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Histological assessment of autoimmune hepatitis (AIH) is challenging. As one of the possible results of these challenges, nonclassical features such as bile-duct injury stays understudied in AIH. We aim to develop a deep learning tool (artificial intelligence for autoimmune hepatitis [AI(H)]) that analyzes the liver biopsies and provides reproducible, quantifiable, and interpretable results directly from routine pathology slides. A total of 123 pre-treatment liver biopsies, whole-slide images with confirmed AIH diagnosis from the archives of the Institute of Pathology at University Hospital Basel, were used to train several convolutional neural network models in the Aiforia artificial intelligence (AI) platform. The performance of AI models was evaluated on independent test set slides against pathologist's manual annotations. The AI models were 99.4%, 88.0%, 83.9%, 81.7%, and 79.2% accurate (ratios of correct predictions) for tissue detection, liver microanatomy, necroinflammation features, bile duct damage detection, and portal inflammation detection, respectively, on hematoxylin and eosin-stained slides. Additionally, the immune cells model could detect and classify different immune cells (lymphocyte, plasma cell, macrophage, eosinophil, and neutrophil) with 72.4% accuracy. On Sirius red-stained slides, the test accuracies were 99.4%, 94.0%, and 87.6% for tissue detection, liver microanatomy, and fibrosis detection, respectively. Additionally, AI(H) showed bile duct injury in 81 AIH cases (68.6%). The AI models were found to be accurate and efficient in predicting various morphological components of AIH biopsies. The computational analysis of biopsy slides provides detailed spatial and density data of immune cells in AIH landscape, which is difficult by manual counting. AI(H) can aid in improving the reproducibility of AIH biopsy assessment and bring new descriptive and quantitative aspects to AIH histology.
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Although breakthroughs have been achieved with immune checkpoint inhibitors (ICI) therapy, some tumors do not respond to those therapies due to primary or acquired resistance. GARP, a type I transmembrane cell surface docking receptor mediating latent transforming growth factor-ß (TGF-ß) and abundantly expressed on regulatory T lymphocytes and platelets, is a potential target to render these tumors responsive to ICI therapy, and enhancing anti-tumor response especially combined with ICI. To facilitate these research efforts, we developed humanized mouse models expressing humanized GARP (hGARP) instead of their mouse counterparts, enabling in vivo assessment of GARP-targeting agents. We created GARP-humanized mice by replacing the mouse Garp gene with its human homolog. Then, comprehensive experiments, including expression analysis, immunophenotyping, functional assessments, and pharmacologic assays, were performed to characterize the mouse model accurately. The Tregs and platelets in the B-hGARP mice (The letter B is the first letter of the company's English name, Biocytogen.) expressed human GARP, without expression of mouse GARP. Similar T, B, NK, DCs, monocytes and macrophages frequencies were identified in the spleen and blood of B-hGARP and WT mice, indicating that the humanization of GARP did not change the distribution of immune cell in these compartments. When combined with anti-PD-1, monoclonal antibodies (mAbs) against GARP/TGF-ß1 complexes demonstrated enhanced in vivo anti-tumor activity compared to monotherapy with either agent. The novel hGARP model serves as a valuable tool for evaluating human GARP-targeting antibodies in immuno-oncology, which may enable preclinical studies to assess and validate new therapeutics targeting GARP. Furthermore, intercrosses of this model with ICI humanized models could facilitate the evaluation of combination therapies.
Assuntos
Anticorpos Monoclonais , Proteínas de Membrana , Neoplasias , Fator de Crescimento Transformador beta , Animais , Humanos , Camundongos , Anticorpos Monoclonais/uso terapêutico , Plaquetas/metabolismo , Modelos Animais de Doenças , Neoplasias/terapia , Linfócitos T Reguladores , Fator de Crescimento Transformador beta/metabolismo , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos Endogâmicos C57BL , Inibidores de Checkpoint Imunológico/uso terapêuticoRESUMO
BACKGROUND: Factors associated with discharge disposition and mortality following aneurysmal subarachnoid hemorrhage (aSAH) are not well-characterized. We used a national all-payer database to identify factors associated with home discharge and in-hospital mortality. METHODS: The National Inpatient Sample was queried for patients with aSAH within a 4-year range. Weighted multivariable logistic regression models were constructed and adjusted for age, sex, race, household income, insurance status, comorbidity burden, National Inpatient Sample SAH Severity Score, disease severity, treatment modality, in-hospital complications, and hospital characteristics (size, teaching status, and region). RESULTS: Our sample included 37,965 patients: 33,605 were discharged alive and 14,350 were discharged home. Black patients had lower odds of in-hospital mortality compared with White patients (adjusted odds ratio [aOR] = 0.67, 95% confidence interval [CI] 0.52-0.86, p = 0.002). Compared with patients with private insurance, those with Medicare were less likely to have a home discharge (aOR = 0.58, 95% CI 0.46-0.74, p < 0.001), whereas those with self-pay (aOR = 2.97, 95% CI 2.29-3.86, p < 0.001) and no charge (aOR = 3.21, 95% CI 1.57-6.55, p = 0.001) were more likely to have a home discharge. Household income percentile was not associated with discharge disposition or in-hospital mortality. Paradoxically, increased number of Elixhauser comorbidities was associated with significantly lower odds of in-hospital mortality. CONCLUSIONS: We demonstrate independent associations with hospital characteristics, patient characteristics, and treatment characteristics as related to discharge disposition and in-hospital mortality following aSAH, adjusted for disease severity.
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Hemorragia Subaracnóidea , Humanos , Idoso , Estados Unidos/epidemiologia , Hemorragia Subaracnóidea/complicações , Alta do Paciente , Mortalidade Hospitalar , Estudos Retrospectivos , MedicareRESUMO
TAK-931, a novel, selective, small-molecule inhibitor of cell division cycle 7 has been investigated in multiple clinical trials in patients with advanced solid tumors. An integrated analysis using data from 2 clinical studies assessed effects of TAK-931 on electrocardiogram QT intervals and heart rate (HR). Pharmacokinetic samples and matched triplicate electrocardiogram data were collected in 48 patients with cancer receiving oral administration of TAK-931 50 or 80 mg once daily. The relationships between TAK-931 plasma concentrations and the HR-corrected QT interval via Fridericia (QTcF) or population (QTcP) and HR were analyzed using linear mixed-effects models with fixed effects for day and time. At the geometric mean maximum TAK-931 plasma concentrations after administration of 50 mg, an HR change of 3.40 beats per minute (90%CI, 1.86-4.80) was predicted. Change in QTcF of -3.41 milliseconds (90%CI, -5.77 to -1.17) and QTcP of -2.02 milliseconds (90%CI, -4.15 to 0.0679) were estimated, indicating there was no effect of TAK-931 on the QT intervals at a recommended phase 2 dose of 50 mg once daily for 14 days in a 21-day cycle.
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Antineoplásicos , Neoplasias , Antineoplásicos/efeitos adversos , Ciclo Celular , Eletrocardiografia , Humanos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Pirazolonas , Pirimidinas/farmacologiaRESUMO
The investigational NEDD8-activating enzyme inhibitor pevonedistat is being evaluated in combination with azacitidine versus single-agent azacitidine in patients with higher-risk myelodysplastic syndrome (higher-risk MDS), higher-risk chronic myelomonocytic leukemia (higher-risk CMML), or low-blast acute myeloid leukemia (AML) in a Phase 3 trial PANTHER. To support Asia-inclusive global development, we applied multiregional clinical trial (MRCT) principles of the International Conference on Harmonisation E17 guidelines by evaluating similarity in drug-related and disease-related intrinsic and extrinsic factors. A PubMed literature review (January 2000-November 2019) supported similarity in epidemiology of higher-risk MDS, AML, and CMML in Western and East Asian populations. Furthermore, the treatment of MDS/AML was similar in both East Asian and Western regions, with the same dose of azacitidine being the standard of care. Median overall survival in MDS following azacitidine treatment was generally comparable across regions, and the types and frequencies of molecular alterations in AML and MDS were comparable. Dose-escalation studies established the same maximum tolerated dose of pevonedistat in combination with azacitidine in Western and East Asian populations. Pevonedistat clearance was similar across races. Taken together, conservation of drug-related and disease-related intrinsic and extrinsic factors supported design of an Asia-inclusive Phase 3 trial and a pooled East Asian region. A sample size of ~ 30 East Asian patients (of ~ 450 randomized) was estimated as needed to demonstrate consistency in efficacy relative to the global population. This analysis is presented as an exemplar to illustrate application of clinical pharmacology and translational science principles in designing Asia-inclusive MRCTs. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Azacitidine is the standard of care for myelodysplastic syndromes/low-blast acute myeloid leukemia (AML) across Western and East Asian patients. The first-in-class small-molecule inhibitor of NEDD8-activating enzyme, pevonedistat, has been investigated as a single agent in multiple studies of hematologic and nonhematologic malignancies and in combination with azacitidine in elderly patients with untreated AML. WHAT QUESTION DID THIS STUDY ADDRESS? By applying clinical pharmacology and translational science and International Conference on Harmonisation E17 principles, this study designed an East Asian-inclusive global pivotal Phase 3 trial of pevonedistat, taking into consideration drug-related and disease-related intrinsic and extrinsic factors. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? These analyses provide scientific rationale for Asia-inclusive globalization of the pivotal, Phase 3 PANTHER trial and for pooling clinical data across the East Asian region for assessing consistency in efficacy. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? We developed a framework to facilitate efficient global clinical development of investigational therapies for rare cancers and orphan diseases in Asia-inclusive multiregional clinical trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ciclopentanos/farmacologia , Drogas em Investigação/farmacologia , Farmacologia Clínica/organização & administração , Pirimidinas/farmacologia , Pesquisa Translacional Biomédica/organização & administração , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ásia/epidemiologia , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Ciclopentanos/uso terapêutico , Drogas em Investigação/uso terapêutico , Carga Global da Doença , Humanos , Incidência , Cooperação Internacional , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mielomonocítica Crônica/epidemiologia , Dose Máxima Tolerável , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/epidemiologia , Pirimidinas/uso terapêutico , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores , Estados Unidos/epidemiologiaRESUMO
OBJECTIVE: The aim of this study was to translate and adapt the Primary Care Assessment Tool to assess the perceptions of the quality of primary care among patients in China and to examine the psychometric properties of the adapted Primary Care Assessment Tool Chinese version (PCAT-C). DESIGN: A cross-sectional survey to assess the validity and reliability of PCAT-C using standard psychometric techniques. SETTING: Outpatient departments of five state-level and provincial-level hospitals and four municipal-level hospitals as well as nine community health centers in Changsha, China. PARTICIPANTS: A total of 2532 patients visiting primary care providers. RESULTS: The PCAT-C was acceptable to patients, as evidenced by low proportions of missing data and a full range of possible scores for all items. Two items were eliminated following principal component analysis and reliability testing. The principal component analysis extracted eight multiple-item scales and one single-item scale. Multiple-item scales had reasonable internal consistency and high item-scale correlations. CONCLUSIONS: This study represents the first attempt to construct an instrument for assessing patient reports on the quality of primary care, which is applicable to the Chinese context. Psychometric assessments indicated that the PCAT-C is a useful instrument for assessing the core attributes of primary care in China.