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Importance: There are persistent questions about suicide deaths among US veterans who served in the Vietnam War. It has been believed that Vietnam War veterans may be at an increased risk for suicide. Objective: To determine whether military service in the Vietnam War was associated with an increased risk of suicide, and to enumerate the number of suicides and analyze patterns in suicides among Vietnam War theater veterans compared with the US population. Design, Setting, and Participants: This cohort study compiled a roster of all Vietnam War-era veterans and Vietnam War theater veterans who served between February 28, 1961, and May 7, 1975. The 2 cohorts included theater veterans, defined as those who were deployed to the Vietnam War, and nontheater veterans, defined as those who served during the Vietnam War era but were not deployed to the Vietnam War. Mortality in these 2 cohorts was monitored from 1979 (beginning of follow-up) through 2019 (end of follow-up). Data analysis was performed between January 2022 and July 2023. Main Outcomes and Measures: The outcome of interest was death by suicide occurring between January 1, 1979, and December 31, 2019. Suicide mortality was ascertained from the National Death Index. Hazard ratios (HRs) that reflected adjusted associations between suicide risk and theater status were estimated with Cox proportional hazards regression models. Standardized mortality rates (SMRs) were calculated to compare the number of suicides among theater and nontheater veterans with the expected number of suicides among the US population. Results: This study identified 2â¯465â¯343 theater veterans (2â¯450â¯025 males [99.4%]; mean [SD] age at year of entry, 33.8 [6.7] years) and 7â¯122â¯976 nontheater veterans (6â¯874â¯606 males [96.5%]; mean [SD] age at year of entry, 33.3 [8.2] years). There were 22â¯736 suicides (24.1%) among theater veterans and 71â¯761 (75.9%) among nontheater veterans. After adjustments for covariates, Vietnam War deployment was not associated with an increased risk of suicide (HR, 0.94; 95% CI, 0.93-0.96). There was no increased risk of suicide among either theater (SMR, 0.97; 95% CI, 0.96-0.99) or nontheater (SMR, 0.97; 95% CI, 0.97-0.98) veterans compared with the US population. Conclusions and Relevance: This cohort study found no association between Vietnam War-era military service and increased risk of suicide between 1979 and 2019. Nonetheless, the 94â¯497 suicides among all Vietnam War-era veterans during this period are noteworthy and merit the ongoing attention of health policymakers and mental health professionals.
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Suicídio , Veteranos , Masculino , Humanos , Estudos de Coortes , Vietnã/epidemiologia , Análise de DadosRESUMO
In September 2020, the Department of Veterans Affairs (VA) launched a novel volunteer research registry to rapidly recruit eligible study participants for research on SARS-CoV-2 and COVID-19 vaccines and treatments at VA Medical Centers selected as study sites for COVID-19 clinical trials. Targeted multimedia outreach campaigns were used to recruit diverse populations, including those historically under-represented in medical research. By November 2022, 58,561 volunteers were enrolled in the registry, 19% of whom were women, 9% Hispanic/Latino, and 8% Black. The registry's strategic approach to outreach proved successful in recruiting diverse volunteers, with geotargeted e-mails recruiting the most diversity.
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PURPOSE: Our objectives were to 1) understand the scope of the current mortality literature on U.S. women Vietnam War-era veterans and 2) identify major themes and knowledge gaps that might guide future research. METHODS: A systematic scoping review was conducted. Electronic bibliographic databases were searched for studies published on women Vietnam War-era veterans' mortality between 1973 and 2020. Inclusion and exclusion criteria were applied, study information was charted using pre-established design parameters, and studies deemed eligible were retained for a more in-depth review. FINDINGS: One hundred nineteen studies were initially identified. Of these, six were ultimately retained for critical review. External cause, all-cause, cancer, and cardiovascular mortality were prominent outcomes across studies. Although both methodology and outcomes varied by study, unifying themes emerged. Prominent themes included a) historic barriers to accurately identifying and classifying this veteran cohort, b) historic barriers to comprehensive assessment of their health and mortality risk, and c) the healthy soldier effect and its limitations. Research gaps identified in this review reflect a need to pay more attention to sex differences in mortality risk and military occupational and sex-specific health risk confounders in mortality models. CONCLUSIONS: The research literature examining mortality among women Vietnam War-era veterans is circumscribed in size and scope. Questions about the roles of salient military occupational exposures and health risk factors on mortality risks and trends in this cohort remain unaddressed. These questions should be areas of focus in next steps research.
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Militares , Veteranos , Feminino , Humanos , Masculino , Vietnã , Fatores de Risco , Guerra do VietnãRESUMO
Background: The US Department of Veterans Affairs (VA) Office of Research and Development (ORD) supports an extensive clinical trials enterprise. Until recently, external partnerships were limited. The VA's potential value as a partner became more apparent during the COVID-19 pandemic because of its large health care system, diverse patient population, and expertise in conducting clinical trials. Observations: By leveraging its infrastructure, the VA was able to participate in 7 large-scale COVID-19 therapeutic and vaccine trials. A key aspect of this enterprise approach is the ability to provide centralized direction and coordination. The VA's partnerships with external groups offered insights into the challenges associated with conducting important trials, especially when rapidity and coordination were essential. The ORD also developed solutions for reducing study startup time that could be established as best practices. We offer lessons for the challenges VA faced: site infrastructure needs and capabilities; study management roles and responsibilities; educational resources; local review; study design demands; contracting and budgeting; central-level systems; and communication. Conclusions: VA participation in major COVID-19 therapeutic and vaccine trials represented a significant part of its research response to the pandemic. These contributions extended beyond the participants, scientists, and data that helped inform subsequent regulatory approvals. The VA also had an opportunity to directly develop partnerships with non-VA groups. These groups became more familiar with the VA while enabling us to gain more experience in the diverse practices used to conduct multisite clinical studies. Ultimately, these efforts empower the VA to further serve the broader scientific and clinical communities.
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The protection provided by natural versus hybrid immunity from COVID-19 is unclear. We reflect on the challenges from trying to conduct a randomized post-SARS-CoV-2 infection vaccination trial study with rapidly evolving scientific data, vaccination guidelines, varying international policies, difficulties with vaccine availability, vaccine hesitancy, and a constantly evolving virus.
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Vacinas contra COVID-19 , COVID-19 , Vacinação , COVID-19/prevenção & controle , COVID-19/terapia , Humanos , Pacientes Internados , Ensaios Clínicos Controlados Aleatórios como Assunto , Vacinação/métodosRESUMO
BACKGROUND: Levels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19. OBJECTIVE: To evaluate whether levels of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma antigen levels in hospitalized patients with SARS-CoV-2. DESIGN: Cross-sectional study of baseline plasma antigen level from 2540 participants enrolled in the TICO (Therapeutics for Inpatients With COVID-19) platform trial from August 2020 to November 2021, with additional data on day 5 outcome and time to discharge. SETTING: 114 centers in 10 countries. PARTICIPANTS: Adults hospitalized for acute SARS-CoV-2 infection with 12 days or less of symptoms. MEASUREMENTS: Baseline plasma viral N antigen level was measured at a central laboratory. Delta variant status was determined from baseline nasal swabs using reverse transcriptase polymerase chain reaction. Associations between baseline patient characteristics and viral factors and baseline plasma antigen levels were assessed using both unadjusted and multivariable modeling. Association between elevated baseline antigen level of 1000 ng/L or greater and outcomes, including worsening of ordinal pulmonary scale at day 5 and time to hospital discharge, were evaluated using logistic regression and Fine-Gray regression models, respectively. RESULTS: Plasma antigen was below the level of quantification in 5% of participants at enrollment, and 1000 ng/L or greater in 57%. Baseline pulmonary severity of illness was strongly associated with plasma antigen level, with mean plasma antigen level 3.10-fold higher among those requiring noninvasive ventilation or high-flow nasal cannula compared with room air (95% CI, 2.22 to 4.34). Plasma antigen level was higher in those who lacked antispike antibodies (6.42 fold; CI, 5.37 to 7.66) and in those with the Delta variant (1.73 fold; CI, 1.41 to 2.13). Additional factors associated with higher baseline antigen level included male sex, shorter time since hospital admission, decreased days of remdesivir, and renal impairment. In contrast, race, ethnicity, body mass index, and immunocompromising conditions were not associated with plasma antigen levels. Plasma antigen level of 1000 ng/L or greater was associated with a markedly higher odds of worsened pulmonary status at day 5 (odds ratio, 5.06 [CI, 3.41 to 7.50]) and longer time to hospital discharge (median, 7 vs. 4 days; subhazard ratio, 0.51 [CI, 0.45 to 0.57]), with subhazard ratios similar across all levels of baseline pulmonary severity. LIMITATIONS: Plasma samples were drawn at enrollment, not hospital presentation. No point-of-care test to measure plasma antigen is currently available. CONCLUSION: Elevated plasma antigen is highly associated with both severity of pulmonary illness and clinically important patient outcomes. Multiple clinical and viral factors are associated with plasma antigen level at presentation. These data support a potential role of ongoing viral replication in the pathogenesis of SARS-CoV-2 in hospitalized patients. PRIMARY FUNDING SOURCE: U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.
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COVID-19 , Adulto , COVID-19/terapia , Estudos Transversais , Humanos , Masculino , Nucleocapsídeo , SARS-CoV-2RESUMO
Rationale: Uncertainty regarding the natural history of coronavirus disease (COVID-19) led to difficulty in efficacy endpoint selection for therapeutic trials. Capturing outcomes that occur after hospital discharge may improve assessment of clinical recovery among hospitalized patients with COVID-19. Objectives: Evaluate 90-day clinical course of patients hospitalized with COVID-19, comparing three distinct definitions of recovery. Methods: We used pooled data from three clinical trials of neutralizing monoclonal antibodies to compare: 1) the hospital discharge approach; 2) the TICO (Therapeutics for Inpatients with COVID-19) trials sustained recovery approach; and 3) a comprehensive approach. At the time of enrollment, all patients were hospitalized in a non-ICU setting without organ failure or major extrapulmonary manifestations of COVID-19. We defined discordance as a difference between time to recovery. Measurements and Main Results: Discordance between the hospital discharge and comprehensive approaches occurred in 170 (20%) of 850 enrolled participants, including 126 hospital readmissions and 24 deaths after initial hospital discharge. Discordant participants were older (median age, 68 vs. 59 years; P < 0.001) and more had a comorbidity (84% vs. 70%; P < 0.001). Of 170 discordant participants, 106 (62%) had postdischarge events captured by the TICO approach. Conclusions: Among patients hospitalized with COVID-19, 20% had clinically significant postdischarge events within 90 days after randomization in patients who would be considered "recovered" using the hospital discharge approach. Using the TICO approach balances length of follow-up with practical limitations. However, clinical trials of COVID-19 therapeutics should use follow-up times up to 90 days to assess clinical recovery more accurately.
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COVID-19 , Assistência ao Convalescente , Idoso , Anticorpos Monoclonais , Humanos , Alta do Paciente , SARS-CoV-2 , Resultado do TratamentoRESUMO
Mental health data from the 2016-2017 Vietnam Era Health Retrospective Observational Study (VE-HEROeS) were analyzed by cohort, represented by United States Vietnam theater veterans (VTs) who served in Vietnam, Cambodia, and Laos; nontheater veterans (NTs) without theater service; and age- and sex-matched nonveterans (NVs) without military service. The exposure of interest was Vietnam theater service. Surveys mailed to random samples of veterans (n = 42,393) and nonveterans (n = 6,885) resulted in response rates of 45.0% for veterans (n = 6,735 VTs, Mage = 70.09, SE = 0.04; n = 12,131 NTs) and 67.0% for NVs (n = 4,530). We examined self-report data on four mental health outcomes: probable posttraumatic stress disorder (PTSD), depression, psychological distress, and overall mental health functioning. Weighted adjusted odds ratios (aORs) between each outcome and cohort were estimated, controlling for covariates in four models: cohort plus sociodemographic variables (Model 1), Model 1 plus physical health variables (Model 2), Model 2 plus potentially traumatic events (PTEs; Model 3), and Model 3 plus other military service variables (Model 4). Mental health outcome prevalence was highest for VTs versus other cohorts, with the largest aOR, 2.88, for PTSD, 95% CI [2.46, 3.37], p < .001 (Model 4, VT:NT). Physical health and PTEs contributed most to observed effects; other service variables contributed least to aORs overall. Mental health dysfunction persists among VTs years after the war's end. The present results reaffirm previous findings and highlight the need for continued mental health surveillance in VTs.
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Transtornos de Estresse Pós-Traumáticos , Veteranos , Idoso , Humanos , Saúde Mental , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Estados Unidos/epidemiologia , Veteranos/psicologia , Vietnã/epidemiologia , Guerra do VietnãRESUMO
BACKGROUND: In a randomized, placebo-controlled, clinical trial, bamlanivimab, a SARS-CoV-2-neutralizing monoclonal antibody, given in combination with remdesivir, did not improve outcomes among hospitalized patients with COVID-19 based on an early futility assessment. OBJECTIVE: To evaluate the a priori hypothesis that bamlanivimab has greater benefit in patients without detectable levels of endogenous neutralizing antibody (nAb) at study entry than in those with antibodies, especially if viral levels are high. DESIGN: Randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04501978). SETTING: Multicenter trial. PATIENTS: Hospitalized patients with COVID-19 without end-organ failure. INTERVENTION: Bamlanivimab (7000 mg) or placebo. MEASUREMENTS: Antibody, antigen, and viral RNA levels were centrally measured on stored specimens collected at baseline. Patients were followed for 90 days for sustained recovery (defined as discharge to home and remaining home for 14 consecutive days) and a composite safety outcome (death, serious adverse events, organ failure, or serious infections). RESULTS: Among 314 participants (163 receiving bamlanivimab and 151 placebo), the median time to sustained recovery was 19 days and did not differ between the bamlanivimab and placebo groups (subhazard ratio [sHR], 0.99 [95% CI, 0.79 to 1.22]; sHR > 1 favors bamlanivimab). At entry, 50% evidenced production of anti-spike nAbs; 50% had SARS-CoV-2 nucleocapsid plasma antigen levels of at least 1000 ng/L. Among those without and with nAbs at study entry, the sHRs were 1.24 (CI, 0.90 to 1.70) and 0.74 (CI, 0.54 to 1.00), respectively (nominal P for interaction = 0.018). The sHR (bamlanivimab vs. placebo) was also more than 1 for those with plasma antigen or nasal viral RNA levels above median level at entry and was greatest for those without antibodies and with elevated levels of antigen (sHR, 1.48 [CI, 0.99 to 2.23]) or viral RNA (sHR, 1.89 [CI, 1.23 to 2.91]). Hazard ratios for the composite safety outcome (<1 favors bamlanivimab) also differed by serostatus at entry: 0.67 (CI, 0.37 to 1.20) for those without and 1.79 (CI, 0.92 to 3.48) for those with nAbs. LIMITATION: Subgroup analysis of a trial prematurely stopped because of futility; small sample size; multiple subgroups analyzed. CONCLUSION: Efficacy and safety of bamlanivimab may differ depending on whether an endogenous nAb response has been mounted. The limited sample size of the study does not allow firm conclusions based on these findings, and further independent trials are required that assess other types of passive immune therapies in the same patient setting. PRIMARY FUNDING SOURCE: U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.
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Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/uso terapêutico , Idoso , Alanina/efeitos adversos , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Neutralizantes/sangue , Antígenos Virais/sangue , Antivirais/efeitos adversos , Biomarcadores/sangue , COVID-19/sangue , COVID-19/virologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Futilidade Médica , Pessoa de Meia-Idade , RNA Viral/sangue , SARS-CoV-2 , Falha de TratamentoRESUMO
Objectives: To examine differences in potentially traumatic events (PTEs), probable PTSD, and health-related quality of life (HRQoL) between lesbian, gay, and bisexual (LGB) and heterosexual Vietnam Era veterans. Method: Data are from the 2016-2017 Vietnam Era Health Retrospective Observational study survey (n = 18,866; 45% response rate). PTEs were defined using the 10-item Brief Trauma Questionnaire and a dichotomous item about whether respondents witnessed sexual assault during military service. Current probable PTSD was measured with the Primary Care PTSD Screen, and mental and physical HRQoL was assessed with the SF-8™. Multivariable regression analyses were first adjusted for sociodemographic and military-related characteristics, and then with PTEs as a count variable ranging from 0-11. Survey weights accounted for the complex sampling design and nonresponse. Results: Approximately 1.5% of veterans were LGB. Compared to heterosexual veterans, LGB veterans were more likely to report exposure to natural disasters, childhood physical abuse, adulthood physical assault, and sexual assault, and they were less likely to report combat exposure, witnessing someone being seriously injured or killed, or witnessing sexual assault while in the military. Compared to heterosexual veterans, LGB veterans had greater odds of current probable PTSD (adjusted odds ratio [aOR] = 1.50, 95% CI [1.04, 2.16]) and poorer mental HRQoL (B = -1.70, SE = .72, p = .018). PTEs attenuated sexual orientation differences in probable PTSD (aOR = 1.27, 95% CI [.82, 1.97]) and poorer mental HRQoL (B = -1.22, SE = .67, p = .067). Conclusions: Among Vietnam Era veterans, PTEs differ based on sexual orientation, and contribute to LGB veterans' greater prevalence of current probable PTSD and poorer mental HRQoL relative to heterosexual veterans. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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Minorias Sexuais e de Gênero , Veteranos , Adulto , Criança , Feminino , Heterossexualidade , Humanos , Masculino , Qualidade de Vida , Comportamento Sexual , VietnãRESUMO
BACKGROUND/AIMS: Safe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines public-private partnership initiated the Therapeutics for Inpatients with COVID-19. Therapeutics for Inpatients with COVID-19 is a multi-arm, multi-stage platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate antiviral therapeutic agents for adults hospitalized with COVID-19. Five agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed. METHODS: Three clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. Therapeutics for Inpatients with COVID-19 utilizes a multi-arm, multi-stage design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo, the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and Data and Safety Monitoring Board schedule was developed for the study of potential therapeutic agents with limited in-human data in hospitalized patients with COVID-19. RESULTS: As of 8 August 2021, five agents have entered the Therapeutics for Inpatients with COVID-19 master protocol and a total of 1909 participants have been randomized to one of these agents or matching placebo. There were a number of challenges faced by the study team that needed to be overcome in order to successfully implement Therapeutics for Inpatients with COVID-19 across a global network of sites. These included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff and obtaining regulatory approvals across a global network of sites. CONCLUSION: Through a robust multi-network partnership, the Therapeutics for Inpatients with COVID-19 protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required to achieve the full potential of this approach in dealing with a global outbreak.
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Antivirais , Tratamento Farmacológico da COVID-19 , Adulto , Antivirais/uso terapêutico , Hospitalização , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
BACKGROUND: LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19. METHODS: In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5. RESULTS: On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47). CONCLUSIONS: Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).
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Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Adulto , Idoso , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Neutralizantes/efeitos adversos , Antivirais/efeitos adversos , COVID-19/mortalidade , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Glucocorticoides/uso terapêutico , Hospitalização , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Falha de TratamentoRESUMO
BACKGROUND: Safe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership initiated the Therapeutics for Inpatients with COVID-19 (TICO). TICO is a multi-arm, multi-stage (MAMS) platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate anti-viral therapeutic agents for adults hospitalized with COVID-19. Four agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed. PROTOCOL DESIGN AND IMPLEMENTATION: Three clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. TICO utilizes a MAMS design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo as well as the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and DSMB schedule was developed for the study of agents with limited in-human data. CHALLENGES: Challenges included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff, and obtaining regulatory approvals across a global network of sites. CONCLUSION: Through a robust multi-network partnership, the TICO protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required.
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Spirometric restriction in herbicide-exposed U.S. Army Chemical Corps Vietnam War veterans was examined because no published research on this topic in Vietnam War veterans exists. Spirometry was conducted on 468 veterans who served in chemical operations in a 2013 study assessing the association between chronic obstructive pulmonary disease (COPD) and herbicide exposure. Exposure was verified based on blood serum values of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Further, the association between herbicide exposure and spirometry restriction (forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ≥ lower limit of normal (LLN) and FVC < LLN) was tested after adjustment for military characteristics, selected anthropometrics, and other predictors using multivariable regression. Spirometric restriction in herbicide sprayers (15.7%, 95% CI: 10.6, 20.9) was almost twice that of nonsprayers (9.91%, 95% CI: 5.9, 13.9) (p = 0.081). While spirometric restriction was not significantly associated with herbicide exposure (adjusted odds ratio (aOR) = 1.64, 95% CI: 0.82, 3.29) despite the greater prevalence of restriction in sprayers versus nonsprayers, spirometric restriction was significantly associated with race/ethnicity (aOR = 3.04, 95% CI: 1.36, 6.79) and waist circumference (aOR = 2.46, 95% CI: 1.25, 4.85). Because restrictive pulmonary disease may result from chemically-induced inflammation or sensitivity, research on chemical exposures and restriction in veterans should continue. Future study should include full pulmonary function testing, targeted research designs, and a wider set of explanatory variables in analysis, such as other determinants of health.
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Exposição Ambiental , Herbicidas/toxicidade , Testes de Função Respiratória , Espirometria , Veteranos , Guerra do Vietnã , Idoso , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Dibenzodioxinas Policloradas/sangue , Prevalência , Estados Unidos , Capacidade VitalRESUMO
BACKGROUND: Research on chronic obstructive pulmonary disease (COPD) and herbicide exposure in Vietnam War veterans is limited. METHODS: Survey data were collected from 3193 US Army Chemical Corps veterans on herbicide exposure and self-reported physician-diagnosed COPD. Three spirometric patterns were used to define airflow obstruction (AFO): (i) FEV1 /FVC < 70% ("fixed ratio"); (ii) FEV1 /FVC < lower limit of normal ("LLN"); and (iii) (FEV1 /FVC < LLN and FVC ≥ LLN and FEV1 Assuntos
Herbicidas
, Exposição Ocupacional/estatística & dados numéricos
, Doença Pulmonar Obstrutiva Crônica/epidemiologia
, Veteranos/estatística & dados numéricos
, Guerra do Vietnã
, Idoso
, Estudos de Coortes
, Volume Expiratório Forçado
, Humanos
, Masculino
, Pessoa de Meia-Idade
, Prevalência
, Doença Pulmonar Obstrutiva Crônica/fisiopatologia
, Análise de Regressão
, Estudos Retrospectivos
, Autorrelato
, Fumar/epidemiologia
, Espirometria
, Estados Unidos/epidemiologia
, Capacidade Vital
RESUMO
OBJECTIVE: We examined hypertension risk in Army Chemical Corps (ACC) veterans who sprayed defoliant in Vietnam. METHODS: We analyzed data from the 2013 health survey of 3086 ACC veterans and investigated the association between self-reported physician-diagnosed-hypertension (SRH) and herbicide-spray-history adjusting for Vietnam-service-status, rank, age, tobacco/alcohol use, race, and body mass index (BMI). Spray-history was verified against serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (nâ=â636). SRH was confirmed by blood pressure (BP) measurement by trained medical technicians and medical record reviews. RESULTS: Herbicide-spray-history (ORadjusted[95%confidence interval {CI}]â=â1.74[1.44,2.11]) and Vietnam-service-status (ORadjustedâ=â1.26[1.05,1.53]) were significantly associated with SRH. The association was highest when comparing Vietnam-service-sprayers to non-Vietnam-service-nonsprayers (ORadjustedâ=â2.21[1.76,2.77]). Serum TCDD was highest for Vietnam-service-sprayers. Mean systolic BPs were significantly higher among veterans with SRH than those without (Pâ≤â0.001). Medical records and SRH overall agreement was 89%. CONCLUSION: Occupational herbicide exposure history and Vietnam-service-status were significantly associated with hypertension risk.
Assuntos
Herbicidas/efeitos adversos , Hipertensão/epidemiologia , Exposição Ocupacional/efeitos adversos , Veteranos , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Dibenzodioxinas Policloradas/sangue , Fatores de Risco , VietnãRESUMO
Chronic hepatitis B virus (HBV) infection screening usually includes only HBV surface antigen (HBsAg) testing; HBV core and surface antibody (anti-HBc, anti-HBs) assays, indicating resolved infection and immunity, are not routinely performed. Yet, serum HBV DNA is measurable in approximately 10% of HBsAg-negative/anti-HBc-positive cases, representing occult HBV infection (OBI). Patient blood samples from 2 Veterans Affairs medical center look-back investigations were screened for HBV infection using HBsAg enzyme immunoassays. Supplementary testing included anti-HBc and anti-HBs enzyme immunoassays. For anti-HBc-positive samples, HBV DNA testing was performed. Background OBI prevalence was further estimated at these 2 facilities based on HBV serology testing results from 1999-2012. Finally, a literature review was performed to determine OBI prevalence in the published literature. Of 1887 HBsAg-negative cohort patients, 98 (5.2%) were anti-HBc positive/anti-HBs negative; and 175 (9.3%), anti-HBc positive/anti-HBs positive. Six of 273 were HBV DNA positive, representing 0.3% of the total tested and 2.2% who were anti-HBc positive/anti-HBs negative or anti-HBc positive/anti-HBs positive. Among 32,229 general population veterans at these 2 sites who had any HBV testing, 4/108 (3.7%) were HBV DNA positive, none of whom were part of the cohort. In 129 publications with HBsAg-negative patients, 1817/1,209,426 (0.15%) had OBI. However, excluding blood bank studies with greater than 1000 patients, the OBI rate increased to 1800/17,893 (10%). OBI is not rare and has implications for transmission and disease detection. HBsAg testing alone is insufficient for detecting all chronic HBV infections. These findings may impact blood donation, patient HBV screening, follow-up protocols for patients assumed to have cleared the infection, and initiation of immunosuppression in patients with distant or undetected HBV.