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Background & Aims: Induction of potent, HBV-specific immune responses is crucial to control and finally cure HBV. The therapeutic hepatitis B vaccine TherVacB combines protein priming with a Modified Vaccinia virus Ankara (MVA)-vector boost to break immune tolerance in chronic HBV infection. Particulate protein and vector vaccine components, however, require a constant cooling chain for storage and transport, posing logistic and financial challenges to vaccine applications. We aimed to identify an optimal formulation to maintain stability and immunogenicity of the protein and vector components of the vaccine using a systematic approach. Methods: We used stabilizing amino acid (SAA)-based formulations to stabilize HBsAg and HBV core particles (HBcAg), and the MVA-vector. We then investigated the effect of lyophilization and short- and long-term high-temperature storage on their integrity. Immunogenicity and safety of the formulated vaccine was validated in HBV-naïve and adeno-associated virus (AAV)-HBV-infected mice. Results: In vitro analysis proved the vaccine's stability against thermal stress during lyophilization and the long-term stability of SAA-formulated HBsAg, HBcAg and MVA during thermal stress at 40 °C for 3 months and at 25 °C for 12 months. Vaccination of HBV-naïve and AAV-HBV-infected mice demonstrated that the stabilized vaccine was well tolerated and able to brake immune tolerance established in AAV-HBV mice as efficiently as vaccine components constantly stored at 4 °C/-80 °C. Even after long-term exposure to elevated temperatures, stabilized TherVacB induced high titre HBV-specific antibodies and strong CD8+ T-cell responses, resulting in anti-HBs seroconversion and strong suppression of the virus in HBV-replicating mice. Conclusion: SAA-formulation resulted in highly functional and thermostable HBsAg, HBcAg and MVA vaccine components. This will facilitate global vaccine application without the need for cooling chains and is important for the development of prophylactic as well as therapeutic vaccines supporting vaccination campaigns worldwide. Impact and implications: Therapeutic vaccination is a promising therapeutic option for chronic hepatitis B that may enable its cure. However, its application requires functional cooling chains during transport and storage that can hardly be guaranteed in many countries with high demand. In this study, the authors developed thermostable vaccine components that are well tolerated and that induce immune responses and control the virus in preclinical mouse models, even after long-term exposure to high surrounding temperatures. This will lower costs and ease application of a therapeutic vaccine and thus be beneficial for the many people affected by hepatitis B around the world.
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SARS-CoV-2 enters host cells after binding through its spike glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor. Soluble ACE2 ectodomains bind and neutralize the virus, yet their short in vivo half-live limits their therapeutic use. This limitation can be overcome by fusing the fragment crystallizable (Fc) part of human immunoglobulin G (IgG) to the ACE2 ectodomain, but this bears the risk of Fc-receptor activation and antibody-dependent cellular cytotoxicity. Here, we describe optimized ACE2-IgG4-Fc fusion constructs that avoid Fc-receptor activation, preserve the desired ACE2 enzymatic activity and show promising pharmaceutical properties. The engineered ACE2-IgG4-Fc fusion proteins neutralize the original SARS-CoV, pandemic SARS-CoV-2 as well as the rapidly spreading SARS-CoV-2 alpha, beta and delta variants of concern. Importantly, these variants of concern are inhibited at picomolar concentrations proving that ACE2-IgG4 maintains - in contrast to therapeutic antibodies - its full antiviral potential. Thus, ACE2-IgG4-Fc fusion proteins are promising candidate anti-antivirals to combat the current and future pandemics.
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Enzima de Conversão de Angiotensina 2 , Antivirais/síntese química , Tratamento Farmacológico da COVID-19 , Imunoglobulina G , Internalização do Vírus/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2/química , Enzima de Conversão de Angiotensina 2/uso terapêutico , Antivirais/uso terapêutico , Humanos , Ligação Proteica , SARS-CoV-2/efeitos dos fármacosRESUMO
The in vivo phenotypic profile of T cells reactive to severe acute respiratory syndrome (SARS)-CoV-2 antigens remains poorly understood. Conventional methods to detect antigen-reactive T cells require in vitro antigenic re-stimulation or highly individualized peptide-human leukocyte antigen (pHLA) multimers. Here, we use single-cell RNA sequencing to identify and profile SARS-CoV-2-reactive T cells from Coronavirus Disease 2019 (COVID-19) patients. To do so, we induce transcriptional shifts by antigenic stimulation in vitro and take advantage of natural T cell receptor (TCR) sequences of clonally expanded T cells as barcodes for 'reverse phenotyping'. This allows identification of SARS-CoV-2-reactive TCRs and reveals phenotypic effects introduced by antigen-specific stimulation. We characterize transcriptional signatures of currently and previously activated SARS-CoV-2-reactive T cells, and show correspondence with phenotypes of T cells from the respiratory tract of patients with severe disease in the presence or absence of virus in independent cohorts. Reverse phenotyping is a powerful tool to provide an integrated insight into cellular states of SARS-CoV-2-reactive T cells across tissues and activation states.
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COVID-19/imunologia , Perfilação da Expressão Gênica/métodos , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Linfócitos T/metabolismo , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , COVID-19/epidemiologia , COVID-19/virologia , Células Cultivadas , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , SARS-CoV-2/fisiologia , Linfócitos T/virologiaRESUMO
BACKGROUND: Health care delivery systems are increasingly integrating physical and mental health services to address patients' complex needs, contain costs, and improve satisfaction. Therefore, it is critical to understand whether adoption of integrated care models is effective in diverse settings. OBJECTIVE: This study examined the effect of integrated care on physical and mental health outcomes among low-income Latino participants on the US-Mexico border. RESEARCH DESIGN: In this quasi-experimental multisite study, individual-level data were pooled from 8 studies of locally adapted integrated care models. SUBJECTS: Participants were 18 years or older and had 1 or more chronic conditions: diabetes, depression, hypertension, or obesity. The study enrolled 4226 participants with 2254 participants in the intervention group and 1972 in the comparison group. MEASURES: Primary outcomes were depressive symptoms as measured by the Patient Health Questionnaire-9 score and blood glucose measured by hemoglobin A1c (HbA1c). Blood pressure, body mass index, and quality of life were secondary outcomes. RESULTS: Multivariable linear regression analyses indicated intervention participants had significantly lower Patient Health Questionnaire-9 scores (ß=-0.39, P=0.03) and HbA1c (ß=-0.14, P=0.02) at 12 months compared with comparison group participants. Stratified analyses showed improvements in HbA1c were even greater among intervention participants who had diabetes, depression, severe and persistent mental illness, were older or female compared with their counterparts in the comparison group. CONCLUSIONS: Health care is constantly transforming, making it critical to study these changes across populations and settings. Findings from this study indicate that integrated care can significantly improve mental and physical health in an underserved Latino population.
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Doença Crônica , Prestação Integrada de Cuidados de Saúde , Depressão/terapia , Diabetes Mellitus/terapia , Hispânico ou Latino/estatística & dados numéricos , Serviços de Saúde Mental , Atenção Primária à Saúde , Adulto , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hipertensão , Masculino , México , Pessoa de Meia-Idade , Pobreza , Inquéritos e Questionários , Estados UnidosRESUMO
Funders are increasingly making strategic investments across multiple grantees, aiming for their portfolio to improve targeted outcomes in a specific issue area. To this end, funders might use multi-site evaluation (MSE) approaches to examine the impact of their collective investments. However, it is important to recognize that each program-and its own program evaluation-must be tailored to its setting, population, and local context to best meet the needs of its target population. Therefore, multi-site evaluations need to account for this complexity. This paper describes the Sí Texas project, a large initiative of eight grantees implementing different integrated behavioral health models to improve physical and mental health outcomes along the Texas-Mexico border. With over 4,200 MSE study participants, the evaluation for Sí Texas used a partnership-centered approach to both enhance the evidence base and build local organizational capacity. This paper describes this approach, the process of tailoring evaluation practices to the grantees' context, and the challenge of balancing consistency at the grantee-level for the portfolio multi-site evaluation. Successes, challenges, and lessons learned related to study design, data collection, grantee partnership, and capacity building are discussed.
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Fortalecimento Institucional , Coleta de Dados , Humanos , México , Avaliação de Programas e Projetos de Saúde , TexasRESUMO
BACKGROUND: Musculoskeletal disorders affect all racial and ethnic groups, including Hispanics. Because these disorders are not life-threatening, decision-making is generally preference-based. Little is known about whether Hispanics in the U.S. differ from non-Hispanic Whites with respect to key decision making preferences. METHODS: We assembled six focus groups of Hispanic and non-Hispanic White patients with chronic back or knee pain at an urban medical center to discuss management of their conditions and the roles they preferred in medical decision-making. Hispanic groups were further stratified by socioeconomic status, using neighborhood characteristics as proxy measures. Discussions were led by a moderator, taped, transcribed and analyzed using a grounded theory approach. RESULTS: The analysis revealed ethnic differences in several areas pertinent to medical decision-making. Specifically, Hispanic participants were more likely to permit their physician to take the predominant role in making health decisions. Also, Hispanics of lower socioeconomic status generally preferred to use non-internet sources of health information to make medical decisions and to rely on advice obtained by word of mouth. Hispanics emphasized the role of faith and religion in coping with musculoskeletal disability. The analysis also revealed broad areas of concordance across ethnic strata including the primary role that pain and achieving pain relief play in patients' experiences and decisions. CONCLUSIONS: These findings suggest differences between Hispanics and non-Hispanic Whites in preferred information sources and decision-making roles. These findings are hypothesis-generating. If confirmed in further research, they may inform the development of interventions to enhance preference-based decision-making among Hispanics.
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Dor nas Costas/etnologia , Comportamento de Escolha , Conhecimentos, Atitudes e Prática em Saúde , Hispânico ou Latino/psicologia , Joelho/fisiopatologia , Dor/etnologia , Preferência do Paciente/etnologia , População Branca/psicologia , Adaptação Psicológica , Idoso , Idoso de 80 Anos ou mais , Dor nas Costas/psicologia , Dor nas Costas/terapia , Boston/epidemiologia , Doença Crônica , Características Culturais , Feminino , Grupos Focais , Humanos , Comportamento de Busca de Informação , Masculino , Pessoa de Meia-Idade , Dor/fisiopatologia , Dor/psicologia , Manejo da Dor , Medição da Dor , Papel do Médico , Relações Médico-Paciente , Pesquisa Qualitativa , Fatores SocioeconômicosRESUMO
Underage alcohol use remains a significant public health problem throughout the United States and has important consequences for the health of individuals and communities. The objective of this study was to assess the impact of distributing an alcohol retailer toolkit via direct mail on increasing positive alcohol retailer attitudes towards checking IDs, encouraging retail managers to formalize ID checking procedures with their employees, and promoting consumers to be prepared to show ID when purchasing alcohol. This community randomized study included five matched Massachusetts community pairs. Our analysis sample consisted of 209 retailers (77 intervention; 132 control). In models adjusted for baseline response and matching community and establishment characteristics, intervention communities reported posting, on average, one additional sign or wall decal in their establishments (ß = 0.937, P = 0.0069), and a twofold higher odds of handing out written materials on ID checking to staff (OR: 2.074, 95%CI: 1.003-4.288) compared to control establishments. However, the intervention was not found to have an effect on changing establishment policies, retailer attitudes, or other establishment practices. Intervention retailers perceived all components of the toolkit to be very useful for their establishments, and nearly all reported having shared materials with their employees and customers. These results suggest that some significant changes in alcohol retailer establishment practices can be achieved among motivated owners or managers through the distribution of a toolkit targeting best retailer practices. We do, however, recommend that future program planners consider alternative dissemination and marketing strategies beyond direct mail to encourage greater utilization.
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Consumo de Bebidas Alcoólicas/prevenção & controle , Bebidas Alcoólicas/provisão & distribuição , Comércio/organização & administração , Adolescente , Consumo de Bebidas Alcoólicas/legislação & jurisprudência , Bebidas Alcoólicas/economia , Comércio/legislação & jurisprudência , Humanos , Massachusetts , Avaliação de Programas e Projetos de Saúde , Características de Residência , Meio Social , Adulto JovemRESUMO
Studies have shown subjective social status (SSS) is associated with multiple health outcomes. This article examines the predictors of SSS, whether these associations vary by race/ethnicity, and whether SSS is sensitive to different referents used for social comparison. Data were from a national US mail survey. Income was strongly associated with SSS only among Whites and Hispanics. While there were no SSS differences by race/ethnicity using a distal referent, Blacks had higher SSS than Whites when using more proximal referents, even after controlling for objective status indicators. Findings indicate SSS measurement may be sensitive to race/ethnicity and the comparison referent.
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Comportamento de Escolha , Etnicidade/estatística & dados numéricos , Serviços de Saúde/estatística & dados numéricos , Encaminhamento e Consulta/estatística & dados numéricos , Humanos , Fatores SocioeconômicosRESUMO
Emerging research has revealed that subjective social status (SSS), or how people perceive their position in the social hierarchy, is significantly associated with multiple health outcomes. Yet few studies have examined how this association is affected by the person or group to whom respondents are comparing themselves. While previous studies have used distal referent groups when assessing SSS, scholars have suggested that individuals may prefer to make comparisons to those who share similar characteristics to themselves. Overall, there has been little empirical analysis assessing the health impact of comparing oneself to one referent group over another. Using a diverse, national US sample (n=3644), this study explores whether the relationship between SSS and self-rated health is sensitive to the referent used for social comparison. Data are from respondents who completed the ConsumerStyles and HealthStyles mail surveys and who have assessed their SSS against four referents: others in American society, others of the same race or ethnicity, neighbors, and parents at the same age. Self-rated health was the dependent variable, while we controlled for household income, education, home ownership, race/ethnicity, and other covariates. In logistic regression models, SSS using each of the four referents was significantly associated with self-rated health, but the model using the referent of others in American society had the strongest association with self-rated health and was the most parsimonious. Findings validate previous studies which typically have used a more distal referent such as others in American society in exploring the SSS-health relationship. However, future work should explore whether this referent is salient to diverse population groups when making social comparisons. Researchers may also want to consider using SSS as an additional status measure since it may capture more subtle differences in the status hierarchy than traditional economic measures.
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Nível de Saúde , Autoimagem , Classe Social , Percepção Social , Coleta de Dados , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fatores Socioeconômicos , Estados UnidosRESUMO
The purpose of this study is to understand people's receptivity to seeking out disease prevention counseling from their primary care provider. Since patients' openness to health messages may vary depending on how they seek out their health information, participants were segmented into one of four unique information-seeking groups. This study explores the differences among these groups, what approaches would be most effective in motivating different health consumers to seek out behavioral counseling in the primary care setting and the opportunities during the medical visit most appropriate for this counseling. To this end, a total of 32 focus groups were conducted with American adults. Participants were segmented by information-seeking orientation (independent actives, doctor-dependent actives, independent passives and doctor-dependent passives), age and gender. Findings showed that participants of the four information-seeking groups possessed distinct differences in their desire for and perceived barriers to requesting counseling from their provider. Overall, participants wanted prevention counseling to include tailored information, encouragement and follow-up. Participants among the various segments identified two key windows of opportunity-during a routine checkup and when discussing their family history-where patients and providers can incorporate more in-depth prevention discussions into the medical visit. Findings from this study suggest that targeting health messages according to health consumers' information-seeking orientations may provide an effective tool for practitioners. Additionally, many health consumers are open to behavioral counseling in the primary care setting and would be satisfied if this counseling were integrated into traditional procedures, such as during a routine checkup or when discussing their family medical history.
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Aconselhamento/organização & administração , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Atenção Primária à Saúde/organização & administração , Prevenção Primária , Adulto , Fatores Etários , Idoso , Atitude Frente a Saúde , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Fatores Sexuais , Fatores de Tempo , Estados UnidosRESUMO
While researchers typically have segmented audiences by demographic or behavioral characteristics, psychobehavioral segmentation schemes may be more useful for developing targeted health information and programs. Previous research described a four segment psychobehavioral segmentation scheme-and a 10-item screening instrument used to identify the segments-based predominantly on people's orientation to their health (active vs. passive) and their degree of independence in health care decision making (independent vs. dependent). This study builds on this prior research by assessing the screening instrument's validity with an independent dataset and exploring whether people with distinct psychobehavioral orientations have different disease prevention attitudes and preferences for receiving information in the primary care setting. Data come from 1,650 respondents to a national mail panel survey. Using the screening instrument, respondents were segmented into four groups-independent actives, doctor-dependent actives, independent passives, and doctor-dependent passives. Consistent with the earlier research, there were clear differences in health-related attitudes and behaviors among the four segments. Members of three segments appear quite receptive to receiving disease prevention information and assistance from professionals in the primary care setting. Our findings provide further indication that the screening instrument and corresponding segmentation strategy may offer a simple, effective tool for targeting and tailoring information and other health programming to the unique characteristics of distinct audience segments.
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Atitude Frente a Saúde , Comportamentos Relacionados com a Saúde , Modelos Psicológicos , Adulto , Idoso , Coleta de Dados , Feminino , Promoção da Saúde , Nível de Saúde , Humanos , Comportamento de Busca de Informação , Masculino , Pessoa de Meia-Idade , Relações Médico-Paciente , AutoeficáciaRESUMO
BACKGROUND: Despite the potential benefits of reducing the risk of osteoporosis in later life, research on adolescent girls' weight-bearing physical activity (WBPA) is limited. This study explores correlates for WBPA in this population. METHODS: A nationally representative telephone survey sponsored by the National Bone Health Campaign was conducted with 1000 girls age 9 to 12 years and a parent. Girls' physical activities were coded as weight bearing or not and correlated with cognitive, social, and environmental variables. RESULTS: Regression analysis revealed that WBPA was significantly associated with self-reported parents' education, parental self-efficacy, girls' normative beliefs about time spent in physical activity, being physically active with a parent, having physically active friends, and perceived availability of after-school physical activities. CONCLUSIONS: Interventions encouraging parents to participate in WBPA with their daughters and increasing parents' positive attitudes and self-efficacy in getting their daughters to be physically active should be tested.
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Motivação , Relações Pais-Filho , Levantamento de Peso , Atitude Frente a Saúde , Criança , Feminino , Inquéritos Epidemiológicos , HumanosRESUMO
INTRODUCTION: Using a social marketing approach, we studied how best to adapt proven, evidence-based strategies to increase physical activity for use with underserved racial or ethnic groups. METHODS: We conducted focus groups with low-income Hispanic women in Texas, Hmong parents and their children in California, low-income African American women and men in the Mississippi Delta, and Native Hawaiian college students in Hawaii. We also interviewed key leaders of these communities. Topics of discussion were participants' perceptions about 1) the benefits of engaging in physical activity, 2) the proposed evidence-based strategies for increasing each community's level of physical activity, and 3) the benefits and barriers to following the proposed interventions for increasing physical activity. A total of 292 individuals participated in the study. RESULTS: All groups considered that being physically active was part of their culture, and participants found culturally relevant suggestions for physical activities appealing. Overwhelmingly, strategies that aimed to create or improve social support and increase access to physical activity venues received the most positive feedback from all groups. Barriers to physical activity were not culturally specific; they are common to all underserved people (lack of time, transportation, access, neighborhood safety, or economic resources). CONCLUSION: Results indicate that evidence-based strategies to increase physical activity need to be adapted for cultural relevance for each racial or ethnic group. Our research shows that members of four underserved populations are likely to respond to strategies that increase social support for physical activity and improve access to venues where they can be physically active. Further research is needed to test how to implement such strategies in ways that are embraced by community members.
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Exercício Físico , Promoção da Saúde/métodos , Grupos Minoritários , Obesidade/prevenção & controle , Marketing Social , Adolescente , Adulto , Negro ou Afro-Americano , Idoso , Asiático , Criança , Participação da Comunidade , Medicina Baseada em Evidências , Feminino , Grupos Focais , Controle de Acesso , Comportamentos Relacionados com a Saúde/etnologia , Hispânico ou Latino , Humanos , Masculino , Pessoa de Meia-Idade , Havaiano Nativo ou Outro Ilhéu do Pacífico , Estados UnidosRESUMO
This study describes a new segmentation strategy exploring smokers' interest levels in counseling in the medical care setting in order to understand how public health communications can be designed to increase consumer demand for cessation services within this population. A subsample of 431 smokers from a large, nationally representative mail survey was analyzed and categorized into three cessation-demand groups: Low demand (LD), medium demand (MD), and high demand (HD). HD smokers were most likely to be heavy smokers, to make quitting a high priority, and to have self-efficacy in quitting. MD and LD smokers were less likely than HD smokers to have been told to quit smoking by a health care provider in the past or to believe that counseling is effective. The first step in the regression analysis revealed that age, cigarettes smoked per month, whether smokers were currently trying to quit, and whether they were ever told to quit smoking by their health care provider accounted for 21% of the variance in smokers' interest in smoking cessation counseling, F(4, 234) = 16.49, p<.001. When additional variables on attitudes toward smoking and quitting and perceived effectiveness of receiving counseling in the medical care setting were added to the model, an additional 11% of the variance in smokers' interest in cessation counseling was explained, F(12, 234) = 10.07, p<.001. Results suggest that by categorizing smokers by interest level in cessation counseling, we emerge with three distinct portraits of smokers who might be activated in different ways to increase consumer demand for cessation counseling.