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.

In chronic non-cancer pain (CNCP), evidence of the effectiveness of strong opioids (SO) is very limited. Despite this, their use is increasingly common. To examine SO prescriptions, we designed a descriptive, longitudinal, retrospective population-based study, including patients aged ≥15 years prescribed SO for ≥3 months continuously in 2013–2017 for CNCP in primary care in Catalonia. Of the 22,691 patients included, 17,509 (77.2%) were women, 10,585 (46.6%) were aged >80 years, and most had incomes of <€18,000 per year. The most common diagnoses were musculoskeletal diseases and psychiatric disorders. There was a predominance of transdermal fentanyl in the defined daily dose (DDD) per thousand inhabitants/day, with the greatest increase for tapentadol (312% increase). There was an increase of 66.89% in total DDD per thousand inhabitants/day for SO between 2013 (0.737) and 2017 (1.230). The mean daily oral morphine equivalent dose/day dispensed for all drugs was 83.09 mg. Transdermal fentanyl and immediate transmucosal release were the largest cost components. In conclusion, there was a sustained increase in the prescription of SO for CNCP, at high doses, and in mainly elderly patients, predominantly low-income women. The new SO are displacing other drugs.

Preterm birth has been related to inequalities in maternal educational level, but the causal mechanism is not entirely known. Some factors associated with preterm birth and low educational level such as chronic medical conditions, pregnancy complications and related-health behaviours could have a mediation role in the pathway. This study aimed to evaluate the association between maternal educational level and preterm birth, analysing the mediation role of these factors. We performed a retrospective cohort study based on hospital electronic records of 10467 deliveries that took place in the Hospital Clínic of Barcelona between 2011 and 2017. Poisson regression was used to obtain crude and adjusted relative risk of preterm birth in women with different educational level and the percentage of change in relative risk was calculated when mediation variables were included in the model. Women with a lower educational level had a higher risk of preterm birth (RR 1.57, 95% CI 1.21, 2.03). The loss of association after the inclusion of body mass index in the model suggests an important mediation role of maternal overweight. Other variables such as smoking, drug use, preeclampsia and genitourinary infections also appear to play a role in the observed inequality between women with different levels of education. Efforts to promote health literacy and to improve preventive interventions, before and during pregnancy, could decrease preterm birth rates and perinatal health inequalities

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