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Background: Besides clinical signs and imaging, in recent years, biomarkers have proven to be a viable diagnostic resource for acute appendicitis (AA).Objective: The objective of this study was to develop a clinical score including clinical signs and a combination of biomarkers to identify children with abdominal pain at low risk of AA.Design/methods: We prospectively included children 2 to 14 years of age with abdominal pain suggestive of AA who presented to the emergency department between July 2016 and September 2017. A new score, the Pediatric Appendicitis Laboratory Score (PALabS) including clinical signs, leucocyte (WBC) and neutrophil (ANC) counts and plasma C-reactive protein (CRP) and calprotectin (CP) levels was developed and validated through secondary analyses of two distinct cohorts The validation sample included visits to a single pediatric emergency department from 2012 to 2013 and 2016 to 2017.Results: The derivation sample included 278 children, 35.9% of whom had AA and the validation sample included 255 children, 49% of whom had AA. Using logistic regression, we created a 6-part score that consisted of nausea (3 points), history of focal right lower quadrant pain (4 points), ANC of ≥7500/μL (7 points), WBC of ≥10,000/μL (4 points), CRP ≥ 10.0 mg/L (2 points) and CP ≥ 0.50 ≥ ng/mL (3 points). This score exhibited a high discriminatory power (area under the curve: 0.88; 95% confidence interval: 0.84 to 0.92) and outperformed the PAS and Kharbanda scores (area under the curve: 0.76; 95% confidence interval: 0.71 to 0.82 and 0.82; 95% confidence interval: 0.77 to 0.87, respectively). A PALabS ≤6 had a sensitivity of 99.2% (95% confidence interval [CI]: 95.6-99.9), negative predictive value of 97.6% (95% CI: 87.7-99.6), and negative likelihood ratio of 0.03 (95% CI: 0.00-0.18) in the validation set.Conclusion: In our validation cohort of patients with acute abdominal pain, the new score can accurately predict which children are at low risk of appendicitis and could be safely managed with close observation. [ABSTRACT FROM AUTHOR]

The population-based Basque Colorectal Cancer (CRC) Screening Programme started in 2009 with a biennial immunochemical quantitative test (FIT) biennial and colonoscopy under sedation in positive cases. The population target of 586,700 residents was from 50 to 69 years old and the total coverage was reached at the beginning of 2014. The aim of our study was to determine possible scenarios in terms of incidence, mortality and reduction of Life-years-Lost (L-y-L) in the medium and long term of CRC.Methods: Invitations were sent out by the Programme from 2009 to 2014, with combined organizational strategies. Simulation was done by MISCAN-colon (Microsimulation Screening Analysis) over 30 years comparing the results of screening vs no-screening, taking the population-based Cancer Registry into account. Lifetime population and real data from the Programme were used from 2008 to 2012. The model was run differentially for men and women.Results: 924,416 invitations were sent out from 2009 to 2014. The average participation rate was 68.4%, CRC detection rate was 3.4% and the Advanced Adenoma detection rate was 24.0‰, with differences observed in sex and age. Future scenarios showed a higher decrease of incidence (17.2% vs 14.7%), mortality (28.1% vs 22.4%) and L-y-L (22.6% vs 18.4%) in men than women in 2030.Conclusions: The Basque Country CRC Programme results are aligned to its strategy and comparable to other programmes. MISCAN model was found to be a useful tool to predict the benefits of the programme in the future. The effectiveness of the Programme has not been formally established as case control studies are required to determine long term benefits from the screening strategy. [ABSTRACT FROM AUTHOR]

Severe coronavirus disease 2019 (COVID-19) often leads to acute respiratory distress syndrome and multi-organ dysfunction, driven by a dysregulated immune response, including a cytokine storm with elevated proinflammatory cytokine levels. Natural killer (NK) cells are part of the innate immune system with a fundamental role in the defense against viral infections. However, during COVID-19 acute infection, they exhibit an altered phenotype and impaired functionality contributing to the immunopathogenesis of the disease. In this work, we have studied a cohort of patients with COVID-19 (ranging from mild to severe) by analyzing IL-15, TGF-β, PlGF and GDF-15 plasma levels and performing multiparametric flow cytometry studies. Our results revealed that severe COVID-19 patients exhibited high levels of IL-15, PlGF and GDF-15, along with an enrichment of an NK cell subset expressing the CD151 tetraspanin, which correlated with IL-15 plasma levels and disease severity. In patients, these CD151+ NK cells displayed a more activated phenotype characterized by an increased expression of HLA-DR, CD38 and granzyme B, a distinct receptor repertoire, with lower levels of CD160 and CD31 and higher levels of CD55 and, remarkably, a higher expression of tissue-resident markers CD103 and the NK cell decidual marker CD9. Last of all, in individuals with severe disease, we identified an expansion of a CD151 bright CD9+ NK cell subset, suggesting that these cells play a specific role in COVID-19. Altogether, our findings suggest that CD151+ NK cells may have a relevant role in COVID-19 immunopathogenesis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The genetic basis of severe COVID-19 has been thoroughly studied, and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we conducted a genome-wide association study (GWAS) for COVID-19 hospitalization in admixed Americans, comprising a total of 4702 hospitalized cases recruited by SCOURGE and seven other participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and were first discovered in Latin American populations ( BAZ2B and DDIAS ). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in CREBBP . Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort. This study constitutes the largest GWAS for COVID-19 hospitalization in admixed Latin Americans conducted to date. This allowed to reveal novel risk loci and emphasize the need of considering the diversity of populations in genomic research., Competing Interests: SD, RC, AL, JL, Md, IQ, RG, VN, MP, JT, JN, JA, CA, SA, VA, BA, NA, ÁA, EA, CA, MA, MA, RB, MB, MB, JB, MB, LB, MB, RB, MB, EC, CC, LC, JC, RC, MC, JC, MC, MD, AD, Vd, Ad, ED, RE, MF, MF, UF, AF, TF, MG, BG, JG, BÁ, FB, AG, JG, JG, MH, AH, MJ, ML, AB, RL, EM, CM, VM, OM, IM, MM, AM, JM, EM, PM, VC, SO, EO, MP, EP, NS, PP, PP, MP, TP, MP, GP, EP, GP, AP, SL, SR, MF, ER, FR, JR, FR, JR, PR, JS, JS, ET, AT, JT, AT, LT, MU, JV, ZY, RZ, Id, AR, PS, LR, EG, CA, EP, JR, AR, CF, PL, ÁC No competing interests declared, (© 2024, Diz-de Almeida, Cruz et al.)

Objective: To update the incidence rate (IR) and trends of type 1 diabetes mellitus (T1DM) in children aged 0-14 years from 2003 to 2022, in Biscay, Spain., Subjects and Method: We used the capture-recapture method: primary cases were prospectively extracted from the hospital registry and a secondary independent data source was obtained from diabetes associations and a public health database. The IRs standardized by age and sex were calculated using the direct method, assuming an equal distribution in each age/sex group. The IR occurring during the various COVID-19 waves was compared with the pre-pandemic IR., Results: A total of 378 new cases were identified. The mean age at diagnosis was 9.7 years (5.8-11.9). The completeness of ascertainment was 99.1%. The mean annual age-standardized IR was 12.92 (95%CI, 11.35-13.91). The mean IRs for the 0-4, 5-9, and 10-14 age groups were 7.67, 13.41 and 17.83 cases/100,000 children/year, respectively. The IR trend was statistically significant in the entire group and in the 5-9 year-old group with a mean annual increase of 1.9% (95%CI, 0.1-3.8) and 3.3% (95%CI, 1.002-1.065); p=0.039. The 5-year period analysis confirmed that the increase was significant only in the last 5 years (20%). When 2020-2022 (pandemic) and 2017-2019 (pre-pandemic) periods were compared this difference goes up to 44.5%; p=0.029., Conclusions: After a long period of stability in the IR of T1DM in children younger than 15 years of age in Biscay, Spain, an increase in recent years has been reported, which is consistent with the SARS-CoV2 pandemic, with the largest increase being reported in the 5-to 9-year-old age group., (Copyright © 2024 SEEN and SED. Published by Elsevier España, S.L.U. All rights reserved.)

CombiVacS study has demonstrated a strong immune response of the heterologous ChAdOx1-S/BNT162b2 vaccine combination. The primary outcomes of the study were to assess the humoral immune response against SARS-CoV-2, 28 days after a third dose of a mRNA vaccine, in subjects that received a previous prime-boost scheme with ChAdOx1-S/BNT162b2. Secondary outcomes extended the study to 3 and 6 months. The third vaccine dose of mRNA-1273 in naive participants previously vaccinated with ChAdOx1-S/BNT162b2 regimen reached higher neutralizing antibodies titers against the variants of concern Delta and BA.1 lineage of Omicron compared with those receiving a third dose of BNT162b2 at day 28. These differences between BNT162b2 and mRNA-1273 arms were observed against the ancestral variant G614 at day 90. Suboptimal neutralizing response was observed against BQ.1.1, XBB.1.5/XBB.1.9, and JN.1 in a relevant proportion of individuals 180 days after the third dose, even after asymptomatic Omicron breakthrough infections. EudraCT (2021-001978-37); ClinicalTrials.gov (NCT04860739)., Competing Interests: J.A. has received fees for educational programs from Gilead, MSD, GSK and Janssen outside of the submitted work. M.C.-A. has participated in advisory boards and has received research funding from GSK, Sanofi Pasteur, Pfizer, Novavax, and Janssen. C.B.-I. is the deputy general manager of the Instituto de Salud Carlos III. J.R.A. has received fees from Janssen, outside of the submitted work. A.M.B. is principal investigator of clinical trials sponsored by GlaxoSmithKline, Daiichi-Sankyo, Janssen, and Farmalider, outside of the submitted work., (© 2024 The Authors.)

(1) Background: The global coronavirus disease 2019 vaccination adapts to protect populations from emerging variants. This communication presents interim findings from the new Omicron XBB.1.16-adapted PHH-1V81 protein-based vaccine compared to an XBB.1.5-adapted mRNA vaccine against various acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains. (2) Methods: In a Phase IIb/III pivotal trial, adults previously vaccinated with a primary scheme and at least one booster dose of an EU-approved mRNA vaccine randomly received either the PHH-1V81 or BNT162b2 XBB.1.5 vaccine booster as a single dose. The primary efficacy endpoint assessed neutralization titers against the Omicron XBB.1.16 variant at day 14. Secondary endpoints evaluated neutralization titers and cellular immunity against different variants. Safety endpoints comprised solicited reactions up to day 7 post-vaccination and serious adverse events until the cut-off date of the interim analysis. Changes in humoral responses were assessed by pseudovirion-based or virus neutralization assays. (3) Results: At the cut-off date, immunogenicity assessments included 599 participants. Both boosters elicited neutralizing antibodies against XBB.1.16, XBB.1.5, and JN.1, with PHH-1V81 inducing a higher response for all variants. The PHH-1V8 booster triggers a superior neutralizing antibody response against XBB variants compared to the mRNA vaccine. A subgroup analysis consistently revealed higher neutralizing antibody responses with PHH-1V81 across age groups, SARS-CoV-2 infection history, and the number of prior vaccination shots. A safety analysis (n = 607) at the day 14 visit revealed favorable safety profiles without any serious vaccine-related adverse events. (4) Conclusions: PHH-1V81 demonstrates superiority on humoral immunogenicity compared to the mRNA vaccine against XBB variants and non-inferiority against JN.1 with a favorable safety profile and lower reactogenicity, confirming its potential as a vaccine candidate.

Background: Psychotic disorders are frequently associated with a public perception of dangerousness and belligerence. This situation has contributed to the social stigmatisation of people with severe mental illness and the resulting discrimination that this scenario entails. Despite efforts to demystify such disorders, the association between violent behaviour and psychosis remains unclear., Aims: To explore the incidence of the main types of violent offences in a cohort of patients presenting with first-episode psychosis (FEP)., Method: Participants were recruited from the First Episode Psychosis Intervention Program (CRUPEP) cohort between 2009 and 2016. The main clinical variables were collected, including medical-forensic records of participants registered at the Basque Institute of Forensic Medicine (BIFM), to identify any violent acts in which participants were involved, either as victims or as offenders., Results: Overall, 79.5% ( n = 182) of the participants had no record of violent crime or offence recorded in the BIFM. Annual crime rates for the 2009-2016 period show a decreasing trend in both the general population (IRR = 0.981, 95% CI 0.978-0.983, P < 0.001) and in the FEP group (IRR = 0.019, 95% CI 0.012-0.028, P < 0.001); this pattern is more pronounced in the FEP group. Victimisation accounted for the vast majority of reported incidents; nevertheless, participants who had committed violent offences were mostly involved in intrafamily violence., Conclusions: Individuals with FEP were not involved in a higher number of crimes than the general population. The types of violent acts committed by people with FEP were heterogeneous, with extreme violence being particularly uncommon.

Background: A SARS-CoV-2 protein-based heterodimer vaccine, PHH-1V, has been shown to be safe and well-tolerated in healthy young adults in a first-in-human, Phase I/IIa study dose-escalation trial. Here, we report the interim results of the Phase IIb HH-2, where the immunogenicity and safety of a heterologous booster with PHH-1V is assessed versus a homologous booster with BNT162b2 at 14, 28 and 98 days after vaccine administration., Methods: The HH-2 study is an ongoing multicentre, randomised, active-controlled, double-blind, non-inferiority Phase IIb trial, where participants 18 years or older who had received two doses of BNT162b2 were randomly assigned in a 2:1 ratio to receive a booster dose of vaccine-either heterologous (PHH-1V group) or homologous (BNT162b2 group)-in 10 centres in Spain. Eligible subjects were allocated to treatment stratified by age group (18-64 versus ≥65 years) with approximately 10% of the sample enrolled in the older age group. The primary endpoints were humoral immunogenicity measured by changes in levels of neutralizing antibodies (PBNA) against the ancestral Wuhan-Hu-1 strain after the PHH-1V or the BNT162b2 boost, and the safety and tolerability of PHH-1V as a boost. The secondary endpoints were to compare changes in levels of neutralizing antibodies against different variants of SARS-CoV-2 and the T-cell responses towards the SARS-CoV-2 spike glycoprotein peptides. The exploratory endpoint was to assess the number of subjects with SARS-CoV-2 infections ≥14 days after PHH-1V booster. This study is ongoing and is registered with ClinicalTrials.gov, NCT05142553., Findings: From 15 November 2021, 782 adults were randomly assigned to PHH-1V (n = 522) or BNT162b2 (n = 260) boost vaccine groups. The geometric mean titre (GMT) ratio of neutralizing antibodies on days 14, 28 and 98, shown as BNT162b2 active control versus PHH-1V, was, respectively, 1.68 (p < 0.0001), 1.31 (p = 0.0007) and 0.86 (p = 0.40) for the ancestral Wuhan-Hu-1 strain; 0.62 (p < 0.0001), 0.65 (p < 0.0001) and 0.56 (p = 0.003) for the Beta variant; 1.01 (p = 0.92), 0.88 (p = 0.11) and 0.52 (p = 0.0003) for the Delta variant; and 0.59 (p ≤ 0.0001), 0.66 (p < 0.0001) and 0.57 (p = 0.0028) for the Omicron BA.1 variant. Additionally, PHH-1V as a booster dose induced a significant increase of CD4 + and CD8 + T-cells expressing IFN-γ on day 14. There were 458 participants who experienced at least one adverse event (89.3%) in the PHH-1V and 238 (94.4%) in the BNT162b2 group. The most frequent adverse events were injection site pain (79.7% and 89.3%), fatigue (27.5% and 42.1%) and headache (31.2 and 40.1%) for the PHH-1V and the BNT162b2 groups, respectively. A total of 52 COVID-19 cases occurred from day 14 post-vaccination (10.14%) for the PHH-1V group and 30 (11.90%) for the BNT162b2 group (p = 0.45), and none of the subjects developed severe COVID-19., Interpretation: Our interim results from the Phase IIb HH-2 trial show that PHH-1V as a heterologous booster vaccine, when compared to BNT162b2, although it does not reach a non-inferior neutralizing antibody response against the Wuhan-Hu-1 strain at days 14 and 28 after vaccination, it does so at day 98. PHH-1V as a heterologous booster elicits a superior neutralizing antibody response against the previous circulating Beta and the currently circulating Omicron BA.1 SARS-CoV-2 variants in all time points assessed, and for the Delta variant on day 98 as well. Moreover, the PHH-1V boost also induces a strong and balanced T-cell response. Concerning the safety profile, subjects in the PHH-1V group report significantly fewer adverse events than those in the BNT162b2 group, most of mild intensity, and both vaccine groups present comparable COVID-19 breakthrough cases, none of them severe., Funding: HIPRA SCIENTIFIC, S.L.U., Competing Interests: The authors of this manuscript declare: J Blanco has received institutional grants from HIPRA, 10.13039/501100016387Grifols, and MSD, royalties for licensed patent from AlbaJuna, honoraria for lectures from FLS Science and CIBER, supporting for meeting and/or travel from 10.13039/100016016Gilead Sciences, and unpaid independent COVID-19 monitoring from GMCSC (Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19) and unpaid participation in COVID-19 advisory group for CCAC (Comitè Científic Assessor de la COVID-19). Outside of this work, J Blanco is the CEO, founder and shareholder of AlbaJuna Therapeutics, S.L. J Corominas, C Garriga, A Barreiro, L González-González, L Madrenas, I Güell, D Raïch-Regué, J G Prado, T Prat, E Torroella, B Trinité, L Ferrer, M Cañete and A Prenafeta have received funding from HIPRA. The funding from HIPRA to R Ramos was paid to his institution. A Soriano has received grants from 10.13039/100004319Pfizer and 10.13039/100005564Gilead Sciences, consulting fees from 10.13039/100004319Pfizer, MSD and 10.13039/501100005612Shionogi, and honoraria for lectures for 10.13039/100004319Pfizer, MSD, 10.13039/100005564Gilead Sciences, 10.13039/501100005612Shionogi, 10.13039/501100006546Angelini, and Menarini. B Trinité declares royalties by an institutional agreement and consulting fees for HIPRA, and is an unpaid member in advisory board for the Health Department of the 10.13039/501100002809Generalitat de Catalunya. N Izquierdo-Useros, D Raïch-Regué and M Gallemí declare institutional grants from HIPRA, Pharma Mar, 10.13039/501100016387Grifols, Dentaid, Palobiofarma, Mynorix and Amassence. N Izquierdo-Useros and M Gallemí have received speaking honoraria from FLS Science. JR Arribas has received consulting fees and payment for participating in advisory board from 10.13039/100005564Gilead Sciences, MSD, GSK, Eli Lilly, 10.13039/100004337Roche, 10.13039/100004319Pfizer and Sobi, honoraria for lectures and support for meetings and/or travel from MSD. A Borobia has received grants from GSK, Moderna and Janssen, speaking honoraria for Janssen, 10.13039/100005564Gilead Sciences and 10.13039/100004319Pfizer, and payment for participating in advisory board for 10.13039/100004319Pfizer, Janssen and MDI. PM García has received consulting fees and speaking honoraria from 10.13039/100005564Gilead Sciences, Mundipharma and 10.13039/100004319Pfizer, payment for expert testimony and participated in advisory board for 10.13039/100005564Gilead Sciences and received support for meeting and/or travel from 10.13039/100004319Pfizer. S Otero-Romero has received speaking honoraria from Genzyme, Biogen-Idec, Novartis, Roche, and MSD. Julia G Prado declares institutional grants from 10.13039/501100016387Grifols. J Corominas, C Garriga, A Prenafeta, A Moros, M Cañete, A Barreiro, L González-González, L Madrenas, I Güell, T Prat, E Torroella and L Ferrer are employees of HIPRA. Some of these authors may have stocks of HIPRA. Several patent applications have been filed by HIPRA SCIENTIFIC S.L.U. and Laboratorios HIPRA, S.A. on different SARS-CoV-2 vaccine candidates and SARS-CoV-2 subunit vaccines, including the novel recombinant RBD fusion heterodimer PHH-1V. A Barreiro, J Corominas, A Prenafeta, L González-González, L Madrenas, L Ferrer, E Torroella, T Prat and C Garriga are the inventors of these patent applications. N Izquierdo-Useros is a patent inventor with no economical compensation for Pharma Mar and Mynorix. The other authors have no relevant conflicts of interest to declare., (© 2023 The Author(s).)

Acute nontraumatic chest pain is a frequent reaso n for consultation in emergency departments and represents a diagnostic challenge. The objective is to estimate the risk of significant coronary artery disease (CAD) in patients with cardiogenic acute chest pain for whom the diagnosis of infarction was ruled out in the emergency department with a nondiagnostic ECG and negative high-sensitivity troponins. We prospectively recruited 1625 patients from emergency departments of seven Spanish hospitals. The outcome was presence of significant CAD determined by presence of ischaemia in functional tests or more than 70% stenosis in imaging tests. In this study, we developed a predictive model and evaluated its performance and clinical utility. The prevalence of significant CAD was 14% [227/1625; 95% confidence interval (CI), 12-16]. MAPAC Cardio-PreTest model included seven predictors: age, sex, smoking, history of hypertension, family history of CAD, history of hyperuricaemia, and type of chest pain. The optimism-adjusted model discrimination was C-statistic 0.654 (95% CI, 0.618-0.693). Calibration plot showed good agreement between the predicted and observed risks, and calibration slope was 0.880 (95% CI, 0.731-1.108) and calibration-in-the-large -0.001 (95% CI, -0.141 to 0.132). The model increased net benefit and improved risk classification over the recommended approach by the European Society of Cardiology [Net Reclassification Index (NRI) of events = 5.3%, NRI of nonevents = 7.0%]. MAPAC Cardio-PreTest model is an online prediction tool to estimate the individualised probability of significant CAD in patients with acute chest pain without a diagnosis of infarction in emergency department. The model was more useful than the current alternatives in helping patients and clinicians make individually tailored choices about the intensity of monitoring or additional coronary tests., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Quantitative reverse transcription PCR (RT-qPCR) is the leading tool to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given that it will almost certainly continue to coexist with other respiratory viruses in the coming years, our study aimed to design a multiplex PCR system not affected by supplier outages and with reduced cost compared to the existing commercially available kits., Methods and Results: In this study, combinations of four primers/probe sets were used to construct a flexible RT-qPCR assay which is capable of discriminating between SARS-CoV-2 and the seasonal human coronavirus HCoV-OC43, or even influenza A virus. Additionally, the human RPP30 gene was used as an internal control. To demonstrate the robustness of the assay, it was applied to a collection of 150 clinical samples. The results showed 100% sensitivity and specificity compared to the automatized system used at the hospital and were better when indeterminate samples were analysed., Conclusions: This study provides an efficient method for the simultaneous detection of SARS-CoV-2, HCoV-OC43 and influenza A virus, and its efficacy has been tested on clinical samples showing outstanding results., Significance and Impact of the Study: The multiplex RT-qPCR design offers an accessible and economical alternative to commercial detection kits for hospitals and laboratories with limited economic resources or facing situations of supply shortage., (© 2022 The Authors. Journal of Applied Microbiology published by John Wiley & Sons Ltd on behalf of Society for Applied Microbiology.)

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ~0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided., (© The Author(s) 2022. Published by Oxford University Press.)

Introduction and Objectives: Optimal medical therapy decreases mortality and heart failure (HF) hospitalizations in HF patients with reduced left ventricular ejection fraction. Women have been underrepresented in clinical trials and not specifically evaluated. This study aimed to compare the safety and effectiveness of drug titration in women vs men., Methods: This post hoc gender study of the ETIFIC multicenter randomized trial included hospitalized patients with new-onset HF with reduced ejection fraction and New York Heart Association II-III and no contraindications to beta-blockers. A structured 4-month titration process was implemented in HF clinics. The primary endpoint was the mean relative dose (% of target dose) of beta-blockers achieved by women vs men. Secondary endpoints included the mean relative doses of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor antagonists, adverse events, and other clinical outcomes at 6 months., Results: A total of 320 patients were included, 83 (25.93%) women and 237 (74.06%) men (76 vs 213 analyzed). The mean±standard deviation of the relative doses achieved by women vs men were as follows: beta-blockers 62.08%±30.72% vs 64.4%±32.77%, with a difference of-2.32% (95%CI,-10.58-5.94), P = .580; and mineralocorticoid receptor antagonists 79.85%±27.72% vs 67.29%±31.43%, P =.003. No other differences in drug dosage were found. Multivariate analysis showed nonsignificant differences. CV mortality was 1 (1.20%) vs 3 (1.26%), P=1, and HF hospitalizations 0 (0.00%) vs 10 (4.22%), P=.125., Conclusions: In a post hoc analysis from the HF-titration ETIFIC trial, we found nonsignificant gender differences in drug dosage, cardiovascular mortality, and HF hospitalizations. Trial registry number: NCT02546856., (Copyright © 2021 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: The CombiVacS study was designed to assess immunogenicity and reactogenicity of the heterologous ChAdOx1-S/BNT162b2 combination, and 14-day results showed a strong immune response. The present secondary analysis addresses the evolution of humoral and cellular response up to day 180., Methods: Between April 24 and 30, 2021, 676 adults primed with ChAdOx1-S were enrolled in five hospitals in Spain, and randomised to receive BNT162b2 as second dose (interventional group [IG]) or no vaccine (control group [CG]). Individuals from CG received BNT162b2 as second dose and also on day 28, as planned based on favourable results on day 14. Humoral immunogenicity, measured by immunoassay for SARS-CoV-2 receptor binding domain (RBD), antibody functionality using pseudovirus neutralisation assays for the reference (G614), Alpha, Beta, Delta, and Omicron variants, as well as cellular immune response using interferon-γ and IL-2 immunoassays were assessed at day 28 after BNT162b2 in both groups, at day 90 (planned only in the interventional group) and at day 180 (laboratory data cut-off on Nov 19, 2021). This study was registered with EudraCT (2021-001978-37) and ClinicalTrials.gov (NCT04860739)., Findings: In this secondary analysis, 664 individuals (441 from IG and 223 from CG) were included. At day 28 post vaccine, geometric mean titres (GMT) of RBD antibodies were 5616·91 BAU/mL (95% CI 5296·49-5956·71) in the IG and 7298·22 BAU/mL (6739·41-7903·37) in the CG ( p  < 0·0001). RBD antibodies titres decreased at day 180 (1142·0 BAU/mL [1048·69-1243·62] and 1836·4 BAU/mL [1621·62-2079·62] in the IG and CG, respectively; p  < 0·0001). Neutralising antibodies also waned from day 28 to day 180 in both the IG (1429·01 [1220·37-1673·33] and 198·72 [161·54-244·47], respectively) and the CG (1503·28 [1210·71-1866·54] and 295·57 [209·84-416·33], respectively). The lowest variant-specific response was observed against Omicron-and Beta variants, with low proportion of individuals exhibiting specific neutralising antibody titres (NT50) >1:100 at day 180 (19% and 22%, respectively)., Interpretation: Titres of RBD antibodies decay over time, similar to homologous regimes. Our findings suggested that delaying administration of the second dose did not have a detrimental effect after vaccination and may have improved the response obtained. Lower neutralisation was observed against Omicron and Beta variants at day 180., Funding: Funded by Instituto de Salud Carlos III (ISCIII)., Competing Interests: JA has received fees for educational programs from Gilead, MSD, GSK and Janssen outside of the submitted work. MC has participated in advisory boards and has received research funding from GSK, Sanofy Pasteur, Pfizer, Novavax and Janssen.CB-I is the deputy general manager of the Instituto de Salud Carlos III. JRA has received fees from Janssen, outside of the submitted work. AMB is principal investigator of clinical trials sponsored by GlaxoSmithKline, Daiichi-Sankyo, Janssen, and Farmalider, outside of the submitted work. All other authors declare no competing interests., (© 2022 The Authors.)

Background: There is no evidence to date on immunogenic response among individuals who participated in clinical trials of COVID-19 experimental vaccines redirected to standard national vaccination regimens., Methods: This multicentre, prospective controlled cohort study included subjects who received a COVID-19 experimental vaccine (CVnCoV)(test group, TG) - and unvaccinated subjects (control group, CG), selected among individuals to be vaccinated according to the Spanish vaccination program. All study subjects received BNT162b2 as a standard national vaccination schedule, except 8 (from CG) who received mRNA-1273 and were excluded from immunogenicity analyses. Anti-RBD antibodies level and neutralising titres (NT50) against G614, Beta, Mu, Delta and Omicron variants were analysed. Reactogenicity was also assessed., Findings: 130 participants (TG:92; CG:38) completed standard vaccination. In TG, median (IQR) of anti-RBD antibodies after first BNT162b2 dose were 10740·0 BAU/mL (4466·0-12500) compared to 29·8 BAU/mL (14·5-47·8) in CG ( p <0·0001). Median NT50 (IQR) of G614 was 2674·0 (1865·0-3997·0) in TG and 63·0 (16·0-123·1) in CG ( p <0·0001). After second BNT162b2 dose, anti-RBD levels increased to ≥12500 BAU/mL (11625·0-12500) in TG compared to 1859·0 BAU/mL (915·4-3820·0) in CG ( p <0·0001). NT50 was 2626·5 (1756·0-5472·0) and 850·4 (525·1-1608·0), respectively ( p <0·0001). Variant-specific (Beta, Mu, Omicron) response was also assessed. Most frequent adverse reactions were headache, myalgia, and local pain. No severe AEs were reported., Interpretation: Heterologous BNT162b2 as third and fourth doses in previously suboptimal immunized individuals elicit stronger immune response than that obtained with two doses of BNT162b2. This apparent benefit was also observed in variant-specific response. No safety concerns arose., Funding: Partly funded by the Institute of Health Carlos-III and COVID-19 Fund, co-financed by the European Regional Development Fund (FEDER) "A way to make Europe"., Competing Interests: Biocruces Bizkaia HRI and Curevac have a clinical trial contract unrelated to the present study. Biodonostia HRI and Curevac have a clinical trial contract unrelated to the present study. Clinico San Carlos HRI and Curevac have a clinical trial contract unrelated to the present study. JA: Consulting fees from EMA, AEMPS, Almirall, Zeltia; payment for educational events on vaccines from Gilead, Haelix Therapeutics, Merck Sharp & Dohme, Janssen. All other authors declare no competing interests., (© 2022 The Authors.)

Background: Additional safe and efficacious vaccines are needed to control the COVID-19 pandemic. We aimed to analyse the efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate., Methods: HERALD is a randomised, observer-blinded, placebo-controlled, phase 2b/3 clinical trial conducted in 47 centres in ten countries in Europe and Latin America. By use of an interactive web response system and stratification by country and age group (18-60 years and ≥61 years), adults with no history of virologically confirmed COVID-19 were randomly assigned (1:1) to receive intramuscularly either two 0·6 mL doses of CVnCoV containing 12 μg of mRNA or two 0·6 mL doses of 0·9% NaCl (placebo) on days 1 and 29. The primary efficacy endpoint was the occurrence of a first episode of virologically confirmed symptomatic COVID-19 of any severity and caused by any strain from 15 days after the second dose. For the primary endpoint, the trial was considered successful if the lower limit of the CI was greater than 30%. Key secondary endpoints were the occurrence of a first episode of virologically confirmed moderate-to-severe COVID-19, severe COVID-19, and COVID-19 of any severity by age group. Primary safety outcomes were solicited local and systemic adverse events within 7 days after each dose and unsolicited adverse events within 28 days after each dose in phase 2b participants, and serious adverse events and adverse events of special interest up to 1 year after the second dose in phase 2b and phase 3 participants. Here, we report data up to June 18, 2021. The study is registered at ClinicalTrials.gov, NCT04652102, and EudraCT, 2020-003998-22, and is ongoing., Findings: Between Dec 11, 2020, and April 12, 2021, 39 680 participants were enrolled and randomly assigned to receive either CVnCoV (n=19 846) or placebo (n=19 834), of whom 19 783 received at least one dose of CVnCoV and 19 746 received at least one dose of placebo. After a mean observation period of 48·2 days (SE 0·2), 83 cases of COVID-19 occurred in the CVnCoV group (n=12 851) in 1735·29 person-years and 145 cases occurred in the placebo group (n=12 211) in 1569·87 person-years, resulting in an overall vaccine efficacy against symptomatic COVID-19 of 48·2% (95·826% CI 31·0-61·4; p=0·016). Vaccine efficacy against moderate-to-severe COVID-19 was 70·7% (95% CI 42·5-86·1; CVnCoV 12 cases in 1735·29 person-years, placebo 37 cases in 1569·87 person-years). In participants aged 18-60 years, vaccine efficacy against symptomatic disease was 52·5% (95% CI 36·2-64·8; CVnCoV 71 cases in 1591·47 person-years, placebo, 136 cases in 1449·23 person-years). Too few cases occurred in participants aged 61 years or older (CVnCoV 12, placebo nine) to allow meaningful assessment of vaccine efficacy. Solicited adverse events, which were mostly systemic, were more common in CVnCoV recipients (1933 [96·5%] of 2003) than in placebo recipients (1344 [67·9%] of 1978), with 542 (27·1%) CVnCoV recipients and 61 (3·1%) placebo recipients reporting grade 3 solicited adverse events. The most frequently reported local reaction after any dose in the CVnCoV group was injection-site pain (1678 [83·6%] of 2007), with 22 grade 3 reactions, and the most frequently reported systematic reactions were fatigue (1603 [80·0%] of 2003) and headache (1541 [76·9%] of 2003). 82 (0·4%) of 19 783 CVnCoV recipients reported 100 serious adverse events and 66 (0·3%) of 19 746 placebo recipients reported 76 serious adverse events. Eight serious adverse events in five CVnCoV recipients and two serious adverse events in two placebo recipients were considered vaccination-related. None of the fatal serious adverse events reported (eight in the CVnCoV group and six in the placebo group) were considered to be related to study vaccination. Adverse events of special interest were reported for 38 (0·2%) participants in the CVnCoV group and 31 (0·2%) participants in the placebo group. These events were considered to be related to the trial vaccine for 14 (<0·1%) participants in the CVnCoV group and for five (<0·1%) participants in the placebo group., Interpretation: CVnCoV was efficacious in the prevention of COVID-19 of any severity and had an acceptable safety profile. Taking into account the changing environment, including the emergence of SARS-CoV-2 variants, and timelines for further development, the decision has been made to cease activities on the CVnCoV candidate and to focus efforts on the development of next-generation vaccine candidates., Funding: German Federal Ministry of Education and Research and CureVac., Competing Interests: Declaration of interests MB declares institutional funding from CureVac during the conduct of this study, institutional funding from Janssen Vaccines, Molecular Partners, and Merck outside the submitted work, and consulting fees from Janssen Vaccines outside the submitted work. EJLDB, MFM-R, TJO, and XS-L declare institutional funding from CureVac during the conduct of this study. LE and LG declare institutional funding from CureVac during the conduct of this study and outside the submitted work. CFL declares institutional funding from CureVac during the conduct of this study and outside the submitted work and is a member of the WHO Covid-19 Vaccine Effectiveness Working Group and the WHO Product Development for Vaccines Advisory Committee. CL declares institutional funding from CureVac during the conduct of this study and is a member of the German Society of Infection board. IL-R declares institutional funding from CureVac during the conduct of this study and institutional funding from Johnson & Johnson and OSE Immunotherapeutics outside the submitted work. PGK declares institutional funding from CureVac during the conduct of this study and is a member of the scientific advisory board for the HERALD clinical trial. VVRH declares institutional funding from CureVac during the conduct of this study and speakers fees from Gilead outside the submitted work. HJ declares consultant fees from CureVac, is the qualified physician for the HERALD clinical trial, and is co-chair of the DSMB for the HERALD clinical trial. AK and PM are employed by CureVac and hold stock options. OS-K declares consultant fees from CureVac during the conduct of this study and is a member of the DSMB for a CVnCoV phase 1 trial. TV declares consultant fees from CureVac during the conduct of this study, and consultant fees from CureVac, AstraZeneca, Pfizer, Johnson & Johnson, and Moderna outside the submitted work. LO is employed by CureVac and holds stock options and is the holder of a pending patent. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: High participation determines the success of colorectal cancer screening programmes in reducing incidence and mortality. The factors that determine participation must be studied from the perspective of professionals that implement the programme. The aim was to identify factors that facilitate or hinder the participation of the invited people in the bowel cancer screening programme of the Basque Country (Spain) from professional's perspective., Methods: Qualitative design based on individual interviews and focus groups. Thirty-eight primary care professionals who implement the programme participated (administrative staff, nurses and general practitioners). Thematic analysis was performed., Results: Professionals show high satisfaction with the programme, and they believe firmly in its benefits. Facilitators for participation include professionals' commitment to the programme, their previous positive experiences, their optimistic attitude towards the prognosis of cancer and their trust in the health system and accessibility. Barriers include invitees' lack of independence to make decisions, fear of a positive test result and patient vulnerability and labour mobility of the health professionals., Conclusions: Professionals show a high degree of involvement and identify primary care is an appropriate place to carry out disease prevention. They identify the closeness to patients, the personal attitude and the characteristics of the health system as key factors that influence participation., (© 2021 The Authors. European Journal of Cancer Care published by John Wiley & Sons Ltd.)

Background: To date, no immunological data on COVID-19 heterologous vaccination schedules in humans have been reported. We assessed the immunogenicity and reactogenicity of BNT162b2 (Comirnaty, BioNTech, Mainz, Germany) administered as second dose in participants primed with ChAdOx1-S (Vaxzevria, AstraZeneca, Oxford, UK)., Methods: We did a phase 2, open-label, randomised, controlled trial on adults aged 18-60 years, vaccinated with a single dose of ChAdOx1-S 8-12 weeks before screening, and no history of SARS-CoV-2 infection. Participants were randomly assigned (2:1) to receive either BNT162b2 (0·3 mL) via a single intramuscular injection (intervention group) or continue observation (control group). The primary outcome was 14-day immunogenicity, measured by immunoassays for SARS-CoV-2 trimeric spike protein and receptor binding domain (RBD). Antibody functionality was assessed using a pseudovirus neutralisation assay, and cellular immune response using an interferon-γ immunoassay. The safety outcome was 7-day reactogenicity, measured as solicited local and systemic adverse events. The primary analysis included all participants who received at least one dose of BNT162b2 and who had at least one efficacy evaluation after baseline. The safety analysis included all participants who received BNT162b2. This study is registered with EudraCT (2021-001978-37) and ClinicalTrials.gov (NCT04860739), and is ongoing., Findings: Between April 24 and 30, 2021, 676 individuals were enrolled and randomly assigned to either the intervention group (n=450) or control group (n=226) at five university hospitals in Spain (mean age 44 years [SD 9]; 382 [57%] women and 294 [43%] men). 663 (98%) participants (n=441 intervention, n=222 control) completed the study up to day 14. In the intervention group, geometric mean titres of RBD antibodies increased from 71·46 BAU/mL (95% CI 59·84-85·33) at baseline to 7756·68 BAU/mL (7371·53-8161·96) at day 14 (p<0·0001). IgG against trimeric spike protein increased from 98·40 BAU/mL (95% CI 85·69-112·99) to 3684·87 BAU/mL (3429·87-3958·83). The interventional:control ratio was 77·69 (95% CI 59·57-101·32) for RBD protein and 36·41 (29·31-45·23) for trimeric spike protein IgG. Reactions were mild (n=1210 [68%]) or moderate (n=530 [30%]), with injection site pain (n=395 [88%]), induration (n=159 [35%]), headache (n=199 [44%]), and myalgia (n=194 [43%]) the most commonly reported adverse events. No serious adverse events were reported., Interpretation: BNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S induced a robust immune response, with an acceptable and manageable reactogenicity profile., Funding: Instituto de Salud Carlos III., Translations: For the French and Spanish translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests CB-I is the deputy general manager of the Instituto de Salud Carlos III. JRA has received fees from Janssen, outside of the submitted work. AMB is principal investigator of clinical trials sponsored by GlaxoSmithKline, Daiichi-Sankyo, Janssen, and Farmalider, outside of the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction and Objectives: Beta-blockers, angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin-II-receptor-blockers (ARB), and mineralocorticoid-receptor antagonists decrease mortality and heart failure (HF) hospitalizations in HF patients with reduced left ventricular ejection fraction. The effect is dose-dependent. Careful titration is recommended. However, suboptimal doses are common in clinical practice. This study aimed to compare the safety and efficacy of dose titration of the aforementioned drugs by HF nurses vs HF cardiologists., Methods: ETIFIC was a multicenter (n=20) noninferiority randomized controlled open label trial. A total of 320 hospitalized patients with new-onset HF, reduced ejection fraction and New York Heart Association II-III, without beta-blocker contraindications were randomized 1:1 in blocks of 4 patients each stratified by hospital: 164 to HF nurse titration vs 156 to HF cardiologist titration (144 vs 145 analyzed). The primary endpoint was the beta-blocker mean relative dose (% of target dose) achieved at 4 months. Secondary endpoints included ACE inhibitors, ARB, and mineralocorticoid-receptor antagonists mean relative doses, associated variables, adverse events, and clinical outcomes at 6 months., Results: The mean±standard deviation relative doses achieved by HF nurses vs HF cardiologists were as follows: beta-blockers 71.09%±31.49% vs 56.29%±31.32%, with a difference of 14.8% (95%CI, 7.5-22.1), P <.001; ACE inhibitors 72.61%±29.80% vs 56.13%±30.37%, P <.001; ARB 44.48%±33.47% vs 43.51%±33.69%, P=.93; and mineralocorticoid-receptor antagonists 71%±32.12% vs 70.47%±29.78%, P=.86; mean±standard deviation visits were 6.41±2.82 vs 2.81±1.58, P <.001, while the number (%) of adverse events were 34 (23.6) vs 30 (20.7), P=.55; and at 6 months HF hospitalizations were 1 (0.69) vs 9 (5.51), P=.01., Conclusions: ETIFIC is the first multicenter randomized trial to demonstrate the noninferiority of HF specialist-nurse titration vs HF cardiologist titration. Moreover, HF nurses achieved higher beta-blocker/ACE inhibitors doses, with more outpatient visits and fewer HF hospitalizations. Trial registry number: NCT02546856., (Copyright © 2020 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: There has been increased interest in pain neuroscience education (PNE) as a therapeutic approach for the management of fibromyalgia (FM)., Methods: A multicentre randomized, open-label, controlled trial was conducted to assess the effectiveness of a structured group intervention based on PNE in patients with FM. A total of 139 patients were included in the study and randomized to the intervention group (7 group sessions of education in neurobiology of pain) or to the control group (treatment as usual only). The primary outcome was the improvement of functional status and pain measured with the Fibromyalgia Impact Questionnaire (FIQ), and secondary outcomes were the reduction in the impact of pain and other symptoms (catastrophizing, anxiety and depression) and number of patients reaching no worse than moderate functional impairment (FIQ score <39). Differences between groups were calculated by linear mixed-effects (intention-to-treat approach) and mediational models through path analyses., Results: At 1 year, improvements in FIQ scores were higher in the intervention group with moderate or high effect size, and decreases of ≥20% in 69.1% of patients (20.9% in the control group) and of ≥50% in 39.7% (4.5% in the control group). Also, 52.9% of patients had a FIQ <39 points (13.4% in the control group)., Conclusions: In this sample of patients with FM, the improvement in quality of life and control of symptoms obtained by adding a PNE intervention showed promising results, equalling or surpassing previously reported outcomes., Significance: A structured group intervention based on pain neuroscience education for 1 year in patients with fibromyalgia was associated with significant amelioration of the impact of the disease on scores of the Fibromyalgia Impact Questionnaire, the Health Assessment Questionnaire, the Hospital Anxiety and Depression Scale, the Pain Catastrophizing Scale and the Polysymptomatic Distress Scale as compared with only treatment as usual. These findings are clinically relevant considering the challenges posed by fibromyalgia to clinicians and patients alike., (© 2021 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

COVID-19 manifests with a wide diversity of clinical phenotypes characterized by dysfunctional and exaggerated host immune responses. Many results have been described on the status of the immune system of patients infected with SARS-CoV-2, but there are still aspects that have not been fully characterized or understood. In this study, we have analyzed a cohort of patients with mild, moderate and severe disease. We performed flow cytometric studies and correlated the data with the clinical characteristics and clinical laboratory values of the patients. Both conventional and unsupervised data analyses concluded that patients with severe disease are characterized, among others, by a higher state of activation in all T cell subsets (CD4, CD8, double negative and T follicular helper cells), higher expression of perforin and granzyme B in cytotoxic cells, expansion of adaptive NK cells and the accumulation of activated and immature dysfunctional monocytes which are identified by a low expression of HLA-DR and an intriguing shift in the expression pattern of CD300 receptors. More importantly, correlation analysis showed a strong association between the alterations in the immune cells and the clinical signs of severity. These results indicate that patients with severe COVID-19 have a broad perturbation of their immune system, and they will help to understand the immunopathogenesis of COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zenarruzabeitia, Astarloa-Pando, Terrén, Orrantia, Pérez-Garay, Seijas-Betolaza, Nieto-Arana, Imaz-Ayo, Pérez-Fernández, Arana-Arri and Borrego.)

Background: New biomarkers like procalcitonin and C-reactive protein may help design an accurate decision support tool used to identify children with pleocytosis at low or high risk of bacterial meningitis. Our objective was to develop and validate a score (that we call the meningitis score for emergencies [MSE]) to distinguish bacterial meningitis from aseptic meningitis in children with pleocytosis when initially evaluated at the emergency department., Methods: We included children between 29 days and 14 years old with meningitis admitted to 25 Spanish emergency departments. A retrospective cohort from between 2011 and 2016 was used as the derivation set and a prospective cohort recruited during 2017 and 2018 was used as the validation set., Results: Among the 1009 patients included, there were 917 cases of aseptic meningitis and 92 of bacterial meningitis. Using multivariable logistic regression analysis, we identified the following predictors of bacterial meningitis from the derivation set: procalcitonin >1.2 ng/mL, cerebrospinal fluid (CSF) protein >80 mg/dL, CSF absolute neutrophil count >1000 cells per mm 3 , and C-reactive protein >40 mg/L. Using the derivation set, we developed the MSE, assigning 3 points for procalcitonin, 2 points for CSF protein, and 1 point for each of the other variables. An MSE ≥1 predicted bacterial meningitis with a sensitivity of 100% (95% confidence interval [CI]: 95.0%-100%), a specificity of 83.2 (95% CI: 80.6-85.5), and a negative predictive value of 100% (95% CI 99.4-100.) CONCLUSIONS: The MSE accurately distinguishes bacterial from aseptic meningitis in children with CSF pleocytosis., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Recent studies suggest an increasing prevalence of nontuberculous mycobacteria (NTM) lung disease. The aim of the present study was to describe incidence rates of NTM lung disease and trends therein in our area over a 20-year period. This was a retrospective study of all cases of NTM lung disease between 1997 and 2016 that met the 2007 American Thoracic Society criteria. We analysed the annual incidence rates, species of mycobacteria isolated, trends over time and annual mortality in 327 patients. Mycobacterium kansasii was the most common mycobacterium isolated (84%), followed by Mycobacterium avium complex (MAC) (13%). We compared two periods: 1997-2006 (257 cases, 79%) and 2007-2016 (70 cases, 21%). The incidence rates tended to decrease across these years, with a peak of incidence in 2000 with 10.6 cases per 100 000. There was a clearly decreasing trend in M. kansasii infection, not only in the first period (incident rate ratio (IRR) 0.915, 95% CI 0.88-0.90; p<0.0001) but also in the second (IRR 0.869, 95% CI 0.780-1.014; p=0.080), reaching 1.8 per 100 000 in 2016. In contrast, MAC infection tended to increase across the two periods (IRR 1.251, 95% CI 1.081-1.447; p=0.003). In our region, the incidence of NTM lung disease has notably decreased in recent years. M. kansasii had high incidence rates in the first decade but clearly decreased in the second decade., Competing Interests: Conflict of interest: S. Pedrero has nothing to disclose. Conflict of interest: E. Tabernero has nothing to disclose. Conflict of interest: E. Arana has nothing to disclose. Conflict of interest: E. Urra has nothing to disclose. Conflict of interest: M. Larrea has nothing to disclose. Conflict of interest: R. Zalacain has nothing to disclose., (Copyright ©ERS 2019.)

Background: Stroke is a leading cause of severe and long-term disability in developed countries. Around 15 million people suffer a stroke each year, being most of them ischemic due to modifiable risk factors. Adequate self-management abilities may help to manage the consequences of stroke, but it is unknown which specific intervention could be effective to booster these self-management abilities., Objective: To evaluate the improvement of self-management in chronic stroke survivors using decision support and self-management system (STARR)., Methods: A randomized, prospective, parallel group, open, and the unicentric pilot trial will be performed. Stroke survivors and their caregivers will be randomly allocated to STARR management or standard of care. Main inclusion criteria are mild to moderate disabled first stroke adult survivor, living at home, able to cope and follow the guidelines and devices, without socio-familial exclusion. All will get a conventional treatment in the acute and subacute phase; however, in the chronic period, cases will use the developed STARR App and Decision Support System. Measurements will be performed at baseline, at 3 months, and at 6 months. Outcome measures are patient-report outcome measure of self-management competency, physical function, risk factor reduction, healthcare resource utilization, knowledge of the condition, mood, and social isolation., Discussion: If effective, the results of this study will enable stroke patients and their caregivers to deal better with the everyday life obstacles of stroke, improve the adherence of the treatment, improve the control of cardiovascular risk, and, in consequence, reduce the recurrence of secondary strokes, the number of complications, the number of consultations, and readmissions; to ultimately reduce the health systems costs. Taking into consideration that the number of stroke survivors is increasing around the world, a large number of individuals could profit from this intervention.

Background: The steady increase in colorectal cancer (CRC) could be reversed through timely secondary prevention (screening) as a main strategy. The aims of this study were to determine the main features of CRC, survival rate and related factors for different types of identified CRCs in a population-based screening programme using the faecal immunochemical test (FIT)., Materials and Methods: The CRCs in the susceptible population to be screened between 2009 and 2014 were identified and classified into four groups: (a) nonscreening-detected CRC (diagnosed before first screening invitation and nonparticipants), (b) screening-detected CRC, (c) interval cancer (IC) FIT (diagnosed between screening rounds after a negative FIT) and (d) IC colonoscopy (diagnosed before the colonoscopy surveillance, which is recommended after the screening colonoscopy). Patient demographics and epidemiological characteristics, tumour characteristics and survival were compared between the four groups., Results: 5909 individuals were diagnosed with a CRC. The median follow-up of survival was 4.6 years (range: 0-9 years). The study highlights a significant difference (P<0.0001) in the 5-year survival in the screening-detected CRC group compared with those who had nonscreening-detected CRCs (90.1 vs. 66.7%). Although ICs are not desirable events, the 5-year survival rate is significantly higher with respect to nonparticipants (P<0.0001) (76.3 vs. 60.5%), this being the group with the lowest survival rate., Conclusion: The significantly higher 5-year survival rate of 23.4% of the participants in the screening programme suggests that incidence and mortality rates of CRC will decrease in the near future for participants in screening programmes. A high participation rate is essential to achieve health benefits, irrespective of the type of participation.

Introduction: Colonoscopy is the diagnostic/therapeutic confirmation test for colorectal cancer. The monitoring of the experience of people who have undergone the test is interesting to improve the quality of the colonoscopy. The aim of the project was to study factors affecting patients' experience and their relationship with the quality indicators of the Clinical Practice Guidelines., Patients and Methods: An observational cross-sectional study was conducted, including quality and experience indicators (adapted mGHAA-9 questionnaire and clinical history) in a sample of 432 participants aged between 40- and 75-years-old who had undergone a colonoscopy in 2015. Univariate and multivariate analysis with multiple logistic regression., Results: Satisfaction was associated in the multivariate analysis with evaluating the waiting time for the colonoscopy as short (OR=3.80) (1.76-10.90, 95% CI),>55-years-old (OR=2.60) (1.19-5.68, 95% CI), rating the experience with the preparation positively (OR=7.34) (3.15-17.09, 95% CI), not reporting pain or discomfort during the procedure (OR=3.71) (1.03-13.40, 95% CI) (P=.006) and being examined in a tertiary hospital (OR=2.81) (1.17-6.72; 95% CI) (P=.020)., Discussion: The mGHAA-9 questionnaire adapted to Spanish is useful to evaluate patient experience factors. There are aspects to improve in terms of waiting time, colon cleansing, satisfaction with preparation and post-colonoscopy problems. Interventions should be implemented to enhance patient experience and colonoscopy quality., (Copyright © 2018 Elsevier España, S.L.U. All rights reserved.)

Severe complications (SC) in colonoscopy represent the most important adverse effect of colorectal cancer screening programs (CRCSP). The objective is to evaluate the risk factors for SC in colonoscopy indicated after a positive fecal occult blood test in population-based CRCSP. The SC (n = 161) identified from 48,730 diagnostic colonoscopies performed in a cohort of all the women and men invited from 2000 to 2012 in 6 CRCSP in Spain. A total of 318 controls were selected, matched for age, sex and period when the colonoscopy was performed. Conditional logistic regression models were estimated. The analysis was performed separately in groups: immediate-SC (same day of the colonoscopy); late-SC (between 1 and 30 days after); perforation; and bleeding events. SC occurred in 3.30‰ of colonoscopies. Prior colon disease showed a higher risk of SC (OR = 4.87). Regular antiplatelet treatment conferred a higher risk of overall SC (OR = 2.80) and late-SC (OR = 9.26), as did regular anticoagulant therapy (OR = 3.47, OR = 7.36). A history of pelvic-surgery or abdominal-radiotherapy was a risk factor for overall SC (OR = 5.03), immediate-SC (OR = 8.49), late-SC (OR = 4.65) and perforation (OR = 21.59). A finding of adenoma or cancer also showed a higher risk of overall SC (OR = 8.71), immediate-SC (OR = 12.67), late-SC (OR = 4.08), perforation (OR = 4.69) and bleeding (OR = 17.02). The risk of SC doesn't vary depending on the type of preparation or type of anesthesia. Knowing the clinical history of patients such as regular previous medication and history of surgery or radiotherapy, as well as the severity of the findings during the colonoscopy process could help to focus prevention measures in order to minimize SC in CRCSP., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background and Objective: Identifying international differences in the epidemiology of acute poisonings in children may help in improving prevention. We sought to evaluate the international epidemiological differences in acute poisonings in children presenting to emergency departments (EDs) from 8 different global regions., Methods: This was an international multicenter cross-sectional prospective study including children younger than 18 years with acute poisonings presenting to 105 EDs in 20 countries was conducted. Data collection started at each ED between January and September 2013, and continued for 1 year., Results: During the study period, we registered 363,245 pediatric ED presentations, of which 1727 were for poisoning (0.47%; 95% confidence interval, 0.45%-0.50%), with a significant variation in incidence between the regions. Full data were obtained for 1688 presentations. Most poisonings (1361 [80.6%]) occurred at home with either ingestion (1504 [89.0%]) or inhalation of the toxin (126 [7.6%]). Nonintentional exposures accounted for 1157 poisonings (68.5%; mainly in South America and Eastern Mediterranean region), with therapeutic drugs (494 [42.7%]), household products (310 [26.8%]), and pesticides (59 [5.1%]) being the most common toxins. Suicide attempts accounted for 233 exposures (13.8%; mainly in the Western Pacific region and North America), with therapeutic drugs (214 [91.8%], mainly psychotropics and acetaminophen) being the most common toxins. Significant differences between regions were found in both types of poisonings. Recreational poisonings were more common in Europe and Western Pacific region. No patient died., Conclusions: There are substantial epidemiological differences in acute poisonings among children in different countries and regions of the globe. International best practices need to be identified for prevention of acute poisonings in childhood.

Background: The overall aim of this study was to describe trends in participation rates and detection of lesions in a colorectal cancer (CRC) screening programme, during three rounds, using faecal immunochemical test (FIT)., Methods: National registers were used to collect data on invitations for CRC screening in the Basque Country (Spain) from 2009 to 2014. Information about participation, age, gender and lesions in each round were collected., Results: A total of 961.533 individuals were included in the analysis; respectively, 584.950, 298.143 and 78.440 in the first, second and third rounds. The average participation rate was 68.4% (66.8, 70.4 and 72.3%, respectively by round; P < 0.001) and the positivity rate was 6.3% (7, 5.5 and 5.4%, respectively by round; P < 0.001). The participation rate increased significantly with age and was found to be higher in women versus men. A total of 15.144 advanced adenomas and 2.131 CRCs were diagnosed, leading to a detection rate of 23.9 and 3.4‰, respectively. Regarding gender, men had the highest rates in all periods and rounds. The detection rate of advanced neoplasia was lower in the regular when compared with irregular paricipants., Conclusions: In a CRC screening, this organization obtained high FIT participation rates. Older participants and women were associated with a higher participation. The detection rate of lesions was higher in men, independent on age and round.

Background and study aims  To compare the quality of colonoscopy in a population-based coordinated program of colorectal cancer screening according to type of hospital (academic or non-academic). Patients and methods  Consecutive patients undergoing colonoscopy after positive FIT (≥ 20 ug Hb/g feces) between January 2009 and September 2016 were prospectively included at five academic and seven non-academic public hospitals. Screening colonoscopy quality indicators considered were adenoma detection rate, cecal intubation rate, complications and bowel preparation quality. Results  A total of 48,759 patients underwent colonoscopy, 34,616 (80 %) in academic hospitals and 14,143 in non-academic hospitals. Among these cases, 19,942 (37.1 %) advanced adenomas and 2,607 (5.3 %) colorectal cancers (CRCs) were detected, representing a total of 22,549 (46.2 %) cases of advanced neoplasia. The adenoma detection rate was 64 %, 63.1 % in academic hospitals and 66.4 % in non-academic hospitals ( P  < 0.001). Rates of advanced adenoma detection, cecal intubation and adequate colonic preparation were 45.8 %, 96.2 % and 88.3 %, respectively, and in all cases were lower (implying worse quality care) in academic hospitals (45.3 % vs 48.7 %; odds ratio [OR] 0.87, 95 % confidence interval [CI] 0.84 - 0.91; 95.9 % vs 97 %; OR 0.48, 95 % CI 0.38 - 0.69; and 86.4 % vs 93 %; OR 0.48, 95 % CI 0.45 - 0.5; respectively; P  < 0.001 in all cases). In 13 patients, all in the academic hospital group, CRC was diagnosed after colonoscopy (0.26 cases × 1000 colonoscopies). Rates of CRC treated by endoscopy were similar in both types of hospital (30 %). The rate of severe complication was 1.2 % (602 patients), with no significant differences by hospital type: bleeding occurred in 1/147 colonoscopies and perforation in 1/329. One patient died within 30 days after screening colonoscopy. Conclusions  The quality of colonoscopy was better in non-academic hospitals. The rate of detection of advanced neoplasia was higher in non-academic hospitals and correlated with the rate of post-colonoscopy CRC.

Mild-moderate blunt chest trauma is defined as a blunt chest trauma that is not caused by a high-energy mechanism, causing thoracic tenderness with or without rib fractures and that has no immediate life-threatening consequences for the patient. It is a frequent clinical situation in the emergency department. The most common radiological techniques that are used in this context are chest X-ray and thoracic computed tomography (CT). The CT scan is set as the gold standard. However, there are no current clinical-radiological guidelines that establish the adequacy of the requests of the CT scan. Therefore, we decided to search for evidence-based recommendations to improve the adequacy of the chest X-ray and CT scan in our daily practice in order to reduce the costs and avoid unnecessary radiation exposure., (Copyright © 2017 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Screening by means of biennial fecal occult blood test has provided a reduction in overall colorectal cancer mortality. Notwithstanding, we should not underestimate the harms that it can produce., Aim: The aim of this article is to identify the independent risk factors of complications after a screening colonoscopy., Methods: A six-year, nested case-control study was conducted. Mortality/complications within 30 days after colonoscopy were registered and its predictors identified through logistic regression., Results: After 39,254 colonoscopies, the complication rate was 1.0%. Independent predictors were sex (OR 1.68 for men; CI 95% 1.18-2.39), ASA physical status classification system (OR 1.73 for ASA II-III; CI 95% 1.53-3.69), history of abdominal surgery (OR 2.37; CI 95% 1.72-4.08), diverticulosis (OR 2.89; CI 95% 1.94-4.30), inadequate cleansing (OR 29.35; CI 95% 6.52-132.17), detection of advanced neoplasia (AN) (OR 4.92; CI 95% 3.29-7.36), detection of stage I adenocarcinoma (OR 9.44; CI 95% 4.46-20.0), polyps in right colon OR 2.27 CI 95% 1.38-3.74) and complex polypectomy (OR 2.00; CI 95% 1.25-3.20). The logistic model explained 82% of the complications (CI 95% 0.798-0.854, p  < 0.001)., Conclusions: Colonoscopy, with or without removal of a lesion, is an invasive procedure with a non-deniable risk of major complications. Factors like inadequate cleansing or detection of AN are determinants. Therefore, it is vital to know which aspects predict their appearance to implement countermeasures.

Objective: To determine the outcome of children aged 2-14 years with cerebrospinal fluid (CSF) pleocytosis and at very low risk for bacterial meningitis managed as outpatients without antibiotics., Methods: Multicentre, prospective, observational study conducted at nine Spanish paediatric EDs. Patients were diagnosed with meningitis based on clinical suspicion of meningitis and CSF pleocytosis when evaluated in the ED. Children between 2 and 14 years of age with pleocytosis and very low-risk criteria for bacterial meningitis (well appearing, Bacterial Meningitis Score (BMS)=0, procalcitonin (PCT)<0.5 ng/mL and observation without deterioration for less than 24 hours in the ED) were treated as outpatients without antibiotics pending CSF cultures. The primary composite outcome was a final diagnosis of bacterial meningitis or return to the ED for clinical deterioration., Results: Of 182 children between 2 and 14 years old diagnosed with meningitis, 56 met the very low-risk criteria and 45 were managed as outpatients. None was diagnosed with bacterial meningitis or returned due to clinical deterioration. Another 31 patients with BMS=1 (due to a peripheral absolute neutrophil count (ANC)>10 000/mm 3 ) and PCT <0.5 ng/mL were managed as outpatients, diagnosed with aseptic meningitis and did well. BMS using PCT had the same sensitivity but greater specificity than classic BMS., Conclusions: This set of low-risk criteria appears safe for the outpatient management without antibiotics of children with CSF pleocytosis. Larger studies are needed to evaluate the predictive values of replacing peripheral ANC with PCT in the BMS., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: The Basque Colorectal Cancer Screening Programme began in 2009 and the implementation has been complete since 2013. Faecal immunological testing was used for screening in individuals between 50 and 69 years old. Colorectal Cancer in Basque country is characterized by unusual epidemiological features given that Colorectal Cancer incidence is similar to other European countries while adenoma prevalence is higher. The object of our study was to economically evaluate the programme via cost-effectiveness and budget impact analyses with microsimulation models., Methods: We applied the Microsimulation Screening Analysis (MISCAN)-Colon model to predict trends in Colorectal Cancer incidence and mortality and to quantify the short- and long-term effects and costs of the Basque Colorectal Cancer Screening Programme. The model was calibrated to the Basque demographics in 2008 and age-specific Colorectal Cancer incidence data in the Basque Cancer Registry from 2005 to 2008 before the screening begun. The model was also calibrated to the high adenoma prevalence observed for the Basque population in a previously published study. The multi-cohort approach used in the model included all the cohorts in the programme during 30 years of implementation, with lifetime follow-up. Unit costs were obtained from the Basque Health Service and both cost-effectiveness analysis and budget impact analysis were carried out., Results: The goodness-of-fit of the model adaptation to observed programme data was evidence of validation. In the cost-effectiveness analysis, the savings from treatment were larger than the added costs due to screening. Thus, the Basque programme was dominant compared to no screening, as life expectancy increased by 29.3 days per person. The savings in the budget analysis appeared 10 years after the complete implementation of the programme. The average annual budget was €73.4 million from year 2023 onwards., Conclusions: This economic evaluation showed a screening intervention with a major health gain that also produced net savings when a long follow-up was used to capture the late economic benefit. The number of colonoscopies required was high but remain within the capacity of the Basque Health Service. So far in Europe, no other population Colorectal Cancer screening programme has been evaluated by budget impact analysis.

Objectives: To assess the efficacy of high-flow nasal cannula (HFNC) oxygen therapy and safety in children with asthma and moderate respiratory failure in the emergency department (ED)., Study Design: This was a prospective randomized pilot trial of children (aged 1-14 years) presenting to a tertiary academic pediatric ED with moderate-to-severe asthma exacerbations between September 2012 and December 2015. Patients with a pulmonary score (PS) ≥6 or oxygen saturation <94% with a face mask despite initial treatment (salbutamol/ipratropium bromide and corticosteroids) were randomized to HFNC or to conventional oxygen therapy. Pharmacologic treatment was at the discretion of attending physicians. The primary outcome was a decrease in PS ≥2 in the first 2 hours. Secondary outcomes included disposition, length of stay, and need for additional therapies., Results: We randomly allocated 62 children to receive either HFNC (n = 30) or standard oxygen therapy (n = 32). Baseline patient characteristics were similar in the 2 groups. At 2 hours after the start of therapy, PS had decreased by ≥2 points in 16 patients in the HFNC group (53%) compared with 9 controls (28%) (P = .01). Between-group differences in disposition, length of stay, and need for additional therapies were not significant. No side effects were reported., Conclusion: HFNC appears to be superior to conventional oxygen therapy for reducing respiratory distress within the first 2 hours of treatment in children with moderate-to-severe asthma exacerbation refractory to first-line treatment. Further studies are needed to demonstrate its overall efficacy in the management of asthma and respiratory failure in the ED., Trial Registration: EudraCT: 2012-001771-36., (Copyright © 2017 Elsevier Inc. All rights reserved.)

To analyze the sociodemographic and organizational factors influencing participation in population-based colorectal cancer screening programs (CRCSP) in Spain, a retrospective study was conducted in a cohort of people invited to participate in the first 3 screening rounds of 6 CRCSP from 2000 to 2012. Mixed logistic regression models were used to analyze the relationship between sociodemographic and organizational factors, such as the type of fecal occult blood test (FOBT) used and the FOBT delivery type. The analysis was performed separately in groups (Initial screening-first invitation, Subsequent invitation for previous never-responders, Subsequent invitation-regular, Subsequent invitation-irregular intervals). The results showed that, in the Initial screening-first invitation group, participation was higher in women than in men in all age groups (OR 1.05 in persons aged 50-59years and OR 1.12 in those aged 60-69years). Participation was also higher when no action was required to receive the FOBT kit, independently of the type of screening (Initial screening-first invitation [OR 2.24], Subsequent invitation for previous never-responders [OR 2.14], Subsequent invitation-regular [OR 2.03], Subsequent invitation-irregular intervals [OR 9.38]) and when quantitative rather than qualitative immunological FOBT (FIT) was offered (Initial screening-first invitation [OR 0.70], Subsequent invitation for previous never-responders [OR 0.12], Subsequent invitation-regular [OR 0.20]) or guaiac testing (Initial screening-first invitation [OR 0.81], Subsequent invitation for previous never-responders [OR 0.88], Subsequent invitation-regular [OR 0.73]). In conclusion, the results of this study show that screening participation could be enhanced by inclusion of the FOBT kit with the screening invitation and the use of the quantitative FIT., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To determine whether 2 doses of dexamethasone is as effective as 5 days of prednisolone/prednisone therapy in improving symptoms and quality of life of children with asthma exacerbations admitted to the emergency department (ED)., Study Design: We conducted a randomized, noninferiority trial including patients aged 1-14 years who presented to the ED with acute asthma to compare the efficacy of 2 doses of dexamethasone (0.6 mg/kg/dose, experimental treatment) vs a 5-day course of prednisolone/prednisone (1.5 mg/kg/d, followed by 1 mg/kg/d on days 2-5, conventional treatment). Two follow-up telephone interviews were completed at 7 and 15 days. The primary outcome measures were the percentage of patients with asthma symptoms and quality of life at day 7. Secondary outcomes were unscheduled returns, admissions, adherence, and vomiting., Results: During the study period, 710 children who met the inclusion criteria were invited to participate and 590 agreed. Primary outcome data were available in 557 patients. At day 7, experimental and conventional groups did not show differences related to persistence of symptoms (56.6%, 95% CI 50.6-62.6 vs 58.3%, 95% CI 52.3-64.2, respectively), quality of life score (80.0 vs 77.7, not significant [ns]), admission rate (23.9% vs 21.7%, ns), unscheduled ED return visits (4.6% vs 3.3%, ns), and vomiting (2.1% vs 4.4%, ns). Adherence was greater in the dexamethasone group (99.3% vs 96.0%, P < .05)., Conclusion: Two doses of dexamethasone may be an effective alternative to a 5-day course of prednisone/prednisolone for asthma exacerbations, as measured by persistence of symptoms and quality of life at day 7., Clinical Trial Registration: clinicaltrialsregister.eu: 2013-003145-42., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The Basque Colorectal Cancer Screening Programme has both high participation rate and high compliance rate of colonoscopy after a positive faecal occult blood test (FIT). Although, colorectal cancer (CRC) screening with biannual (FIT) has shown to reduce CRC mortality, the ultimate effectiveness of the screening programmes depends on the accuracy of FIT and post-FIT colonoscopy, and thus, harms related to false results might not be underestimated. Current CRC screening programmes use a single faecal haemoglobin concentration (f-Hb) cut-off for colonoscopy referral for both sexes and all ages. We aimed to determine optimum f-Hb cut-offs by sex and age without compromising neoplasia detection and interval cancer proportion., Methods: Prospective cohort study using a single-sample faecal immunochemical test (FIT) on 444,582 invited average-risk subjects aged 50-69 years. A result was considered positive at ≥20 μg Hb/g faeces. Outcome measures were analysed by sex and age for a wide range of f-Hb cut-offs., Results: We analysed 17,387 positive participants in the programme who underwent colonoscopy. Participation rate was 66.5%. Men had a positivity rate for f-Hb of 8.3% and women 4.8% (p < 0.0001). The detection rate for advanced neoplasia (cancer plus advanced adenoma) was 44.0‰ for men and 15.9‰ for women (p < 0.0001). The number of colonoscopies required decreased in both sexes and all age groups through increasing the f-Hb cut-off. However, the loss in CRC detection increased by up to 28.1% in men and 22.9% in women. CRC missed were generally at early stages (Stage I-II: from 70.2% in men to 66.3% in women)., Conclusions: This study provides detailed outcomes in men and women of different ages at a range of f-Hb cut-offs. We found differences in positivity rates, neoplasia detection rate, number needed to screen, and interval cancers in men and women and in younger and older groups. However, there are factors other than sex and age to consider when consideration is given to setting the f-Hb cut-off.

Background and Objectives: Identifying international differences in the management of acute pediatric poisonings may help improve the quality of care. The objective of this study was to assess the international variation and appropriateness of gastrointestinal decontamination (GID) procedures performed in children and adolescents who present with acute poisonings to emergency departments., Methods: This was an international, multicenter, cross-sectional prospective study including children <18 years with poisoning exposures presenting to 105 emergency departments in 20 countries from 8 global regions belonging to the Pediatric Emergency Research Networks. Data collection started between January and September 2013 and continued for 1 year. The appropriateness of GID procedures performed was analyzed using the American Academy of Clinical Toxicology and the European Association of Poisons Centres and Clinical Toxicologists' recommendations. Multivariate logistic regression was performed to identify independent risk factors for performing GID procedures., Results: We included 1688 patients, 338 of whom (20.0%, 95% confidence interval 18.1%-22.0%) underwent the following GID procedures: activated charcoal (166, 49.1%), activated charcoal and gastric lavage (122, 36.1%), gastric lavage (47, 13.9%), and ipecac (3, 0.9%). In 155 (45.8%, 40.5%-51.2%), the GID procedure was considered appropriate, with significant differences between regions. Independent risk factors for GID procedures included age, toxin category, mechanism of poisoning, absence of symptoms, and the region where the intoxication occurred ( P < .001)., Conclusions: Globally, there are substantial differences in the use and appropriateness of GID procedures in the management of pediatric poisonings. International best practices need to be better implemented., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Aim: To assess proportions, related conditions and survival of interval cancer (IC)., Methods: The programme has a linkage with different clinical databases and cancer registers to allow suitable evaluation. This evaluation involves the detection of ICs after a negative faecal inmunochemical test (FIT), interval cancer FIT (IC-FIT) prior to a subsequent invitation, and the detection of ICs after a positive FIT and confirmatory diagnosis without colorectal cancer (CRC) detected and before the following recommended colonoscopy, IC-colonoscopy. We conducted a retrospective observational study analyzing from January 2009 to December 2015 1193602 invited people onto the Programme (participation rate of 68.6%)., Results: Two thousand five hundred and eighteen cancers were diagnosed through the programme, 18 cases of IC-colonoscopy were found before the recommended follow-up (43542 colonoscopies performed) and 186 IC-FIT were identified before the following invitation of the 769200 negative FITs. There was no statistically significant relation between the predictor variables of ICs with sex, age and deprivation index, but there was relation between location and stage. Additionally, it was observed that there was less risk when the location was distal rather than proximal (OR = 0.28, 95%CI: 0.20-0.40, P < 0.0001), with no statistical significance when the location was in the rectum as opposed to proximal. When comparing the screen-detected cancers (SCs) with ICs, significant differences in survival were found ( P < 0.001); being the 5-years survival for SCs 91.6% and IC-FIT 77.8%., Conclusion: These findings in a Population Based CRC Screening Programme indicate the need of population-based studies that continue analyzing related factors to improve their detection and reducing harm., Competing Interests: Conflict-of-interest statement: No conflicts of interest.

Objective: To identify the incidence rate (IR) and epidemiologic trends of childhood type 1 diabetes mellitus (T1DM) in children aged 0 to 14-yr-old from 1990 to 2013, in the north of Spain (Biscay)., Subjects and Methods: A prospective-retrospective study was performed. Capture-recapture method was used: primary cases were ascertained from hospital register and a secondary independent data source was obtained from diabetes associations and public health plan database. Age and sex-standardized incidence rates were calculated using direct method, assuming an equal distribution in each age/sex group. In order to identify and analyse trends the period studied was divided into two (1990-2001 and 2002-2013) 11-year periods. The 95% confidence interval (CI) was estimated assuming the Poisson distribution., Results: A total of 399 new cases were identified throughout the study. Mean age at diagnosis was 8.9 ± 3.7 yr. Completeness of ascertainment was 99.1%. Mean annual age-standardized IR was 10.7 (95% CI: 9.6-11.7). The mean incidence for the 0-4, 5-9 and 10-14 age groups was 5.1, 14.6 and 13.2 per 100,000 children/yr, respectively. The incidence rate trend in the whole group was not statistically significant. In the 10-14 age group we found a yearly average increase (2.5% [CI 95% 0.4-4.6]; P < 0.05) and analysing by sex, this statistically significant incidence trend was observed only in boys. We did not find a seasonal onset pattern., Conclusions: The IR did not increase in this population during the period studied unlike the results in other Spanish regions and European Countries., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and study aims: The European guidelines for quality assurance in colorectal cancer (CRC) screening have established high-risk (≥ 5 adenomas or an adenoma ≥ 20 mm) and intermediate-risk (3 - 4 adenomas or at least one adenoma 10 - 19 mm in size, or villous histology, or high grade dysplasia) groups with different endoscopic surveillance intervals. The aim of this study was to evaluate the difference in the incidence of advanced neoplasia (advanced adenoma or CRC) between the two risk groups. Patients and methods: This retrospective group study included patients meeting high- or intermediate-risk criteria for adenomas detected in CRC screening programs and the COLONPREV study before European guidelines were adopted in Spain (June 2011) with a 3-year surveillance recommendation according to Spanish guidelines. The primary outcome measure was the incidence of advanced neoplasia in patients undergoing surveillance. The secondary outcome measure was the CRC incidence. We used an adjusted proportional hazards regression model to control confounding variables. Results: The study included 5401 patients (3379 intermediate risk, 2022 high risk). Endoscopic surveillance was performed in 65.5 % of the patients (2.8 ± 1 years). The incidence of advanced neoplasia in the high- and intermediate-risk groups was 16.0 % (59.0 cases/1000 patient-years) and 12.3 % (41.2 cases/1000 patient-years), respectively. The CRC incidence was 0.5 % (1.4 cases/1000 patient-years) and 0.4 % (1 case/1000 patient-years), respectively. The advanced neoplasia and CRC attributable risk to the high risk group was of 3.7 % and 0.1 %, respectively. In the proportional hazards analysis, the risk of advanced neoplasia was greater in the high-risk group (hazard ratio [HR] 1.5, 95 % confidence interval [CI] 1.2 - 1.8), with no significant differences in the CRC incidence (HR 1.6, 95 %CI 0.6 - 3.8). Conclusions: Patients meeting high-risk criteria have a higher incidence of advanced neoplasia during endoscopic surveillance. No differences were found in the CRC incidence at a 3-year surveillance recommendation., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: While it is known that a variety of factors (biological, behavioural and interventional) play a major role in the health of individuals and populations, the importance of the role of social determinants is less clear. The effect of social inequality on population-based screening for colorectal cancer (CRC) could limit the value of such programmes. The present study aims to determine whether such inequalities exist., Methods: Data was obtained from the population-based screening programme administered in the Autonomous Community of the Basque Country, Spain, with a target population aged 50 to 69, first invited to participate between 2009 and 2011. The magnitude of inequality was analysed using the odds ratio (taking the least disadvantaged socioeconomic quintile as the reference population), the population attributable risk and the relative index of inequality, based on the regression, which is the ratio of the rates in the most and least disadvantaged socioeconomic groups., Results: The target population comprised 242,394 people, with the test kit successfully sent to 95.1 % (230,510). The overall response rate was 64.3 % (67.1 in women and 61.4 % men). Among women, the highest participation was in the third quintile (71.5 %) and the lowest in the first - the least disadvantaged (65.7 %). The lowest and highest rates of people with identified lesions were in the second and fourth quintiles (14.7/1000 and 17.0/1000 respectively). Among men, the response rate was lowest in the fifth - most disadvantaged - quintile (60.2 %). The highest rate of identified lesions was in the fifth quintile; 38 % higher than the first (55.7/1000 compared to 41.0/1000)., Conclusions: Sex and socioeconomic group influence the rate of participation in the CRC programme and the rate of lesions found in the participants. Any public health programme is morally and ethically obliged to strive for equity and effectiveness. Improving participation of men and socially disadvantaged groups should be taken in account.

Unlabelled: The increasing interest for evaluating indirect consequences of health care interventions and their interaction with patients' behavior have put the focus on health promotion interventions including nutrition and the need to measure and evaluate them., Objective: In this review we have aimed to analyze current status of written and published reports on nutrition and nutrition interventions by HTA doers, how assessment has been approached and which metrics and designs have been proposed., Methods: For that purpose, we searched the Center for Reviews and Dissemination databases (CRD) comprising the International Network of Agencies for HTA database (INAHTA), the database of effects (DARE) and the National Health Service Economic Evaluation Database (NHS EED). The words used include nutrition and nutrition interventions and there was no limit on data coverage. We complemented the search by manually seek for further reports on INAHTA's agencies webpages. We extracted the reports for their classification and analysis., Results: We found 82 reports from different sources and after applying inclusion and exclusion criteria, we finally included 42. All the reports correspond to High income Countries (HiC) including agencies from Europe, North America and Oceania. The agencies or programs most represented correspond to the NIHR (UK) and AHRQ (USA). There were general reports around the role of functional foods and specific reports on the impact of establishing nutrition specific strategies in hospitals. 6 out of 42 analyzed the economic consequences of nutrition interventions and 4 reports were related to the methodologies used or the appliance of systematic review methods to the field of nutrition., Conclusions: the reports included correspond to HiC while those HTA agencies established in Low and Middle Income countries (LMiC) have no reported or written activities on the role of nutrition and nutrition interventions. Retrieved reports written by HTA doers/producers confirm the use and utility of systematic reviews and economic analysis methods and its applicability for nutrition interventions. However, some measurements such as Quality Adjusted Life Years (QALY) need to be refined to better reflect the impact of these interventions.