Toenail selenium, plasma selenoprotein P and risk of advanced prostate cancer: A nested case-control study.

Low selenium status may be associated with increased risk of prostate cancer (PC), particularly aggressive PC, and variation in selenoprotein genes may constitute an important modifying factor. We aimed to investigate the association between two selenium status biomarkers [toenail selenium, plasma selenoprotein P (SELENOP)] and risk of advanced, high-grade and advanced-stage PC. We further studied whether variations in selenoprotein genes were associated with PC risk and selenium biomarker concentrations. In the "Diet, Cancer and Health" cohort, 27 178 men aged 50 to 65 years were enrolled from 1993 to 1997. Between baseline and 2012, 1160 cohort participants were diagnosed with advanced PC; among these 462 had high-grade and 281 had advanced-stage disease at diagnosis. Each case was risk set-matched to one control. Toenail selenium and plasma SELENOP concentrations were measured by neutron activation analysis and a SELENOP-ELISA, respectively, and genotyping was performed for 27 selected single nucleotide polymorphisms (SNPs) in 12 selenium pathway genes (including seven selenoproteins) by allele-specific PCR. Toenail selenium and circulating SELENOP concentrations were not associated with advanced, high-grade or advanced-stage PC. After adjustment for multiple testing, none of the genes were associated with PC risk. Neither toenail selenium nor plasma SELENOP was associated with advanced, high-grade or advanced-stage PC.

Evaluating the effectiveness and cost effectiveness of the 'strengthening families, strengthening communities' group-based parenting programme: study protocol and initial insights.

BACKGROUND: Up to 20% of UK children experience socio-emotional difficulties which can have serious implications for themselves, their families and society. Stark socioeconomic and ethnic inequalities in children's well-being exist. Supporting parents to develop effective parenting skills is an important preventive strategy in reducing inequalities. Parenting interventions have been developed, which aim to reduce the severity and impact of these difficulties. However, most parenting interventions in the UK focus on early childhood (0-10 years) and often fail to engage families from ethnic minority groups and those living in poverty. Strengthening Families, Strengthening Communities (SFSC) is a parenting programme designed by the Race Equality Foundation, which aims to address this gap. Evidence from preliminary studies is encouraging, but no randomised controlled trials have been undertaken so far. METHODS/DESIGN: The TOGETHER study is a multi-centre, waiting list controlled, randomised trial, which aims to test the effectiveness of SFSC in families with children aged 3-18 across seven urban areas in England with ethnically and socially diverse populations. The primary outcome is parental mental well-being (assessed by the Warwick-Edinburgh Mental Well-Being Scale). Secondary outcomes include child socio-emotional well-being, parenting practices, family relationships, self-efficacy, quality of life, and community engagement. Outcomes are assessed at baseline, post intervention, three- and six-months post intervention. Cost effectiveness will be estimated using a cost-utility analysis and cost-consequences analysis. The study is conducted in two stages. Stage 1 comprised a 6-month internal pilot to determine the feasibility of the trial. A set of progression criteria were developed to determine whether the stage 2 main trial should proceed. An embedded process evaluation will assess the fidelity and acceptability of the intervention. DISCUSSION: In this paper we provide details of the study protocol for this trial. We also describe challenges to implementing the protocol and how these were addressed. Once completed, if beneficial effects on both parental and child outcomes are found, the impact, both immediate and longer term, are potentially significant. As the intervention focuses on supporting families living in poverty and those from minority ethnic communities, the intervention should also ultimately have a beneficial impact on reducing health inequalities. TRIAL REGISTRATION: Prospectively registered Randomised Controlled Trial ISRCTN15194500 .

Immunoassays are not immune to errors: Examples from two studies of steroid output from freshwater trout farms.

A "reproducibility crisis" is widespread across scientific disciplines, where results and conclusions of studies are not supported by subsequent investigation. Here we provide a steroid immunoassay example where human errors generated unreproducible results and conclusions. Our study was triggered by a scientific report citing abnormally high concentrations (means of 4-79 ng L-1) of three natural sex steroids [11-ketotestosterone (11-KT), testosterone (T) and oestradiol (E2)] in water samples collected from two UK rivers over 4 years (2002-6). Furthermore, the data suggested that trout farms were a major source because reported steroid concentrations were 1.3-6 times higher downstream than upstream. We hypothesised that the reported levels were erroneous due to substances co-extracted from the water causing matrix effects (i.e. "false positives") during measurement by enzyme-linked immunoassay (EIA). Thus, in collaboration with three other groups (including the one that had conducted the 2002-6 study), we carried out field sampling and assaying to examine this hypothesis. Water samples were collected in 2010 from the same sites and prepared for assay using an analogous method [C18 solid phase extraction (SPE) followed by extract clean-up with aminopropyl SPE]. Additional quality control ("spiked" and "blank") samples were processed. Water extracts were assayed for steroids using radioimmunoassay (RIA) as well as EIA. Although there were statistically significant differences between EIA and RIA (and laboratories), there was no indication of matrix effects in the EIAs. Both the EIAs and RIAs (uncorrected for recovery) measured all three natural steroids at <0.6 ng L-1 in all river water samples, indicating that the trout farms were not a significant source of natural steroids. The differences between the two studies were considerable: E2 and T concentrations were ca. 100-fold lower and 11-KT ca. 1000-fold lower than those reported in the 2002-6 study. In the absence of evidence for any marked changes in husbandry practice (e.g. stock, diet) or environmental conditions (e.g. water flow rate) between the study periods, we concluded that calculation errors were probably made in the first (2002-6) study associated with confusion between extract and water sample concentrations. The second (2010) study also had several identified examples of calculation error (use of an incorrect standard curve; extrapolation below the minimum standard; confusion of assay dilutions during result work-up; failure to correct for loss during extraction) and an example of sample contamination. Similar and further errors have been noted in other studies. It must be recognised that assays do not provide absolute measurements and are prone to a variety of errors, so published steroid levels should be viewed with caution until independently confirmed.

Polygenic risk-tailored screening for prostate cancer: A benefit-harm and cost-effectiveness modelling study.

BACKGROUND: The United States Preventive Services Task Force supports individualised decision-making for prostate-specific antigen (PSA)-based screening in men aged 55-69. Knowing how the potential benefits and harms of screening vary by an individual's risk of developing prostate cancer could inform decision-making about screening at both an individual and population level. This modelling study examined the benefit-harm tradeoffs and the cost-effectiveness of a risk-tailored screening programme compared to age-based and no screening. METHODS AND FINDINGS: A life-table model, projecting age-specific prostate cancer incidence and mortality, was developed of a hypothetical cohort of 4.48 million men in England aged 55 to 69 years with follow-up to age 90. Risk thresholds were based on age and polygenic profile. We compared no screening, age-based screening (quadrennial PSA testing from 55 to 69), and risk-tailored screening (men aged 55 to 69 years with a 10-year absolute risk greater than a threshold receive quadrennial PSA testing from the age they reach the risk threshold). The analysis was undertaken from the health service perspective, including direct costs borne by the health system for risk assessment, screening, diagnosis, and treatment. We used probabilistic sensitivity analyses to account for parameter uncertainty and discounted future costs and benefits at 3.5% per year. Our analysis should be considered cautiously in light of limitations related to our model's cohort-based structure and the uncertainty of input parameters in mathematical models. Compared to no screening over 35 years follow-up, age-based screening prevented the most deaths from prostate cancer (39,272, 95% uncertainty interval [UI]: 16,792-59,685) at the expense of 94,831 (95% UI: 84,827-105,630) overdiagnosed cancers. Age-based screening was the least cost-effective strategy studied. The greatest number of quality-adjusted life-years (QALYs) was generated by risk-based screening at a 10-year absolute risk threshold of 4%. At this threshold, risk-based screening led to one-third fewer overdiagnosed cancers (64,384, 95% UI: 57,382-72,050) but averted 6.3% fewer (9,695, 95% UI: 2,853-15,851) deaths from prostate cancer by comparison with age-based screening. Relative to no screening, risk-based screening at a 4% 10-year absolute risk threshold was cost-effective in 48.4% and 57.4% of the simulations at willingness-to-pay thresholds of GBP£20,000 (US$26,000) and £30,000 ($39,386) per QALY, respectively. The cost-effectiveness of risk-tailored screening improved as the threshold rose. CONCLUSIONS: Based on the results of this modelling study, offering screening to men at higher risk could potentially reduce overdiagnosis and improve the benefit-harm tradeoff and the cost-effectiveness of a prostate cancer screening program. The optimal threshold will depend on societal judgements of the appropriate balance of benefits-harms and cost-effectiveness.

Localising occult prostate cancer metastasis with advanced imaging techniques (LOCATE trial): a prospective cohort, observational diagnostic accuracy trial investigating whole-body magnetic resonance imaging in radio-recurrent prostate cancer.

BACKGROUND: Accurate whole-body staging following biochemical relapse in prostate cancer is vital in determining the optimum disease management. Current imaging guidelines recommend various imaging platforms such as computed tomography (CT), Technetium 99 m (99mTc) bone scan and 18F-choline and recently 68Ga-PSMA positron emission tomography (PET) for the evaluation of the extent of disease. Such approach requires multiple hospital attendances and can be time and resource intensive. Recently, whole-body magnetic resonance imaging (WB-MRI) has been used in a single visit scanning session for several malignancies, including prostate cancer, with promising results, providing similar accuracy compared to the combined conventional imaging techniques. The LOCATE trial aims to investigate the application of WB-MRI for re-staging of patients with biochemical relapse (BCR) following external beam radiotherapy and brachytherapy in patients with prostate cancer. METHODS/DESIGN: The LOCATE trial is a prospective cohort, multi-centre, non-randomised, diagnostic accuracy study comparing WB-MRI and conventional imaging. Eligible patients will undergo WB-MRI in addition to conventional imaging investigations at the time of BCR and will be asked to attend a second WB-MRI exam, 12-months following the initial scan. WB-MRI results will be compared to an enhanced reference standard comprising all the initial, follow-up imaging and non-imaging investigations. The diagnostic performance (sensitivity and specificity analysis) of WB-MRI for re-staging of BCR will be investigated against the enhanced reference standard on a per-patient basis. An economic analysis of WB-MRI compared to conventional imaging pathways will be performed to inform the cost-effectiveness of the WB-MRI imaging pathway. Additionally, an exploratory sub-study will be performed on blood samples and exosome-derived human epidermal growth factor receptor (HER) dimer measurements will be taken to investigate its significance in this cohort. DISCUSSION: The LOCATE trial will compare WB-MRI versus the conventional imaging pathway including its cost-effectiveness, therefore informing the most accurate and efficient imaging pathway. TRIAL REGISTRATION: LOCATE trial was registered on ClinicalTrial.gov on 18th of October 2016 with registration reference number NCT02935816.

Barrett's oESophagus trial 3 (BEST3): study protocol for a randomised controlled trial comparing the Cytosponge-TFF3 test with usual care to facilitate the diagnosis of oesophageal pre-cancer in primary care patients with chronic acid reflux.

BACKGROUND: Early detection of oesophageal cancer improves outcomes; however, the optimal strategy for identifying patients at increased risk from the pre-cancerous lesion Barrett's oesophagus (BE) is not clear. The Cytosponge, a novel non-endoscopic sponge device, combined with the biomarker Trefoil Factor 3 (TFF3) has been tested in four clinical studies. It was found to be safe, accurate and acceptable to patients. The aim of the BEST3 trial is to evaluate if the offer of a Cytosponge-TFF3 test in primary care for patients on long term acid suppressants leads to an increase in the number of patients diagnosed with BE. METHODS: The BEST3 trial is a pragmatic multi-site cluster-randomised controlled trial set in primary care in England. Approximately 120 practices will be randomised 1:1 to either the intervention arm, invitation to a Cytosponge-TFF3 test, or the control arm usual care. Inclusion criteria are men and women aged 50 or over with records of at least 6 months of prescriptions for acid-suppressants in the last year. Patients in the intervention arm will receive an invitation to have a Cytosponge-TFF3 test in their general practice. Patients with a positive TFF3 test will receive an invitation for an upper gastro-intestinal endoscopy at their local hospital-based endoscopy clinic to test for BE. The primary objective is to compare histologically confirmed BE diagnosis between the intervention and control arms to determine whether the offer of the Cytosponge-TFF3 test in primary care results in an increase in BE diagnosis within 12 months of study entry. DISCUSSION: The BEST3 trial is a well-powered pragmatic trial testing the use of the Cytosponge-TFF3 test in the same population that we envisage it being used in clinical practice. The data generated from this trial will enable NICE and other clinical bodies to decide whether this test is suitable for routine clinical use. TRIAL REGISTRATION: This trial was prospectively registered with the ISRCTN Registry on 19/01/2017, trial number ISRCTN68382401 .

Effectiveness of an intervention to facilitate prompt referral to memory clinics in the United Kingdom: Cluster randomised controlled trial.

BACKGROUND: Most people with dementia do not receive timely diagnosis, preventing them from making informed plans about their future and accessing services. Many countries have a policy to increase timely diagnosis, but trials aimed at changing general practitioner (GP) practice have been unsuccessful. We aimed to assess whether a GP's personal letter, with an evidence-based leaflet about overcoming barriers to accessing help for memory problems-aimed at empowering patients and families-increases timely dementia diagnosis and patient presentation to general practice. METHODS AND FINDING: Multicentre, cluster-randomised controlled trial with raters masked to an online computer-generated randomisation system assessing 1 y outcome. We recruited 22 general practices (August 2013-September 2014) and 13 corresponding secondary care memory services in London, Hertfordshire, and Essex, United Kingdom. Eligible patients were aged ≥70 y, without a known diagnosis of dementia, living in their own homes. There were 6,387 such patients in 11 intervention practices and 8,171 in the control practices. The primary outcome was cognitive severity on Mini Mental State Examination (MMSE). Main secondary outcomes were proportion of patients consulting their GP with suspected memory disorders and proportion of those referred to memory clinics. There was no between-group difference in cognitive severity at diagnosis (99 intervention, mean MMSE = 22.04, 95% confidence intervals (CIs) = 20.95 to 23.13; 124 control, mean MMSE = 22.59, 95% CI = 21.58 to 23.6; p = 0.48). GP consultations with patients with suspected memory disorders increased in intervention versus control group (odds ratio = 1.41; 95% CI = 1.28, 1.54). There was no between-group difference in the proportions of patients referred to memory clinics (166, 2.5%; 220, 2.7%; p = .077 respectively). The study was limited as we do not know whether the additional patients presenting to GPs had objective as well as subjective memory problems and therefore should have been referred. In addition, we aimed to empower patients but did not do anything to change GP practice. CONCLUSIONS: Our intervention to access timely dementia diagnosis resulted in more patients presenting to GPs with memory problems, but no diagnoses increase. We are uncertain as to the reason for this and do not know whether empowering the public and targeting GPs would have resulted in a successful intervention. Future interventions should be targeted at both patients and GPs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN19216873.

Genome-wide association study of selenium concentrations.

Selenium (Se) is an essential trace element in human nutrition, but its role in certain health conditions, particularly among Se sufficient populations, is controversial. A genome-wide association study (GWAS) of blood Se concentrations previously identified a locus at 5q14 near BHMT. We performed a GW meta-analysis of toenail Se concentrations, which reflect a longer duration of exposure than blood Se concentrations, including 4162 European descendants from four US cohorts. Toenail Se was measured using neutron activation analysis. We identified a GW-significant locus at 5q14 (P < 1 × 10(-16)), the same locus identified in the published GWAS of blood Se based on independent cohorts. The lead single-nucleotide polymorphism (SNP) explained ∼1% of the variance in toenail Se concentrations. Using GW-summary statistics from both toenail and blood Se, we observed statistical evidence of polygenic overlap (P < 0.001) and meta-analysis of results from studies of either trait (n = 9639) yielded a second GW-significant locus at 21q22.3, harboring CBS (P < 4 × 10(-8)). Proteins encoded by genes at 5q14 and 21q22.3 function in homocysteine (Hcy) metabolism, and index SNPs for each have previously been associated with betaine and Hcy levels in GWAS. Our findings show evidence of a genetic link between Se and Hcy pathways, both involved in cardiometabolic disease.

Effects of evidence-based strategies to reduce the socioeconomic gradient of uptake in the English NHS Bowel Cancer Screening Programme (ASCEND): four cluster-randomised controlled trials.

BACKGROUND: Uptake in the national colorectal cancer screening programme in England varies by socioeconomic status. We assessed four interventions aimed at reducing this gradient, with the intention of improving the health benefits of screening. METHODS: All people eligible for screening (men and women aged 60-74 years) across England were included in four cluster-randomised trials. Randomisation was based on day of invitation. Each trial compared the standard information with the standard information plus the following supplementary interventions: trial 1 (November, 2012), a supplementary leaflet summarising the gist of the key information; trial 2 (March, 2012), a supplementary narrative leaflet describing people's stories; trial 3 (June, 2013), general practice endorsement of the programme on the invitation letter; and trial 4 (July-August, 2013) an enhanced reminder letter with a banner that reiterated the screening offer. Socioeconomic status was defined by the Index of Multiple Deprivation score for each home address. The primary outcome was the socioeconomic status gradient in uptake across deprivation quintiles. This study is registered, number ISRCTN74121020. FINDINGS: As all four trials were embedded in the screening programme, loss to follow-up was minimal (less than 0·5%). Trials 1 (n=163,525) and 2 (n=150,417) showed no effects on the socioeconomic gradient of uptake or overall uptake. Trial 3 (n=265 434) showed no effect on the socioeconomic gradient but was associated with increased overall uptake (adjusted odds ratio [OR] 1·07, 95% CI 1·04-1·10, p<0·0001). In trial 4 (n=168 480) a significant interaction was seen with socioeconomic status gradient (p=0·005), with a stronger effect in the most deprived quintile (adjusted OR 1·11, 95% CI 1·04-1·20, p=0·003) than in the least deprived (1·00, 0·94-1·06, p=0·98). Overall uptake was also increased (1·07, 1·03-1·11, p=0·001). INTERPRETATION: Of four evidence-based interventions, the enhanced reminder letter reduced the socioeconomic gradient in screening uptake, but further reducing inequalities in screening uptake through written materials alone will be challenging. FUNDING: National Institute for Health Research.

Reducing the socioeconomic gradient in uptake of the NHS bowel cancer screening Programme using a simplified supplementary information leaflet: a cluster-randomised trial.

BACKGROUND: Uptake of colorectal cancer screening is low in the English NHS Bowel Cancer Screening Programme (BCSP). Participation in screening is strongly associated with socioeconomic status. The aim of this study was to determine whether a supplementary leaflet providing the 'gist' of guaiac-based Faecal Occult Blood test (gFOBt) screening for colorectal cancer could reduce the socioeconomic status (SES) gradient in uptake in the English NHS BCSP. METHODS: The trial was integrated within routine BCSP operations in November 2012. Using a cluster randomised controlled design all adults aged 59-74 years who were being routinely invited to complete the gFOBt were randomised based on day of invitation. The Index of Multiple Deprivation was used to create SES quintiles. The control group received the standard information booklet ('SI'). The intervention group received the SI booklet and the Gist leaflet ('SI + Gist') which had been designed to help people with lower literacy engage with the invitation. Blinding of hubs was not possible and invited subjects were not made aware of a comparator condition. The primary outcome was the gradient in uptake across IMD quintiles. RESULTS: In November 2012, 163,525 individuals were allocated to either the 'SI' intervention (n = 79,104) or the 'SI + Gist' group (n = 84,421). Overall uptake was similar between the intervention and control groups (SI: 57.3% and SI + Gist: 57.6%; OR = 1.02, 95% CI: 0.92-1.13, p = 0.77). Uptake was 42.0% (SI) vs. 43.0% (SI + Gist) in the most deprived quintile and 65.6% vs. 65.8% in the least deprived quintile (interaction p = 0.48). The SES gradient in uptake was similar between the study groups within age, gender, hub and screening round sub-groups. CONCLUSIONS: Providing supplementary simplified information in addition to the standard information booklet did not reduce the SES gradient in uptake in the NHS BCSP. The effectiveness of the Gist leaflet when used alone should be explored in future research. TRIAL REGISTRATION: ISRCTN74121020 , registered: 17/20/2012.

Streamlining staging of lung and colorectal cancer with whole body MRI; study protocols for two multicentre, non-randomised, single-arm, prospective diagnostic accuracy studies (Streamline C and Streamline L).

BACKGROUND AND AIMS: Rapid and accurate cancer staging following diagnosis underpins patient management, in particular the identification of distant metastatic disease. Current staging guidelines recommend sequential deployment of various imaging platforms such as computerised tomography (CT) and positron emission tomography (PET) which can be time and resource intensive and onerous for patients. Recent studies demonstrate that whole body magnetic resonance Imaging (WB-MRI) may stage cancer efficiently in a single visit, with potentially greater accuracy than current staging investigations. The Streamline trials aim to evaluate whether WB-MRI increases per patient detection of metastases in non-small cell lung and colorectal cancer compared to standard staging pathways. METHODS: The Streamline trials are multicentre, non-randomised, single-arm, prospective diagnostic accuracy studies with a novel design to capture patient management decisions during staging pathways. The two trials recruit adult patients with proven or highly suspected new diagnosis of primary colorectal (Streamline C) or non-small cell lung cancer (Streamline L) referred for staging. Patients undergo WB-MRI in addition to standard staging investigations. Strict blinding protocols are enforced for those interpreting the imaging. A first major treatment decision is made by the multi-disciplinary team prior to WB-MRI revelation based on standard staging investigations only, then based on the WB-MRI and any additional tests precipitated by WB-MRI, and finally based on all available test results. The reference standard is derived by a multidisciplinary consensus panel who assess 12 months of follow-up data to adjudicate on the TNM stage at diagnosis. Health psychology assessment of patients' experiences of the cancer staging pathway will be undertaken via interviews and questionnaires. A cost (effectiveness) analysis of WB-MRI compared to standard staging pathways will be performed. DISCUSSION: We describe a novel approach to radiologist and clinician blinding to ascertain the 'true' diagnostic accuracy of differing imaging pathways and discuss our approach to assessing the impact of WB-MRI on clinical decision making in real-time. The Streamline trials will compare WB-MRI and standard imaging pathways in the same patients, thereby informing the most accurate and efficient approach to staging. TRIAL REGISTRATION: Streamline C ISRCTN43958015 (registered 25/7/2012). Streamline L ISRCTN50436483 (registered 31/7/2012).

Promoting independence, health and well-being for older people: a feasibility study of computer-aided health and social risk appraisal system in primary care.

BACKGROUND: With population ageing, research is needed into new low-cost, scalable methods of effective promotion of health and wellbeing for older people. We aimed to assess feasibility, reach and costs of implementing a new tailored computer-aided health and social risk appraisal system in primary care. METHODS: Design: Feasibility study. SETTING: Five General Practices in London (Ealing) and Hertfordshire, United Kingdom (UK) Participants: Random sample of patients aged 65 + years. INTERVENTION: The Multi-dimensional Risk Appraisal for Older people (MRA-O) system includes: 1) Postal questionnaire including health, lifestyle, social and environmental domains; 2) Software system generating a personalised feedback report with advice on health and wellbeing; 3) Follow-up of people with new concerning or complex needs by GPs or practice nurses. EVALUATION: Feasibility of implementation; participant wellbeing, functional ability and quality of life; social needs, health risks, potential lifestyle changes; and costs of implementation. RESULTS: Response rates to initial postal invitations were low (526/1550, 34%). Of these, 454/526 (86%) completed MRA-O assessments. Compared to local UK Census data on older people, participants were younger, more were owner-occupiers and fewer were from ethnic minority groups than expected. A range of problems was identified by participants, including pain in last week (269/438, 61.4%), low physical activity (173/453, 38.2%), sedentary lifestyle (174/447, 38.3%), falls (117/439, 26.7%), incontinence (111/441 25.2%), impaired vision 116/451 (25.7%), impaired hearing (145/431, 33.6%), depressed mood (71/451, 15.7%), impaired memory (44/444 9.9%), social isolation (46/449, 10.2%) and loneliness (31/442, 7.0%). Self-rated health was good/excellent in 312/437 (71.4%), and quality of life and well-being were slightly above age-specific population norms. Implementation costs were low. Practices reviewed medical records of 143/454 (31.5%) of participants as a consequence of their responses, and actively followed up 110/454 (24.2%) of their patients. CONCLUSIONS: A computer-aided risk appraisal system was feasible for General Practices to implement, yields useful information about health and social problems, and identifies individual needs. Participation rates were however low, particularly for the oldest old, the poorest, and ethnic minority groups, and this type of intervention may increase inequalities in access. Widespread implementation of this approach would require work to address potential inequalities.

Validation of the OECD reproduction test guideline with the New Zealand mudsnail Potamopyrgus antipodarum using trenbolone and prochloraz.

The Organisation for Economic Cooperation and Development (OECD) provides several standard test methods for the environmental hazard assessment of chemicals, mainly based on primary producers, arthropods, and fish. In April 2016, two new test guidelines with two mollusc species representing different reproductive strategies were approved by OECD member countries. One test guideline describes a 28-day reproduction test with the parthenogenetic New Zealand mudsnail Potamopyrgus antipodarum. The main endpoint of the test is reproduction, reflected by the embryo number in the brood pouch per female. The development of a new OECD test guideline involves several phases including inter-laboratory validation studies to demonstrate the robustness of the proposed test design and the reproducibility of the test results. Therefore, a ring test of the reproduction test with P. antipodarum was conducted including eight laboratories with the test substances trenbolone and prochloraz and results are presented here. Most laboratories could meet test validity criteria, thus demonstrating the robustness of the proposed test protocol. Trenbolone did not have an effect on the reproduction of the snails at the tested concentration range (nominal: 10-1000 ng/L). For prochloraz, laboratories produced similar EC10 and NOEC values, showing the inter-laboratory reproducibility of results. The average EC10 and NOEC values for reproduction (with coefficient of variation) were 26.2 µg/L (61.7%) and 29.7 µg/L (32.9%), respectively. This ring test shows that the mudsnail reproduction test is a well-suited tool for use in the chronic aquatic hazard and risk assessment of chemicals.

A novel multimodality endoscopic device for colonic submucosal dissection using a combination of bipolar radiofrequency and microwave modalities.

BACKGROUND AND STUDY AIMS: Current submucosal dissection devices are technically challenging to use, resulting in long and sometimes incomplete colonic polyp resections. The aim of this feasibility preclinical study was to evaluate a new, multimodality instrument with novel electrocautery properties. METHODS: Six female adult pigs underwent colonic submucosal resections. The novel device was used to cut mucosa and submucosa using bipolar radiofrequency (BRF; at 400 KHz), provide hemostasis with microwave coagulation (MWC; at 5.8 GHz), and inject fluid via a retractable needle. The main outcomes measured were safety (histological analysis post-recovery), performance, and time needed to achieve complete resection. RESULTS: A total of 12 consecutive colonic pseudopolyps were completely excised (two per subject) using BRF cutting. The median time to complete resection was 44.3 minutes (SD 8.9). The median defect size was 32.8 mm (SD 4.3). MWC was applied on 37 occasions for pre-coagulation or treatment of bleeding vessels. One microperforation was treated successfully with endoscopic clips. All animals recovered uneventfully during the 28-day survival period. Histology confirmed adequate healing in all postmortem defects. CONCLUSIONS: In this preclinical evaluation, the novel multimodality endoscopic device facilitated rapid and safe en bloc resection of colonic pseudopolyps.

Comparing the mapping between EQ-5D-5L, EQ-5D-3L and the EORTC-QLQ-C30 in non-small cell lung cancer patients.

BACKGROUND: Several mapping algorithms have been published with the EORTC-QLQ-C30 for estimating EQ-5D-3L utilities. However, none are available with EQ-5D-5L. Moreover, a comparison between mapping algorithms in the same set of patients has not been performed for these two instruments simultaneously. In this prospective data set of 100 non-small cell lung cancer (NSCLC) patients, we investigate three mapping algorithms using the EQ-5D-3L and EQ-5D-5L and compare their performance. METHODS: A prospective non-interventional cohort of 100 NSCLC patients were followed up for 12 months. EQ-5D-3L, EQ-5D-5L and EORTC-QLQ-C30 were assessed monthly. EQ-5D-5L was completed at least 1 week after EQ-5D-3L. A random effects linear regression model, a beta-binomial (BB) and a Limited Variable Dependent Mixture (LVDM) model were used to determine a mapping algorithm between EQ-5D-3L, EQ-5D-5L and QLQ-C30. Simulation and cross validation and other statistical measures were used to compare the performances of the algorithms. RESULTS: Mapping from the EQ-5D-5L was better: lower AIC, RMSE, MAE and higher R(2) were reported with the EQ-5D-5L than with EQ-5D-3L regardless of the functional form of the algorithm. The BB model proved to be more useful for both instruments: for the EQ-5D-5L, AIC was -485, R(2) of 75 %, MAE of 0.075 and RMSE was 0.092. This was -385, 69 %, 0.099 and 0.113 for EQ-5D-3L respectively. The mean observed vs. predicted utilities were 0.572 vs. 0.577 and 0.515 vs. 0.523 for EQ-5D-5L and EQ-5D-3L respectively, for OLS; for BB, these were 0.572 vs. 0.575 and 0.515 vs. 0.518 respectively and for LVDMM 0.532 vs 0.515 and 0.569 vs 0.572 respectively. Less over-prediction at poorer health states was observed with EQ-5D-5L. CONCLUSIONS: The BB mapping algorithm is confirmed to offer a better fit for both EQ-5D-3L and EQ-5D-5L. The results confirm previous and more recent results on the use of BB type modelling approaches for mapping. It is recommended that in studies where EQ-5D utilities have not been collected, an EQ-5D-5L mapping algorithm is used.

The cost of local, multi-professional obstetric emergencies training.

INTRODUCTION: We aim to outline the annual cost of setting up and running a standard, local, multi-professional obstetric emergencies training course, PROMPT (PRactical Obstetric Multi-Professional Training), at Southmead Hospital, Bristol, UK - a unit caring for approximately 6500 births per year. MATERIAL AND METHODS: A retrospective, micro-costing analysis was performed. Start-up costs included purchasing training mannequins and teaching props, printing of training materials and assembly of emergency boxes (real and training). The variable costs included administration time, room hire, additional printing and the cost of releasing all maternity staff in the unit, either as attendees or trainers. Potential, extra start-up costs for maternity units without established training were also included. RESULTS: The start-up costs were €5574 and the variable costs for 1 year were €143 232. The total cost of establishing and running training at Southmead for 1 year was €148 806. Releasing staff as attendees or trainers accounted for 89% of the total first year costs, and 92% of the variable costs. The cost of running training in a maternity unit with around 6500 births per year was approximately €23 000 per 1000 births for the first year and around €22 000 per 1000 births in subsequent years. CONCLUSIONS: The cost of local, multi-professional obstetric emergencies training is not cheap, with staff costs potentially representing over 90% of the total expenditure. It is therefore vital that organizations consider the clinical effectiveness of local training packages before implementing them, to ensure the optimal allocation of finite healthcare budgets.

Estimating the cost of caring for people with cancer at the end of life: A modelling study.

BACKGROUND: People with advanced cancer require a range of health, social and informal care during the final phases of life. The cost of providing care to this group as they approach the end of their lives is unknown, but represents a significant cost to health and social care systems, charities patients and their families. AIM: In this study, we estimate the direct and indirect costs for lung, breast, colorectal and prostate cancer patients at the end of life (from the start of strong opioids to death) in England and Wales. METHODS: We use a modelling-based approach to estimate the costs of care. Data are estimated from the literature and publicly available data sets. Probabilistic sensitivity analysis is used to reflect uncertainty in model estimates. RESULTS: Total estimated costs for treating people with these four cancers at the end of life are £ 641 million. Breast and prostate cancer patients have the highest expected cost per person at £ 12,663 (95% credible interval (CI): £ 1249-£ 38,712) and £ 14,859 (95% CI: £ 1391-£ 46,424), respectively. Lung cancer has the highest expected total cost (£ 226 m). The value of informal care giving accounts for approximately one-third of all costs. CONCLUSION: The cost to society of providing care to people at the end of their lives is significant. Much of this cost is borne by informal care givers. The cost to formal care services of replacing this care with paid care giving would be significant and demand for care will increase as the demographic profile of the population ages.

Longitudinal assessment of colonoscopy quality indicators: a report from the Gastroenterology Practice Management Group.

BACKGROUND: There is increasing demand for colonoscopy quality measures for procedures performed in ambulatory surgery centers. Benchmarks such as adenoma detection rate (ADR) are traditionally reported as static, one-dimensional point estimates at a provider or practice level. OBJECTIVE: To evaluate 6-year variability of ADRs for 370 gastroenterologists from across the nation. DESIGN: Observational cross-sectional analysis. SETTING: Collaborative quality metrics database from 2007 to 2012. PATIENTS: Patients who underwent colonoscopies in ambulatory surgery centers. INTERVENTIONS: Colonoscopy. MAIN OUTCOME MEASUREMENTS: The number of colonoscopies with an adenomatous polyp divided by the total number of colonoscopies (ADR-T), inclusive of indication and patient's sex. RESULTS: Data from 368,157 colonoscopies were included for analysis from 11 practices. Three practice sites (5, 8, and 10) were significantly above and 2 sites (3, 7) were significantly below mean ADR-T, with a 95% confidence interval (CI). High-performing sites had 9.0% higher ADR-T than sites belonging to the lowest quartile (P < .001). The mean ADR-T remained stable for 9 of 11 sites. Regression analysis showed that the 2 practice sites where ADR-T varied had significant improvements in ADR-T during the 6-year period. For each, mean ADR-T improved an average of 0.5% per quarter for site 2 (P = .001) and site 3 (P = .021), which were average and low performers, respectively. LIMITATIONS: Summary-level data, which does not allow cross-reference of variables at an individual level. CONCLUSION: We found performance disparities among practice sites remaining relatively consistent over a 6-year period. The ability of certain sites to sustain their high-performance over 6 years suggests that further research is needed to identify key organizational processes and physician incentives that improve the quality of colonoscopy.

METRIC (MREnterography or ulTRasound in Crohn's disease): a study protocol for a multicentre, non-randomised, single-arm, prospective comparison study of magnetic resonance enterography and small bowel ultrasound compared to a reference standard in those aged 16 and over.

BACKGROUND: Crohn's disease (CD) is a lifelong, relapsing and remitting inflammatory condition of the intestine. Medical imaging is crucial for diagnosis, phenotyping, activity assessment and detecting complications. Diverse small bowel imaging tests are available but a standard algorithm for deployment is lacking. Many hospitals employ tests that impart ionising radiation, of particular concern to this young patient population. Magnetic resonance enterography (MRE) and small bowel ultrasound (USS) are attractive options, as they do not use ionising radiation. However, their comparative diagnostic accuracy has not been compared in large head to head trials. METRIC aims to compare the diagnostic efficacy, therapeutic impact and cost effectiveness of MRE and USS in newly diagnosed and relapsing CD. METHODS: METRIC (ISRCTN03982913) is a multicentre, non-randomised, single-arm, prospective comparison study. Two patient cohorts will be recruited; those newly diagnosed with CD, and those with suspected relapse. Both will undergo MRE and USS in addition to other imaging tests performed as part of clinical care. Strict blinding protocols will be enforced for those interpreting MRE and USS. The Harvey Bradshaw index, C-reactive protein and faecal calprotectin will be collected at recruitment and 3 months, and patient experience will be assessed via questionnaires. A multidisciplinary consensus panel will assess all available clinical and imaging data up to 6 months after recruitment of each patient and will define the standard of reference for the presence, localisation and activity of disease against which the diagnostic accuracy of MRE and USS will be judged. Diagnostic impact of MRE and USS will be evaluated and cost effectiveness will be assessed. The primary outcome measure is the difference in per patient sensitivity between MRE and USS for the correct identification and localisation of small bowel CD. DISCUSSION: The trial is open at 5 centres with 46 patients recruited. We highlight the importance of stringent blinding protocols in order to delineate the true diagnostic accuracy of both imaging tests and discuss the difficulties of diagnostic accuracy studies in the absence of a single standard of reference, describing our approach utilising a consensus panel whilst minimising incorporation bias. TRIAL REGISTRATION: METRIC - ISRCTN03982913 - 05.11.13.