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Summer temperature extremes can have large impacts on humans and the biosphere, and an increase in heat extremes is one of the most visible symptoms of climate change. Multiple mechanisms have been proposed that would predict faster warming of heat extremes than typical summer days, but it is unclear whether this is occurring. Here, we show that, in both observations and historical climate model simulations, the hottest summer days have warmed at the same pace as the median globally, in each hemisphere, and in the tropics from 1959 to 2023. In contrast, the coldest summer days have warmed more slowly than the median in the global average, a signal that is not simulated in any of 262 simulations across 28 CMIP6 models. The observed stretching of the cold tail indicates that observed summertime temperatures have become more variable despite the lack of hot day amplification. The interannual variability and trend in the warming of both hot and cold extremes compared to the median can be explained from a surface energy balance perspective based on changes in net surface radiation and evaporative fraction. Tropical hot day amplification is projected to emerge in the future (2024-2099, SSP3-7.0 scenario), while Northern Hemisphere heat extremes are expected to continue to follow the median.
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Arid and semi-arid regions of the world are particularly vulnerable to greenhouse gas-driven hydroclimate change. Climate models are our primary tool for projecting the future hydroclimate that society in these regions must adapt to, but here, we present a concerning discrepancy between observed and model-based historical hydroclimate trends. Over the arid/semi-arid regions of the world, the predominant signal in all model simulations is an increase in atmospheric water vapor, on average, over the last four decades, in association with the increased water vapor-holding capacity of a warmer atmosphere. In observations, this increase in atmospheric water vapor has not happened, suggesting that the availability of moisture to satisfy the increased atmospheric demand is lower in reality than in models in arid/semi-arid regions. This discrepancy is most clear in locations that are arid/semi-arid year round, but it is also apparent in more humid regions during the most arid months of the year. It indicates a major gap in our understanding and modeling capabilities which could have severe implications for hydroclimate projections, including fire hazard, moving forward.
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Previous work from our group and others has shown that patients with breast cancer can generate a T cell response against specific human epidermal growth factor 2 (HER2) epitopes. In addition, preclinical work has shown that this T cell response can be augmented by Ag-directed mAb therapy. This study evaluated the activity and safety of a combination of dendritic cell (DC) vaccination given with mAb and cytotoxic therapy. We performed a phase I/II study using autologous DCs pulsed with two different HER2 peptides given with trastuzumab and vinorelbine to a study cohort of patients with HER2-overexpressing and a second with HER2 nonoverexpressing metastatic breast cancer. Seventeen patients with HER2-overexpressing and seven with nonoverexpressing disease were treated. Treatment was well tolerated, with one patient removed from therapy because of toxicity and no deaths. Forty-six percent of patients had stable disease after therapy, with 4% achieving a partial response and no complete responses. Immune responses were generated in the majority of patients but did not correlate with clinical response. However, in one patient, who has survived >14 y since treatment in the trial, a robust immune response was demonstrated, with 25% of her T cells specific to one of the peptides in the vaccine at the peak of her response. These data suggest that autologous DC vaccination when given with anti-HER2-directed mAb therapy and vinorelbine is safe and can induce immune responses, including significant T cell clonal expansion, in a subset of patients.
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Neoplasias de la Mama , Neoplasias Mamarias Animales , Humanos , Femenino , Animales , Epítopos/metabolismo , Vinorelbina/metabolismo , Vinorelbina/uso terapéutico , Receptor ErbB-2 , Neoplasias de la Mama/metabolismo , Inmunoterapia , Péptidos/metabolismo , Células Dendríticas , Trastuzumab/uso terapéutico , Trastuzumab/metabolismoRESUMEN
Streamflow often increases after fire, but the persistence of this effect and its importance to present and future regional water resources are unclear. This paper addresses these knowledge gaps for the western United States (WUS), where annual forest fire area increased by more than 1,100% during 1984 to 2020. Among 72 forested basins across the WUS that burned between 1984 and 2019, the multibasin mean streamflow was significantly elevated by 0.19 SDs (P < 0.01) for an average of 6 water years postfire, compared to the range of results expected from climate alone. Significance is assessed by comparing prefire and postfire streamflow responses to climate and also to streamflow among 107 control basins that experienced little to no wildfire during the study period. The streamflow response scales with fire extent: among the 29 basins where >20% of forest area burned in a year, streamflow over the first 6 water years postfire increased by a multibasin average of 0.38 SDs, or 30%. Postfire streamflow increases were significant in all four seasons. Historical fire-climate relationships combined with climate model projections suggest that 2021 to 2050 will see repeated years when climate is more fire-conducive than in 2020, the year currently holding the modern record for WUS forest area burned. These findings center on relatively small, minimally managed basins, but our results suggest that burned areas will grow enough over the next 3 decades to enhance streamflow at regional scales. Wildfire is an emerging driver of runoff change that will increasingly alter climate impacts on water supplies and runoff-related risks.
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Cambio Climático , Bosques , Estaciones del Año , Abastecimiento de Agua , Incendios Forestales , Estados UnidosRESUMEN
Mental health and substance use disorders can negatively affect physical health, illness management, care access, and quality of life. These behavioral health conditions are prevalent and undertreated among people with HIV and may worsen outcomes along the entire HIV Care Continuum. This narrative review of tested interventions for integrating care for HIV and behavioral health disorders summarizes and contextualizes findings from systematic reviews and meta-analyses conducted in the past decade. We sought to identify gaps in research that hinder implementing evidence-based integrated care approaches. Using terms from the Substance Abuse and Mental Health Services Administration-Health Resources & Services Administration standard framework for integrated health care, we searched PubMed and PsycInfo to identify peer-reviewed systematic reviews or meta-analyses of intervention studies to integrate behavioral health and HIV published between 2010 and 2020. Among 23 studies identified, only reviews and meta-analyses that described interventions from the United States designed to integrate BH services into HIV settings for adults were retained, leaving six studies for narrative review by the study team. Demonstrated benefits from the relatively small literature on integrated care interventions include improved patient- and service-level outcomes, particularly for in-person case management and outreach interventions. Needed are systems-level integration interventions with assessments of long-term outcomes on behavioral health symptoms, HIV viral suppression, HIV transmission rates, and mortality. HIV, primary care, and other providers must include behavioral health as a part of overall healthcare and must play a central role in behavioral health care delivery. Research is needed to guide their way.
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Prestación Integrada de Atención de Salud , Infecciones por VIH , Trastornos Relacionados con Sustancias , Humanos , Infecciones por VIH/terapia , Infecciones por VIH/psicología , Prestación Integrada de Atención de Salud/organización & administración , Estados Unidos/epidemiología , Trastornos Relacionados con Sustancias/terapia , Trastornos Mentales/terapia , Adulto , Calidad de Vida , Servicios de Salud Mental/organización & administraciónRESUMEN
The federal Ending the HIV Epidemic (EHE) initiative was created to reduce new US HIV infections, largely through pre-exposure prophylaxis and HIV treatments that reduce HIV transmissibility to zero. Behavioral health disorders (mental health and substance use) remain significant barriers to achieving EHE goals. Addressing behavioral health (BH) disorders within HIV primary care settings has been promoted as a critical EHE strategy. Implementation of efficacious HIV-BH care integration and its impact on HIV-related health outcomes is not well documented. In a federally-funded, exploratory phase implementation science study, we used the Collective Impact Framework to engage partners in seven EHE jurisdictions about the feasibility, acceptability, and sustainability of implementing HIV-BH integration interventions within local HIV settings. Partners concluded that full integration will remain the exception unless health systems invest in collaborative practice, professional training, appropriate health technology, and inter-system communication. Partners supported smaller incremental improvements including transdiagnostic approaches to reinforce each team member's sense of value in the shared endeavor. This early phase implementation science study identified research and implementation gaps that are critical to fill to end the HIV epidemic. Both the Collective Impact Framework and implementation science show promise for guiding future implementation of evidence-based HIV-BH intervention integration.
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Prestación Integrada de Atención de Salud , Infecciones por VIH , Humanos , Infecciones por VIH/prevención & control , Infecciones por VIH/epidemiología , Prestación Integrada de Atención de Salud/organización & administración , Epidemias/prevención & control , Ciencia de la Implementación , Estados Unidos/epidemiología , Atención Primaria de Salud/organización & administración , Profilaxis Pre-Exposición/métodos , Trastornos Mentales/epidemiología , Trastornos Mentales/terapia , Práctica Clínica Basada en la Evidencia , Trastornos Relacionados con Sustancias/prevención & control , Trastornos Relacionados con Sustancias/epidemiologíaRESUMEN
PURPOSE: Breast cancer is the most prevalent malignancy in women. Prehabilitation may offer improvements in physical and psychological wellbeing among participants prior to treatment. This systematic review aimed to determine the efficacy of prehabilitation in participants diagnosed with breast cancer. METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. Studies exploring the impact of prehabilitation in participants with breast cancer were included. Studies were assessed independently according to pre-eligibility criteria, with data extraction and methodological quality assessed in parallel. RESULTS: 3184 records were identified according to our search criteria, and 14 articles were included. Articles comprised of quantitative randomised controlled trials (n = 7), quantitative non-randomised studies (n = 5), a qualitative study (n = 1), and a mixed-method study (n = 1). The majority of selected studies completed exercise programs (n = 4) or had exercise components (n = 2), with two focusing on upper-limb exercise. Five articles reported complementary and alternative therapies (n = 5). Two articles reported smoking cessation (n = 2), with a single study reporting multi-modal prehabilitation (n = 1). Mostly, prehabilitation improved outcomes including physical function, quality of life, and psychosocial variables (P < 0.05). The qualitative data identified preferences for multimodal prehabilitation, compared to unimodal with an interest in receiving support for longer. CONCLUSIONS: Prehabilitation for patients with breast cancer is an emerging research area that appears to improve outcomes, however, ensuring that adequate intervention timeframes, follow-up, and population groups should be considered for future investigations. IMPLICATIONS FOR CANCER SURVIVORS: The implementation of prehabilitation interventions for individuals diagnosed with breast cancer should be utilised by multidisciplinary teams to provide holistic care to patients as it has the potential to improve outcomes across the cancer care trajectory.
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Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/cirugía , Atención a la Salud , Ejercicio Físico , Ejercicio Preoperatorio , Calidad de Vida/psicología , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos Controlados como AsuntoRESUMEN
BACKGROUND: To end the HIV epidemic, we need to better understand how to address HIV-related stigmas in healthcare settings, specifically the common theoretical bases across interventions so that we can generalize about their potential effectiveness. PURPOSE: We describe theory-based components of stigma interventions by identifying their functions/types, techniques, and purported mechanisms of change. METHODS: This systematic review examined studies published by April 2021. We applied a transtheoretical ontology developed by the Human Behaviour Change Project, consisting of 9 intervention types (ITs), 93 behavior change techniques (BCTs), and 26 mechanisms of action (MOAs). We coded the frequency and calculated the potential effectiveness of each IT, BCT, and MOA. We evaluated study quality with a 10-item adapted tool. RESULTS: Among the nine highest quality studies, indicated by the use of an experimental design, the highest potentially effective IT was "Persuasion" (i.e. using communication to induce emotions and/or stimulate action; 66.7%, 4/6 studies). The highest potentially effective BCTs were "Behavioral practice/rehearsal" (i.e. to increase habit and skill) and "Salience of consequences" (i.e. to make consequences of behavior more memorable; each 100%, 3/3 studies). The highest potentially effective MOAs were "Knowledge" (i.e. awareness) and "Beliefs about capabilities" (i.e. self-efficacy; each 67%, 2/3 studies). CONCLUSIONS: By applying a behavior change ontology across studies, we synthesized theory-based findings on stigma interventions. Interventions typically combined more than one IT, BCT, and MOA. Practitioners and researchers can use our findings to better understand and select theory-based components of interventions, including areas for further evaluation, to expedite ending the HIV epidemic.
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Terapia Conductista , Infecciones por VIH , Humanos , Terapia Conductista/métodos , Aprendizaje , Comunicación , Personal de SaludRESUMEN
We surveyed all licensed outpatient mental health programs in New York to examine sexual health services and training needs of providers. Gaps were found in processes for assessing whether patients were sexually active, engaging in sexual risk behaviours, and in need of HIV testing and pre-exposure prophylaxis. Significant differences between urban, suburban, and rural settings statewide were found in how the following sexual health services were delivered: education; on-site sexually transmitted infection screenings; and condom distribution and barriers to distribution. Staff training in sexual health services delivery is critically needed for optimal sexual health and recovery of patients in community mental healthcare.
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Infecciones por VIH , Servicios de Salud Mental , Humanos , New York , Pacientes Ambulatorios , Conducta Sexual , Población Rural , Infecciones por VIH/prevención & controlRESUMEN
Stigma remains a pervasive barrier to Ending the HIV Epidemic (EHE) in New York City (NYC). As part of an EHE implementation science planning process, we mapped multi-level HIV-related stigma-reduction activities, assessed their evidence base, and characterized barriers and facilitators. We interviewed and surveyed a convenience sample of 27 HIV prevention and/or treatment services organizations in NYC, March-August, 2020, using an embedded mixed-methods design. The greatest facilitators of stigma reduction included integration of health services, hiring staff who represent the community, and trainings. Intersecting stigmas were primarily addressed through the integration of HIV with mental health and substance use services. Barriers were multilevel, with organizational structure and capacity most challenging. A strong base of stigma-reduction activities was utilized by organizations, but intersectional frameworks and formal evaluation of activities' impact on stigma were lacking. Effectiveness-implementation hybrid research designs are needed to evaluate and increase the uptake of effective stigma-reduction approaches in NYC.
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Síndrome de Inmunodeficiencia Adquirida , Infecciones por VIH , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Infecciones por VIH/psicología , Humanos , Ciencia de la Implementación , Ciudad de Nueva York/epidemiología , Estigma SocialRESUMEN
BACKGROUND: People with serious mental illness (SMI) have sexual health needs but there is little evidence to inform effective interventions to address them. In fact, there are few studies that have addressed this topic for people with SMI outside USA and Brazil. Therefore, the aim of the study was to establish the acceptability and feasibility of a trial of a sexual health promotion intervention for people with SMI in the UK. METHOD: The RESPECT study was a two-armed randomised controlled, open feasibility trial (RCT) comparing Sexual health promotion intervention (3 individual sessions of 1 h) (I) or treatment as usual (TAU) for adults aged 18 or over, with SMI, within community mental health services in four UK cities. The main outcome of interest was the percentage who consented to participate, and retained in each arm of the trial, retention for the intervention, and completeness of data collection. A nested qualitative study obtained the views of participants regarding the acceptability of the study using individual telephone interviews conducted by lived experience researchers. RESULTS: Of a target sample of 100, a total of 72 people were enrolled in the trial over 12 months. Recruitment in the initial months was low and so an extension was granted. However this extension meant that the later recruited participants would only be followed up to the 3 month point. There was good retention in the intervention and the study as a whole; 77.8% of those allocated to intervention (n = 28) received it. At three months, 81.9% (30 I; 29 TAU) and at 6 months, 76.3% (13 I and 16 TAU) completed the follow-up data collection. No adverse events were reported. There was good completeness of the data. The sexual health outcomes for the intervention group changed in favour of the intervention. Based on analysis of the qualitative interviews, the methods of recruitment, the quality of the participant information, the data collection, and the intervention were deemed to be acceptable to the participants (n = 22). CONCLUSIONS: The target of 100 participants was not achieved within the study's timescale. However, effective strategies were identified that improved recruitment in the final few months. Retention rates and completeness of data in both groups indicate that it is acceptable and feasible to undertake a study promoting sexual health for people with SMI. A fully powered RCT is required to establish effectiveness of the intervention in adoption of safer sex. STUDY REGISTRATION: ISRCTN Registry ISRCTN15747739 prospectively registered 5th July 2016.
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Servicios Comunitarios de Salud Mental , Trastornos Mentales , Salud Sexual , Adolescente , Adulto , Brasil , Estudios de Factibilidad , Promoción de la Salud , Humanos , Trastornos Mentales/terapia , Reino UnidoRESUMEN
Neisseria gonorrhoeae is an exclusive human pathogen that evades the host immune system through multiple mechanisms. We have shown that N. gonorrhoeae suppresses the capacity of antigen-presenting cells to induce CD4+ T cell proliferation. In this study, we sought to determine the gonococcal factors involved in this adaptive immune suppression. We show that suppression of the capacity of antigen-pulsed dendritic cells to induce T cell proliferation is recapitulated by administration of a high-molecular-weight fraction of conditioned medium from N. gonorrhoeae cultures, which includes outer membrane vesicles that are shed during growth of the bacteria. N. gonorrhoeae PorB is the most abundant protein in N. gonorrhoeae-derived vesicles, and treatment of dendritic cells with purified recombinant PorB inhibited the capacity of the cells to stimulate T cell proliferation. This immunosuppressive feature of purified PorB depended on proper folding of the protein. PorB from N. gonorrhoeae, as well as other Neisseria species and other Gram-negative bacterial species, are known to activate host Toll-like receptor 2 (TLR2) signaling. Published studies have demonstrated that purified Neisseria PorB forms proteinacious nanoparticles, termed proteosomes, when detergent micelles are removed. Unlike folded, detergent-solubilized PorB, PorB proteosomes stimulate immune responses. We now demonstrate that the formation of PorB proteosomes from structurally intact PorB eliminates the immunosuppressive property of the protein while enhancing TLR2 stimulation. These findings suggest that gonococcal PorB present in shed outer membrane vesicles plays a role in suppression of adaptive immune responses to this immune-evasive pathogen.
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Linfocitos T CD4-Positivos/inmunología , Proliferación Celular , Células Dendríticas/inmunología , Gonorrea/inmunología , Neisseria gonorrhoeae/inmunología , Porinas/química , Pliegue de Proteína , Linfocitos T CD4-Positivos/microbiología , Células Cultivadas , Células Dendríticas/microbiología , Gonorrea/microbiología , Humanos , Activación de Linfocitos , Porinas/metabolismo , Transducción de Señal , Receptor Toll-Like 2/metabolismoRESUMEN
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that affects the function and development of immune cells. Here, we show that recipient mice receiving AhR-/- T cells have improved survival and decreased acute graft-versus-host disease (aGVHD) in 2 different murine allogeneic bone marrow transplant (BMT) models. We also show that CD4+ T cells lacking AhR demonstrate reduced accumulation in secondary lymphoid tissue because of low levels of proliferation 4 days after BMT. Additionally, we found a significant increase in the quantity of peripherally induced regulatory donor T (pTreg) cells in the colon of recipients transplanted with AhR-/- T cells 14 days after transplant. Blockade of AhR using a clinically available AhR antagonist greatly enhanced the in vitro generation of inducible Treg (iTreg) cells from naïve CD4+ human T cells. We have identified AhR as a novel target on donor T cells that is critical to the pathogenesis of aGVHD.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/inmunología , Trasplante de Médula Ósea , Colon/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Receptores de Hidrocarburo de Aril/inmunología , Linfocitos T Reguladores/inmunología , Enfermedad Aguda , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/deficiencia , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proliferación Celular , Colon/patología , Regulación de la Expresión Génica , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Humanos , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Purinas/farmacología , Receptores de Hidrocarburo de Aril/deficiencia , Receptores de Hidrocarburo de Aril/genética , Sirolimus/farmacología , Análisis de Supervivencia , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/trasplante , Trasplante HeterólogoRESUMEN
OBJECTIVE: We evaluated the psychometric properties of a new instrument "Mental Illness Sexual Stigma Questionnaire" (MISS-Q). METHODS: We interviewed 641 sexually active adults (ages 18-80) attending public outpatient psychiatric clinics in Rio de Janeiro about their stigma experiences. RESULTS: Nine factors were extracted through exploratory factor analysis (EFA) and labeled: 'individual discrimination by others'; 'staff willingness to talk about sexuality'; 'staff and family prohibitions'; 'sexual devaluation of self'; 'perceived attractiveness'; 'mental illness concealment'; 'perceived sexual role competence'; 'withdrawal'; and 'locus of social-sexual control'. 'Withdrawal' and 'locus of social-sexual control' showed poor psychometric properties and were excluded from further analysis. The remaining seven factors had high factorial loadings (.39 to .86), varying from sufficient to optimal reliability (Ordinal α ranged from .57 to .88), and good convergent and discriminant validity. CONCLUSIONS: The resulting MISS-Q is the first instrument assessing mental illness sexual stigma with demonstrated psychometric properties. It may prove useful in reducing stigma, protecting sexual health, and promoting recovery.
OBJETIVO: Avaliamos as propriedades psicométricas de um novo instrumento "Mental Illness Sexual Stigma Questionnaire" (MISS-Q; Questionário de Estigma Sexual na Doença Mental). MÉTODOS: Entrevistamos 641 adultos sexualmente ativos (18 a 80 anos), frequentando clínicas psiquiátricas ambulatoriais públicas no Rio de Janeiro sobre suas experiências de estigma. RESULTADOS: Foram extraídos nove fatores por meio da análise exploratória fatorial e rotulados: 'discriminação individual por parte de outros'; 'disposição pessoal para falar sobre sexualidade'; proibições pessoais e familiares; 'desvalorização sexual de si mesmo'; 'percepção de atratividade'; 'dissimulação da doença mental'; 'percepção da competência de papel sexual'; 'retirada'; e 'locus de sociosexual ao controle'. 'Retirada' e 'locus de controle social-sexual' mostraram propriedades psicométricas fracas e foram excluídos da análise posterior. Os sete fatores restantes tinham altas cargas fatoriais (0,39 a 0,86), variando de suficiente até confiabilidade ótima (Ordinal α variou de ,57 a ,88), e boa validade convergente e discriminante. CONCLUSÕES: O resultante MISS-Q é o primeiro instrumento que avalia o estigma sexual da doença mental com propriedades psicométricas demonstradas. Pode ser útil na redução do estigma, proteção da saúde sexual e promoção à recuperação.
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Approximately 500,000 people are hospitalized with severe dengue illness annually. Antibody-dependent enhancement (ADE) of dengue virus (DENV) infection is believed to contribute to the pathogenic cytokine storm described in severe dengue patients, but the precise signaling pathways contributing to elevated cytokine production are not elucidated. IL-1ß is a potent inflammatory cytokine that is frequently elevated during severe dengue, and the unique dual regulation of IL-1ß provides an informative model to study ADE-induced cytokines. This work utilizes patient-derived anti-DENV mAbs and primary human monocytes to study ADE-induced IL-1ß and other cytokines. ADE of DENV serotype 2 (DENV-2) elevates mature IL-1ß secretion by monocytes independent of DENV replication by 4 h postinoculation (hpi). Prior to this, DENV immune complexes activate spleen tyrosine kinase (Syk) within 1 hpi. Syk induces elevated IL1B, TNF, and IL6 mRNA by 2 hpi. Syk mediates elevated IL-1ß secretion by activating ERK1/2, and both Syk and ERK1/2 inhibitors ablated ADE-induced IL-1ß secretion. Maturation of pro-IL-1ß during ADE requires caspase-1 and NLRP3, but caspase-1 is suboptimally increased by ADE and can be significantly enhanced by a typical inflammasome agonist, ATP. Importantly, this inflammatory Syk-ERK signaling axis requires DENV immune complexes, because DENV-2 in the presence of serotype-matched anti-DENV-2 mAb, but not anti-DENV-1 mAb, activates Syk, ERK, and IL-1ß secretion. This study provides evidence that DENV-2 immune complexes activate Syk to mediate elevated expression of inflammatory cytokines. Syk and ERK may serve as new therapeutic targets for interfering with ADE-induced cytokine expression during severe dengue.
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Virus del Dengue/inmunología , Virus del Dengue/patogenicidad , Interleucina-1beta/biosíntesis , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Monocitos/inmunología , Monocitos/virología , Proteínas Tirosina Quinasas/metabolismo , Anticuerpos Antivirales/metabolismo , Acrecentamiento Dependiente de Anticuerpo , Complejo Antígeno-Anticuerpo/metabolismo , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Caspasa 1/metabolismo , Células Cultivadas , Dengue/genética , Dengue/inmunología , Dengue/virología , Virus del Dengue/fisiología , Gliburida/farmacología , Humanos , Interleucina-1beta/genética , Sistema de Señalización de MAP Quinasas , Monocitos/enzimología , Proteína con Dominio Pirina 3 de la Familia NLR , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , Quinasa Syk , Replicación ViralRESUMEN
The infusion of donor regulatory T cells (Tregs) has been used to prevent acute graft-versus-host disease (GVHD) in mice and has shown promise in phase 1 clinical trials. Previous work suggested that early Treg migration into lymphoid tissue was important for GVHD prevention. However, it is unclear how and where Tregs function longitudinally to affect GVHD. To better understand their mechanism of action, we studied 2 Treg-associated chemokine receptors in murine stem cell transplant models. CC chemokine receptor (CCR) 4 was dispensable for donor Treg function in the transplant setting. Donor Tregs lacking CCR8 (CCR8(-/-)), however, were severely impaired in their ability to prevent lethal GVHD because of increased cell death. By itself, CCR8 stimulation was unable to rescue Tregs from apoptosis. Instead, CCR8 potentiated Treg survival by promoting critical interactions with dendritic cells. In vivo, donor bone marrow-derived CD11c(+) antigen-presenting cells (APCs) were important for promoting donor Treg maintenance after transplant. In contrast, host CD11c(+) APCs appeared to be dispensable for early activation and expansion of donor Tregs. Collectively, our data indicate that a sustained donor Treg presence is critical for their beneficial properties, and that their survival depends on CCR8 and donor but not host CD11c(+) APCs.
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Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/prevención & control , Receptores CCR8/fisiología , Linfocitos T Reguladores/fisiología , Animales , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Células Presentadoras de Antígenos/fisiología , Antígeno CD11c/metabolismo , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Células Cultivadas , Supervivencia de Injerto/genética , Supervivencia de Injerto/inmunología , Enfermedad Injerto contra Huésped/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Transgénicos , Receptores CCR8/genética , Receptores CCR8/metabolismo , Linfocitos T Reguladores/metabolismo , Donantes de TejidosRESUMEN
Ideal nanoparticle (NP)-based drug and vaccine delivery vectors should be free of inherent cytotoxic or immunostimulatory properties. Therefore, determining baseline immune responses to nanomaterials is of utmost importance when designing human therapeutics. We characterized the response of human immune cells to hydrogel NPs fabricated using Particle Replication in Non-wetting Templates (PRINT) technology. We found preferential NP uptake by primary CD14(+) monocytes, which was significantly reduced upon PEGylation of the NP surface. Multiplex cytokine analysis of NP treated primary human peripheral blood mononuclear cells suggests that PRINT based hydrogel NPs do not evoke significant inflammatory responses nor induce cytotoxicity or complement activation. We furthered these studies using an in vivo humanized mouse model and similarly found preferential NP uptake by human CD14(+) monocytes without systemic inflammatory cytokine responses. These studies suggest that PRINT hydrogel particles form a desirable platform for vaccine and drug delivery as they neither induce inflammation nor toxicity. From the clinical editor: The authors here fabricated hydrogel nanorods using the PRINT (Particle Replication In Nonwetting Templates) fabrication process. They tested the interaction of human immune cells with these particles and found no immunoreactivity. This finding would suggest that monodisperse PRINT particles of identical shape and size could serve a variety of clinical applications.
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Sistemas de Liberación de Medicamentos , Inmunidad Innata , Inmunización/métodos , Monocitos/inmunología , Nanopartículas/química , Animales , Línea Celular Tumoral , Citocinas/inmunología , Evaluación Preclínica de Medicamentos , Humanos , Receptores de Lipopolisacáridos/inmunología , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Monocitos/citología , Vacunas/química , Vacunas/farmacologíaAsunto(s)
Docentes Médicos , Internado y Residencia , Salud Mental , Psiquiatría/educación , Sexualidad , Humanos , Conducta SexualRESUMEN
The Affordable Care Act (ACA) creates incentives to coordinate primary care, mental health (MH) care, and addiction services. Integration of clinical HIV and MH services has been shown to improve quality of life and physical and MH of people living with HIV/AIDS. However, few studies have investigated the practice of service integration systematically. We examined the practice patterns of 515 direct service providers in New York State who received training about HIV MH between May 2010 and July 2012. We sought to identify provider and treatment setting characteristics associated with an integrated spectrum of care. Using factor analysis and linear modeling, we found that patterns of service integration varied by type of health-care setting, service setting location, providers' HIV caseload, and the discipline of the provider describing the direct services. Understanding the existing capacities of clinicians providing care in a variety of settings throughout New York will help to guide staffing and linkage to enhance HIV MH service integration as significant shifts in the organization of health care occur.
Asunto(s)
Prestación Integrada de Atención de Salud , Seropositividad para VIH/psicología , Servicios de Salud Mental/organización & administración , Patient Protection and Affordable Care Act , Atención Primaria de Salud/organización & administración , Calidad de la Atención de Salud , Análisis Factorial , Seropositividad para VIH/terapia , Humanos , Modelos Lineales , Salud Mental , Modelos Organizacionales , New York/epidemiología , Pautas de la Práctica en Medicina , Investigación Cualitativa , Calidad de VidaRESUMEN
People living with mental illness are at increased risk for HIV. There are scarce data on correlates and prevalence of HIV infection, and none with a nationally representative sample. We report on correlates of HIV infection from a cross-sectional national sample of adults receiving care in 26 publicly funded mental health treatment settings throughout Brazil. Weighted prevalence rate ratios were obtained using multiple log-binomial regression modeling. History of homelessness, ever having an STD, early age of first sexual intercourse before 18 years old, having suffered sexual violence, previous HIV testing, self-perception of high risk of HIV infection and not knowing one's risk were statistically associated with HIV infection. Our study found an elevated HIV seroprevalence and correlates of infection were not found to include psychiatric diagnoses or hospitalizations but instead reflected marginalized living circumstances and HIV testing history. These adverse life circumstances (history of homelessness, having suffered sexual violence, reporting a sexually transmitted disease, and early sexual debut) may not be unique to people living with mental illness but nonetheless the mental health care system can serve as an important point of entry for HIV prevention in this population.