Design and rationale of GUARDD-US: A pragmatic, randomized trial of genetic testing for APOL1 and pharmacogenomic predictors of antihypertensive efficacy in patients with hypertension.

RATIONALE AND OBJECTIVE: APOL1 risk alleles are associated with increased cardiovascular and chronic kidney disease (CKD) risk. It is unknown whether knowledge of APOL1 risk status motivates patients and providers to attain recommended blood pressure (BP) targets to reduce cardiovascular disease. STUDY DESIGN: Multicenter, pragmatic, randomized controlled clinical trial. SETTING AND PARTICIPANTS: 6650 individuals with African ancestry and hypertension from 13 health systems. INTERVENTION: APOL1 genotyping with clinical decision support (CDS) results are returned to participants and providers immediately (intervention) or at 6 months (control). A subset of participants are re-randomized to pharmacogenomic testing for relevant antihypertensive medications (pharmacogenomic sub-study). CDS alerts encourage appropriate CKD screening and antihypertensive agent use. OUTCOMES: Blood pressure and surveys are assessed at baseline, 3 and 6 months. The primary outcome is change in systolic BP from enrollment to 3 months in individuals with two APOL1 risk alleles. Secondary outcomes include new diagnoses of CKD, systolic blood pressure at 6 months, diastolic BP, and survey results. The pharmacogenomic sub-study will evaluate the relationship of pharmacogenomic genotype and change in systolic BP between baseline and 3 months. RESULTS: To date, the trial has enrolled 3423 participants. CONCLUSIONS: The effect of patient and provider knowledge of APOL1 genotype on systolic blood pressure has not been well-studied. GUARDD-US addresses whether blood pressure improves when patients and providers have this information. GUARDD-US provides a CDS framework for primary care and specialty clinics to incorporate APOL1 genetic risk and pharmacogenomic prescribing in the electronic health record. TRIAL REGISTRATION: ClinicalTrials.govNCT04191824.

Potential inhibitors for SARS-CoV-2 Mpro from marine compounds† † Electronic supplementary information (ESI) available: Marine compounds and docking energy to SARS-CoV-2 Mpro, docked and MD-refined structures of SARS-CoV-2 Mpro + top-lead ligands, pulling force in displacement dependence over FPL simulations, the computational values using FPL simulations of available inhibitors, and ADME profile of potential compounds. See DOI: 10.1039/d1ra03852d

Preventing the biological activity of SARS-CoV-2 main protease using natural compounds is of great interest. In this context, using a combination of AutoDock Vina and fast pulling of ligand simulations, eleven marine fungi compounds were identified that probably play as highly potent inhibitors for preventing viral replication. In particular, four compounds including M15 (3-O-(6-O-α-l-arabinopyranosyl)-β-d-glucopyranosyl-1,4-dimethoxyxanthone), M8 (wailupemycins H), M11 (cottoquinazolines B), and M9 (wailupemycins I) adopted the predicted ligand-binding free energy of −9.87, −9.82, −9.62, and −9.35 kcal mol−1, respectively, whereas the other adopted predicted ligand-binding free energies in the range from −8.54 to −8.94 kcal mol−1. The results were obtained using a combination of Vina and FPL simulations. Notably, although, AutoDock4 adopted higher accurate results in comparison with Vina, Vina is proven to be a more suitable technique for rapidly screening ligand-binding affinity with a large database of compounds since it requires much smaller computing resources. Furthermore, FPL is better than Vina to classify inhibitors upon ROC-AUC analysis. Preventing the biological activity of SARS-CoV-2 main protease using natural compounds is of great interest.

Utilizing a Human-Computer Interaction Approach to Evaluate the Design of Current Pharmacogenomics Clinical Decision Support.

A formal assessment of pharmacogenomics clinical decision support (PGx-CDS) by providers is lacking in the literature. The objective of this study was to evaluate the usability of PGx-CDS tools that have been implemented in a healthcare setting. We enrolled ten prescribing healthcare providers and had them complete a 60-min usability session, which included interacting with two PGx-CDS scenarios using the "Think Aloud" technique, as well as completing the Computer System Usability Questionnaire (CSUQ). Providers reported positive comments, negative comments, and suggestions for the two PGx-CDS during the usability testing. Most provider comments were in favor of the current PGx-CDS design, with the exception of how the genotype and phenotype information is displayed. The mean CSUQ score for the PGx-CDS overall satisfaction was 6.3 ± 0.95, with seven strongly agreeing and one strongly disagreeing for overall satisfaction. The implemented PGx-CDS at our institution was well received by prescribing healthcare providers. The feedback collected from the session will guide future PGx-CDS designs for our healthcare system and provide a framework for other institutions implementing PGx-CDS.

Chloroquine/Hydroxychloroquine Use and Suicide Risk: Hypotheses for Confluent Etiopathogenetic Mechanisms?

Chloroquine (CQ) and hydroxychloroquine (HCQ) are classical anti-malarial and anti-inflammatory treatments, which were used as first-line therapy at the beginning of the 2019 coronavirus disease (COVID-19) pandemic. Besides the emerging data on their lack of efficacy against COVID-19 infection, such treatments have been associated with some severe health concerns, including those of neuropsychiatric nature, such as a possible increase in suicide risk. Here we report a case of a patient with no history of psychiatric illnesses, who abruptly developed depression with melancholic features, severe suicidal ideation (SI), and attempted suicide (SA) shortly after receiving HCQ for his COVID-19 infection. The case was followed by a mini-review of the heterogeneous scientific literature on the hypothetical association between neuropsychiatric symptoms, with a focus on SI and suicidal behavior (SB, including SA and death by suicide), when CQ and HCQ are used in COVID-19, rheumatologic diseases, and malaria settings. Considering the anti-inflammatory properties of CQ and HCQ and the implications for neuroinflammation in suicide pathogenesis, the possible increase in suicide risk caused by these medications appears paradoxical and suggests that other underlying pathological trajectories might account for this eventuality. In this regard, some of these latter mechanistic postulates were proposed. Certainly the role and contribution of psycho-social factors that a COVID-19 patient had to face can neither be minimized nor excluded in the attempt to understand his suffering until the development of SI/SB. However, while this case report represents a rare scenario in clinical practice and no consensus exists in the literature on this topic, a psychiatric screening for suicide risk in patients using of CQ and HCQ could be carefully considered.

Use of Outpatient-Derived COVID-19 Convalescent Plasma in COVID-19 Patients Before Seroconversion.

Background: Transfusion of COVID-19 convalescent plasma (CCP) containing high titers of anti-SARS-CoV-2 antibodies serves as therapy for COVID-19 patients. Transfusions early during disease course was found to be beneficial. Lessons from the SARS-CoV-2 pandemic could inform early responses to future pandemics and may continue to be relevant in lower resource settings. We sought to identify factors correlating to high antibody titers in convalescent plasma donors and understand the magnitude and pharmacokinetic time course of both transfused antibody titers and the endogenous antibody titers in transfused recipients. Methods: Plasma samples were collected up to 174 days after convalescence from 93 CCP donors with mild disease, and from 16 COVID-19 patients before and after transfusion. Using ELISA, anti-SARS-CoV-2 Spike RBD, S1, and N-protein antibodies, as well as capacity of antibodies to block ACE2 from binding to RBD was measured in an in vitro assay. As an estimate for viral load, viral RNA and N-protein plasma levels were assessed in COVID-19 patients. Results: Anti-SARS-CoV-2 antibody levels and RBD-ACE2 blocking capacity were highest within the first 60 days after symptom resolution and markedly decreased after 120 days. Highest antibody titers were found in CCP donors that experienced fever. Effect of transfused CCP was detectable in COVID-19 patients who received high-titer CCP and had not seroconverted at the time of transfusion. Decrease in viral RNA was seen in two of these patients. Conclusion: Our results suggest that high titer CCP should be collected within 60 days after recovery from donors with past fever. The much lower titers conferred by transfused antibodies compared to endogenous production in the patient underscore the importance of providing CCP prior to endogenous seroconversion.

Potential inhibitors for SARS-CoV-2 Mpro from marine compounds.

Preventing the biological activity of SARS-CoV-2 main protease using natural compounds is of great interest. In this context, using a combination of AutoDock Vina and fast pulling of ligand simulations, eleven marine fungi compounds were identified that probably play as highly potent inhibitors for preventing viral replication. In particular, four compounds including M15 (3-O-(6-O-α-l-arabinopyranosyl)-ß-d-glucopyranosyl-1,4-dimethoxyxanthone), M8 (wailupemycins H), M11 (cottoquinazolines B), and M9 (wailupemycins I) adopted the predicted ligand-binding free energy of -9.87, -9.82, -9.62, and -9.35 kcal mol-1, respectively, whereas the other adopted predicted ligand-binding free energies in the range from -8.54 to -8.94 kcal mol-1. The results were obtained using a combination of Vina and FPL simulations. Notably, although, AutoDock4 adopted higher accurate results in comparison with Vina, Vina is proven to be a more suitable technique for rapidly screening ligand-binding affinity with a large database of compounds since it requires much smaller computing resources. Furthermore, FPL is better than Vina to classify inhibitors upon ROC-AUC analysis.

Efficient Identification of High-Titer Anti-Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibody Plasma Samples by Pooling Method.

CONTEXT.­: The ongoing COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has elicited a surge in demand for serologic testing to identify previously infected individuals. In particular, antibody testing is crucial in identifying COVID-19 convalescent plasma, which has been approved by the Food and Drug Administration under the Emergency Use Authorization for use as passive immunotherapy for hospitalized patients infected with COVID-19. Currently, high-titer COVID-19 convalescent plasma can be qualified by Ortho's Vitros COVID-19 IgG antibody test. OBJECTIVE.­: To explore the use of an efficient testing method to identify high-titer COVID-19 convalescent plasma for use in treating COVID-19-infected patients and track COVID-19 positivity over time. DESIGN.­: We evaluated an enzyme-linked immunosorbent assay (ELISA)-based method that detects antibodies specific to the SARS-CoV-2 receptor binding domain (RBD) with individual and pooled plasma samples and compared its performance against the Vitros COVID-19 IgG antibody test. Using the pooled RBD-ELISA (P-RE) method, we also screened more than 10 000 longitudinal healthy blood donor samples to assess seroprevalence. RESULTS.­: P-RE demonstrates 100% sensitivity in detecting Food and Drug Administration-defined high-titer samples when compared with the Vitros COVID-19 IgG antibody test. Overall sensitivity of P-RE when compared with the Vitros COVID-19 IgG antibody test and our individual sample RBD-ELISA (I-RE) were 83% and 56%, respectively. When screening 10 218 healthy blood donor samples by P-RE, we found the seroprevalence correlated with the local infection rates with a correlation coefficient of 0.21 (P < .001). CONCLUSIONS.­: Pooling plasma samples can be used to efficiently screen large populations for individuals with high-titer anti-RBD antibodies, important for COVID-19 convalescent plasma identification.

How the Affective Quality of Social Connections May Contribute to Public Health: Prosocial Tendencies Account for the Links Between Positivity Resonance and Behaviors that Reduce the Spread of COVID-19.

Although behaviors such as handwashing, mask wearing, and social distancing are known to limit viral spread, early in the COVID-19 pandemic, many individuals in the United States did not adopt them. The positivity resonance theory of co-experienced positive affect (Fredrickson, 2016) holds that shared pleasant states that include the key features of mutual care and a sense of oneness through behavioral synchrony function to build prosocial tendencies (e.g., self-transcendent and other-oriented dispositions of felt unity, empathy, altruism, and general positivity toward humanity). We tested the theory-driven hypothesis that prosocial tendencies are associated with high-quality social connections characterized by the affective state of positivity resonance and, in turn, account for behaviors to slow the spread of COVID-19. We measured perceived positivity resonance at the level of social episodes either during the COVID-19 pandemic (study 1, N = 1059, April-May 2020) or before it (study 2, N = 227, March-November 2019). In both studies, cross-sectionally and prospectively, results suggest that perceived positivity resonance had a positive indirect effect on self-reported hygienic behaviors (e.g., handwashing and mask wearing), which was mediated by a latent measure of prosocial tendencies. Sensitivity analyses confirmed these mediation effects to be independent of competing predictors of prosocial tendencies (e.g., overall positive and negative affect, frequency of social interaction) and competing predictors of health behaviors (e.g., political orientation, high-risk status, illness symptoms). Effects for social distancing were mixed. Overall, findings are consistent with the view that positivity resonance builds self-transcendent prosocial tendencies that motivate behaviors to protect community health. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s42761-021-00035-z.

Shared B cell memory to coronaviruses and other pathogens varies in human age groups and tissues.

Vaccination and infection promote the formation, tissue distribution, and clonal evolution of B cells, which encode humoral immune memory. We evaluated pediatric and adult blood and deceased adult organ donor tissues to determine convergent antigen-specific antibody genes of similar sequences shared between individuals. B cell memory varied for different pathogens. Polysaccharide antigen-specific clones were not exclusive to the spleen. Adults had higher clone frequencies and greater class switching in lymphoid tissues than blood, while pediatric blood had abundant class-switched convergent clones. Consistent with reported serology, prepandemic children had class-switched convergent clones to severe acute respiratory syndrome coronavirus 2 with weak cross-reactivity to other coronaviruses, while adult blood or tissues showed few such clones. These results highlight the prominence of early childhood B cell clonal expansions and cross-reactivity for future responses to novel pathogens.

Will Protective Innovations Like the "Airway Box" Become Routine Practice After the Pandemic?: An Opinion Survey.

Background Tracheal intubation carries an elevated risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to the generation of aerosols containing high concentrations of the virus. An airway box was designed to mitigate the exposure of healthcare professionals performing intubations. Aim We evaluated usability and sustainability in the routine practice of the "airway box" as a protective device during high-risk airway procedures.  Materials and methods After institutional review board approval, clinicians were educated on using the device through simulation, intranet learning modules, and emailed resources. The airway box was made available in the emergency department, critical care units, perioperative area, and operating rooms. QR codes affixed to the box, emailed, and displayed in common areas provided easy access to complete a REDcap survey (Vanderbilt University Nashville, USA) eliciting providers' experience. Data was collected and analyzed between April 1 and July 31, 2020, on REDcap, and the results were analyzed. Results 687 emergent intubations took place. 232 were performed by anesthesiologists, 315 by emergency department providers, and 140 by critical care specialists. 39 surveys were completed, 29 from intubations in the operating room, three from the critical care units, five from interventional radiology suites, and two perioperatively. Providers found the device to be readily available, with a score of 4.51/5, and the majority of providers, 60%, found the device easy to use, rating it either a 4 or 5 out of 5. Providers acquired a mean Mallampati score of 1.75 and 1.40 mean laryngoscopic grade view. Conclusion Intubation boxes may effectively mitigate high-risk viral exposure during airway procedures. Survey responses show that devices were easy to use and did not significantly affect visualization of the airway. Similar to mask use, enclosure devices in clinical practice could become a vital part of medical protective equipment even after the SARS-CoV-2 pandemic if they are effectively implemented.