Disparities in breast cancer mortality trends between 30 European countries: retrospective trend analysis of WHO mortality database

Objective To examine changes in temporal trends in breast cancer mortality in women living in 30 European countries

The economic case for investing in the prevention of mental health conditions in the UK

This report provides an overview of the economic case for the prevention of mental health conditions. To do this, we first estimated the societal costs of living with mental health conditions in the UK in 2019 and then reviewed what is known about the cost-effectiveness of wellevidenced actions to prevent these mental health conditions. To estimate costs, we used a prevalencebased costing approach. This measures the number of people living with mental health conditions over a specific short time period (usually one year) and estimates the average costs associated with these conditions over this time period. Our prevalencebased costing model makes use of data on prevalence from the 2019 Institute of Health Metrics and Evaluation Global Burden of Disease (GBD) study. The GBD study quantifies the impact of all health conditions, both infectious and non-communicable, including mental health conditions, as well as the impacts on injury, including intentional self-harm. As part of the study, the GBD systematically searches for and assesses mental health surveys around the globe. To allow for comparability in measurement, case definitions used by GBD predominantly adhered to international diagnostic criteria guidance, either the DSM-IV-TR, mainly used in the United States or the ICD-10 criteria used mainly elsewhere, as these are used by the majority of mental health surveys included in the GBD. The GBD study estimates are periodically updated, apply a common methodology, are subject to peer review, and are routinely used by the World Health Organization (WHO) when looking at the global impact of mental health conditions. Furthermore, GBD estimates are provided separately for all four nations of the UK, as well as at English Region level. These estimates are conservative, as the GBD does not include the impact of sub-diagnostic threshold mental health conditions, as well as risk factors such as undue stress which do not fit into diagnostic criteria, all of which will also have economic costs. We included 11 of 12 broad categories of mental disorder meeting diagnosable thresholds used in the GBD1. These were depressive disorders (major depressive disorder and dysthymia), anxiety disorders, bipolar affective disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder (ADHD), eating disorders (anorexia nervosa and bulimia nervosa), and a final category of other mental disorders (which mainly covers personality disorders). A detailed list of conditions is listed in Table A-2 in the appendix. We excluded the idiopathic intellectual disabilities category in the GBD. Neurological conditions such as dementia, as well as alcohol and substance use disorders, are not included. Although not all intentional self-harm is linked with a mental health condition, we also separately provide an estimate of the health and intangible costs associated with intentional self-harm, including suicide, reported in the GBD. All costs are calculated and reported in 2020 pounds sterling

Predictive phage therapy for Escherichia coli urinary tract infections: cocktail selection for therapy based on machine learning models

This study supports the development of predictive bacteriophage (phage) therapy: the concept of phage cocktail selection to treat a bacterial infection based on machine learning (ML) models. For this purpose, ML models were trained on thousands of measured interactions between a panel of phage and sequenced bacterial isolates. The concept was applied to Escherichia coli associated with urinary tract infections. This is an important common infection in humans and companion animals from which multidrug-resistant (MDR) bloodstream infections can originate. The global threat of MDR infection has reinvigorated international efforts into alternatives to antibiotics including phage therapy. E. coli exhibit extensive genome-level variation due to horizontal gene transfer via phage and plasmids. Associated with this, phage selection for E. coli is difficult as individual isolates can exhibit considerable variation in phage susceptibility due to differences in factors important to phage infection including phage receptor profiles and resistance mechanisms. The activity of 31 phage was measured on 314 isolates with growth curves in artificial urine. Random Forest models were built for each phage from bacterial genome features, and the more generalist phage, acting on over 20% of the bacterial population, exhibited F1 scores of &gt;0.6 and could be used to predict phage cocktails effective against previously untested strains. The study demonstrates the potential of predictive ML models which integrate bacterial genomics with phage activity datasets allowing their use on data derived from direct sequencing of clinical samples to inform rapid and effective phage therapy.</p

Predictive phage therapy for Escherichia coli urinary tract infections: cocktail selection for therapy based on machine learning models

This study supports the development of predictive bacteriophage (phage) therapy: the concept of phage cocktail selection to treat a bacterial infection based on machine learning models (MLM). For this purpose, MLM were trained on thousands of measured interactions between a panel of phage and sequenced bacterial isolates. The concept was applied to Escherichia coli (E. coli) associated with urinary tract infections. This is an important common infection in humans and companion animals from which multi-drug resistant (MDR) bloodstream infections can originate. The global threat of MDR infection has reinvigorated international efforts into alternatives to antibiotics including phage therapy. E. coli exhibit extensive genome-level variation due to horizontal gene transfer via phage and plasmids. Associated with this, phage selection for E. coli is difficult as individual isolates can exhibit considerable variation in phage susceptibility due to differences in factors important to phage infection including phage receptor profiles and resistance mechanisms. The activity of 31 phage were measured on 314 isolates with growth curves in artificial urine. Random Forest models were built for each phage from bacterial genome features and the more generalist phage, acting on over 20% of the bacterial population, exhibited F1 scores of &gt;0.6 and could be used to predict phage cocktails effective against previously untested strains. The study demonstrates the potential of predictive models which integrate bacterial genomics with phage activity datasets allowing their use on data derived from direct sequencing of clinical samples to inform rapid and effective phage therapy.Significance Statement With the growing challenge of antimicrobial resistance there is an urgency for alternative treatments for common bacterial diseases including urinary tract infections (UTIs). Escherichia coli is the main causative agent of UTIs in both humans and companion animals with multidrug resistant strains such as the globally disseminated ST131 becoming more common. Bacteriophage (phage) are natural predators of bacteria and potentially an alternative therapy. However, a major barrier for phage therapy is the specificity of phage on target bacteria and therefore difficulty efficiently selecting the appropriate phage. Here, we demonstrate a genomics driven approach using machine learning prediction models combined with phage activity clustering to select phage cocktails based only on the genome sequence of the infecting bacterial strain

Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction (HARP-2) trial : study protocol for a randomized controlled trial

Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI

Structure and Function of a Mycobacterial NHEJ DNA Repair Polymerase

Non homologous end-joining (NHEJ)-mediated repair of DNA double-strand breaks in prokaryotes requires Ku and a specific multidomain DNA ligase (LigD). We present crystal structures of the primase/polymerisation domain (PolDom) of Mycobacterium tuberculosis LigD, alone and complexed with nucleotides. The PolDom structure combines the general fold of the archaeo-eukaryotic primase (AEP) superfamily with additional loops and domains that together form a deep cleft on the surface, likely used for DNA binding. Enzymatic analysis indicates that the PolDom of LigD, even in the absence of accessory domains and Ku proteins, has the potential to recognise DNA end-joining intermediates. Strikingly, one of the main signals for the specific and efficient binding of PolDom to DNA is the presence of a 5'-phosphate group, located at the single/double-stranded junction at both gapped and 3'-protruding DNA molecules. Although structurally unrelated, Pol lambda and Pol mu, the two eukaryotic DNA polymerases involved in NHEJ, are endowed with a similar capacity to bind a 5'-phosphate group. Other properties that are beneficial for NHEJ, such as the ability to generate template distortions and realignments of the primer, displayed by Pol lambda and Pol mu, are shared by the PolDom of bacterial LigD. In addition, PolDom can perform non-mutagenic translesion synthesis on termini containing modified bases. Significantly, ribonucleotide insertion appears to be a recurrent theme associated with NHEJ, maximised in this case by the deployment of a dedicated primase, although its in vivo relevance is unknown

Vitamin D receptor ChIP-seq in primary CD4+ cells: relationship to serum 25-hydroxyvitamin D levels and autoimmune disease

PMCID: PMC3710212This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

QGP Theory: Status and Perspectives

The current status of Quark-Gluon-Plasma Theory is reviewed. Special emphasis is placed on QGP signatures, the interpretation of current data and what to expect from RHIC in the near future.Comment: 20 pages, invited overview talk at the 4th International Conference on the Physcis and Astrophysics of the Quark-Gluon-Plasma, November 2001, Jaipur, India, to appear in Praman