The purpose of this study was to enhance the understanding of the health-promoting potential of trees in an urbanized region of the United States. This was done using high-resolution LiDAR and ...imagery data to quantify tree cover within 250m of the residence of 7910 adult participants in the California Health Interview Survey, then testing for main and mediating associations between tree cover and multiple health measures. The results indicated that more neighborhood tree cover, independent from green space access, was related to better overall health, primarily mediated by lower overweight/obesity and better social cohesion, and to a lesser extent by less type 2 diabetes, high blood pressure, and asthma. These findings suggest an important role for trees and nature in improving holistic population health in urban areas.
Simultaneous inhibition of multiple components of the BRAF-MEK-ERK cascade (vertical inhibition) has become a standard of care for treating BRAF-mutant melanoma. However, the molecular mechanism of ...how vertical inhibition synergistically suppresses intracellular ERK activity, and consequently cell proliferation, are yet to be fully elucidated.
We develop a mechanistic mathematical model that describes how the mutant BRAF inhibitor, dabrafenib, and the MEK inhibitor, trametinib, affect BRAFV600E-MEK-ERK signalling. The model is based on a system of chemical reactions that describes cascade signalling dynamics. Using mass action kinetics, the chemical reactions are re-expressed as ordinary differential equations that are parameterised by in vitro data and solved numerically to obtain the temporal evolution of cascade component concentrations.
The model provides a quantitative method to compute how dabrafenib and trametinib can be used in combination to synergistically inhibit ERK activity in BRAFV600E-mutant melanoma cells. The model elucidates molecular mechanisms of vertical inhibition of the BRAFV600E-MEK-ERK cascade and delineates how elevated BRAF concentrations generate drug resistance to dabrafenib and trametinib. The computational simulations further suggest that elevated ATP levels could be a factor in drug resistance to dabrafenib.
The model can be used to systematically motivate which dabrafenib-trametinib dose combinations, for treating BRAFV600E-mutated melanoma, warrant experimental investigation.
We compared the prevalence of human and animal methicillin-resistant Staphylococcus aureus (MRSA) at pig farms in The Netherlands, and related this to individual and farm-level characteristics. More ...than half of the farms investigated (28/50) had MRSA in pigs or stable dust and about one third (15/50) of person(s) were identified as MRSA carriers. Human carriage was found only on farms with MRSA-positive pigs or dust. MRSA strains in human samples were the same spa-type as found in pigs and all were not typable by pulsed-field gel electrophoresis (NT-MRSA). Multivariate analyses showed that risk factors for human MRSA carriage were: working in pig stables (OR 40, 95% CI 8–209) and the presence of sows and finishing pigs (OR 9, 95% CI 3–30). Veterinary sample collectors sampling the pigs showed transient MRSA carriage only during the day of the farm visit. Working in pig stables with MRSA-positive pigs poses a high risk for acquiring MRSA, increasingly so when contact with live pigs is more intensive or long lasting.
We reviewed the literature on standard case management (SCM), intensive case management (ICM), assertive community treatment (ACT), and critical time intervention (CTI) for homeless adults. We ...searched databases for peer-reviewed English articles published from 1985 to 2011 and found 21 randomized controlled trials or quasi-experimental studies comparing case management to other services. We found little evidence for the effectiveness of ICM. SCM improved housing stability, reduced substance use, and removed employment barriers for substance users. ACT improved housing stability and was cost-effective for mentally ill and dually diagnosed persons. CTI showed promise for housing, psychopathology, and substance use and was cost-effective for mentally ill persons. More research is needed on how case management can most effectively support rapid-rehousing approaches to homelessness.
Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical ...hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case-control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen's d=-0.232; P=3.50 × 10
) and thalamus (d=-0.148; P=4.27 × 10
) and enlarged lateral ventricles (d=-0.260; P=3.93 × 10
) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.
We describe here the design and initial implementation of the eMERGE‐PGx project. eMERGE‐PGx, a partnership of the Electronic Medical Records and Genomics Network and the Pharmacogenomics Research ...Network, has three objectives: (i) to deploy PGRNseq, a next‐generation sequencing platform assessing sequence variation in 84 proposed pharmacogenes, in nearly 9,000 patients likely to be prescribed drugs of interest in a 1‐ to 3‐year time frame across several clinical sites; (ii) to integrate well‐established clinically validated pharmacogenetic genotypes into the electronic health record with associated clinical decision support and to assess process and clinical outcomes of implementation; and (iii) to develop a repository of pharmacogenetic variants of unknown significance linked to a repository of electronic health record–based clinical phenotype data for ongoing pharmacogenomics discovery. We describe site‐specific project implementation and anticipated products, including genetic variant and phenotype data repositories, novel variant association studies, clinical decision support modules, clinical and process outcomes, approaches to managing incidental findings, and patient and clinician education methods.
Clinical Pharmacology & Therapeutics (2014); 96 4, 482–489. doi:10.1038/clpt.2014.137
The development, homeostasis, and repair of intrahepatic and extrahepatic bile ducts are thought to involve distinct mechanisms including proliferation and maturation of cholangiocyte and progenitor ...cells. This study aimed to characterize human extrahepatic cholangiocyte organoids (ECO) using canonical Wnt-stimulated culture medium previously developed for intrahepatic cholangiocyte organoids (ICO). Paired ECO and ICO were derived from common bile duct and liver tissue, respectively. Characterization showed both organoid types were highly similar, though some differences in size and gene expression were observed. Both ECO and ICO have cholangiocyte fate differentiation capacity. However, unlike ICO, ECO lack the potential for differentiation towards a hepatocyte-like fate. Importantly, ECO derived from a cystic fibrosis patient showed no CFTR channel activity but normal chloride channel and MDR1 transporter activity. In conclusion, this study shows that ECO and ICO have distinct lineage fate and that ECO provide a competent model to study extrahepatic bile duct diseases like cystic fibrosis.
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