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INTRODUCTION: Understanding attitudes toward participation among diverse preclinical Alzheimer's disease (AD) trial participants could yield insights to instruct future recruitment. METHODS: Using data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study, we examined differences among mutually exclusive racial and ethnic groups in views and perceptions of amyloid imaging (VPAI), a measure of motivations to undergo amyloid biomarker testing in the setting of preclinical AD. We used linear regression to quantify differences at baseline. RESULTS: Compared to non-Hispanic or Latino (NH) White participants, Hispanic or Latino (3.52 points, 95% confidence interval [CI]: [2.61, 4.42]); NH Asian (2.97 points, 95% CI: [1.71, 4.22]); and NH Black participants (2.79 points, 95% CI: [1.96, 3.63]) participants demonstrated higher levels of endorsement of the VPAI items at baseline. DISCUSSION: Differences may exist among participants from differing ethnic and racial groups in motivations to undergo biomarker testing in the setting of a preclinical AD trial. HIGHLIGHTS: Representative samples in AD clinical trials are vital to result in generalizability. We assessed motivations to undergo amyloid imaging in a preclinical AD trial. Racial and ethnic minority groups showed higher endorsement of VPAI items. Differences were driven by perceived risk, plan/prepare, and curiosity domains. Few observations among racial and ethnic groups changed after biomarker disclosure.
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Introduction: Persons living with HIV (PLWH) experience the early onset of age-related illnesses, even in the setting of successful human immunodeficiency virus (HIV) suppression with highly active antiretroviral therapy (HAART). HIV infection is associated with accelerated epigenetic aging as measured using DNA methylation (DNAm)-based estimates of biological age and of telomere length (TL). Methods: DNAm levels (Infinium MethylationEPIC BeadChip) from peripheral blood mononuclear cells from 200 PLWH and 199 HIV-seronegative (SN) participants matched on chronologic age, hepatitis C virus, and time intervals were used to calculate epigenetic age acceleration, expressed as age-adjusted acceleration residuals from 4 epigenetic clocks [Horvath's pan-tissue age acceleration residual (AAR), extrinsic epigenetic age acceleration (EEAA), phenotypic epigenetic age acceleration (PEAA), and grim epigenetic age acceleration (GEAA)] plus age-adjusted DNAm-based TL (aaDNAmTL). Epigenetic age acceleration was compared for PLWH and SN participants at two visits: up to 1.5 years prior and 2-3 years after HAART (or equivalent visits). Flow cytometry was performed in PLWH and SN participants at both visits to evaluate T-cell subsets. Results: Epigenetic age acceleration in PLWH decreased after the initiation of HAART but remained greater post-HAART than that in age-matched SN participants, with differences in medians of 6.6, 9.1, and 7.7 years for AAR, EEAA, and PEAA, respectively, and 0.39 units of aaDNAmTL shortening (all p < 0.001). Cumulative HIV viral load after HAART initiation was associated with some epigenetic acceleration (EEAA, PEAA, and aaDNAmTL), but even PLWH with undetectable HIV post-HAART showed persistent epigenetic age acceleration compared to SN participants (p < 0.001). AAR, EEAA, and aaDNAmTL showed significant associations with total, naïve, and senescent CD8 T-cell counts; the total CD4 T-cell counts were associated with AAR, EEAA, and PEAA (p = 0.04 to <0.001). In an epigenome-wide analysis using weighted gene co-methylation network analyses, 11 modules demonstrated significant DNAm differences pre- to post-HAART initiation. Of these, nine were previously identified as significantly different from pre- to post-HIV infection but in the opposite direction. Discussion: In this large longitudinal study, we demonstrated that, although the magnitude of the difference decreases with HAART is associated with the cumulative viral load, PLWH are persistently epigenetically older than age-matched SN participants even after the successful initiation of HAART, and these changes are associated with changes in T-cell subsets.
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Introduction: Highly active antiretroviral therapy (HAART) helps improve some measures of accelerated epigenetic aging in persons living with HIV (PLWH), but its overall impact on the epigenome is not fully understood. Methods: In this study, we analyzed the DNA methylation profiles of PLWH (n = 187) shortly before and approximately 2-3 years after they started HAART, as well as matched seronegative (SN) controls (n = 187), taken at two time intervals. Our aim was to identify specific CpGs and biologic pathways associated with HIV infection and initiation of HAART. Additionally, we attempted to identify epigenetic changes associated with HAART initiation that were independent of HIV-associated changes, using matched HIV seronegative (SN) controls (matched on age, hepatitis C status, and interval between visits) to identify CpGs that did not differ between PLWH and SN pre-HAART but were significantly associated with HAART initiation while being unrelated to HIV viral load. Epigenome-wide association studies (EWAS) on >850,000 CpG sites were performed using pre- and post-HAART samples from PLWH. The results were then annotated using the Genomic Regions Enrichment of Annotations Tool (GREAT). Results: When only pre- and post-HAART visits in PLWH were compared, gene ontologies related to immune function and diseases related to immune function were significant, though with less significance for PLWH with detectable HIV viral loads (>50 copies/mL) at the post-HAART visit. To specifically elucidate the effects of HAART separately from HIV-induced methylation changes, we performed EWAS of HAART while also controlling for HIV viral load, and found gene ontologies associated with transplant rejection, transplant-related diseases, and other immunologic signatures. Additionally, we performed a more focused analysis that examined CpGs reaching genome-wide significance (p < 1 × 10-7) from the viral load-controlled EWAS that did not differ between all PLWH and matched SN controls pre-HAART. These CpGs were found to be near genes that play a role in retroviral drug metabolism, diffuse large B cell lymphoma proliferation, and gastric cancer metastasis. Discussion: Overall, this study provides insight into potential biological functions associated with DNA methylation changes induced by HAART initiation in persons living with HIV.
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[This corrects the article DOI: 10.1016/j.isci.2022.104488.].
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Adolescent girls and young women in low- to middle-income countries are disproportionately at risk of becoming HIV-1 infected. New non-vaccine biomedical products aimed at overcoming this global health challenge need to provide a range of safe, effective, and discreet dosage forms based on the delivery of one or more antiviral compounds. An overarching strategy involves vaginal drug administration through inserts/tablets, gels, films, and intravaginal rings. The approach derives its appeal from being women-controlled and topical, there-by potentially minimizing systemic exposure to the agents and their metabolites. Oral regimens based on tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are established and effective in HIV-1 pre-exposure prophylaxis (PrEP), and form a promising basis for vaginal PrEP. Here, we used bone marrow/liver/thymus humanized mice to measure the in vivo efficacy against HIV-1 of single and combination antiviral compounds applied vaginally, coupled with data analysis using the Chou-Talalay mathematical model to study the dose-effect characteristics. Unexpectedly, strong antagonism was observed in drug combinations composed of TDF-FTC coupled with a third agent using a different mode of action against HIV-1. The antagonistic effect was remedied when TDF was omitted from the regimen. Our approach provides a translational template for the preclinical, rational, and systematic evaluation of drug combinations for the prevention of HIV-1, and other viral diseases.
Subject(s)
Anti-HIV Agents , HIV Infections , HIV-1 , Female , Mice , Animals , Male , HIV Infections/drug therapy , HIV Infections/prevention & control , Anti-HIV Agents/therapeutic use , Tenofovir/therapeutic use , Emtricitabine , Drug CombinationsABSTRACT
BACKGROUND: To examine the contribution of B-cell activation molecules to B-cell follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), a prospective study was conducted using pre-diagnosis serial serum samples from the US Department of Defense Serum Repository. METHODS: Each case (n = 142 FL, n = 211 DLBCL) was matched to two controls on age, gender, race, military branch, and blood collection dates. Immune activation molecules (IL1ß, IL2, IL4, IL5, IL6, IL10, IL12, CXCL13, IL8, TNFα, IFNγ, GM-CSF, VEGF, sCD30, IgE) were quantified using ELISA or multiplex immunometric (Luminex) assay. Longitudinal data were analyzed using linear mixed modeling. As serial specimens were collected over several years before diagnosis, we evaluated the temporal dynamics of these markers. RESULTS: Increased serum levels of sCD30, CXCL13, and to a lesser extent IL10, were associated with both FL and DLBCL in cases compared with controls, with a median follow-up of 5.5 years from the earliest specimen collection to diagnosis date. Significant increasing sCD30 and CXCL13 trajectories for FL and DLBCL subtypes were noted starting at the earliest time points and with IL10 levels increasing significantly at time points closer to diagnosis. CONCLUSIONS: These results suggest that sCD30, CXCL13, and IL10 may contribute to the etiology of FL and DLBCL and are potential biomarkers for these non-Hodgkin lymphoma subtypes. IMPACT: The increasing trajectories of the B-cell activation molecules, sCD30, CXCL13, and to a lesser extent IL10, may indicate early disease-induced effects or reflect the chronic stimulation of B-cells that promotes the development of FL and DLBCL subtypes.
Subject(s)
Lymphoma, Follicular , Lymphoma, Large B-Cell, Diffuse , Lymphoma, Non-Hodgkin , Humans , Interleukin-10 , Prospective Studies , Case-Control Studies , Lymphoma, Non-Hodgkin/diagnosis , Lymphoma, Large B-Cell, Diffuse/diagnosis , Biomarkers, TumorABSTRACT
PURPOSE: Long-acting formulations of the potent antiretroviral prodrug tenofovir alafenamide (TAF) hold potential as biomedical HIV prevention modalities. Here, we present a rigorous comparison of three animal models, C57BL/6 J mice, beagle dogs, and merino sheep for evaluating TAF implant pharmacokinetics (PKs). METHODS: Implants delivering TAF over a wide range of controlled release rates were tested in vitro and in mice and dogs. Our existing PK model, supported by an intravenous (IV) dosing dog study, was adapted to analyze mechanistic aspects underlying implant TAF delivery. RESULTS: TAF in vitro release in the 0.13 to 9.8 mg d-1 range with zero order kinetics were attained. Implants with equivalent fabrication parameters released TAF in mice and sheep at rates that were not statistically different, but were 3 times higher in dogs. When two implants were placed in the same subcutaneous pocket, a two-week creep to Cmax was observed in dogs for systemic drug and metabolite concentrations, but not in mice. Co-modeling IV and TAF implant PK data in dogs led to an apparent TAF bioavailability of 9.6 in the single implant groups (compared to the IV group), but only 1.5 when two implants were placed in the same subcutaneous pocket. CONCLUSIONS: Based on the current results, we recommend using mice and sheep, with macaques as a complementary species, for preclinical TAF implant evaluation with the caveat that our observations may be specific to the implant technology used here. Our report provides fundamental, translatable insights into multispecies TAF delivery via long-acting implants.
Subject(s)
Anti-HIV Agents , HIV Infections , Pre-Exposure Prophylaxis , Animals , Mice , Dogs , Sheep , Tenofovir , HIV Infections/drug therapy , HIV Infections/prevention & control , Pre-Exposure Prophylaxis/methods , Mice, Inbred C57BL , Adenine , AlanineABSTRACT
Background: A comprehensive understanding of the SARS-CoV-2 infection dynamics and the ensuing host immune responses is needed to explain the pathogenesis as it relates to viral transmission. Knowledge gaps exist surrounding SARS-CoV-2 in vivo kinetics, particularly in the earliest stages after exposure. Methods: An ongoing, workplace clinical surveillance study was used to intensely sample a small cohort longitudinally. Nine study participants who developed COVID-19 between November, 2020 and March, 2021 were monitored at high temporal resolution for three months in terms of viral loads as well as associated inflammatory biomarker and antibody responses. CD8 + T cells targeting SARS-CoV-2 in blood samples from study participants were evaluated. Results: Here we show that the resulting datasets, supported by Bayesian modeling, allowed the underlying kinetic processes to be described, yielding a number of unexpected findings. Early viral replication is rapid (median doubling time, 3.1 h), providing a narrow window between exposure and viral shedding, while the clearance phase is slow and heterogeneous. Host immune responses different widely across participants. Conclusions: Results from our small study give a rare insight into the life-cycle of COVID-19 infection and hold a number of important biological, clinical, and public health implications.
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Living with HIV infection is associated with early onset of aging-related chronic conditions, sometimes described as accelerated aging. Epigenetic DNA methylation patterns can evaluate acceleration of biological age relative to chronological age. The impact of initial HIV infection on five epigenetic measures of aging was examined before and approximately 3 years after HIV infection in the same individuals (n=102). Significant epigenetic age acceleration (median 1.9-4.8 years) and estimated telomere length shortening (all p≤ 0.001) were observed from pre-to post-HIV infection, and remained significant in three epigenetic measures after controlling for T cell changes. No acceleration was seen in age- and time interval-matched HIV-uninfected controls. Changes in genome-wide co-methylation clusters were also significantly associated with initial HIV infection (p≤ 2.0 × 10-4). These longitudinal observations clearly demonstrate an early and substantial impact of HIV infection on the epigenetic aging process, and suggest a role for HIV itself in the earlier onset of clinical aging.
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The emerging Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and its variants have raised tantalizing questions about evolutionary mechanisms that continue to shape biology today. We have compared the nucleotide sequence of SARS-CoV-2 RNA to that of genomes of many different viruses, of endosymbiotic proteobacterial and bacterial DNAs, and of human mitochondrial DNA. The entire 4,641,652 nt DNA sequence of Escherichia coli K12 has been computer-matched to SARS-CoV-2 RNA. Numerous, very similar micro-modular clusters of 3 to 13 nucleotides lengths were detected with sequence identities of 40 to >50% in specific genome segments between SARS-CoV-2 and the investigated genomes. These clusters were part of patch-type homologies. Control sequence comparisons between 1000 randomly computer-composed sequences of 29.9 kb and with the A, C, G, T base composition of SARS-CoV-2 genome versus the reference Wuhan SARS-CoV-2 sequence showed similar patterns of sequence homologies. The universal A, C, G, T genetic coding mode might have succeeded in evolution due in part to its built-in capacity to select for a substantial reservoir of micro-modular domains and employ them as platforms for integrative recombination. Their role in SARS-CoV-2 interspecies transition and the generation of variants appears likely, but their actual involvement will require detailed investigations.
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COVID-19 , DNA, Mitochondrial , Bacteria/genetics , DNA, Mitochondrial/genetics , Genome, Viral , Humans , RNA, Viral/genetics , Recombination, Genetic , SARS-CoV-2/geneticsABSTRACT
Misperceptions about COVID-19 health risks may be associated with preferences for school and business closures and fear of becoming seriously ill. We analyzed data from the Franklin Templeton-Gallup Economic of Recovery Study (July-December 2020, N = 35,068). Primary outcomes were whether a respondent favored closure of businesses or in-person schooling for elementary/secondary students. We also assessed respondents' fear of COVID-19 illness. We assessed risk misperceptions using respondents' estimates of the proportion of deaths from COVID-19 that occurred in persons under 55 years-old, the proportion of hospitalizations for COVID-19 that occurred in persons under 55 years-old, the mortality rate among patients hospitalized with COVID-19, and the rate of hospitalization for patients infected with COVID-19. The proportion of respondents who favored business closures ranged from 37% to 53%, and the proportion of respondents who favored school closures ranged from 38% to 44%. Most participants reported beliefs about COVID-19 health risks that were inaccurate, and overestimation of health risk was most common. For example, while deaths in persons younger than 55 years-old accounted for 7% of total U.S. deaths, respondents estimated that this population represented 43% of deaths. Overestimating COVID-19 health harms was associated with increased likelihood of fear of serious illness if infected, preferences for business closures, and preferences for school closures. U.S. survey respondents overestimated several COVID-19 risks, and overestimation was associated with increased fear of serious illness and stronger preferences for business/school lockdowns.
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BACKGROUND: Adverse mental and emotional health outcomes are increasingly recognized as a public health challenge associated with the COVID-19 pandemic. OBJECTIVE: The goal of this study was to examine the association of COVID-19 risk misperceptions with self-reported household isolation, a potential risk factor for social isolation and loneliness. METHODS: We analyzed data from the Franklin Templeton-Gallup Economics of Recovery Study (July to December 2020) of 24,649 US adults. We also analyzed data from the Gallup Panel (March 2020 to February 2021), which included 123,516 observations about loneliness. The primary outcome was self-reported household isolation, which we defined as a respondent having no contact or very little contact with people outside their household, analogous to quarantining. RESULTS: From July to December 2020, 53% to 57% of respondents reported living in household isolation. Most participants reported beliefs about COVID-19 health risks that were inaccurate, and overestimation of health risk was most common. For example, while deaths in persons younger than 55 years old accounted for 7% of total US deaths, respondents estimated that this population represented 43% of deaths. Overestimating COVID-19 health risks was associated with increased self-reported household isolation, with percentage differences ranging from 5.6 to 11.8 (P<.001 at each time point). Characteristics associated with self-reported household isolation from the July and August 2020 surveys and persisting in the December 2020 survey included younger age (18 to 39 years), having a serious medical condition, having a household member with a serious medical condition, and identifying as a Democrat. In the Gallup Panel, self-reported household isolation was associated with a higher prevalence of loneliness. CONCLUSIONS: Pandemic-related harms to emotional and mental well-being may be attenuated by reducing risk overestimation and household isolation preferences that exceed public health guidelines.
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Public health practices and high vaccination rates currently represent the primary interventions for managing the spread of coronavirus disease 2019 (COVID-19). We initiated a clinical study based on frequent, longitudinal workplace disease surveillance to control severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission among employees and their household members. We hypothesized that the study would reduce the economic burden and loss of productivity of both individuals and small businesses resulting from standard isolation methods, while providing new insights into virus-host dynamics. Study participants (27 employees and 27 household members) consented to provide frequent nasal or oral swab samples that were analyzed by reverse transcription-quantitative PCR (RT-qPCR) for SARS-CoV-2 RNA. Two study participants were found to be infected by SARS-CoV-2 during the study. One subject, a household member, was SARS-CoV-2 RNA positive for at least 71 days and had quantifiable serum virus-specific antibody concentrations for over 1 year. One unrelated employee became positive for SARS-CoV-2 RNA over the course of the study but remained asymptomatic, with low associated viral RNA copy numbers, no detectable serum IgM and IgG concentrations, and IgA concentrations that decayed rapidly (half-life: 1.3 days). A COVID-19 infection model was used to predict that without surveillance intervention, up to 7 employees (95% confidence interval [CI] = 3 to 10) would have become infected, with at most 1 of them requiring hospitalization. Our scalable and transferable surveillance plan met its primary objectives and represents a powerful example of an innovative public health initiative dovetailed with scientific discovery. IMPORTANCE The rapid spread of SARS-CoV-2 and the associated COVID-19 has precipitated a global pandemic heavily challenging our social behavior, economy, and health care infrastructure. In the absence of widespread, worldwide access to safe and effective vaccines and therapeutics, public health measures represent a key intervention for curbing the devastating impacts from the pandemic. We are conducting an ongoing clinical study based on frequent, longitudinal workplace disease surveillance to control SARS-CoV-2 transmission among employees and their household members. Our study was successful in surveying the viral and immune response dynamics in two participants with unusual infections: one remained positive for SARS-CoV-2 for 71 days, while the other was asymptomatic, with low associated viral RNA copy numbers. A COVID-19 infection model was used to predict that without surveillance intervention, up to 7 employees would have become infected, with at most 1 of them requiring hospitalization, underscoring the importance of our program.
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COVID-19/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/virology , Child , Female , Humans , Longitudinal Studies , Male , Middle Aged , Pandemics/prevention & control , Public Health , RNA, Viral/immunology , Workplace , Young AdultABSTRACT
BACKGROUND: Increasing naloxone access in communities has been a priority to mitigate the increasing rate of opioid-related overdose deaths. OBJECTIVES: The aims of this telephone survey were to estimate the availability of naloxone furnishing (provided without a prescription) by community pharmacists in California and examine the changes that occurred between 2018 and 2020. METHODS: A telephone audit of a random representative sample of 1271 California licensed community pharmacies was conducted from January 22, 2020, to February 24, 2020. The results were compared with those of a survey of 1147 California licensed community pharmacies that was conducted from January 23, 2018, to February 28, 2018. The primary outcomes measured were naloxone availability without a prescription, information on formulations, cost, insurance billing, and stocking status. RESULTS: There was a statistically significant increase in the furnishing of naloxone, as well as stocking and billing, in California from 2018 to 2020. Although fewer than half of the pharmacies were willing to provide naloxone without a prescription in 2020 (n = 487, 42.4%), this was an 80% increase from 2018 (P < 0.001). Of the pharmacies furnishing naloxone, many (n = 399, 81.9%) had nasal naloxone in stock, a large and statistically significant increase from 2018 when only 50.6% reported having it in stock (P < 0.001). In 2020, 90% of the pharmacies reported correctly that pharmacist-furnished naloxone could be billed to insurance compared with 56.9% in 2018 (P < 0.001). The median cash price of nasal naloxone (pack of 2) at chain pharmacies in 2020 was $131 (interquartile range [IQR] $129-$138) compared with $153 (IQR, $141-$163; P = 0.001) at independent pharmacies. CONCLUSION: Community pharmacy-based access to naloxone increased in a statistically significant manner in California, although more than half of the pharmacies still do not provide such access. This study demonstrates the need for further efforts to expand community pharmacy-based access to naloxone.
Subject(s)
Drug Overdose , Opioid-Related Disorders , Pharmacies , California , Drug Overdose/drug therapy , Follow-Up Studies , Humans , Naloxone/therapeutic use , Narcotic Antagonists/therapeutic use , Opioid-Related Disorders/drug therapy , PharmacistsABSTRACT
We and others previously reported that the direct-acting agents (DAA) NS5A inhibitors (NS5Ai) and the host-targeting agents cyclophilin inhibitors (CypIs) inhibit HCV replication in vitro. In this study, we investigated whether the combination of NS5Ai and CypI offers a potent anti-HCV effect in vivo. A single administration of NS5Ai or CypI alone to HCV-infected humanized-mice inhibits HCV replication. The combination of NS5Ai with CypI suppresses HCV (GT1a, GT2a, GT3a and GT4a) replication in an additive manner. NS5Ai/CypI combinations provide a statistically more profound anti-HCV inhibition for GT2a and GT3a than GT1a and GT4a, leading to a fastest and deepest inhibition of GT2a and GT3a replications. Combining CypI with NS5Ai prevents the viral rebound normally observed in mice treated with NS5Ai alone. Results were confirmed in mice implanted with human hepatocytes from different donors. Therefore, the combination of NS5Ai with CypI may serve as a regimen for the treatment of HCV patients with specific genotypes and disorder conditions, which diminish sustain viral response levels to DAA, such as GT3a infection, cirrhosis, and DAA resistance associated with the selection of resistance-associated substitutions present at baseline or are acquired during treatment.
Subject(s)
Antiviral Agents/pharmacology , Cyclophilins/genetics , Hepacivirus/drug effects , Liver Cirrhosis/drug therapy , Animals , Cyclophilins/antagonists & inhibitors , Drug Resistance, Viral/genetics , Genotype , Hepacivirus/pathogenicity , Hepatocytes/drug effects , Hepatocytes/virology , Humans , Liver Cirrhosis/genetics , Liver Cirrhosis/virology , Mice , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effectsABSTRACT
Envelope phosphatidylserine (PtdSer) and phosphatidylethanolamine (PtdEtr) have been shown to mediate binding of enveloped viruses. However, commonly used PtdSer binding molecules such as Annexin V cannot block PtdSer-mediated viral infection. Lack of reagents that can conceal envelope PtdSer and PtdEtr and subsequently inhibit infection hinders elucidation of the roles of the envelope phospholipids in viral infection. Here, we developed sTIM1dMLDR801, a reagent capable of blocking PtdSer- and PtdEtr-dependent infection of enveloped viruses. Using sTIM1dMLDR801, we found that envelope PtdSer and/or PtdEtr can support ZIKV infection of not only human but also mosquito cells. In a mouse model for ZIKV infection, sTIM1dMLDR801 reduced ZIKV load in serum and the spleen, indicating envelope PtdSer and/or PtdEtr support in viral infection in vivo. sTIM1dMLDR801 will enable elucidation of the roles of envelope PtdSer and PtdEtr in infection of various virus species, thereby facilitating identification of their receptors and transmission mechanisms.
Subject(s)
Antiviral Agents/pharmacology , Phosphatidylethanolamines/antagonists & inhibitors , Phosphatidylserines/antagonists & inhibitors , Virus Attachment/drug effects , Virus Internalization/drug effects , Zika Virus/drug effects , A549 Cells , Animals , Cell Line , Chlorocebus aethiops , Culicidae/virology , Female , HEK293 Cells , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Receptor, Interferon alpha-beta/genetics , Vero Cells , Viral Envelope/metabolism , Viral Load/drug effects , Zika Virus/growth & development , Zika Virus Infection/drug therapy , Zika Virus Infection/pathology , Zika Virus Infection/transmission , Axl Receptor Tyrosine KinaseABSTRACT
Males are at higher risk relative to females of severe outcomes following COVID-19 infection. Focusing on COVID-19-attributable mortality in the United States (U.S.), we quantify and contrast years of potential life lost (YPLL) attributable to COVID-19 by sex based on data from the U.S. National Center for Health Statistics as of 31 March 2021, specifically by contrasting male and female percentages of total YPLL with their respective percent population shares and calculating age-adjusted male-to-female YPLL rate ratios both nationally and for each of the 50 states and the District of Columbia. Using YPLL before age 75 to anchor comparisons between males and females and a novel Monte Carlo simulation procedure to perform estimation and uncertainty quantification, our results reveal a near-universal pattern across states of higher COVID-19-attributable YPLL among males compared to females. Furthermore, the disproportionately high COVID-19 mortality burden among males is generally more pronounced when measuring mortality in terms of YPLL compared to age-irrespective death counts, reflecting dual phenomena of males dying from COVID-19 at higher rates and at systematically younger ages relative to females. The U.S. COVID-19 epidemic also offers lessons underscoring the importance of a public health environment that recognizes sex-specific needs as well as different patterns in risk factors, health behaviors, and responses to interventions between men and women. Public health strategies incorporating focused efforts to increase COVID-19 vaccinations among men are particularly urged.
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Scientists and the public were alarmed at the first large viral variant of SARS-CoV-2 reported in December 2020. We have followed the time course of emerging viral mutants and variants during the SARS-CoV-2 pandemic in ten countries on four continents. We examined > 383,500 complete SARS-CoV-2 nucleotide sequences in GISAID (Global Initiative of Sharing All Influenza Data) with sampling dates extending until April 05, 2021. These sequences originated from ten different countries: United Kingdom, South Africa, Brazil, United States, India, Russia, France, Spain, Germany, and China. Among the 77 to 100 novel mutations, some previously reported mutations waned and some of them increased in prevalence over time. VUI2012/01 (B.1.1.7) and 501Y.V2 (B.1.351), the so-called UK and South Africa variants, respectively, and two variants from Brazil, 484K.V2, now called P.1 and P.2, increased in prevalence. Despite lockdowns, worldwide active replication in genetically and socio-economically diverse populations facilitated selection of new mutations. The data on mutant and variant SARS-CoV-2 strains provided here comprise a global resource for easy access to the myriad mutations and variants detected to date globally. Rapidly evolving new variant and mutant strains might give rise to escape variants, capable of limiting the efficacy of vaccines, therapies, and diagnostic tests.
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COVID-19/prevention & control , Genome, Viral , SARS-CoV-2/genetics , COVID-19/pathology , COVID-19/therapy , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Humans , Mutation , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/genetics , Viral Nonstructural Proteins/geneticsABSTRACT
The coronavirus disease 2019 (COVID-19) epidemic in the United States has disproportionately impacted communities of color across the country. Focusing on COVID-19-attributable mortality, we expand upon a national comparative analysis of years of potential life lost (YPLL) attributable to COVID-19 by race/ethnicity (Bassett et al., 2020), estimating percentages of total YPLL for non-Hispanic Whites, non-Hispanic Blacks, Hispanics, non-Hispanic Asians, and non-Hispanic American Indian or Alaska Natives, contrasting them with their respective percent population shares, as well as age-adjusted YPLL rate ratios-anchoring comparisons to non-Hispanic Whites-in each of 45 states and the District of Columbia using data from the National Center for Health Statistics as of 30 December 2020. Using a novel Monte Carlo simulation procedure to perform estimation, our results reveal substantial racial/ethnic disparities in COVID-19-attributable YPLL across states, with a prevailing pattern of non-Hispanic Blacks and Hispanics experiencing disproportionately high and non-Hispanic Whites experiencing disproportionately low COVID-19-attributable YPLL. Furthermore, estimated disparities are generally more pronounced when measuring mortality in terms of YPLL compared to death counts, reflecting the greater intensity of the disparities at younger ages. We also find substantial state-to-state variability in the magnitudes of the estimated racial/ethnic disparities, suggesting that they are driven in large part by social determinants of health whose degree of association with race/ethnicity varies by state.
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COVID-19 , Ethnicity , District of Columbia , Health Status Disparities , Hispanic or Latino , Humans , Life Expectancy , SARS-CoV-2 , United States/epidemiologyABSTRACT
Predictions of COVID-19 case growth and mortality are critical to the decisions of political leaders, businesses, and individuals grappling with the pandemic. This predictive task is challenging due to the novelty of the virus, limited data, and dynamic political and societal responses. We embed a Bayesian time series model and a random forest algorithm within an epidemiological compartmental model for empirically grounded COVID-19 predictions. The Bayesian case model fits a location-specific curve to the velocity (first derivative) of the log transformed cumulative case count, borrowing strength across geographic locations and incorporating prior information to obtain a posterior distribution for case trajectories. The compartmental model uses this distribution and predicts deaths using a random forest algorithm trained on COVID-19 data and population-level characteristics, yielding daily projections and interval estimates for cases and deaths in U.S. states. We evaluated the model by training it on progressively longer periods of the pandemic and computing its predictive accuracy over 21-day forecasts. The substantial variation in predicted trajectories and associated uncertainty between states is illustrated by comparing three unique locations: New York, Colorado, and West Virginia. The sophistication and accuracy of this COVID-19 model offer reliable predictions and uncertainty estimates for the current trajectory of the pandemic in the U.S. and provide a platform for future predictions as shifting political and societal responses alter its course.