Perturbational phenotyping of human blood cells reveals genetically determined latent traits associated with subsets of common diseases.

Although genome-wide association studies (GWAS) have successfully linked genetic risk loci to various disorders, identifying underlying cellular biological mechanisms remains challenging due to the complex nature of common diseases. We established a framework using human peripheral blood cells, physical, chemical and pharmacological perturbations, and flow cytometry-based functional readouts to reveal latent cellular processes and performed GWAS based on these evoked traits in up to 2,600 individuals. We identified 119 genomic loci implicating 96 genes associated with these cellular responses and discovered associations between evoked blood phenotypes and subsets of common diseases. We found a population of pro-inflammatory anti-apoptotic neutrophils prevalent in individuals with specific subsets of cardiometabolic disease. Multigenic models based on this trait predicted the risk of developing chronic kidney disease in type 2 diabetes patients. By expanding the phenotypic space for human genetic studies, we could identify variants associated with large effect response differences, stratify patients and efficiently characterize the underlying biology.

MAS-DNP enables NMR studies of insect wings.

NMR is a valuable tool for studying insects. Solid-state NMR has been used to obtain the chemical composition and gain insight into the sclerotization process of exoskeletons. There is typically little difficulty in obtaining sufficient sample quantity for exoskeletons. However, obtaining enough sample of other insect components for solid-state NMR experiments can be problematic while isotopically enriching them is near impossible. This is especially the case for insect wing membranes which is of interest to us. Issues with obtaining sufficient sample are the thickness of wing membranes is on the order of microns, each membrane region is surrounded by veins and occupies a small area, and the membranes are separated from the wing by physical dissection. Accordingly, NMR signal enhancement methods are needed. MAS-DNP has a track record of providing significant signal enhancements for a wide variety of materials. Here we demonstrate that MAS-DNP is useful for providing high quality one-dimensional and two-dimensional solid-state NMR spectra on cicada wing membrane at natural isotopic abundance.

PIEZO1 mediates a mechanothrombotic pathway in diabetes.

Thrombosis is the leading complication of common human disorders including diabetes, coronary heart disease, and infection and remains a global health burden. Current anticoagulant therapies that target the general clotting cascade are associated with unpredictable adverse bleeding effects, because understanding of hemostasis remains incomplete. Here, using perturbational screening of patient peripheral blood samples for latent phenotypes, we identified dysregulation of the major mechanosensory ion channel Piezo1 in multiple blood lineages in patients with type 2 diabetes mellitus (T2DM). Hyperglycemia activated PIEZO1 transcription in mature blood cells and selected high Piezo1­expressing hematopoietic stem cell clones. Elevated Piezo1 activity in platelets, red blood cells, and neutrophils in T2DM triggered discrete prothrombotic cellular responses. Inhibition of Piezo1 protected against thrombosis both in human blood and in zebrafish genetic models, particularly in hyperglycemia. Our findings identify a candidate target to precisely modulate mechanically induced thrombosis in T2DM and a potential screening method to predict patient-specific risk. Ongoing remodeling of cell lineages in hematopoiesis is an integral component of thrombotic risk in T2DM, and related mechanisms may have a broader role in chronic disease.

Eya2 promotes cell cycle progression by regulating DNA damage response during vertebrate limb regeneration.

How salamanders accomplish progenitor cell proliferation while faithfully maintaining genomic integrity and regenerative potential remains elusive. Here we found an innate DNA damage response mechanism that is evident during blastema proliferation (early- to late-bud) and studied its role during tissue regeneration by ablating the function of one of its components, Eyes absent 2. In eya2 mutant axolotls, we found that DNA damage signaling through the H2AX histone variant was deregulated, especially within the proliferating progenitors during limb regeneration. Ultimately, cell cycle progression was impaired at the G1/S and G2/M transitions and regeneration rate was reduced. Similar data were acquired using acute pharmacological inhibition of the Eya2 phosphatase activity and the DNA damage checkpoint kinases Chk1 and Chk2 in wild-type axolotls. Together, our data indicate that highly-regenerative animals employ a robust DNA damage response pathway which involves regulation of H2AX phosphorylation via Eya2 to facilitate proper cell cycle progression upon injury.

The emergency to home project: impact of an emergency department care coordinator on hospital admission and emergency department utilization among seniors.

BACKGROUND: Seniors comprise 14% to 21% of all emergency department (ED) visits, yet are disproportionately larger users of ED and inpatient resources. ED care coordinators (EDCCs) target seniors at risk for functional decline and connect them to home care and other community services in hopes of avoiding hospitalization. The goal of this study was to measure the association between the presence of EDCCs and admission rates for seniors aged ≥ 65. Secondary outcomes included length of stay, recidivism at 30 days, and revisit resulting in admission at 30 days. METHODS: This was a matched pairs study using administrative data from eight EDs in six Alberta cities. Four of these hospitals were intervention sites, in which patients were seen by an EDCC, while the other four sites had no EDCC presence. All seniors aged ≥ 65 with a discharge diagnosis of fall or musculoskeletal pathology were included. Cases were matched by CTAS category, age, gender, mode of arrival, and home living environment. McNemar's test for matched pairs was used to compare admission and recidivism rates at EDCC and non-EDCC hospitals. A paired t-test was used to compare length of stay between groups. RESULTS: There were no statistically significant differences for baseline admission rate, revisit rate at 30 days, and readmission rate at 30 days between EDCC and non-EDCC patients. CONCLUSIONS: This study showed no reduction in senior patients' admission rates, recidivism at 30 days, or hospital length of stay when comparing seniors seen by an EDCC with those not seen by an EDCC.

Tratamiento de los pacientes con fractura de diafisis de tibia con clavo tipo encore en el Hospital Escuela Dr. Roberto Calderón Gutiérrez en el período de enero de 2003 a junio de 2005 / The patients' treatment with diafisis fracture of lukewarm with nail type encore in the Hospital School Dr. Roberto Calderón Gutiérrez in the period of January of 2003 to June of 2005

El siguiente trabajo monográfico se realizó en el servicio de Ortopedia y Traumatología del Hospital Escuela Dr. Roberto Calderón Gutiérrez en el período de enero de 2003 a junio de 2005, donde se recopilaron un total de 32 pacientes que cumplieron con los requisitos adecuados de ingreso al estudio, el cual consistió en tratar las fracturas de tibia con clavo tipo ENCORE, obteniéndose que el grupo etáreo que prevaleció fue entre 20- 30 años de edad con un 62.5 por ciento. Apreciándose que el sexo masculino fue el que predominó, y los pacientes provenían en su mayoría de zona urbana, a su vez dichas fracturas fueron provocadas por lesiones de gran energia como accidentes automovilísticos y caídas. En lo correspondiente a la clasificación de la AO, se obtuvo un predominio del grupo A, donde prevaleió el subgrupo a2, y con mayor afectación del tercio medio. En cuanto a tiempo quirúrgico, se obtuvo un rango adecuado aun sin contar con intensificador de imagen, obteniéndose una estancia intrahospitalria menor de 5 días. En cuanto a la evolución del tratamiento de la fractura, se logró un buen resultado deel rango de movilidad de rodilla y tobillo; y se obtuvo datos de formación de callo óseo en la mayor parte de casos en el primer mes, consolidando en su mayoría a las 16 semanas de intervención, con bajo porcentaje de complicaciones...