Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

Development of a Tool to Guide Parents Carrying a BRCA1/2 Mutation Share Genetic Results with Underage Children.

Although most parents carrying a BRCA1/2 genetic mutation share their test result with their underage children, they report needing support to decide if, when, and how to share risk information and what reactions to expect from their children. We developed a tool to guide parents carrying a BRCA1/2 mutation share their genetic result with underage children. Here, we report on the development of this tool using a qualitative methodology. A tool prototype was developed based on the International Patient Decision Aids Standards Collaboration framework. Content was assessed using feedback from focus groups, individual interviews, and a 12-item reading grid. Participants were nine BRCA1/2 mutation carriers with underage children and three cancer genetics health professionals. Thematic content analysis was conducted on interview transcripts. The tool was developed using an iterative process until saturation of data. An independent advisory committee was involved in all steps of tool development until reaching consensus. Rather than a decision aid per se (to communicate or not), the parents wanted a more comprehensive tool to help them communicate genetic test result to their children. To meet parents' needs, a communication guidance booklet was developed, setting out the pros and cons of communication, steps to prepare sharing the test result, communication tips, and parents' testimonies. This communication tool responds to a significant unmet need faced by parents carrying a genetic predisposition to cancer. Future studies are needed to assess how the information from the parent's genetic test result impacts the child's development, health behaviors, and relationship with the parent.

Platelet-activating factor induces Th17 cell differentiation.

Th17 cells have been implicated in a number of inflammatory and autoimmune diseases. The phospholipid mediator platelet-activating factor (PAF) is found in increased concentrations in inflammatory lesions and has been shown to induce IL-6 production. We investigated whether PAF could affect the development of Th17 cells. Picomolar concentrations of PAF induced IL-23, IL-6, and IL-1ß expression in monocyte-derived Langerhans cells (LCs) and in keratinocytes. Moreover, when LC were pretreated with PAF and then cocultured with anti-CD3- and anti-CD28-activated T cells, the latter developed a Th17 phenotype, with a significant increase in the expression of the transcriptional regulator RORγt and enhanced expression of IL-17, IL-21, and IL-22. PAF-induced Th17 development was prevented by the PAF receptor antagonist WEB2086 and by neutralizing antibodies to IL-23 and IL-6R. This may constitute a previously unknown stimulus for the development and persistence of inflammatory processes that could be amenable to pharmacologic intervention.

Absence of cognitive symptoms in a 6-year-old male with post-traumatic increased intracranial pressure - A case report.

INTRODUCTION: Traumatic Brain Injuries (TBIs) can range from mild to severe, and may result in increased intracranial pressure (ICP). Increased ICP causes hallmark physical signs, such as diaphoresis, emesis, fixed pupils, and altered mental status. Monitoring the patient's score on the Glasgow Coma Scale (GCS) and cranial CT scans are routine measures used in clinical practice to monitor the development of a TBI. PRESENTATION OF THE CASE: A 6-year-old male fell off his father's shoulders and subsequently presented to ED for suspected head trauma. He was transferred to our Level 1 Trauma Center after a head CT scan demonstrated a subdural hematoma. His GCS score remained 15. The next day he began to have episodes of apnea and desaturation. Further imaging indicated expansion of the hematoma with a 5mm midline shift. He remained consistently alert and a neurological exam revealed cranial nerves to be grossly intact. Increased ICP was reduced with several days of hypertonic saline treatment without surgical intervention. DISCUSSION: TBIs can have long-lasting effects in pediatric patients and are typically assessed using both diagnostic imaging and clinical judgment. CT scans are used to assess for hematoma development, while loss of consciousness (LOC) and altered mental status are standard clinical diagnostic indicators of increased ICP. This patient remained alert with a GCS score of 15, although he had clinical signs of increased ICP including apnea and bradycardia with a midline shift confirmed on imaging. CONCLUSION: While GCS is an important prognostic indicator in TBI, patients should still be monitored to assure resolution of all symptoms.

POEMS Syndrome Complicated by Extensive Calciphylaxis: A Remarkable Recovery.

BACKGROUND AND OBJECTIVE: Calciphylaxis is life threatening. It has traditionally been associated with end-stage renal disease and hyperparathyroidism but is increasingly common in other clinical contexts. The association of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome and calciphylaxis has been reported only in a few cases. This case is the first of patient survival in such widespread disease. METHODS AND RESULTS: A 42-year-old man with POEMS syndrome developed extensive calciphylaxis despite normal renal and parathyroid function. Rapid diagnosis, treatment, and supportive care contributed to full clinical resolution. CONCLUSION: This is the fifth case of POEMS syndrome associated with calciphylaxis. The observations from this report suggest that POEMS syndrome might be an independent risk factor for the development of calciphylaxis. This case underlines the importance of careful follow-up in patients with POEMS syndrome and prompt diagnosis and treatment of associated calciphylaxis.

Move to improve: the feasibility of using an early mobility protocol to increase ambulation in the intensive and intermediate care settings.

BACKGROUND: Prolonged bed rest in hospitalized patients leads to deconditioning, impaired mobility, and the potential for longer hospital stays. OBJECTIVE: The purpose of this study was to determine the effectiveness of a nurse-driven mobility protocol to increase the percentage of patients ambulating during the first 72 hours of their hospital stay. DESIGN: A quasi-experimental design was used before and after intervention in a 16-bed adult medical/surgical intensive care unit (ICU) and a 26-bed adult intermediate care unit (IMCU) at a large community hospital. METHOD: A multidisciplinary team developed and implemented a mobility order set with an embedded algorithm to guide nursing assessment of mobility potential. Based on the assessments, the protocol empowers the nurse to consult physical therapists or occupational therapists when appropriate. Daily ambulation status reports were reviewed each morning to determine each patient's activity level. Retrospective and prospective chart reviews were performed to evaluate the effectiveness of the protocol for patients 18 years of age and older who were hospitalized 72 hours or longer. RESULTS: In the 3 months prior to implementation of the Move to Improve project, 6.2% (12 of 193) of the ICU patients and 15.5% (54 of 349) of the IMCU patients ambulated during the first 72 hours of their hospitalization. During the 6 months following implementation, those rates rose to 20.2% (86 of 426) and 71.8% (257 of 358), respectively. LIMITATIONS: The study was carried out at only one center. CONCLUSION: The initial experience with a nurse-driven mobility protocol suggests that the rate of patient ambulation in an adult ICU and IMCU during the first 72 hours of a hospital stay can be increased.