Violence in first-episode psychosis: evidence from an early intervention in psychosis programme.

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.

Safety and immunogenicity of the protein-based PHH-1V compared to BNT162b2 as a heterologous SARS-CoV-2 booster vaccine in adults vaccinated against COVID-19: a multicentre, randomised, double-blind, non-inferiority phase IIb trial.

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.

Prediction of significant coronary artery disease in acute chest pain without infarction in emergency department: MAPAC Cardio-PreTest model.

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.

Flexible multiplex PCR to detect SARS-CoV-2, coronavirus OC43 and influenza A virus in nasopharyngeal swab samples.

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.

Immune response and reactogenicity after immunization with two-doses of an experimental COVID-19 vaccine (CVnCOV) followed by a third-fourth shot with a standard mRNA vaccine (BNT162b2): RescueVacs multicenter cohort study.

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".

Immunogenic dynamics and SARS-CoV-2 variant neutralisation of the heterologous ChAdOx1-S/BNT162b2 vaccination: Secondary analysis of the randomised CombiVacS study.

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).

Novel genes and sex differences in COVID-19 severity.

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.

Efectividad de la autotoma del exudado vaginorrectal para el cribado prenatal de la infección por Streptococcus agalactiae. Estudio GALL / Effectiveness of the vagino-rectal exudate self-sampling for prenatal screening of Streptococcus agalactiae infection. GALL study

Objetivo: Evaluar la efectividad de la autotoma del exudado vaginorrectal para el cribado prenatal de la infección por EGB e identificar barreras y facilitadores que encuentra la gestante para esta intervención. Diseño: Estudio transversal de pruebas diagnósticas. Participantes y emplazamiento: Participaron 213 gestantes que acudieron a la consulta de la matrona de atención primaria en 6 centros de salud del Servicio Vasco de Salud/Osakidetza en Bizkaia, que cumplían los criterios de inclusión y aceptaban participar en el estudio. Mediciones principales: Se comparó el resultado del cultivo vaginorrectal obtenido por la gestante con el resultado del cultivo vaginorrectal tomado por la matrona en consulta el mismo día, y se recogieron barreras y facilitadores encontrados por las mujeres en la autotoma. Resultados: Se ha observado que la autotoma como prueba para detectar el EGB tiene una sensibilidad del 93,3% (IC 95%, 78,7-98,2), una especificidad del 99,4% (IC 95%, 96,5-99,9), un valor predictivo positivo del 96% (IC 95% 82,8-99,4) y un valor predictivo negativo del 98,8% (IC 95%, 95,6-99,7). El 27,3% de los encuestadas encontraron alguna dificultad en la recogida, solo el 4,8% no se vieron capacitadas, el 84,2% se sintieron cómodas, el 99,5% consideraron la información proporcionada adecuada y completa, al 94,7% no le resultaron complicados los pasos a seguir, y el 96% están satisfechas con el estudio. Conclusiones: La autotoma del exudado vaginorrectal para la detección del EGB ha resultado ser válida y fiable, lo que permitiría ofrecer esta opción a las gestantes en el cribado sistemático de la infección por EGB.(AU)

Objetive: To evaluate the effectiveness of vagino-rectal swab autotomy for prenatal screening for GBS infection and to identify the barriers and facilitators encountered by the pregnant woman for this intervention. Design: Cross-sectional study of diagnostic tests. Participants and site: A total of 213 pregnant women who attended the primary care midwife's office in 6 health centers of the Basque Health Service/Osakidetza in Bizkaia, who met the inclusion criteria and agreed to participate in the study, participated in the study. Main measurements: The result of the vagino-rectal culture obtained by the pregnant woman was compared with the result of the vagino-rectal culture taken by the midwife in consultation on the same day, and the barriers and facilitators encountered by the women in the self-test were collected. Results: Self-testing as a test for GBS was found to have a sensitivity of 93.3% (95% CI 78.7–98.2), a specificity of 99.4% (95% CI 96.5–99.9), a positive predictive value of 96% (95% CI 82.8–99.4) and a negative predictive value of 98.8% (95% CI 95.6–99.7). 27.3% of respondents encountered some difficulty in the collection, only 4.8% did not feel qualified, 84.2% felt comfortable, 99.5% considered the information provided to be adequate and complete, 94.7% did not find the steps to follow complicated, and 96% were satisfied with the study. Conclusions: Self-collection of vagino-rectal exudate for GBS detection has proved to be valid and reliable, which would make it possible to offer this option to pregnant women in the systematic screening for GBS infection.(AU)

[Effectiveness of the vagino-rectal exudate self-sampling for prenatal screening of Streptococcus agalactiae infection. GALL study]. / Efectividad de la autotoma del exudado vaginorrectal para el cribado prenatal de la infección por Streptococcus agalactiae. Estudio GALL.

OBJETIVE: To evaluate the effectiveness of vagino-rectal swab autotomy for prenatal screening for GBS infection and to identify the barriers and facilitators encountered by the pregnant woman for this intervention. DESIGN: Cross-sectional study of diagnostic tests. PARTICIPANTS AND SITE: A total of 213 pregnant women who attended the primary care midwife's office in 6 health centers of the Basque Health Service/Osakidetza in Bizkaia, who met the inclusion criteria and agreed to participate in the study, participated in the study. MAIN MEASUREMENTS: The result of the vagino-rectal culture obtained by the pregnant woman was compared with the result of the vagino-rectal culture taken by the midwife in consultation on the same day, and the barriers and facilitators encountered by the women in the self-test were collected. RESULTS: Self-testing as a test for GBS was found to have a sensitivity of 93.3% (95% CI 78.7-98.2), a specificity of 99.4% (95% CI 96.5-99.9), a positive predictive value of 96% (95% CI 82.8-99.4) and a negative predictive value of 98.8% (95% CI 95.6-99.7). 27.3% of respondents encountered some difficulty in the collection, only 4.8% did not feel qualified, 84.2% felt comfortable, 99.5% considered the information provided to be adequate and complete, 94.7% did not find the steps to follow complicated, and 96% were satisfied with the study. CONCLUSIONS: Self-collection of vagino-rectal exudate for GBS detection has proved to be valid and reliable, which would make it possible to offer this option to pregnant women in the systematic screening for GBS infection.

Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): a randomised, observer-blinded, placebo-controlled, phase 2b/3 trial.

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.

Gender differences in drug titration among heart failure patients with reduced ejection fraction in the ETIFIC trial.

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.

Facilitators and barriers to participation in population-based colorectal cancer screening programme from the perspective of healthcare professionals: Qualitative research study.

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.

Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial.

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.

T Cell Activation, Highly Armed Cytotoxic Cells and a Shift in Monocytes CD300 Receptors Expression Is Characteristic of Patients With Severe COVID-19.

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.

[Involvement of the Primary Healthcare professionals in the Colorectal Cancer Screening Programme of the Basque Country.] / Implicación de los profesionales de atención primaria en el programa de detección precoz de cáncer colorrectal del País Vasco.

OBJECTIVE: The Basque Government (Spain) approved a population based Colorectal Cancer Screening Programme in 2008 with its base on Primary Healthcare. Since then, a coverage of 100% of the population and an average participation rate of 68.4% have been achieved. General Practitioners and nurses play a central role on its implementation. The aim of this work was to describe the characteristics, involvement and attitudes of the health professionals that implement the programme. METHODS: A cross-sectional descriptive study was conducted in Primary Healthcare to general practitioners and nurses between May and June of 2016. An ad-hoc online questionnaire was designed. The data included socio-demographic information and questions regarding their involvement on the programme. RESULTS: 1,216 health professionals answered the questionnaire, 50.7% were general practitioners and 49.3% nurses. 78% of the responders were women. The 75.8% considered the programme very important although differences were found between general practitioners and nurses. The 89% of the professionals attended training and 34% scientific workshops about screening at least once. There were differences between general practitioners and nurses on the attendance to the training and importance they give to the programme, and on their participation on workshops. CONCLUSIONS: There is a high level of involvement of Primary Healthcare professionals in the programme as they consider it very important; this could be one of the keys for its success. The differences between professionals on their opinion and experience should be taken into account on its design, as they are the ones with a closer contact with the population.

OBJETIVO: El Gobierno Vasco (España) aprobó en 2008 un programa de detección del cáncer colorrectal de base poblacional en Atención Primaria. Se ha logrado una cobertura del 100% con una tasa de participación media del 68,4%. Los profesionales de medicina y enfermería desempeñan un papel fundamental en su implementación. El objetivo fue describir las características, implicación y actitudes de los profesionales de la salud que implementan el programa. METODOS: Estudio descriptivo transversal a personal de medicina y enfermería entre mayo y junio de 2016. Se diseñó un cuestionario en línea ad-hoc. Los datos incluían información sociodemográfica y preguntas relativas a su implicación en el programa. RESULTADOS: 1.216 profesionales de la salud respondieron al cuestionario (50,7% medicina y 49,3% enfermería). El 78% eran mujeres. El 75,8% consideró que el programa era muy importante, aunque se encontraron diferencias entre profesionales de medicina y de enfermería. El 89% asistió a formación y el 34% a jornadas científicas sobre el cribado por lo menos una vez. Se observaron diferencias entre médicos y profesionales de la enfermería en cuanto a la asistencia a formación y jornadas y en la importancia que daban al programa. CONCLUSIONES: Existe un alto nivel de participación de los profesionales de la atención primaria de la salud en el programa y lo consideran muy importante. Las diferencias entre los profesionales en cuanto a su opinión y experiencia deben ser tenidas en cuenta en el diseño de los programas, ya que son ellos los que tienen un contacto más estrecho con la población.

Effectiveness of a structured group intervention based on pain neuroscience education for patients with fibromyalgia in primary care: A multicentre randomized open-label controlled trial.

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.

Noninferiority of heart failure nurse titration versus heart failure cardiologist titration. ETIFIC multicenter randomized trial.

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.

Clinical Prediction Rule for Distinguishing Bacterial From Aseptic Meningitis.

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 mm3, 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.

Changing epidemiology of nontuberculous mycobacterial lung disease over the last two decades in a region of the Basque country.

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.

Efficacy and Usability of eHealth Technologies in Stroke Survivors for Prevention of a New Stroke and Improvement of Self-Management: Phase III Randomized Control Trial.

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.