Citations

AbstractProhormone convertase 2 (PC2) is essential for the biosynthesis of many neuropeptides, including several of them in hippocampus. In mouse brain, lacking an enzymatically active PC2 (PC2‐null) causes accumulation of many neuropeptides in their precursor or intermediate forms. Little is known about how a PC2‐null state may affect the function of the hippocampus. In this study, adult PC2‐null mice and their wildtype (WT) littermates were subjected to three analyses to determine possible changes associated with PC2‐null at physiological, behavioral, and molecular levels, respectively, under normal and stressed conditions. Electrophysiological recordings of hippocampal slices were performed to measure evoked field‐excitatory postsynaptic potentials (EPSP), long‐term potentiation (LTP), and paired‐pulse facilitation (PPF). Morris water maze (MWM) testing was conducted to examine behavioral changes that are indicative of hippocampal integrity. Quantitative mass spectrometry analysis was used to determine changes in the hippocampal proteome in response to a focal cerebral ischemic insult. We found that there were no significant differences in the threshold of evoked EPSPs between PC2‐null and WT animals. However, an increase in LTP in both triggering rate and amplitude was observed in PC2‐null mice, suggesting that PC2 may be involved in regulating synaptic strength. The PPF, on the other hand, showed a decrease in PC2‐null mice, suggesting a presynaptic mechanism. Consistent with changes in LTP, PC2‐null mice displayed decreased latencies in finding the escape platform in the MWM test. Further, after distal focal cerebral ischemia, the hippocampal proteomes incurred changes in both WT and PC2‐null mice, with a prominent change in proteins associated with neurotransmission, exocytosis, and transport processes seen in the PC2‐null but not WT mice. Taken together, our results suggest that PC2 is involved in regulating hippocampal synaptic plasticity, learning, and memory behaviors, as well as the hippocampal response to stresses originating in other regions of the brain.

Abstract Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk. Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined. Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96; 95% confidence interval (CI) = 0.93–0.98; P = 5.2 × 10−4] and α-linolenic acid (ORALA = 0.95; 95% CI = 0.92–0.97; P = 5.4 × 10−5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06; 95% CI = 1.03–1.08; P = 3.3 × 10−5), eicosapentaenoic (OREPA = 1.04; 95% CI = 1.01–1.07; P = 2.5 × 10−3), and docosapentaenoic acids (ORDPA = 1.03; 95% CI = 1.01–1.06; P = 1.2 × 10−2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses. Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk. Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.

AbstractBackgroundThe objective of this meta‐analysis of observational studies was to evaluate the efficacy and safety profiles of febuxostat in treating hyperuricemia among kidney transplant patients.MethodsWe conducted electronic searches in PubMed, Embase, and Cochrane Central Register of Controlled Trials from January 1960 to July 2019 to identify studies that investigated the effects of febuxostat in kidney transplant patients on uric acid as well as safety profiles including estimated glomerular filtration rate (eGFR), hemoglobin level (Hb), white blood cell counts (WBC), liver enzymes, and trough level of tacrolimus.ResultsSeven observational studies with 367 participants were included in this meta‐analysis. Compared with allopurinol, the febuxostat group demonstrated a higher odds of achieving target uric acid levels lower than 6 mg/dL within 12 months (OR = 2.9, P = .004). However, there was no statistical difference in change of uric acid (WMD = −1.0 mg/dL/y, P = .32) and change in allograft eGFR within a year (WMD = 0.01 mL/min/1.73 m2/y, P = .98) between febuxostat and allopurinol. Regarding safety profiles, there were no statistical differences in eGFR, Hb, WBC, liver enzymes (AST, ALT), and trough level of tacrolimus between baseline and at the study end. Only one study reported suspected graft loss among febuxostat group.ConclusionAmong kidney transplant patients, treating hyperuricemia with febuxostat showed a higher odds of reaching the target of serum uric acid < 6 mg/dL compared with allopurinol without causing significant side effects including change in tacrolimus level, liver function, decline in renal graft function, and bone marrow function.

Abstract Background Most articles on hand hygiene report either overall compliance or compliance with specific hand hygiene moments. These moments vary in the level of risk to patients if healthcare workers (HCWs) are noncompliant. We assessed how task type affected HCWs’ hand hygiene compliance. Methods We linked consecutive tasks individual HCWs performed during the Strategies to Reduce Transmission of Antimicrobial Resistant Bacteria in Intensive Care Units (STAR*ICU) study into care sequences and identified task pairs—2 consecutive tasks and the intervening hand hygiene opportunity. We defined tasks as critical and/or contaminating. We determined the odds of critical and contaminating tasks occurring, and the odds of hand hygiene compliance using logistic regression for transition with a random effect adjusting for isolation precautions, glove use, HCW type, and compliance at prior opportunities. Results Healthcare workers were less likely to do hand hygiene before critical tasks than before other tasks (adjusted odds ratio [aOR], 0.97 [95% confidence interval {CI}, .95–.98]) and more likely to do hand hygiene after contaminating tasks than after other tasks (aOR, 1.12 [95% CI, 1.10–1.13]). Nurses were more likely to perform both critical and contaminating tasks, but nurses’ hand hygiene compliance was better than physicians’ (aOR, 0.94 [95% CI, .91–.97]) and other HCWs’ compliance (aOR, 0.87 [95% CI, .87–.94]). Conclusions Healthcare workers were more likely to do hand hygiene after contaminating tasks than before critical tasks, suggesting that habits and a feeling of disgust may influence hand hygiene compliance. This information could be incorporated into interventions to improve hand hygiene practices, particularly before critical tasks and after contaminating tasks.

AbstractBuilding on an initiative to enhance clinical trial participation involving the Society for Neuro-Oncology, the Response Assessment in Neuro-Oncology Working Group, patient advocacy groups, clinical trial cooperative groups, and other partners, we evaluate the impact of eligibility criteria and trial conduct on neuro-oncology clinical trial participation. Clinical trials often carry forward eligibility criteria from prior studies that may be overly restrictive and unnecessary and needlessly limit patient accrual. Inclusion and exclusion criteria should be evaluated based on the goals and design of the study and whether they impact patient safety and/or treatment efficacy. In addition, we evaluate clinical trial conduct as a barrier to accrual and discuss strategies to minimize such barriers for neuro-oncology trials.

Abstract Purpose: With increasing incidence of renal mass, it is important to make a pretreatment differentiation between benign renal mass and malignant tumor. We aimed to develop a deep learning model that distinguishes benign renal tumors from renal cell carcinoma (RCC) by applying a residual convolutional neural network (ResNet) on routine MR imaging. Experimental Design: Preoperative MR images (T2-weighted and T1-postcontrast sequences) of 1,162 renal lesions definitely diagnosed on pathology or imaging in a multicenter cohort were divided into training, validation, and test sets (70:20:10 split). An ensemble model based on ResNet was built combining clinical variables and T1C and T2WI MR images using a bagging classifier to predict renal tumor pathology. Final model performance was compared with expert interpretation and the most optimized radiomics model. Results: Among the 1,162 renal lesions, 655 were malignant and 507 were benign. Compared with a baseline zero rule algorithm, the ensemble deep learning model had a statistically significant higher test accuracy (0.70 vs. 0.56, P = 0.004). Compared with all experts averaged, the ensemble deep learning model had higher test accuracy (0.70 vs. 0.60, P = 0.053), sensitivity (0.92 vs. 0.80, P = 0.017), and specificity (0.41 vs. 0.35, P = 0.450). Compared with the radiomics model, the ensemble deep learning model had higher test accuracy (0.70 vs. 0.62, P = 0.081), sensitivity (0.92 vs. 0.79, P = 0.012), and specificity (0.41 vs. 0.39, P = 0.770). Conclusions: Deep learning can noninvasively distinguish benign renal tumors from RCC using conventional MR imaging in a multi-institutional dataset with good accuracy, sensitivity, and specificity comparable with experts and radiomics.