A retrospective study of adverse drug events in anticoagulant administration with relevance to COVID-19.

Initial studies in COVID-19 patients reported lower mortality rates associated with the use of the drug heparin, a widely used anticoagulant. The objective of this analysis was to determine whether there are adverse events associated with the administration of anticoagulants, and specifically how this might apply in patients known to have COVID-19. Data for this study were obtained from the Food and Drug Administration's Adverse Event Reporting System (FAERS) public database and from the NIH's clinical trials website. Proportional Reporting Ratios (PRR) with lower 95% confidence intervals (lower CI) and empirical Bayes geometric mean (EBGM) scores with lower 95% confidence limits were calculated for data from the FAERS database where the adverse events studied mimicked COVID-19 symptoms.

Dumbbell-type triplex molecular switch-based logic molecular assays of SARS-CoV-2.

Accurate detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of great importance to control the COVID-19 pandemic. The gold standard assays for COVID-19 diagnostics are mainly based on separately detecting open reading frame 1ab (ORF1ab) and nucleoprotein (N) genes by RT-PCR. However, the current approaches often obtain false positive-misdiagnose caused by cross-contamination or undesired amplification. To address this issue, herein, we proposed a dumbbell-type triplex molecular switch (DTMS)-based, logic-gated strategy for high-fidelity SARS-CoV-2 RNA detection. The DTMS consists of a triple-helical stem region and two-loop regions for recognizing the ORF1ab and N genes of SARS-CoV-2. Only when the ORF1ab and N gene are concurrent, DTMS experiences a structural rearrangement, thus, bringing the two pyrenes into spacer proximity and leading to a new signal readout. This strategy allows detecting SARS-CoV-2 RNA with a detection limit of 1.3 nM, independent of nucleic acid amplification, holding great potential as an indicator probe for screening of COVID-19 and other population-wide epidemics.

Data mining methodology for response to hypertension symptomology-application to COVID-19-related pharmacovigilance.

Background: Potential therapy and confounding factors including typical co-administered medications, patient's disease states, disease prevalence, patient demographics, medical histories, and reasons for prescribing a drug often are incomplete, conflicting, missing, or uncharacterized in spontaneous adverse drug event (ADE) reporting systems. These missing or incomplete features can affect and limit the application of quantitative methods in pharmacovigilance for meta-analyses of data during randomized clinical trials. Methods: Data from patients with hypertension were retrieved and integrated from the FDA Adverse Event Reporting System; 134 antihypertensive drugs out of 1131 drugs were filtered and then evaluated using the empirical Bayes geometric mean (EBGM) of the posterior distribution to build ADE-drug profiles with an emphasis on the pulmonary ADEs. Afterward, the graphical least absolute shrinkage and selection operator (GLASSO) captured drug associations based on pulmonary ADEs by correcting hidden factors and confounder misclassification. Selected drugs were then compared using the Friedman test in drug classes and clusters obtained from GLASSO. Results: Following multiple filtering stages to exclude insignificant and noise-driven reports, we found that drugs from antihypertensives agents, urologicals, and antithrombotic agents (macitentan, bosentan, epoprostenol, selexipag, sildenafil, tadalafil, and beraprost) form a similar class with a significantly higher incidence of pulmonary ADEs. Macitentan and bosentan were associated with 64% and 56% of pulmonary ADEs, respectively. Because these two medications are prescribed in diseases affecting pulmonary function and may be likely to emerge among the highest reported pulmonary ADEs, in fact, they serve to validate the methods utilized here. Conversely, doxazosin and rilmenidine were found to have the least pulmonary ADEs in selected drugs from hypertension patients. Nifedipine and candesartan were also found by signal detection methods to form a drug cluster, shown by several studies an effective combination of these drugs on lowering blood pressure and appeared an improved side effect profile in comparison with single-agent monotherapy. Conclusions: We consider pulmonary ADE profiles in multiple long-standing groups of therapeutics including antihypertensive agents, antithrombotic agents, beta-blocking agents, calcium channel blockers, or agents acting on the renin-angiotensin system, in patients with hypertension associated with high risk for coronavirus disease 2019 (COVID-19). We found that several individual drugs have significant differences between their drug classes and compared to other drug classes. For instance, macitentan and bosentan from endothelin receptor antagonists show major concern while doxazosin and rilmenidine exhibited the least pulmonary ADEs compared to the outcomes of other drugs. Using techniques in this study, we assessed and confirmed the hypothesis that drugs from the same drug class could have very different pulmonary ADE profiles affecting outcomes in acute respiratory illness. Funding: GJW and MJD accepted funding from BioNexus KC for funding on this project, but BioNexus KC had no direct role in this article.

Facilitating Antiviral Drug Discovery Using Genetic and Evolutionary Knowledge.

Over the course of human history, billions of people worldwide have been infected by various viruses. Despite rapid progress in the development of biomedical techniques, it is still a significant challenge to find promising new antiviral targets and drugs. In the past, antiviral drugs mainly targeted viral proteins when they were used as part of treatment strategies. Since the virus mutation rate is much faster than that of the host, such drugs feature drug resistance and narrow-spectrum antiviral problems. Therefore, the targeting of host molecules has gradually become an important area of research for the development of antiviral drugs. In recent years, rapid advances in high-throughput sequencing techniques have enabled numerous genetic studies (such as genome-wide association studies (GWAS), clustered regularly interspersed short palindromic repeats (CRISPR) screening, etc.) for human diseases, providing valuable genetic and evolutionary resources. Furthermore, it has been revealed that successful drug targets exhibit similar genetic and evolutionary features, which are of great value in identifying promising drug targets and discovering new drugs. Considering these developments, in this article the authors propose a host-targeted antiviral drug discovery strategy based on knowledge of genetics and evolution. We first comprehensively summarized the genetic, subcellular location, and evolutionary features of the human genes that have been successfully used as antiviral targets. Next, the summarized features were used to screen novel druggable antiviral targets and to find potential antiviral drugs, in an attempt to promote the discovery of new antiviral drugs.

[Moxibustion on mental disorder in close contacts of coronavirus disease 2019: a randomized controlled trial].

OBJECTIVE: To observe the effect of moxibustion combined with Daiwenjiu plaster on mental disorder and self rating symptoms in close contacts of coronavirus disease 2019 (COVID-19) during quarantine. METHODS: A total of 240 close contacts of COVID-19 were randomized into an observation group (120 cases, 18 cases dropped off) and a control group (120 cases, 58 cases dropped off). Conventional observation was adopted in the control group. Moxibustion combined with Daiwenjiu plaster was given in the observation group, moxibustion was applied at Zusanli (ST 36), Hegu (LI 4) and Shenque (CV 8), 10 min each acupoint, once a day; Daiwenjiu plaster was applied at Dazhui (GV 14) and Feishu (BL 13) for 3 to 6 h each time, once every 2 days, the treatment was required for 2 weeks. Before and after treatment and in the follow-up of 2 weeks after treatment, self-reporting questionnaire 20 (SRQ-20), self-rating anxiety scale (SAS) scores and self rating symptoms were evaluated in the two groups. RESULTS: In the follow-up, SRQ-20 score was decreased compared before treatment (P<0.01), SAS score was decreased compared before and after treatment (P<0.01, P<0.05) in the observation group. After treatment and in the follow-up, SRQ-20 scores in the observation group were lower than those in the control group (P<0.05, P<0.01). After treatment, the case proportion of fatigue in the observation group was higher than that in the control group (P<0.05). In the follow-up, the case proportion of tension was lower than that in the control group (P<0.05). CONCLUSION: Moxibustion combined with Daiwenjiu plaster can effectively improve the mental disorder in close contacts of COVID-19.

Targeting SARS-CoV-2 Variants with Nucleic Acid Therapeutic Nanoparticle Conjugates.

The emergence of SARS-CoV-2 variants is cause for concern, because these may become resistant to current vaccines and antiviral drugs in development. Current drugs target viral proteins, resulting in a critical need for RNA-targeted nanomedicines. To address this, a comparative analysis of SARS-CoV-2 variants was performed. Several highly conserved sites were identified, of which the most noteworthy is a partial homopurine palindrome site with >99% conservation within the coding region. This sequence was compared among recently emerged, highly infectious SARS-CoV-2 variants. Conservation of the site was maintained among these emerging variants, further contributing to its potential as a regulatory target site for SARS-CoV-2. RNAfold was used to predict the structures of the highly conserved sites, with some resulting structures being common among coronaviridae. An RNA-level regulatory map of the conserved regions of SARS-CoV-2 was produced based on the predicted structures, with each representing potential target sites for antisense oligonucleotides, triplex-forming oligomers, and aptamers. Additionally, homopurine/homopyrimidine sequences within the viral genome were identified. These sequences also demonstrate appropriate target sites for antisense oligonucleotides and triplex-forming oligonucleotides. An experimental strategy to investigate these is summarized along with potential nanoparticle types for delivery, and the advantages and disadvantages of each are discussed.

Electronic Consults (eConsults) in the Largest Public Health System to Improve Timely Access to Specialty Care

Research ObjectiveTo improve access to specialty care, NYC Health + Hospitals (H + H), the nation's largest public health system serving over 1 million New Yorkers, implemented eConsult in 2016 – an electronic health record (EHR) integrated referral management system. A pre‐ and post‐intervention study that was conducted early on in the pilot showed that the eConsult implementation was associated with substantial reduction in wait times for specialty care appointments. However, due to an enterprise EHR upgrade and referral operational change during the prior study period, comparative evidence controlling for time‐varying factors is needed to support inference. Now that eConsult has been expanded further, we have a more stable study sample to evaluate the impact of eConsult on access to specialty care.Study DesignWe used a quasi‐experimental difference‐in‐difference approach with data from January 2018 to December 2020. Data from March–May 2020 was excluded due to the NYC COVID‐19 first wave outbreak. Non‐eConsult clinics (controls) were matched to each eConsult clinic based on specialty and parallel trend. Our primary outcome was the percentage of referrals scheduled for an appointment occurring within 30 days. Secondary outcomes were monthly number of referrals requiring appointment and the percentage of referrals resolved without appointment. We performed bivariate comparison to assess any differences during pre and post implementation for both eConsult and control groups. eConsult main effect was estimated by multi‐level log‐binomial model with random intercepts of comparison groups and clinic as well as fixed effects of eConsult program and pre/post periods. Generalized estimating equations (GEE) were also run for each comparison pair to investigate variation among specialties.Population StudiedWe identified 125,708 referrals in 15 eConsult clinics and 20 non‐eConsult clinics across 10 hospitals at NYC H + H. Nine specialties were identified: hematology, dermatology, otolaryngology, general surgery, neurology, orthopedic surgery, podiatry, pulmonary, and rehabilitation.Principal FindingsAfter implementation, the monthly number of referrals requiring appointments decreased 27.7% in eConsult clinics (271 to 196, p < 0.001) but increased 16% in control clinics (243 to 281, p < 0.001);within 30 days, the scheduled appointment rate increased by 30% in eConsult clinics (25.4% to 40.7%, p < 0.001) but decreased by 7% in control clinics (29.5% to 27.4%, p < 0.001). In eConsult clinics, 7% of referrals were resolved without an appointment (ranged 1% to 22%). Multi‐level model showed the adjusted eConsult program effect is RR = 1.53 (95% CI: 1.48–1.59). GEE models showed effect sizes differ by comparison pairs (RR ranged 0.73–7.06,10 out of 13 pairs showed improvement).ConclusionsThe increased rate of appointments received within 30 days and the reduction of assumed unnecessary visits were greater among eConsult clinics, varied by specialty. The eConsult rate in this sample is substantially smaller than the overall H + H eConsult rate as well as that reported from other health systems, indicating that the reduction in referral visit demand might not be the only mediator. Programmatic engagement to streamline referral workflow and referring provider behavior change might also be driving factors.Implications for Policy or PracticeeConsult implementation could lead to improved access to specialty care in addition to other programmatic enhancements, ongoing support and monitoring of referral management workflows and practitioner edification value.

Pulmonary adverse drug event data in hypertension with implications on COVID-19 morbidity.

Hypertension is a recognized comorbidity for COVID-19. The association of antihypertensive medications with outcomes in patients with hypertension is not fully described. However, angiotensin-converting enzyme 2 (ACE2), responsible for host entry of the novel coronavirus (SARS-CoV-2) leading to COVID-19, is postulated to be upregulated in patients taking angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). Here, we evaluated the occurrence of pulmonary adverse drug events (ADEs) in patients with hypertension receiving ACEIs/ARBs to determine if disparities exist between individual drugs within the respective classes using data from the FDA Spontaneous Reporting Systems. For this purpose, we proposed the proportional reporting ratio to provide a statistical summary for the commonality of an ADE for a specific drug as compared to the entire database for drugs in the same or other classes. In addition, a statistical procedure, multiple logistic regression analysis, was employed to correct hidden confounders when causative covariates are underreported or untrusted to correct analyses of drug-ADE combinations. To date, analyses have been focused on drug classes rather than individual drugs which may have different ADE profiles depending on the underlying diseases present. A retrospective analysis of thirteen pulmonary ADEs showed significant differences associated with quinapril and trandolapril, compared to other ACEIs and ARBs. Specifically, quinapril and trandolapril were found to have a statistically significantly higher incidence of pulmonary ADEs compared with other ACEIs as well as ARBs (P < 0.0001) for group comparison (i.e., ACEIs vs. ARBs vs. quinapril vs. trandolapril) and (P ≤ 0.0007) for pairwise comparison (i.e., ACEIs vs. quinapril, ACEIs vs. trandolapril, ARBs vs. quinapril, or ARBs vs. trandolapril). This study suggests that specific members of the ACEI antihypertensive class (quinapril and trandolapril) have a significantly higher cluster of pulmonary ADEs.

Pharmacovigilance in patients with diabetes: A data-driven analysis identifying specific RAS antagonists with adverse pulmonary safety profiles that have implications for COVID-19 morbidity and mortality.

OBJECTIVES: The current demographic information from China reports that 10%-19% of patients hospitalized with coronavirus disease (COVID-19) were diabetic. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are considered first-line agents in patients with diabetes because of their nephroprotective effects, but administration of these drugs leads to upregulation of angiotensin-converting enzyme 2 (ACE2), which is responsible for the viral entry of severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2). Data are lacking to determine what pulmonary effects ACEIs or ARBs may have in patients with diabetes, which could be relevant in the management of patients infected with SARS-CoV-2. This study aims to assess the prevalence of pulmonary adverse drug effects (ADEs) in patients with diabetes who were taking ACEI or ARBs to provide guidance as to how these medications could affect outcomes in acute respiratory illnesses such as SARS-CoV-2 infection. METHODS: 1DATA, a unique data platform resulting from collaboration across veterinary and human health care, used an intelligent medicine recommender system (1DrugAssist) developed using several national and international databases to evaluate all ADEs reported to the Food and Drug Administration for patients with diabetes taking ACEIs or ARBs. RESULTS: Mining of this data elucidated the proportion of a cluster of pulmonary ADEs associated with specific medications in these classes, which may aid health care professionals in understanding how these medications could worsen or predispose patients with diabetes to infections affecting the respiratory system, specifically COVID-19. Based on this data mining process, captopril was found to have a statistically significantly higher incidence of pulmonary ADEs compared with other ACEIs (P = 0.005) as well as ARBs (P = 0.012), though other specific drugs also had important pulmonary ADEs associated with their use. CONCLUSION: These analyses suggest that pharmacists and clinicians will need to consider the specific medication's adverse event profile, particularly captopril, on how it may affect infections and other acute disease states that alter pulmonary function, such as COVID-19.

Clinical characteristics of patients with 2019 coronavirus disease in a non-Wuhan area of Hubei Province, China: a retrospective study.

BACKGROUND: Since December 2019, the 2019 coronavirus disease (COVID-19) has expanded to cause a worldwide outbreak that more than 600,000 people infected and tens of thousands died. To date, the clinical characteristics of COVID-19 patients in the non-Wuhan areas of Hubei Province in China have not been described. METHODS: We retrospectively analyzed the clinical characteristics and treatment progress of 91 patients diagnosed with COVID-19 in Jingzhou Central Hospital. RESULTS: Of the 91 patients diagnosed with COVID-19, 30 cases (33.0%) were severe and two patients (2.2%) died. The severe disease group tended to be older (50.5 vs. 42.0 years; p = 0.049) and have more chronic disease (40% vs. 14.8%; p = 0.009) relative to mild disease group. Only 73.6% of the patients were quantitative polymerase chain reaction (qPCR)-positive on their first tests, while typical chest computed tomography images were obtained for each patient. The most common complaints were cough (n = 75; 82.4%), fever (n = 59; 64.8%), fatigue (n = 35; 38.5%), and diarrhea (n = 14; 15.4%). Non-respiratory injury was identified by elevated levels of aspartate aminotransferase (n = 18; 19.8%), creatinine (n = 5; 5.5%), and creatine kinase (n = 14; 15.4%) in laboratory tests. Twenty-eight cases (30.8%) suffered non-respiratory injury, including 50% of the critically ill patients and 21.3% of the mild patients. CONCLUSIONS: Overall, the mortality rate of patients in Jingzhou was lower than that of Wuhan. Importantly, we found liver, kidney, digestive tract, and heart injuries in COVID-19 cases besides respiratory problems. Combining chest computed tomography images with the qPCR analysis of throat swab samples can improve the accuracy of COVID-19 diagnosis.