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.

Objectives: Primary objective: to evaluate the efficacy of melatonin as a prophylactic treatment on prevention of symptomatic SARS-CoV-2 infection among healthcare workers at high risk of SARS-CoV-2 exposure. Secondary objectives:-To evaluate the efficacy of melatonin as a prophylactic treatment on prevention of asymptomatic SARS-CoV-2 infection.-To evaluate the efficacy of melatonin to prevent the development of severe COVID-19 in the participants enrolled in this study who develop SARS-CoV-2 infection along the trial.-To evaluate the duration of COVID-19 symptoms in participants receiving melatonin before the infection.-To evaluate seroconversion timing post-symptom onset.

Drug-Induced Liver Injury (DILI) is the fourth leading cause of liver damage in Western countries, increasingly becoming a matter of concern for drug prescription. 1 Despite data on antidepressant-induced liver injury being scarce, 0.5%-3% of patients treated with antidepressants may develop hepatitis, 2,3 being the most susceptible population the elderly and those with polypharmacy. 2 Liver damage is in most cases idiosyncratic and unpredictable, and it is generally unrelated to drug dosage. 2 Patients with DILI by antidepressants should be presumed to have increased risk of developing DILI with the same antidepressant or with any other antidepressant that may display cross-toxicity, limiting therapeutic options.

Introduction: Valproic acid (VPA) is an antiepileptic drug extensively used for treating partial and generalised seizures, acute mania and as prophylaxis for bipolar disorder. Drug-induced liver injury (DILI) persists as a significant issue related to fatal outcomes by VPA. The aim of this study was to increase our knowledge about this condition and to better identify patients affected. Methods: We conducted an observational retrospective case-control study that identified cases of DILI by VPA from the Pharmacovigilance Programme from our Laboratory Signals at La Paz University Hospital from January 2007 to December 2019. From the Therapeutic VPA Monitoring program, two control groups were assigned, VPA-tolerant patients and the other with patients who developed mild VPA-related liver injury but who did not meet the DILI criteria, matched for date, age and sex. Results: A total of 60 patients were included in the study: 15 cases of DILI, 30 VPA-tolerant controls and 15 controls with mild liver injury. Mean age for the cases was 45.7 years, 4 (26.7%) were women and 5 (33.34%) were children under 18 years, of them 3 (20%) were fatal. Polytherapy with other antiepileptic drugs (p = 0.047) and alcohol consumption (p < 0.001) were associated with a greater risk of developing DILI by VPA. A diagnosis of epileptic seizure was more frequently related to DILI when compared with the VPA-tolerant controls (p < 0.001). The cases developed hepatocellular liver injury (p < 0.001), while the mild hepatic damage controls had a higher rate of cholestatic liver injury (p < 0.001). The laboratory lactate dehydrogenase values were statistically higher (even at baseline) in patients with DILI than in both control groups (p = 0.033 and p = 0.039). Conclusions: VPA hepatotoxicity remains a considerable problem. This study offers interesting findings for characterising VPA-induced liver injury and at-risk patients.

Background In April 2020, two independent clinical trials to assess SARS-CoV-2 prophylaxis strategies among health care workers were initiated at our hospital: MeCOVID (melatonin vs placebo) and EPICOS (tenofovir disoproxil/emtricitabine vs hydroxychloroquine vs combination therapy vs placebo). Objective This study aimed to evaluate the reasons why health care workers chose to participate in the MeCOVID and EPICOS trials, as well as why they chose one over the other. Methods Both trials were offered to health care workers through an internal news bulletin. After an initial screening visit, all subjects were asked to respond to a web-based survey. Results In the first month, 206 health care workers were screened and 160 were randomized. The survey participation was high at 73.3%. Health care workers cited “to contribute to scientific knowledge” (n=80, 53.0%), followed by “to avoid SARS-CoV-2 infection” (n=33, 21.9%) and “the interest to be tested for SARS-CoV-2” (n=28, 18.5%), as their primary reasons to participate in the trials. We observed significant differences in the expected personal benefits across physicians and nurses (P=.01). The vast majority of volunteers (n=202, 98.0%) selected the MeCOVID trial, their primary reason being their concern regarding adverse reactions to treatments in the EPICOS trial (n=102, 69.4%). Conclusions Health care workers’ reasons to participate in prophylaxis trials in an acute pandemic context appear to be driven largely by their desire to contribute to science and to gain health benefits. Safety outweighed efficacy when choosing between the two clinical trials.

Introduction: Valproic acid (VPA) is an antiepileptic drug extensively used for treating partial and generalised seizures, acute mania and as prophylaxis for bipolar disorder. Drug-induced liver injury (DILI) persists as a significant issue related to fatal outcomes by VPA. The aim of this study was to increase our knowledge about this condition and to better identify patients affected. Methods: We conducted an observational retrospective case-control study that identified cases of DILI by VPA from the Pharmacovigilance Programme from our Laboratory Signals at La Paz University Hospital from January 2007 to December 2019. From the Therapeutic VPA Monitoring Programme, two control groups were assigned, VPA-tolerant patients and the other with patients who developed mild VPA-related hepatitis but who did not meet the DILI criteria, matched for date, age and sex. Results: A total of 60 patients were included in the study: 15 cases of DILI, 30 VPA-tolerant controls and 15 controls with mild hepatitis. Mean age for the cases was 45.7 years, 4(26.7%) were women and 5(33.34%) were children under 18 years, of them 3(20%) were fatal. Polytherapy with other antiepileptic drugs (p=0.047) and alcohol consumption (p&lt;0.001) were associated with a greater risk of developing DILI by VPA. A diagnosis of epileptic seizure was more frequently related to DILI when compared with the VPA-tolerant controls (p&lt;0.001). The cases developed hepatocellular hepatitis (p&lt;0.001), while the mild hepatitis controls had a higher rate of cholestatic hepatitis (p&lt;0.001). The laboratory lactate dehydrogenase values were statistically higher (even at baseline) in patients with DILI than in both control groups (p= 0.033 and p=0.039). Conclusions: VPA hepatotoxicity remains a considerable problem. This study offers interesting findings for characterising VPA-induced liver injury and at-risk patients.

BACKGROUND In April 2020, two independent clinical trials (CT) to assess SARS-Cov-2 prophylaxis in healthcare workers were started in our Hospital: MeCOVID (melatonin vs placebo) and EPICOS (tenofovir disoproxil/emtricitabine vs hydroxychloroquine vs the combination of both vs placebo). OBJECTIVE We aim to evaluate the motivations to participate and the reasons to choose one or another. METHODS Both CTs were offered to personnel through the internal news bulletin. After the screening visit, all subjects were asked to answer a web-based survey. RESULTS In the first month, 206 healthcare workers were screened and 160 randomized. Survey participation was quite high, 73.3%. The main motivation to participate was “to contribute to scientific knowledge” 53.0%, followed by “to avoid SARS-Cov-2 infection” and “the interest to be tested for SARS-CoV-2”. We found differences between physicians and nurses in the expected personal benefits (P<0.05). The vast majority of the volunteers selected the MeCOVID study, the main reason was the fear of adverse reactions associated with treatments in EPICOS, 69.4%. CONCLUSIONS Healthcare workers´ motivations to participate in prophylaxis trials in a pandemic context appear to be driven mostly by their desire to contribute to science and getting some health benefits. Safety seems to weight way more than efficacy to choose between CTs.

Kounis syndrome (KS) is an acute coronary syndrome (ACS) described in relationship with drugs or stents. KS was suspected in a full-term newborn who underwent a Rashkind-atrioseptostomy and stenting that periodically developed episodes of ACS. Skin test with nickel and titanium were performed being negatives. Basophil activation (BAT) and lymphocyte transformation (LTT) tests were performed for the suspected drugs. Non-responder basophils in BAT and a positive LTT for heparin were found. A new dose of heparin was administered by error, after which a new ACS was developed. We described the first report of KS by drug in a newborn.