVID-19 knowledge (e.g. symptoms, risks) at a medium effect size, but not to information-seeking skills, prevention intentions, or prevention behaviors. Health literacy was independently related to all measured aspects of COVID-19 health information and did not interact with neurocognition in any COVID-19 health domain.Conclusions: Individual differences in neurocognition and health literacy played independent and meaningful roles in the initial acquisition of knowledge related to COVID-19, which is a novel human health condition. Future studies might examine whether neurocognitive supports (e.g. spaced retrieval practice, elaboration) can improve COVID-19-related knowledge and health behaviors in vulnerable populations.

COVID-19-related disease severity in pregnancy.

The pandemic caused by COVID-19 is affecting populations and healthcare systems worldwide. As we gain experience managing COVID-19, more data become available on disease severity, course, and treatment in patients infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, data in pregnancy remain limited. This narrative review of COVID-19 during pregnancy underscores key knowledge gaps in our understanding of the impact of this viral infection on reproductive health. Current data suggest that pregnant people have similar disease course and outcomes compared to nonpregnant people, with the majority experiencing mild disease; however, pregnant people may have increased risk of hospitalization and intensive care unit (ICU) admission. Among patients who develop severe and critical disease, major maternal morbidity and mortality have been described including cardiomyopathy, mechanical ventilation, extracorporeal membrane oxygenation, and death. Many questions remain regarding maternal severity of disease in COVID-19. Further research is needed to better understand disease course in pregnancy. Additionally, the inclusion of pregnant patients in therapeutic trials will provide vital data on treatment options for patients. As we continue to treat more patients affected by SARS-CoV-2, multidisciplinary care and continued research are both needed to achieve optimal outcomes for mother and fetus.