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PURPOSE: Health care is advancing toward a collaborative and integrative approach that promotes general health and wellness while addressing health inequities through the consideration of broader social and economic factors that influence the well-being of the entire population. Recently, there has been growing evidence of public health concept applications in fields related to speech, language, and hearing. However, there is an outstanding need to explicitly define the intersection of public health, including prevention and health promotion, and the discipline of communication sciences and disorders (CSD) across the areas of education, clinical practice, research, and policy. The authors propose a definition for this intersection using the new term communication public health. METHOD: This tutorial provides guidance on how to conceptualize communication public health and invites refinement and expansion of the intersection between public health and CSD. Because readers are experts in CSD, this tutorial aims to supplement existing knowledge with information on public health to achieve three main objectives: (a) increase knowledge of the application of public health concepts among speech, language, hearing, and related professionals (SLHP+); (b) introduce the concept of communication public health; and (c) discuss the relevance of communication public health across domains within CSD. The authors utilize the socioecological model to provide examples of applications. RESULTS: The concept of communication public health is proposed as the collaborative area of CSD and public health, which encompasses prevention and promotion of equity in communication health through individual-, community-, and population-level efforts. The goals of communication public health are achieved through applications of public health principles in CSD education, clinical practice, research, and policy. CONCLUSION: Communication public health defines an area of collaboration between public health and CSD in which SLHP+ can apply public health concepts to both advance communication health and address health disparities.
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Audiologia , Transtornos da Comunicação , Saúde Pública , Patologia da Fala e Linguagem , Humanos , Audiologia/métodos , Patologia da Fala e Linguagem/métodos , Comunicação , Promoção da Saúde/métodosRESUMO
BACKGROUND: Hearing loss is prevalent following ototoxic therapy for childhood cancer. Associations between hearing loss, self-perceived hearing handicap, and functional outcomes have not been examined in survivors. METHODS: Adult survivors treated with platinum or head and neck radiotherapy with hearing loss were recruited. A total of 237 survivors (median age at survey = 37.0 years [range = 30.0-45.0 years]; median = 29.1 years [range = 22.4-35.0 years] since diagnosis; median = 4.0 years [range = 2.9-7.7 years] from last audiogram to survey) completed the Hearing Handicap Inventory for Adults and questionnaires on social and emotional functioning and hearing aid use. Hearing loss severity was defined according to Chang criteria. Multivariable logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between hearing loss, hearing handicap, functional outcomes, and hearing aid use with adjustment for sex, race, age at hearing loss diagnosis, and age at survey. RESULTS: Two-thirds of survivors had severe hearing loss, which was associated with increased likelihood of hearing handicap (mild-moderate handicap: OR = 2.72, 95% CI = 1.35 to 5.47; severe handicap: OR = 5.99, 95% CI = 2.72 to 13.18). Survivors with severe hearing handicap had an increased likelihood of social isolation (OR = 8.76, 95% CI = 3.62 to 21.20), depression (OR = 9.11, 95% CI = 3.46 to 24.02), anxiety (OR = 17.57, 95% CI = 3.77 to 81.84), reduced personal income (OR = 2.82, 95% CI = 1.46 to 5.43), and less than full-time employment (OR = 2.47, 95% CI = 1.30 to 4.70). Survivors who did not use a recommended hearing aid were twice as likely to have less than full-time employment (OR = 2.26, 95% CI = 1.10 to 4.61) and reduced personal income (OR = 2.24, 95% CI = 1.08 to 4.63) compared with survivors who wore a hearing aid. CONCLUSION: Self-perceived hearing handicap beyond measured hearing loss is associated with reduced functional outcomes. Assessment of hearing handicap may facilitate targeted interventions in adult survivors with hearing loss.
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Sobreviventes de Câncer , Auxiliares de Audição , Perda Auditiva , Neoplasias , Adulto , Humanos , Criança , Pessoa de Meia-Idade , Perda Auditiva/epidemiologia , Perda Auditiva/etiologia , Perda Auditiva/reabilitação , SobreviventesRESUMO
Local immune activation at mucosal surfaces, mediated by mucosal lymphoid tissues, is vital for effective immune responses against pathogens. While pathogens like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can spread to multiple organs, patients with coronavirus disease 2019 (COVID-19) primarily experience inflammation and damage in their lungs. To investigate this apparent organ-specific immune response, we develop an analytical framework that recognizes the significance of mucosal lymphoid tissues. This framework combines histology, immunofluorescence, spatial transcript profiling, and mathematical modeling to identify cellular and gene expression differences between the lymphoid tissues of the lung and the gut and predict the determinants of those differences. Our findings indicate that mucosal lymphoid tissues are pivotal in organ-specific immune response to SARS-CoV-2, mediating local inflammation and tissue damage and contributing to immune dysfunction. The framework developed here has potential utility in the study of long COVID and may streamline biomarker discovery and treatment design for diseases with differential pathologies at the organ level.
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COVID-19 , SARS-CoV-2 , Humanos , Síndrome de COVID-19 Pós-Aguda , Inflamação , ImunidadeRESUMO
Background: Cochlear implants are a neural prosthesis used to restore the perception of hearing in individuals with severe-to-profound hearing loss by stimulating the auditory nerve with electrical current through a surgically implanted electrode array. The integrity of the interface between the implanted electrode array and the auditory nerve contributes to the variability in outcomes experienced by cochlear implant users. Strategies to identify and eliminate poorly encoding electrodes have been found to be effective in improving outcomes with the device, but application is limited in a clinical setting. Objective: The purpose of this study was to evaluate a clinical method used to identify and selectively deactivate cochlear implants (CI) electrodes related to poor electrode-neural interface. Methods: Thirteen adult CI users participated in a pitch ranking task to identify indiscriminate electrode pairs. Electrodes associated with indiscriminate pairs were selectively deactivated, creating an individualized experimental program. Speech perception was evaluated in the baseline condition and with the experimental program before and after an acclimation period. Participant preference responses were recorded at each visit. Results: Statistically significant improvements using the experimental program were found in at least one measure of speech perception at the individual level in four out of 13 participants when tested before acclimation. Following an acclimation period, ten out of 13 participants demonstrated statistically significant improvements in at least one measure of speech perception. Statistically significant improvements were found with the experimental program at the group level for both monosyllabic words (p = 0.006) and sentences in noise (p = 0.020). Additionally, ten participants preferred the experimental program prior to the acclimation period and eleven preferred the experimental program following the acclimation period. Conclusion: Results from this study suggest that electrode deactivation may yield improvement in speech perception following an acclimation period. A majority of CI users in our study reported a preference for the experimental program. This method proved to be a suitable clinical strategy for identifying and deactivating poorly encoding electrodes in adult CI users.
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The utility of spatial immunobiomarker quantitation in prognostication and therapeutic prediction is actively being investigated in triple-negative breast cancer (TNBC). Here, with high-plex quantitative digital spatial profiling, we map and quantitate intraepithelial and adjacent stromal tumor immune protein microenvironments in systemic treatment-naïve (female only) TNBC to assess the spatial context in immunobiomarker-based prediction of outcome. Immune protein profiles of CD45-rich and CD68-rich stromal microenvironments differ significantly. While they typically mirror adjacent, intraepithelial microenvironments, this is not uniformly true. In two TNBC cohorts, intraepithelial CD40 or HLA-DR enrichment associates with better outcomes, independently of stromal immune protein profiles or stromal TILs and other established prognostic variables. In contrast, intraepithelial or stromal microenvironment enrichment with IDO1 associates with improved survival irrespective of its spatial location. Antigen-presenting and T-cell activation states are inferred from eigenprotein scores. Such scores within the intraepithelial compartment interact with PD-L1 and IDO1 in ways that suggest prognostic and/or therapeutic potential. This characterization of the intrinsic spatial immunobiology of treatment-naïve TNBC highlights the importance of spatial microenvironments for biomarker quantitation to resolve intrinsic prognostic and predictive immune features and ultimately inform therapeutic strategies for clinically actionable immune biomarkers.
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Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo , Biomarcadores/metabolismo , Antígeno B7-H1/metabolismo , Linfócitos do Interstício Tumoral , Antígenos CD40/metabolismo , Ativação Linfocitária , Biomarcadores Tumorais/metabolismo , Microambiente TumoralRESUMO
Loss of protein expression of the tumor suppressor PTEN is associated with increased cancer aggressiveness, decreased tumor immune infiltration, and resistance to immune and targeted therapies in melanoma. We assessed a unique cohort of eight melanoma samples with focal loss of PTEN protein expression to understand the features and mechanisms of PTEN loss in this disease. We compared the PTEN-negative (PTEN[-]) areas to their adjacent PTEN-positive (PTEN[+]) areas using DNA sequencing, DNA methylation, RNA expression, digital spatial profiling, and immunohistochemical platforms. Variations or homozygous deletions of PTEN were identified in PTEN(-) areas that were not detected in the adjacent PTEN(+) areas in three cases (37.5%), but no clear genomic or DNA methylation basis for loss was identified in the remaining PTEN(-) samples. RNA expression data from two independent platforms identified a consistent increase in chromosome segregation gene expression in PTEN(-) versus adjacent PTEN(+) areas. Proteomic analysis showed a relative paucity of tumor-infiltrating lymphocytes in PTEN(-) versus adjacent PTEN(+) areas. The findings add to our understanding of potential molecular intratumoral heterogeneity in melanoma and the features associated with the loss of PTEN protein in this disease.
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Melanoma , PTEN Fosfo-Hidrolase , Humanos , PTEN Fosfo-Hidrolase/genética , Proteômica , Melanoma/genética , Melanoma/patologia , Genes Supressores de Tumor , RNARESUMO
OBJECTIVES: The purpose of this study was to explore clinician attitudes regarding selective electrode deactivation and to investigate the primary methodology used to identify poorly encoded electrodes, deactivate identified electrodes, and measure outcomes. METHODS: An online survey consisting of 32 questions was administered to certified clinical and research cochlear implant (CI) audiologists. Questions asked participants about their demographic information, device programming patterns, and attitudes regarding selective electrode deactivation. RESULTS: Fifty-four audiologists completed the survey. When asked whether they believed selectively deactivating poorly encoded electrodes could improve speech perception outcomes, 43% of respondents selected 'Probably Yes,' 39% selected 'Definitely Yes,' and 18% selected 'Might or Might Not.' Of those who reported deactivating electrodes as part of CI programming, various methodology was reported to identify and deactivate poorly encoding electrodes and evaluate effectiveness of deactivation. General reasons against deactivation were also reported. DISCUSSION: CI audiologists generally believed selective electrode deactivation could be used to improve speech perception outcomes for patients; however, few reported implementing selective electrode deactivation in practice. Among those who do perform selective electrode deactivation, the reported methodology was highly variable. CONCLUSION: These findings support the need for clinical practice guidelines to assist audiologists in performing selective electrode deactivation.
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Implante Coclear , Implantes Cocleares , Percepção da Fala , Humanos , Implante Coclear/métodos , Audiologistas , Inquéritos e QuestionáriosRESUMO
Background: Hearing loss is associated with a range of poor psychosocial outcomes. Cochlear implants (CI) are an available treatment option for significant hearing loss and have been linked to improved quality of life in patients. Evidence suggests that audiologists lack the skills to appropriately detect, address, and refer for psychosocial needs among patients with hearing loss. The objective of this study is to examine the attitudes and practice patterns related to psychosocial care among audiologists who work with CI users. Methods: A cross-sectional survey was administered to clinical audiologists who work with CI recipients in the United States. The survey evaluated participants' attitudes toward psychosocial services and factors that contribute to their abilities to address the psychosocial needs of their patients. Additionally, participants were surveyed about their practice patterns including the use of psychosocial screeners, clinical protocols regarding psychosocial care, and referral patterns for coordinated psychosocial services. Descriptive statistics were used to summarize survey responses. Results: Sixty-eight audiologists completed the survey. Of these audiologists, a majority (73.6%) held the attitude that most or all CI patients would benefit from psychosocial intervention. Despite clinicians' recognition of psychosocial needs in this population, over 90% of participants reported never screening for psychosocial symptoms. Additionally, a majority of respondents indicated that they seldom refer their patients for psychosocial services, with referrals occurring less than half the time (58%) or never (27%). Additionally, few audiologists reported utilizing protocols or resources for guiding psychosocial practices. Audiologists indicated that the primary factors that influence their psychosocial practices include time available to spend with the patient and their comfort level in counseling. Conclusion: Audiologists working with CI patients recognize the potential benefit of psychosocial intervention in this population. Nevertheless, audiologists encounter barriers in clinical practice which limit their ability to identify and address the psychosocial needs of their patients. Strategies designed to enhance audiologists' capacity to recognize the psychosocial needs of CI users, in addition to improved interprofessional practice on CI teams, implies significant opportunities to improve the provision of patient-centered hearing care.
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Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5-20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment-response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients.
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Antirreumáticos , Artrite Reumatoide , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Biomarcadores/análise , Biópsia , Humanos , Rituximab/uso terapêuticoRESUMO
Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here, we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an IFN-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4+ and CD8+ T cells. LDRT elicited predominantly CD4+ cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand RAE1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide, and immune checkpoint blockade to patients with immune-desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4+ cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low T cell-infiltrated tumors. SIGNIFICANCE: Low-dose radiation reprogrammed the tumor microenvironment of tumors with scarce immune infiltration and together with immunotherapy induced simultaneous mobilization of innate and adaptive immunity, predominantly CD4+ effector T cells, to achieve tumor control dependent on NKG2D. The combination induced important responses in patients with metastatic immune-cold tumors.This article is highlighted in the In This Issue feature, p. 1.
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Adenocarcinoma Papilar/radioterapia , Neoplasias Ovarianas/radioterapia , Imunidade Adaptativa , Adenocarcinoma Papilar/imunologia , Animais , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Modelos Animais de Doenças , Feminino , Humanos , Linfócitos do Interstício Tumoral , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Ovarianas/imunologia , Dosagem Radioterapêutica , Microambiente TumoralRESUMO
Breast cancer is a heterogenous disease with variability in tumor cells and in the surrounding tumor microenvironment (TME). Understanding the molecular diversity in breast cancer is critical for improving prediction of therapeutic response and prognostication. High-plex spatial profiling of tumors enables characterization of heterogeneity in the breast TME, which can holistically illuminate the biology of tumor growth, dissemination and, ultimately, response to therapy. The GeoMx Digital Spatial Profiler (DSP) enables researchers to spatially resolve and quantify proteins and RNA transcripts from tissue sections. The platform is compatible with both formalin-fixed paraffin-embedded and frozen tissues. RNA profiling was developed at the whole transcriptome level for human and mouse samples and protein profiling of 100-plex for human samples. Tissue can be optically segmented for analysis of regions of interest or cell populations to study biology-directed tissue characterization. The GeoMx Breast Cancer Consortium (GBCC) is composed of breast cancer researchers who are developing innovative approaches for spatial profiling to accelerate biomarker discovery. Here, the GBCC presents best practices for GeoMx profiling to promote the collection of high-quality data, optimization of data analysis and integration of datasets to advance collaboration and meta-analyses. Although the capabilities of the platform are presented in the context of breast cancer research, they can be generalized to a variety of other tumor types that are characterized by high heterogeneity.
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In less than nine months, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) killed over a million people, including >25,000 in New York City (NYC) alone. The COVID-19 pandemic caused by SARS-CoV-2 highlights clinical needs to detect infection, track strain evolution, and identify biomarkers of disease course. To address these challenges, we designed a fast (30-minute) colorimetric test (LAMP) for SARS-CoV-2 infection from naso/oropharyngeal swabs and a large-scale shotgun metatranscriptomics platform (total-RNA-seq) for host, viral, and microbial profiling. We applied these methods to clinical specimens gathered from 669 patients in New York City during the first two months of the outbreak, yielding a broad molecular portrait of the emerging COVID-19 disease. We find significant enrichment of a NYC-distinctive clade of the virus (20C), as well as host responses in interferon, ACE, hematological, and olfaction pathways. In addition, we use 50,821 patient records to find that renin-angiotensin-aldosterone system inhibitors have a protective effect for severe COVID-19 outcomes, unlike similar drugs. Finally, spatial transcriptomic data from COVID-19 patient autopsy tissues reveal distinct ACE2 expression loci, with macrophage and neutrophil infiltration in the lungs. These findings can inform public health and may help develop and drive SARS-CoV-2 diagnostic, prevention, and treatment strategies.
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COVID-19/genética , COVID-19/virologia , SARS-CoV-2/genética , Adulto , Idoso , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antivirais/farmacologia , COVID-19/epidemiologia , Teste de Ácido Nucleico para COVID-19 , Interações Medicamentosas , Feminino , Perfilação da Expressão Gênica , Genoma Viral , Antígenos HLA/genética , Interações entre Hospedeiro e Microrganismos/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Cidade de Nova Iorque/epidemiologia , Técnicas de Amplificação de Ácido Nucleico , Pandemias , RNA-Seq , SARS-CoV-2/classificação , SARS-CoV-2/efeitos dos fármacos , Tratamento Farmacológico da COVID-19RESUMO
The relationship of SARS-CoV-2 pulmonary infection and severity of disease is not fully understood. Here we show analysis of autopsy specimens from 24 patients who succumbed to SARS-CoV-2 infection using a combination of different RNA and protein analytical platforms to characterize inter-patient and intra-patient heterogeneity of pulmonary virus infection. There is a spectrum of high and low virus cases associated with duration of disease. High viral cases have high activation of interferon pathway genes and a predominant M1-like macrophage infiltrate. Low viral cases are more heterogeneous likely reflecting inherent patient differences in the evolution of host response, but there is consistent indication of pulmonary epithelial cell recovery based on napsin A immunohistochemistry and RNA expression of surfactant and mucin genes. Using a digital spatial profiling platform, we find the virus corresponds to distinct spatial expression of interferon response genes demonstrating the intra-pulmonary heterogeneity of SARS-CoV-2 infection.
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COVID-19 , Interações entre Hospedeiro e Microrganismos , Interferons/metabolismo , Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácido Aspártico Endopeptidases/metabolismo , Autopsia , COVID-19/imunologia , COVID-19/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Células Epiteliais/virologia , Feminino , Humanos , Imunidade , Imuno-Histoquímica , Hibridização In Situ , Interferons/genética , Pulmão/patologia , Pulmão/virologia , Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Mucinas/genética , Mucinas/metabolismo , Tensoativos/metabolismo , Transcriptoma , Carga ViralRESUMO
The relationship of SARS-CoV-2 lung infection and severity of pulmonary disease is not fully understood. We analyzed autopsy specimens from 24 patients who succumbed to SARS-CoV-2 infection using a combination of different RNA and protein analytical platforms to characterize inter- and intra- patient heterogeneity of pulmonary virus infection. There was a spectrum of high and low virus cases that was associated with duration of disease and activation of interferon pathway genes. Using a digital spatial profiling platform, the virus corresponded to distinct spatial expression of interferon response genes and immune checkpoint genes demonstrating the intra-pulmonary heterogeneity of SARS-CoV-2 infection.
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Purpose: The study's objectives were to (1) evaluate benefit from a novel bimodal fitting formula (Adaptive Phonak Digital Bimodal Fitting Formula [APDB]), and (2) compare outcomes with APDB and a traditional fitting formula (NAL-NL2). Methods: This prospective study evaluated outcomes in ten adults with unilateral Advanced Bionics (AB) cochlear implants (CI). Participants were tested bimodally with NAL-NL2 and APDB programed on Naída Link UP HAs. Measures of speech perception, sound quality, and preference were obtained with two bimodal configurations (CI + HANAL-NL2 and CI + HAAPDB). Participants used the CI + HAAPDB configuration for an acclimation period, after which measures were repeated. Results: Significant bimodal benefit was measured from both HA fitting formulae for speech perception in noise compared to the CI-only condition. Improved individual outcomes with the APDB were observed, but group differences were not statistically significant. Participants reported subjective benefit from APDB on blind comparisons of preference and sound quality. Conclusions: Significant benefit was found with both bimodal conditions compared to the CI-only condition; however, bimodal speech perception results were not significantly different. Users reported benefit from the APDB formula over NAL-NL2 formula. Due to individual improved speech perception and overall subjective preference for APDB, clinicians should consider APDB with AB CI recipients.
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Biônica/métodos , Implantes Cocleares , Perda Auditiva/cirurgia , Ajuste de Prótese/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Implante Coclear , Feminino , Perda Auditiva/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Ruído , Estudos Prospectivos , Localização de Som , Percepção da Fala , Resultado do Tratamento , Adulto JovemRESUMO
Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous hematological malignancy. Although immunotherapy may be an attractive modality to exploit in patients with AML, the ability to predict the groups of patients and the types of cancer that will respond to immune targeting remains limited. This study dissected the complexity of the immune architecture of AML at high resolution and assessed its influence on therapeutic response. Using 442 primary bone marrow samples from three independent cohorts of children and adults with AML, we defined immune-infiltrated and immune-depleted disease classes and revealed critical differences in immune gene expression across age groups and molecular disease subtypes. Interferon (IFN)-γ-related mRNA profiles were predictive for both chemotherapy resistance and response of primary refractory/relapsed AML to flotetuzumab immunotherapy. Our compendium of microenvironmental gene and protein profiles provides insights into the immuno-biology of AML and could inform the delivery of personalized immunotherapies to IFN-γ-dominant AML subtypes.
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Anticorpos Biespecíficos , Antineoplásicos , Leucemia Mieloide Aguda , Adulto , Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos/uso terapêutico , Criança , Humanos , Imunoterapia , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
OBJECTIVE: The Aluetta™ reusable pen device and instructions for use (IFU) for growth hormone (r-hGH; Saizen®, Merck KGaA, Darmstadt, Germany) administration were tested for Human-Factors Usability, to ensure it could be used safely and effectively by the intended users in the intended use environment. RESEARCH DESIGN AND METHODS: Usability testing was conducted under simulated conditions in three groups of participants: pediatric or adult patients with growth hormone deficiency (GHD), participants without GHD, and healthcare professionals (HCPs). The testing comprised a 45-minute training session, a 2-hour testing session, and a participant-feedback session. RESULTS: Twenty-six participants completed the training session and performed all critical tasks related to the pen use across three scenarios. The most difficult tasks were related to the preparation, checking, and maintenance of the device; only 8% of use errors occurred during tasks related to the injection process. Eighty-five percent considered the pen safe and effective to use without further modifications and the training to be clear and effective. CONCLUSIONS: The pen device and associated materials benefited from Human Factors Engineering throughout the development process. These evaluations show that patients and HCPs could safely and effectively use the pen device, and the IFU and training were clear and effective.
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Ergonomia , Hormônio do Crescimento Humano/administração & dosagem , Adolescente , Adulto , Idoso , Feminino , Humanos , Injeções/instrumentação , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Autoadministração/instrumentaçãoRESUMO
PURPOSE: Protein expression in formalin-fixed, paraffin-embedded tissue is routinely measured by IHC or quantitative fluorescence (QIF) on a handful of markers on a single section. Digital spatial profiling (DSP) allows spatially informed simultaneous assessment of multiple biomarkers. Here we demonstrate the DSP technology using a 44-plex antibody cocktail to find protein expression that could potentially be used to predict response to immune therapy in melanoma.Experimental Design: The NanoString GeoMx DSP technology is compared with automated QIF (AQUA) for immune marker compartment-specific measurement and prognostic value in non-small cell lung cancer (NSCLC). Then we use this tool to search for novel predictive markers in a cohort of 60 patients with immunotherapy-treated melanoma on a tissue microarray using a 44-plex immune marker panel measured in three compartments (macrophage, leukocyte, and melanocyte) generating 132 quantitative variables. RESULTS: The spatially informed variable assessment by DSP validates by both regression and variable prognostication compared with QIF for stromal CD3, CD4, CD8, CD20, and PD-L1 in NSCLC. From the 132 variables, 11 and 15 immune markers were associated with prolonged progression-free survival (PFS) and overall survival (OS). Notably, we find PD-L1 expression in CD68-positive cells (macrophages) and not in tumor cells was a predictive marker for PFS, OS, and response. CONCLUSIONS: DSP technology shows high concordance with QIF and validates based on both regression and outcome assessment. Using the high-plex capacity, we found a series of expression patterns associated with outcome, including that the expression of PD-L1 in macrophages is associated with response.
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Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais , Melanoma/diagnóstico , Melanoma/tratamento farmacológico , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Feminino , Imunofluorescência , Humanos , Imuno-Histoquímica , Imunoterapia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Melanoma/etiologia , Melanoma/mortalidade , Técnicas de Diagnóstico Molecular , Terapia de Alvo Molecular , Prognóstico , Modelos de Riscos Proporcionais , Análise Serial de Tecidos , Resultado do TratamentoRESUMO
Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real-time imaging with single-cell RNA sequencing analysis and mouse models to uncover anti-PD-1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor-infiltrating dendritic cells (DCs), which produced interleukin 12 (IL-12). These DCs did not bind anti-PD-1 but produced IL-12 upon sensing interferon γ (IFN-γ) that was released from neighboring T cells. In turn, DC-derived IL-12 stimulated antitumor T cell immunity. These findings suggest that full-fledged activation of antitumor T cells by anti-PD-1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN-γ and IL-12. Furthermore, we found that activating the non-canonical NF-κB transcription factor pathway amplified IL-12-producing DCs and sensitized tumors to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade.