Antimicrobial Drugs and Community–acquired Clostridium difficile–associated Disease, UK

In a population-based case-control study of community-acquired Clostridium difficile–associated disease (CDAD), we matched 1,233 cases to 12,330 controls. CDAD risk increased 3-fold with use of any antimicrobial agent and 6-fold with use of fluoroquinolones. Prior use of antimicrobial agent did not affect risk for CDAD after 6 months

Health equity in the New Zealand health care system: a national survey

<p>Abstract</p> <p>Introduction</p> <p>In all countries people experience different social circumstances that result in avoidable differences in health. In New Zealand, Māori, Pacific peoples, and those with lower socioeconomic status experience higher levels of chronic illness, which is the leading cause of mortality, morbidity and inequitable health outcomes. Whilst the health system can enable a fairer distribution of good health, limited national data is available to measure health equity. Therefore, we sought to find out whether health services in New Zealand were equitable by measuring the level of development of components of chronic care management systems across district health boards. Variation in provision by geography, condition or ethnicity can be interpreted as inequitable.</p> <p>Methods</p> <p>A national survey of district health boards (DHBs) was undertaken on macro approaches to chronic condition management with detail on cardiovascular disease, chronic obstructive pulmonary disease, congestive heart failure, stroke and diabetes. Additional data from expert informant interviews on program reach and the cultural needs of Māori and Pacific peoples was sought. Survey data were analyzed on dimensions of health equity relevant to strategic planning and program delivery. Results are presented as descriptive statistics and free text. Interviews were transcribed and NVivo 8 software supported a general inductive approach to identify common themes.</p> <p>Results</p> <p>Survey responses were received from the majority of DHBs (15/21), some PHOs (21/84) and 31 expert informants. Measuring, monitoring and targeting equity is not systematically undertaken. The Health Equity Assessment Tool is used in strategic planning but not in decisions about implementing or monitoring disease programs. Variable implementation of evidence-based practices in disease management and multiple funding streams made program implementation difficult. Equity for Māori is embedded in policy, this is not so for other ethnic groups or by geography. Populations that conventional practitioners find hard to reach, despite recognized needs, are often underserved. Nurses and community health workers carried a disproportionate burden of care. Cultural and diversity training is not a condition of employment.</p> <p>Conclusions</p> <p>There is a struggle to put equity principles into practice, indicating will without enactment. Equity is not addressed systematically below strategic levels and equity does not shape funding decisions, program development, implementation and monitoring. Equity is not incentivized although examples of exceptional practice, driven by individuals, are evident across New Zealand.</p

Factors associated with initiation of antihyperglycaemic medication in UK patients with newly diagnosed type 2 diabetes

<p>Abstract</p> <p>Aim</p> <p>To assess the factors associated with antihyperglycaemic medication initiation in UK patients with newly diagnosed type 2 diabetes.</p> <p>Methods</p> <p>In a retrospective cohort study, patients with newly diagnosed type 2 diabetes were identified during the index period of 2003-2005. Eligible patients were ≥ 30 years old at the date of the first observed diabetes diagnosis (referred to as index date) and had at least 2 years of follow-up medical history (N = 9,158). Initiation of antihyperglycaemic medication (i.e., treatment) was assessed in the 2-year period following the index date. Adjusted Cox regression models were used to examine the association between time to medication initiation and patient age and other factors.</p> <p>Results</p> <p>Mean (SD) HbA_1cat diagnosis was 8.1% (2.3). Overall, 51% of patients initiated antihyperglycaemic medication within 2 years (65%, 55%, 46% and 40% for patients in the 30- < 45, 45- < 65, 65- < 75, 75+ age groups, respectively). Among the treated patients, median (25^th, 75^thpercentile) time to treatment initiation was 63 (8, 257) days. Of the patients with HbA_1c≥ 7.5% at diagnosis, 87% initiated treatment within 2 years. These patients with a higher HbA_1calso had shorter time to treatment initiation (adjusted hazard ratio (HR) = 2.44 [95% confidence interval (CI): 1.61, 3.70]; p < 0.0001). Increasing age (in years) was negatively associated with time to treatment initiation (HR = 0.98 [95% CI: 0.97, 0.99]; p < 0.001). Factors significantly associated with shorter time to treatment initiation included female gender and use of cardiovascular medications at baseline or initiated during follow up.</p> <p>Conclusions</p> <p>In this UK cohort of patients with newly diagnosed type 2 diabetes, only 51% had antihyperglycaemic medication initiated over a 2-year period following diagnosis. Older patients were significantly less likely to have been prescribed antihyperglycaemic medications. Elevated HbA_1cwas the strongest factor associated with initiating antihyperglycaemic medication in these patients.</p

Modulation of Mrp1 (ABCc1) and Pgp (ABCb1) by Bilirubin at the Blood-CSF and Blood-Brain Barriers in the Gunn Rat

Accumulation of unconjugated bilirubin (UCB) in the brain causes bilirubin encephalopathy. Pgp (ABCb1) and Mrp1 (ABCc1), highly expressed in the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) respectively, may modulate the accumulation of UCB in brain. We examined the effect of prolonged exposure to elevated concentrations of UCB on expression of the two transporters in homozygous, jaundiced (jj) Gunn rats compared to heterozygous, not jaundiced (Jj) littermates at different developmental stages (2, 9, 17 and 60 days after birth). BBB Pgp protein expression was low in both jj and Jj pups at 9 days (about 16–27% of adult values), despite the up-regulation in jj animals (2 and 1.3 fold higher than age matched Jj animals at P9 and P17–P60, respectively); Mrp1 protein expression was barely detectable. Conversely, at the BCSFB Mrp1 protein expression was rather high (60–70% of the adult values) in both jj and Jj at P2, but was markedly (50%) down-regulated in jj pups starting at P9, particularly in the 4th ventricle choroid plexuses: Pgp was almost undetectable. The Mrp1 protein down regulation was accompanied by a modest up-regulation of mRNA, suggesting a translational rather than a transcriptional inhibition. In vitro exposure of choroid plexus epithelial cells obtained from normal rats to UCB, also resulted in a down-regulation of Mrp1 protein. These data suggest that down-regulation of Mrp1 protein at the BSCFB, resulting from a direct effect of UCB on epithelial cells, may impact the Mrp1-mediated neuroprotective functions of the blood-cerebrospinal fluid barrier and actually potentiate UCB neurotoxicity

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe

A biallelic multiple nucleotide length polymorphism explains functional causality at 5p15.33 prostate cancer risk locus

Abstract To date, single-nucleotide polymorphisms (SNPs) have been the most intensively investigated class of polymorphisms in genome wide associations studies (GWAS), however, other classes such as insertion-deletion or multiple nucleotide length polymorphism (MNLPs) may also confer disease risk. Multiple reports have shown that the 5p15.33 prostate cancer risk region is a particularly strong expression quantitative trait locus (eQTL) for Iroquois Homeobox 4 (IRX4) transcripts. Here, we demonstrate using epigenome and genome editing that a biallelic (21 and 47 base pairs (bp)) MNLP is the causal variant regulating IRX4 transcript levels. In LNCaP prostate cancer cells (homozygous for the 21 bp short allele), a single copy knock-in of the 47 bp long allele potently alters the chromatin state, enabling de novo functional binding of the androgen receptor (AR) associated with increased chromatin accessibility, Histone 3 lysine 27 acetylation (H3K27ac), and ~3-fold upregulation of IRX4 expression. We further show that an MNLP is amongst the strongest candidate susceptibility variants at two additional prostate cancer risk loci. We estimated that at least 5% of prostate cancer risk loci could be explained by functional non-SNP causal variants, which may have broader implications for other cancers GWAS. More generally, our results underscore the importance of investigating other classes of inherited variation as causal mediators of human traits

Non-medical prescribing in Australasia and the UK: the case of podiatry

Background: the last decade has witnessed a rapid transformation in the role boundaries of the allied healthprofessions, enabled through the creation of new roles and the expansion of existing, traditional roles. A strategyof health care ‘modernisation’ has encompassed calls for the redrawing of professional boundaries and identities,linked with demands for greater workforce flexibility. Several tasks and roles previously within the exclusive domainof medicine have been delegated to, or assumed by, allied health professionals, as the workforce is reshaped tomeet the challenges posed by changing demographic, social and political contexts. The prescribing of medicinesby non-medically qualified healthcare professionals, and in particular the podiatry profession, reflects thesechanges.Methods: using a range of key primary documentary sources derived from published material in the publicdomain and unpublished material in private possession, this paper traces the development of contemporary UKand Australasian podiatric prescribing, access, supply and administration of medicines. Documentary sourcesinclude material from legislative, health policy, regulatory and professional bodies (including both State and Federalsources in Australia).Results: tracing a chronological, comparative, socio-historical account of the emergence and development of‘prescribing’ in podiatry in both Australasia and the UK enables an analysis of the impact of health policy reformson the use of, and access to, medicines by podiatrists. The advent of neo-liberal healthcare policies, coupled withdemands for workforce flexibility and role transfer within a climate of demographic, economic and social changehas enabled allied health professionals to undertake an expanding number of tasks involving the sale, supply,administration and prescription of medicines.Conclusion: as a challenge to medical dominance, these changes, although driven by wider healthcare policy,have met with resistance. As anticipated in the theory of medical dominance, inter-professional jurisdictionaldisputes centred on the right to access, administer, supply and prescribe medicines act as obstacles to workforcechange. Nevertheless, the broader policy agenda continues to ensure workforce redesign in which podiatry hasassumed wider roles and responsibilities in prescribing