Improved pregnancy outcomes in women with type 1 and type 2 diabetes but substantial clinic-to-clinic variations: a prospective nationwide study

Aims/hypothesis: The aim of this prospective nationwide study was to examine antenatal pregnancy care and pregnancy outcomes in women with type 1 and type 2 diabetes, and to describe changes since 2002/2003. Methods: This national population-based cohort included 3036 pregnant women with diabetes from 155 maternity clinics in England and Wales who delivered during 2015. The main outcome measures were maternal glycaemic control, preterm delivery (before 37 weeks), infant large for gestational age (LGA), and rates of congenital anomaly, stillbirth and neonatal death. Results: Of 3036 women, 1563 (51%) had type 1, 1386 (46%) had type 2 and 87 (3%) had other types of diabetes. The percentage of women achieving HbA1c < 6.5% (48 mmol/mol) in early pregnancy varied greatly between clinics (median [interquartile range] 14.3% [7.7–22.2] for type 1, 37.0% [27.3–46.2] for type 2). The number of infants born preterm (21.7% vs 39.7%) and LGA (23.9% vs 46.4%) were lower for women with type 2 compared with type 1 diabetes (both p < 0.001). The prevalence rates for congenital anomaly (46.2/1000 births for type 1, 34.6/1000 births for type 2) and neonatal death (8.1/1000 births for type 1, 11.4/1000 births for type 2) were unchanged since 2002/2003. Stillbirth rates are almost 2.5 times lower than in 2002/2003 (10.7 vs 25.8/1000 births for type 1, p = 0.0012; 10.5 vs 29.2/1000 births for type 2, p = 0.0091). Conclusions/interpretation: Stillbirth rates among women with type 1 and type 2 diabetes have decreased since 2002/2003. Rates of preterm delivery and LGA infants are lower in women with type 2 compared with type 1 diabetes. In women with type 1 diabetes, suboptimal glucose control and high rates of perinatal morbidity persist with substantial variations between clinics

Formylated Peptide Receptor-1 (FPR1) mediated gut inflammation as a therapeutic target in Inflammatory Bowel Disease

Background: Formylated peptide receptor (FPR)-1 is a G-coupled receptor that senses foreign bacterial and host-derived mitochondrial formylated peptides (FPs), leading to innate immune system activation. Aim: We sought to investigate the role of FPR1-mediated inflammation and its potential as a therapeutic target in inflammatory bowel disease (IBD). Methods: We characterized FPR1 gene and protein expression in 8 human IBD (~1000 patients) datasets with analysis on disease subtype, mucosal inflammation, and drug response. We performed in vivo dextran-sulfate sodium (DSS) colitis in C57/BL6 FPR1 knockout mice. In ex vivo studies, we studied the role of mitochondrial FPs and pharmacological blockade of FPR1 using cyclosporin H in human peripheral blood neutrophils. Finally, we assess mitochondrial FPs as a potential mechanistic biomarker in the blood and stools of patients with IBD. Results: Detailed in silico analysis in human intestinal biopsies showed that FPR1 is highly expressed in IBD (n = 207 IBD vs 67 non-IBD controls, P &lt; .001), and highly correlated with gut inflammation in ulcerative colitis (UC) and Crohn’s disease (CD) (both P &lt; .001). FPR1 receptor is predominantly expressed in leukocytes, and we showed significantly higher FPR1+ve neutrophils in inflamed gut tissue section in IBD (17 CD and 24 UC; both P &lt; .001). Further analysis in 6 independent IBD (data available under Gene Expression Omnibus accession numbers GSE59071, GSE206285, GSE73661, GSE16879, GSE92415, and GSE235970) showed an association with active gut inflammation and treatment resistance to infliximab, ustekinumab, and vedolizumab. FPR1 gene deletion is protective in murine DSS colitis with lower gut neutrophil inflammation. In the human ex vivo neutrophil system, mitochondrial FP, nicotinamide adenine dinucleotide dehydrogenase subunit-6 (ND6) is a potent activator of neutrophils resulting in higher CD62L shedding, CD63 expression, reactive oxygen species production, and chemotactic capacity; these effects are inhibited by cyclosporin H. We screened for mitochondrial ND6 in IBD (n = 54) using ELISA and detected ND6 in stools with median values of 2.2 gg/mL (interquartile range [IQR] 0.0–4.99; range 0–53.3) but not in blood. Stool ND6 levels, however, were not significantly correlated with paired stool calprotectin, C-reactive protein, and clinical IBD activity. Conclusions: Our data suggest that FPR1-mediated neutrophilic inflammation is a tractable target in IBD; however, further work is required to clarify the clinical utility of mitochondrial FPs as a potential mechanistic marker for future stratification.</p

Developing an adult safeguarding outcome measure in England

Purpose – There are currently no national adult safeguarding outcome measures that focus on people who have been through an adult safeguarding investigation in England. There is a need for local authorities (LAs) and their partners to be able to measure whether the services provided to adults at risk of abuse and neglect are effective. The paper aims to discuss these issues. Design/methodology/approach – This paper describes the cognitive testing phase of a study to develop and implement a standardised adult at risk outcome measure in adult safeguarding for use by LAs in England. An outcome measure (a set of seven survey questions administered in a face to face interview) was cognitively tested in three LAs with adults at risk (or their carers/advocates) for whom an investigation of abuse had been concluded (n=40), with the aim of assessing whether it was commonly understood. A set of guidance notes was designed and LA staff (n=12) who assisted with the survey were interviewed about its usability and the feasibility of administering the survey. Findings – The survey questions required modifications to improve their reliability, validity and comparability. LA staff also suggested improvements were needed in the guidance document and survey. LA managers, adults at risk (and their relatives/carers/advocates) were willing to be involved in the survey and it was considered feasible to proceed with piloting the measure. Originality/value – The development of this unique survey is of interest to those working in adult safeguarding, user involvement, survey management and outcome measurement in LAs. </jats:sec

The feasibility of introducing an adult safeguarding measure (survey) for inclusion in the adult social care outcomes framework (ASCOF): projecting costs

Purpose – The Health and Social Care Information Centre undertook the development and piloting of a new adult safeguarding outcome measure (a face-to-face survey) for local authorities (LAs) that could be added to the adult social care outcomes framework (ASCOF). The ASCOF is a national collection of social care outcomes performance indicators collected from the perspective of people receiving partial or total funding from a LA for care services. The projected costs of introducing the survey as a new statutory measure in England were assessed. The paper aims to discuss these issues. Design/methodology/approach – An outcome measure (a face-to-face interview based survey consisting of seven questions) was piloted during 2014 in 40 LAs with 20 adults at risk (or other informant) in each site who had been the subject of a safeguarding investigation (n=382). LAs were asked to estimate the cost to their LA of conducting the survey for two years, interviewing at least 15 per cent of their completed safeguarding cases each year. Findings – Extrapolating cost findings to the full 152 LAs in England would give an estimated total cost of implementing the survey of approximately £3 million in Year 1 and £2.1 million in Year 2. Set-up costs for the survey can therefore be estimated at around £900,000. Wide variations were identified in the costs per interview between LAs and reasons for this are discussed. Originality/value – The benefits of this unique survey are it enables LAs to measure how they are undertaking their adult safeguarding work from the perspective of adults at risk and others with a close interest. It also enables LAs to meet their new obligations under the Care Act 2014 Guidance to “understand what adults at risk think of adult safeguarding”. </jats:sec

Thiopurine methyltransferase genotype-phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia

AIMS: In children with acute lymphoblastic leukaemia (ALL) bone marrow activity can influence red blood cell (RBC) kinetics, the surrogate tissue for thiopurine methyltransferase (TPMT) measurements. The aim of this study was to investigate TPMT phenotype-genotype concordance in ALL, and the influence of TPMT on thiopurine metabolite formation. METHODS: We measured TPMT (activity, as units ml(-1) packed RBCs and genotype) at diagnosis (n = 1150) and TPMT and thioguanine nucleotide (TGN) and methylmercaptopurine nucleotide (MeMPN) metabolites (pmol/8 × 10(8) RBCs) during chemotherapy (n = 1131) in children randomized to thioguanine or mercaptopurine on the United Kingdom trial ALL97. RESULTS: Median TPMT activity at diagnosis (8.5 units) was significantly lower than during chemotherapy (13.8 units, median difference 5.1 units, 95% confidence interval (CI) 4.8, 5.4, P < 0.0001). At diagnosis genotype-phenotype was discordant. During chemotherapy the overall concordance was 92%, but this fell to 55% in the intermediate activity cohort (45% had wild-type genotypes). For both thiopurines TGN concentrations differed by TPMT status. For mercaptopurine, median TGNs were higher in TPMT heterozygous genotype (754 pmol) than wild-type (360 pmol) patients (median difference 406 pmol, 95% CI 332, 478, P < 0.0001), whilst median MeMPNs, products of the TPMT reaction, were higher in wild-type (10 650 pmol) than heterozygous patients (3868 pmol) (P < 0.0001). In TPMT intermediate activity patients with a wild-type genotype, TGN (median 366 pmol) and MeMPN (median 8590 pmol) concentrations were similar to those in wild-type, high activity patients. CONCLUSIONS: In childhood ALL, TPMT activity should not be used to predict heterozygosity particularly in blood samples obtained at disease diagnosis. Genotype is a better predictor of TGN accumulation during chemotherapy

Additional file 1: of The feasibility of introducing an adult safeguarding measure for inclusion in the Adult Social Care Outcomes Framework (ASCOF): findings from a pilot study

Adult Social Care Safeguarding Survey Interview Schedule – adult at risk. (DOCX 368 kb

Additional file 1: of The feasibility of introducing an adult safeguarding measure for inclusion in the Adult Social Care Outcomes Framework (ASCOF): findings from a pilot study

Adult Social Care Safeguarding Survey Interview Schedule – adult at risk. (DOCX 368 kb