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C-reactive protein is a systemic inflammatory biomarker that is positively associated with the development of disease. Salivary C-reactive protein (sCRP) has previously been reported to have a diurnal rhythm with higher levels upon awakening and lower levels thereafter. The aims of this study were to evaluate the stability of sCRP across two days, characterize the daily sCRP pattern, compute morning sCRP parameters, and evaluate associations with biobehavioral health in US Navy Explosive Ordnance Disposal (EOD) technicians. Seventy male EOD technicians (ageâ¯=â¯34.9⯱â¯6.5â¯years) participated in this study, which included a tablet-based survey, measures of health and fitness, and saliva collection. In a free-living setting, participants self-collected saliva on 2 consecutive days at WAKE, WAKE+30, WAKE+60, 4p.m., and 9p.m., for a total of 10 samples. Parameters (e.g., area under the curve) were computed to characterize the morning sCRP magnitude and pattern. Pearson product-moment correlation analyses were used to assess the stability of sCRP samples and parameters across the study period and to examine associations with biobehavioral health. Average sCRP concentrations for the 2-day period were evaluated using an analysis of variance with repeated measures. The stabilities between corresponding time points on Days 1 and 2 were very high (rsâ¯=â¯0.87-.94, all psâ¯≤â¯0.001). sCRP concentrations were highest at WAKE, decreased by 73.6â¯% at WAKE+30, and then plateaued for the rest of the day. Parameters stabilities were good to excellent (rsâ¯=â¯0.77-.98, all psâ¯≤â¯0.001). We also observed associations between sCRP parameters, self-reported health behaviors, and objective measures of health and fitness. In this study of a military population, we characterized sCRP as diurnal with robust stability across 2 consecutive days, which demonstrates the feasibility of sCRP as a biomarker. These results have significant implications for study methodology and for using sCRP as a marker of dysfunction or disease.
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ABSTRACT: Hernández, LM, Coffin, SD, and Taylor, MK. Greater fitness is associated with improved functional movement characteristics in explosive ordnance disposal technicians. J Strength Cond Res 36(6): 1731-1737, 2022-Low fitness and poor functional movement (FM) have been linked to higher musculoskeletal injury risk. The FM Screen (FMS) and Y-Balance Test (YBT) are useful indicators of potential injury risk in military personnel. U.S. Navy Explosive Ordnance Disposal (EOD) technicians are the premier combat force for countering explosive hazards and must operate in austere environments. To safeguard health and mission success, it is critical to assess factors related to injury risk in this specialized military population. This study evaluated the relationship between fitness and FM characteristics in 64 male EOD technicians (mean age ± SD = 34.2 ± 7.0 years). Body fat percentage (BF%), maximum volume of oxygen uptake (VÌo2max), muscular strength, and FM (i.e., FMS, YBT) were assessed. Body fat percentage and VÌo2max were associated with FMS and YBT scores (all p < 0.05). A nonlinear model further revealed that the group with the lowest VÌo2max values had the bottommost FMS and YBT scores (all p < 0.01), but FM scores did not differ among those with a higher VÌo2max, implying a "threshold" effect. No correlations were observed with muscular strength. By characterizing the unique and shared contributions of BF% and VÌo2max, and exploring the nonlinear relationship between VÌo2max and FM, this study expands on accruing data that indicate individuals who are more physically fit have better FM and lower injury risk. Although muscular strength is a critical element of overall fitness, body composition and cardiorespiratory fitness may more strongly influence FM and injury risk.
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Substâncias Explosivas , Consumo de Oxigênio , Exercício Físico , Teste de Esforço , Humanos , Masculino , Força MuscularRESUMO
CONTEXT: In March, 2020, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), was spreading in the Bay Area, especially in Santa Clara County, causing increases in cases, hospitalizations, and deaths. PROGRAM: The Association of Bay Area Health Officials (ABAHO) represents 13 Bay Area health jurisdictions. IMPLEMENTATION: On March 15, 2020, the local health officers of 7 ABAHO members (counties of Alameda, Contra Costa, Marin, San Francisco, San Mateo, and Santa Clara and the city of Berkeley) decided to issue legal orders on March 16 for 6.7 million residents to shelter in place to prevent the spread of SARS-CoV-2, the causal agent of COVID-19. The Bay Area was the first region in the United States to shelter in place, and within days, other regions in the United States followed. EVALUATION: Subsequent comparative analyses have confirmed that acting early in issuing shelter-in-place orders prevented a large number of cases, hospitalizations, and deaths in the Bay Area throughout the United States. The quality of a decision-in this case, for crisis decision making-cannot be judged by the outcome. A good decision can have a bad outcome, and a bad decision can have a good outcome. The quality of a decision depends only on the quality of the decision-making process at the time the decision was made. DISCUSSION: In this Field Report, we review how we made this collective decision. With the benefit of hindsight and reflection, we recount our story through the lens of public health legal authority, meta-leadership, and decision intelligence. Our purpose is to improve the crisis decision-making skills of public health officials by improving how we make high-stakes decisions each day in our continuing fight to contain the SARS-CoV-2 pandemic, to save lives, and to eliminate COVID-19 racial/ethnic inequities.
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COVID-19/prevenção & controle , Guias como Assunto , Pandemias/legislação & jurisprudência , Pandemias/prevenção & controle , Política , Saúde Pública/legislação & jurisprudência , Saúde Pública/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , California/epidemiologia , Tomada de Decisões , Feminino , Humanos , Liderança , Masculino , Pessoa de Meia-Idade , New York/epidemiologia , Pandemias/estatística & dados numéricos , SARS-CoV-2 , Estados Unidos/epidemiologiaRESUMO
We recently established daily, free-living profiles of the adrenal hormone cortisol, the (primarily adrenal) anabolic precursor dehydroepiandrosterone (DHEA) and the (primarily gonadal) anabolic hormone testosterone in elite military men. A prevailing view is that adrenal and gonadal systems reciprocally modulate each other; however, recent paradigm shifts prompted the characterization of these systems as parallel, cooperative processes (i.e. the "positive coupling" hypothesis). In this study, we tested the positive coupling hypothesis in 57 elite military men by evaluating associations between adrenal and gonadal biomarkers across the day. Salivary DHEA was moderately and positively coupled with salivary cortisol, as was salivary testosterone. Anabolic processes (i.e. salivary DHEA and testosterone) were also positively and reliably coupled across the day. In multivariate models, salivary DHEA and cortisol combined to account for substantial variance in salivary testosterone concentrations across the day, but this was driven almost exclusively by DHEA. This may reflect choreographed adrenal release of DHEA with testicular and/or adrenal release of testosterone, systemic conversion of DHEA to testosterone, or both. DHEA and testosterone modestly and less robustly predicted cortisol concentrations; this was confined to the morning, and testosterone was the primary predictor. Altogether, top-down co-activation of adrenal and gonadal hormone secretion may complement bottom-up counter-regulatory functions to foster anabolic balance and neuronal survival; hence, the "yin and yang" of adrenal and gonadal systems. This may be an adaptive process that is amplified by stress, competition, and/or dominance hierarchy.
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Desidroepiandrosterona/metabolismo , Hidrocortisona/metabolismo , Militares , Saliva/química , Testosterona/metabolismo , Actigrafia , Adulto , Fatores Etários , Biomarcadores/metabolismo , Humanos , Masculino , Análise Multivariada , Yin-YangRESUMO
Innumerable teams have emerged in health care, spurred by the desire to improve patient quality and satisfaction, provide better population outcomes, and reduce per capita cost. Team leaders are faced with many choices in team development, such as collaboration or competition. Although each approach has unique advantages and disadvantages, is one approach better suited to building the teams needed in today's environment? This review examines these two distinct team-building approaches. A literature review of these two approaches in light of the theoretical frameworks of social identity theory and team role theory shows support for both ends of the spectrum; however, collaboration was linked more often with highly successful and effective teams. Ultimately, the literature demonstrates that collaboration is better suited to developing teamwork capable of achieving today's complex health care goals.
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Comportamento Cooperativo , Equipe de Assistência ao Paciente , Atenção à Saúde , HumanosRESUMO
OBJECTIVE: Egg consumption is often discouraged due to cholesterol content; however, recent studies have not demonstrated a clear adverse influence of eggs on blood lipids. Furthermore, exercise training promotes improved lipids and blood pressure. The purpose of the study was to examine the effect of eating an isoenergetic (400 kcal) egg-based (including two eggs per day) versus bagel-based breakfasts, daily, combined with resistance training three times per week, prior to breakfast, on plasma lipids, glucose, insulin, insulin sensitivity and blood pressure in untrained individuals. METHODS: Twenty-five healthy adult men and women (18-35 years of age) participated in the twelve week study following random assignment to study groups. Lipids and blood pressure were examined at baseline and after 6 and 12 weeks. RESULTS: Plasma triglycerides (TG) decreased significantly in the egg- based breakfast (EBB) group from baseline to six weeks (p = 0.011) and from six to twelve weeks (p = 0.045). A significant (p = 0.033) decrease in insulin sensitivity was observed in the bagel-based breakfast (BBB) group from zero to six weeks. No significant effects on systolic blood pressure, diastolic blood pressure, total cholesterol, high density lipoprotein- cholesterol or low density lipoprotein cholesterol were detected. CONCLUSION: Overall, daily breakfasts including two eggs for twelve weeks did not adversely affect lipids during a resistance training program and promoted improvements in plasma TG.
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Pão , Desjejum/fisiologia , Ovos , Condicionamento Físico Humano/métodos , Treinamento Resistido , Adolescente , Adulto , Glicemia/análise , Pressão Sanguínea , Composição Corporal , Colesterol/sangue , Doença Crônica , Dieta , Ingestão de Alimentos , Feminino , Humanos , Resistência à Insulina , Lipídeos/sangue , Masculino , Distribuição Aleatória , Fatores de Risco , Fatores de Tempo , Triglicerídeos/sangue , Adulto JovemRESUMO
Epidemiologic evidence supports that diets rich in polyphenols promote health and may delay the onset of colon cancer. Cocoa and chocolate products have some of the highest polyphenolic concentrations compared to other polyphenolic food sources. This study tested the hypothesis that a diet including dark chocolate can protect against colon cancer by inhibiting aberrant crypt foci (ACF) formation, downregulating gene expression of inflammatory mediators, and favorably altering cell kinetics. We also investigated whether bloomed dark chocolate retains the antioxidant capacity and protects against colon cancer. Forty-eight rats received either a diet containing control (no chocolate), regular dark chocolate, or bloomed dark chocolate and were injected subcutaneously with saline or azoxymethane. Relative to control, both regular and bloomed dark chocolate diets lowered the total number of ACF (P = 0.022). Chocolate diet-fed animals downregulated transcription levels of COX-2 (P = 0.035) and RelA (P = 0.045). Both chocolate diets lowered the proliferation index (P = 0.001). These results suggest that a diet including dark chocolate can reduce cell proliferation and some gene expression involving inflammation, which may explain the lower number of early preneoplastic lesions. These results provide new insight on polyphenol-rich chocolate foods and colon cancer prevention.
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Focos de Criptas Aberrantes/prevenção & controle , Azoximetano/toxicidade , Cacau , Doces , Colo/efeitos dos fármacos , Neoplasias Colorretais/prevenção & controle , Focos de Criptas Aberrantes/induzido quimicamente , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Carcinógenos/toxicidade , Proliferação de Células/efeitos dos fármacos , Colo/patologia , Neoplasias Colorretais/induzido quimicamente , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo , Masculino , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismoRESUMO
OBJECTIVE: The aim of this study was to determine the unique and combined associations of various military stress exposures with positive and negative mental health symptoms in active duty service members. MATERIALS AND METHODS: We investigated 87 male U.S. Navy Explosive Ordnance Disposal (EOD) technicians (age M ± SE, range 33.7 ± 0.6, 22-47 years). Those who endorsed a positive traumatic brain injury diagnosis were excluded to eliminate the confounding effects on mental health symptoms. Using a survey platform on a computer tablet, EOD technicians self-reported combat exposure, deployment frequency (total number of deployments), blast exposure (vehicle crash/blast or 50-m blast involvement), depression, anxiety, posttraumatic stress, perceived stress, and life satisfaction during an in-person laboratory session. RESULTS: When controlling for other military stressors, EOD technicians with previous involvement in a vehicle crash/blast endorsed worse mental health than their nonexposed counterparts. The interactions of vehicle crash/blast with deployment frequency and combat exposure had moderate effect sizes, and combat and deployment exposures demonstrated protective, rather than catalytic, effects on negative mental health scores. CONCLUSIONS: Military stressors may adversely influence self-reported symptoms of negative mental health, but deployment experience and combat exposure may confer stress inoculation.
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Lesões Encefálicas Traumáticas , Substâncias Explosivas , Militares , Transtornos de Estresse Pós-Traumáticos , Humanos , Masculino , Saúde Mental , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/etiologia , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Substâncias Explosivas/efeitos adversosRESUMO
PURPOSE: This report describes the development and validation of the U.S. Navy Explosive Ordnance Disposal (EOD) Combat Mindset Scale-Training (CMS-T), a population-specific measure of psychological strategy use in EOD training environments. METHODS: Scale items were developed by a working group composed of active-duty technicians from EOD Training and Evaluation Unit 1, Naval Health Research Center scientists, and a psychometrician. The working group developed 30 candidate items, which were administered to EOD accessions (new recruits), advanced students, and technicians (N = 164). Factor structure was explored with principal axis factoring and Varimax rotation with Kaiser normalization. Internal consistencies were established via Cronbach alpha, and convergent validity was evaluated with correlational and ANOVA models. RESULTS: Five internally stable subscales were derived from 19 essential items, explaining 65% of total variance. The subscales were named relaxation, attentional-emotional control (AEC), goal setting-visualization (GSV), internal dialogue (ID), and automaticity. The most frequently used strategies were GSV and ID. Expected relationships emerged between strategies, most notably AEC and mental health. The scale also differentiated between subgroups. CONCLUSION: The EOD CMS-T demonstrates a stable factor structure, internal reliability, and convergent validity. This study yields a valid, practical, and easily administered instrument to support EOD training and evaluation.
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Substâncias Explosivas , Humanos , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
Electrodermal activity (EDA)-a measure of electrical skin conductance reflecting (exclusive) sympathetic control of the eccrine sweat gland-holds promise as an indicator of central sympathetic activation. The aim of this study was to determine whether combat and blast exposure modulate the EDA response to acute exercise stress in specialised military men. Fifty-one men (age M = 36.1, SD = 6.5) participated in this study as part of the Explosive Ordnance Disposal Operational Health Surveillance System. The EDA complex (i.e., tonic + phasic conductance) was continuously measured throughout a maximal effort, graded exercise test. As expected, exercise stress resulted in measurable, stepwise increases in EDA before tapering at higher exercise intensities. Individuals with more substantial combat exposure and those with blast exposure demonstrated blunted EDA patterns in comparison to their low/nonexposed counterparts. This blunted pattern might imply sub-optimal sympathetic nervous system function in the exposed cohorts and enhances our knowledge of factors influencing resilience in these men.
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Militares , Exercício Físico , Teste de Esforço , Resposta Galvânica da Pele , Humanos , Masculino , Sistema Nervoso SimpáticoRESUMO
INTRODUCTION: Retention is a top priority for the U.S. Navy. However, our understanding of factors influencing retention of Navy personnel is limited. Current research implies that poor mental health, low appraisals of unit cohesion, low leadership satisfaction, and low social support may adversely affect retention. There is a need to understand how these and other factors influence retention in U.S. Navy personnel. We evaluated a broad range of factors influencing job satisfaction and career intentions (proxies of retention) in a large sample of Navy service members. MATERIALS AND METHODS: Seven hundred and ninety-eight U.S. Navy men and women participated in this study as part of the Naval Unit Behavioral Health Needs Survey (NHRC.2014.0006). Independent variables included personal and unit morale, unit cohesion, affective organizational commitment, social support, behavioral health, sleep, leadership satisfaction, and perceived stress. Dependent variables include job satisfaction and career intentions. Separate multivariate regression models examined the unique and combined associations of independent and demographic variables with each dependent variable, respectively. RESULTS: Regression models accounted for 48% of variance in job satisfaction and 55% of variance in career intentions, respectively. The most robust predictors of job satisfaction were affective organizational commitment (i.e., one's emotional attachment to, identification with, and involvement in an organization), depressive symptoms, unit cohesion, and perceived stress; primary predictors of career intentions included affective organizational commitment, years of military service, marital status, and race/ethnicity. CONCLUSION: In this study, we identified diverse predictors of job satisfaction and career intentions of Navy men and women, with overall models accounting for substantial variance in both outcomes. This study informs evidence-based policies, programs, practices, and processes designed to influence job satisfaction, career intentions, and retention in U.S. Navy service members. These study findings also inform the development of a dashboard indicator of retention of U.S. Navy men and women.
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INTRODUCTION: Amassing evidence suggests that post-awakening salivary cortisol rhythms (changes in cortisol throughout the day) may indicate health status. We previously established summary parameters for salivary cortisol in U.S. Navy Sea, Air, and Land and reported excellent parameter stability across 2 days of repeated sampling. To confirm the generalizability of our original findings to other military populations, we replicated the procedures of our prior report in another specialized military group. The purpose of this study was to (1) establish summary parameters of daily salivary cortisol rhythms, (2) evaluate summary parameter stability, and (3) assess the impact of sampling compliance in U.S. Navy Explosive Ordnance Disposal (EOD) technicians. MATERIALS AND METHODS: Seventy active duty, male Explosive Ordnance Disposal technicians (mean ± SD age; 34.9 ± 6.5 years) self-collected saliva samples in a nondeployed setting on two consecutive weekdays at WAKE, WAKE + 30 min, WAKE + 60 min, 4 p.m., and 9 p.m. For salivary cortisol, we computed summary parameters, i.e., measures of magnitude and measures of pattern, and then evaluated their stabilities via correlational analyses and Cronbach's alpha (α). Compliance was objectively and subjectively evaluated using actigraphy and self-reported data, respectively. This research was conducted under a Naval Health Research Center Institutional Review Board approved study (NHRC.2015.0013). RESULTS: Average salivary cortisol concentrations increased at WAKE + 30 (mean ± SE reactivity; 48.9 + 6.8%) from WAKE, followed by a swift recovery at WAKE + 60. Approximately 10.9% of the group were classified as negative-responders (i.e., < 0% change from WAKE to WAKE + 30). The measures of magnitude demonstrated fair stability across two days (r value range: 0.37-0.45, ps < 0.01; α range: 0.54-0.62). Fifty-five percent of the sample was classified as compliant (defined as <15 min deviation from target sampling times) across both days. Compliance decreased to 31% when compliance criteria were refined to <5 min deviation; however, controlling for compliance did not overwhelmingly influence the more stable summary parameters of magnitude. CONCLUSIONS: These findings demonstrate a thorough replication, with some additional refinement, of our prior study, implying generalizability across diverse military populations. Study limitations include unsupervised saliva collection in a free-living setting, which is counterbalanced by ecological validity. The noninvasive salivary sampling protocol used in this study yields stable estimations of daily cortisol rhythms in specialized military men and is recommended as an operational health surveillance tool by which to monitor chronically stressed military members.
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We describe 10 patients with 2009 H1N1 influenza and concurrent invasive group A streptococcal infection with marked associated morbidity and mortality. Seven patients required intensive care, 8 required mechanical ventilation, and 7 died. Five of the patients, including 4 of the fatalities, were previously healthy.
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Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Influenza Humana/complicações , Influenza Humana/virologia , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/isolamento & purificação , Adulto , Idoso , Criança , Pré-Escolar , Comorbidade , Cuidados Críticos , Feminino , Humanos , Influenza Humana/mortalidade , Influenza Humana/terapia , Masculino , Pessoa de Meia-Idade , Respiração Artificial , Infecções Estreptocócicas/mortalidade , Infecções Estreptocócicas/terapiaRESUMO
Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study.
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Antagonistas dos Receptores Histamínicos H1/química , Indenos/química , Piridazinas/química , Receptores Histamínicos H1/química , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Citocromo P-450 CYP2D6/metabolismo , Dimetideno/química , Eletroencefalografia , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Indenos/farmacocinética , Indenos/uso terapêutico , Microssomos Hepáticos/metabolismo , Modelos Animais , Piridazinas/farmacocinética , Piridazinas/uso terapêutico , Ratos , Receptores Histamínicos H1/metabolismo , Relação Estrutura-AtividadeRESUMO
SAR of lead benzothiophene H(1)-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H(1)-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound.
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Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Tiofenos/farmacologia , Tiofenos/farmacocinética , Antagonistas dos Receptores Histamínicos H1/química , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Receptores Histamínicos H1/metabolismo , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/uso terapêuticoRESUMO
CONTEXT: Tactical athletes commonly experience high levels of physical stress, which may increase their risk of musculoskeletal injury. It is critical to understand psychological predictors of functional movement (FM), which may help prevent musculoskeletal injury in this population. OBJECTIVE: To determine the associations of combat and trauma exposure with FM characteristics of male tactical athletes. Secondary objectives were to explore confounding influences of age and physical injury history as well as the mediating role of bodily pain. DESIGN: Cross-sectional study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: Eighty-two healthy, male, active-duty US Navy Explosive Ordnance Disposal personnel (age = 34.0 ± 6.7 years). MAIN OUTCOME MEASURE(S): Participants completed measures of combat exposure, trauma exposure, physical injury history, and bodily pain. We assessed FM characteristics (ie, Functional Movement Screen [FMS], Y-Balance Test), from which we derived a composite functional status (CFS) measure. Hypotheses were tested using correlational and multiple regression (causal-steps) models. RESULTS: In unadjusted models, trauma exposure was inversely associated with the FMS (P = .005) and CFS (P = .009) scores. In adjusted models, these relationships were robust to the confounding influences of age and physical injury history. Trauma exposure and bodily pain were substantive, independent predictors of FMS and CFS in causal-steps models (all P values < .05), implying additive rather than mediated effects (R2adj = 0.18-0.20). Combat exposure did not predict FM characteristics. CONCLUSIONS: To our knowledge, this is the first evidence of the influence of trauma exposure on the FM characteristics of male tactical athletes, independent of age, physical injury, and bodily pain. This program of research may help to advance the prevention and treatment of musculoskeletal injuries in the tactical environment.
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Atletas/psicologia , Traumatismos em Atletas , Dor Musculoesquelética/psicologia , Trauma Psicológico/fisiopatologia , Ferimentos e Lesões , Adulto , Traumatismos em Atletas/prevenção & controle , Traumatismos em Atletas/psicologia , Estudos Transversais , Humanos , Masculino , Militares , Exposição Ocupacional/efeitos adversos , Exame Físico/métodos , Desempenho Físico Funcional , Ferimentos e Lesões/complicações , Ferimentos e Lesões/prevenção & controle , Ferimentos e Lesões/psicologiaRESUMO
We introduce a novel experimental method to determine both the extent of ex vivo receptor occupancy of administered compound and its dissociation rate constant (k4). [Here, we reference k4 as the rate of offset of unlabeled ligand in convention with Motulsky and Mahan (1)]. We derived a kinetic rate equation based on the dissociation rate constant for an unlabeled compound competing for the same site as a labeled compound and describe a model to simulate fractional occupancy. To validate our model, we performed in vitro kinetics and ex vivo occupancy experiments in rat cortex with varying concentrations of (R)-dimethindene, a sedating antihistamine. Brain tissue was removed at various times post oral administration, and histamine H1 receptor ligand [3H]-doxepin binding to homogenates from drug-treated or vehicle-treated rats was measured at multiple time points at room temperature. Fractional occupancy and k4 for (R)-dimethindene binding to H1 receptors were calculated by using our proposed model. Rats dosed with 30 and 60 mg/kg (R)-dimethindene showed 42% and 67% occupancy of central H1 receptors, respectively. These results were comparable to occupancy data determined by equilibrium radioligand binding. In addition, drug k4 rate determined by using our ex vivo method was equivalent to k4 determined by in vitro competition kinetics (dissociation half-life t(1/2) approximately 30 min). The outlined method can be used to assess, by simulation and experiment, occupancy for compounds based on dissociation rate constants and contributes to current efforts in drug optimization to profile antagonist efficacy in terms of its kinetic drug-target binding parameters. Data described by the method may be analyzed with commercially available software. Suggested fitting procedures are given in the appendix.
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Dimetideno/metabolismo , Antagonistas dos Receptores Histamínicos H1/metabolismo , Ensaio Radioligante , Receptores de Droga/metabolismo , Receptores Histamínicos H1/metabolismo , Animais , Ligação Competitiva , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Dimetideno/química , Dimetideno/farmacologia , Doxepina/metabolismo , Antagonistas dos Receptores Histamínicos H1/química , Antagonistas dos Receptores Histamínicos H1/farmacologia , Cinética , Masculino , Ratos , Receptores de Droga/química , Receptores de Droga/efeitos dos fármacos , Receptores Histamínicos H1/químicaRESUMO
The benzimidazole core of the selective non-brain-penetrating H(1)-antihistamine mizolastine was used to identify a series of brain-penetrating H(1)-antihistamines for the potential treatment of insomnia. Using cassette PK studies, brain-penetrating H(1)-antihistamines were identified and in vivo efficacy was demonstrated in a rat EEG/EMG model. Further optimization focused on strategies to attenuate an identified hERG liability, leading to the discovery of 4i with a promising in vitro profile.
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Benzimidazóis/antagonistas & inibidores , Benzimidazóis/química , Encéfalo/efeitos dos fármacos , Química Farmacêutica/métodos , Antagonistas dos Receptores Histamínicos/síntese química , Antagonistas dos Receptores Histamínicos/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Desenho de Fármacos , Canal de Potássio ERG1 , Eletroencefalografia/métodos , Eletromiografia/métodos , Canais de Potássio Éter-A-Go-Go/química , Humanos , Modelos Químicos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: Cardiorespiratory fitness (CRF) is a crucial performance requirement of specialized military occupations. Age and physical activity are established predictors of CRF, but it is not clear how these predictors combine with each other and/or with genetic predisposition. The goal of this study was to derive inclusive explanatory models of CRF in US Navy Explosive Ordnance Disposal (EOD) operators, synthesizing conventional (e.g., age, body composition, and physical activity) and novel influences (e.g., genetic variance). MATERIALS AND METHODS: In this cross-sectional study, 40 male, active duty EOD operators completed a graded exercise test to assess maximal oxygen consumption and ventilatory threshold (VT) using the Bruce protocol. Aerobic performance was further quantified via time of test termination and time at which VT was achieved. Body composition was determined via dual x-ray absorptiometry, and physical activity was assessed by self-report. Genetic variants underlying human stress systems (5HTTLPR, BclI, -2 C/G, and COMT) were assayed. Descriptive analyses were conducted to summarize subject characteristics. Hypotheses were tested with linear regression models. Specifically, separate univariate regression models first determined associations between each of the independent and dependent variables. This protocol was approved by the Naval Health Research Center Institutional Review Board (NHRC.2015.0013). RESULTS: In univariate regression models, age, body composition, physical activity, and 5HTTLPR consistently predicted CRF and/or aerobic performance (R2 range 0.07-0.55). Multivariate regression models routinely outperformed the univariate models, explaining 36-62% of variance. CONCLUSION: This study signifies a shift toward inclusive explanatory models of CRF and aerobic performance, accounting for combined roles of genetic, physiologic, and behavioral influences. Although we were able to quantify combined effects, we were unable to evaluate interaction effects (e.g., gene-gene, gene-behavior) due to limited statistical power. Other limitations are that this specialized military population may not readily generalize to broader populations, and the current sample was all male. Considering these limitations, we aim to replicate this study in various populations, both male and female. Despite its limitations, this study reflects a shift toward more comprehensive predictive models of CRF, explaining the unique and shared contributions of genetic predisposition, physiology, and behavior. These findings have implications for assessment, selection, and training of specialized military members, and may also impact mission success and survivability. Future studies are needed to better characterize additive, interactive, and mediated effects.
Assuntos
Aptidão Cardiorrespiratória/fisiologia , Aptidão Genética/genética , Militares/psicologia , Adulto , Composição Corporal/fisiologia , Índice de Massa Corporal , Aptidão Cardiorrespiratória/psicologia , Estudos Transversais , Teste de Esforço/métodos , Teste de Esforço/estatística & dados numéricos , Feminino , Aptidão Genética/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Militares/estatística & dados numéricos , Análise Multivariada , Especialização/estatística & dados numéricos , Inquéritos e QuestionáriosRESUMO
The first of its kind, this study determined whether blast exposure interacts with genetic variant 5HTTLPR to predict posttraumatic stress (PTS) symptoms in 78 military explosives operators. In all models, blast-exposed 5HTTLPR S carriers registered definitively higher PTS symptoms in comparison to non-exposed S carriers, as well as exposed and non-exposed LL carriers (all p < 0.01). All findings were robust to confounding influences of age and traumatic brain injury diagnosis. Not only is blast exposure prevalent in EOD personnel, but it also interacts with genetic predisposition to predict trauma symptoms in this unique, at-risk military population.