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Joan Miquel Nolla,1 Esperanza Martín,2 Pilar Llamas,3 Javier Manero,4 Arturo Rodríguez de la Serna,5 Manuel Francisco Fernández-Miera,6 Mercedes Rodríguez,6 José Manuel López,7 Alexandra Ivanova,8 Belén Aragón9 1Rheumatology Department, IDIBELL-Hospital Universitari de Bellvitge, Barcelona, 2Hospital Universitario de Getafe, Madrid, 3Hospital Universitario Fundación Jiménez Díaz, Madrid, 4Hospital Universitario Miguel Servet, Zaragoza, 5Hospital de la Santa Creu i Sant Pau, Barcelona, 6Hospital Universitario Marqués de Valdecilla, Santander, 7Hospital Universitario Virgen del Rocío, Sevilla, 8Max Weber Institute, Madrid, 9MSD, Madrid, Spain Objective: To estimate the unit costs of administering intravenous (IV) biological agents in day hospitals (DHs) in the Spanish National Health System.Patients and methods: Data were obtained from 188 patients with rheumatoid arthritis, collected from nine DHs, receiving one of the following IV therapies: infliximab (n=48), rituximab (n=38), abatacept (n=41), or tocilizumab (n=61). The fieldwork was carried out between March 2013 and March 2014. The following three groups of costs were considered: 1) structural costs, 2) material costs, and 3) staff costs. Staff costs were considered a fixed cost and were estimated according to the DH theoretical level of activity, which includes, as well as personal care of each patient, the DH general activities (complete imputation method, CIM). In addition, an alternative calculation was performed, in which the staff costs were considered a variable cost imputed according to the time spent on direct care (partial imputation method, PIM). All costs were expressed in euros for the reference year 2014.Results: The average total cost was €146.12 per infusion (standard deviation [SD] ±87.11; CIM) and €29.70 per infusion (SD ±11.42; PIM). The structure-related costs per infusion varied between €2.23 and €62.35 per patient and DH; the cost of consumables oscillated between €3.48 and €20.34 per patient and DH. In terms of the care process, the average difference between the shortest and the longest time taken by different hospitals to administer an IV biological therapy was 113 minutes.Conclusion: The average total cost of infusion was less than that normally used in models of economic evaluation coming from secondary sources. This cost is even less when the staff costs are imputed according to the PIM. A high degree of variability was observed between different DHs in the cost of the consumables, in the structure-related costs, and in those of the care process. Keywords: day hospitals, rheumatoid arthritis, intravenous biological agents, unit cost of infusion, variability, care process 

Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3–19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8–144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries. http://purl.org/eprint/status/PeerReviewed published version Article

Background Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. Objective To report the first year's screening results for all men at enrolment in the study. Design, setting and participants We recruited men aged 40–69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrolment, and those men with PSA >3 ng/ml were offered prostate biopsy. Outcome measurements and statistical analysis PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. Results and limitations We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%—double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. Conclusions The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease. Patient summary In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment. Take Home Message This report demonstrates that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these higher-risk men resulted in the identification of tumours that were more likely to require treatment.

Background: Allergic rhinitis (AR) management has changed in recent years following the switch from the concept of disease severity to the concept of disease control, publication of the AR clinical decision support system (CDSS) and development of mobile health (m-health) tools for patients (eg Allergy Diary). The Allergy Diary Companion app for healthcare providers is currently being developed and will be launched in 2018. It incorporates the AR CDSS to provide evidence-based treatment recommendations, linking all key stakeholders in AR management. Objective: To produce an electronic version of the AR CDSS (e-CDSS) for incorporation into the Allergy Diary Companion, to describe the app interfaces used to collect information necessary to inform the e-CDSS and to summarize some key features of the Allergy Diary Companion. Methods: The steps involved in producing the e-CDSS and incorporating it into the Allergy Diary Companion were (a) generation of treatment management scenarios; (b) expert consensus on treatment recommendations; (c) generation of electronic decisional algorithms to describe all AR CDSS scenarios; (d) digitization of these algorithms to form the e-CDSS; and (e) embedding the e-CDSS into the app to permit easy user e-CDSS interfacing. Results: Key experts in the AR field agreed on the AR CDSS approach to AR management and on specific treatment recommendations provided by Allergy Diary Companion. Based on this consensus, decision processes were developed and programmed into the Allergy Diary Companion using Titanium Appcelerator (JavaScript) for IOS tablets. To our knowledge, this is the first time the development of any m-health tool has been described in this transparent and detailed way, providing confidence, not only in the app, but also in the provided management recommendations. Conclusion: The Allergy Diary Companion for providers provides guideline and expert-endorsed AR management recommendations. [MASK paper No 32]. © 2018 John Wiley & Sons Ltd

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10−8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction. B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This study made use of data generated by the Wellcome Trust Case Control consortium. Functional studies were supported by the Florida Breast Cancer Foundation. A full description of funding and acknowledgments is provided in Supplementary Note 1.

Background Environment and diet in early life can affect development and health throughout the life course. Metabolic phenotyping of urine and serum represents a complementary systems-wide approach to elucidate environment–health interactions. However, large-scale metabolome studies in children combining analyses of these biological fluids are lacking. Here, we sought to characterise the major determinants of the child metabolome and to define metabolite associations with age, sex, BMI and dietary habits in European children, by exploiting a unique biobank established as part of the Human Early-Life Exposome project (http://www.projecthelix.eu). Methods Metabolic phenotypes of matched urine and serum samples from 1192 children (aged 6–11) recruited from birth cohorts in six European countries were measured using high-throughput 1H nuclear magnetic resonance (NMR) spectroscopy and a targeted LC-MS/MS metabolomic assay (Biocrates AbsoluteIDQ p180 kit). Results We identified both urinary and serum creatinine to be positively associated with age. Metabolic associations to BMI z-score included a novel association with urinary 4-deoxyerythreonic acid in addition to valine, serum carnitine, short-chain acylcarnitines (C3, C5), glutamate, BCAAs, lysophosphatidylcholines (lysoPC a C14:0, lysoPC a C16:1, lysoPC a C18:1, lysoPC a C18:2) and sphingolipids (SM C16:0, SM C16:1, SM C18:1). Dietary-metabolite associations included urinary creatine and serum phosphatidylcholines (4) with meat intake, serum phosphatidylcholines (12) with fish, urinary hippurate with vegetables, and urinary proline betaine and hippurate with fruit intake. Population-specific variance (age, sex, BMI, ethnicity, dietary and country of origin) was better captured in the serum than in the urine profile; these factors explained a median of 9.0% variance amongst serum metabolites versus a median of 5.1% amongst urinary metabolites. Metabolic pathway correlations were identified, and concentrations of corresponding metabolites were significantly correlated (r > 0.18) between urine and serum. Conclusions We have established a pan-European reference metabolome for urine and serum of healthy children and gathered critical resources not previously available for future investigations into the influence of the metabolome on child health. The six European cohort populations studied share common metabolic associations with age, sex, BMI z-score and main dietary habits. Furthermore, we have identified a novel metabolic association between threonine catabolism and BMI of children. Electronic supplementary material The online version of this article (10.1186/s12916-018-1190-8) contains supplementary material, which is available to authorized users.

Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.

1. Evaluate reliability and construct validity of the newly-developed Family Needs Questionnaire - Pediatric (FNQ-P), a 40-item measure assessing the extent to which family's needs are met after a child has an acquired brain injury (ABI). 2. Explore the impact of selected child characteristics on FNQ-P scores.Methods: Parents/caregivers of children with ABI (2-18 years) were recruited across four sites (Canada, Sweden, Lithuania, Australia) for FNQ-P test-retest evaluation. These sites plus a fifth (United Kingdom) completed construct validity evaluation with the Family Burden of Injury Inventory and Strengths and Difficulties Questionnaire. Associations between FNQ-P score and age, injury severity, time post-injury and site were evaluated via stepwise regression.FNQ-P mean scores (n=61) were 64.1% (SD 22.3) and 58.8% (SD 22.6) on test and retest, respectively. Test-retest reliability was good overall (ICC=0.78, 95% CI 0.65-0.86). There was a weak association between FNQ-P and FBII (r=-0.23,The FNQ-P demonstrated good test-retest reliability. Further validity assessment is recommended. Lack of relationship between FNQ-P and variables studied suggests independence of family needs.

BACKGROUND AND AIMS: The relationship between alcohol consumption and cirrhosis is well established. Policies that can influence population-level use of alcohol should, in turn, impact cirrhosis. We examined the effect of population-level alcohol control policies on cirrhosis mortality rates in Lithuania –a high-income European Union country with high levels of alcohol consumption. METHODS: Age-standardized, monthly liver mortality data (deaths per 100,000 adults, aged 15+) from Lithuania were analysed from 2001 to 2018 (n = 216 months) while controlling for economic confounders (gross domestic product and inflation). An interrupted time-series analysis was conducted to estimate the effect of three alcohol control policies implemented in 2008, 2017 and 2018 and the number of cirrhosis deaths averted. RESULTS: There was a significant effect of the 2008 (P < .0001) and 2017 (P = .0003) alcohol control policies but a null effect of the 2018 policy (P = .40). Following the 2008 policy, the cirrhosis mortality rate dropped from 4.93 to 3.41 (95% CI: 3.02–3.80) deaths per 100,000 adults, which equated to 493 deaths averted. Further, we found that following the 2017 policy, the mortality rate dropped from 2.85 to 2.01 (95% CI: 1.50–2.52) deaths per 100,000 adults, corresponding to 245 deaths averted. CONCLUSIONS: Our findings support the hypothesis that alcohol control policies can have a significant, immediate effect on cirrhosis mortality. These policy measures are cost-effective and aid in reducing the burden of liver disease.