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T cell responses play an important role in protection against beta-coronavirus infections, including SARS-CoV-2, where they associate with decreased COVID-19 disease severity and duration. To enhance T cell immunity across epitopes infrequently altered in SARS-CoV-2 variants, we designed BNT162b4, an mRNA vaccine component that is intended to be combined with BNT162b2, the spike-protein-encoding vaccine. BNT162b4 encodes variant-conserved, immunogenic segments of the SARS-CoV-2 nucleocapsid, membrane, and ORF1ab proteins, targeting diverse HLA alleles. BNT162b4 elicits polyfunctional CD4+ and CD8+ T cell responses to diverse epitopes in animal models, alone or when co-administered with BNT162b2 while preserving spike-specific immunity. Importantly, we demonstrate that BNT162b4 protects hamsters from severe disease and reduces viral titers following challenge with viral variants. These data suggest that a combination of BNT162b2 and BNT162b4 could reduce COVID-19 disease severity and duration caused by circulating or future variants. BNT162b4 is currently being clinically evaluated in combination with the BA.4/BA.5 Omicron-updated bivalent BNT162b2 (NCT05541861).
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Vacina BNT162 , COVID-19 , Animais , Cricetinae , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/prevenção & controle , Epitopos , SARS-CoV-2/genéticaRESUMO
Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4+ and CD8+ T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors (Clinicaltrials.gov: NCT02897765).
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Vacinas Anticâncer/imunologia , Imunoterapia/métodos , Medicina de Precisão/métodos , Idoso , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/tratamento farmacológico , Melanoma/imunologia , Pessoa de Meia-Idade , Mutação , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/imunologiaRESUMO
Cells have evolved an elaborate DNA repair network to ensure complete and accurate DNA replication. Defects in these repair machineries can fuel genome instability and drive carcinogenesis while creating vulnerabilities that may be exploited in therapy. Here, we use nascent chromatin capture (NCC) proteomics to characterize the repair of replication-associated DNA double-strand breaks (DSBs) triggered by topoisomerase 1 (TOP1) inhibitors. We reveal profound changes in the fork proteome, including the chromatin environment and nuclear membrane interactions, and identify three classes of repair factors according to their enrichment at broken and/or stalled forks. ATM inhibition dramatically rewired the broken fork proteome, revealing that ataxia telangiectasia mutated (ATM) signalling stimulates DNA end resection, recruits PLK1, and concomitantly suppresses the canonical DSB ubiquitination response by preventing accumulation of RNF168 and BRCA1-A. This work and collection of replication fork proteomes provide a new framework to understand how cells orchestrate homologous recombination repair of replication-associated DSBs.
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Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas de Ciclo Celular/genética , Replicação do DNA , DNA Topoisomerases Tipo I/genética , DNA/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Reparo de DNA por Recombinação , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Camptotecina/farmacologia , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Cromatina/química , Cromatina/metabolismo , DNA/metabolismo , Quebras de DNA de Cadeia Dupla , DNA Topoisomerases Tipo I/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação da Expressão Gênica , Células HeLa , Humanos , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Proteômica/métodos , Proteínas Proto-Oncogênicas/metabolismo , Piridinas/farmacologia , Quinolinas/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Inibidores da Topoisomerase I/farmacologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/efeitos dos fármacos , Quinase 1 Polo-LikeRESUMO
Women Living with HIV (WLHIV) who use substances face stigma related to HIV and substance use (SU). The relationship between the intersection of these stigmas and adherence to antiretroviral therapy (ART), as well as the underlying mechanisms, remains poorly understood. This study aimed to examine the association between intersectional HIV and SU stigma and ART adherence, while also exploring the potential role of depression and fear of negative evaluation (FNE) by other people in explaining this association. We analyzed data from 409 WLHIV collected between April 2016 and April 2017, Using Multidimensional Latent Class Item Response Theory analysis. We identified five subgroups (i.e., latent classes [C]) of WLHIV with different combinations of experienced SU and HIV stigma levels: (C1) low HIV and SU stigma; (C2) moderate SU stigma; (C3) higher HIV and lower SU stigma; (C4) moderate HIV and high SU stigma; and (C5) high HIV and moderate SU stigma. Medication adherence differed significantly among these classes. Women in the class with moderate HIV and high SU stigma had lower adherence than other classes. A serial mediation analysis suggested that FNE and depression symptoms are mechanisms that contribute to explaining the differences in ART adherence among WLHIV who experience different combinations of intersectional HIV and SU stigma. We suggest that FNE is a key intervention target to attenuate the effect of intersectional stigma on depression symptoms and ART adherence, and ultimately improve health outcomes among WLHIV.
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Depressão , Medo , Infecções por HIV , Adesão à Medicação , Estigma Social , Transtornos Relacionados ao Uso de Substâncias , Humanos , Feminino , Infecções por HIV/psicologia , Infecções por HIV/tratamento farmacológico , Adesão à Medicação/psicologia , Adesão à Medicação/estatística & dados numéricos , Adulto , Medo/psicologia , Depressão/psicologia , Depressão/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Pessoa de Meia-Idade , Análise de Mediação , Análise de Classes Latentes , Fármacos Anti-HIV/uso terapêutico , Estudos TransversaisRESUMO
Mothers living with HIV are faced with managing their own complex healthcare and wellness needs while caring for their children. Understanding the lived experiences of mothers living with HIV, including grandmothers and mothers with older children - who are less explicitly represented in existing literature, may guide the development of interventions that best support them and their families. This study sought to explore the role of motherhood and related social/structural factors on engagement with HIV care, treatment-seeking behaviour, and overall HIV management among mothers living with HIV in the USA to inform such efforts. Semi-structured interviews were conducted between June and December 2015 with 52 mothers living with HIV, recruited from the Women's Interagency HIV Study (WIHS) sites in four US cities. Five broad themes were identified from the interviews: children as a motivation for optimal HIV management; children as providing logistical support for HIV care and treatment; the importance of social support for mothers; stressors tied to responsibilities of motherhood; and stigma about being a mother living with HIV. Findings underscore the importance of considering the demands of motherhood when developing more effective strategies to support mothers in managing HIV and promoting the overall health and well-being of their families.
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Distracted driving, the act of focusing on something else while operating a vehicle, is a significant health problem among adolescents. Although some studies have reported on prevalence among adolescents in the United States, limited studies have examined differences by sexual identity status. The purpose of the present study was to examine past 30-day distracted driving by sexual identity status among a large, national sample of adolescents ages 14 to 18 years. A secondary analysis was conducted on the 2019 Youth Risk Behavioral Surveillance System (YRBSS) data, and associations between distracted driving and demographics (e.g., biological sex, age, race/ethnicity) were assessed with weighted logistic regression analyses. A total of 13,590 adolescents ages 14 to 18 years were part of the final analytic sample. Twenty-three percent of adolescents reported distracted driving in the past 30 days. Compared with heterosexual adolescents, gay/lesbian (14.3%), bisexual (18.1%), and questioning (12.9%) adolescents reported lower distracted driving in the past 30 days. Findings through a health equity approach may inform harm reduction efforts and behavioral interventions.
Assuntos
Comportamento do Adolescente , Minorias Sexuais e de Gênero , Feminino , Humanos , Adolescente , Estados Unidos/epidemiologia , Assunção de Riscos , Comportamento Sexual , HeterossexualidadeRESUMO
Caregivers who interact with children at home can provide a critical, complementary perspective on a child's behaviour functioning. This research used a parent-administered measure of problem behaviours to study perceptions of child behaviours across home situations. We applied latent profile analysis to identify subgroups of children with common behavioural tendencies in a nationally representative sample (N = 709) of 4- to 13-year-old children in Trinidad and Tobago. This study (a) identified latent profiles of children's over- and underactive behaviour problems in varied home settings and (b) examined how profile membership predicted academic skills and teacher-observed problem behaviours. The best-fitting four-profile model included one profile of adjusted behaviours (56%), one of the elevated attention-seeking behaviours (21%), a profile featuring withdrawn and disengaged behaviours (15%) and a relatively rare profile emphasising aggressive behaviours (8%). Children classified in the last profile displayed the poorest academic outcomes and the highest levels of teacher-observed behaviour problems.
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Constitutive activation of the canonical NF-κB signaling pathway is a major factor in Kaposi's sarcoma-associated herpes virus pathogenesis where it is essential for the survival of primary effusion lymphoma. Central to this process is persistent upregulation of the inhibitor of κB kinase (IKK) complex by the virally encoded oncoprotein vFLIP. Although the physical interaction between vFLIP and the IKK kinase regulatory component essential for persistent activation, IKKγ, has been well characterized, it remains unclear how the kinase subunits are rendered active mechanistically. Using a combination of cell-based assays, biophysical techniques, and structural biology, we demonstrate here that vFLIP alone is sufficient to activate the IKK kinase complex. Furthermore, we identify weakly stabilized, high molecular weight vFLIP-IKKγ assemblies that are key to the activation process. Taken together, our results are the first to reveal that vFLIP-induced NF-κB activation pivots on the formation of structurally specific vFLIP-IKKγ multimers which have an important role in rendering the kinase subunits active through a process of autophosphorylation. This mechanism of NF-κB activation is in contrast to those utilized by endogenous cytokines and cellular FLIP homologues.
Assuntos
Herpesvirus Humano 8 , Sarcoma de Kaposi , Ativação Enzimática/genética , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/metabolismo , Humanos , Quinase I-kappa B/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Proteínas Oncogênicas/metabolismo , Sarcoma de Kaposi/enzimologia , Sarcoma de Kaposi/virologia , Proteínas Virais/metabolismoRESUMO
Food insecurity disproportionately affects people with HIV and women in the United States (US). More evidence is needed to understand the interplay between levels of food insecurity and levels of antiretroviral therapy (ART) adherence over time, as well as how food insecurity relates to engagement in HIV care. We used random effects models with longitudinal data from the US Women's Interagency HIV Study to estimate the (1) adjusted associations of current and 6-month lagged food security with ART adherence categories (n = 1646), and (2) adjusted associations of food security with engagement-in-care (n = 1733). Very low food security was associated with a higher relative risk of ART non-adherence at prior and current visits compared with food security, and this association increased across non-adherence categories. Very low food security was associated with lower odds of receiving HIV care and higher odds of a missed visit. Food insecurity among US women with HIV is associated with poorer engagement in care and degree of ART non-adherence over time.
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Infecções por HIV , Humanos , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Antirretrovirais/uso terapêutico , Cooperação do PacienteRESUMO
Background: Orodispersible film (ODF) formulation offers ease of use, convenience of administration, and other advantages, especially for patients who have difficulty in swallowing or are on liquid restriction compared with conventional oral formulations for the treatment of erectile dysfunction. Objectives: These studies compared the bioequivalence of 50 mg sildenafil citrate ODF formulation (test drug) with the marketed 50 mg sildenafil citrate film-coated tablet (FCT) (Viagraâ; Pfizer, New York, NY) (reference drug), with and without water in 2 randomized cross-over studies. Methods: Two randomized cross-over studies were conducted. The first study explored the bioequivalence of test drug administered with and without water compared with the reference drug with water. The second study investigated the bioequivalence of test drug, without water, compared with the reference drug with water. Forty-two and 80 healthy male volunteers were recruited in the first and second study, respectively. All volunteers fasted for 10 hours pre-dose. A 1-day washout period between doses was observed. Blood samples were collected at both before (up to 120 minutes before dosing) and after dosing (at different intervals up to 14 hours) stages. Statistical analyses on pharmacokinetic parameters were performed. Safety and tolerability for both the formulations were evaluated. Results: In the first study, bioequivalence was demonstrated for sildenafil citrate ODF administered with water when compared with the Viagraâ FCT. The ratios of adjusted geometric means (90% confidence interval (CI)) were maximum plasma concentration: 1.02 (94.91-108.78) and area under the plasma concentration-time curve: 1.09 (104.49-113.21) for sildenafil citrate ODF administered with water vs Viagraâ FCT. These ratios were within the bioequivalence acceptance range of 80% to 125%, indicating that the bioequivalence criteria were met. The pharmacokinetic parameters for the second study also showed bioequivalence for sildenafil citrate ODF (without water) compared with Viagraâ FCT. The ratios of adjusted geometric means (90% CI) were maximum plasma concentration: 1.02 (95.47-109.36) and area under the plasma concentration-time curve: 1.06 (103.42-108.40) for sildenafil citrate ODF administered without water vs Viagraâ FCT. Adverse events in both the studies occurred at similar rates for the 2 formulations and were mild in intensity. Conclusions: These results suggest that the new ODF formulation can be used interchangeably with the marketed FCT formulation. Sildenafil citrate ODF administered with and without water met bioequivalence criteria compared with Viagraâ FCT administered with water under fasted conditions in healthy adult male volunteers. The new ODF formulation can be used as a suitable alternative to the conventional oral solid dosage form.
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miR-140 is selectively expressed in cartilage. Deletion of the entire Mir140 locus in mice results in growth retardation and early-onset osteoarthritis-like pathology; however, the relative contribution of miR-140-5p or miR-140-3p to the phenotype remains to be determined. An unbiased small RNA sequencing approach identified miR-140-3p as significantly more abundant (>10-fold) than miR-140-5p in human cartilage. Analysis of these data identified multiple miR-140-3p isomiRs differing from the miRBase annotation at both the 5' and 3' end, with >99% having one of two seed sequences (5' bases 2-8). Canonical (miR-140-3p.2) and shifted (miR-140-3p.1) seed isomiRs were overexpressed in chondrocytes and transcriptomics performed to identify targets. miR-140-3p.1 and miR-140-3p.2 significantly down-regulated 694 and 238 genes, respectively, of which only 162 genes were commonly down-regulated. IsomiR targets were validated using 3'UTR luciferase assays. miR-140-3p.1 targets were enriched within up-regulated genes in rib chondrocytes of Mir140-null mice and within down-regulated genes during human chondrogenesis. Finally, through imputing the expression of miR-140 from the expression of the host gene WWP2 in 124 previously published data sets, an inverse correlation with miR-140-3p.1 predicted targets was identified. Together these data suggest the novel seed containing isomiR miR-140-3p.1 is more functional than original consensus miR-140-3p seed containing isomiR.
Assuntos
Cartilagem/química , MicroRNAs/genética , Análise de Sequência de RNA/métodos , Regiões 3' não Traduzidas , Regiões 5' não Traduzidas , Animais , Condrogênese , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Camundongos , Anotação de Sequência Molecular , Especificidade de Órgãos , Regulação para CimaRESUMO
BACKGROUND: Nanopore sequencing is direct sequencing of a single-stranded DNA molecule using biological pores. A portable nanopore-based sequencing device from Oxford Nanopore Technologies (MinION) depends on driving a DNA molecule through nanopores embedded in a membrane using a voltage. Changes in current are then measured by a sensor, thousands of times per second and translated to nucleobases. METHODS: Genomic DNA (gDNA) samples (n = 13) were tested for Rh blood group D antigen (RHD) gene zygosity using droplet digital PCR. The RHD gene was amplified in 6 overlapping amplicons using long-range PCR. Amplicons were purified, and the sequencing library was prepared following the 1D Native barcoding gDNA protocol. Sequencing was carried out with 1D flow cells R9 version. Data analysis included basecalling, aligning to the RHD reference sequence, and calling variants. Variants detected were compared to the results acquired previously by the Ion Personal Genome Machine (Ion PGM). RESULTS: Up to 500× sequence coverage across the RHD gene allowed accurate variant calling. Exonic changes in the RHD gene allowed RHD allele determination for all samples sequenced except 1 RHD homozygous sample, where 2 heterozygous RHD variant alleles are suspected. There were 3 known variant RHD alleles (RHD*01W.02, RHD*11, and RHD*15) and 6 novel RHD variant alleles, as previously seen in Ion PGM sequencing data for these samples. CONCLUSIONS: MinION was effective in blood group genotyping, provided enough sequencing data to achieve high coverage of the RHD gene, and enabled confident calling of variants and RHD allele determination.
Assuntos
Sequenciamento por Nanoporos , Nanoporos , Alelos , Genótipo , Humanos , Sistema do Grupo Sanguíneo Rh-Hr/genéticaRESUMO
Social support is associated with improved HIV care and quality of life. We utilized latent class analysis to identify three classes of baseline emotional and tangible perceived social support, termed "Strong", "Wavering" and "Weak". "Weak" vs. "Strong" perceived social support was associated over time with an 8% decreased risk of optimal antiretroviral therapy (ART) adherence for emotional and 6% decreased risk for tangible perceived social support. Importantly, "Wavering" vs "Strong" social support also showed a decreased risk of ART adherence of 6% for emotional and 3% for tangible support. "Strong" vs. "Weak" perceived support had a similar association with undetectable viral load, but the association for "Strong" vs. "Wavering" support was not statistically significant. Intensity of social support is associated with HIV care outcomes, and strong social support may be needed for some individuals. It is important to quantify the level or intensity of social support that is needed to optimize HIV outcomes.
RESUMEN: El apoyo social está asociado con una mejor atención y calidad de vida del virus de inmunodeficiencia humana (VIH). Utilizamos el análisis de clase latente para identificar tres clases de apoyo social percibido emocional y tangible de referencia, denominado "fuerte", "vacilante" y "débil". El apoyo social percibido "débil" versus el "fuerte" se asoció con el tiempo con una disminución del 8% en el riesgo de una adherencia óptima al terapia antirretroviral (TAR) para el apoyo emocional y del 6% en el riesgo de un apoyo social percibido tangible. Es importante destacar que el apoyo social "vacilante" frente a "fuerte" también mostró una disminución del riesgo de adherencia al TAR del 6% para el apoyo emocional y del 3% para el apoyo tangible. El apoyo percibido "fuerte" frente a "débil" tuvo una asociación similar con una carga viral indetectable, pero la asociación entre el apoyo "fuerte" y el apoyo "vacilante" no fue estadísticamente significativa. La intensidad del apoyo social está asociada con los resultados de la atención del VIH, y algunas personas pueden necesitar un fuerte apoyo social. Es importante cuantificar el nivel o la intensidad del apoyo social que se necesita para optimizar los resultados del VIH.
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Infecções por HIV , Qualidade de Vida , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Análise de Classes Latentes , Adesão à Medicação , Avaliação de Resultados em Cuidados de Saúde , Apoio Social , Carga ViralRESUMO
In this mixed-methods study, we examine the relationship between provider communication and patient health literacy on HIV continuum of care outcomes among women living with HIV in the United States. We thematically coded qualitative data from focus groups and interviews (N = 92) and conducted mediation analyses with quantitative survey data (N = 1455) collected from Women's Interagency HIV Study participants. Four qualitative themes related to provider communication emerged: importance of respect and non-verbal cues; providers' expressions of condescension and judgement; patient health literacy; and unclear, insufficient provider communication resulting in diminished trust. Quantitative mediation analyses suggest that higher health literacy is associated with higher perceived patient-provider interaction quality, which in turn is associated with higher levels of trust in HIV providers, improved antiretroviral medication adherence, and reduced missed clinical visits. Findings indicate that enhancing provider communication and bolstering patient health literacy could have a positive impact on the HIV continuum of care.
RESUMEN: En este estudio de métodos mixtos, examinamos la relación entre la comunicación del proveedor y la alfabetización sanitaria del paciente sobre los resultados de la atención continua del VIH entre las mujeres que viven con el VIH en los Estados Unidos. Codificamos temáticamente datos cualitativos de grupos focales y entrevistas (N = 92) y realizamos análisis de mediación con datos de encuestas cuantitativas (N = 1455) recopilados de participantes del Estudio de VIH entre agencias de mujeres. Surgieron cuatro temas cualitativos relacionados con la comunicación con el proveedor: la importancia del respeto y las señales no verbales; las expresiones de condescendencia y juicio de los proveedores; alfabetización en salud del paciente; y una comunicación poco clara e insuficiente con el proveedor que da como resultado una disminución de la confianza. Los análisis de mediación cuantitativa sugieren que una mayor alfabetización en salud se asocia con una mayor calidad de interacción percibida entre el paciente y el proveedor, que a su vez se asocia con niveles más altos de confianza en los proveedores de VIH, una mejor adherencia a la medicación antirretroviral y una reducción de las visitas clínicas perdidas. Los resultados indican que mejorar la comunicación con los proveedores y reforzar la alfabetización sanitaria del paciente podría tener un impacto positivo en la atención continua del VIH.
Assuntos
Infecções por HIV , Letramento em Saúde , Antirretrovirais/uso terapêutico , Comunicação , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Confiança , Estados Unidos/epidemiologiaRESUMO
The complete molecular mechanisms underlying the pathophysiology of Alzheimer's disease (AD) remain to be elucidated. Recently, microRNA-455-3p has been identified as a circulating biomarker of early AD, with increased expression in post-mortem brain tissue of AD patients. MicroRNA-455-3p also directly targets and down-regulates APP, with the overexpression of miR-455-3p suppressing its toxic effects. Here, we show that miR-455-3p expression decreases with age in the brains of wild-type mice. We generated a miR-455 null mouse utilising CRISPR-Cas9 to explore its function further. Loss of miR-455 resulted in increased weight gain, potentially indicative of metabolic disturbances. Furthermore, performance on the novel object recognition task diminished significantly in miR-455 null mice (p = 0.004), indicating deficits in recognition memory. A slight increase in anxiety was also captured on the open field test. BACE1 and TAU were identified as new direct targets for miR-455-3p, with overexpression of miR-455-3p leading to a reduction in the expression of APP, BACE1 and TAU in neuroblastoma cells. In the hippocampus of miR-455 null mice at 14 months of age, the levels of protein for APP, BACE1 and TAU were all increased. Such findings reinforce the involvement of miR-455 in AD progression and demonstrate its action on cognitive performance.
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Doença de Alzheimer/etiologia , Ansiedade/genética , Transtornos da Memória/genética , MicroRNAs/genética , Fenótipo , Deleção de Sequência , Regiões 3' não Traduzidas , Fatores Etários , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/genética , Sequência de Bases , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Estudos de Associação Genética , Predisposição Genética para Doença , Camundongos , Camundongos Knockout , MicroRNAs/química , Interferência de RNA , Proteínas tau/genéticaRESUMO
We conducted a narrative literature review to examine contributing factors of disparities in tobacco usage and outcomes affecting Black Americans. We propose potential solutions that can be used to effectively address these disparities. We identified historical factors; socioeconomic factors; targeted marketing/advertising; the influence of racism/discrimination; neighborhood socioeconomic disadvantage; and mass incarceration. We call for more thorough examinations of these factors as a key element of tobacco-focused research and interventions to eliminate the disproportionate burdens faced by Black Americans. We advocate for greater emphases on the impacts of personal and structural racism on tobacco usage and outcomes affecting Black Americans.
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BACKGROUND: Prior studies suggest neighborhood poverty and deprivation are associated with adverse health outcomes including death, but evidence is limited among persons with HIV, particularly women. We estimated changes in mortality risk from improvement in three measures of area-level socioeconomic context among participants of the Women's Interagency HIV Study. METHODS: Starting in October 2013, we linked geocoded residential census block groups to the 2015 Area Deprivation Index (ADI) and two 2012-2016 American Community Survey poverty variables, categorized into national tertiles. We used parametric g-computation to estimate, through March 2018, impacts on mortality of improving each income or poverty measure by one and two tertiles maximum versus no improvement. RESULTS: Of 1596 women with HIV (median age 49), 91 (5.7%) were lost to follow-up and 83 (5.2%) died. Most women (62%) lived in a block group in the tertile with the highest proportions of individuals with income:poverty <1; 13% lived in areas in the tertile with the lowest proportions. Mortality risk differences comparing a one-tertile improvement (for those in the two highest poverty tertiles) in income:poverty <1 versus no improvement increased over time; the risk difference was -2.2% (95% confidence interval [CI] = -3.7, -0.64) at 4 years. Estimates from family income below poverty level (-1.0%; 95% CI = -2.7, 0.62) and ADI (-1.5%; 95% CI = -2.8, -0.21) exposures were similar. CONCLUSIONS: Consistent results from three distinct measures of area-level socioeconomic environment support the hypothesis that interventions to ameliorate neighborhood poverty or deprivation reduce mortality risk for US women with HIV. See video abstract at, http://links.lww.com/EDE/B863.
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Infecções por HIV , Pobreza , Censos , Feminino , Humanos , Renda , Pessoa de Meia-Idade , Características de Residência , Fatores Socioeconômicos , Estados Unidos/epidemiologiaRESUMO
To explore the associations of urbanicity with clinical/behavioral outcomes and sociodemographic factors among women living with HIV in the Southern United States, 523 participants of the Women's Interagency HIV Study were classified into population density quartiles. Rural-Urban Commuting Area codes revealed that 7% resided in areas where >30% commute to urban areas, 2% resided in small towns or rural areas, and 91% resided in varying densities of urban areas. Although women in lower density, mostly suburban areas reported higher socioeconomic indicators such as advanced education and greater annual household income, larger proportions of women in the lowest density quartile perceived discrimination in health care settings and agreed with several internalized HIV stigma scale items. Women in the lower quartiles had higher CD4 counts, while those in the lowest quartile were more likely to have a suppressed HIV viral load, report being employed, and not report a history of drug use or current heavy alcohol use. More research is needed to understand the interplay between population density and mechanisms contributing to HIV control as well as increased internalized stigma and perceived discrimination, along with how to target interventions to improve outcomes for individuals with HIV across urban, suburban, and rural areas.
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Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/psicologia , Densidade Demográfica , População Rural , Estigma Social , População Urbana , Adulto , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/epidemiologia , Humanos , Características de Residência , Fatores Socioeconômicos , Estados Unidos/epidemiologiaRESUMO
Our objective was to examine the association between healthcare payer type and missed HIV care visits among 1,366 US women living with HIV (WLWH) enrolled in the prospective Women's Interagency HIV Study (WIHS). We collected secondary patient-level data (October 1, 2017-September 30, 2018) from WLWH at nine WIHS sites. We used bivariate and multivariable binary logistic regression to examine the relationship between healthcare payer type (cross-classification of patients' ADAP and health insurance enrollment) and missed visits-based retention in care, defined as no-show appointments for which patients did not reschedule. Our sample included all WLWH who self-reported having received HIV care at least once during the two consecutive biannual WIHS visits a year prior to October 1, 2017-September 30, 2018. In the bivariate model, compared to uninsured WLWH without ADAP, WLWH with private insurance + ADAP were more likely to be retained in care, as were WLWH with Medicaid only and private insurance only. In the adjusted model, WLWH with private insurance only were more likely to be retained in care compared to uninsured WLWH without ADAP. Private health insurance and ADAP are associated with increased odds of retention in care among WLWH.
Assuntos
Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Preparações Farmacêuticas , Retenção nos Cuidados , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Seguro Saúde , Estudos Prospectivos , Estados UnidosRESUMO
BACKGROUND: There is a positive cross-sectional relationship between alcohol-related proactive dietary restriction to feel the effects of alcohol faster (APDR) and binge drinking, a health and safety issue impacting college students. Objective: To examine: 1) the longitudinal predictive ability of varying levels of APDR on binge drinking frequency; and 1a) the strength of the relationship between varying levels of APDR and binge drinking frequency during freshman year of college (n = 1,149). METHODS: Ordinal logistic regression was used to model the relationship between APDR and binge drinking frequency. RESULTS: Main findings suggest APDR of students who reported eating less than usual (low APDR) prior to drinking to feel the effects of alcohol faster was a significant predictor of binge drinking frequency (1.27 (95% CI, 0.06 to 0.42), Wald χ2 (1) = 8.46, p=.009) at baseline, but not at 7-month follow-up (1.02 (95% CI, -0.18 to 0.23), Wald χ2 (1) = .51, p=.83). APDR for students who reported skipping one or more meals (high APDR) to feel the effects of alcohol faster was not a significant predictor of binge drinking frequency at baseline nor at 7-month follow-up. CONCLUSION: Low APDR is a significant predictor of binge drinking frequency that is established early in the first semester of college with no significant change occurring in binge drinking frequency over the course of students' freshman year at 7-month follow-up. Campus health professionals are urged to emphasize the detrimental health effects of low APDR early in the first semester of college.