ArCH: improving the performance of clonal hematopoiesis variant calling and interpretation.

MOTIVATION: The acquisition of somatic mutations in hematopoietic stem and progenitor stem cells with resultant clonal expansion, termed clonal hematopoiesis (CH), is associated with increased risk of hematologic malignancies and other adverse outcomes. CH is generally present at low allelic fractions, but clonal expansion and acquisition of additional mutations leads to hematologic cancers in a small proportion of individuals. With high depth and high sensitivity sequencing, CH can be detected in most adults and its clonal trajectory mapped over time. However, accurate CH variant calling is challenging due to the difficulty in distinguishing low frequency CH mutations from sequencing artifacts. The lack of well-validated bioinformatic pipelines for CH calling may contribute to lack of reproducibility in studies of CH. RESULTS: Here, we developed ArCH, an Artifact filtering Clonal Hematopoiesis variant calling pipeline for detecting single nucleotide variants and short insertions/deletions by combining the output of four variant calling tools and filtering based on variant characteristics and sequencing error rate estimation. ArCH is an end-to-end cloud-based pipeline optimized to accept a variety of inputs with customizable parameters adaptable to multiple sequencing technologies, research questions, and datasets. Using deep targeted sequencing data generated from six acute myeloid leukemia patient tumor: normal dilutions, 31 blood samples with orthogonal validation, and 26 blood samples with technical replicates, we show that ArCH improves the sensitivity and positive predictive value of CH variant detection at low allele frequencies compared to standard application of commonly used variant calling approaches. AVAILABILITY AND IMPLEMENTATION: The code for this workflow is available at: https://github.com/kbolton-lab/ArCH.

pVACview: an interactive visualization tool for efficient neoantigen prioritization and selection.

Background: Neoantigen targeting therapies including personalized vaccines have shown promise in the treatment of cancers, particularly when used in combination with checkpoint blockade therapy. At least 100 clinical trials involving these therapies are underway globally. Accurate identification and prioritization of neoantigens is highly relevant to designing these trials, predicting treatment response, and understanding mechanisms of resistance. With the advent of massively parallel DNA and RNA sequencing technologies, it is now possible to computationally predict neoantigens based on patient-specific variant information. However, numerous factors must be considered when prioritizing neoantigens for use in personalized therapies. Complexities such as alternative transcript annotations, various binding, presentation and immunogenicity prediction algorithms, and variable peptide lengths/registers all potentially impact the neoantigen selection process. There has been a rapid development of computational tools that attempt to account for these complexities. While these tools generate numerous algorithmic predictions for neoantigen characterization, results from these pipelines are difficult to navigate and require extensive knowledge of the underlying tools for accurate interpretation. This often leads to over-simplification of pipeline outputs to make them tractable, for example limiting prediction to a single RNA isoform or only summarizing the top ranked of many possible peptide candidates. In addition to variant detection, gene expression and predicted peptide binding affinities, recent studies have also demonstrated the importance of mutation location, allele-specific anchor locations, and variation of T-cell response to long versus short peptides. Due to the intricate nature and number of salient neoantigen features, presenting all relevant information to facilitate candidate selection for downstream applications is a difficult challenge that current tools fail to address. Results: We have created pVACview, the first interactive tool designed to aid in the prioritization and selection of neoantigen candidates for personalized neoantigen therapies including cancer vaccines. pVACview has a user-friendly and intuitive interface where users can upload, explore, select and export their neoantigen candidates. The tool allows users to visualize candidates across three different levels, including variant, transcript and peptide information. Conclusions: pVACview will allow researchers to analyze and prioritize neoantigen candidates with greater efficiency and accuracy in basic and translational settings The application is available as part of the pVACtools pipeline at pvactools.org and as an online server at pvacview.org.

Cytokines drive the formation of memory-like NK cell subsets via epigenetic rewiring and transcriptional regulation.

Activation of natural killer (NK) cells with the cytokines interleukin-12 (IL-12), IL-15, and IL-18 induces their differentiation into memory-like (ML) NK cells; however, the underlying epigenetic and transcriptional mechanisms are unclear. By combining ATAC-seq, CITE-seq, and functional analyses, we discovered that IL-12/15/18 activation results in two main human NK fates: reprogramming into enriched memory-like (eML) NK cells or priming into effector conventional NK (effcNK) cells. eML NK cells had distinct transcriptional and epigenetic profiles and enhanced function, whereas effcNK cells resembled cytokine-primed cNK cells. Two transcriptionally discrete subsets of eML NK cells were also identified, eML-1 and eML-2, primarily arising from CD56bright or CD56dim mature NK cell subsets, respectively. Furthermore, these eML subsets were evident weeks after transfer of IL-12/15/18-activated NK cells into patients with cancer. Our findings demonstrate that NK cell activation with IL-12/15/18 results in previously unappreciated diverse cellular fates and identifies new strategies to enhance NK therapies.

[Suicide in ethnic and cultural minorities - a research on literature]. / Suizid in ethnischen und kulturellen Minderheiten - eine Literaturstudie.

Suicide plays an important role in the history of civilization. For health, moral, cultural, social and psychological reasons it exhibits an impressive phenomenon all over the world. From a sociological point of wiev globalization leads to migration and enlarges ethnic minorities. Thus it influences the suicide risk of ethnicities - usually in different terms for both genders. Our review is based on data from a few countries. Found protective or risk factors refer to specific minorities and cannot implicitly be generalized. Poor methodological preciseness regards varying definitions of minority, ethnicitiy and immigrant as well as the heterogeneous description of interactions between minority and host country, of social inclusion and cultural peculiarities. On the other hand ethnic aspects involved in suicide are so relevant that they have to be explored as exactly as possible.

The association between suicide and the utilization of mental health services in South Tirol, Italy: a psychological autopsy study.

AIMS: The aim of the present study was to investigate potential differences between suicide decedents who had contact with a psychologist or psychiatrist before committing suicide and those individuals who had not had previous contact with a mental health professional prior to ending their lives. METHODS: Psychological autopsy interviews (N = 396) were conducted for individuals who died by suicide between 1997 and 2007 in South Tirol, Italy. RESULTS: The study found that suicide decedents known to mental health professionals were more frequently women and more frequently unemployed or with unstable employment. These decedents were significantly more likely than those unknown to mental health professionals to have a family history of mental illness, one or more past suicide attempts, and more frequent substance abuse, and likely to have frequent alcohol abuse. They more often had visited a physician in the last four weeks before dying and more frequently complained about psychological symptoms. In the prediction of group membership, individuals whom were known to mental health professionals prior to their suicidal act were 3 times more likely to have a family history of mental illness, 5.8 times more likely to have one past suicide attempt, 9.7 times more likely to have two or more past suicide attempts and 3.5 times more likely to have visited a physician in the four weeks prior to their death. CONCLUSION: Our findings indicate that suicide decedents who had contact with mental health services can be distinguished from those who were not known to mental health professionals.

Relação entre os aspectos das alterações funcionais e seu impactona qualidade de vida das pessoas com sequelas de Acidente Vascular Encefálico (AVE) / Relación entre los aspectos de las alteraciones funcionales y su impacto en la calidad de vida de las personas con secuelas de Accidente Vascular Encefálico (AVE) / Relationship between the aspects of functional alterations and their impact in the quality of life people with sequels of Encephalic Vascular Accidents (EVA)

O aumento da expectativa de vida trouxe consigo uma mudança no perfil da morbidade de doenças como o Acidente Vascular Encefálico (AVE), deixando sequelas que influenciam a Qualidade de Vida dos sobreviventes, tornando necessário compreender e quantificar o impacto dessa patologia. Este trabalho se propôs a estabelecer uma correlação entre as escalas de Medida de Independência Funcional (MIF) e a Escala de Qualidade de Vida Específica para Acidente Vascular Encefálico, sendo realizado com 15 pacientes com diagnóstico de AVE do Setor de Terapia Ocupacional da Clínica Escola Promove do Centro Universitário São Camilo, após aprovação pelo comitê de ética. As escalas foram aplicadas nos 15 pacientes hemiplégicos com idade média de 64,6 anos. A análise dos dados mostra uma correlação entre dois domínios (trabalho e produtividade e autocuidado), dos doze domínios da EQVE-AVE com a MIF. Todavia, o estudo não demonstra correlação entre o grau de independência funcional e os demais domínios de Qualidade de Vida de EQVE-AVE. Outros resultados estatísticos relevantes deste estudo são: o escore de mobilidade no sexo masculino é significativamente maior que do feminino; os escores de papéis sociais são estatisticamente maiores entre pacientes solteiros, divorciados e viúvos do que os dos pacientes casados ou com companheiros; e que pacientes sinistros têm melhores escores em papéis sociais, mesmo tendo acometimento do hemisfério direito, desencadeando hemiplegia/hemiparesia à esquerda. Ao comparar as questões funcionais e o impacto na Qualidade de Vida desses indivíduos, podemos favorecer ao aprimoramento de intervenções e tratamento em Terapia Ocupacional de pacientes pós-AVE.

The increase of life expectancy produces a change in the profile of morbity of diseases such as Encephalic Vascular Accident (EVA), causing sequels that influence the Quality of Life of survivors, something which makes necessary to understand and to quantify the impact of that pathology. This work aimed at establishing a correlation between Functional Independence Measurement (FIM) scales and the Stroke Specific Quality of Life Scale (SS-QOL), and was carried out with 15 patients with EVA diagnosis in the Sector of Occupational Therapy of the Clinic School Promove of University Center São Camilo after receiving approval by the Ethics Committee. The scales were applied to 15 hemiplegic patients with an average age of 64.6 years. Data analysis shows a correlation between two domains (work and productivity and self-medication) among the twelve presented by SS-QOL with FIM. The study does not show any correlation between the degree of functional independence and the other domains of Quality of Life of SS-QOL. Other relevant statistical results of this study were: mobility scores in males are significantly higher than those of females; social roles scores are statistically higher among single and divorced patients and widows and widowers than those of married patients or those who have partners; lefthanders present better scores in social roles, even with the right hemisphere affected so as to cause n emiplegia/hemiparesis. Comparing functional questions to the impact in the Quality of Life of those individuals, we can favor the improvement of interventions and treatments in Occupational Therapy for post-EVA patients.

El aumento de la expectativa de vida produce un cambio en el perfil de la morbidad de enfermedades como el Accidente Vascular Encefálico (AVE), dejando secuelas que influencian la Calidad de Vida de los sobrevivientes, lo que hace necesario comprender y cuantificar el impacto de esa patología. Este trabajo se propuso a establecer una correlación entre las escalas de Medida de Independencia Funcional (MIF) y la Escala de Cualidad de Vida Específica para Accidente Vascular Encefálico, y ha sido realizado con 15 pacientes con diagnóstico de AVE del Sector de Terapia Ocupacional de la Clínica Escola Promove do Centro Universitário São Camilo, y ha recibido aprobación por el Comité de Ética. Las escalas fueron aplicadas en los 15 pacientes hemipléjicos con edad media de 64,6 años. La análisis de los datos muestra una correlación entre dos dominios (trabajo y productividad y autocuidado), de entre los doce dominios del EQVE-AVE con MIF. Entretanto, el estudio no demuestra ninguna correlación entre el grado de independencia funcional y losotros dominios de Calidad de Vida del EQVE-AVE. Otros resultados estadísticos relevantes de este estudio son: el escore de movilidad en el sexo masculinoes significativamente mayor que el del femenino; los escores de roles sociales son estadísticamente mayores entre pacientes solteros, divorciados y viudos que los de los pacientes casados o con compañeros; pacientes non diestros presentan mejores escores en roles sociales, aunque con el hemisferio derecho afectado, lo que resulta en hemiplejia/hemiparesía izquierda. Comparando las cuestiones funcionales y el impacto en la Calidad de Vida de esos individuos, podemos favorecer la mejoría de intervenciones y tratamientos en Terapia Ocupacional de pacientes post-AVE.