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Board of Directors, Forest History Foundation, Inc.

Professional correspondenc

Efficacy of metformin in pregnant obese women: a randomised controlled trial.

Publisher version available.INTRODUCTION: Increasing evidence suggests obesity has its origins prior to birth. There is clear correlation between maternal obesity, high birthweight and offspring risk of obesity in later life. It is also clear that women who are obese during pregnancy are at greater risk of adverse outcomes, including gestational diabetes and stillbirth. The mechanism(s) by which obesity causes these problems is unknown, although hyperglycaemia and insulin resistance are strongly implicated. We present a protocol for a study to test the hypothesis that metformin will improve insulin sensitivity in obese pregnant women, thereby reducing the incidence of high birthweight babies and other pregnancy complications. METHODS AND ANALYSIS: The Efficacy of Metformin in Pregnant Obese Women, a Randomised controlled (EMPOWaR) trial is a double-masked randomised placebo-controlled trial to determine whether metformin given to obese (body mass index >30 kg/m(2)) pregnant women from 16 weeks' gestation until delivery reduces the incidence of high birthweight babies. A secondary aim is to test the mechanism(s) of any effect. Obese women with a singleton pregnancy and normal glucose tolerance will be recruited prior to 16 weeks' gestation and prescribed study medication, metformin or placebo, to be taken until delivery. Further study visits will occur at 28 and 36 weeks' gestation for glucose tolerance testing and to record anthropometric measurements. Birth weight and other measurements will be recorded at time of delivery. Anthropometry of mother and baby will be performed at 3 months postdelivery. As of January 2014, 449 women had been randomised across the UK. ETHICS AND DISSEMINATION: The study will be conducted in accordance with the principles of Good Clinical Practice. A favourable ethical opinion was obtained from Scotland A Research Ethics Committee, reference number 10/MRE00/12. Results will be disseminated at conferences and published in peer-reviewed journals.SCD/09/Chief Scientist Office/United Kingdom MC_G1002463/Medical Research Council/United Kingdom 103782/Wellcome Trust/United Kingdom CZG/2/478/Chief Scientist Office/United Kingdo

Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial.

Open Access article distributed under the terms of CC BY.BACKGROUND: Maternal obesity is associated with increased birthweight, and obesity and premature mortality in adult offspring. The mechanism by which maternal obesity leads to these outcomes is not well understood, but maternal hyperglycaemia and insulin resistance are both implicated. We aimed to establish whether the insulin sensitising drug metformin improves maternal and fetal outcomes in obese pregnant women without diabetes. METHODS: We did this randomised, double-blind, placebo-controlled trial in antenatal clinics at 15 National Health Service hospitals in the UK. Pregnant women (aged >/=16 years) between 12 and 16 weeks' gestation who had a BMI of 30 kg/m(2) or more and normal glucose tolerance were randomly assigned (1:1), via a web-based computer-generated block randomisation procedure (block size of two to four), to receive oral metformin 500 mg (increasing to a maximum of 2500 mg) or matched placebo daily from between 12 and 16 weeks' gestation until delivery of the baby. Randomisation was stratified by study site and BMI band (30-39 vs >/=40 kg/m(2)). Participants, caregivers, and study personnel were masked to treatment assignment. The primary outcome was Z score corresponding to the gestational age, parity, and sex-standardised birthweight percentile of liveborn babies delivered at 24 weeks or more of gestation. We did analysis by modified intention to treat. This trial is registered, ISRCTN number 51279843. FINDINGS: Between Feb 3, 2011, and Jan 16, 2014, inclusive, we randomly assigned 449 women to either placebo (n=223) or metformin (n=226), of whom 434 (97%) were included in the final modified intention-to-treat analysis. Mean birthweight at delivery was 3463 g (SD 660) in the placebo group and 3462 g (548) in the metformin group. The estimated effect size of metformin on the primary outcome was non-significant (adjusted mean difference -0.029, 95% CI -0.217 to 0.158; p=0.7597). The difference in the number of women reporting the combined adverse outcome of miscarriage, termination of pregnancy, stillbirth, or neonatal death in the metformin group (n=7) versus the placebo group (n=2) was not significant (odds ratio 3.60, 95% CI 0.74-17.50; p=0.11). INTERPRETATION: Metformin has no significant effect on birthweight percentile in obese pregnant women. Further follow-up of babies born to mothers in the EMPOWaR study will identify longer-term outcomes of metformin in this population; in the meantime, metformin should not be used to improve pregnancy outcomes in obese women without diabetes.FUNDING: The Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council and National Institute for Health Research partnership

Use of evidence based practices to improve survival without severe morbidity for very preterm infants: results from the EPICE population based cohort.

Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0)OBJECTIVES: To evaluate the implementation of four high evidence practices for the care of very preterm infants to assess their use and impact in routine clinical practice and whether they constitute a driver for reducing mortality and neonatal morbidity. DESIGN: Prospective multinational population based observational study. SETTING: 19 regions from 11 European countries covering 850 000 annual births participating in the EPICE (Effective Perinatal Intensive Care in Europe for very preterm births) project. PARTICIPANTS: 7336 infants born between 24+0 and 31+6 weeks' gestation in 2011/12 without serious congenital anomalies and surviving to neonatal admission. MAIN OUTCOME MEASURES: Combined use of four evidence based practices for infants born before 28 weeks' gestation using an "all or none" approach: delivery in a maternity unit with appropriate level of neonatal care; administration of antenatal corticosteroids; prevention of hypothermia (temperature on admission to neonatal unit >/=36 degrees C); surfactant used within two hours of birth or early nasal continuous positive airway pressure. Infant outcomes were in-hospital mortality, severe neonatal morbidity at discharge, and a composite measure of death or severe morbidity, or both. We modelled associations using risk ratios, with propensity score weighting to account for potential confounding bias. Analyses were adjusted for clustering within delivery hospital. RESULTS: Only 58.3% (n=4275) of infants received all evidence based practices for which they were eligible. Infants with low gestational age, growth restriction, low Apgar scores, and who were born on the day of maternal admission to hospital were less likely to receive evidence based care. After adjustment, evidence based care was associated with lower in-hospital mortality (risk ratio 0.72, 95% confidence interval 0.60 to 0.87) and in-hospital mortality or severe morbidity, or both (0.82, 0.73 to 0.92), corresponding to an estimated 18% decrease in all deaths without an increase in severe morbidity if these interventions had been provided to all infants. CONCLUSIONS: More comprehensive use of evidence based practices in perinatal medicine could result in considerable gains for very preterm infants, in terms of increased survival without severe morbidity

Measure of activity performance of the hand (MAP-Hand) questionnaire: linguistic validation, cultural adaptation and psychometric testing in people with rheumatoid arthritis in the UK

Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0)BACKGROUND: Developed in the Norway, the Measure of Activity Performance of the Hand (MAP-Hand) assesses 18 activities performed using the hands. It was developed for people with rheumatoid arthritis (RA) using patient generated items, which are scored on a 0-3 scale and summarised into a total score range (0 to 54). This study reports the development and psychometric testing of the British English MAP-Hand in a UK population of people with RA. METHODS: Recruitment took place in the National Health Service (NHS) through 17 Rheumatology outpatient clinics. Phase 1 (cross-cultural adaptation) involved: forward translation to British English; synthesis; expert panel review and cognitive debriefing interviews with people with RA. Phase 2 (psychometric testing) involved postal completion of the MAP-Hand, Health Assessment Questionnaire (HAQ), Upper Limb HAQ (ULHAQ), Short-Form 36 (SF-36v2) and Disabilities of the Arm Shoulder Hand (DASH) to measure internal consistency (Cronbach's alpha); concurrent validity (Spearman's correlations) and Minimal Detectable Difference (MDC(95)). The MAP-Hand was repeated three-weeks later to assess test-retest reliability (linear weighted kappa and Intra-Class Correlations (ICC (2,1)). Unidimensionality (internal construct validity) was assessed using (i) Confirmatory Factor Analysis (CFA) (ii) Mokken scaling and (iii) Rasch model. The RUMM2030 software was used, applying the Rasch partial credit model. RESULTS: In Phase 1, 31 participants considered all items relevant. In Phase 2, 340 people completed Test-1 and 273 (80%) completed Test-2 questionnaires. Internal consistency was excellent (alpha = 0.96). Test-retest reliability was good (ICC (2,1) = 0.96 (95% CI 0.94, 0.97)). The MAP-Hand correlated strongly with HAQ20 (rs = .88), ULHAQ (rs = .91), SF-36v2 Physical Functioning (PF) Score (rs = -.80) and DASH (rs = .93), indicating strong concurrent validity. CFA failed to support unidimensionality (Chi-Square 236.0 (df 120; p < 0.001)). However, Mokken scaling suggested a probabilistic ordering. There was differential item functioning (DIF) for gender. Four testlets were formed, resulting in much improved fit and unidimensionality. Following this, testlets were further merged in pairs where opposite bias existed. This resulted in perfect fit to the model. CONCLUSIONS: The British English version of the MAP-Hand has good validity and reliability in people with RA and can be used in both research and clinical practice

Drooling Reduction Intervention randomised trial (DRI): comparing the efficacy and acceptability of hyoscine patches and glycopyrronium liquid on drooling in children with neurodisability.

Open access.OBJECTIVE: Investigate whether hyoscine patch or glycopyrronium liquid is more effective and acceptable to treat drooling in children with neurodisability. DESIGN: Multicentre, single-blind, randomised controlled trial. SETTING: Recruitment through neurodisability teams; treatment by parents. PARTICIPANTS: Ninety children with neurodisability who had never received medication for drooling (55 boys, 35 girls; median age 4 years). EXCLUSION CRITERIA: medication contraindicated; in a trial that could affect drooling or management. INTERVENTION: Children were randomised to receive a hyoscine skin patch or glycopyrronium liquid. Dose was increased over 4 weeks to achieve optimum symptom control with minimal side-effects; steady dose then continued to 12 weeks. PRIMARY AND SECONDARY OUTCOMES: Primary outcome: Drooling Impact Scale (DIS) score at week-4. SECONDARY OUTCOMES: change in DIS scores over 12 weeks, Drooling Severity and Frequency Scale and Treatment Satisfaction Questionnaire for Medication; adverse events; children's perception about treatment. RESULTS: Both medications yielded clinically and statistically significant reductions in mean DIS at week-4 (25.0 (SD 22.2) for hyoscine and 26.6 (SD 16) for glycopyrronium). There was no significant difference in change in DIS scores between treatment groups. By week-12, 26/47 (55%) children starting treatment were receiving hyoscine compared with 31/38 (82%) on glycopyrronium. There was a 42% increased chance of being on treatment at week-12 for children randomised to glycopyrronium relative to hyoscine (1.42, 95% CI 1.04 to 1.95). CONCLUSIONS: Hyoscine and glycopyrronium are clinically effective in treating drooling in children with neurodisability. Hyoscine produced more problematic side effects leading to a greater chance of treatment cessation

Alterations in maternally perceived fetal movement and their association with late stillbirth: findings from the Midland and North of England stillbirth case-control study.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license.OBJECTIVE: To report perception of fetal movements in women who experienced a stillbirth compared with controls at a similar gestation with a live birth. DESIGN: Case-control study. SETTING: 41 maternity units in the UK. PARTICIPANTS: Cases were women who had a late stillbirth >/=28 weeks gestation (n=291) and controls were women with an ongoing pregnancy at the time of the interview (n=733). Controls were frequency matched to cases by obstetric unit and gestational age. METHODS: Data were collected using an interviewer-administered questionnaire which included questions on maternal perception of fetal movement (frequency, strength, increased and decreased movements and hiccups) in the 2 weeks before the interview/stillbirth. Five fetal movement patterns were identified incorporating the changes in strength and frequency in the last 2 weeks by combining groups of similar pattern and risk. Multivariable analysis adjusted for known confounders. PRIMARY OUTCOME MEASURE: Association of maternally perceived fetal movements in relation to late stillbirth. RESULTS: In multivariable analyses, women who reported increased strength of movements in the last 2 weeks had decreased risk of late stillbirth compared with those whose movements were unchanged (adjusted OR (aOR) 0.18, 95% CI 0.13 to 0.26). Women with decreased frequency (without increase in strength) of fetal movements were at increased risk (aOR 4.51, 95% CI 2.38 to 8.55). Daily perception of fetal hiccups was protective (aOR 0.31, 95% CI 0.17 to 0.56). CONCLUSIONS: Increased strength of fetal movements and fetal hiccups is associated with decreased risk of stillbirth. Alterations in frequency of fetal movements are important in identifying pregnancies at increased risk of stillbirth, with the greatest risk in women noting a reduction in fetal activity. Clinical guidance should be updated to reflect that increase in strength and frequency of fetal movements is associated with the lowest risk of stillbirth, and that decreased fetal movements are associated with stillbirth.TRIAL REGISTRATION NUMBER: NCT02025530

Prognostic accuracy of emergency department triage tools for children with suspected COVID-19: The PRIEST observational cohort study.

Preprint CC-BY 4.0 International license.Objectives: Emergency department clinicians can use triage tools to predict adverse outcome and support management decisions for children presenting with suspected COVID-19. We aimed to estimate the accuracy of triage tools for predicting severe illness in children presenting to the emergency department (ED) with suspected COVID-19 infection. Methods: We undertook a mixed prospective and retrospective observational cohort study in 44 EDs across the United Kingdom (UK). We collected data from children attending with suspected COVID-19 between 26 March 2020 and 28 May 2020, and used presenting data to determine the results of assessment using the WHO algorithm, swine flu hospital pathway for children (SFHPC), Paediatric Observation Priority Score (POPS) and Childrens Observation and Severity Tool (COAST). We recorded 30-day outcome data (death or receipt of respiratory, cardiovascular or renal support) to determine prognostic accuracy for adverse outcome. Results: We collected data from 1530 children, including 26 (1.7%) with an adverse outcome. C-statistics were 0.80 (95% confidence interval 0.73-0.87) for the WHO algorithm, 0.80 (0.71-0.90) for POPS, 0.76 (0.67-0.85) for COAST, and 0.71 (0.59-0.82) for SFHPC. Using pre-specified thresholds, the WHO algorithm had the highest sensitivity (0.85) and lowest specificity (0.75), but POPS and COAST could optimise sensitivity (0.96 and 0.92 respectively) at the expense of specificity (0.25 and 0.38 respectively) by using a threshold of any score above zero instead of the pre-specified threshold. Conclusion: Existing triage tools have good but not excellent prediction for adverse outcome in children with suspected COVID-19. POPS and COAST could achieve an appropriate balance of sensitivity and specificity for supporting decisions to discharge home by considering any score above zero to be positive.United Kingdom National Institute for Health Research Health Technology Assessment (HTA) programm

Total versus partial knee replacement in patients with medial compartment knee osteoarthritis: the TOPKAT RCT

All NIHR Journals Library reports have been produced under the terms of a commissioning contract issued by the Secretary of State for Health. Reports may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising.Background: Late-stage medial compartment knee osteoarthritis can be treated using total knee replacement or partial (unicompartmental) knee replacement. There is high variation in treatment choice and insufficient evidence to guide selection. Objective: To assess the clinical effectiveness and cost-effectiveness of partial knee replacement compared with total knee replacement in patients with medial compartment knee osteoarthritis. The findings are intended to guide surgical decision-making for patients, surgeons and health-care providers. Design: This was a randomised, multicentre, pragmatic comparative effectiveness trial that included an expertise component. The target sample size was 500 patients. A web-based randomisation system was used to allocate treatments.This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme