Milk pasteurization: efficiency of the HTST process according to its bacterial concentration

Em estudo crítico sobre o processo de pasteurização do leite pelo método HTST, os autores demonstraram que taxas elevadas de contaminação inicial do produto cru não constituem variável capaz de influenciar a eficiência do processo, aferida em termos da amplitude entre a carga bacteriana apatogênica mesófila aeróbia inicial e final do produto, sendo essa tanto menor quanto menor for o teor de tais bactérias no leite cru. Conceberam, ainda, modelo teórico cuja utilização possibilita o desenvolvimento de modelos simulados tanto para o monitoramento do controle da qualidade como para a avaliação da própria técnica de contagem bacteriana do leite (SPC).The efficiency of milk pasteurization (HTST) related to its standard plate count (SPC) values were assessed in 41 milk samples using a laboratory designed pasteurizing equipment. Based on results, it is demonstrated that efficiency of the process is affected by its bacterial concentration, where lower SPC values mean decrease in efficiency and that the performance of the process is not affected in presence of high SPC values in raw product

Genetic risk factors in Finnish patients with Parkinson's disease

Introduction Variation contributing to the risk of Parkinson's disease (PD) has been identified in several genes and at several loci including GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT, but the frequencies of risk variants seem to vary according to ethnic background. Our aim was to analyze how variation in these genes contributes to PD in the Finnish population. Methods The subjects consisted of 527 Finnish patients with early-onset PD, 325 patients with late-onset PD and 403 population controls. We screened for known genetic risk variants in GBA, SMPD1, LRRK2, POLG1, CHCHD10 and MAPT. In addition, DNA from 225 patients with early-onset Parkinson's disease was subjected to whole exome sequencing (WES). Results We detected a significant difference in the length variation of the CAG repeat in POLG1 between patients with early-onset PD compared to controls. The p.N370S and p.L444P variants in GBA contributed to a relative risk of 3.8 in early-onset PD and 2.5 in late-onset PD. WES revealed five variants in LRRK2 and SMPD1 that were found in the patients but not in the Finnish ExAC sequences. These are possible risk variants that require further confirmation. The p.G2019S variant in LRRK2, common in North African Arabs and Ashkenazi Jews, was not detected in any of the 849 PD patients. Conclusions The POLG1 CAG repeat length variation and the GBA p.L444P variant are associated with PD in the Finnish population.Peer reviewe

Finnish Parkinson's disease study integrating protein-protein interaction network data with exome sequencing analysis

Variants associated with Parkinson's disease (PD) have generally a small effect size and, therefore, large sample sizes or targeted analyses are required to detect significant associations in a whole exome sequencing (WES) study. Here, we used protein-protein interaction (PPI) information on 36 genes with established or suggested associations with PD to target the analysis of the WES data. We performed an association analysis on WES data from 439 Finnish PD subjects and 855 controls, and included a Finnish population cohort as the replication dataset with 60 PD subjects and 8214 controls. Single variant association (SVA) test in the discovery dataset yielded 11 candidate variants in seven genes, but the associations were not significant in the replication cohort after correction for multiple testing. Polygenic risk score using variants rs2230288 and rs2291312, however, was associated to PD with odds ratio of 2.7 (95% confidence interval 1.4-5.2; p < 2.56e-03). Furthermore, an analysis of the PPI network revealed enriched clusters of biological processes among established and candidate genes, and these functional networks were visualized in the study. We identified novel candidate variants for PD using a gene prioritization based on PPI information, and described why these variants may be involved in the pathogenesis of PD

Within-Neighborhood Patterns and Sources of Particle Pollution: Mobile Monitoring and Geographic Information System Analysis in Four Communities in Accra, Ghana

BACKGROUND: Sources of air pollution in developing country cities include transportation and industrial pollution, biomass and coal fuel use, and resuspended dust from unpaved roads. OBJECTIVES: Our goal was to understand within-neighborhood spatial variability of particulate matter (PM) in communities of varying socioeconomic status (SES) in Accra, Ghana, and to quantify the effects of nearby sources on local PM concentration. METHODS: We conducted 1 week of morning and afternoon mobile and stationary air pollution measurements in four study neighborhoods. PM with aerodynamic diameters RESULTS: In our measurement campaign, the geometric means of PM2.5 and PM10 along the mobile monitoring path were 21 and 49 microg/m3, respectively, in the neighborhood with highest SES and 39 and 96 microg/m3, respectively, in the neighborhood with lowest SES and highest population density. PM2.5 and PM10 were as high as 200 and 400 microg/m3, respectively, in some segments of the path. After adjusting for other factors, the factors that had the largest effects on local PM pollution were nearby wood and charcoal stoves, congested and heavy traffic, loose dirt road surface, and trash burning. CONCLUSIONS: Biomass fuels, transportation, and unpaved roads may be important determinants of local PM variation in Accra neighborhoods. If confirmed by additional or supporting data, the results demonstrate the need for effective and equitable interventions and policies that reduce the impacts of traffic and biomass pollution

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/

CMB-S4: Forecasting Constraints on Primordial Gravitational Waves

CMB-S4---the next-generation ground-based cosmic microwave background (CMB) experiment---is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the Universe, from the highest energies at the dawn of time through the growth of structure to the present day. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semi-analytic projection tool, targeted explicitly towards optimizing constraints on the tensor-to-scalar ratio, $r$, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2--3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments given a desired scientific goal. To form a closed-loop process, we couple this semi-analytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for $r > 0.003$ at greater than $5\sigma$, or, in the absence of a detection, of reaching an upper limit of $r < 0.001$ at $95\%$ CL.Comment: 24 pages, 8 figures, 9 tables, submitted to ApJ. arXiv admin note: text overlap with arXiv:1907.0447

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR&nbsp;=&nbsp;2.05, 95%CI&nbsp;=&nbsp;1.39–3.02, p&nbsp;&lt;&nbsp;0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR&nbsp;=&nbsp;0.42, 95%CI&nbsp;=&nbsp;0.18–0.99, p&nbsp;=&nbsp;0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis