Vaccine Safety and Immunogenicity in Patients With Multiple Sclerosis Treated With Natalizumab.

Importance: Vaccination in patients with highly active multiple sclerosis (MS) requiring prompt treatment initiation may result in impaired vaccine responses and/or treatment delay. Objective: To assess the immunogenicity and safety of inactivated vaccines administered during natalizumab treatment. Design, Setting, and Participants: This self-controlled, prospective cohort study followed adult patients with MS from 1 study center in Spain from September 2016 to February 2022. Eligible participants included adults with MS who completed immunization for hepatitis B virus (HBV), hepatitis A virus (HAV), and COVID-19 during natalizumab therapy. Data analysis was conducted from November 2022 to February 2023. Exposures: Patients were categorized according to their time receiving natalizumab treatment at the time of vaccine administration as short-term (≤1 year) or long-term (>1 year). Main Outcomes and Measures: Demographic, clinical, and radiological characteristics were collected during the year before vaccination (prevaccination period) and the year after vaccination (postvaccination period). Seroprotection rates and postvaccination immunoglobulin G titers were determined for each vaccine within both periods. Additionally, differences in annualized relapse rate (ARR), new T2 lesions (NT2L), Expanded Disability Status Scale (EDSS) scores, and John Cunningham virus (JCV) serostatus between the 2 periods were assessed. Results: Sixty patients with MS (mean [SD] age, 43.2 [9.4] years; 44 female [73.3%]; 16 male [26.7%]; mean [SD] disease duration, 17.0 [8.7] years) completed HBV, HAV, and mRNA COVID-19 immunization during natalizumab treatment, with 12 patients in the short-term group and 48 patients in the long-term group. The global seroprotection rate was 93% (95% CI, 86%-98%), with individual vaccine rates of 92% for HAV (95% CI, 73%-99%), 93% for HBV (95% CI, 76%-99%), and 100% for the COVID-19 messenger RNA vaccine (95% CI, 84%-100%). Between the prevaccination and postvaccination periods there was a significant reduction in the mean (SD) ARR (0.28 [0.66] vs 0.01 [0.12]; P = .004) and median (IQR) NT2L (5.00 [2.00-10.00] vs 0.81 [0.00-0.50]; P = .01). No changes in disability accumulation were detected (median [IQR] EDSS score 3.5 [2.0-6.0] vs 3.5 [2.0-6.0]; P = .62). No differences in safety and immunogenicity were observed for all vaccines concerning the duration of natalizumab treatment. Conclusions and Relevance: The findings of this cohort study suggest that immunization with inactivated vaccines during natalizumab therapy was both safe and immunogenic, regardless of the treatment duration. Natalizumab may be a valuable option for proper immunization, averting treatment delays in patients with highly active MS; however, this strategy needs to be formally evaluated.

Hepatitis B reactivation is a rare event among patients with resolved infection undergoing anti-CD20 antibodies in monotherapy without antiviral prophylaxis: results from the HEBEM study.

INTRODUCTION: Prospective data on the risk of hepatitis B reactivation (HBVr) among patients with resolved HBV infection undergoing anti-CD20 antibodies monotherapy is scarce. We aimed to assess the risk of HBVr in patients with resolved HBV infection treated with rituximab or ocrelizumab in monotherapy for multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) without antiviral prophylaxis. METHODS: HEBEM is a prospective study that included all consecutive adults HBsAg-negative/anti-HBc-positive who initiated anti-CD20 antibodies for MS or NMOSD at Cemcat. Inclusion criteria encompassed undetectable HBV-DNA, absence of other immunosuppressants or antiviral therapy. Every 6 months HBsAg, ALT and HBV-DNA were performed to rule out HBVr (defined by 2-log increase in HBV-DNA or seroconversion to HBsAg+). RESULTS: From August/2019 to August/2022, 540 subjects initiated anti-CD20 antibodies, 28 (5.2%) were anti-HBc-positive and were included. Twenty-two received rituximab and 6 ocrelizumab. The majority (89.3%) had previously received ≥ 1 immunomodulatory drug, with corticosteroids (82.1%) and interferon (42.9%) as the most common. At inclusion, all presented normal transaminases and undetectable HBV-DNA. Median anti-HBs levels were 105.5 mIU/mL (IQR 0-609). Median follow-up was 3.1 years (2.1-4.0). Median number of cycles of anti-CD20 antibodies was 6 (3-7), with a cumulative dose of 8.5 g (5.8-11.2) of rituximab and 3 g (1.8-3.8) of ocrelizumab. Neither cases of HBVr nor changes in anti-HBs titers were observed per 83.6 patient-years treated with monotherapy with anti-CD20 antibodies. CONCLUSIONS: In this cohort of patients with MS or NMOSD and resolved HBV infection, anti-CD20 monotherapy was not associated with detectable risk of HBV reactivation despite the lack of antiviral prophylaxis.

Influenza Vaccine Effectiveness against Hospitalization, Season 2021/22: A Test-Negative Design Study in Barcelona.

BACKGROUND: Vaccination is considered the most effective measure for preventing influenza and its complications. The influenza vaccine effectiveness (IVE) varies annually due to the evolution of influenza viruses and the update of vaccine composition. Assessing the IVE is crucial to facilitate decision making in public health policies. AIM: to estimate the IVE against hospitalization and its determinants in the 2021/22 season in a Spanish tertiary hospital. METHODS: We conducted a prospective observational test-negative design study within the Development of Robust and Innovative Vaccine Effectiveness (DRIVE) project. Hospitalized patients with severe acute respiratory infection (SARI) and an available influenza reverse transcription polymerase chain reaction (RT-PCR) were selected and classified as cases (positive influenza RT-PCR) or controls (negative influenza RT-PCR). Vaccine information was obtained from electronic clinical records shared by public healthcare providers. Information about potential confounders was obtained from hospital clinical registries. The IVE was calculated by subtracting the ratio of the odds of vaccination in cases and controls from one, as a percentage (IVE = (1 - odds ratio (OR)) × 100). Multivariate IVE estimates were calculated using logistic regression. RESULTS: In total, 260 severe acute respiratory infections (SARI) were identified, of which 34 were positive for influenza, and all were subtype A(H3N2). Fifty-three percent were vaccinated. Adjusted IVE against hospitalization was 26.4% (95% CI -69% to 112%). IVE determinants could not be explored due to sample size limitations. CONCLUSION: Our data revealed non-significant moderate vaccine effectiveness against hospitalization for the 2021/2022 season.

A single-dose strategy for immunization with live attenuated vaccines is an effective option before treatment initiation in multiple sclerosis patients.

BACKGROUND: Mumps-Measles-Rubella (MMR) and Varicella zoster vaccines (VAR) are live attenuated vaccines, usually administered in a two-dose scheme at least 4 weeks apart. However, single-dose immunization schemes may also be effective and can reduce delays in immunosuppressive treatment initiation in patients with multiple sclerosis (pwMS) who need to be immunized. OBJECTIVES: To evaluate the immunogenicity of a single-dose attempt (SDA) versus the standard immunization scheme (SIS) with VAR and/or MMR in pwMS. METHODS: Retrospective observational study in pwMS vaccinated against VAR and/or MMR. We compared seroprotection rates and antibody geometric mean titers (GMTs) between the two strategies. RESULTS: Ninety-six patients were included. Thirty-one patients received VAR and 67 MMR. In the SDA group, the seroprotection rate was 66.7% (95% confidence interval (CI): 53.3-78.3) versus 97.2% (95% CI: 85.5-99.9) in the SIS (p < 0.001). For the seroprotected patients, GMTs were similar for both schemes. CONCLUSION: An SDA of VAR and/or MMR vaccines could be sufficient to protect almost two-thirds of patients. Testing immunogenicity after a single dose of VZ and/or MMR could be included in routine clinical practice to achieve rapid immunization.

Protection against COVID-19 hospitalisation conferred by primary-series vaccination with AZD1222 in non-boosted individuals: first vaccine effectiveness results of the European COVIDRIVE study and meta-regression analysis.

Background: Vaccine effectiveness (VE) studies with long-term follow-up are needed to understand durability of protection against severe COVID-19 outcomes conferred by primary-series vaccination in individuals not receiving boosters. COVIDRIVE is a European public-private partnership evaluating brand-specific vaccine effectiveness (VE). We report a prespecified interim analysis of primary-series AZD1222 (ChAdOx1 nCoV-19) VE. Methods: Seven Study Contributors in Europe collected data on individuals aged ≥18 years who were hospitalised with severe acute respiratory infection (June 1st, 2021-September 5th, 2022) and eligible for COVID-19 vaccination prior to hospitalisation. In this test-negative case-control study, individuals were defined as test-positive cases or test-negative controls (SARS-CoV-2 RT-PCR) and were either fully vaccinated (two AZD1222 doses, 4-12 weeks apart, completed ≥14 days prior to symptom onset; no booster doses) or unvaccinated (no COVID-19 vaccine prior to hospitalisation). The primary objective was to estimate AZD1222 VE against COVID-19 hospitalisation. A literature review and meta-regression were conducted to contextualise findings on durability of protection. Findings: 761 individuals were included during the 15-month analysis period. Overall AZD1222 VE estimate was 72.8% (95% CI, 53.4-84.1). VE was 93.8% (48.6-99.3) in participants who received second AZD1222 doses ≤8 weeks prior to hospitalisation, with spline-based VE estimates demonstrating protection (VE ≥ 50%) 30 weeks post-second dose. Meta-regression analysis (data from seven publications) showed consistent results, with ≥80% protection against COVID-19 hospitalisation through ∼43 weeks post-second dose, with some degree of waning. Interpretation: Primary-series AZD1222 vaccination confers protection against COVID-19 hospitalisation with enduring levels of VE through ≥6 months. Funding: AstraZeneca.

A Comparative Study of Ultrasmall Calcium Carbonate Nanoparticles for Targeting and Imaging Atherosclerotic Plaque.

Atherosclerosis is a complex disease that can lead to life-threatening events, such as myocardial infarction and ischemic stroke. Despite the severity of this disease, diagnosing plaque vulnerability remains challenging due to the lack of effective diagnostic tools. Conventional diagnostic protocols lack specificity and fail to predict the type of atherosclerotic lesion and the risk of plaque rupture. To address this issue, technologies are emerging, such as noninvasive medical imaging of atherosclerotic plaque with customized nanotechnological solutions. Modulating the biological interactions and contrast of nanoparticles in various imaging techniques, including magnetic resonance imaging, is possible through the careful design of their physicochemical properties. However, few examples of comparative studies between nanoparticles targeting different hallmarks of atherosclerosis exist to provide information about the plaque development stage. Our work demonstrates that Gd (III)-doped amorphous calcium carbonate nanoparticles are an effective tool for these comparative studies due to their high magnetic resonance contrast and physicochemical properties. In an animal model of atherosclerosis, we compare the imaging performance of three types of nanoparticles: bare amorphous calcium carbonate and those functionalized with the ligands alendronate (for microcalcification targeting) and trimannose (for inflammation targeting). Our study provides useful insights into ligand-mediated targeted imaging of atherosclerosis through a combination of in vivo imaging, ex vivo tissue analysis, and in vitro targeting experiments.

Identification and comparison of the main variables affecting early university dropout rates according to knowledge area and institution.

The dropout rate in universities is a widely studied issue that concerns both universities and public organizations. Most studies focus on quantifying the phenomenon and identifying the variables involved. This paper uses a multidisciplinary approach to parameterize the factors that define the entry profile of undergraduates at the national level in Spain in collaboration with three universities in different regions and with different disciplines. The aim is to reduce the dropout rate in the first year of study towards a degree. The research questions focus on the weighting of personal variables about students by tutors and whether there are differences in the weighting systems for the main variables as differentiated by discipline, university and/or region. The document is organized to describe the method and context of the study, present the main results, show the application of the survey instrument in a case study, and provide conclusions. The method is based on the two fundamental factors, including the influence of certain student characteristics at matriculation and the importance of a positive experience in the first year of the degree. The study is focused on two elements that inspire the current proposal: the need to identify and rapidly detect students who, due to their entry characteristics, are at a greater risk of dropout and the importance of guaranteeing a good start in the first year of the degree. The study uses a multidisciplinary approach and combines qualitative and quantitative methods to gather data. The study also uses a survey instrument that measures the risk of student dropout based on the weighting of personal variables by tutors. The results of the study have allowed us to categorize the main variables of the student profile that affect the risk of dropout and establish them as aspects to be monitored by the tutors in the first weeks. Furthermore, it has been shown that although there are no significant differences in the averages of dropout risk calculated with either global or specific weighting systems (by centre or studies), there is a tendency observed by the tutors that the weighted averages generated by disciplinary focus are closer to identifying the student's real risk of dropping out.

Association of Very Early Treatment Initiation With the Risk of Long-term Disability in Patients With a First Demyelinating Event.

BACKGROUND AND OBJECTIVES: Early treatment is associated with better long-term outcomes in patients with a first demyelinating event and early multiple sclerosis (MS). However, magnetic resonance (MR) findings are not usually integrated to construct propensity scores (PSs) when evaluating outcomes. We assessed the association of receiving very early treatment with the risk of long-term disability including an MR score (MRS) in patients with a first demyelinating event. METHODS: We included 580 patients with a first demyelinating event prospectively collected between 1994 and 2021, who received at least 1 disease-modifying drug (DMD). Patients were classified into tertiles according to the cohort's distribution of the time from the first demyelinating event to the first DMD: first tertile (FT) or very early treatment (6 months; n = 194), second tertile (6.1-16 months, n = 192), and third tertile (TT) (16.1 months, n = 194). A 5-point MRS was built according to the sum of the following indicators: ≥9 brain lesions (1 point); ≥1 infratentorial lesion (1 point); ≥1 spinal cord (SC) lesion (1 point); ≥1 contrast-enhancing (CE) brain lesion (1 point); and ≥1 CE SC lesion (1 point). PS based on covariates and the MRS was computed for each of the outcomes. Inverse PS-weighted Cox and linear regression models assessed the risk of different outcomes between tertile groups. Finally, to confirm the role of MR in treatment decision, we studied the time elapsed from the first demyelinating event to treatment initiation according to the MRS in all patients with radiologic available information, renamed as raw-MRS. RESULTS: Very early treatment decreased the risk of reaching Expanded Disability Status Scale 3.0 (hazard ratio [HR] 0.55, 95% CI 0.32-0.97), secondary progressive MS (HR 0.40, 95% CI 0.19-0.85), and sustained disease progression at 12 months after treatment initiation (HR 0.50, 95% CI 0.29-0.84), when compared with patients from the TT group. Patients from the FT group had a lower disability progression rate (ß estimate -0.009, 95% CI -0.016 to -0.002) and a lower severe disability measured by the Patient-Determined Disease Step (ß estimate -0.52, 95% CI -0.91 to -0.13) than the TT group. Finally, there was a 62.4% reduction in the median time between the first demyelinating event and the first-ever treatment initiation from patients displaying a raw-MRS 1 to patients with a raw-MRS 5. DISCUSSION: Using PS models with and without MRS, we showed that treatment initiation at very early stages is associated with a reduction in the risk of long-term disability accrual in patients with a first demyelinating event. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that earlier treatment of patients with MS presenting with a first demyelinating event is associated with improved clinical outcomes.

ECTRIMS/EAN consensus on vaccination in people with multiple sclerosis: Improving immunization strategies in the era of highly active immunotherapeutic drugs.

BACKGROUND: With the new highly active drugs available for people with multiple sclerosis (pwMS), vaccination becomes an essential part of the risk management strategy. OBJECTIVE: To develop a European evidence-based consensus for the vaccination strategy of pwMS who are candidates for disease-modifying therapies (DMTs). METHODS: This work was conducted by a multidisciplinary working group using formal consensus methodology. Clinical questions (defined as population, interventions, and outcomes) considered all authorized DMTs and vaccines. A systematic literature search was conducted and quality of evidence was defined according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. The recommendations were formulated based on the quality of evidence and the risk-benefit balance. RESULTS: Seven questions, encompassing vaccine safety, vaccine effectiveness, global vaccination strategy and vaccination in sub-populations (pediatric, pregnant women, elderly and international travelers) were considered. A narrative description of the evidence considering published studies, guidelines, and position statements is presented. A total of 53 recommendations were agreed by the working group after three rounds of consensus. CONCLUSION: This first European consensus on vaccination in pwMS proposes the best vaccination strategy according to current evidence and expert knowledge, with the goal of homogenizing the immunization practices in pwMS.

European Committee for Treatment and Research in Multiple Sclerosis and European Academy of Neurology consensus on vaccination in people with multiple sclerosis: Improving immunization strategies in the era of highly active immunotherapeutic drugs.

BACKGROUND AND PURPOSE: With the new highly active drugs available for people with multiple sclerosis (pwMS), vaccination becomes an essential part of the risk management strategy. We aimed to develop a European evidence-based consensus for the vaccination strategy of pwMS who are candidates for disease-modifying therapies (DMTs). METHODS: This work was conducted by a multidisciplinary working group using formal consensus methodology. Clinical questions (defined as population, interventions and outcomes) considered all authorized DMTs and vaccines. A systematic literature search was conducted and quality of evidence was defined according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. The recommendations were formulated based on the quality of evidence and the risk-benefit balance. RESULTS: Seven questions, encompassing vaccine safety, vaccine effectiveness, global vaccination strategy and vaccination in subpopulations (pediatric, pregnant women, elderly and international travelers) were considered. A narrative description of the evidence considering published studies, guidelines and position statements is presented. A total of 53 recommendations were agreed by the working group after three rounds of consensus. CONCLUSION: This first European consensus on vaccination in pwMS proposes the best vaccination strategy according to current evidence and expert knowledge, with the goal of homogenizing the immunization practices in pwMS.

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.

Luminescent Carbon Nanodots Doped with Gadolinium (III): Purification Criteria, Chemical and Biological Characterization of a New Dual Fluorescence/MR Imaging Agent.

Carbon Dots (CDs) are luminescent quasi-spherical nanoparticles, possessing water solubility, high biocompatibility, and tunable chemical and physical properties for a wide range of applications, including nanomedicine and theranostics. The evaluation of new purification criteria, useful to achieve more reliable CDs, free from the interference of artifacts, is currently an object of debate in the field. Here, new CDs doped with gadolinium (Gd (III)), named Gd@CNDs, are presented as multifunctional probes for Magnetic Resonance Imaging (MRI). This new system is a case of study, to evaluate and/or combine different purification strategies, as a crucial approach to generate CDs with a better performance. Indeed, these new amorphous Gd@CNDs display good homogeneity, and they are free from emissive side products. Gd@CNDs (7-10 nm) contain 7% of Gd (III) w/w, display suitable and stable longitudinal relaxivity (r1 ) and with emissive behavior, therefore potentially useful for both MR and fluorescence imaging. They show good biocompatibility in both cellular and in vivo studies, cell permeability, and the ability to generate contrast in cellular pellets. Finally, MRI recording T1 -weighted images on mice after intravenous injection of Gd@CNDs, show signal enhancement in the liver, spleen, and kidney 30 min postinjection.

Association of Early Progression Independent of Relapse Activity With Long-term Disability After a First Demyelinating Event in Multiple Sclerosis.

Importance: Progression independent of relapse activity (PIRA) is the main event responsible for irreversible disability accumulation in relapsing multiple sclerosis (MS). Objective: To investigate clinical and neuroimaging predictors of PIRA at the time of the first demyelinating attack and factors associated with long-term clinical outcomes of people who present with PIRA. Design, Setting, and Participants: This cohort study, conducted from January 1, 1994, to July 31, 2021, included patients with a first demyelinating attack from multiple sclerosis; patients were recruited from 1 study center in Spain. Patients were excluded if they refused to participate, had alternative diagnoses, did not meet protocol requirements, had inconsistent demographic information, or had less than 3 clinical assessments. Exposures: Exposures included (1) clinical and neuroimaging features at the first demyelinating attack and (2) presenting PIRA, ie, confirmed disability accumulation (CDA) in a free-relapse period at any time after symptom onset, within (vs after) the first 5 years of the disease (ie, early/late PIRA), and in the presence (vs absence) of new T2 lesions in the previous 2 years (ie, active/nonactive PIRA). Main Outcomes and Measures: Expanded Disability Status Scale (EDSS) yearly increase rates since the first attack and adjusted hazard ratios (HRs) for predictors of time to PIRA and time to EDSS 6.0. Results: Of the 1128 patients (mean [SD] age, 32.1 [8.3] years; 781 female individuals [69.2%]) included in the study, 277 (25%) developed 1 or more PIRA events at a median (IQR) follow-up time of 7.2 (4.6-12.4) years (for first PIRA). Of all patients with PIRA, 86 of 277 (31%) developed early PIRA, and 73 of 144 (51%) developed active PIRA. Patients with PIRA were slightly older, had more brain lesions, and were more likely to have oligoclonal bands than those without PIRA. Older age at the first attack was the only predictor of PIRA (HR, 1.43; 95% CI, 1.23-1.65; P < .001 for each older decade). Patients with PIRA had steeper EDSS yearly increase rates (0.18; 95% CI, 0.16-0.20 vs 0.04; 95% CI, 0.02-0.05; P < .001) and an 8-fold greater risk of reaching EDSS 6.0 (HR, 7.93; 95% CI, 2.25-27.96; P = .001) than those without PIRA. Early PIRA had steeper EDSS yearly increase rates than late PIRA (0.31; 95% CI, 0.26-0.35 vs 0.13; 95% CI, 0.10-0.16; P < .001) and a 26-fold greater risk of reaching EDSS 6.0 from the first attack (HR, 26.21; 95% CI, 2.26-303.95; P = .009). Conclusions and Relevance: Results of this cohort study suggest that for patients with multiple sclerosis, presenting with PIRA after a first demyelinating event was not uncommon and suggests an unfavorable long-term prognosis, especially if it occurs early in the disease course.

Impacto de la vacunación de las embarazadas frente a la tosferina en las hospitalizaciones de menores de un año en un hospital de tercer nivel de Cataluña / Impact of vaccinating pregnant women against pertussis on hospitalizations of children under one year of age in a tertiary hospital in Catalonia

Introducción: La recomendación de la vacunación frente a la tosferina en embarazadas se instauró en Cataluña en febrero del 2014. El objetivo del presente estudio fue comparar la tasa de hospitalización por tosferina en niños menores de un año de edad antes y después de la implantación del programa de vacunación. Métodos: Estudio observacional y retrospectivo de pacientes menores de un año ingresados con diagnóstico de tosferina. Se comparó la tasa de hospitalización del periodo previo al programa de vacunación (2008-2013) con la del periodo con programa de vacunación (2014-2019) en el total de menores de un año y en 2subgrupos: en menores de 3 meses y en lactantes de 3 a 11 meses. Resultados: La tasa de hospitalización fue significativamente menor en el periodo con programa de vacunación en menores de un año y en menores de 3 meses (2,43 vs. 4,72 por 1.000 personas-año y 6,47 vs. 13,11 por 1.000 personas-año, respectivamente). Las razones de tasas entre períodos fueron: 0,51 (IC del 95%, 0,36-0,73) para los menores de un año; 0,49 (IC del 95%, 0,32-0,75) para los menores de 3 meses y 0,56 (IC del 95%, 0,30-1,03) para los de 3-11 meses. No se observaron diferencias estadísticamente significativas en la gravedad de los cuadros clínicos de los pacientes entre ambos periodos. Conclusión: La instauración del programa de vacunación contra la tosferina en embarazadas se ha asociado a una menor tasa de hospitalización por tosferina de forma global en los menores de un año de edad y específicamente en los menores de 3 meses.(AU)

Introduction: The recommendation for pertussis vaccination in pregnancy was established in Catalonia in February 2014. The objective of this study was to compare the hospitalization rate for pertussis in children under one year of age before and after the implementation of the vaccination program. Methods: Observational and retrospective study of patients under one year of age admitted to hospital with a diagnosis of pertussis. The hospitalization rate of patients under one year of age of the period prior to the vaccination program (2008-2013) was compared with the period with vaccination program (2014-2019) in the total of children under one year of age and in 2subgroups: children under 3 months and between 3-11 months. Results: Hospitalization rate was significantly lower in the period with vaccination program in children under one year of age and specifically in children under 3 months (2.43 vs. 4.72 per 1,000 person-years and 6.47 vs. 13.11 per 1,000 person-years, respectively). The rate ratios were: 0.51 (95% CI 0.36-0.73) for children under one year of age; 0.49 (95% CI 0.32-0.75) for those younger than 3 months and 0.56 (95% CI 0.30-1.03) for those with 3-11 months. No statistically significant differences were observed in the clinical severity between both periods. Conclusion: The introduction of the pertussis vaccination program in pregnancy was associated with a global lower hospitalization rate for pertussis in children under one year of age and specifically in those under 3 months of age.(AU)

Un nuevo desafío para los médicos del Paraguay: la nefritis intersticial crónica de comunidades agrícolas (CINAC)

RESUMEN Se presenta revisión narrativa sobre nefritis intersticial crónica de comunidades agrícolas (CINAC, siglas del inglés Chronic Interstitial Nephritis in Agricultural Communities). Se discute la etiología, manifestaciones clínicas, manejo diagnóstico y terapéutico de esta afección.

ABSTRACT A narrative review on Chronic Interstitial Nephritis in Agricultural Communities (CINAC) is presented. The etiology, clinical manifestations, diagnostic and therapeutic management of this condition are discussed.

Biodegradable particles for protein delivery: Estimation of the release kinetics inside cells.

A methodology to quantify the efficiency of the protein loading and in-vitro delivery for biodegradable capsules with different architectures based on polyelectrolytes (dextran sulfate, poly-L-arginine and polyethylenimine) and SiO2 was developed. The capsules were loaded with model proteins such as ovalbumin and green fluorescent protein (GFP), and the protein release profile inside cells (either macrophages or HeLa cells) after endocytosis was analysed. Both, protein loading and release kinetics were evaluated by analysing confocal laser scanning microscopy images using MatLab and CellProfiler software. Our results indicate that silica capsules showed the most efficient release of proteins as cargo molecules within 48 h, as compared to their polymeric counterparts. This developed method for the analysis of the intracellular cargo release kinetics from carrier structures could be used in the future for a better control of drug release profiles.

Impact of vaccinating pregnant women against pertussis on hospitalizations of children under one year of age in a tertiary hospital in Catalonia.

INTRODUCTION: The recommendation for pertussis vaccination in pregnancy was established in Catalonia in February 2014. The objective of this study was to compare the hospitalisation rate for pertussis in children under one year of age before and after the implementation of the vaccination programme. METHODS: Observational and retrospective study of patients under one year of age admitted to hospital with a diagnosis of pertussis. The hospitalisation rate of patients under one year of age of the period prior to the vaccination programme (2008-2013) was compared with the period with vaccination programme (2014-2019) in the total of children under one year of age and in 2 subgroups: children under 3 months and between 3-11 months. RESULTS: Hospitalization rate was significantly lower in the period with vaccination programme in children under one year of age and specifically in children under 3 months (2.43 vs. 4.72 per 1000 person-years and 6.47 vs. 13.11 per 1000 person-years, respectively). The rate ratios were: 0.51 (95% CI 0.36-0.73) for children under one year of age; 0.49 (95% CI 0.32-0.75) for those younger than 3 months and 0.56 (95% CI 0.30-1.03) for those with 3-11 months. No statistically significant differences were observed in the clinical severity between both periods. CONCLUSION: The introduction of the pertussis vaccination programme in pregnancy was associated with a global lower hospitalisation rate for pertussis in children under one year of age and specifically in those under 3 months of age.

The kappa free light chain index and oligoclonal bands have a similar role in the McDonald criteria.

Intrathecal production of kappa free light chains occurs in multiple sclerosis and can be measured using the kappa free light chain index. Kappa free light chain index values can be determined more easily than oligoclonal bands detection and seem more sensitive than the immunoglobulin (Ig)G index to diagnose multiple sclerosis. We assessed the value of oligoclonal bands, kappa free light chain index cut-offs 5.9, 6.6 and 10.61, and IgG index to diagnose multiple sclerosis with prospectively acquired data from a clinically isolated syndrome inception cohort. We selected patients with sufficient data to determine oligoclonal bands positivity, MRI dissemination in space and time, IgG index and sufficient quantities of paired CSF and blood samples to determine kappa free light chain indexes (n = 214). We used Kendall's Tau coefficient to estimate concordance, calculated the number of additional diagnoses when adding each positive index to dissemination in space and positive oligoclonal bands, performed survival analyses for oligoclonal bands and each index with the outcomes second attack and 2017 MRI dissemination in space and time and estimated the diagnostic properties of oligoclonal bands and the different indexes for the previously mentioned outcomes at 5 years. Oligoclonal bands were positive in 138 patients (64.5%), kappa free light chain-5.9 in 136 (63.6%), kappa free light chain-6.6 in 135 (63.1%), kappa free light chain-10.61 in 126 (58.9%) and IgG index in 101 (47.2%). The highest concordance was between oligoclonal bands and kappa free light chain-6.6 (τ = 0.727) followed by oligoclonal bands and kappa free light chain-5.9 (τ = 0.716). Combining dissemination in space plus oligoclonal bands or kappa free light chain-5.9 increased the number of diagnosed patients by 11 (5.1%), with kappa free light chain-6.6 by 10 (4.7%), with kappa free light chain-10.61 by 9 (4.2%) and with IgG index by 3 (1.4%). Patients with positive oligoclonal bands or indexes reached second attack and MRI dissemination in space and time faster than patients with negative results (P < 0.0001 except IgG index in second attack: P = 0.016). In multivariable Cox models [adjusted hazard ratio (95% confidence interval)], the risk for second attack was very similar between kappa free light chain-5.9 [2.0 (0.9-4.3), P = 0.068] and kappa free light chain-6.6 [2.1 (1.1-4.2), P = 0.035]. The highest risk for MRI dissemination in space and time was demonstrated with kappa free light chain-5.9 [4.9 (2.5-9.6), P < 0.0001], followed by kappa free light chain-6.6 [3.4 (1.9-6.3), P < 0.0001]. Kappa free light chains-5.9 and -6.6 had a slightly higher diagnostic accuracy than oligoclonal bands for second attack (70.5, 71.1 and 67.8) and MRI dissemination in space and time (85.7, 85.1 and 81.0). Kappa free light chain indexes 5.9 and 6.6 performed slightly better than oligoclonal bands to assess multiple sclerosis risk and in terms of diagnostic accuracy. Given the concordance between oligoclonal bands and these indexes, we suggest using dissemination in space plus positive oligoclonal bands or positive kappa free light chain index as a modified criterion to diagnose multiple sclerosis.

Delayed alveolar clearance of nanoparticles through control of coating composition and interaction with lung surfactant protein A.

The coating composition of nanomedicines is one of the main features in determining the medicines' fate, clearance, and immunoresponse in the body. To highlight the coatings' impact in pulmonary administration, two micellar superparamagnetic iron oxide nanoparticles (SPION) were compared. These nanoparticles are similar in size and charge but have different coatings: either phosphatidylcholine (PC-SPION) or bovine serum albumin (BSA-SPION). The aim of the study was to increase the understanding of the nano-bio interaction with the cellular and non-cellular components of the lung and underline valuable coatings either for local lung-targeted drug delivery in theranostic application or patient-friendly route systemic administration. PC-SPION and BSA-SPION were deposited in the alveoli by in vivo instillation and, despite the complexity of imaging the lung, SPION were macroscopically visualized by MRI. Impressively, PC-SPION were retained within the lungs for at least a week, while BSA-SPION were cleared more rapidly. The different lung residence times were confirmed by histological analysis and supported by a flow cytometry analysis of the SPION interactions with different myeloid cell populations. To further comprehend the way in which these nanoformulations interact with lung components at the molecular level, we used fluorescence spectroscopy, turbidity measurements, and dynamic light scattering to evaluate the interactions of the two SPION with surfactant protein A (SP-A), a key protein in setting up the nanoparticle behavior in the alveolar fluid. We found that SP-A induced aggregation of PC-SPION, but not BSA-SPION, which likely caused PC-SPION retention in the lung without inducing inflammation. In conclusion, the two SPION show different outcomes from interaction with SP-A leading to distinctive fate in the lung. PC-SPION hold great promise as imaging and theranostic agents when prolonged pulmonary drug delivery is required.