Citations

AbstractSummaryBuilding a high-quality annotation corpus requires expenditure of considerable time and expertise, particularly for biomedical and clinical research applications. Most existing annotation tools provide many advanced features to cover a variety of needs where the installation, integration and difficulty of use present a significant burden for actual annotation tasks. Here, we present MedTator, a serverless annotation tool, aiming to provide an intuitive and interactive user interface that focuses on the core steps related to corpus annotation, such as document annotation, corpus summarization, annotation export and annotation adjudication.Availability and implementationMedTator and its tutorial are freely available from https://ohnlp.github.io/MedTator. MedTator source code is available under the Apache 2.0 license: https://github.com/OHNLP/MedTator.Supplementary informationSupplementary data are available at Bioinformatics online.

BACKGROUND: Basal cell carcinoma of the perianal region is a rare anorectal disease. This condition is not related to exposure to ultraviolet radiation. Because of the low prevalence and poor detection, there is a paucity of data relating to this condition in the literature. Perianal basal cell carcinoma presents surgical challenges different from other anatomic locations and may not share the same prevalence or natural history. Here, we describe the largest series to date on the surgical management of perianal basal cell carcinoma. OBJECTIVE: We aimed to present our 35-year experience in managing perianal basal cell carcinoma in this study. DESIGN: This was a retrospective single-center analysis. SETTING: The study was conducted at a large tertiary referral academic health care system. PATIENTS: All patients undergoing surgical management of pathology confirmed perianal basal cell carcinoma. INTERVENTIONS: All patients underwent surgical management of their disease. MAIN OUTCOME MEASURES: The primary outcomes were disease recurrence, mortality, and wound complications. RESULTS: A total of 29 patients were identified with an average follow-up of 5.5 years. At index presentation, 27.6% of patients had multiple basal cell carcinoma in other anatomic locations. Ninety-three percent of patients were adequately treated with local excision, but 60% had wound dehiscence at the time of their first follow-up visit. Ultimately, there were no recurrences or disease-related mortality during the follow-up period. LIMITATIONS: Limitations to our study include its nonrandomized retrospective nature, single-institution experience, and small patient sample size. CONCLUSIONS: Perianal basal cell carcinoma carries a high rate of synchronous presentation in other locations and should prompt a thorough evaluation. Perianal basal cell carcinomas can and should be successfully treated with local excision despite the high rate of wound complications. See Video Abstract at http://links.lww.com/DCR/B883. Carcinoma perianal de células basales: 35 años de experiencia ANTECEDENTES: El carcinoma de células basales de la región perianal es una enfermedad anorrectal rara. Esta condición no está relacionada con la exposición a la radiación ultravioleta. Debido a la baja prevalencia y detección pobre, hay escasez de datos relacionados con esta condición en la literatura. El carcinoma de células basales perianal presenta diferentes desafíos quirúrgicos en otras ubicaciones anatómicas y puede no compartir la misma prevalencia o historia natural. A continuación, describimos la serie más grande hasta la fecha sobre el tratamiento quirúrgico del carcinoma de células basales perianal. OBJETIVO: Presentar nuestra experiencia de 35 años en el manejo del carcinoma de células basales perianal. DISEÑO: Este fue un análisis retrospectivo de un solo centro. ENTORNO CLINICO: El estudio se llevó a cabo en un gran centro de salud académico de referencia terciaria. PACIENTES: Todos los pacientes sometidos a tratamiento quirúrgico con patología confirmatoria de carcinoma basocelular perianal. INTERVENCIONES: Todos los pacientes fueron sometidos a tratamiento quirúrgico de su enfermedad. PRINCIPALES MEDIDAS DE RESULTADO: Los resultados primarios fueron la recurrencia de la enfermedad, mortalidad, y complicaciones de la herida. RESULTADOS: Se identificaron un total de 29 pacientes con un seguimiento promedio de 5.5 años. El 27,6% de los pacientes tenían carcinoma basocelular múltiple en otras localizaciones anatómicas en la presentación inicial. El 93% de los pacientes fueron tratados adecuadamente con escisión local, pero el 60% tuvo dehiscencia de la herida en el momento de la primera visita de seguimiento. En última instancia, no hubo recurrencias ni mortalidad relacionada con la enfermedad durante el período de seguimiento. LIMITACIONES: Las limitaciones de nuestro estudio incluyen su naturaleza retrospectiva no aleatorizada, la experiencia de una sola institución y el tamaño pequeño de la muestra de pacientes. CONCLUSIONES: El carcinoma de células basales perianal tiene una alta tasa de presentación sincrónica en otras localizaciones y debe dar lugar a una evaluación exhaustiva. Los CBC perianales pueden y deben ser tratados exitosamente con escisión local a pesar de la alta tasa de complicaciones de herida. Consulte Video Resumen en http://links.lww.com/DCR/B883. (Tradducción—Dr. Francisco M. Abarca-Rendon)

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have dramatically changed the landscape of cancer therapy. Both remarkable and durable responses have been observed in patients with melanoma, non-small-cell lung cancer (NSCLC), and other malignancies. However, the PD-1/PD-L1 blockade has demonstrated meaningful clinical responses and benefits in only a subset of patients. In addition, several severe and life-threatening adverse events were observed in these patients. Therefore, the identification of predictive biomarkers is urgently needed to select patients who are more likely to benefit from ICI therapy. PD-L1 expression level is the most commonly used biomarker in clinical practice for PD-1/PD-L1 inhibitors. However, negative PD-L1 expression cannot reliably exclude a response to a PD-1/PD-L1 blockade. Other factors, such as tumor microenvironment and other tumor genomic signatures, appear to impact the response to ICIs. In this review, we examine emerging data for novel biomarkers that may have a predictive value for optimizing the benefit from anti-PD-1/PD-L1 immunotherapy.

Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results is unclear. In addition, the majority of discovered variants are currently classified as variants of uncertain significance, limiting clinical actionability. Methods: The eMERGE-III study (Electronic Medical Records and Genomics Phase III) is a multicenter prospective cohort that included 21 846 participants without previous indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with electronic health record–derived phenotypes and follow-up clinical examination. Selected variants of uncertain significance (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells. Results: As previously reported, 3.0% of participants had P/LP variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared with noncarriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their electronic health records. Fifty-four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long-QT syndrome), and 12 of these 19 diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance, we reclassified 11 variants: 3 to likely benign and 8 to P/LP. Conclusions: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As the genomes of large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, electronic health record phenotypes, and in vitro functional studies. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier; NCT03394859.

Abstract Family involvement in end-of-life (EOL) care is critical to ensure older adults’ health and quality of life. Older adults’ self-efficacy in discussing EOL care plans with family members can facilitate family involvement in EOL care planning. Research shows that family relationships are associated with self-efficacy in discussing EOL care with family members among older Chinese Americans. However, the roles of family conflict and acculturation remain unknown. This study examines the association between family conflict and self-efficacy in discussing EOL care with family members and whether such an association differs by acculturation levels among older Chinese Americans. Data were collected from 207 Chinese Americans aged 65-102 in two metropolitan areas in 2017. Ordinary least squares regression was conducted to examine the association between family conflict, acculturation, and self-efficacy in discussing EOL care with family. Family conflict was negatively associated with older adults’ self-efficacy in discussing EOL care with family. More specifically, the negative association between family conflict and self-efficacy in discussing EOL care with family members was more pronounced for those with higher levels of acculturation. Findings highlighted differential effects of family conflict on self-efficacy of EOL care plan discussion for older adults with different acculturation levels. Those with higher acculturation may be more independent in their EOL care planning and aware of the possible negative effects of family conflict in their EOL care planning discussions. Acculturation needs to be considered by geriatric health providers to develop family-centered interventions in improving end-of-life care planning for this population.

Aim There is an association between heart failure with preserved ejection fraction (HFpEF) and insulin resistance, but less is known about the diabetic continuum, and in particular about pre‐diabetes, in HFpEF. We examined characteristics and outcomes of participants with diabetes or pre‐diabetes in PARAGON‐HF. Methods and results Patients aged ≥50 years with left ventricular ejection fraction ≥45%, structural heart disease and elevated N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) were eligible. Patients were classified according to glycated haemoglobin (HbA1c): (i) normal HbA1c, <6.0%; (ii) pre‐diabetes, 6.0%–6.4%; (iii) diabetes, ≥6.5% or history of diabetes. The primary outcome was a composite of cardiovascular (CV) death and total heart failure hospitalizations (HFH). Of 4796 patients, 50% had diabetes and 18% had pre‐diabetes. Compared to patients with normal HbA1c, patients with pre‐diabetes and diabetes more often were obese, had a history of myocardial infarction and had lower Kansas City Cardiomyopathy Questionnaire scores, while patients with diabetes had more clinical evidence of congestion, but similar NT‐proBNP concentrations. The risks of the primary composite outcome (rate ratio [RR] 1.59, 95% confidence interval [CI] 1.35–1.88), total HFH (RR 1.67, 95% CI 1.39–2.02) and CV death (hazard ratio [HR] 1.35, 95% CI 1.07–1.71) were higher among patients with diabetes, compared to those with normal HbA1c. Patients with pre‐diabetes had a higher risk (which was intermediate between that of patients with diabetes and those with normal HbA1c) of the primary outcome (HR 1.27, 95% CI 1.00–1.60) and HFH (HR 1.35, 95% CI 1.03–1.77), but not of CV death (HR 1.02, 95% CI 0.75–1.40). Patients with diabetes treated with insulin had worse outcomes than those not, and those with ‘lean diabetes’ had similar mortality rates to those with a higher body mass index, but lower rates of HFH. Conclusion Pre‐diabetes is common in patients with HFpEF and is associated with worse clinical status and greater risk of HFH. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT01920711.

Abstract Cytotoxic CD8+ T cells (CTL) are a crucial component of the immune system notable for their ability to eliminate rapidly proliferating malignant cells. However, the T-cell intrinsic factors required for human CTLs to accomplish highly efficient antitumor cytotoxicity are not well defined. By evaluating human CD8+ T cells from responders versus nonresponders to treatment with immune checkpoint inhibitors, we sought to identify key factors associated with effective CTL function. Single-cell RNA-sequencing analysis of peripheral CD8+ T cells from patients treated with anti–PD-1 therapy showed that cells from nonresponders exhibited decreased expression of the cytolytic granule-associated molecule natural killer cell granule protein-7 (NKG7). Functional assays revealed that reduced NKG7 expression altered cytolytic granule number, trafficking, and calcium release, resulting in decreased CD8+ T-cell–mediated killing of tumor cells. Transfection of T cells with NKG7 mRNA was sufficient to improve the tumor-cell killing ability of human T cells isolated from nonresponders and increase their response to anti–PD-1 or anti–PD-L1 therapy in vitro. NKG7 mRNA therapy also improved the antitumor activity of murine tumor antigen–specific CD8+ T cells in an in vivo model of adoptive cell therapy. Finally, we showed that the transcription factor ETS1 played a role in regulating NKG7 expression. Together, our results identify NKG7 as a necessary component for the cytotoxic function of CD8+ T cells and establish NKG7 as a T-cell–intrinsic therapeutic target for enhancing cancer immunotherapy. See related article by Li et al., p. 154.