Risk of cardiovascular events after influenza: A population-based Self Controlled Case Series study, Spain 2011-2018.

This study explores the relationship between influenza infection, both clinically diagnosed in primary-care and laboratory confirmed in hospital, and atherothrombotic events (acute myocardial infarction and ischemic stroke) in Spain. A population-based self-controlled case series design was used with individual-level data from electronic registries (n = 2,230,015). The risk of atherothrombotic events in subjects ≥50 years old increased more than 2-fold during the 14 days after the mildest influenza cases in patients with fewer risk factors and more than 4-fold after severe cases in the most vulnerable patients, remaining in them more than 2-fold for 2 months. The transient increase of the association, its gradient after influenza infection and the demonstration by 4 different sensitivity analyses provide further evidence supporting causality. This work reinforces the official recommendations for influenza prevention in at-risk groups and should also increase the awareness of even milder influenza infection and its possible complications in the general population.

Incidence of Invasive and Noninvasive Pneumococcal Pneumonia Hospitalizations in People Aged ≥50 Years: Assessing Variability Across Denmark and Spain.

Determining pneumococcal pneumonia (PP) burden in the elderly population is challenging due to limited data on invasive PP (IPP) and, in particular, noninvasive PP (NIPP) incidence. Using retrospective cohorts of adults aged ≥50 years in Denmark (2 782 303) and the Valencia region, Spain (2 283 344), we found higher IPP hospitalization rates in Denmark than Valencia (18.3 vs 9/100 000 person-years [PY], respectively). Conversely, NIPP hospitalization rates were higher in Valencia (48.2 vs 7.2/100 000 PY). IPP and NIPP rates increased with age and comorbidities in both regions, with variations by sex and case characteristics (eg, complications, mortality). The burden of PP in adults is substantial, yet its true magnitude remains elusive. Discrepancies in clinical practices impede international comparisons; for instance, Valencia employed a higher frequency of urinary antigen tests compared to Denmark. Additionally, coding practices and prehospital antibiotic utilization may further influence these variations. These findings could guide policymakers and enhance the understanding of international disparities in disease burden assessments.

Evaluation of antibody-based preventive alternatives for respiratory syncytial virus: a novel multi-criteria decision analysis framework and assessment of nirsevimab in Spain.

BACKGROUND: Respiratory syncytial virus (RSV) is a highly infectious disease that poses a significant clinical and medical burden, as well as social disruption and economic costs, recognized by the World Health Organization as a public health issue. After several failed attempts to find preventive candidates (compounds, products, including vaccines), new alternatives might be available, one being nirsevimab, the first and only option approved for RSV prevention in neonates and infants during their first RSV season. The objective of this study was to develop a novel multi-criteria decision analysis (MCDA) framework for RSV antibody-based preventive alternatives and to use it to assess the value of nirsevimab vs. placebo as a systematic immunization approach to prevent RSV in neonates and infants during their first RSV season in Spain. METHODS: Based on a pre-established model called Vaccinex, an ad-hoc MCDA framework was created to reflect relevant attributes for the assessment of current and future antibody-based preventive measures for RSV. The estimated value of nirsevimab was obtained by means of an additive linear model combining weights and scores assigned by a multidisciplinary committee of 9 experts. A retest and three sensitivity analyses were conducted. RESULTS: Nirsevimab was evaluated through a novel framework with 26 criteria by the committee as a measure that adds value (positive final estimated value: 0.56 ± 0.11) to the current RSV scenario in Spain, by providing a high efficacy for prevention of neonates and infants. In addition, its implementation might generate cost savings in hospitalizations and to the healthcare system and increase the level of public health awareness among the general population, while reducing health inequities. CONCLUSIONS: Under a methodology with increasing use in the health field, nirsevimab has been evaluated as a measure which adds value for RSV prevention in neonates and infants during their first RSV season in Spain.

Effectiveness of self-financed rotavirus vaccines on acute gastroenteritis primary care episodes using real-world data in Spain: a propensity score-matched analysis of cohort study.

The objective of this study was to estimate, by a novel spatiotemporal approach in an environment of non-funded rotavirus (RV) vaccines, the RV vaccine effectiveness (VE) to prevent acute gastroenteritis primary care (AGE-PC)-attended episodes, demonstrating how indirect protection leads to underestimation of direct VE under high vaccine coverage (VC). This population-based retrospective cohort study used electronic healthcare registries including all children 2 months-5 years old, born from 2009 to 2018 in the Valencia Region (Spain). Direct RV VE preventing AGE-PC episodes was estimated using propensity score matching and Poisson regressions stratified by VC, adjusted by age and calendar season. Indirect VE was estimated by Poisson regression comparing AGE-PC rates in unvaccinated children among the different VC levels. A total of 563,442 children were included for the RV VC estimation; of them, 360,576 were included in the birth-cohort for VE analysis. RV VC showed strong variability among districts and seasons, rising on average from 21% in 2009/2010 to 55% in 2017/2018. The highest direct VE was found in vaccinated children from districts with 0-30% RV VC (16.4%) and the lowest in those from districts with ≥ 70% RV VC (9.7%). The indirect protection in unvaccinated children raised from 6 to 16.6% for those living with 20-30% and ≥ 70% VC, respectively. CONCLUSION: Considering that RV is the causative agent in 20% of AGE cases, a direct effectiveness of 82% preventing AGE-PC episodes due to RV could be deduced using a novel spatiotemporal approach. A reduction of 17% of AGE-PC episodes in unvaccinated was observed in areas with VC over 70% because of indirect protection. WHAT IS KNOWN: • The effectiveness of RV vaccines preventing hospitalizations due to RV-acute gastroenteritis (RV-AGE) has been extensively studied. However, RV also burdens the primary care (PC) setting, and data on vaccine effectiveness (VE) in preventing AGE-PC visits are scarce. • The RV vaccine distribution in Spain (non-funded), with large differences in vaccine coverage (VC) among healthcare districts, provides an ideal scenario to assess the actual VE in preventing AGE-PC consultations, including the direct and indirect protection. WHAT IS NEW: • A direct effectiveness of 82% preventing AGE-PC episodes due to RV could be deduced using a novel spatiotemporal approach. A reduction of 17% of AGE-PC episodes in unvaccinated was observed in areas with high VC because of indirect protection. • These findings, together with existing data on the impact on hospitalizations due to RV-AGE, offer valuable insights for implementing vaccination initiatives in countries that have not yet commenced such programs.

Early estimates of nirsevimab immunoprophylaxis effectiveness against hospital admission for respiratory syncytial virus lower respiratory tract infections in infants, Spain, October 2023 to January 2024.

The monoclonal antibody nirsevimab was at least 70% effective in preventing hospitalisations in infants with lower respiratory tract infections (LRTI) positive for respiratory syncytial virus (RSV) in Spain (Oct 2023-Jan 2024), where a universal immunisation programme began late September (coverage range: 79-99%). High protection was confirmed by two methodological designs (screening and test-negative) in a multicentre active surveillance in nine hospitals in three regions. No protection against RSV-negative LRTI-hospitalisations was shown. These interim results could guide public-health decision-making.

Bronchiolitis, Regardless of Its Etiology and Severity, Is Associated With Increased Risk of Asthma: A Population-Based Study.

An association exists between severe respiratory syncytial virus (RSV)-bronchiolitis and a subsequent increased risk of recurrent wheezing (RW) and asthma. However, a causal relationship remains unproven. Using a retrospective population-based cohort study (339 814 children), bronchiolitis during the first 2 years of life (regardless of etiology and severity) was associated with at least a 3-fold increased risk of RW/asthma at 2-4 years and an increased prevalence of asthma at ≥5 years of age. The risk was similar in children with mild bronchiolitis as in those with hospitalized RSV-bronchiolitis and was higher in children with hospitalized non-RSV-bronchiolitis. The rate of RW/asthma was higher when bronchiolitis occurred after the first 6 months of life. Our results seem to support the hypothesis of a shared predisposition to bronchiolitis (irrespective of etiology) and RW/asthma. However, 60% of hospitalized bronchiolitis cases in our setting are due to RSV, which should be paramount in decision-making on imminent RSV prevention strategies.

Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression.

Current antidepressants act principally by blocking monoamine reuptake by high-affinity transporters in the brain. However, these antidepressants show important shortcomings such as slow action onset and limited efficacy in nearly a third of patients with major depression disorder. Here, we report the development of a prodrug targeting organic cation transporters (OCT), atypical monoamine transporters recently implicated in the regulation of mood. Using molecular modeling, we designed a selective OCT2 blocker, which was modified to increase brain penetration. This compound, H2-cyanome, was tested in a rodent model of chronic depression induced by 7-week corticosterone exposure. In male mice, prolonged administration of H2-cyanome induced positive effects on several behaviors mimicking symptoms of depression, including anhedonia, anxiety, social withdrawal, and memory impairment. Importantly, in this validated model, H2-cyanome compared favorably with the classical antidepressant fluoxetine, with a faster action on anhedonia and better anxiolytic effects. Integrated Z-scoring across these depression-like variables revealed a lower depression score for mice treated with H2-cyanome than for mice treated with fluoxetine for 3 weeks. Repeated H2-cyanome administration increased ventral tegmental area dopaminergic neuron firing, which may underlie its rapid action on anhedonia. H2-cyanome, like fluoxetine, also modulated several intracellular signaling pathways previously involved in antidepressant response. Our findings provide proof-of-concept of antidepressant efficacy of an OCT blocker, and a mechanistic framework for the development of new classes of antidepressants and therapeutic alternatives for resistant depression and other psychiatric disturbances such as anxiety.

Feasibility of a hybrid clinical trial for respiratory virus detection in toddlers during the influenza season.

BACKGROUND: Traditional clinical trials are conducted at investigator sites. Participants must visit healthcare facilities several times for the trial procedures. Decentralized clinical trials offer an interesting alternative. They use telemedicine and other technological solutions (apps, monitoring devices or web platforms) to decrease the number of visits to study sites, minimise the impact on daily routine, and decrease geographical barriers for participants. Not much information is available on the use of decentralization in randomized clinical trials with vaccines. METHODS: A hybrid clinical trial may be assisted by parental recording of symptoms using electronic log diaries in combination with home collected nasal swabs. During two influenza seasons, children aged 12 to 35 months with a history of recurrent acute respiratory infections were recruited in 12 primary health centers of the Valencia Region in Spain. Parents completed a symptom diary through an ad hoc mobile app that subsequently assessed whether it was an acute respiratory infection and requested collection of a nasal swab. Feasibility was measured using the percentage of returned electronic diaries and the validity of nasal swabs collected during the influenza season. Respiratory viruses were detected by real-time PCR. RESULTS: Ninety-nine toddlers were enrolled. Parents completed 10,476 electronic diaries out of the 10,804 requested (97%). The mobile app detected 188 potential acute respiratory infections (ARIs) and requested a nasal swab. In 173 (92%) ARI episodes a swab was taken. 165 (95.4%) of these swabs were collected at home and 144 (87.3%) of them were considered valid for laboratory testing. Overall, 152 (81%) of the ARIs detected in the study had its corresponding valid sample collected. CONCLUSIONS: Hybrid procedures used in this clinical trial with the influenza vaccine in toddlers were considered adequate, as we diagnosed most of the ARI cases on time, and had a valid swab in 81% of the cases. Hybrid clinical trials improve participant adherence to the study procedures and could improve recruitment and quality of life of the participants and the research team by decreasing the number of visits to the investigator site. This report emphasises that the conduct of hybrid CTs is a valid alternative to traditional CTs with vaccines. This hybrid CT achieved high adherence of participant to the study procedures. TRIAL REGISTRATION: 2019-001186-33 (EudraCT).

European data sources for computing burden of (potential) vaccine-preventable diseases in ageing adults.

BACKGROUND: To guide decision-making on immunisation programmes for ageing adults in Europe, one of the aims of the Vaccines and InfecTious diseases in the Ageing popuLation (IMI2-VITAL) project is to assess the burden of disease (BoD) of (potentially) vaccine-preventable diseases ((P)VPD). We aimed to identify the available data sources to calculate the BoD of (P)VPD in participating VITAL countries and to pinpoint data gaps. Based on epidemiological criteria and vaccine availability, we prioritized (P) VPD caused by Extra-intestinal pathogenic Escherichia coli (ExPEC), norovirus, respiratory syncytial virus, Staphylococcus aureus, and pneumococcal pneumonia. METHODS: We conducted a survey on available data (e.g. incidence, mortality, disability-adjusted life years (DALY), quality-adjusted life years (QALY), sequelae, antimicrobial resistance (AMR), etc.) among national experts from European countries, and carried out five pathogen-specific literature reviews by searching MEDLINE for peer-reviewed publications published between 2009 and 2019. RESULTS: Morbidity and mortality data were generally available for all five diseases, while summary BoD estimates were mostly lacking. Available data were not always stratified by age and risk group, which is especially important when calculating BoD for ageing adults. AMR data were available in several countries for S. aureus and ExPEC. CONCLUSION: This study provides an exhaustive overview of the available data sources and data gaps for the estimation of BoD of five (P) VPD in ageing adults in the EU/EAA, which is useful to guide pathogen-specific BoD studies and contribute to calculation of (P)VPDs BoD.

The impact of childhood RSV infection on children's and parents' quality of life: a prospective multicenter study in Spain.

BACKGROUND:  Several immunisation candidates against RSV are in late-stage clinical trials. To evaluate the benefits of a potential vaccination programme, both economic and health benefits will be needed. Health benefits are usually measured in Health-related Quality of Life (HRQoL) loss using standardised questionnaires. However, there are no RSV-specific questionnaires validated for children under 2 years, in whom most RSV episodes occur. Therefore, HRQoL estimates are taken from literature or inadequate tools. We determined HRQoL loss and direct costs due to an RSV episode in children younger than 2 years and their caregivers during a month of follow up, using a new questionnaire administered online. METHODS:  An observational prospective multicentre surveillance study was conducted in children aged younger than two years. Children were recruited from 8 primary care centres and 1 hospital in the Valencia region and Catalonia (Spain). RSV-positive cases were obtained by immunochromatographic test. HRQoL was assessed using a new ad-hoc 38 item-questionnaire developed. Parents of infected children completed 4 questionnaires at four timepoints (day 0, 7, 14 and 30) after diagnosis. RESULTS:  117 children were enrolled in the study and 86 (73.5%) were RSV + . Median (interquartile range; IQR) scores were 0.52 (0.42-0.68), 0.65 (0.49-0.79), 0.82 (0.68-0.97) and 0.94 (0.81-1), for days 0, 7, 14 and 30, respectively. Compared to total recovery (Q30), HRQoL loss was 37.5%, 31.5% and 8.9% on days 0, 7 and 14 since diagnosis of the disease. The total median cost per patient (including treatments) was €598.8 (IQR: 359.63-2425.85). CONCLUSIONS:  RSV had almost 40% impact on HRQoL during the first week since onset of symptoms and the median cost per episode and patient was about €600. These results represent a substantial input for health-economic evaluations of future RSV-related interventions such as vaccination.

Herpes zoster risk and burden of disease in immunocompromised populations: a population-based study using health system integrated databases, 2009-2014.

BACKGROUND: Estimate the incidence of herpes zoster (HZ), its complications and healthcare utilization rates in adults (≥ 18-years-old) with a wide range of immunocompromised (IC) conditions compared to IC-free cohort. METHOD: A population-based retrospective study using the Valencia healthcare Integrated Databases (VID) (2009-2014). HZ and IC were defined using ICD-9 codes in primary care (PC) and hospitalization registers. Incidence rates (IR), risk of HZ, HZ-recurrence, HZ-complications and healthcare utilization rates were estimated in the IC-cohort compared to IC-free. RESULTS: The study population consisted of 4,382,590 subjects, of which 578,873 were IC (13%). IR (in 1000 persons-year) of HZ overall, in IC and in IC-free cohort was 5.02, 9.15 and 4.65, respectively. IR of HZ increased with age in both cohorts and it was higher for all IC conditions studied, reaching up to twelvefold in subjects with stem cell transplantation. IC subjects had 51% higher risk of developing HZ, 25% higher HZ-recurrence and the risk of HZ-complications was 2.37 times higher than in IC-free. HZ-related healthcare utilization was higher in the IC-cohort than in IC-free (number of hospitalizations 2.93 times greater, hospital stays 12% longer, 66% more HZ-specialist visits, 2% more PC visits, sick leaves 18% longer and 20% higher antiviral dispensation). CONCLUSIONS: Patients suffering from all the IC conditions studied are at higher risk of developing HZ, HZ-recurrence and post-herpetic complications, which implies a substantial morbidity and a high consumption of resources. These results should be considered for vaccine policy implementation.

Spatio-temporal impact of self-financed rotavirus vaccination on rotavirus and acute gastroenteritis hospitalisations in the Valencia region, Spain.

BACKGROUND: Several studies have shown a substantial impact of Rotavirus (RV) vaccination on the burden of RV and all-cause acute gastroenteritis (AGE). However, the results of most impact studies could be confused by a dynamic and complex space-time process. Therefore, there is a need to analyse the impact of RV vaccination on RV and AGE hospitalisations in a space-time framework to detect geographical-time patterns while avoiding the potential confusion caused by population inequalities in the impact estimations. METHODS: A retrospective population-based study using real-world data from the Valencia Region was performed among children aged less than 3 years old in the period 2005-2016. A Bayesian spatio-temporal model was constructed to analyse RV and AGE hospitalisations and to estimate the vaccination impact measured in averted hospitalisations. RESULTS: We found important spatio-temporal patterns in RV and AGE hospitalisations, RV vaccination coverage and in their associated adverted hospitalisations. Overall, ~ 1866 hospital admissions for RV were averted by RV vaccination during 2007-2016. Despite the low-medium vaccine coverage (~ 50%) in 2015-2016, relevant 36 and 20% reductions were estimated in RV and AGE hospitalisations respectively. CONCLUSIONS: The introduction of the RV vaccines has substantially reduced the number of RV hospitalisations, averting ~ 1866 admissions during 2007-2016 which were space and time dependent. This study improves the methodologies commonly used to estimate the RV vaccine impact and their interpretation.

Long-term impact of self-financed rotavirus vaccines on rotavirus-associated hospitalizations and costs in the Valencia Region, Spain.

BACKGROUND: Rotavirus vaccines are available in Spain from 2007. They are recommended by the Spanish Pediatric Association, but not funded by the National Health System (NHS) and its coverage rate reached 40-50%. The hospitalization rate reduction of rotavirus caused gastroenteritis (RVAGE) directly attributable to vaccination remains unclear due to the large differences described in published studies, ranging from 14 to 44.5% in children <5 years of age, even with similar vaccination coverage. These results could be partly explained by variability in hospitalization policies, different study designs and the timeframe of observation. In addition, the direct economic impact of the reduction of hospitalizations has never been estimated. Therefore, there is a need to analyze the long-term impact of rotavirus vaccines on RVAGE and all cause gastroenteritis (AGE) hospitalizations and the national health system associated costs, minimizing potential confounders or biases. METHODS: A population-based, ecological study using the hospital discharge registry's Minimum Basic Data Set (MBDS) and the vaccine register (SIV) was performed, among Valencia Region's children <5 years old, during 2002 - 2015. RVAGE and AGE hospitalization risk was analyzed by vaccine coverage and adjusted by the total hospitalization rate for all causes to avoid external biases. The impact of AGE-associated health care utilization in prevaccine (2003-2006) versus postvaccine (2008-2014) years was also assessed. RESULTS: After vaccines licensure, the incidence of RVAGE-associated hospitalizations decreased markedly. A general vaccine coverage-related reduction in RVAGE or AGE-hospitalizations risk was observed in all age groups. Compared with unvaccinated children, RVAGE hospitalization risk decreased by 67% (95% CI: 55-67), 71% (95% CI: 58-81) and 68% (95% CI: 18-92) in children 0, 1 and 4 years of age, respectively, with a vaccination coverage between 40 and 42%. Overall, the hospital related costs were reduced around EUR 6 Mill per 105 children in 7 years. CONCLUSIONS: Despite the low-medium vaccine coverage, the introduction of rotavirus vaccines had a specific coverage-related response impact in the hospitalizations for RVAGE and AGE in children <5 years and their use substantially reduced hospital related costs. The model used reassures that the estimated impact is due to the vaccination and not to other external factors.

Risk of herpes zoster in adults with SARS-CoV-2 infection in Spain: A population-based, retrospective cohort study.

OBJECTIVES: We aimed to compare the risk of herpes zoster (HZ) in adults with and without laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: This retrospective dynamic cohort study analyzed data from a public healthcare database in Spain between November 2020 and October 2021. The main outcome was incident cases of HZ in individuals ≥18-year-old. Relative risk (RR) of HZ in SARS-CoV-2-confirmed versus SARS-CoV-2-free individuals was estimated by a multivariable negative binomial regression adjusted by age, sex, and comorbidities. RESULTS: Data from 4,085,590 adults were analyzed. The overall HZ incidence rate in adults was 5.76 (95% confidence interval [CI], 5.66-5.85) cases per 1000 person-years. Individuals ≥18-year-old with SARS-CoV-2-confirmed infection had a 19% higher risk of developing HZ versus SARS-CoV-2-free ≥18-year-olds (adjusted RR = 1.19; 95% CI, 1.09-1.29); this percentage was 16% (adjusted RR = 1.16; 95% CI, 1.05-1.29) in ≥50-year-olds. Severe (hospitalized) cases of SARS-CoV-2 infection had a 64% (if ≥18 years old) or 44% (if ≥50 years old) higher risk of HZ versus nonhospitalized cases. CONCLUSION: These results support an association between SARS-CoV-2 infection and HZ, with a greater HZ risk in severe cases of SARS-CoV-2 infection.

Enhanced Timeliness and Co-Administration of Meningitis B Vaccination in Children: Impact of Funding in Valencian Community, Spain.

Public funding of vaccines may enhance vaccination rates, co-administration, and timeliness. The impacts of including the serogroup B meningococcus vaccine (MenB) into the national immunisation schedule on vaccination rates, co-administration rates, and timeliness were assessed using a population-based pre-funding (2022) and post-funding (2023) study design. MenB vaccination rates improved after funding and were in line with previously funded vaccines. Co-administration rates also increased significantly. Timely administration increased, protecting children at an early age. Public funding has a positive impact on vaccine accessibility and early protection. Consistent population characteristics highlight the role of funding.

Cellular Immunity of SARS-CoV-2 in the Borriana COVID-19 Cohort: A Nested Case-Control Study.

Our goal was to determine the cellular immune response (CIR) in a sample of the Borriana COVID-19 cohort (Spain) to identify associated factors and their relationship with infection, reinfection and sequelae. We conducted a nested case-control study using a randomly selected sample of 225 individuals aged 18 and older, including 36 individuals naïve to the SARS-CoV-2 infection and 189 infected patients. We employed flow-cytometry-based immunoassays for intracellular cytokine staining, using Wuhan and BA.2 antigens, and chemiluminescence microparticle immunoassay to detect SARS-CoV-2 antibodies. Logistic regression models were applied. A total of 215 (95.6%) participants exhibited T-cell response (TCR) to at least one antigen. Positive responses of CD4+ and CD8+ T cells were 89.8% and 85.3%, respectively. No difference in CIR was found between naïve and infected patients. Patients who experienced sequelae exhibited a higher CIR than those without. A positive correlation was observed between TCR and anti-spike IgG levels. Factors positively associated with the TCR included blood group A, number of SARS-CoV-2 vaccine doses received, and anti-N IgM; factors inversely related were the time elapsed since the last vaccine dose or infection, and blood group B. These findings contribute valuable insights into the nuanced immune landscape shaped by SARS-CoV-2 infection and vaccination.

Efficacy and effectiveness of influenza vaccination in healthy children. A review of current evidence.

Influenza is common in healthy children and adolescents and is associated with a high rate of hospitalization in this group, especially for those <5 years. Although the WHO has recommended vaccination in children under 5 years of age since 2012, it is really implemented in few countries today. The aim of this paper was to review the available evidence on the efficacy/effectiveness of influenza vaccination in healthy children <18 years of age through a non-systematic search of studies conducted between 2010 and 2020. Despite the high variability in results due to differences in design, vaccine type and season included in the 41 selected studies, statistically significant studies show efficacy values for the influenza vaccine of between 25.6% and 74.2%, and effectiveness from 26% to 78.8%. Although a systematic review would be necessary to corroborate the evidence, this review suggests that paediatric vaccination is generally an effective measure for preventing influenza in healthy children in line with international organisms' recommendations.

Long COVID Prevalence and the Impact of the Third SARS-CoV-2 Vaccine Dose: A Cross-Sectional Analysis from the Third Follow-Up of the Borriana Cohort, Valencia, Spain (2020-2022).

BACKGROUND: In March 2020, a COVID-19 outbreak linked to mass gathering dinners at the Falles Festival in Borriana, Spain, resulted in an estimated attack rate of 42.6% among attendees. METHODS: In June 2022, we conducted a cross-sectional follow-up study of 473 adults aged 18 to 64 who attended the dinners at the Falles Festival in 2020, examining the cumulative experience after SARS-CoV-2 infection and vaccination responses. Data included demographic details, lifestyle habits, medical history, infection records, and vaccinations from a population-based vaccine registry. Blood samples were analyzed for SARS-CoV-2 antibodies and cellular immunity. We employed a doubly robust inverse-probability weighting analysis to estimate the booster vaccine dose's impact on long COVID prevalence and symptom count. RESULTS: A total of 28.1% of participants met the WHO criteria for long COVID, with older individuals showing higher rates. Long COVID diagnosis was less likely with factors including O blood group, higher occupational status, physical activity, three vaccine doses, strong SARS-CoV-2-S-reactive IFNγ-producing-CD8+ response, and infection during the Omicron period. Increased age, high or low social activity, underlying health conditions, a severe initial COVID episode, and reinfection were associated with higher long COVID likelihood. A booster dose, compared to one or two doses, reduced long COVID risk by 74% (95% CI: 56% to 92%) and symptom count by 55% (95% CI: 32% to 79%). CONCLUSION: Long COVID was prevalent in a significant portion of those who contracted COVID-19, underscoring the need for sustained follow-up and therapeutic strategies. Vaccinations, notably the booster dose, had a substantial beneficial effect on long-term infection outcomes, affirming the vaccination's role in mitigating SARS-CoV-2 infection consequences.

Organic cation transporter 2 contributes to SSRI antidepressant efficacy by controlling tryptophan availability in the brain.

Selective serotonin reuptake inhibitors (SSRI) are common first-line treatments for major depression. However, a significant number of depressed patients do not respond adequately to these pharmacological treatments. In the present preclinical study, we demonstrate that organic cation transporter 2 (OCT2), an atypical monoamine transporter, contributes to the effects of SSRI by regulating the routing of the essential amino acid tryptophan to the brain. Contrarily to wild-type mice, OCT2-invalidated mice failed to respond to prolonged fluoxetine treatment in a chronic depression model induced by corticosterone exposure recapitulating core symptoms of depression, i.e., anhedonia, social withdrawal, anxiety, and memory impairment. After corticosterone and fluoxetine treatment, the levels of tryptophan and its metabolites serotonin and kynurenine were decreased in the brain of OCT2 mutant mice compared to wild-type mice and reciprocally tryptophan and kynurenine levels were increased in mutants' plasma. OCT2 was detected by immunofluorescence in several structures at the blood-cerebrospinal fluid (CSF) or brain-CSF interface. Tryptophan supplementation during fluoxetine treatment increased brain concentrations of tryptophan and, more discreetly, of 5-HT in wild-type and OCT2 mutant mice. Importantly, tryptophan supplementation improved the sensitivity to fluoxetine treatment of OCT2 mutant mice, impacting chiefly anhedonia and short-term memory. Western blot analysis showed that glycogen synthase kinase-3ß (GSK3ß) and mammalian/mechanistic target of rapamycin (mTOR) intracellular signaling was impaired in OCT2 mutant mice brain after corticosterone and fluoxetine treatment and, conversely, tryptophan supplementation recruited selectively the mTOR protein complex 2. This study provides the first evidence of the physiological relevance of OCT2-mediated tryptophan transport, and its biological consequences on serotonin homeostasis in the brain and SSRI efficacy.