Target-agnostic drug prediction integrated with medical record analysis uncovers differential associations of statins with increased survival in COVID-19 patients.

Drug repurposing requires distinguishing established drug class targets from novel molecule-specific mechanisms and rapidly derisking their therapeutic potential in a time-critical manner, particularly in a pandemic scenario. In response to the challenge to rapidly identify treatment options for COVID-19, several studies reported that statins, as a drug class, reduce mortality in these patients. However, it is unknown if different statins exhibit consistent function or may have varying therapeutic benefit. A Bayesian network tool was used to predict drugs that shift the host transcriptomic response to SARS-CoV-2 infection towards a healthy state. Drugs were predicted using 14 RNA-sequencing datasets from 72 autopsy tissues and 465 COVID-19 patient samples or from cultured human cells and organoids infected with SARS-CoV-2. Top drug predictions included statins, which were then assessed using electronic medical records containing over 4,000 COVID-19 patients on statins to determine mortality risk in patients prescribed specific statins versus untreated matched controls. The same drugs were tested in Vero E6 cells infected with SARS-CoV-2 and human endothelial cells infected with a related OC43 coronavirus. Simvastatin was among the most highly predicted compounds (14/14 datasets) and five other statins, including atorvastatin, were predicted to be active in > 50% of analyses. Analysis of the clinical database revealed that reduced mortality risk was only observed in COVID-19 patients prescribed a subset of statins, including simvastatin and atorvastatin. In vitro testing of SARS-CoV-2 infected cells revealed simvastatin to be a potent direct inhibitor whereas most other statins were less effective. Simvastatin also inhibited OC43 infection and reduced cytokine production in endothelial cells. Statins may differ in their ability to sustain the lives of COVID-19 patients despite having a shared drug target and lipid-modifying mechanism of action. These findings highlight the value of target-agnostic drug prediction coupled with patient databases to identify and clinically evaluate non-obvious mechanisms and derisk and accelerate drug repurposing opportunities.

Heme, Heme Oxygenase-1, Statins, and SARS-CoV-2.

Heme, a metalloporphyrin, or more specifically, a tetrapyrrole containing ferrous iron, is an ancient molecule [...].

Diazoxide Choline Extended-Release Tablet in People With Prader-Willi Syndrome: A Double-Blind, Placebo-Controlled Trial.

CONTEXT: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if not controlled. OBJECTIVE: The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones. METHODS: In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo. RESULTS: DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145]; P = .198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896]; P = .012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P = .029; fat mass; P = .023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P = .037) and secondary end points were all improved (CGI-I; P = .015; Caregiver Global Impression of Change; P = .031; fat mass; P = .003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant). CONCLUSION: DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes.

COVID-19 lockdown emission reductions have the potential to explain over half of the coincident increase in global atmospheric methane

Compared with 2019, measurements of the global growth rate of background (marine air) atmospheric methane rose by 5.3 ppb yr-1 in 2020, reaching 15.0 ppb yr-1. Global atmospheric chemistry models have previously shown that reductions in nitrogen oxide (NOx) emissions reduce levels of the hydroxyl radical (OH) and lengthen the methane lifetime. Acting in the opposite sense, reductions in carbon monoxide (CO) and non-methane volatile organic compound (NMVOC) emissions increase OH and shorten methane's lifetime. Using estimates of NOx, CO, and NMVOC emission reductions associated with COVID-19 lockdowns around the world in 2020 as well as model-derived regional and aviation sensitivities of methane to these emissions, we find that NOx emission reductions led to a 4.8 (3.8 to 5.8) ppb yr-1 increase in the global methane growth rate. Reductions in CO and NMVOC emissions partly counteracted this, changing (reducing) the methane growth rate by -1.4 (-1.1 to -1.7) ppb yr-1 (CO) and -0.5 (-0.1 to -0.9) ppb yr-1 (NMVOC), yielding a net increase of 2.9 (1.7 to 4.0) ppb yr-1. Uncertainties refer to ±1 standard deviation model ranges in sensitivities. Whilst changes in anthropogenic emissions related to COVID-19 lockdowns are probably not the only important factor that influenced methane during 2020, these results indicate that they have had a large impact and that the net effect of NOx, CO, and NMVOC emission changes can explain over half of the observed 2020 methane changes. Large uncertainties remain in both emission changes during the lockdowns and methane's response to them;nevertheless, this analysis suggests that further research into how the atmospheric composition changed over the lockdown periods will help us to interpret past methane changes and to constrain future methane projections.

Characteristic changes of ozone and its precursors in London during COVID-19 lockdown and the ozone surge reason analysis.

The London COVID-19 lockdown reduced emissions from anthropogenic sources, providing unique conditions for air contamination research. This research uses tropospheric ozone (O3), volatile organic compounds (VOCs) and NOx (NO+NO2) hourly monitoring data at the London Marylebone Road station from 2001 to 2020 to investigate the effects of lockdown on (O3) and its precursors. Both NOx and VOCs pollution showed a decreasing trend between 2001 and 2021, with a gradual increase in O3 in contrast. During the COVID-19 lockdown period (from 23rd March to July 4, 2020), there was a surge in O3 concentration, accompanied by a sharp reduction in NOx concentrations. Because all the monitoring VOCs/NOx results were less than eight during the lockdown, indicating that O3 formation in urban London was in the VOC-limited regime. The rapid increase in O3 concentrations caused by the lockdown was closely related to the rapid decrease in NOx emissions.

Mortality Risk Among Patients With COVID-19 Prescribed Selective Serotonin Reuptake Inhibitor Antidepressants.

Importance: Antidepressant use may be associated with reduced levels of several proinflammatory cytokines suggested to be involved with the development of severe COVID-19. An association between the use of selective serotonin reuptake inhibitors (SSRIs)-specifically fluoxetine hydrochloride and fluvoxamine maleate-with decreased mortality among patients with COVID-19 has been reported in recent studies; however, these studies had limited power due to their small size. Objective: To investigate the association of SSRIs with outcomes in patients with COVID-19 by analyzing electronic health records (EHRs). Design, Setting, and Participants: This retrospective cohort study used propensity score matching by demographic characteristics, comorbidities, and medication indication to compare SSRI-treated patients with matched control patients not treated with SSRIs within a large EHR database representing a diverse population of 83 584 patients diagnosed with COVID-19 from January to September 2020 and with a duration of follow-up of as long as 8 months in 87 health care centers across the US. Exposures: Selective serotonin reuptake inhibitors and specifically (1) fluoxetine, (2) fluoxetine or fluvoxamine, and (3) other SSRIs (ie, not fluoxetine or fluvoxamine). Main Outcomes and Measures: Death. Results: A total of 3401 adult patients with COVID-19 prescribed SSRIs (2033 women [59.8%]; mean [SD] age, 63.8 [18.1] years) were identified, with 470 receiving fluoxetine only (280 women [59.6%]; mean [SD] age, 58.5 [18.1] years), 481 receiving fluoxetine or fluvoxamine (285 women [59.3%]; mean [SD] age, 58.7 [18.0] years), and 2898 receiving other SSRIs (1733 women [59.8%]; mean [SD] age, 64.7 [18.0] years) within a defined time frame. When compared with matched untreated control patients, relative risk (RR) of mortality was reduced among patients prescribed any SSRI (497 of 3401 [14.6%] vs 1130 of 6802 [16.6%]; RR, 0.92 [95% CI, 0.85-0.99]; adjusted P = .03); fluoxetine (46 of 470 [9.8%] vs 937 of 7050 [13.3%]; RR, 0.72 [95% CI, 0.54-0.97]; adjusted P = .03); and fluoxetine or fluvoxamine (48 of 481 [10.0%] vs 956 of 7215 [13.3%]; RR, 0.74 [95% CI, 0.55-0.99]; adjusted P = .04). The association between receiving any SSRI that is not fluoxetine or fluvoxamine and risk of death was not statistically significant (447 of 2898 [15.4%] vs 1474 of 8694 [17.0%]; RR, 0.92 [95% CI, 0.84-1.00]; adjusted P = .06). Conclusions and Relevance: These results support evidence that SSRIs may be associated with reduced severity of COVID-19 reflected in the reduced RR of mortality. Further research and randomized clinical trials are needed to elucidate the effect of SSRIs generally, or more specifically of fluoxetine and fluvoxamine, on the severity of COVID-19 outcomes.

Persistence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Virus and Viral RNA in Relation to Surface Type and Contamination Concentration.

The transmission of SARS-CoV-2 is likely to occur through a number of routes, including contact with contaminated surfaces. Many studies have used reverse transcription-PCR (RT-PCR) analysis to detect SARS-CoV-2 RNA on surfaces, but seldom has viable virus been detected. This paper investigates the viability over time of SARS-CoV-2 dried onto a range of materials and compares viability of the virus to RNA copies recovered and whether virus viability is concentration dependent. Viable virus persisted for the longest time on surgical mask material and stainless steel, with a 99.9% reduction in viability by 122 and 114 h, respectively. Viability of SARS-CoV-2 reduced the fastest on a polyester shirt, with a 99.9% reduction within 2.5 h. Viability on the bank note was reduced second fastest, with 99.9% reduction in 75 h. RNA on all surfaces exhibited a 1-log reduction in genome copy number recovery over 21 days. The findings show that SARS-CoV-2 is most stable on nonporous hydrophobic surfaces. RNA is highly stable when dried on surfaces, with only 1-log reduction in recovery over 3 weeks. In comparison, SARS-CoV-2 viability reduced more rapidly, but this loss in viability was found to be independent of starting concentration. Expected levels of SARS-CoV-2 viable environmental surface contamination would lead to undetectable levels within 2 days. Therefore, when RNA is detected on surfaces, it does not directly indicate the presence of viable virus, even at low cycle threshold values. IMPORTANCE This study shows the impact of material type on the viability of SARS-CoV-2 on surfaces. It demonstrates that the decay rate of viable SARS-CoV-2 is independent of starting concentration. However, RNA shows high stability on surfaces over extended periods. This has implications for interpretation of surface sampling results using RT-PCR to determine the possibility of viable virus from a surface, where RT-PCR is not an appropriate technique to determine viable virus. Unless sampled immediately after contamination, it is difficult to align RNA copy numbers to quantity of viable virus on a surface.

Decreased Mortality Rate Among COVID-19 Patients Prescribed Statins: Data From Electronic Health Records in the US.

The severe respiratory illness due to SARS-CoV-2, the virus responsible for coronavirus disease 2019 (COVID-19), is triggered by an intense pro-inflammatory host response. Statins, prescribed primarily for lipid reduction, are known to have anti-inflammatory and immunomodulatory properties and have been associated with a reduced mortality rate among COVID-19 patients taking statins as reported in two recent retrospective studies. However, a meta-analysis that included nine studies showed that statin use did not improve in-hospital outcomes of those with COVID-19. In addition, concerns regarding the use of statins and an increase in COVID-19 infections have been raised, as statins may increase the expression of angiotensin-converting enzyme 2 (ACE2), the primary receptor for the SARS-CoV-2 virus. Our goal was to investigate the effect of statins in COVID-19 patients in a large, diverse patient population across the United States containing nearly 120,000 patients diagnosed with COVID-19. We used propensity score matching of demographics, comorbidities, and medication indication to compare statin-treated patients (N = 2,297) with matched controls (N = 4,594). We observed a small, but statistically significant, decrease in mortality among patients prescribed statins (16.1%) when compared with matched COVID-19-positive controls (18.0 to 20.6%). These results support previous evidence that statins do not increase COVID-19-related mortality and may, in fact, have a mitigating effect on severity of the disease reflected in a slight reduction in mortality. Mixed findings on effects of statins in COVID-19 patients reported in the literature should prompt prospective randomized controlled trials in order to define better who might be advantaged with respect to clinical outcomes.

Nursing home oversight during the COVID-19 pandemic.

BACKGROUND/OBJECTIVES: Regulatory oversight has been a central strategy to assure nursing home quality of care for decades. In response to COVID-19, traditional elements of oversight that relate to resident care have been curtailed in favor of implementing limited infection control surveys and targeted complaint investigations. We seek to describe the state of nursing home oversight during the pandemic to facilitate a discussion of whether and how these activities should be altered going forward. DESIGN AND SETTING: In a retrospective study, we describe national oversight activities in January-June 2020 and compare these activities to the same time period from 2019. We also examine state-level oversight activities during the peak months of the pandemic. PARTICIPANTS: United States nursing homes. DATA: Publicly available Quality, Certification, and Oversight Reports (QCOR) data from the Centers for Medicare and Medicaid Services (CMS). MEASUREMENTS: Number of standard, complaint, and onsite infection surveys, number of deficiencies from standard and complaint surveys, number of citations by deficiency tag, and number and amount of civil monetary penalties. RESULTS: The number of standard and complaint surveys declined considerably in the second quarter of 2020 relative to the same time frame in 2019. Deficiency citations generally decreased to near zero by April 2020 with the exception of infection prevention and control deficiencies and citations for failure to report COVID-19 data to the national health safety network. Related enforcement actions were down considerably in 2020, relative to 2019. CONCLUSION: In the months since COVID-19 first impacted nursing homes, regulatory oversight efforts have fallen off considerably. While CMS implemented universal infection control surveys and targeted complaint investigations, other routine aspects of oversight dropped in light of justifiable limits on nursing home entry. Going forward, we must develop policies that allow regulators to balance the demands of the pandemic while fulfilling their responsibilities effectively.

Reproductive sequelae of parental severe illness before the pandemic: implications for the COVID-19 pandemic.

OBJECTIVE: To investigate, with pre-COVID-19 data, whether parental exposure to severe systemic infections near the time of conception is associated with pregnancy outcomes. DESIGN: Retrospective cohort study. SETTING: Population-based study covering births within the United States from 2009 to 2016. PARTICIPANTS: The IBM MarketScan Research database covers reimbursed health care claims data on inpatient and outpatient encounters that are privately insured through employment-sponsored health insurance. Our analytic sample included pregnancies to paired fathers and mothers. INTERVENTIONS(S): Parental preconception exposure (0-6 months before conception) to severe systemic infection (e.g., sepsis, hypotension, respiratory failure, critical care evaluation). MAIN OUTCOME MEASURE(S): Preterm birth (i.e., live birth before 37 weeks) and pregnancy loss. RESULT(S): A total of 999,866 pregnancies were recorded with 214,057 pregnancy losses (21.4%) and 51,759 preterm births (5.2%). Mothers receiving intensive care in the preconception period had increased risk of pregnancy loss, as did fathers. Mothers with preconception sepsis had higher risk of preterm birth and pregnancy loss, and paternal sepsis exposure was associated with an increased risk of pregnancy loss. Similar results were noted for hypotension. In addition, a dose response was observed for both mothers and fathers between preconception time in intensive care and the risk of preterm birth and pregnancy loss. CONCLUSION(S): In a pre-COVID-19 cohort, parental preconception severe systemic infection was associated with increased odds of preterm birth and pregnancy loss when conception was soon after the illness.