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1.
Nat Immunol ; 22(8): 1052-1063, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34168370

RESUMEN

Immune-checkpoint blockade (ICB) has shown remarkable clinical success in boosting antitumor immunity. However, the breadth of its cellular targets and specific mode of action remain elusive. We find that tumor-infiltrating follicular regulatory T (TFR) cells are prevalent in tumor tissues of several cancer types. They are primarily located within tertiary lymphoid structures and exhibit superior suppressive capacity and in vivo persistence as compared with regulatory T cells, with which they share a clonal and developmental relationship. In syngeneic tumor models, anti-PD-1 treatment increases the number of tumor-infiltrating TFR cells. Both TFR cell deficiency and the depletion of TFR cells with anti-CTLA-4 before anti-PD-1 treatment improve tumor control in mice. Notably, in a cohort of 271 patients with melanoma, treatment with anti-CTLA-4 followed by anti-PD-1 at progression was associated with better a survival outcome than monotherapy with anti-PD-1 or anti-CTLA-4, anti-PD-1 followed by anti-CTLA-4 at progression or concomitant combination therapy.


Asunto(s)
Antígeno CTLA-4/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Linfocitos T Reguladores/inmunología , Animales , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Células T Auxiliares Foliculares/inmunología , Microambiente Tumoral/inmunología
2.
Nat Immunol ; 18(8): 940-950, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28628092

RESUMEN

Therapies that boost the anti-tumor responses of cytotoxic T lymphocytes (CTLs) have shown promise; however, clinical responses to the immunotherapeutic agents currently available vary considerably, and the molecular basis of this is unclear. We performed transcriptomic profiling of tumor-infiltrating CTLs from treatment-naive patients with lung cancer to define the molecular features associated with the robustness of anti-tumor immune responses. We observed considerable heterogeneity in the expression of molecules associated with activation of the T cell antigen receptor (TCR) and of immunological-checkpoint molecules such as 4-1BB, PD-1 and TIM-3. Tumors with a high density of CTLs showed enrichment for transcripts linked to tissue-resident memory cells (TRM cells), such as CD103, and CTLs from CD103hi tumors displayed features of enhanced cytotoxicity. A greater density of TRM cells in tumors was predictive of a better survival outcome in lung cancer, and this effect was independent of that conferred by CTL density. Here we define the 'molecular fingerprint' of tumor-infiltrating CTLs and identify potentially new targets for immunotherapy.


Asunto(s)
Adenocarcinoma/inmunología , Carcinoma de Células Escamosas/inmunología , Neoplasias de Cabeza y Cuello/inmunología , Memoria Inmunológica/inmunología , Neoplasias Pulmonares/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos T Citotóxicos/inmunología , Adenocarcinoma/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/genética , Carcinoma de Células Escamosas/mortalidad , Femenino , Perfilación de la Expresión Génica , Receptor 2 Celular del Virus de la Hepatitis A/genética , Humanos , Inmunoterapia , Cadenas alfa de Integrinas/genética , Neoplasias Pulmonares/mortalidad , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Receptor de Muerte Celular Programada 1/genética , Receptores de Antígenos de Linfocitos T/genética , Carcinoma de Células Escamosas de Cabeza y Cuello , Tasa de Supervivencia , Linfocitos T Citotóxicos/metabolismo , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética
3.
J Allergy Clin Immunol ; 153(5): 1369-1380.e15, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38184075

RESUMEN

BACKGROUND: Solar urticaria is a rare photodermatosis characterized by rapid-onset sunlight-induced urticaria, but its pathophysiology is not well understood. OBJECTIVE: We sought to define cutaneous cellular and molecular events in the evolution of solar urticaria following its initiation by solar-simulated UV radiation (SSR) and compare with healthy controls (HC). METHODS: Cutaneous biopsy specimens were taken from unexposed skin and skin exposed to a single low (physiologic) dose of SSR at 30 minutes, 3 hours, and 24 hours after exposure in 6 patients with solar urticaria and 6 HC. Biopsy specimens were assessed by immunohistochemistry and bulk RNA-sequencing analysis. RESULTS: In solar urticaria specimens, there was enrichment of several innate immune pathways, with striking early involvement of neutrophils, which was not observed in HC. Multiple proinflammatory cytokine and chemokine genes were upregulated (including IL20, IL6, and CXCL8) or identified as upstream regulators (including TNF, IL-1ß, and IFN-γ). IgE and FcεRI were identified as upstream regulators, and phosphorylated signal transducer and activator of transcription 3 expression in mast cells was increased in solar urticaria at 30 minutes and 3 hours after SSR exposure, suggesting a mechanism of mast cell activation. Clinical resolution of solar urticaria by 24 hours mirrored resolution of inflammatory gene signature profiles. Comparison with available datasets of chronic spontaneous urticaria showed transcriptomic similarities relating to immune activation, but several transcripts were identified solely in solar urticaria, including CXCL8 and CSF2/3. CONCLUSIONS: Solar urticaria is characterized by rapid signal transducer and activator of transcription 3 activation in mast cells and involvement of multiple chemotactic and innate inflammatory pathways, with FcεRI engagement indicated as an early event.


Asunto(s)
Mastocitos , Infiltración Neutrófila , Receptores de IgE , Factor de Transcripción STAT3 , Urticaria , Humanos , Urticaria/inmunología , Mastocitos/inmunología , Receptores de IgE/genética , Femenino , Adulto , Factor de Transcripción STAT3/metabolismo , Masculino , Infiltración Neutrófila/inmunología , Persona de Mediana Edad , Piel/inmunología , Piel/patología , Luz Solar/efectos adversos , Citocinas/metabolismo , Citocinas/inmunología , Trastornos por Fotosensibilidad/inmunología , Rayos Ultravioleta/efectos adversos , Neutrófilos/inmunología , Urticaria Solar
4.
J Viral Hepat ; 31(5): 266-270, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38366329

RESUMEN

Dried blood spots (DBS) have emerged as a promising alternative to traditional venous blood for hepatitis C virus (HCV) testing. However, their capacity to accurately reflect the genetic diversity of HCV remains poorly understood. We employed deep sequencing and advanced phylogenetic analyses on paired plasma and DBS samples from two common subtypes to evaluate the suitability of DBS for genomic surveillance. Results demonstrated that DBS captured equivalent viral diversity compared to plasma with no phylogenetic discordance observed. The ability of DBS to accurately reflect the profile of viral genetic diversity suggests it may be a promising avenue for future surveillance efforts to curb HCV outbreaks.


Asunto(s)
Hepacivirus , Hepatitis C , Humanos , Hepacivirus/genética , Filogenia , Anticuerpos contra la Hepatitis C , Sensibilidad y Especificidad , Hepatitis C/diagnóstico , Hepatitis C/epidemiología , Genómica
5.
BMC Med Res Methodol ; 24(1): 94, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38654219

RESUMEN

BACKGROUND: Accurate prevalence estimates of drug use and its harms are important to characterize burden and develop interventions to reduce negative health outcomes and disparities. Lack of a sampling frame for marginalized/stigmatized populations, including persons who use drugs (PWUD) in rural settings, makes this challenging. Respondent-driven sampling (RDS) is frequently used to recruit PWUD. However, the validity of RDS-generated population-level prevalence estimates relies on assumptions that should be evaluated. METHODS: RDS was used to recruit PWUD across seven Rural Opioid Initiative studies between 2018-2020. To evaluate RDS assumptions, we computed recruitment homophily and design effects, generated convergence and bottleneck plots, and tested for recruitment and degree differences. We compared sample proportions with three RDS-adjusted estimators (two variations of RDS-I and RDS-II) for five variables of interest (past 30-day use of heroin, fentanyl, and methamphetamine; past 6-month homelessness; and being positive for hepatitis C virus (HCV) antibody) using linear regression with robust confidence intervals. We compared regression estimates for the associations between HCV positive antibody status and (a) heroin use, (b) fentanyl use, and (c) age using RDS-1 and RDS-II probability weights and no weights using logistic and modified Poisson regression and random-effects meta-analyses. RESULTS: Among 2,842 PWUD, median age was 34 years and 43% were female. Most participants (54%) reported opioids as their drug of choice, however regional differences were present (e.g., methamphetamine range: 4-52%). Many recruitment chains were not long enough to achieve sample equilibrium. Recruitment homophily was present for some variables. Differences with respect to recruitment and degree varied across studies. Prevalence estimates varied only slightly with different RDS weighting approaches, most confidence intervals overlapped. Variations in measures of association varied little based on weighting approach. CONCLUSIONS: RDS was a useful recruitment tool for PWUD in rural settings. However, several violations of key RDS assumptions were observed which slightly impacts estimation of proportion although not associations.


Asunto(s)
Población Rural , Humanos , Población Rural/estadística & datos numéricos , Femenino , Masculino , Adulto , Trastornos Relacionados con Opioides/epidemiología , Persona de Mediana Edad , Prevalencia , Consumidores de Drogas/estadística & datos numéricos , Muestreo , Trastornos Relacionados con Sustancias/epidemiología , Selección de Paciente
6.
Harm Reduct J ; 21(1): 23, 2024 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-38282000

RESUMEN

BACKGROUND: Hepatitis C virus (HCV) disproportionately affects rural communities, where health services are geographically dispersed. It remains unknown whether proximity to a syringe services program (SSP) is associated with HCV infection among rural people who inject drugs (PWID). METHODS: Data are from a cross-sectional sample of adults who reported injecting drugs in the past 30 days recruited from rural counties in New Hampshire, Vermont, and Massachusetts (2018-2019). We calculated the road network distance between each participant's address and the nearest fixed-site SSP, categorized as ≤ 1 mile, 1-3 miles, 3-10 miles, and > 10 miles. Staff performed HCV antibody tests and a survey assessed past 30-day injection equipment sharing practices: borrowing used syringes, borrowing other used injection equipment, and backloading. Mixed effects modified Poisson regression estimated prevalence ratios (aPR) and 95% confidence intervals (95% CI). Analyses were also stratified by means of transportation. RESULTS: Among 330 PWID, 25% lived ≤ 1 mile of the nearest SSP, 17% lived 1-3 miles of an SSP, 12% lived 3-10 miles of an SSP, and 46% lived > 10 miles from an SSP. In multivariable models, compared to PWID who lived within 1 mile of an SSP, those who lived 3 to 10 miles away had a higher prevalence of HCV seropositivity (aPR: 1.25, 95% CI 1.06-1.46), borrowing other used injection equipment (aPR: 1.23, 95% CI 1.04-1.46), and backloading (aPR: 1.48, 95% CI 1.17-1.88). Similar results were observed for PWID living > 10 miles from an SSP: aPR [HCV]: 1.19, 95% CI 1.01-1.40; aPR [borrowing other used equipment]:1.45, 95% CI 1.29-1.63; and aPR [backloading]: 1.59, 95% CI 1.13-2.24. Associations between living 1 to 3 miles of an SSP and each outcome did not reach statistical significance. When stratified by means of transportation, associations between distance to SSP and each outcome (except borrowing other used injection equipment) were only observed among PWID who traveled by other means (versus traveled by automobile). CONCLUSIONS: Among PWID in rural New England, living farther from a fixed-site SSP was associated with a higher prevalence of HCV seropositivity, borrowing other used injection equipment, and backloading, reinforcing the need to increase SSP accessibility in rural areas. Means of transportation may modify this relationship.


Asunto(s)
Consumidores de Drogas , Infecciones por VIH , Hepatitis C , Abuso de Sustancias por Vía Intravenosa , Adulto , Humanos , Estados Unidos , Hepacivirus , Abuso de Sustancias por Vía Intravenosa/epidemiología , Infecciones por VIH/epidemiología , Población Rural , Estudios Transversales , Hepatitis C/epidemiología , New England , Programas de Intercambio de Agujas
7.
Harm Reduct J ; 21(1): 77, 2024 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-38582851

RESUMEN

BACKGROUND: Drug overdose deaths in the United States exceeded 100,000 in 2021 and 2022. Substance use stigma is a major barrier to treatment and harm reduction utilization and is a priority target in ending the overdose epidemic. However, little is known about the relationship between stigma and overdose, especially in rural areas. We aimed to characterize the association between felt stigma and non-fatal overdose in a multi-state sample of rural-dwelling people who use drugs. METHODS: Between January 2018 and March 2020, 2,608 people reporting past 30-day opioid use were recruited via modified chain-referral sampling in rural areas across 10 states. Participants completed a computer-assisted survey of substance use and substance-related attitudes, behaviors, and experiences. We used multivariable logistic regression with generalized estimating equations to test the association between felt stigma and recent non-fatal overdose. RESULTS: 6.6% of participants (n = 173) reported an overdose in the past 30 days. Recent non-fatal overdose was significantly associated with felt stigma after adjusting for demographic and substance use-related covariates (aOR: 1.47, 95% CI: 1.20-1.81). The association remained significant in sensitivity analyses on component fear of enacted stigma items (aOR: 1.48, 95% CI: 1.20-1.83) and an internalized stigma item (aOR: 1.51, 95% CI: 1.07-2.14). CONCLUSIONS: Felt stigma related to substance use is associated with higher risk of non-fatal overdose in rural-dwelling people who use drugs. Stigma reduction interventions and tailored services for those experiencing high stigma are underutilized approaches that may mitigate overdose risk.


Asunto(s)
Sobredosis de Droga , Trastornos Relacionados con Opioides , Humanos , Sobredosis de Droga/epidemiología , Trastornos Relacionados con Opioides/epidemiología , Miedo , Reducción del Daño , Estigma Social , Analgésicos Opioides
8.
Harm Reduct J ; 20(1): 157, 2023 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-37880724

RESUMEN

BACKGROUND: Research conducted in urban areas has highlighted the impact of housing instability on people who inject drugs (PWID), revealing that it exacerbates vulnerability to drug-related harms and impedes syringe service program (SSP) use. However, few studies have explored the effects of houselessness on SSP use among rural PWID. This study examines the relationship between houselessness and SSP utilization among PWID in eight rural areas across 10 states. METHODS: PWID were recruited using respondent-driven sampling for a cross-sectional survey that queried self-reported drug use and SSP utilization in the prior 30 days, houselessness in the prior 6 months and sociodemographic characteristics. Using binomial logistic regression, we examined the relationship between experiencing houselessness and any SSP use. To assess the relationship between houselessness and the frequency of SSP use, we conducted multinomial logistic regression analyses among participants reporting any past 30-day SSP use. RESULTS: Among 2394 rural PWID, 56.5% had experienced houselessness in the prior 6 months, and 43.5% reported past 30-day SSP use. PWID who had experienced houselessness were more likely to report using an SSP compared to their housed counterparts (adjusted odds ratio [aOR] = 1.24 [95% confidence intervals [CI] 1.01, 1.52]). Among those who had used an SSP at least once (n = 972), those who experienced houselessness were just as likely to report SSP use two (aOR = 0.90 [95% CI 0.60, 1.36]) and three times (aOR = 1.18 [95% CI 0.77, 1.98]) compared to once. However, they were less likely to visit an SSP four or more times compared to once in the prior 30 days (aOR = 0.59 [95% CI 0.40, 0.85]). CONCLUSION: This study provides evidence that rural PWID who experience houselessness utilize SSPs at similar or higher rates as their housed counterparts. However, housing instability may pose barriers to more frequent SSP use. These findings are significant as people who experience houselessness are at increased risk for drug-related harms and encounter additional challenges when attempting to access SSPs.


Asunto(s)
Consumidores de Drogas , Infecciones por VIH , Abuso de Sustancias por Vía Intravenosa , Humanos , Abuso de Sustancias por Vía Intravenosa/epidemiología , Programas de Intercambio de Agujas , Estudios Transversales , Recolección de Datos
9.
Subst Use Misuse ; 58(3): 320-330, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36629127

RESUMEN

Background: This study examined fidelity of implementation strategies used in an organizational process improvement intervention (OPII) designed to improve evidence-based practices related to assessments for drug-involved clients exiting incarceration. Leadership was studied as a moderating factor between fidelity and outcomes. Methods: A mixed-method cluster randomized design was used to randomize 21 sites to early- or delayed-start within 9 research centers. Parent study protocol was reviewed to develop fidelity constructs (i.e., responsiveness, dose, quality, adherence). Outcomes were site-level success in achieving goals and objectives completed during the OPII (e.g., percent goals achieved). Correlations, analyses of covariance, regressions and moderation analyses were performed. Qualitative interviews assessed facilitators/barriers to implementation. Results: Fidelity constructs related to outcomes. No differences were found in fidelity by early or delayed condition. At low levels of leadership, high staff responsiveness (i.e., engagement in the OPII) related to poorer outcome. Conclusions: It is important to consider contextual factors (e.g., leadership) that may influence implementation strategy fidelity when deploying evidence-based practices. Findings are relevant to researchers, clinicians, administrators and policy makers, and suggest that goal completion during implementation of evidence-based practices requires monitoring of leadership competence, fidelity to implementation strategies (i.e., staff responsiveness to strategies) and attendance to goal importance.


Asunto(s)
Práctica Clínica Basada en la Evidencia , Humanos , Prisioneros , Trastornos Relacionados con Sustancias , Liderazgo
10.
Infant Ment Health J ; 44(2): 166-183, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36859776

RESUMEN

Home visiting programs can provide critical support to mothers in recovery from substance use disorders (SUDs) and young children prenatally exposed to substances. However, families impacted by maternal SUDs may not benefit from traditional child-focused developmental home visiting services as much as families not impacted by SUDs, suggesting the need to adjust service provision for this population. Given the need to implement tailored services within home visiting programs for families impacted by SUDs, we sought to investigate the implementation barriers and facilitators to inform future integration of a relationship-based parenting intervention developed specifically for parents with SUDs (Mothering from the Inside Out) into home visiting programs. We conducted nine interviews and five focus groups with a racially diverse sample (N = 38) of parents and providers delivering services for families affected by SUDs in the USA. Qualitative content analysis yielded three most prominent themes related to separate implementation domains and their associated barriers and facilitators: (1) engagement, (2) training, and (3) sustainability. We concluded that the home visiting setting may mitigate the logistical barriers to access for families affected by SUDs, whereas relationship-based services may mitigate the emotional barriers that parents with SUDs experience when referred to home visiting programs.


Los programas de visita a casa pueden ofrecer un apoyo clave a madres en recuperación de trastornos por abusos de sustancias (SUD) y los niños pequeños expuestos a sustancia prenatalmente. Sin embargo, las familias que recibieron el impacto de SUD materno pudieran no beneficiarse de los servicios tradicionales de visita a casa en cuanto al desarrollo enfocados en el niño tanto como las familias que no sufren el impacto de SDU, lo cual sugiere la necesidad de ajustar el ofrecimiento de servicios para este grupo de población. Dada la necesidad de implementar servicios amoldados dentro de los programas de visita a casa para familias que sufren el impacto de SUD, nos propusimos investigar las barreras y los aspectos que facilitan la implementación a manera de informar la futura integración de una intervención de crianza con base en la relación, específicamente desarrollada para progenitores con SUD (Cuidados Maternales Desde Dentro) en los programas de visita a casa. Llevamos a cabo nueve entrevistas y cinco grupos de enfoque con un grupo muestra racialmente diverso (N = 38) de progenitores y proveedores que ofrecen los servicios a familias que sufren el impacto de SUD en los Estados Unidos. Los análisis de contenido cualitativo arrojaron tres temas más prominentes relacionados con dominios de implementación separados y las asociadas barreras y aspectos que la facilitan: (1) involucramiento, (2) entrenamiento, y (3) sostenibilidad. Concluimos que el escenario de visita a casa pudiera mitigar las barreras logísticas de acceso para familias afectadas por SUD, mientras que los servicios con base en la relación pudieran mitigar las barreras emocionales que los progenitores con SUD experimentan cuando se les refiere a programas de visita a casa.


Les programmes de visite à domicile peuvent offrir un soutien critique aux mères qui se rétablissent d'un trouble lié à l'usage d'une substance (TUS) et aux jeunes enfants exposés à des substances avant leur naissance. Cependant les familles impactées par des TUS maternels ne bénéficient pas de services de visite à domicile traditionnels autant que des familles non impactées par un TUS, suggérant le besoin d'ajuster des prestations de service pour cette population. Vu le besoin de mettre en place des services adaptés au sein des programmes de visite à domicile pour les familles impactées par des TUS, nous avons décidé d'étudier les barrières et les facteurs de facilitation de mise en place afin d'éclairer l'intégration future d'une intervention de parentage basée sur une relation développée spécifiquement pour des parents avec des TUS (le maternage de l'intérieur suivant l'anglais Mothering from the Inside Out) dans des programmes de visite à domicile. Nous avons procédé à neuf entretiens et cinq groupes d'étude avec un échantille variés du point de vue racial (N = 38) de parents et de prestataires offrant des services pour des familles affectées par des TUS aux Etats-Unis d'Amérique. Une analyse qualitative de contenu a donné trois groupes importants lié à des domaines de mise en place séparés et les barrières et facteurs de facilitation y étant liés: (1) l'engagement, (2) la formation, et (3) la durabilité. Nous concluons que le contexte de visite à domicile peut mitiger les barrières logistiques à l'accès pour les familles affectées par des TUS, alors que les services relationnels peuvent mitiger les barrières émotionnelles dont les parents avec des TUS font l'expérience lorsqu'on leur recommande des programmes de visite à domicile.


Asunto(s)
Padres , Trastornos Relacionados con Sustancias , Femenino , Humanos , Preescolar , Responsabilidad Parental/psicología , Madres , Trastornos Relacionados con Sustancias/terapia , Visita Domiciliaria
11.
Neuroendocrinology ; 112(4): 370-383, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34157710

RESUMEN

INTRODUCTION: Neuroendocrine tumours (NETs) are rare tumours with an increasing incidence. While low- and intermediate-grade pancreatic NET (PanNET) and small intestinal NET (siNET) are slow growing, they have a relatively high rate of metastasizing to the liver, leading to substantially worse outcomes. In many solid tumours, the outcome is determined by the quality of the antitumour immune response. However, the quality and significance of antitumour responses in NETs are incompletely understood. This study provides clinico-pathological analyses of the tumour immune microenvironment in PanNET and siNETs. METHODS: Formalin-fixed paraffin-embedded tissue from consecutive resected PanNETs (61) and siNETs (131) was used to construct tissue microarrays (TMAs); 1-mm cores were taken from the tumour centre, stroma, tumour edge, and adjacent healthy tissue. TMAs were stained with antibodies against CD8, CD4, CD68, FoxP3, CD20, and NCR1. T-cell counts were compared with counts from lung cancers. RESULTS: For PanNET, median counts were CD8+ 35.4 cells/mm2, CD4+ 7.6 cells/mm2, and CD68+ macrophages 117.7 cells/mm2. For siNET, there were CD8+ 39.2 cells/mm2, CD4+ 24.1 cells/mm2, and CD68+ 139.2 cells/mm2. The CD8+ cell density in the tumour and liver metastases were significantly lower than in the adjacent normal tissues, without evidence of a cell-rich area at the tumour edge that might have suggested immune exclusion. T-cell counts in lung cancer were significantly higher than those in PanNET and siNETs: CD8+ 541 cells/mm2 and CD4+ 861 cells/mm2 (p ≤ 0.0001). CONCLUSION: PanNETs and siNETs are immune cold with no evidence of T cell exclusion; the low density of immune infiltrates indicates poor antitumour immune responses.


Asunto(s)
Tumores Neuroendocrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/patología , Pronóstico , Microambiente Tumoral
12.
J Allergy Clin Immunol ; 147(5): 1830-1837.e15, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33058932

RESUMEN

BACKGROUND: ß-lactam antibiotics are associated with a variety of immune-mediated or hypersensitivity reactions, including immediate (type I) reactions mediated by antigen-specific IgE. OBJECTIVE: We sought to identify genetic predisposing factors for immediate reactions to ß-lactam antibiotics. METHODS: Patients with a clinical history of immediate hypersensitivity reactions to either penicillins or cephalosporins, which were immunologically confirmed, were recruited from allergy clinics. A genome-wide association study was conducted on 662 patients (the discovery cohort) with a diagnosis of immediate hypersensitivity and the main finding was replicated in a cohort of 98 Spanish cases, recruited using the same diagnostic criteria as the discovery cohort. RESULTS: Genome-wide association study identified rs71542416 within the Class II HLA region as the top hit (P = 2 × 10-14); this was in linkage disequilibrium with HLA-DRB1∗10:01 (odds ratio, 2.93; P = 5.4 × 10-7) and HLA-DQA1∗01:05 (odds ratio, 2.93, P = 5.4 × 10-7). Haplotype analysis identified that HLA-DRB1∗10:01 was a risk factor even without the HLA-DQA1∗01:05 allele. The association with HLA-DRB1∗10:01 was replicated in another cohort, with the meta-analysis of the discovery and replication cohorts showing that HLA-DRB1∗10:01 increased the risk of immediate hypersensitivity at a genome-wide level (odds ratio, 2.96; P = 4.1 × 10-9). No association with HLA-DRB1∗10:01 was identified in 268 patients with delayed hypersensitivity reactions to ß-lactams. CONCLUSIONS: HLA-DRB1∗10:01 predisposed to immediate hypersensitivity reactions to penicillins. Further work to identify other predisposing HLA and non-HLA loci is required.


Asunto(s)
Antibacterianos/efectos adversos , Cefalosporinas/efectos adversos , Hipersensibilidad a las Drogas/genética , Hipersensibilidad Inmediata/inducido químicamente , Hipersensibilidad Inmediata/genética , Penicilinas/efectos adversos , Adulto , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Cadenas alfa de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple
13.
Subst Abus ; 42(4): 618-624, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32870122

RESUMEN

Background: Understanding the impact of medications for opioid use disorder on health related quality of life (QOL) may help to explain why few individuals with legal involvement remain in treatment, specifically those receiving opioid antagonists. QOL is an established predictor of treatment retention and has been shown to improve with some treatment for opioid use disorder. Yet limited research has examined QOL with opioid antagonists. We examined the impact of extended release naltrexone (XR-NTX) on QOL and retention in treatment in a randomized, multi-site trial of individuals with legal involvement. Methods: The participants were 308 community-dwelling adults with current or recent legal involvement with opioid dependence at five site across United States. They were randomized to receive XR-NTX or treatment as usual for 6 months. QOL was measured every 2 weeks using Euro QOL individual items, summary index score, and health state today metric. Results: No significant difference in QOL scores were observed between the two groups at the completion of active treatment or on follow up at 52 and 78 weeks. There were no time effects of treatment on scores. Contrary to expectation, baseline and average QOL did not predict retention in treatment. Conclusion: In contrast to prior research, our findings did not demonstrate significant changes (improvements or decreases) in QOL associated with XR-NTX treatment. Clinicians may consider that individuals receiving XR-NTX may not experience changes in perceived well-being in response to treatment and consider discussing with patients that they may not necessarily perceive improvement in their QOL. This may help to ground patient's expectations about the effects of treatment and potentially reduce attrition from treatment with opioid antagonists.


Asunto(s)
Trastornos Relacionados con Opioides , Calidad de Vida , Adulto , Preparaciones de Acción Retardada/uso terapéutico , Humanos , Inyecciones Intramusculares , Naltrexona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico
14.
Subst Abus ; 42(4): 1022-1029, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33798013

RESUMEN

Background: Despite being highly motivated to recover, pregnant and postpartum women with opioid use disorders (OUD) are at high risk of relapse and death. While many services mitigate this risk, engagement in voluntary, outpatient services remains low. Our aim was to understand the experiences of and factors influencing outpatient service engagement during the perinatal period among women in recovery from OUD. Methods: We conducted semi-structured interviews about perinatal experiences engaging with outpatient services, with 20 women in recovery aged 22-46 years who had children between 6 months and 10 years old. Interviews were audio-recorded, transcribed, coded, and analyzed using conventional content analysis. Results: Women described a continuum of 'collaborative engagement' experiences, defined by the extent to which they perceived their providers or service organizations were invested in their journeys as a partners and advocates. The ability to achieve collaborative engagement depended upon two factors: (1) the woman's transformational development as a mother and woman in recovery, and (2) her perception of the providers' ability to meet her multifaceted needs. Conclusions: Women in recovery from OUD may experience deeper engagement in voluntary outpatient perinatal services when they perceive that their providers are invested and collaboratively engaging in their recovery and personal growth. Future research should test whether collaborative engagement improves service retention.Abbreviations: IPV: Intimate Partner Violence; OUD: opioid use disorder.


Asunto(s)
Violencia de Pareja , Trastornos Relacionados con Opioides , Atención Ambulatoria , Niño , Preescolar , Femenino , Humanos , Lactante , Madres , Periodo Posparto , Embarazo
15.
N Engl J Med ; 374(13): 1232-42, 2016 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-27028913

RESUMEN

BACKGROUND: Extended-release naltrexone, a sustained-release monthly injectable formulation of the full mu-opioid receptor antagonist, is effective for the prevention of relapse to opioid dependence. Data supporting its effectiveness in U.S. criminal justice populations are limited. METHODS: In this five-site, open-label, randomized trial, we compared a 24-week course of extended-release naltrexone (Vivitrol) with usual treatment, consisting of brief counseling and referrals for community treatment programs, for the prevention of opioid relapse among adult criminal justice offenders (i.e., persons involved in the U.S. criminal justice system) who had a history of opioid dependence and a preference for opioid-free rather than opioid maintenance treatments and who were abstinent from opioids at the time of randomization. The primary outcome was the time to an opioid-relapse event, which was defined as 10 or more days of opioid use in a 28-day period as assessed by self-report or by testing of urine samples obtained every 2 weeks; a positive or missing sample was computed as 5 days of opioid use. Post-treatment follow-up occurred at weeks 27, 52, and 78. RESULTS: A total of 153 participants were assigned to extended-release naltrexone and 155 to usual treatment. During the 24-week treatment phase, participants assigned to extended-release naltrexone had a longer median time to relapse than did those assigned to usual treatment (10.5 vs. 5.0 weeks, P<0.001; hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.68), a lower rate of relapse (43% vs. 64% of participants, P<0.001; odds ratio, 0.43; 95% CI, 0.28 to 0.65), and a higher rate of opioid-negative urine samples (74% vs. 56%, P<0.001; odds ratio, 2.30; 95% CI, 1.48 to 3.54). At week 78 (approximately 1 year after the end of the treatment phase), rates of opioid-negative urine samples were equal (46% in each group, P=0.91). The rates of other prespecified secondary outcome measures--self-reported cocaine, alcohol, and intravenous drug use, unsafe sex, and reincarceration--were not significantly lower with extended-release naltrexone than with usual treatment. Over the total 78 weeks observed, there were no overdose events in the extended-release naltrexone group and seven in the usual-treatment group (P=0.02). CONCLUSIONS: In this trial involving criminal justice offenders, extended-release naltrexone was associated with a rate of opioid relapse that was lower than that with usual treatment. Opioid-use prevention effects waned after treatment discontinuation. (Funded by the National Institute on Drug Abuse; ClinicalTrials.gov number, NCT00781898.).


Asunto(s)
Criminales , Naltrexona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Trastornos Relacionados con Opioides/tratamiento farmacológico , Adulto , Servicios de Salud Comunitaria , Consejo , Preparaciones de Acción Retardada , Sobredosis de Droga , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Naltrexona/efectos adversos , Antagonistas de Narcóticos/efectos adversos , Trastornos Relacionados con Opioides/complicaciones , Trastornos Relacionados con Opioides/terapia , Prevención Secundaria , Abuso de Sustancias por Vía Intravenosa/complicaciones
16.
Am J Public Health ; 109(6): 885-891, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30998407

RESUMEN

Objectives. To assess states' provision of technical assistance and allocation of block grants for treatment, prevention, and outreach after the expansion of health insurance coverage for addiction treatment in the United States under the Affordable Care Act (ACA). Methods. We used 2 waves of survey data collected from Single State Agencies in 2014 and 2017 as part of the National Drug Abuse Treatment System Survey. Results. The percentage of states providing technical assistance for cross-sector collaboration and workforce development increased. States also shifted funds from outpatient to residential treatment services. However, resources for opioid use disorder medications changed little. Subanalyses indicated that technical assistance priorities and allocation of funds for treatment services differed between Medicaid expansion and nonexpansion states. Public Health Implications. The ACA's infusion of new public and private funds enabled states to reallocate funds to residential services, which are not as likely to be covered by health insurance. The limited allocation of block grant funds for effective opioid medications is concerning in light of the opioid crisis, especially in states that did not implement the ACA's Medicaid expansion.


Asunto(s)
Financiación Gubernamental , Cobertura del Seguro/economía , Patient Protection and Affordable Care Act/economía , Gobierno Estatal , Trastornos Relacionados con Sustancias/terapia , Asignación de Costos , Humanos , Medicaid/economía , Medicaid/organización & administración , Trastornos Relacionados con Opioides/prevención & control , Trastornos Relacionados con Opioides/terapia , Trastornos Relacionados con Sustancias/prevención & control , Estados Unidos
17.
Am J Public Health ; 109(3): 434-436, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30676789

RESUMEN

OBJECTIVES: To examine how utilization restrictions on state Medicaid benefits for buprenorphine are related to addiction treatment programs' decision to offer the drug. METHODS: We used data from 2 waves of the National Drug Abuse Treatment System Survey conducted in 2014 and 2017 in the United States to assess the relationship of utilization restrictions to buprenorphine availability. RESULTS: The proportion of programs offering buprenorphine was 43.2% in states that did not impose any utilization restrictions, 25.5% in states that imposed only annual limits, 17.3% in states that imposed only prior authorization, and 12.8% in states that imposed both. Programs in states requiring prior authorization from Medicaid had substantially lower odds of offering buprenorphine (odds ratio = 0.50; 95% confidence interval = 0.29, 0.87). CONCLUSIONS: Medicaid prior authorization was linked to lower odds of buprenorphine provision among addiction treatment programs. Public Health Implications. State Medicaid prior authorization requirements are linked to reduced odds of buprenorphine provision among addiction treatment programs and may discourage prescribing.


Asunto(s)
Buprenorfina/provisión & distribución , Buprenorfina/uso terapéutico , Equipos y Suministros de Hospitales/economía , Medicaid/economía , Trastornos Relacionados con Opioides/tratamiento farmacológico , Centros de Tratamiento de Abuso de Sustancias/economía , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estados Unidos
18.
Prev Med ; 128: 105740, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31158400

RESUMEN

The opioid crisis presents substantial challenges to public health in New England's rural states, where access to pharmacotherapy for opioid use disorder (OUD), harm reduction, HIV and hepatitis C virus (HCV) services vary widely. We present an approach to characterizing the epidemiology, policy and resource environment for OUD and its consequences, with a focus on eleven rural counties in Massachusetts, New Hampshire and Vermont between 2014 and 2018. We developed health policy summaries and logic models to facilitate comparison of opioid epidemic-related polices across the three states that could influence the risk environment and access to services. We assessed sociodemographic factors, rates of overdose and infectious complications tied to OUD, and drive-time access to prevention and treatment resources. We developed GIS maps and conducted spatial analyses to assess the opioid crisis landscape. Through collaborative research, we assessed the potential impact of available resources to address the opioid crisis in rural New England. Vermont's comprehensive set of policies and practices for drug treatment and harm reduction appeared to be associated with the lowest fatal overdose rates. Franklin County, Massachusetts had good access to naloxone, drug treatment and SSPs, but relatively high overdose and HIV rates. New Hampshire had high proportions of uninsured community members, the highest overdose rates, no HCV surveillance data, and no local access to SSPs. This combination of factors appeared to place PWID in rural New Hampshire at elevated risk. Study results facilitated the development of vulnerability indicators, identification of locales for subsequent data collection, and public health interventions.


Asunto(s)
Epidemias/legislación & jurisprudencia , Epidemias/estadística & datos numéricos , Política de Salud/legislación & jurisprudencia , Trastornos Relacionados con Opioides/epidemiología , Vigilancia de la Población , Población Rural/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Massachusetts/epidemiología , Persona de Mediana Edad , New Hampshire/epidemiología , Vermont/epidemiología
19.
Br J Clin Pharmacol ; 84(8): 1719-1728, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29607554

RESUMEN

AIMS: To quantify the anti-inflammatory potency of topical corticosteroids and topical calcineurin inhibitors by measuring the contact allergic response to a diphenylcyclopropenone (DPCP) challenge in de novo sensitized human volunteers. METHODS: Two randomized, double-blind, vehicle-controlled studies were performed encompassing 76 volunteers: 29 in the first and 47 in the second study. Topical drugs were applied pre- and/or post-treatment in block designs. The compounds were tested simultaneously under occluded patch tests covering DPCP-induced dermatitis. Inhibitory responses were assessed by visual scoring and measurements of the oedema thickness with ultrasound. RESULTS: When applied both before and after the DPCP challenge, significant anti-inflammatory effects were seen in descending order for tacrolimus 0.1% ointment, clobetasol propionate ointment, betamethasone valerate ointment and hydrocortisone butyrate ointment, while pimecrolimus cream, hydrocortisone ointment and vehicles had no significant effect. Only tacrolimus ointment (P < 0.01) demonstrated a consistent significant pre-treatment inhibitory effect compared with an untreated DPCP control. CONCLUSIONS: This human testing method in which the inflammation of experimentally induced allergic patch test reactions is quantified by objective measurement allows an analysis of the anti-inflammatory potency of not only topical corticosteroids, but also of drugs that have no effect on vasoconstriction. The method allowed comparison of the potencies of four topical corticosteroids and two calcineurin inhibitors.


Asunto(s)
Antiinflamatorios/administración & dosificación , Inhibidores de la Calcineurina/administración & dosificación , Dermatitis Alérgica por Contacto/tratamiento farmacológico , Fármacos Dermatológicos/administración & dosificación , Glucocorticoides/administración & dosificación , Administración Cutánea , Adulto , Ciclopropanos/administración & dosificación , Ciclopropanos/inmunología , Dermatitis Alérgica por Contacto/diagnóstico por imagen , Dermatitis Alérgica por Contacto/inmunología , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Masculino , Pomadas/administración & dosificación , Índice de Severidad de la Enfermedad , Piel/irrigación sanguínea , Piel/diagnóstico por imagen , Piel/efectos de los fármacos , Piel/inmunología , Resultado del Tratamiento , Ultrasonografía , Vasoconstricción/efectos de los fármacos , Adulto Joven
20.
Am J Drug Alcohol Abuse ; 44(4): 426-430, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29261341

RESUMEN

BACKGROUND: Established in 2014, state health insurance exchanges have greatly expanded substance use disorder (SUD) treatment coverage in the United States as qualified health plans (QHPs) within the exchanges are required to conform to parity provisions laid out by the Affordable Care Act and the Mental Health Parity and Addiction Equity Act (MHPAEA). Coverage improvements, however, have not been even as states have wide discretion over how they meet these regulations. OBJECTIVE: How states regulate SUD treatment benefits offered by QHPs has implications for the accessibility and quality of care. In this study, we assessed the extent to which state insurance departments regulate the types of SUD services and medications plans must provide, as well as their use of utilization controls. METHODS: Data were collected as part of the National Drug Abuse Treatment System Survey, a nationally-representative, longitudinal study of substance use disorder treatment. Data were obtained from state Departments of Insurance via a 15-minute internet-based survey. RESULTS: States varied widely in regulations on QHPs' administration of SUD treatment benefits. Some states required plans to cover all 11 SUD treatment services and medications we assessed in the study, whereas others did not require plans to cover anything at all. Nearly all states allowed the plans to employ utilization controls, but reported little guidance regarding how they should be used. CONCLUSION: Although some states have taken full advantage of the health insurance exchanges to increase access to SUD treatment, others seem to have done the bare minimum required by the ACA. By not requiring coverage for the entire SUD continuum of care, states are hindering client access to appropriate types of care necessary for recovery.


Asunto(s)
Intercambios de Seguro Médico , Cobertura del Seguro/legislación & jurisprudencia , Trastornos Relacionados con Sustancias/terapia , Bases de Datos Factuales , Humanos , Patient Protection and Affordable Care Act , Estados Unidos
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