The genetic architecture of type 2 diabetes.

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees.

A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.

Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.

BigDataScript: a scripting language for data pipelines.

MOTIVATION: The analysis of large biological datasets often requires complex processing pipelines that run for a long time on large computational infrastructures. We designed and implemented a simple script-like programming language with a clean and minimalist syntax to develop and manage pipeline execution and provide robustness to various types of software and hardware failures as well as portability. RESULTS: We introduce the BigDataScript (BDS) programming language for data processing pipelines, which improves abstraction from hardware resources and assists with robustness. Hardware abstraction allows BDS pipelines to run without modification on a wide range of computer architectures, from a small laptop to multi-core servers, server farms, clusters and clouds. BDS achieves robustness by incorporating the concepts of absolute serialization and lazy processing, thus allowing pipelines to recover from errors. By abstracting pipeline concepts at programming language level, BDS simplifies implementation, execution and management of complex bioinformatics pipelines, resulting in reduced development and debugging cycles as well as cleaner code. AVAILABILITY AND IMPLEMENTATION: BigDataScript is available under open-source license at http://pcingola.github.io/BigDataScript.

Genome-wide mouse mutagenesis reveals CD45-mediated T cell function as critical in protective immunity to HSV-1.

Herpes simplex encephalitis (HSE) is a lethal neurological disease resulting from infection with Herpes Simplex Virus 1 (HSV-1). Loss-of-function mutations in the UNC93B1, TLR3, TRIF, TRAF3, and TBK1 genes have been associated with a human genetic predisposition to HSE, demonstrating the UNC93B-TLR3-type I IFN pathway as critical in protective immunity to HSV-1. However, the TLR3, UNC93B1, and TRIF mutations exhibit incomplete penetrance and represent only a minority of HSE cases, perhaps reflecting the effects of additional host genetic factors. In order to identify new host genes, proteins and signaling pathways involved in HSV-1 and HSE susceptibility, we have implemented the first genome-wide mutagenesis screen in an in vivo HSV-1 infectious model. One pedigree (named P43) segregated a susceptible trait with a fully penetrant phenotype. Genetic mapping and whole exome sequencing led to the identification of the causative nonsense mutation L3X in the Receptor-type tyrosine-protein phosphatase C gene (Ptprc(L3X)), which encodes for the tyrosine phosphatase CD45. Expression of MCP1, IL-6, MMP3, MMP8, and the ICP4 viral gene were significantly increased in the brain stems of infected Ptprc(L3X) mice accounting for hyper-inflammation and pathological damages caused by viral replication. Ptprc(L3X) mutation drastically affects the early stages of thymocytes development but also the final stage of B cell maturation. Transfer of total splenocytes from heterozygous littermates into Ptprc(L3X) mice resulted in a complete HSV-1 protective effect. Furthermore, T cells were the only cell population to fully restore resistance to HSV-1 in the mutants, an effect that required both the CD4⁺ and CD8⁺ T cells and could be attributed to function of CD4⁺ T helper 1 (Th1) cells in CD8⁺ T cell recruitment to the site of infection. Altogether, these results revealed the CD45-mediated T cell function as potentially critical for infection and viral spread to the brain, and also for subsequent HSE development.

Adjusted sequence kernel association test for rare variants controlling for cryptic and family relatedness.

Recent progress in sequencing technologies makes it possible to identify rare and unique variants that may be associated with complex traits. However, the results of such efforts depend crucially on the use of efficient statistical methods and study designs. Although family-based designs might enrich a data set for familial rare disease variants, most existing rare variant association approaches assume independence of all individuals. We introduce here a framework for association testing of rare variants in family-based designs. This framework is an adaptation of the sequence kernel association test (SKAT) which allows us to control for family structure. Our adjusted SKAT (ASKAT) combines the SKAT approach and the factored spectrally transformed linear mixed models (FaST-LMMs) algorithm to capture family effects based on a LMM incorporating the realized proportion of the genome that is identical by descent between pairs of individuals, and using restricted maximum likelihood methods for estimation. In simulation studies, we evaluated type I error and power of this proposed method and we showed that regardless of the level of the trait heritability, our approach has good control of type I error and good power. Since our approach uses FaST-LMM to calculate variance components for the proposed mixed model, ASKAT is reasonably fast and can analyze hundreds of thousands of markers. Data from the UK twins consortium are presented to illustrate the ASKAT methodology.

Intronic non-CG DNA hydroxymethylation and alternative mRNA splicing in honey bees.

BACKGROUND: Previous whole-genome shotgun bisulfite sequencing experiments showed that DNA cytosine methylation in the honey bee (Apis mellifera) is almost exclusively at CG dinucleotides in exons. However, the most commonly used method, bisulfite sequencing, cannot distinguish 5-methylcytosine from 5-hydroxymethylcytosine, an oxidized form of 5-methylcytosine that is catalyzed by the TET family of dioxygenases. Furthermore, some analysis software programs under-represent non-CG DNA methylation and hydryoxymethylation for a variety of reasons. Therefore, we used an unbiased analysis of bisulfite sequencing data combined with molecular and bioinformatics approaches to distinguish 5-methylcytosine from 5-hydroxymethylcytosine. By doing this, we have performed the first whole genome analyses of DNA modifications at non-CG sites in honey bees and correlated the effects of these DNA modifications on gene expression and alternative mRNA splicing. RESULTS: We confirmed, using unbiased analyses of whole-genome shotgun bisulfite sequencing (BS-seq) data, with both new data and published data, the previous finding that CG DNA methylation is enriched in exons in honey bees. However, we also found evidence that cytosine methylation and hydroxymethylation at non-CG sites is enriched in introns. Using antibodies against 5-hydroxmethylcytosine, we confirmed that DNA hydroxymethylation at non-CG sites is enriched in introns. Additionally, using a new technique, Pvu-seq (which employs the enzyme PvuRts1l to digest DNA at 5-hydroxymethylcytosine sites followed by next-generation DNA sequencing), we further confirmed that hydroxymethylation is enriched in introns at non-CG sites. CONCLUSIONS: Cytosine hydroxymethylation at non-CG sites might have more functional significance than previously appreciated, and in honey bees these modifications might be related to the regulation of alternative mRNA splicing by defining the locations of the introns.

Variant Annotation and Functional Prediction: SnpEff.

Variant annotations, in general, refer to the process of information enrichment of genomic variants from a sequencing experiment. Typically these annotations include functional predictions, such as predicting the amino acid sequence changes from the DNA variant, predicting whether the variant will induce a splice anomaly, or predicting nonsense mediated decay. But other annotations also include combining with genomic databases, adding conservation scores, or comparing to allele frequencies from large population databases. Finally, all these annotations are combined to prioritize and filter variants into a reduced set of highly relevant variants for the study or clinical assay.

"Never Event" en cirugía: Análisis Causa-Raíz / "Never Event" in surgery: Root-Cause Analysis

RESUMEN La seguridad del paciente es un elemento imprescindible de la calidad asistencial. Al menos la mitad de los eventos adversos en pacientes hospitalizados están en relación con la práctica quirúrgica. El Análisis Causa-Raíz es un estudio sistemático de estos eventos mediante una revisión paso a paso de la cronología de los hechos, para identificar las causas que podrían haber llevado a la producción del evento. El Diagrama de Ishikawa o "espina de pescado" es una herramienta gráfica es una herramienta útil. El éxito radica en lograr responder qué sucedió, por qué sucedió, y qué puede hacerse para evitar que suceda nuevamente algún evento que vulnera la seguridad del paciente. El propósito último es la mejora de los procesos asistenciales impidiendo la repetición del evento adverso y priorizando el aprendizaje y mejora a partir de su análisis. La comunicación institucional de los hallazgos del análisis y las medidas para implementar, la discusión de casos en ateneos de morbimortalidad y la educación continua del personal son pilares para el cambio en la cultura hacia una centrada en la seguridad y calidad, sustituyendo la cultura "reactiva" por una "proactiva", que toma los eventos como instrumento para el aprendizaje y la mejora continua.

ABSTRACT At least half of the adverse events on hospitalized patients are associated with surgery. Root cause analysis (RCA) is a systematic way of analyzing these events to find their causes through a step-by-step review of the chronology of facts, identifying those that could have caused the event. An Ishikawa diagram (also called fishbone diagram) is a visual method for root cause analysis that allows the identification and categorization of all possible causes of an event. The goal is to answer what happened, why did it happen, and what can be done to prevent it from happening again. The ultimate goal is to improve healthcare processes by preventing the recurrence of the adverse event and prioritizing learning and improvement based on its analysis. Communicating the findings of the analysis and the measures to be implemented, discussing cases in morbidity and mortality meetings and continuous education of staff are the cornerstones for changing the culture towards one centered on safety and quality, replacing the "reactive" culture with a "proactive" culture, which considers events as an instrument for learning and continuous improvement.

Cierre dinámico y toxina botulínica: una alternativa novedosa para el cierre definitivo del abdomen abierto y contenido / Dynamic closure system and botulinum toxin: a novel alternative for definitive closure of open abdomen

RESUMEN Se presenta el caso de un paciente masculino de 54 años que, cursando internación por neumonía- COVID-19, intercurrió con shock séptico por diverticulitis aguda Hinchey IV, por lo que se realizó cirugía de Hartmann. Evolucionó con isquemia colónica, se realizó colectomía total y abdomen abierto y contenido (AAyC). El manejo del AAyC se realizó con sistema de vacío (VAC) durante 7 semanas, resultando un AAyC tipo IIIa (Björck) con un gap de 16 cm. Se decidió iniciar, una vez dadas las condiciones clínicas del paciente, el cierre dinámico (CD) con tracción fascial con malla de polipropileno asociado a inyección de toxina botulínica (TB). Esta estrategia permitió el cierre fascial primario (CFP) de la pared abdominal en la quinta semana de comenzado el tratamiento, evitando de esta manera la morbilidad de un cierre por segunda intención.

ABSTRACT We report the case of a 54-year-old male patient hospitalized for COVID-19 pneumonia who developed septic shock due to acute Hinchey IV diverticulitis and required Hartmann's surgery. The patient evolved with colonic ischemia and underwent total colectomy and open abdomen (OA) with temporary abdominal closure (TAC) that was managed with a vacuum-assisted wound closure (VAWC) system for 7 weeks, resulting in a Björck grade 3A OA with a 16-cm gap. As he had a favorable clinic course, dynamic closure with mesh-mediated fascial traction was decided, associated with botulinum toxin (BT) injection. This strategy allowed primary fascial closure (PFC) of the abdominal wall 5 weeks after treatment was initiated, thus avoiding the complications of healing by secondary intention.

Erratum: Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

This corrects the article DOI: 10.1038/sdata.2017.179.

A Bioinformatics-Based Alternative mRNA Splicing Code that May Explain Some Disease Mutations Is Conserved in Animals.

Deep sequencing of cDNAs made from spliced mRNAs indicates that most coding genes in many animals and plants have pre-mRNA transcripts that are alternatively spliced. In pre-mRNAs, in addition to invariant exons that are present in almost all mature mRNA products, there are at least 6 additional types of exons, such as exons from alternative promoters or with alternative polyA sites, mutually exclusive exons, skipped exons, or exons with alternative 5' or 3' splice sites. Our bioinformatics-based hypothesis is that, in analogy to the genetic code, there is an "alternative-splicing code" in introns and flanking exon sequences, analogous to the genetic code, that directs alternative splicing of many of the 36 types of introns. In humans, we identified 42 different consensus sequences that are each present in at least 100 human introns. 37 of the 42 top consensus sequences are significantly enriched or depleted in at least one of the 36 types of introns. We further supported our hypothesis by showing that 96 out of 96 analyzed human disease mutations that affect RNA splicing, and change alternative splicing from one class to another, can be partially explained by a mutation altering a consensus sequence from one type of intron to that of another type of intron. Some of the alternative splicing consensus sequences, and presumably their small-RNA or protein targets, are evolutionarily conserved from 50 plant to animal species. We also noticed the set of introns within a gene usually share the same splicing codes, thus arguing that one sub-type of splicesosome might process all (or most) of the introns in a given gene. Our work sheds new light on a possible mechanism for generating the tremendous diversity in protein structure by alternative splicing of pre-mRNAs.

Resultados de la utilización de malla única en la reparación laparoscópica transabdominal (TAPP) de hernias inguinales bilaterales directas / Outcomes of laparoscopic transabdominal (TAPP) inguinal hernia repair with single mesh in bilateral direct inguinal hernias

RESUMEN Antecedentes: La cirugía laparoscópica presenta ventajas que son claramente observadas en la reparación de hernias bilaterales y recidivadas. El uso de una malla única como alternativa en la reparación de las inguinales bilaterales laparoscópicas con técnica transabdominal (TAPP) puede reducir el índice de recidivas y las chances de dolor crónico. Objetivo: describir y analizar los beneficios del uso de una malla única en el tratamiento de las hernias inguinales bilaterales con técnica TAPP. Material y métodos: análisis retrospectivo de hernioplastias inguinales laparoscópicas directas o mixtas operadas por vía transabdominal con malla única, efectuadas en pacientes con hernias inguinales bilaterales. Resultados: entre enero de 2016 y enero de 2017 se operaron 177 pacientes con hernia inguinal. Noventa y tres (93) pacientes presentaron hernias bilaterales, de las cuales 39 fueron operadas mediante el uso de la técnica con malla única, incluidas en este estudio. Conclusión: la utilización de una malla única es una alternativa segura en el tratamiento de las hernias inguinales bilaterales directas o mixtas operadas por vía laparoscópica con técnica TAPP.

ABSTRACT Background: The laparoscopic approach has clear advantages for repairing bilateral hernias and recurrent hernias. The use of a single mesh as an option in the laparoscopic treatment of direct bilateral inguinal hernias with the transabdominal preperitoneal (TAPP) technique, may reduce the recurrence rate and chronic pain. Objective: The aim of this study is to analyze the benefits of single mesh for the treatment of bilateral inguinal hernias with the TAPP technique. Material and methods: We conducted a retrospective analysis of patients with bilateral direct inguinal hernias undergoing laparoscopic hernia repair with the TAPP technique using a single mesh. Results: Between January 2016 and January 207 177 patients underwent inguinal hernia repair. Of the 93 patients with bilateral hernias, a single mesh was used in 39, which were included in this study. Conclusion: The use of a single mesh is a safe option for the laparoscopic treatment of direct bilateral inguinal hernias with the TAPP technique.

Condiciones laborales y sus consecuencias en la satisfacción laboral en un hospital de emergencia / Working conditions and their consequences on job satisfaction in an emergency hospital

INTRODUCCIÓN: Las condiciones laborales están dadas por los factores psicosociales del trabajo y estas influyen en la satisfacción laboral. Durante la pandemia de COVID-19 la demanda laboral aumentó y se complejizó. Esto supuso un desafío para la gestión de recursos humanos en salud, debiendo fortalecer los recursos laborales ofrecidos a los trabajadores. OBJETIVO: Conocer los factores psicosociales del trabajo (demandas y recursos) y la asociación con la satisfacción laboral de un hospital de emergencia. MATERIAL Y MÉTODOS: Estudio observacional transversal con una encuesta sobre las demandas y recursos laborales y la satisfacción del trabajo realizado. La población fueron las personas que se desempeñaron en un hospital de emergencia que atendía exclusivamente pacientes con diagnóstico de COVID. Se analizó con estadística descriptiva e inferencial. RESULTADOS: Participaron 151 personas. En la escala de 1 al 4 la satisfacción fue de 3,46. La carga de trabajo fue de 1,24 y el apoyo social de 3,43. Los factores de demanda (conflictos interpersonales (r: -0,21). inequidad (r: -0,48). conflicto de rol (r: -0,28) y carga de trabajo (r: -0,39) se correlacionan de forma negativa y estadísticamente significativa con la satisfacción laboral. Los recursos se relacionan de forma positiva con la satisfacción laboral (apoyo social (r: 0,40); retroalimentación (r: 0,39) y autonomía (r: 0,320). CONCLUSIÓN: Entre los factores de demanda, la carga de trabajo fue la mayormente percibida y el apoyo social y organizativo el recurso más valorado. La satisfacción laboral fue alta y ésta aumentó con el apoyo social, la retroalimentación y la autonomía.

INTRODUCTION: Working conditions are determined by psychosocial factors at work and these influences job satisfaction. In the context of the COVID-19 pandemic working demand increased and became more complex and this supposed a challenge for the management of human resources in healthcare, having to strengthen the working resources offered to workers. OBJECTIVE: To know the psychosocial factors of work (demands and resources) and their consequences on job satisfaction in an emergency hospital. METHODS AND MATERIAL: Cross-sectional study with a self-administered survey on job demands and resources and satisfaction with job done. It was analyzed with descriptive and inferential statistics. RESULTS: 151 people participated. On a scale from 1 to 4. Satisfaction was 3.46. The workload was 1.24 and the social support was 3.43. The demand factors (interpersonal conflicts (r: -0.21). inequity (r: -0.48). role conflict (r: -0.28) and workload (r: -0.39) are negatively correlated and statistically significant with job satisfaction. Resources are positively related to job satisfaction (social support (r: 0.40). feedback (r: 0.39) and autonomy (r: 0.320). CONCLUSION: Among the demand factors workload was the most perceived and social and organizational support the most valued resource. Job satisfaction was high and these increased with social support feedback and autonomy.

Clinical application of a cancer genomic profiling assay to guide precision medicine decisions.

AIM: Develop and apply a comprehensive and accurate next-generation sequencing based assay to help clinicians to match oncology patients to therapies. MATERIALS & METHODS: The performance of the CANCERPLEX® assay was assessed using DNA from well-characterized routine clinical formalin-fixed paraffin-embedded (FFPE) specimens and cell lines. RESULTS: The maximum sensitivity of the assay is 99.5% and its accuracy is virtually 100% for detecting somatic alterations with an allele fraction of as low as 10%. Clinically actionable variants were identified in 93% of patients (930 of 1000) who underwent testing. CONCLUSION: The test's capacity to determine all of the critical genetic changes, tumor mutation burden, microsatellite instability status and viral associations has important ramifications on clinical decision support strategies, including identification of patients who are likely to benefit from immune checkpoint blockage therapies.

Prioritisation of structural variant calls in cancer genomes.

Sensitivity of short read DNA-sequencing for gene fusion detection is improving, but is hampered by the significant amount of noise composed of uninteresting or false positive hits in the data. In this paper we describe a tiered prioritisation approach to extract high impact gene fusion events from existing structural variant calls. Using cell line and patient DNA sequence data we improve the annotation and interpretation of structural variant calls to best highlight likely cancer driving fusions. We also considerably improve on the automated visualisation of the high impact structural variants to highlight the effects of the variants on the resulting transcripts. The resulting framework greatly improves on readily detecting clinically actionable structural variants.

Sequence data and association statistics from 12,940 type 2 diabetes cases and controls.

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.

A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk.

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.

Independent test assessment using the extreme value distribution theory.

The new generation of whole genome sequencing platforms offers great possibilities and challenges for dissecting the genetic basis of complex traits. With a very high number of sequence variants, a naïve multiple hypothesis threshold correction hinders the identification of reliable associations by the overreduction of statistical power. In this report, we examine 2 alternative approaches to improve the statistical power of a whole genome association study to detect reliable genetic associations. The approaches were tested using the Genetic Analysis Workshop 19 (GAW19) whole genome sequencing data. The first tested method estimates the real number of effective independent tests actually being performed in whole genome association project by the use of an extreme value distribution and a set of phenotype simulations. Given the familiar nature of the GAW19 data and the finite number of pedigree founders in the sample, the number of correlations between genotypes is greater than in a set of unrelated samples. Using our procedure, we estimate that the effective number represents only 15 % of the total number of independent tests performed. However, even using this corrected significance threshold, no genome-wide significant association could be detected for systolic and diastolic blood pressure traits. The second approach implements a biological relevance-driven hypothesis tested by exploiting prior computational predictions on the effect of nonsynonymous genetic variants detected in a whole genome sequencing association study. This guided testing approach was able to identify 2 promising single-nucleotide polymorphisms (SNPs), 1 for each trait, targeting biologically relevant genes that could help shed light on the genesis of the human hypertension. The first gene, PFH14, associated with systolic blood pressure, interacts directly with genes involved in calcium-channel formation and the second gene, MAP4, encodes a microtubule-associated protein and had already been detected by previous genome-wide association study experiments conducted in an Asian population. Our results highlight the necessity of the development of alternative approached to improve the efficiency on the detection of reasonable candidate associations in whole genome sequencing studies.

Impacto de la infección por SARS-CoV-2 (COVID-19) en el tratamiento de una lesión duodenal por arma de fuego / Impact of SARS-CoV-2 infection (COVID-19) in the treatment of duodenal gunshot injury

RESUMEN Se presenta el caso clínico de un paciente con traumatismo abdominal por herida de arma de fuego (HAF). En otra institución se realizó cirugía de exclusión pilórica y hepatorrafia por lesión hepatoduo denal. Fue derivado a nuestra institución a las 12 horas posoperatorias. Intercurre en el posoperatorio con neumonía grave por COVID-19 y complicaciones de su cirugía ini cial. La presentación severa de la enfermedad nos inclina por el manejo no operatorio. La utilización de drenajes percutáneos permitió el manejo de colecciones evitando una cirugía mayor inicial. La recuperación pulmonar facilitó la cirugía definitiva. La neumonía severa por COVID-19 en un paciente con lesión duodenal grave por HAF condiciona la toma de decisiones.

ABSTRACT We report the case of a patient with an abdominal gunshot trauma with liver and duodenal injury who underwent pyloric exclusion and liver repair in another institution. The patient was transferred to our institution 12 hours after surgery. During hospitalization, severe pneumonia due to COVID-19 and complications of the initial surgery developed. Non-surgical management was decided due to the severity of the disease. Percutaneous drainage allowed for the management of the collections avoiding a major initial surgery. Once he recovered from the pneumonia, the definite surgery was performed. Severe COVID-19 pneumonia in a patient with serious duodenal shotgun injury is a determining factor for decision-making of treatment options.