105 research outputs found
Core components for effective infection prevention and control programmes: new WHO evidence-based recommendations
Abstract
Health care-associated infections (HAI) are a major public health problem with a significant impact on morbidity, mortality and quality of life. They represent also an important economic burden to health systems worldwide. However, a large proportion of HAI are preventable through effective infection prevention and control (IPC) measures. Improvements in IPC at the national and facility level are critical for the successful containment of antimicrobial resistance and the prevention of HAI, including outbreaks of highly transmissible diseases through high quality care within the context of universal health coverage. Given the limited availability of IPC evidence-based guidance and standards, the World Health Organization (WHO) decided to prioritize the development of global recommendations on the core components of effective IPC programmes both at the national and acute health care facility level, based on systematic literature reviews and expert consensus. The aim of the guideline development process was to identify the evidence and evaluate its quality, consider patient values and preferences, resource implications, and the feasibility and acceptability of the recommendations. As a result, 11 recommendations and three good practice statements are presented here, including a summary of the supporting evidence, and form the substance of a new WHO IPC guideline
Understanding high pressure hydrogen with a hierarchical machine-learned potential
The hydrogen phase diagram has a number of unusual features which are
generally well reproduced by density functional calculations. Unfortunately,
these calculations fail to provide good physical insights into why those
features occur. In this paper, we parameterize a model potential for molecular
hydrogen which permits long and large simulations. The model shows excellent
reproduction of the phase diagram, including the broken-symmetry Phase II, an
efficiently-packed phase III and the maximum in the melt curve. It also gives
an excellent reproduction of the vibrational frequencies, including the maximum
in the vibrational frequency and negative thermal expansion. By
detailed study of lengthy molecular dynamics, we give intuitive explanations
for observed and calculated properties. All solid structures approximate to
hexagonal close packed, with symmetry broken by molecular orientation. At high
pressure, Phase I shows significant short-ranged correlations between molecular
orientations. The turnover in Raman frequency is due to increased coupling
between neighboring molecules, rather than weakening of the bond. The liquid is
denser than the close-packed solid because, at molecular separations below
2.3\AA, the favoured relative orientation switches from
quadrupole-energy-minimising to steric-repulsion-minimising. The latter allows
molecules to get closer together, without atoms getting closer but this cannot
be achieved within the constraints of a close-packed layer
The prognostic and predictive power of redox rotein expression for anthracycline-based chemotherapy response in locally advanced breast cancer
Neoadjuvant chemotherapy has become the standard of care for locally advanced primary breast cancer. Anthracycline-based regimens have proven to be one of the most effective treatments in this setting. As certain cytotoxic antineoplastic agents, such as anthracyclines, generate reactive oxygen species as a by-product of their mechanism of action, we examined whether redox protein expression was involved in the response to anthracycline-based chemotherapy and with clinical outcome. Pre treatment needle core biopsy and postanthracycline treatment tumour sections were analysed from 98 cases. In all, 32 individuals had a complete clinical response and 17 had a complete pathological response. Immunohistochemical staining was performed for eight redox proteins: thioredoxin, thioredoxin reductase thioredoxin interacting protein (TxNIP), glutathione S-transferase (GST) p, h and a, catalase and manganese superoxide dismutase. GST p (P¼0.05) and catalase (P¼0.045) were associated with pathological complete response in pre-chemotherapy samples. TxNIP (P¼0.017) and thioredoxin reductase (P¼0.022) were independent prognostic factors for distant metastasis free survival and TxNIP for overall survival (P¼0.014). In oestrogen receptor negative patients that are known to have a poor overall survival, a considerably worse prognosis was seen in cases that exhibited low expression of TxNIP (P¼0.000003), stratifying patients into more defined groups. This study indicates the importance of redox regulation in determining breast cancer response to anthracycline-based chemotherapy and provides ways of further stratifying pre-chemotherapy patients to potentially allow more tailored treatments
Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci
We characterized DNA methylation quantitative trait loci (mQTLs) in a large collection (n = 166) of human fetal brain samples spanning 56-166 d post-conception, identifying >16,000 fetal brain mQTLs. Fetal brain mQTLs were primarily cis-acting, enriched in regulatory chromatin domains and transcription factor binding sites, and showed substantial overlap with genetic variants that were also associated with gene expression in the brain. Using tissue from three distinct regions of the adult brain (prefrontal cortex, striatum and cerebellum), we found that most fetal brain mQTLs were developmentally stable, although a subset was characterized by fetal-specific effects. Fetal brain mQTLs were enriched amongst risk loci identified in a recent large-scale genome-wide association study (GWAS) of schizophrenia, a severe psychiatric disorder with a hypothesized neurodevelopmental component. Finally, we found that mQTLs can be used to refine GWAS loci through the identification of discrete sites of variable fetal brain methylation associated with schizophrenia risk variants
Predicting genome-wide DNA methylation using methylation marks, genomic position, and DNA regulatory elements
Background: Recent assays for individual-specific genome-wide DNA methylation
profiles have enabled epigenome-wide association studies to identify specific
CpG sites associated with a phenotype. Computational prediction of CpG
site-specific methylation levels is important, but current approaches tackle
average methylation within a genomic locus and are often limited to specific
genomic regions. Results: We characterize genome-wide DNA methylation patterns,
and show that correlation among CpG sites decays rapidly, making predictions
solely based on neighboring sites challenging. We built a random forest
classifier to predict CpG site methylation levels using as features neighboring
CpG site methylation levels and genomic distance, and co-localization with
coding regions, CGIs, and regulatory elements from the ENCODE project, among
others. Our approach achieves 91% -- 94% prediction accuracy of genome-wide
methylation levels at single CpG site precision. The accuracy increases to 98%
when restricted to CpG sites within CGIs. Our classifier outperforms
state-of-the-art methylation classifiers and identifies features that
contribute to prediction accuracy: neighboring CpG site methylation status, CpG
island status, co-localized DNase I hypersensitive sites, and specific
transcription factor binding sites were found to be most predictive of
methylation levels. Conclusions: Our observations of DNA methylation patterns
led us to develop a classifier to predict site-specific methylation levels that
achieves the best DNA methylation predictive accuracy to date. Furthermore, our
method identified genomic features that interact with DNA methylation,
elucidating mechanisms involved in DNA methylation modification and regulation,
and linking different epigenetic processes
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/
A genome-wide association scan implicates <i>DCHS2, RUNX2, GLI3, PAX1</i> and <i>EDAR</i> in human facial variation
We report a genome-wide association scan for facial features in ∼6,000 Latin Americans. We evaluated 14 traits on an ordinal scale and found significant association (P values−8) at single-nucleotide polymorphisms (SNPs) in four genomic regions for three nose-related traits: columella inclination (4q31), nose bridge breadth (6p21) and nose wing breadth (7p13 and 20p11). In a subsample of ∼3,000 individuals we obtained quantitative traits related to 9 of the ordinal phenotypes and, also, a measure of nasion position. Quantitative analyses confirmed the ordinal-based associations, identified SNPs in 2q12 associated to chin protrusion, and replicated the reported association of nasion position with SNPs in PAX3. Strongest association in 2q12, 4q31, 6p21 and 7p13 was observed for SNPs in the EDAR, DCHS2, RUNX2 and GLI3 genes, respectively. Associated SNPs in 20p11 extend to PAX1. Consistent with the effect of EDAR on chin protrusion, we documented alterations of mandible length in mice with modified Edar function
Molecular Biomechanics: The Molecular Basis of How Forces Regulate Cellular Function
Recent advances have led to the emergence of molecular biomechanics as an essential element of modern biology. These efforts focus on theoretical and experimental studies of the mechanics of proteins and nucleic acids, and the understanding of the molecular mechanisms of stress transmission, mechanosensing and mechanotransduction in living cells. In particular, single-molecule biomechanics studies of proteins and DNA, and mechanochemical coupling in biomolecular motors have demonstrated the critical importance of molecular mechanics as a new frontier in bioengineering and life sciences. To stimulate a more systematic study of the basic issues in molecular biomechanics, and attract a broader range of researchers to enter this emerging field, here we discuss its significance and relevance, describe the important issues to be addressed and the most critical questions to be answered, summarize both experimental and theoretical/computational challenges, and identify some short-term and long-term goals for the field. The needs to train young researchers in molecular biomechanics with a broader knowledge base, and to bridge and integrate molecular, subcellular and cellular level studies of biomechanics are articulated.National Institutes of Health (U.S.) (grant UO1HL80711-05 to GB)National Institutes of Health (U.S.) (grant R01GM076689-01)National Institutes of Health (U.S.) (grant R01AR033236-26)National Institutes of Health (U.S.) (grant R01GM087677-01A1)National Institutes of Health (U.S.) (grant R01AI44902)National Institutes of Health (U.S.) (grant R01AI38282)National Science Foundation (U.S.) (grant CMMI-0645054)National Science Foundation (U.S.) (grant CBET-0829205)National Science Foundation (U.S.) (grant CAREER-0955291
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