Characteristics and Outcomes of Serious Traumatic Injury in Older Adults

Objectives: The aims were to: 1) describe the seriously injured older adult; 2) characterize and compare the differences in injury characteristics and outcomes in three subgroups of seriously injured older adults: 65-74 years, 75-84 years, and \u3e85 years of age; 3) identify risk factors for death, complications, and discharge placement at hospital discharge. Design: A retrospective secondary analysis of a statewide trauma data set from 1988-1997. Setting: Data submitted from all designated trauma centers in Pennsylvania. Participants: The data set yielded 38,707 patients with a mean age of 77.5 years with serious injury (mean number of injuries = 3.6, mean number of body systems involved = 2). Measurements: Key outcomes were mortality, complications, and discharge placement. Abbreviated Injury Score categorized injuries and Injury Severity Score (ISS) quantified anatomic severity of injury. Results: Mortality was 10%. Mean length of stay 11.5 days. 52.2% of survivors were discharged home and 25.4% to a skilled nursing facility. Injury severity, total number of injuries, complications and increasing age were predictors of mortality (p\u3c.01). The presence of pre-existing co-morbid medical conditions increased the odds of experiencing a complication over three-fold. Increasing age, total number of injuries, injury to extremities or abdominal contents, injuries due to falls, and lower functional level predicted discharge to a skilled nursing facility (p\u3c.01). Conclusions: Traumatic injury in older adults are typically multisystem, life-threatening, and affects older adults of all ages. The standard ISS does not fully capture the potential for mortality in older adults and does not predict discharge placement. The majority of older adults survive multisystem injury. Our findings indicate the need to examine outcomes beyond mortality and to make the identification and management of co-morbid conditions a priority. A geriatric consultation service could be an important additional to the interdisciplinary trauma team

American Telemedicine Association’s Principles for Delivering Telerehabilitation Services

Telehealth is a broad term used to describe the use of electronic or digital information and communications technologies to support clinical healthcare, patient and professional health related education, and public health and health administration. Telerehabilitation refers to the delivery of rehabilitation and habilitation services via information and communication technologies (ICT), also commonly referred to as” telehealth” technologies. Telerehabilitation services can include evaluation, assessment, monitoring, prevention, intervention, supervision, education, consultation, and coaching. Telerehabilitation services can be deployed across all patient populations and multiple healthcare settings including clinics, homes, schools, or community-based worksites. This document was adapted from the American Telemedicine Association’s (ATA) “A Blueprint for Telerehabilitation Guidelines” (2010) and reflects the current utilization of telerehabilitation services. It was developed collaboratively by members of the ATA Telerehabilitation Special Interest Group, with input and guidance from other practitioners in the field, strategic stakeholders, and ATA staff. Its purpose is to inform and assist practitioners in providing effective and secure services that are based on client needs, current empirical evidence, and available technologies. Rehabilitation professionals, in conjunction with professional associations and other organizations are encouraged to use this document as a resource for developing discipline-specific standards, guidelines, and practice requirements.Keywords: American Telemedicine Association, Habilitation, Rehabilitation, Telehealth, Telepractice

Routine Multiplex Mutational Profiling of Melanomas Enables Enrollment in Genotype-Driven Therapeutic Trials

Purpose: Knowledge of tumor mutation status is becoming increasingly important for the treatment of cancer, as mutation-specific inhibitors are being developed for clinical use that target only sub-populations of patients with particular tumor genotypes. Melanoma provides a recent example of this paradigm. We report here development, validation, and implementation of an assay designed to simultaneously detect 43 common somatic point mutations in 6 genes (BRAF, NRAS, KIT, GNAQ, GNA11, and CTNNB1) potentially relevant to existing and emerging targeted therapies specifically in melanoma. Methods: The test utilizes the SNaPshot method (multiplex PCR, multiplex primer extension, and capillary electrophoresis) and can be performed rapidly with high sensitivity (requiring 5–10% mutant allele frequency) and minimal amounts of DNA (10–20 nanograms). The assay was validated using cell lines, fresh-frozen tissue, and formalin-fixed paraffin embedded tissue. Clinical characteristics and the impact on clinical trial enrollment were then assessed for the first 150 melanoma patients whose tumors were genotyped in the Vanderbilt molecular diagnostics lab. Results: Directing this test to a single disease, 90 of 150 (60%) melanomas from sites throughout the body harbored a mutation tested, including 57, 23, 6, 3, and 2 mutations in BRAF, NRAS, GNAQ, KIT, and CTNNB1, respectively. Among BRAF V600 mutations, 79%, 12%, 5%, and 4% were V600E, V600K, V600R, and V600M, respectively. 23 of 54 (43%) patients with mutation harboring metastatic disease were subsequently enrolled in genotype-driven trials. Conclusion: We present development of a simple mutational profiling screen for clinically relevant mutations in melanoma. Adoption of this genetically-informed approach to the treatment of melanoma has already had an impact on clinical trial enrollment and prioritization of therapy for patients with the disease

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

IQGAP1 is a novel CXCR2-interacting protein and essential component of the "chemosynapse".

Chemotaxis is essential for a number of physiological processes including leukocyte recruitment. Chemokines initiate intracellular signaling pathways necessary for chemotaxis through binding seven transmembrane G protein-couple receptors. Little is known about the proteins that interact with the intracellular domains of chemokine receptors to initiate cellular signaling upon ligand binding. CXCR2 is a major chemokine receptor expressed on several cell types, including endothelial cells and neutrophils. We hypothesize that multiple proteins interact with the intracellular domains of CXCR2 upon ligand stimulation and these interactions comprise a "chemosynapse", and play important roles in transducing CXCR2 mediated signaling processes.In an effort to define the complex of proteins that assemble upon CXCR2 activation to relay signals from activated chemokine receptors, a proteomics approach was employed to identify proteins that co-associate with CXCR2 with or without ligand stimulation. The components of the CXCR2 "chemosynapse" are involved in processes ranging from intracellular trafficking to cytoskeletal modification. IQ motif containing GTPase activating protein 1 (IQGAP1) was among the novel proteins identified to interact directly with CXCR2. Herein, we demonstrate that CXCR2 co-localizes with IQGAP1 at the leading edge of polarized human neutrophils and CXCR2 expressing differentiated HL-60 cells. Moreover, amino acids 1-160 of IQGAP1 directly interact with the carboxyl-terminal domain of CXCR2 and stimulation with CXCL8 enhances IQGAP1 association with Cdc42.Our studies indicate that IQGAP1 is a novel essential component of the CXCR2 "chemosynapse"