Differential IL-1 signaling induced by BMPR2 deficiency drives pulmonary vascular remodeling.

Bone morphogenetic protein receptor type 2 (BMPR2) mutations are present in patients with heritable and idiopathic pulmonary arterial hypertension (PAH). Circulating levels of interleukin-1 (IL-1) are raised in patients and animal models. Whether interplay between BMP and IL-1 signaling can explain the local manifestation of PAH in the lung remains unclear. Cell culture, siRNA, and mRNA microarray analysis of RNA isolated from human pulmonary artery (PASMC) and aortic (AoSMC) smooth muscle cells were used. R899X+/- BMPR2 transgenic mice fed a Western diet for six weeks were given daily injections of IL-1ß prior to assessment for PAH and tissue collection. PASMC have reduced inflammatory activation in response to IL-1ß compared with AoSMCs; however, PASMC with reduced BMPR2 demonstrated an exaggerated response. Mice treated with IL-1ß had higher white blood cell counts and significantly raised serum protein levels of IL-6 and osteoprotegerin (OPG) plasma levels recapitulating in vitro data. Phenotypically, IL-1ß treated mice demonstrated increased pulmonary vascular remodeling. IL-1ß induces an exaggerated pulmonary artery specific transcriptomic inflammatory response when BMPR2 signaling is reduced

Using Calibrated Peer Review⢠to Assess and Improve the Quality of Student Documentation of Clinical Encounters at the University of New Mexico School of Medicine (UNMSOM).

The UNMSOM adapted Calibrated Peer Review™, an internet based writing tool, to assist medical students in assessing the structure and content of their clinical notes. Students watch videotaped clinical encounters and write notes based on these patient visits. Students then apply faculty-established standards to assess three calibration notes, the notes of three peers, and their own note. CRR will be demonstrated and student satisfaction described

Integrating aphasia into stroke best practices: A Canadian KTE strategy

This poster reports on the activities to date of the Stroke and Aphasia Canada team including results of a Canadian Institutes of Health Research (CIHR) Knowledge Translation (KT) planning grant (grant #290592, 2013)

Informe final del proyecto: Generando valor a partir de datos históricos del programa de mejoramiento genético de arroz de INIA

El Programa de Mejoramiento Genético de Arroz de INIA (PMGA) busca obtener mejores cultivares de arroz para el sector productivo. Para ello genera líneas experimentales y las selecciona en base al comportamiento evaluado en ensayos de campo y laboratorio. La precisión de esta selección depende de la calidad de los ensayos, el número de repeticiones, localidades y años de evaluación, y la magnitud de efectos y variabilidad debida a factores ambientales (año, localidad), y de interacción genotipo por ambiente (respuesta diferencial de las líneas a los ambientes). Cuantificar estas fuentes permitiría encontrar la distribución de recursos que maximice la ganancia genética con menores costos y tiempo. Para ello se requiere el análisis conjunto de ensayos a través de múltiples años y ambientes. Sin embargo, actualmente los ensayos del PMGA son analizados por separado debido a que los datos están fragmentados en una multiplicidad de soportes y formatos que impiden su análisis conjunto. Esta sub-utilización de la información disminuye la precisión de las estimaciones y por ende la ganancia genética y la eficiencia del PMGA. Este proyecto buscó mejorar la eficiencia del PMGA mediante la consolidación de todos los datos generados por el PMGA y el posterior análisis conjunto de toda la información para la selección de líneas experimentales, mejorando la ganancia genética y la estimación de los parámetros genéticos del PMGA. Se encontró una mejora de más del 20% en la precisión de las estimaciones del valor genético de las líneas en evaluación temprana cuando se analiza en forma conjunta la información de múltiples años y ensayos. Se estimó la ganancia del PMGA para rendimiento y resistencia a las principales enfermedades del cultivo, encontrándose una tendencia genética significativa y favorable en las mejores líneas evaluadas por el programa.Agencia Nacional de Investigación e Innovació

Informe final del proyecto: Generando valor a partir de datos históricos del programa de mejoramiento genético de arroz de INIA

El Programa de Mejoramiento Genético de Arroz de INIA (PMGA) busca obtener mejores cultivares de arroz para el sector productivo. Para ello genera líneas experimentales y las selecciona en base al comportamiento evaluado en ensayos de campo y laboratorio. La precisión de esta selección depende de la calidad de los ensayos, el número de repeticiones, localidades y años de evaluación, y la magnitud de efectos y variabilidad debida a factores ambientales (año, localidad), y de interacción genotipo por ambiente (respuesta diferencial de las líneas a los ambientes). Cuantificar estas fuentes permitiría encontrar la distribución de recursos que maximice la ganancia genética con menores costos y tiempo. Para ello se requiere el análisis conjunto de ensayos a través de múltiples años y ambientes. Sin embargo, actualmente los ensayos del PMGA son analizados por separado debido a que los datos están fragmentados en una multiplicidad de soportes y formatos que impiden su análisis conjunto. Esta sub-utilización de la información disminuye la precisión de las estimaciones y por ende la ganancia genética y la eficiencia del PMGA. Este proyecto buscó mejorar la eficiencia del PMGA mediante la consolidación de todos los datos generados por el PMGA y el posterior análisis conjunto de toda la información para la selección de líneas experimentales, mejorando la ganancia genética y la estimación de los parámetros genéticos del PMGA. Se encontró una mejora de más del 20% en la precisión de las estimaciones del valor genético de las líneas en evaluación temprana cuando se analiza en forma conjunta la información de múltiples años y ensayos. Se estimó la ganancia del PMGA para rendimiento y resistencia a las principales enfermedades del cultivo, encontrándose una tendencia genética significativa y favorable en las mejores líneas evaluadas por el programa.Agencia Nacional de Investigación e Innovació

Abstracts from the NIHR INVOLVE Conference 2017

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Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

A General Approach for Haplotype Phasing across the Full Spectrum of Relatedness

Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally 'unrelated' individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570