Machine Learning to Quantitate Neutrophil NETosis

We introduce machine learning (ML) to perform classifcation and quantitation of images of nuclei from human blood neutrophils. Here we assessed the use of convolutional neural networks (CNNs) using free, open source software to accurately quantitate neutrophil NETosis, a recently discovered process involved in multiple human diseases. CNNs achieved \u3e94% in performance accuracy in diferentiating NETotic from non-NETotic cells and vastly facilitated dose-response analysis and screening of the NETotic response in neutrophils from patients. Using only features learned from nuclear morphology, CNNs can distinguish between NETosis and necrosis and between distinct NETosis signaling pathways, making them a precise tool for NETosis detection. Furthermore, by using CNNs and tools to determine object dispersion, we uncovered diferences in NETotic nuclei clustering between major NETosis pathways that is useful in understanding NETosis signaling events. Our study also shows that neutrophils from patients with sickle cell disease were unresponsive to one of two major NETosis pathways. Thus, we demonstrate the design, performance, and implementation of ML tools for rapid quantitative and qualitative cell analysis in basic science

Mapping adipose and muscle tissue expression quantitative trait loci in African Americans to identify genes for type 2 diabetes and obesity

Relative to European Americans, type 2 diabetes (T2D) is more prevalent in African Americans (AAs). Genetic variation may modulate transcript abundance in insulin-responsive tissues and contribute to risk; yet published studies identifying expression quantitative trait loci (eQTLs) in African ancestry populations are restricted to blood cells. This study aims to develop a map of genetically regulated transcripts expressed in tissues important for glucose homeostasis in AAs, critical for identifying the genetic etiology of T2D and related traits. Quantitative measures of adipose and muscle gene expression, and genotypic data were integrated in 260 non-diabetic AAs to identify expression regulatory variants. Their roles in genetic susceptibility to T2D, and related metabolic phenotypes were evaluated by mining GWAS datasets. eQTL analysis identified 1,971 and 2,078 cis-eGenes in adipose and muscle, respectively. Cis-eQTLs for 885 transcripts including top cis-eGenes CHURC1, USMG5, and ERAP2, were identified in both tissues. 62.1% of top cis-eSNPs were within ±50kb of transcription start sites and cis-eGenes were enriched for mitochondrial transcripts. Mining GWAS databases revealed association of cis-eSNPs for more than 50 genes with T2D (e.g. PIK3C2A, RBMS1, UFSP1), gluco-metabolic phenotypes, (e.g. INPP5E, SNX17, ERAP2, FN3KRP), and obesity (e.g. POMC, CPEB4). Integration of GWAS meta-analysis data from AA cohorts revealed the most significant association for cis-eSNPs of ATP5SL and MCCC1 genes, with T2D and BMI, respectively. This study developed the first comprehensive map of adipose and muscle tissue eQTLs in AAs (publically accessible at https://mdsetaa.phs.wakehealth.edu) and identified genetically-regulated transcripts for delineating genetic causes of T2D, and related metabolic phenotypes

Pimavanserin for the Treatment of Parkinson\u27s Disease Psychosis: Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed

OBJECTIVE: Our aim was to describe the efficacy and tolerability of pimavanserin, a highly selective serotonin 5-HT2A receptor inverse agonist/antagonist indicated for the treatment of hallucinations and delusions associated with Parkinson\u27s disease psychosis (PDP), using the metrics of number needed to treat (NNT) and number needed to harm (NNH). METHODS: Categorical efficacy and tolerability data were extracted from the clinical trial databases of the double-blind placebo-controlled studies of pimavanserin in persons with PDP. NNT and NNH values were calculated with their respective 95% confidence intervals. The likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response versus discontinuation because of an adverse event. RESULTS: NNT values for pimavanserin 34 mg/d versus placebo for several definitions of clinical response are 10, and/or are not statistically significant, and/or show an advantage for pimavanserin over placebo (such as for postural hypotension). In terms of LHH, pimavanserin 34 mg/d is about five times more likely to result in clinical response (as measured by a greater than/=3 point decrease from baseline on the Scale for the Assessment of Positive Symptoms adapted for Parkinson\u27s disease) versus discontinuation due to an adverse event. CONCLUSIONS: Using the metrics of NNT, NNH, and LHH, pimavanserin 34 mg/d for the treatment of PDP appears to have a compelling benefit/risk profile

Effects of a renal rehabilitation exercise program in patients with CKD: a randomized, controlled trial.

BACKGROUND AND OBJECTIVES: Patients with CKD have a high prevalence of cardiovascular disease associated with or exacerbated by inactivity. This randomized, controlled study investigated whether a renal rehabilitation exercise program for patients with stages 3 or 4 CKD would improve their physical function and quality of life. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 119 adults with CKD stages 3 and 4 were randomized, and 107 of these patients proceeded to usual care or the renal rehabilitation exercise intervention consisting of usual care plus guided exercise two times per week for 12 weeks (24 sessions). Physical function was determined by three well established performance-based tests: 6-minute walk test, sit-to-stand test, and gait-speed test. Health-related quality of life was assessed by the RAND 36-Item Short Form Health Survey. RESULTS: At baseline, no differences in self-reported level of activity, 6-minute walk test, and sit-to-stand test scores were observed between the usual care (n=48) and renal rehabilitation exercise (n=59) groups, although baseline gait-speed test score was higher in the renal rehabilitation exercise group (P CONCLUSIONS: A 12-week/24-session renal rehabilitation exercise program improved physical capacity and quality of life in patients with CKD stages 3 and 4. Longer follow-up is needed to determine if these findings will translate into decreased mortality rates

The EBR-II skull reclamation process.

Includes bibliography references : p. 27.Mode of access: Internet

Lidar Temperature Measurements During the SOLVE Campaign and the Absence of PSCs from Regions of Very Cold Air

NASA Goddard Space Flight Center's Airborne Raman Ozone, Temperature and Aerosol Lidar (AROTEL) measured extremely cold temperatures during all three deployments (December 1-16, 1999, January 14-29, 2000 and February 27-March 15, 2000) of the Sage III Ozone Loss and Validation Experiment (SOLVE). Temperatures were significantly below values observed in previous years with large regions regularly below 191 K and frequent temperature retrievals yielding values at or below 187 K. Temperatures well below the saturation point of type I polar stratospheric clouds (PSCs) were regularly encountered but their presence was not well correlated with PSCs observed by the NASA Langley Research Center's Aerosol Lidar co-located with AROTEL. Temperature measurements by meteorological sondes launched within areas traversed by the DC-8 showed minimum temperatures consistent in time and vertical extent with those derived from AROTEL data. Calculations to establish whether PSCs could exist at measured AROTEL temperatures and observed mixing ratios of nitric acid and water vapor showed large regions favorable to PSC formation. On several occasions measured AROTEL temperatures up to 10 K below the NAT saturation temperature were insufficient to produce PSCs even though measured values of nitric acid and water were sufficient for their formation

An Assessment of the Ozone Loss During the 1999-2000 SOLVE Arctic Campaign

Ozone observations from ozonesondes, the lidars aboard the DC-8, in situ ozone measurements from the ER-2, and satellite ozone measurements from Polar Ozone and Aerosol Measurement III (POAM) were used to assess ozone loss during the Sage III Ozone Loss and Validation Experiment (SOLVE) 1999-2000 Arctic campaign. Two methods of analysis were used. In the first method a simple regression analysis is performed on the ozonesonde and POAM measurements within the vortex. In the second method, the ozone measurements from all available ozone data were injected into a free running diabatic trajectory model and carried forward in time from December 1 to March 15. Vortex ozone loss was then estimated by comparing the ozone values of those parcels initiated early in the campaign with those parcels injected later in the campaign. Despite the variety of observational techniques used during SOLVE, the measurements provide a fairly consistent picture. Over the whole vortex, the largest ozone loss occurs between 550 and 400 K potential temperatures (approximately 23-16 km) with over 1.5 ppmv lost by March 15, the end of the SOLVE mission period. An ozone loss rate of 0.04-0.05 ppmv/day was computed for March 15. Ozonesondes launched after March 15 suggest that an additional 0.5 ppmv or more ozone was lost between March 15 and April 1. The small disagreement between ozonesonde and POAM analysis of January ozone loss is found to be due to biases in vortex sampling. POAM makes most of its solar occultation measurements at the vortex edge during January 2000 which bias samples toward air parcels that have been exposed to sunlight and likely do experience ozone loss. Ozonesonde measurements and the trajectory technique use observations that are more distributed within the interior of the vortex. Thus the regression analysis of the POAM measurements tends to overestimate mid-winter vortex ozone loss. Finally, our loss calculations are broadly consistent with other loss computations using ER-2 tracer data and MLS satellite data, but we find no evidence for the 1992 high mid-January loss reported using the Match technique