Decoding complex inherited phenotypes in rare disorders: the DECIPHERD initiative for rare undiagnosed diseases in Chile.

Rare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the "diagnostic odyssey" for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international collaboration with Baylor College of Medicine, and the local development was structured as a hybrid model, where clinical and bioinformatics analysis were performed in-house and sequencing outsourced abroad, due to lack of high-throughput equipment in Chile. We describe the implementation process and findings of the first 103 patients. They had heterogeneous phenotypes, including congenital anomalies, intellectual disabilities and/or immune system dysfunction. Patients underwent clinical exome or research exome sequencing, as solo cases or with parents using a trio design. We identified pathogenic, likely pathogenic or variants of unknown significance in genes related to the patients´ phenotypes in 47 (45.6%) of them. Half were de novo informative variants, and half of the identified variants have not been previously reported in public databases. DECIPHERD ended the diagnostic odyssey for many participants. This hybrid strategy may be useful for settings of similarly limited genomic resources and lead to discoveries in understudied populations.

Homology-based reconstruction of regulatory networks for bacterial and archaeal genomes.

Gene regulation is a key process for all microorganisms, as it allows them to adapt to different environmental stimuli. However, despite the relevance of gene expression control, for only a handful of organisms is there related information about genome regulation. In this work, we inferred the gene regulatory networks (GRNs) of bacterial and archaeal genomes by comparisons with six organisms with well-known regulatory interactions. The references we used are: Escherichia coli K-12 MG1655, Bacillus subtilis 168, Mycobacterium tuberculosis, Pseudomonas aeruginosa PAO1, Salmonella enterica subsp. enterica serovar typhimurium LT2, and Staphylococcus aureus N315. To this end, the inferences were achieved in two steps. First, the six model organisms were contrasted in an all-vs-all comparison of known interactions based on Transcription Factor (TF)-Target Gene (TG) orthology relationships and Transcription Unit (TU) assignments. In the second step, we used a guilt-by-association approach to infer the GRNs for 12,230 bacterial and 649 archaeal genomes based on TF-TG orthology relationships of the six bacterial models determined in the first step. Finally, we discuss examples to show the most relevant results obtained from these inferences. A web server with all the predicted GRNs is available at https://regulatorynetworks.unam.mx/ or http://132.247.46.6/.

La artroplastía total bilateral de rodilla en un acto anestésico. Un procedimiento seguro, comparable a la artroplastía de rodilla unilateral / Bilateral total knee arthroplasty is a safe procedure compared to unilateral total knee arthroplasty

Introducción: El objetivo de este trabajo es comparar los resultados clínicos y complicaciones de la artroplastia total de rodilla bilateral (ATRB) con los de la artroplastia total de rodilla unilateral (ATRU).Materiales y métodos: estudio caso control. Se analizaron quince pacientes (treinta rodillas) con ATRB y ciento dos con ATRU, operados entre marzo del 2016 a agosto del 2018 por un mismo equipo quirúrgico, centro y modelo de prótesis. Se excluyeron artroplastias con componentes constreñidos. Se analizaron los datos demográficos, estadía hospitalaria (EH), caída del hematocrito, necesidad de transfusión sanguínea, días con drenaje, complicaciones postoperatorias, mortalidad, tiempo de isquemia y rango de movilidad (ROM). Se utilizó la encuesta KOOS Jr. para medir resultados funcionales y otra para valorar satisfacción. El análisis estadístico se realizó con t de Student, prueba exacta de Fisher y modelos mixtos (p <0.05).Resultados: ambos grupos fueron comparables en edad, IMC, tabaquismo, riesgo anestésico según la Sociedad Americana de Anestesiología (ASA), depresión y hematocrito. El grupo ATRB presentó una EH, días de drenaje, descenso del hematocrito postoperatorio y necesidad de transfusiones significativamente mayor. No hubo diferencias significativas en cuanto a tiempo de isquemia, complicaciones postoperatorias, mortalidad y en el ROM logrado a corto y mediano plazo. Se observó una tendencia a lograr antes el ROM objetivo (0-120°) en las ATRB. No hubo diferencias significativas en los resultados funcionales ni en satisfacción. Conclusión: en nuestro centro y en pacientes seleccionados, la ATRB es un procedimiento seguro sin una mayor tasa de complicaciones ni mortalidad asociada, con resultados clínicos similares a la ATRU. Nivel de Evidencia: III

Introduction: The aim of this study is to compares the clinical results and complications of bilateral total knee arthroplasty (BTKA) with unilateral total knee arthroplasty (UTKA).Materials and methods: case control study. Fifteen patients (thirty knees) with BTKA and hundred two patients with UTKA were analyzed, operated from March 2016 to August 2018 by the same surgical team, center and prosthetic model. Arthroplasties with constrained components were excluded. Demographic data, length of hospital stay (LOS), hematocrit drop, need for blood transfusion, days with drainage, post-operative complications, mortality, tourniquet time and range of motion (ROM) were analyzed. KOOS Jr. survey was answered, and satisfaction was reported. Statistical analysis was performed with t-Student, Fisher's test and mixed models (p <0.05).Results: the groups were comparable (age, BMI, smoking, anesthetic risk according to the classification system of the American Society of Anesthesiology (ASA), depression, hematocrit). The BTKA group presented LOS, drainage days, decrease in post operative hematocrit and need for transfusions significantly higher. There were no significant differences in terms of tourniquet time, post-operative complications, mortality and ROM achieved at short term. There is a tendency to achieve the target ROM (0-120 °) earlier on the BTKA group. There were no significant differences in functional results or satisfaction.Conclusion: In our center and in selected patients, the BTKA is a safe procedure without a higher rate of complications or associated mortality, with clinical results similar to the UTKA. Level of Evidence: III