Citations

Alzheimer’s disease (AD) is an age-associated neurodegenerative disease characterized by amyloidosis, tauopathy, and activation of microglia, the brain resident innate immune cells. We show that a RiboTag translational profiling approach can bypass biases due to cellular enrichment/cell sorting. Using this approach in models of amyloidosis, tauopathy, and aging, we revealed a common set of alterations and identified a central APOE-driven network that converged on CCL3 and CCL4 across all conditions. Notably, aged females demonstrated a significant exacerbation of many of these shared transcripts in this APOE network, revealing a potential mechanism for increased AD susceptibility in females. This study has broad implications for microglial transcriptomic approaches and provides new insights into microglial pathways associated with different pathological aspects of aging and AD.

AbstractWe aimed to validate the prognostic association of p16 expression in ovarian high‐grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical‐grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis‐associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47–2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30–2.75, p = 0.004), while absence was associated with shorter OS in low‐grade serous carcinomas (HR: 2.95, 95% CI 1.61–5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype‐specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low‐grade serous carcinoma justifies CDK4 inhibition.

Objectives: To evaluate the epidemiology of hyperammonemia unrelated to liver failure in the critical care setting. Design: Retrospective case series. Setting: Critically ill patients admitted to ICUs at Mayo Clinic, Rochester, MN (medical ICU, two mixed medical-surgical ICUs, coronary care unit, or the cardiosurgical ICU) between July 1, 2004, and October 31, 2015. Patients: Adult critically ill patients with hyperammonemia not related to acute or chronic liver failure. We excluded patients with diagnosis of moderate or severe liver disease, hyperbilirubinemia, and patients who denied the use of their medical records. Interventions: None. Measurements and Main Results: Of 3,908 ICU patients with hyperammonemia, 167 (4.5%) had no evidence of acute or chronic liver failure. One-hundred one patients (60.5%) were male with median age of 65.7 years (interquartile range, 50–74.5 yr) and median serum ammonia level of 68 µg/dL (interquartile range, 58–87 µg/dL). Acute encephalopathy was present in 119 patients (71%). Predisposing conditions included malnutrition 27 (16%), gastric bypass six (3.6%), total parenteral nutrition four (2.4%); exposure to valproic acid 17 (10%); status epilepticus 11 (6.6%), high tumour burden 19 (11.3%), and renal failure 82 (49.1%). Urea cycle defects were diagnosed in seven patients (4.1%). Hospital mortality was high (30%), and median ammonia level was higher among the nonsurvivors (74 vs 67 µg/dL; p = 0.05). Deaths were more likely in hyperammonemic patients who were older (p = 0.016), had greater illness severity (higher Acute Physiology and Chronic Health Evaluation III score, p < 0.01), malignancy (p < 0.01), and solid organ transplantation (p = 0.04), whereas seizure disorder was more common in survivors (p = 0.02). After adjustment, serum ammonia level was not associated with increased mortality. Conclusions: Hyperammonemia occurs in a substantial minority of critically ill patients without liver failure. These patients have a poor prognosis, although ammonia level per se is not independently associated with mortality. Serum ammonia should be measured when risk factors are present, such as nutritional deficiencies and protein refeeding, treatment with valproic acid, high tumour burden, and known or suspected urea cycle abnormalities.

Evidence of prior autoerotic asphyxia is often difficult to establish due to the decedent's efforts to hide the activity from others. In this case report, we suggest that a healed fracture of the thyroid cartilage is indicative of prior autoerotic asphyxia activity. The decedent was a 45-year-old man who was found unclothed on the floor of his bedroom with a belt ligature around the neck. A second rope ligature was loosely wrapped around the decedent's wrists, scrotum, and penis. A definitive escape mechanism was not identified, but a nearby towel and barbell weight may have comprised a possible escape mechanism. There was no known history of depression or prior autoerotic activity. Autopsy was notable for the presence of a healed fracture of the right superior horn of the thyroid cartilage. Three-dimensional (3D) surface scanning and 3D printing was utilized to preserve the anatomical findings prior to histologic sampling. To our knowledge, this is the first reported use of 3D surface scanning and 3D printing for the purpose of documenting a forensic finding prior to alteration of the anatomical specimen for histologic sampling. Acute fractures of the superior horns of the thyroid cartilage are not infrequently seen in ligature hanging. Therefore, the presence of a healed fracture in the setting of autoerotic asphyxia likely indicates prior activity. Histologic sampling of the laryngeal cartilages to detect occult healed fractures in autoerotic asphyxia may be useful. Three-dimensional scanning and printing may alleviate concerns for specimen alteration due to histology sampling.

Background Type 1 diabetes (T1D) care requires multiple daily self-management behaviors (SMBs). Preliminary studies on SMBs rely mainly on self-reported survey and interview data. There is little information on adult T1D SMBs, along with corresponding compensation techniques (CTs), gathered in real-time. Objective The article aims to use a patient-centered approach to design iDECIDE, a smartphone application that gathers daily diabetes SMBs and CTs related to meal and alcohol intake and exercise in real-time, and contrast patients' actual behaviors against those self-reported with the app. Methods Two usability studies were used to improve iDECIDE's functionality. These were followed by a 30-day pilot test of the redesigned app. A survey designed to capture diabetes SMBs and CTs was administered prior to the 30-day pilot test. Survey results were compared against iDECIDE logs. Results Usability studies revealed that participants desired advanced features for self-tracking meals and alcohol intake. Thirteen participants recorded over 1,200 CTs for carbohydrates during the 30-day study. Participants also recorded 76 alcohol and 166 exercise CTs. Comparisons of survey responses and iDECIDE logs showed mean% (standard deviation) concordance of 77% (25) for SMBs related to meals, where concordance of 100% indicates a perfect match. There was low concordance of 35% (35) and 46% (41) for alcohol and exercise events, respectively. Conclusion The high variability found in SMBs and CTs highlights the need for real-time diabetes self-tracking mechanisms to better understand SMBs and CTs. Future work will use the developed app to collect SMBs and CTs and identify patient-specific diabetes adherence barriers that could be addressed with individualized education interventions.

Purpose To evaluate the validity of scores from three instruments measuring achievement goal motivation-related constructs: a shortened version of Dweck’s Implicit Theories of Intelligence Scale (ITIS-S), measuring incremental and entity mindsets; Elliot’s Achievement Goal Questionnaire–Revised (AGQ-R), measuring mastery-approach, mastery-avoidance, performance-approach, and performance-avoidance achievement goals; and Midgley’s Patterns of Adaptive Learning Scales (PALS), measuring mastery, performance-approach, and performance-avoidance achievement goals. Method High school students participating in a medical simulation training activity in May 2017 completed each instrument. The authors evaluated internal structure using reliability and factor analysis and relations with other variables using the multitrait–multimethod matrix. Results There were 178 participants. Internal consistency reliability (Cronbach alpha) was > 0.70 for all subscores. Confirmatory factor analysis of ITIS-S scores demonstrated good model fit. Confirmatory factor analysis of AGQ-R scores demonstrated borderline fit; exploratory factor analysis suggested a three-domain model (approach, mastery-avoidance, performance-avoidance). Confirmatory factor analysis of PALS scores also demonstrated borderline fit; exploratory factor analyses suggested consistent distinction between mastery and performance goals but inconsistent distinction between performance-approach and performance-avoidance goals. Correlations among AGQ-R and PALS scores were large for mastery ( r = 0.72) and moderate for performance (≥ 0.45) domains; correlations among incremental and mastery scores were moderate (≥ 0.34). Contrary to expectations, correlations between entity and performance scores were negligible. Correlations between conceptually unrelated domains were small or negligible. Conclusions All instrument scores had good internal consistency and generally appropriate relations with other variables, but empirically determined domain structures did not consistently match theory.