A mechanistic spatio-temporal framework for modelling individual-to-individual transmission—With an application to the 2014-2015 West Africa Ebola outbreak

In recent years there has been growing availability of individual-level spatio-temporal disease data, particularly due to the use of modern communicating devices with GPS tracking functionality. These detailed data have been proven useful for inferring disease transmission to a more refined level than previously. However, there remains a lack of statistically sound frameworks to model the underlying transmission dynamic in a mechanistic manner. Such a development is particularly crucial for enabling a general epidemic predictive framework at the individual level. In this paper we propose a new statistical framework for mechanistically modelling individual-to-individual disease transmission in a landscape with heterogeneous population density. Our methodology is first tested using simulated datasets, validating our inferential machinery. The methodology is subsequently applied to data that describes a regional Ebola outbreak in Western Africa (2014-2015). Our results show that the methods are able to obtain estimates of key epidemiological parameters that are broadly consistent with the literature, while revealing a significantly shorter distance of transmission. More importantly, in contrast to existing approaches, we are able to perform a more general model prediction that takes into account the susceptible population. Finally, our results show that, given reasonable scenarios, the framework can be an effective surrogate for susceptible-explicit individual models which are often computationally challenging

The Physiology and Proteomics of Drought Tolerance in Maize: Early Stomatal Closure as a Cause of Lower Tolerance to Short-Term Dehydration?

Understanding the response of a crop to drought is the first step in the breeding of tolerant genotypes. In our study, two maize (Zea mays L.) genotypes with contrasting sensitivity to dehydration were subjected to moderate drought conditions. The subsequent analysis of their physiological parameters revealed a decreased stomatal conductance accompanied by a slighter decrease in the relative water content in the sensitive genotype. In contrast, the tolerant genotype maintained open stomata and active photosynthesis, even under dehydration conditions. Drought-induced changes in the leaf proteome were analyzed by two independent approaches, 2D gel electrophoresis and iTRAQ analysis, which provided compatible but only partially overlapping results. Drought caused the up-regulation of protective and stress-related proteins (mainly chaperones and dehydrins) in both genotypes. The differences in the levels of various detoxification proteins corresponded well with the observed changes in the activities of antioxidant enzymes. The number and levels of up-regulated protective proteins were generally lower in the sensitive genotype, implying a reduced level of proteosynthesis, which was also indicated by specific changes in the components of the translation machinery. Based on these results, we propose that the hypersensitive early stomatal closure in the sensitive genotype leads to the inhibition of photosynthesis and, subsequently, to a less efficient synthesis of the protective/detoxification proteins that are associated with drought tolerance

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Methodology of research of environmental parameters on scaffolding

Zmieniające się parametry klimatyczne oddziałują niekorzystnie na osoby pracujące na rusztowaniu, mogąc zwiększać ryzyko wystąpienia sytuacji niebezpiecznych. Celowe jest pokazanie, na jakie zmiany narażony jest pracownik. W pracy zaprezentowano przykładowe wyniki badań środowiskowych, jakie otrzymano dla trzech rusztowań zlokalizowanych w Łodzi: temperatury powietrza, wilgotności względnej oraz ciśnienia atmosferycznego. W artykule przedstawiono również opis badań rusztowań budowlanych oraz metodykę badań parametrów środowiskowych w otoczeniu pracowników na rusztowaniu. Wyniki analiz wykazały, że zaproponowana metodyka badań gwarantuje otrzymanie wyników przydatnych w analizie środowiska pracy na rusztowaniu.People working on scaffolding are exposed to changing climatic parameters. They can increase the risk of dangerous situations. It is important to what changes a worker is exposed to. The article presents the sample results of environmental tests (air temperature, relative humidity, atmospheric pressure) performed on three scaffolding located in Lodz. The article presents a description of the research of construction scaffolding and methodology of research of environmental parameters. Analysis results showed that the proposed test methodology guarantees obtaining results useful in analyzing the working environment on scaffolding

The replication capacity of intact mammalian nuclei in Xenopus egg extracts declines with quiescence, but the residual DNA synthesis is independent of Xenopus MCM proteins

In eukaryotes, the initiation of DNA synthesis requires the assembly of a pre-replicative complex (pre-RC) at origins of replication. This involves the sequential binding of ORC (origin-recognition-complex), Cdc6 and MCM proteins, a process referred to as licensing. After origin firing, the Cdc6 and MCM proteins dissociate from the chromatin, and do not rebind until after the completion of mitosis, thereby restricting replication to a single round in each cell cycle. Although nuclei normally become licensed for replication as they enter G(1), the extent to which the license is retained when cells enter the quiescent state (G(0)) is controversial. Here we show that the replication capacity of nuclei from Swiss 3T3 cells, in Xenopus egg extracts, is not lost abruptly with the onset of quiescence, but instead declines gradually. The decline in replication capacity, which affects both the number of nuclei induced to replicate and their subsequent rate of DNA synthesis, is accompanied by a fall in the level of chromatin-bound MCM2. When quiescent nuclei are incubated in egg extracts, they do not bind further MCMs unless the nuclei are first permeabilized. The residual replication capacity of intact nuclei must therefore be dependent on the remaining endogenous MCMs. Although high levels of Cdk activity are known to block MCM binding, we show that the failure of intact nuclei in egg extracts to increase their bound MCMs is not due to their uptake and accumulation of Cdk complexes. Instead, the failure of binding must be due to exclusion of some other binding factor from the nucleus, or to the presence within nuclei of an inhibitor of binding other than Cdk activity. In contrast to the situation in Xenopus egg extracts, following serum stimulation of intact quiescent cells, the level of bound MCMs does increase before the cells reach S phase, without any disruption of the nuclear envelope

Gd(III)-Doped Carbon Dots as a Dual Fluorescent-MRI Probe

We describe the synthesis of Gd(III)-doped carbon dots as dual fluorescence-MRI probes for biomedical applications. The derived Gd(III)-doped carbon dots show uniform particle size (3–4 nm) and gadolinium distribution and form stable dispersions in water. More importantly, they exhibit bright fluorescence, strong T1-weighted MRI contrast and low cytotoxicity