Plastic pollution is a pervasive and growing problem. To estimate the effectiveness of interventions to reduce plastic pollution, we modeled stocks and flows of municipal solid waste and four sources ...of microplastics through the global plastic system for five scenarios between 2016 and 2040. Implementing all feasible interventions reduced plastic pollution by 40% from 2016 rates and 78% relative to "business as usual" in 2040. Even with immediate and concerted action, 710 million metric tons of plastic waste cumulatively entered aquatic and terrestrial ecosystems. To avoid a massive build-up of plastic in the environment, coordinated global action is urgently needed to reduce plastic consumption; increase rates of reuse, waste collection, and recycling; expand safe disposal systems; and accelerate innovation in the plastic value chain.
This book presents applied probability and stochastic processes in an elementary but mathematically precise manner, with numerous examples and exercises to illustrate the range of engineering and ...science applications of the concepts. The book is designed to give the reader an intuitive understanding of probabilistic reasoning, in addition to an understanding of mathematical concepts and principles. The initial chapters present a summary of probability and statistics and then Poisson processes, Markov chains, Markov processes and queuing processes are introduced. Advanced topics include simulation, inventory theory, replacement theory, Markov decision theory, and the use of matrix geometric procedures in the analysis of queues. Included in the second edition are appendices at the end of several chapters giving suggestions for the use of Excel in solving the problems of the chapter. Also new in this edition are an introductory chapter on statistics and a chapter on Poisson processes that includes some techniques used in risk assessment. The old chapter on queues has been expanded and broken into two new chapters: one for simple queuing processes and one for queuing networks. Support is provided through the web site http://apsp.tamu.edu where students will have the answers to odd numbered problems and instructors will have access to full solutions and Excel files for homework. TOC:Basic Probability Review.- Basic of Monte Carlo Simulation.- Basic Statistical Review.- Poisson Processes.- Markov Chains.- Markov Processes.- Queueing Processes.- Queueing Networks.- Event-Driven Simulation and Output Analyses.- Inventory Theory.- Replacement Theory.- Markov Decision Processes.- Advanced Queues.- Matrix Review.- Index.
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FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from the rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) ...dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in the midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in the VTA. By reducing H3Q5dop in the VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in the VTA.
Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib-rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and ...describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio HR, 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-sample Mendelian randomization (2SMR) and bypassing the ...need for individual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base (<ext-link ext-link-type="uri" xlink:href="http://www.mrbase.org">http://www.mrbase.org</ext-link>): a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR. The software includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions. The database currently comprises 11 billion single nucleotide polymorphism-trait associations from 1673 GWAS and is updated on a regular basis. Integrating data with software ensures more rigorous application of hypothesis-driven analyses and allows millions of potential causal relationships to be efficiently evaluated in phenome-wide association studies.
Abstract
Background
Evidence concerning the potential repurposing of antihypertensives for Alzheimer’s disease prevention is inconclusive. We used Mendelian randomization, which can be more robust to ...confounding by indication and patient characteristics, to investigate the effects of lowering systolic blood pressure, via the protein targets of different antihypertensive drug classes, on Alzheimer’s disease.
Methods
We used summary statistics from genome-wide association studies of systolic blood pressure and Alzheimer’s disease in a two-sample Mendelian randomization analysis. We identified single-nucleotide polymorphisms (SNPs) that mimic the action of antihypertensive protein targets and estimated the effect of lowering systolic blood pressure on Alzheimer’s disease in three ways: (i) combining the protein targets of antihypertensive drug classes, (ii) combining all protein targets and (iii) without consideration of the protein targets.
Results
There was limited evidence that lowering systolic blood pressure, via the protein targets of antihypertensive drug classes, affected Alzheimer’s disease risk. For example, the protein targets of calcium channel blockers had an odds ratio (OR) per 10 mmHg lower systolic blood pressure of 1.53 95% confidence interval (CI): 0.94 to 2.49; p = 0.09; SNPs = 17. We also found limited evidence for an effect when combining all protein targets (OR per 10 mmHg lower systolic blood pressure: 1.14; 95% CI: 0.83 to 1.56; p = 0.41; SNPs = 59) and without consideration of the protein targets (OR per 10 mmHg lower systolic blood pressure: 1.04; 95% CI: 0.95 to 1.13; p = 0.45; SNPs = 153).
Conclusions
Mendelian randomization suggests that lowering systolic blood pressure via the protein targets of antihypertensive drugs is unlikely to affect the risk of developing Alzheimer’s disease. Consequently, if specific antihypertensive drug classes do affect the risk of Alzheimer’s disease, they may not do so via systolic blood pressure.
Adaptive sampling is a method of software-controlled enrichment unique to nanopore sequencing platforms. To test its potential for enrichment of rarer species within metagenomic samples, we create a ...synthetic mock community and construct sequencing libraries with a range of mean read lengths. Enrichment is up to 13.87-fold for the least abundant species in the longest read length library; factoring in reduced yields from rejecting molecules the calculated efficiency raises this to 4.93-fold. Finally, we introduce a mathematical model of enrichment based on molecule length and relative abundance, whose predictions correlate strongly with mock and complex real-world microbial communities.
Physical exercise is an important component in the management of type 1 diabetes across the lifespan. Yet, acute exercise increases the risk of dysglycaemia, and the direction of glycaemic excursions ...depends, to some extent, on the intensity and duration of the type of exercise. Understandably, fear of hypoglycaemia is one of the strongest barriers to incorporating exercise into daily life. Risk of hypoglycaemia during and after exercise can be lowered when insulin-dose adjustments are made and/or additional carbohydrates are consumed. Glycaemic management during exercise has been made easier with continuous glucose monitoring (CGM) and intermittently scanned continuous glucose monitoring (isCGM) systems; however, because of the complexity of CGM and isCGM systems, both individuals with type 1 diabetes and their healthcare professionals may struggle with the interpretation of given information to maximise the technological potential for effective use around exercise (i.e. before, during and after). This position statement highlights the recent advancements in CGM and isCGM technology, with a focus on the evidence base for their efficacy to sense glucose around exercise and adaptations in the use of these emerging tools, and updates the guidance for exercise in adults, children and adolescents with type 1 diabetes.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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