Binding of Nucleotide Inhibitors to the NS5 RdRp of the ZIKA Virus in the Replication Initiation State.

INTRODUCTION: The bindings of several ribonucleoside triphosphate (NTP) inhibitors to the RNA-dependent RNA polymerase (RdRp) of the Zika virus (ZIKV) are studied herein to identify potential drug-like candidates that can inhibit the replication of the viral genome by RdRp. METHOD: In this study, a guanosine triphosphate (GTP) bound RdRp structure is generated to model the replication initiation state of RdRp. Subsequently, the bindings of 30 NTP inhibitors to the GTP binding site of RdRp are studied in detail by using the molecular docking method. Based on the docking scores, four NTP inhibitors, such as 2'-Cmethyl- adenosine-5'-triphosphate (mATP), 7-deaza-2'-C-methyladenosine-TP (daza-- mATP), 1-N6-Ethenoadenosine-5'-triphosphate (eATP), and Remdesivir-5'-triphosphate (RTP) are shortlisted for further analysis by employing molecular dynamics simulations and binding free-energy methods. RESULTS: These inhibitors are found to bind to RdRp quite strongly, as evident from their relative binding free energies that lie between -31.54±4.54 to -89.46±4.58 kcal/- mol. As the binding of RTP to the GTP site of RdRp generates the most stable complex, which is about 45 kcal/mol more stable than the binding of GTP to RdRp, it is most likely that RTP may inhibit the replication of the Zika viral genome efficiently. CONCLUSION: However, experimental studies are required to measure the potency of RTP and other drugs before their clinical use.

Structure and stability of different triplets involving artificial nucleobases: clues for the formation of semisynthetic triple helical DNA.

A triple helical DNA can control gene expression, help in homologous recombination, induce mutations to facilitate DNA repair mechanisms, suppress oncogene formations, etc. However, the structure and function of semisynthetic triple helical DNA are not known. To understand this, various triplets formed between eight artificial nucleobases (P, Z, J, V, B, S, X, and K) and four natural DNA bases (G, C, A, and T) are studied herein by employing a reliable density functional theoretic (DFT) method. Initially, the triple helix-forming artificial nucleobases interacted with the duplex DNA containing GC and AT base pairs, and subsequently, triple helix-forming natural bases (G and C) interacted with artificial duplex DNA containing PZ, JV, BS, and XK base pairs. Among the different triplets formed in the first category, the C-JV triplet is found to be the most stable with a binding energy of about - 31 kcal/mol. Similarly, among the second category of triplets, the Z-GC and V-GC triplets are the most stable. Interestingly, Z-GC and V-GC are found to be isoenergetic with a binding energy of about - 30 kcal/mol. The C-JV, and Z-GC or V-GC triplets are about 12-14 kcal/mol more stable than the JV and GC base pairs respectively. Microsolvation of these triplets in 5 explicit water molecules further enhanced their stability by 16-21 kcal/mol. These results along with the consecutive stacking of the C-JV triplet (C-JV/C-JV) data indicate that the synthetic nucleobases can form stable semisynthetic triple helical DNA. However, consideration of a full-length DNA containing one or more semisynthetic bases or base pairs is necessary to understand the formation of semisynthetic DNA in living cells.

Repurposing of antiparasitic drugs against the NS2B-NS3 protease of the Zika virus.

To date, no approved drugs are available to treat the Zika virus (ZIKV) infection. Therefore, it is necessary to urgently identify potential drugs against the ZIKV infection. Here, the repurposing of 30 antiparasitic drugs against the NS2B-NS3 protease of the ZIKV has been carried out by using combined docking and molecular dynamics- (MD) simulations. Based on the docking results, 5 drugs, such as Amodiaquine, Primaquine, Paromomycin, Dichlorophene, and Ivermectin were screened for further analysis by MD simulations and free energy calculations. Among these drugs, Amodiaquine and Dichlorophen are found to produce the most stable complexes and possess relative binding free energies of about -44.3 ± 3.7 kcal/mol and -41.1 ± 5.3 kcal/mol respectively. Therefore, they would act as potent small-molecule inhibitors of the ZIKV protease.However, evaluations of biological and safety activities of these drugs against the ZIKV protease are required before their clinical use.Communicated by Ramaswamy H. Sarma.

Peptide inhibitors derived from the nsp7 and nsp8 cofactors of nsp12 targeting different substrate binding sites of nsp12 of the SARS-CoV-2.

SARS-COV-2 is responsible for the COVID-19 pandemic, which has infected more than 767 million people worldwide including about 7 million deaths till 5 June 2023. Despite the emergency use of certain vaccines, deaths due to COVID-19 have not yet stopped completed. Therefore, it is imperative to design and develop drugs that can be used to treat patients suffering from COVID-19. Here, two peptide inhibitors derived from nsp7 and nsp8 cofactors of nsp12 have been shown to block different substrate binding sites of nsp12 that are mainly responsible for the replication of the viral genome of SARS-CoV-2. By using the docking, molecular dynamics (MD), and MM/GBSA techniques, it is shown that these inhibitors can bind to multiple binding sites of nsp12, such as the interface of nsp7 and nsp12, interface of nsp8 and nsp12, RNA primer entry site, and nucleoside triphosphate (NTP) entry site. The relative binding free energies of the most stable protein-peptide complexes are found to lie between ∼-34.20 ± 10.07 to -59.54 ± 9.96 kcal/mol. Hence, it is likely that these inhibitors may bind to different sites of nsp12 to block the access of its cofactors and the viral genome, thereby affecting the replication. It is thus proposed that these peptide inhibitors may be further developed as potential drug candidates to suppress the viral loads in COVID-19 patients.Communicated by Ramaswamy H. Sarma.

Complementary base pair interactions between different rare tautomers of the second-generation artificial genetic alphabets.

The functionality of a semisynthetic DNA in the biological environment will depend on the base pair nature of its complementary base pairs. To understand this, base pair interactions between complementary bases of recently proposed eight second-generation artificial nucleobases are studied herein by considering their rare tautomeric conformations and a dispersion-corrected density functional theoretic method. It is found that the binding energies of two hydrogen-bonded complementary base pairs are more negative than those of the three hydrogen-bonded base pairs. However, as the former base pairs are endothermic, the semisynthetic duplex DNA would involve the latter base pairs.

Posttraumatic stress symptom severity predicts cognitive decline beyond the effect of Alzheimer's disease biomarkers in Veterans.

Chronic stress is a risk factor for dementia but whether it explains unique variance in cognitive decline in older adults above Alzheimer's disease (AD) biomarkers is unknown. In a preclinical cohort of Vietnam Veterans, we examined the relationship between posttraumatic stress disorder (PTSD) symptom severity, AD biomarkers of beta-amyloid (Aß) and tau, and change in cognitive performance on two widely-used screeners, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Analyses indicated that PTSD symptom severity was associated with a greater decline on the MMSE (p < 0.04) and MoCA (p < 0.024) after adjusting for biomarkers of AD, notably on the attention scale of the MoCA and the memory index of the MMSE. These analyses survived multiple comparison corrections. Taken together, PTSD symptom severity is associated with accelerated cognitive decline. Treating PTSD should be considered instrumental to maintaining cognitive function as adults age.

Hybrid nucleobases as new and efficient unnatural genetic letters.

To expand the existing genetic letters beyond the natural four nucleotides, such as G, C, A, and T, it is necessary to design robust nucleotides that can not only produce stable and unperturbed DNA but also function naturally in living cells. Although hydrophobic bases, such as d5SICS (2,6-dimethyl-2H-isoquiniline-1-thione) and dNaM (2-methoxy-3-methylnaphthalene) were shown to be replicated in bacterial cells, the d5SICS:dNaM base-pair was found to perturb the structure of the duplex DNA. Therefore, it is necessary to design nucleobases that can form base pairs like the natural G:C and A:T pairs. Here, a reliable dispersion-corrected density functional theory has been used to design several nucleobases that can produce three-hydrogen-bonded base pairs like the G:C pair. In doing so, the Watson-Crick faces of d5SICS and dNaM were modified by replacing the hydrophobic groups with hydrogen bond donors and acceptors. As dNaM contains an unnatural C-glycosidic bond (C-dNaM), it was also modified to contain the natural N-glycosidic bond (N-dNaM). This technique produced 91 new bases (N-d5SICS-X (X = 1-33), C-dNaM-X (X = 1-35), and N-dNaM-X (X = 1-23), where X is the different types of modifications applied to d5SICS and dNaM) and 259 base-pairs. Among these base pairs, 76 base pairs are found to be more stable than the G:C pair. Interestingly, the N-d5SICS-32:C-dNaM-32 and N-d5SICS-32:N-dNaM-20 pairs are found to be the most stable with binding energies of about -28.0 kcal/mol. The base-pair patterns of these pairs are also analogous to that of the G:C pair. Hence, it is proposed that N-d5SICS-32, C-dNaM-32, and N-dNaM-20 would act as efficient new genetic letters to produce stable and unperturbed artificial DNA.Communicated by Ramaswamy H. Sarma.

Structures and dynamics of peptide and peptidomimetic inhibitors bound to the NS2B-NS3 protease of the ZIKA virus.

Infections caused by the Zika virus (ZIKV) have detrimental effects on human health, in particular on infants. As no potent drug or vaccine is available to date to contain this viral disease, it is necessary to design inhibitors that can target the NS2B-NS3 protease of the ZIKV, which is mainly responsible for the proliferation of the virus inside the host cells . Here, molecular dynamics (MD) simulation and molecular mechanics energies combined with the generalized Born and surface area continuum solvation model (MM/GBSA) are used to understand the binding modes and stabilities of R, KR, KKR, WKR, WKKR, YKKR, and FKKR peptide inhibitors bound to the NS3-NS2B protease. The results are compared with the corresponding results obtained for covalent (compound 1) and non-covalent (compound 4*) peptidomimetic inhibitors . It is revealed that peptide inhibitors can bind strongly with the ZIKV protease with the ΔGbind ranging from -12 kcal/mol to -73 kcal/mol. Among these peptides, YKKR is found to make the most stable complex with the protease and fully occupy the electrostatically active substrate binding site. Hence, it would inhibit the protease activities of ZIKV strongly. The residue-wise decomposition of ΔGbind indicates that Asp75, Asp129, Tyr130, Ser135, Gly151, Asn152, Glys153, and Tyr161 of NS3 and Ser81, Asp83, and Phe84 of NS2B play a prominent role in the inhibitor binding. Therefore, any future design of inhibitors should be aimed to target these residues.

Age of First Concussion and Cognitive, Psychological, and Physical Outcomes in NCAA Collegiate Student Athletes.

OBJECTIVE: Concussions are common among youth athletes and could disrupt critical neurodevelopment. This study examined the association between age of first concussion (AFC) and neurocognitive performance, psychological distress, postural stability, and symptoms commonly associated with concussion in healthy collegiate men and women student athletes. METHODS: Participants included 4267 collegiate athletes from various contact, limited-contact, and non-contact sports (1818 women and 2449 men) who completed baseline assessments as part of the Concussion Assessment, Research and Education (CARE) Consortium. Psychological distress was assessed with the Brief Symptom Inventory 18; neurocognitive performance was assessed with the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT); symptoms commonly associated with concussion were assessed with the ImPACT Post-Concussion Symptom Scale; postural stability was assessed with the Balance Error Scoring System. Generalized linear models were used to examine the effects of AFC on clinical outcomes separately in men and women. RESULTS: Later AFC was associated with lower global (Exp(B) = 0.96, P = 0.001) and somatic (Exp(B) = 0.96, P = 0.002) psychological distress on the Brief Symptom Inventory 18 and faster ImPACT reaction time (B = - 0.003, P = 0.001) in women. AFC was not associated with any clinical outcomes in men. CONCLUSION: Younger AFC was associated with some differences in psychological distress and reaction time among women but not men; however, these results are likely not clinically meaningful. Sociodemographic disparities, pre-existing conditions, and sport type may impact clinical and cognitive outcomes in collegiate athletes more than concussion history. Future work should examine the relationship between AFC and lifespan-related outcomes.

Posttraumatic stress disorder symptom severity is associated with reduced Montreal Cognitive Assessment scores in a sample of Vietnam War Veterans.

The goal of the present study was to examine associations between posttraumatic stress disorder (PTSD) symptom severity, the number of stressors experienced, and cognitive outcomes in a sample of U.S. Vietnam War Veterans (N = 274). Adults between 60 and 85 years of age completed a Vietnam Veterans Alzheimer's Disease Neuroimaging Initiative Project visit. A modified version of the Life Stressor Checklist-Revised (LSC-R) was used to assess the number of stressful experiences participants experienced, current PTSD severity scores were measured via the Clinician-Administered PTSD Scale for DSM-IV (CAPS-IV), and cognition was assessed using the Montreal Cognitive Assessment (MoCA). Linear regressions were conducted to examine the effect of CAPS-IV and LSC-R scores on cognitive performance. Higher CAPS-IV scores were associated with worse cognitive outcomes on the MoCA, ΔF(1, 264) = 12.686, p < .001, R2 = .142. In contrast, the number of reported stressful experiences was not associated with cognitive outcomes. After accounting for multiple comparisons, findings indicated that CAPS-IV severity scores were significantly associated with the MoCA memory index. In a sample of older Veterans, PTSD symptom severity, but not the number of reported stressors, was associated with poorer performance on a well-established cognitive function screening tool. Analyses of specific MoCA domains indicated that memory may be driving this association. These findings suggest that highly arousing stressors characteristic of PTSD, rather than stressful experiences more broadly, contribute to this association. Future work can use these findings to explore whether treating PTSD symptoms may help maintain cognitive function during the aging process.

Contribution of cerebral microvascular mechanisms to age-related cognitive impairment and dementia.

Cognitive impairment and dementia are significant health burdens worldwide. Aging, hypertension, and diabetes are the primary risk factors for Alzheimer's disease and Alzheimer's disease and related dementias (AD/ADRD). There are no effective treatments for AD/ADRD to date. An emerging body of evidence indicates that cerebral vascular dysfunction and hypoperfusion precedes the development of other AD pathological phenotypes and cognitive impairment. However, vascular contribution to dementia is not currently well understood. This commentary highlights the emerging concepts and mechanisms underlying the microvascular contribution to AD/ADRD, including hypotheses targeting the anterograde and retrograde cerebral vascular pathways, as well as the cerebral capillaries and the venous system. We also briefly discuss vascular endothelial dysfunction, oxidative stress, inflammation, and cellular senescence that may contribute to impaired cerebral blood flow autoregulation, neurovascular uncoupling, and dysfunction of cerebral capillaries and the venous system.

Rare Tautomers of Artificially Expanded Genetic Letters and their Effects on the Base Pair Stabilities.

In order to expand the existing genetic letters, it is necessary to design robust nucleotides that can function naturally in living cells. Therefore, it is desirable to examine the roles of recently-proposed second-generation artificially genetic letters in producing stable duplex DNA. Herein, a reliable dispersion-corrected density functional theory method is used to shed light on the electronic structures and properties of different rare tautomers of proposed expanded genetic letters and their effects on the base pair stabilities in the duplex DNA. It is found that the rare tautomers are not only stable in the aqueous medium but can also pair with natural bases to produce stable mispairs. Except for J and V, all of the artificial genetic letters are found to produce mispairs that are about 1-7 kcal mol-1 more stable than their complementary counterparts. They are also appreciably more stable than the naturally occurring G : C, A : T, and G : T pairs. Mainly attractive electrostatic interactions and polarity of the monomers are responsible for the higher base pair stabilities.

The COVID-19 Pandemic and Access to Selected Ambulatory Care Services Among Populations With Severely Uncontrolled Diabetes and Hypertension in Massachusetts.

OBJECTIVES: The outbreak of COVID-19 in Massachusetts may have reduced ambulatory care access. Our study aimed to quantify this impact among populations with severely uncontrolled diabetes and hypertension; these populations are at greatest risk for adverse outcomes caused by disruptions in care. METHODS: We analyzed multidisciplinary ambulatory electronic health record data from MDPHnet. We established 3 cohorts of patients with severely uncontrolled diabetes and 3 cohorts of patients with severely uncontrolled hypertension using 2017, 2018, and 2019 data, then followed each cohort through the subsequent 15 months. For the diabetes cohorts, we generated quarterly counts of glycated hemoglobin A1c (HbA1c) tests. For the hypertension cohorts, we generated monthly counts of blood pressure measurements. Finally, we assessed telehealth use among the 2019 diabetes and hypertension cohorts from January 2020 through March 2021. RESULTS: HbA1c testing and blood pressure monitoring dropped considerably during the pandemic compared with previous years. In the 2019 diabetes cohort, HbA1c measurements declined from 44.0% in January-March 2020 (baseline) to 15.9% in April-June 2020 and was 11.8 percentage points below baseline in January-March 2021. In the 2019 hypertension cohort, blood pressure measurements declined from 40.0% in January 2020 to 4.5% in April 2020 and was 23.5 percentage points below baseline in March 2021. Telehealth use increased precipitously during the pandemic but was not uniform across subpopulations. CONCLUSIONS: Access to selected diabetes and hypertension services declined sharply during the pandemic among populations with severely uncontrolled disease. Although telehealth is an important strategy, ensuring equity in access is essential. Telehealth hybrid models can also minimize disruptions in care.

Artificially expanded genetic information systems (AEGISs) as potent inhibitors of the RNA-dependent RNA polymerase of the SARS-CoV-2.

The recent outbreak of the SARS-CoV-2 infection has affected the lives and economy of more than 200 countries. The unavailability of virus-specific drugs has created an opportunity to identify potential therapeutic agents that can control the rapid transmission of this pandemic. Here, the mechanisms of the inhibition of the RNA-dependent RNA polymerase (RdRp), responsible for the replication of the virus in host cells, are examined by different ligands, such as Remdesivir (RDV), Remdesivir monophosphate (RMP), and several artificially expanded genetic information systems (AEGISs) including their different sequences by employing molecular docking, MD simulations, and MM/GBSA techniques. It is found that the binding of RDV to RdRp may block the RNA binding site. However, RMP would acquire a partially flipped conformation and may allow the viral RNA to enter into the binding site. The internal dynamics of RNA and RdRp may help RMP to regain its original position, where it may inhibit the RNA-chain elongation reaction. Remarkably, AEGISs are found to obstruct the binding site of RNA. It is shown that dPdZ, a two-nucleotide sequence containing P and Z would bind to RdRp very strongly and may occupy the positions of two nucleotides in the RNA strand, thereby denying access of the substrate-binding site to the viral RNA. Thus, it is proposed that the AEGISs may act as novel therapeutic candidates against the SARS-CoV-2. However, in vivo evaluations of their potencies and toxicities are needed before using them against COVID-19.Communicated by Ramaswamy H. Sarma.

Inhibition of the RNA-dependent RNA Polymerase of the SARS-CoV-2 by Short Peptide Inhibitors.

The rapid proliferation of SARS-CoV-2 in COVID-19 patients has become detrimental to their lives. However, blocking the replication cycle of SARS-CoV-2 will help in suppressing the viral loads in patients, which would ultimately help in the early recovery. To discover such drugs, molecular docking, MD-simulations, and MM/GBSA approaches have been used herein to examine the role of several short ionic peptides in inhibiting the RNA binding site of the RNA-dependent RNA polymerase (RdRp). Out of the 49 tri- and tetrapeptide inhibitors studied, 8 inhibitors were found to bind RdRp strongly as revealed by the docking studies. Among these inhibitors, the Ala1-Arg2-Lys3-Asp4 and Ala1-Lys2-Lys3-Asp4 are found to make the most stable complexes with RdRp and possess the ΔGbind of -17.41 and -14.21 kcal/mol respectively as revealed by the MD and MM/GBSA studies. Hence these peptide inhibitors would be highly potent in inhibiting the activities of RdRp. It is further found that these inhibitors can occupy the positions of the nucleotide triphosphate (NTP) insertion site, thereby inhibiting the replication of the viral genome by obstructing the synthesis of new nucleotides. Structural and energetic comparisons of these inhibitors with Remdesivir and similar nucleotide drugs show that these peptides would be more specific and hence may act as promiscuous antiviral agents against RdRp.

Machine learning identifies novel markers predicting functional decline in older adults.

The ability to carry out instrumental activities of daily living, such as paying bills, remembering appointments and shopping alone decreases with age, yet there are remarkable individual differences in the rate of decline among older adults. Understanding variables associated with a decline in instrumental activities of daily living is critical to providing appropriate intervention to prolong independence. Prior research suggests that cognitive measures, neuroimaging and fluid-based biomarkers predict functional decline. However, a priori selection of variables can lead to the over-valuation of certain variables and exclusion of others that may be predictive. In this study, we used machine learning techniques to select a wide range of baseline variables that best predicted functional decline in two years in individuals from the Alzheimer's Disease Neuroimaging Initiative dataset. The sample included 398 individuals characterized as cognitively normal or mild cognitive impairment. Support vector machine classification algorithms were used to identify the most predictive modality from five different data modality types (demographics, structural MRI, fluorodeoxyglucose-PET, neurocognitive and genetic/fluid-based biomarkers). In addition, variable selection identified individual variables across all modalities that best predicted functional decline in a testing sample. Of the five modalities examined, neurocognitive measures demonstrated the best accuracy in predicting functional decline (accuracy = 74.2%; area under the curve = 0.77), followed by fluorodeoxyglucose-PET (accuracy = 70.8%; area under the curve = 0.66). The individual variables with the greatest discriminatory ability for predicting functional decline included partner report of language in the Everyday Cognition questionnaire, the ADAS13, and activity of the left angular gyrus using fluorodeoxyglucose-PET. These three variables collectively explained 32% of the total variance in functional decline. Taken together, the machine learning model identified novel biomarkers that may be involved in the processing, retrieval, and conceptual integration of semantic information and which predict functional decline two years after assessment. These findings may be used to explore the clinical utility of the Everyday Cognition as a non-invasive, cost and time effective tool to predict future functional decline.

Body Mass Index and Polygenic Risk for Alzheimer's Disease Predict Conversion to Alzheimer's Disease.

Body mass index (BMI) is a risk factor for Alzheimer's disease (AD) although the relationship is complex. Obesity in midlife is associated with increased risk for AD, whereas evidence supports both higher and lower BMI increasing risk for AD in late life. This study examined the influence of individual differences in genetic risk for AD to further clarify the relationship between late-life BMI and conversion to AD. Participants included 52 individuals diagnosed as having mild cognitive impairment (MCI) at baseline who converted to AD within 24 months and 52 matched MCI participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. BMI was measured at baseline. Genetic risk for AD was assessed via genome-wide polygenic risk scores. Conditional logistic regression models were run to determine if BMI and polygenic risk predicted conversion to AD. Results showed an interaction between BMI and genetic risk, such that individuals with lower BMI and higher polygenic risk were more likely to convert to AD relative to individuals with higher BMI. These results remained significant after adjusting for cerebrospinal fluid biomarkers of AD. Exploratory sex-stratified analyses revealed this relationship only remained significant in males. These results show that higher genetic risk in the context of lower BMI predicts conversion to AD in the next 24 months, particularly among males. These findings suggest that genetic risk for AD in the context of lower BMI may serve as a prodromal risk factor for future conversion to AD.

Racial disparities in COVID-19 hospitalizations do not lead to disparities in outcomes.

OBJECTIVES: The objective of the study is the identification of racial differences in characteristics and comorbidities in patients hospitalized for COVID-19 and the impact on outcomes. STUDY DESIGN: The study design is a retrospective observational study. METHODS: Data for all patients admitted to seven community hospitals in Michigan, United States, with polymerase chain reaction confirmed diagnosis of COVID-19 from March 10 to April 15, 2020 were analyzed. The primary outcomes of racial disparity in inpatient mortality and intubation were analyzed using descriptive statistics and multivariate regression models. RESULTS: The study included 336 Black and 408 White patients. Black patients were younger (62.9 ± 15.0 years vs 71.8 ± 16.4, P < .001), had a higher mean body mass index (32.4 ± 8.6 kg/m2 vs 28.8 ± 7.5, P < .001), had higher prevalence of diabetes (136/336 vs 130/408, P = .02), and presented later (6.6 ± 5.3 days after symptom onset vs. 5.4 ± 5.4, P = .006) compared with White patients. Younger Black patients had a higher prevalence of obesity (age <65 years, 69.9%) than older Black patients (age >65 years, 39.2%) and younger White patients (age < 65, 55.1%). Intubation did not reach statistical significance for racial difference (Black patients 61/335 vs. 54/406, P = .08). Mortality was not higher in Black patients (65/335 vs. 142/406 in White patients, odds ratio 0.61, 95% confidence interval: 0.37 to 0.99, 2-sided P = .05) in multivariate analysis, accounting for other risk factors associated with mortality. CONCLUSIONS: Higher prevalence of obesity and diabetes in young Black populations may be the critical factor driving disproportionate COVID-19 hospitalizations in Black populations. Hospitalized Black patients do not have worse outcomes compared with White patients.

Role of different tautomers in the base-pairing abilities of some of the vital antiviral drugs used against COVID-19.

Repurposed drugs are now considered as attractive therapeutics against COVID-19. It is shown that Remdesivir, a nucleoside drug that was originally invented for the Ebola virus, is effective in suppressing the replication of SARS-CoV-2 that causes COVID-19. Similarly, Galidesivir, Favipiravir, Ribavirin, N4-hydroxycytidine (EIDD-1931), and EIDD-2801 (a prodrug of EIDD-1931) were also found to be effective against COVID-19. However, the mechanisms of action of these drugs are not yet fully understood. For example, in some experimental studies, these drugs were proposed to act as a RNA-chain terminator, while in other studies, these were proposed to induce base-pair mutations above the error catastrophe limit to stall the replication of the viral RNA. To understand the mutagenic effects of these drugs, the role of different tautomers in their base-pairing abilities is studied here in detail by employing a reliable dispersion-corrected density functional theoretic method. It is found that Remdesivir and Galidesivir can adopt both amino and imino tautomeric conformations to base-pair with RNA bases. While the insertions of G and U are preferred against the amino tautomers of these drugs, the insertion of C is mainly possible against the imino tautomers. However, although Favipiravir and Ribavirin can make stable base pair interactions by using their keto and enol tautomers, the formation of the latter pairs would be less probable due to the endothermic nature of the products. Interestingly, the insertions of all of the RNA bases are found to be possible against the keto tautomer of Favipiravir, while the keto tautomer of Ribavirin has a clear preference for G. Remarkably, due to the negligible difference in the stability of EIDD-2801 and EIDD-1931, these tautomers would coexist in the biological environment. The insertion of G is found to be preferred against EIDD-1931 and the incorporations of U, A, and G are preferred opposite EIDD-2801. These findings suggest that base-pair mutations are the main causes of the antiviral properties of these drugs.