Study of pediatric invasive pneumococcal disease in the 13-pneumococcal conjugated vaccine era.

BACKGROUND: Invasive pneumococcal disease (IPD) remains a significant concern among children under 5, despite vaccination efforts. This study assessed IPD prevalence and associated risks in pediatric population. METHODS: An observational, retrospective, multicenter study in Comunidad Valenciana, Spain, of IPD cases in children under 13 from January 2012 to September 2022. Data from the CV Microbiology Surveillance Network (RedMIVA) and medical records were reviewed. RESULTS: A total of 379 IPD cases in 377 patients were analyzed, predominantly males (54.11 %) under 5 (81.17 %). PCV13 vaccination notably reduced PCV13-serotypes IPD (p=0.0002), except serotype 3. Pneumonia was common, with half having underlying conditions (50.40 %). Worse outcomes occurred in patients with neurological disorders (ANOVA, p=0.57). Vaccine failures often involved underlying conditions (63 %) and serotypes 3 and 19A. Immunodeficiencies may relate to recurrent IPD, but evidence is limited. CONCLUSION: Despite vaccination, IPD still impacts children, influenced by immunological status, affecting severity and mortality.

The Chem-Sex Inventory Scale (CSI): A Tool to Assess the Mental Health Risk of Chemsex Behaviors in Men Who Have Sex with Men.

Background: Chemsex has been defined as the deliberate use of drugs for prolonged sexual intercourse between gay and bisexual men and other men who have sex with men (MSM). Drugs associated with chemsex can trigger mental health problems such as anxiety, depression, risk of psychosis and suicidal ideation, social isolation, stigmatization, and even loss of impulse control and lack of coping strategies. Currently, the increase in illicit drugs in a sexual context is considered an outbreak of a public health emergency. Objective: The aim of this study is the construction and validation of the Chem-Sex Inventory (CSI), a new scale to assess the mental health risk of chemsex behaviors. Methods: A cross-sectional design was conducted to study 563 participants. Data were collected through an online questionnaire between January and April 2023, and the construct validity of the CSI was assessed through exploratory and confirmatory factor analysis. Results: The sample was, on average, 36 years old (SD: ±9.2). The majority of gender identity was cisgender (97.7%). A factor structure was found that can be summarized in four dimensions: emotional instability, risk of psychosis, altered body perception, and risk of suicide. The confirmatory factor analysis (CFA) presents adequate reliability values, with a Cronbach's alpha above 0.87 for all dimensions and a McDonald's omega above 0.88 with a good fit of the 42 items. Conclusions: Our study has shown that the Chem-Sex Inventory (CSI) scale has factorial validity and could be used in clinical practice and research to measure the behavioral contribution of the chemsex phenomenon in MSM.

Coronene-Based 2D Networks by On-Surface Skeletal Rearrangement of Sumanene Precursors.

The design of novel low-dimensional carbon materials is at the forefront of modern chemistry. Recently, on-surface covalent synthesis has emerged as a powerful strategy to synthesize previously precluded compounds and polymers. Here, we report a scanning probe microscopy study, complemented by theoretical calculations, about the sequential skeletal rearrangement of sumanene-based precursors into a coronene-based organometallic network by stepwise intra- and inter-molecular reactions on Au(111). Interestingly, upon higher annealing, the formed organometallic networks evolve into two-dimensional coronene-based covalently-linked patches through intermolecular homocoupling reactions. A new reaction mechanism is proposed based on the role of C-Au-C motifs to promote two stepwise carbon-carbon couplings to form cyclobutadiene bridges. Our results pave avenues for the conversion of molecular precursors on surfaces, affording the design of unexplored two-dimensional organometallic and covalent materials.

A CRISPR-dCas13 RNA-editing tool to study alternative splicing.

Alternative splicing allows multiple transcripts to be generated from the same gene to diversify the protein repertoire and gain new functions despite a limited coding genome. It can impact a wide spectrum of biological processes, including disease. However, its significance has long been underestimated due to limitations in dissecting the precise role of each splicing isoform in a physiological context. Furthermore, identifying key regulatory elements to correct deleterious splicing isoforms has proven equally challenging, increasing the difficulty of tackling the role of alternative splicing in cell biology. In this work, we take advantage of dCasRx, a catalytically inactive RNA targeting CRISPR-dCas13 ortholog, to efficiently switch alternative splicing patterns of endogenous transcripts without affecting overall gene expression levels cost-effectively. Additionally, we demonstrate a new application for the dCasRx splice-editing system to identify key regulatory RNA elements of specific splicing events. With this approach, we are expanding the RNA toolkit to better understand the regulatory mechanisms underlying alternative splicing and its physiological impact in various biological processes, including pathological conditions.

Changes in EEG Activity and Cognition Related to Physical Activity in Older Adults: A Systematic Review.

Aging is generally associated with a decline in important cognitive functions that can be observed in EEG. Physical activity in older adults should be considered one of the main strategies to promote health and prevent disease in the elderly. The present study aimed to systematically review studies of EEG activity and cognitive function changes associated with physical activity in older adults. Records from PubMed, Scopus, and EBSCO databases were searched and, following the PRISMA guidelines, nine studies were included in the present systematic review. A risk of bias assessment was performed using the National Institute of Health Quality Assessment Tool for Case-control Studies instrument. The studies analyzed used two main strategies to determine the effects of physical activity on cognition and EEG: (1) multiscale entropy and power frequencies; and (2) event-related potentials. In terms of EEG activity, it can be concluded that exercise-induced neuroplasticity underlies improvements in cognitive function in healthy older adults.

Role of the first WHO mutation catalogue in the diagnosis of antibiotic resistance in Mycobacterium tuberculosis in the Valencia Region, Spain: a retrospective genomic analysis.

BACKGROUND: In June, 2021, WHO published the most complete catalogue to date of resistance-conferring mutations in Mycobacterium tuberculosis. Here, we aimed to assess the performance of genome-based antimicrobial resistance prediction using the catalogue and its potential for improving diagnostics in a real low-burden setting. METHODS: In this retrospective population-based genomic study M tuberculosis isolates were collected from 25 clinical laboratories in the low-burden setting of the Valencia Region, Spain. Culture-positive tuberculosis cases reported by regional public health authorities between Jan 1, 2014, and Dec 31, 2016, were included. The drug resistance profiles of these isolates were predicted by the genomic identification, via whole-genome sequencing (WGS), of the high-confidence resistance-causing variants included in the catalogue and compared with the phenotype. We determined the minimum inhibitory concentration (MIC) of the isolates with discordant resistance profiles using the resazurin microtitre assay. FINDINGS: WGS was performed on 785 M tuberculosis complex culture-positive isolates, and the WGS resistance prediction sensitivities were: 85·4% (95% CI 70·8-94·4) for isoniazid, 73·3% (44·9-92·2) for rifampicin, 50·0% (21·1-78·9) for ethambutol, and 57·1% (34·0-78·2) for pyrazinamide; all specificities were more than 99·6%. Sensitivity values were lower than previously reported, but the overall pan-susceptibility accuracy was 96·4%. Genotypic analysis revealed that four phenotypically susceptible isolates carried mutations (rpoB Leu430Pro and rpoB Ile491Phe for rifampicin and fabG1 Leu203Leu for isoniazid) known to give borderline resistance in standard phenotypic tests. Additionally, we identified three putative resistance-associated mutations (inhA Ser94Ala, katG Leu48Pro, and katG Gly273Arg for isoniazid) in samples with substantially higher MICs than those of susceptible isolates. Combining both genomic and phenotypic data, in accordance with the WHO diagnostic guidelines, we could detect two new multidrug-resistant cases. Additionally, we detected 11 (1·6%) of 706 isolates to be monoresistant to fluoroquinolone, which had been previously undetected. INTERPRETATION: We showed that the WHO catalogue enables the detection of resistant cases missed in phenotypic testing in a low-burden region, thus allowing for better patient-tailored treatment. We also identified mutations not included in the catalogue, relevant at the local level. Evidence from this study, together with future updates of the catalogue, will probably lead in the future to the partial replacement of culture testing with WGS-based drug susceptibility testing in our setting. FUNDING: European Research Council and the Spanish Ministerio de Ciencia.

Frequency effects in Spanish phonological speech errors: Weak sources in the context of weak syllables and words.

The present study examines the effects of the frequency of phoneme, syllable, and word units in the Granada corpus of Spanish phonological speech errors. We computed several measures of phoneme and syllable frequency and selected the most sensitive ones, along with word (lexeme) frequency to compare the frequencies of source, target, and error units at the phoneme, syllable, and word levels. Results showed that phoneme targets have equivalent frequency to matched controls, whereas source phonemes are lower in frequency than chance (the Weak Source effect) and target phonemes (the David effect). Target, source, and error syllables and words also were of lower frequency than chance, and error words (when they occur) were lowest in frequency. Contrary to most current theories, which focus on faulty processing of the target units, present results suggest that faulty processing of the source units (phonemes, syllables, and words) is an important factor contributing to phonological speech errors. Low-frequency words and syllables have more difficulty ensuring that their phonemes, especially those of low frequency, are output only in their correct locations.

State of the art and new directions of Quantitative Electroencephalography use in Differential Diagnosis of ADHD / Estado de la cuestión y uso de la electroencefalografía cuantitativa en el diagnóstico diferencial del TDAH

Advances in technology in recent years have made the use of quantitative electroencephalogram more accessible to clinicians. The incorporation ofnormative databases in QEEG studies and the possibility of detecting different electroencephalographic patterns in patients with a given pathology,despite showing an apparent symptomatology homogeneity, make it an interesting source of information. The relationship of these patterns with apossible response to treatment or with prognostic estimates would justify its inclusion as a routine test in the process of the differential diagnosisof ADHD. In this paper, we present the possible benefits of the use of QEEG in the differential diagnosis of ADHD, the different electroencephalographic patterns associated with ADHD most common in the literature, and a case showcasing the use of the technique in a patient with ADHD. (AU)

El avance de la tecnología en los últimos años ha hecho que el uso del electroencefalograma cuantitativo sea más accesible a los clínicos. La incorporación de bases de datos normativas enlos estudios de QEEG y la posibilidad de detectar diferentes patrones electroencefalográficos en pacientes con una patología determinada, a pesarde mostrar una aparente homogeneidad sintomatológica, hacen que sea una fuente de información interesante. La relación de estos patrones conuna posible respuesta a tratamientos o con estimaciones pronósticas justificarían su inclusión como prueba rutinaria en el proceso de diagnósticodiferencial del TDAH. En este trabajo se presentan los posibles beneficios del uso del QEEG en el diagnóstico diferencial del TDAH, los diferentespatrones electroencefalográficos asociados al TDAH más comunes en la literatura y un caso ilustrativo del uso de la técnica en un paciente con TDAH. (AU)

Population-based sequencing of Mycobacterium tuberculosis reveals how current population dynamics are shaped by past epidemics.

Transmission is a driver of tuberculosis (TB) epidemics in high-burden regions, with assumed negligible impact in low-burden areas. However, we still lack a full characterization of transmission dynamics in settings with similar and different burdens. Genomic epidemiology can greatly help to quantify transmission, but the lack of whole genome sequencing population-based studies has hampered its application. Here, we generate a population-based dataset from Valencia region and compare it with available datasets from different TB-burden settings to reveal transmission dynamics heterogeneity and its public health implications. We sequenced the whole genome of 785 Mycobacterium tuberculosis strains and linked genomes to patient epidemiological data. We use a pairwise distance clustering approach and phylodynamic methods to characterize transmission events over the last 150 years, in different TB-burden regions. Our results underscore significant differences in transmission between low-burden TB settings, i.e., clustering in Valencia region is higher (47.4%) than in Oxfordshire (27%), and similar to a high-burden area as Malawi (49.8%). By modeling times of the transmission links, we observed that settings with high transmission rate are associated with decades of uninterrupted transmission, irrespective of burden. Together, our results reveal that burden and transmission are not necessarily linked due to the role of past epidemics in the ongoing TB incidence, and highlight the need for in-depth characterization of transmission dynamics and specifically tailored TB control strategies.

Exploring Inflammatory Status in Febrile Seizures Associated with Urinary Tract Infections: A Two-Step Cluster Approach.

BACKGROUND: Urinary tract infections (UTIs) are considered common facilitating factors, along with other infections, in triggering febrile seizures (FS). The main purpose of our study was to identify specific inflammatory patterns of UTI cases from other infections in a specific cluster, using a combination of inflammatory biomarkers to differentiate UTIs from other bacterial diseases triggering FS. METHOD: This prospective study included a number of 136 patients with 197 distinct FS events, from patients hospitalized in the Pediatric Clinical Hospital Sibiu, among which 10.2% were diagnosed with UTIs. RESULTS: In one-third of the patients with UTIs (20 cases), the symptoms were limited to fever and FS. Using two-step cluster analysis, a distinct UTI inflammatory pattern has emerged: highest platelet values (PLT), median value 331 × 103/mm3 and intermediate C-reactive protein (CRP), median value 15 mg/dL, platelet distribution width (PDW), median value 9.65%, platelet-large cell ratio (P-LCR), median value 14.45%, mean platelet volume (MPV), median value 8.60 fL and neutrophil-to-lymphocyte values (NLR), median value 3.64. Furthermore, higher PDW (median value 12.25%), P-LCR (median value 28.55%), MPV (median value 10.40 fL), CRP (median value 74.00 mg/dL) and NLR values (median value 4.11) were associated mainly (85.7%) with bacterial lower respiratory infections. UTIs were highly unlikely in these patients with significantly increased CRP values and normal values of platelet indices. CONCLUSIONS: Considering the nonspecific clinical picture of UTIs at an early age, to optimize the management of FS, a fast diagnosis of UTI is mandatory. The analysis of the inflammatory biomarker clusters (rather than individual parameters) correlated with urine leukocyte and nitrite stick evaluation for specific age groups could help in identifying even oligosymptomatic UTIs patients. The study limitation (20 UTI cases) recommends future multicentric trials on larger datasets to validate the model.

A Decision-Tree Approach to Assist in Forecasting the Outcomes of the Neonatal Brain Injury.

Neonatal brain injury or neonatal encephalopathy (NE) is a significant morbidity and mortality factor in preterm and full-term newborns. NE has an incidence in the range of 2.5 to 3.5 per 1000 live births carrying a considerable burden for neurological outcomes such as epilepsy, cerebral palsy, cognitive impairments, and hydrocephaly. Many scoring systems based on different risk factor combinations in regression models have been proposed to predict abnormal outcomes. Birthweight, gestational age, Apgar scores, pH, ultrasound and MRI biomarkers, seizures onset, EEG pattern, and seizure duration were the most referred predictors in the literature. Our study proposes a decision-tree approach based on clinical risk factors for abnormal outcomes in newborns with the neurological syndrome to assist in neonatal encephalopathy prognosis as a complementary tool to the acknowledged scoring systems. We retrospectively studied 188 newborns with associated encephalopathy and seizures in the perinatal period. Etiology and abnormal outcomes were assessed through correlations with the risk factors. We computed mean, median, odds ratios values for birth weight, gestational age, 1-min Apgar Score, 5-min Apgar score, seizures onset, and seizures duration monitoring, applying standard statistical methods first. Subsequently, CART (classification and regression trees) and cluster analysis were employed, further adjusting the medians. Out of 188 cases, 84 were associated to abnormal outcomes. The hierarchy on etiology frequencies was dominated by cerebrovascular impairments, metabolic anomalies, and infections. Both preterms and full-terms at risk were bundled in specific categories defined as high-risk 75-100%, intermediate risk 52.9%, and low risk 0-25% after CART algorithm implementation. Cluster analysis illustrated the median values, profiling at a glance the preterm model in high-risk groups and a full-term model in the inter-mediate-risk category. Our study illustrates that, in addition to standard statistics methodologies, decision-tree approaches could provide a first-step tool for the prognosis of the abnormal outcome in newborns with encephalopathy.

Enhancing the Effects of Neurofeedback Training: The Motivational Value of the Reinforcers.

The brain activity that is measured by electroencephalography (EEG) can be modified through operant conditioning, specifically using neurofeedback (NF). NF has been applied to several disorders claiming that a change in the erratic brain activity would be accompanied by a reduction of the symptoms. However, the expected results are not always achieved. Some authors have suggested that the lack of an adequate response may be due to an incorrect application of the operant conditioning principles. A key factor in operant conditioning is the use of reinforcers and their value in modifying behavior, something that is not always sufficiently taken into account. This work aims to clarify the relevance of the motivational value versus the purely informational value of the reinforcer. In this study, 113 subjects were randomly assigned two different reinforcer conditions: a selected reinforcer-the subjects subjectively selected the reinforcers-or an imposed reinforcer-the reinforcers were assigned by the experimenter-and both groups undertook NF sessions to enhance the sensorimotor rhythm (SMR). In addition, the selected reinforcer group was divided into two subgroups: one receiving real NF and the other one sham NF. There were no significant differences between the groups at baseline in terms of SMR amplitude. After the intervention, only those subjects belonging to the selected reinforcer group and receiving real NF increased their SMR. Our results provide evidence for the importance of the motivational value of the reinforcer in Neurofeedback success.

Influence of the operating conditions of the intermediate thermal hydrolysis on the energetic efficiency of the sludge treatment process.

The application of steam explosion between two stages of anaerobic digestion may improve energy recovery from sludge while increasing organic matter removal. The influence of the operating conditions of the thermal process: temperature (130-210 °C), retention time (5-45 min) and TS concentration (5.4-10.8%), on the efficiency of VS removal, the biochemical methane potential of hydrolysed sludge and the kinetic constant of the degradation were evaluated using a Taguchi design. Increasing temperature and time increased the removal of VS and the potential of methane production but the kinetic constant was higher at lower temperatures. An optimal operating scheme was found at 170 °C (6 barg), 25 min at the greatest TS concentration in the feeding. Under such conditions, the thermal energy obtained from biogas combustion in a CHP covered the requirements for vapour generation and a profit of 3.54 € m-3 of sludge was estimated.

Individual Alpha Peak Frequency, an Important Biomarker for Live Z-Score Training Neurofeedback in Adolescents with Learning Disabilities.

Learning disabilities (LDs) have an estimated prevalence between 5% and 9% in the pediatric population and are associated with difficulties in reading, arithmetic, and writing. Previous electroencephalography (EEG) research has reported a lag in alpha-band development in specific LD phenotypes, which seems to offer a possible explanation for differences in EEG maturation. In this study, 40 adolescents aged 10-15 years with LDs underwent 10 sessions of Live Z-Score Training Neurofeedback (LZT-NF) Training to improve their cognition and behavior. Based on the individual alpha peak frequency (i-APF) values from the spectrogram, a group with normal i-APF (ni-APF) and a group with low i-APF (li-APF) were compared in a pre-and-post-LZT-NF intervention. There were no statistical differences in age, gender, or the distribution of LDs between the groups. The li-APF group showed a higher theta absolute power in P4 (p = 0.016) at baseline and higher Hi-Beta absolute power in F3 (p = 0.007) post-treatment compared with the ni-APF group. In both groups, extreme waves (absolute Z-score of ≥1.5) were more likely to move toward the normative values, with better results in the ni-APF group. Conversely, the waves within the normal range at baseline were more likely to move out of the range after treatment in the li-APF group. Our results provide evidence of a viable biomarker for identifying optimal responders for the LZT-NF technique based on the i-APF metric reflecting the patient's neurophysiological individuality.

Effects of quantitative electroencephalogram normalization using 4-channel live z-score training neurofeedback for children with learning disabilities: Preliminary data / Efectos de normalización del electroencefalograma cuantitativo utilizando neurorretroalimentación de puntuaciones Z de 4 canales en tiempo real para niños con trastornos de aprendizaje: datos preliminares

Children with learning disabilities (LD) can have difficulties in reading at word level, text comprehension, writing or arithmetic. Several studies have shown the efficacy of neurofeedback (NF) in improving learning skills through brainwave operant conditioning in children with LD. The aim of this work was to show the efficacy of live z-score NF training (LZT) for quantitative electroencephalogram (QEEG) normalization in school children with LD. Twenty-eight children aged 10-15 years with LD participated. Ten 30-min sessions of QEEG-guided LZT using patient's highly preferred feedback were applied. After 10 sessions of QEEGguided LZT, participants showed statistically significant improvements in QEEG normalization and a statistically significant small to medium improvement in the Cognitive and Emotional Checklist. The results suggest that LZT-NF produces a tendency towards normalization of brain waves in children with LD, and might be advised as a therapeutic alternative or coadjuvant along with cognitive interventions

Los niños con trastornos de aprendizaje (TA) pueden manifestar dificultades en la lectura a nivel de palabra, comprensión de textos, escritura o matemáticas. Algunos estudios han mostrado la eficacia de la neurorretroalimentación (NR) en la mejora de las habilidades de aprendizaje a través del condicionamiento operante de las ondas cerebrales en niños con TA. El objetivo de este trabajo fue mostrar datos preliminares de la eficacia de la neurorretroalimentación de puntuaciones z en tiempo real (LZT) para la normalización del electroencefalograma cuantitativo (QEEG) en escolares con TA. Participaron 28 niños de entre 10-15 años de edad con TA. Se aplicaron diez sesiones de 30 minutos de LZT guiado por QEEG utilizando retroalimentación de alta preferencia de los sujetos. Tras 10 sesiones de LZT guiado por QEEG, los participantes mostraron mejoras estadísticamente significativas en la normalización del QEEG y una mejora de pequeña a media estadísticamente significativa en la "Lista de comprobación cognitiva y emocional". Los resultados sugieren que LZT-NR produce una tendencia hacia la normalización de las ondas cerebrales en niños con TA, y podría suponer una alternativa terapéutica o coadyuvante junto con la intervención cognitiva

Sample pre-treatment and analytical methodology for the simultaneous determination of pharmaceuticals and personal care products in sewage sludge.

This work describes the design, optimization and validation of an analytical method for the simultaneous determination of 14 pharmaceuticals and personal care products (PPCPs) in sewage sludge. A thorough optimization of the sample pre-treatment was carried out. As a result, microwave-assisted extraction (MAE) was combined with an in-situ clean-up stage and a filtration step. A combination of MilliQ® water/MeOH 95:5 (v/v) adjusted to pH 9 turned out to be the optimal solvent mixture for extraction. The instrumental part of the method presents a significant novelty based on a fully automated sample preparation for the analysis of PPCPs. It consisted of a direct immersion solid phase microextraction followed by on-fiber derivatization, online coupled to gas chromatography - mass spectrometry (DI-SPME-On-fiber derivatization - GC-MS). An isotope dilution approach was used for quantifying, which conferred high reliability to the method. This methodology was validated for 10 compounds with good analytical performance, limit of detection below 20 ng g-1 and absolute recovery in the range of 30-70% for most of the compounds. It supposes an ecological analytical alternative for many routine analysis laboratories around the world. The developed method was applied to different real samples generated in both a pilot-scale thermal hydrolysis treatment plant and an anaerobic digester operated in mesophilic conditions. Salicylic acid and naproxen were found at concentrations above 1000 ng g-1.

Traceability of organic contaminants in the sludge line of wastewater treatment plants: A comparison study among schemes incorporating thermal hydrolysis treatment and the conventional anaerobic digestion.

The traceability of conventional pollutants and 10 organic microcontaminants in the sludge line of a wastewater treatment plant (WWTP) was evaluated. The application of thermal hydrolysis (TH) as pre-treatment to anaerobic digestion (AD) or as inter-treatment (between two AD stages) was considered and compared with the conventional digestion scheme. TH scenarios reduced the mass flow rate of biosolids (40-60%) as well as the ratio of solids (50-100%), organic matter (5-26%) and nitrogen (8-13%) destined to biosolids. Micropollutants showed a strong tendency to accumulate in the solid phase (more than 90% were sorbed) in spite of thermal and dewatering processes, but TH scenarios exhibited greater removal efficiency (80%) in comparison to conventional AD (50%), reducing the ratio of micropollutants destined to biosolids from a conventional 48% to 7-8%. These findings reveal that TH could increase the value of biosolids from sewage sludge treatment because of greater removal of pollutants and dewaterability.

PRIMVAC vaccine adjuvanted with Alhydrogel or GLA-SE to prevent placental malaria: a first-in-human, randomised, double-blind, placebo-controlled study.

BACKGROUND: PRIMVAC is a VAR2CSA-derived placental malaria vaccine candidate aiming to prevent serious clinical outcomes of Plasmodium falciparum infection during pregnancy. We assessed the safety and immunogenicity of PRIMVAC adjuvanted with Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) in French and Burkinabe women who were not pregnant. METHODS: This first-in-human, randomised, double-blind, placebo-controlled, dose escalation trial was done in two staggered phases, a phase 1A trial in 18-35-year-old women who were malaria naive in a hospital in France and a subsequent phase 1B trial in women who were naturally exposed to P falciparum and nulligravid in the clinical site of a research centre in Burkina Faso. Volunteers were recruited into four sequential cohorts receiving PRIMVAC intramuscularly at day 0, 28, and 56: two cohorts in France receiving 20 µg or 50 µg of PRIMVAC and then two in Burkina Faso receiving 50 µg or 100 µg of PRIMVAC. Volunteers were randomly assigned (1:1) to two groups (PRIMVAC adjuvanted with either Alhydrogel or GLA-SE) in France and randomly assigned (2:2:1) to three groups (PRIMVAC adjuvanted with either Alhydrogel, GLA-SE, or placebo) in Burkina Faso. Randomisation was centralised, using stratification by cohort and blocks of variable size, and syringes were masked by opaque labels. The primary endpoint was the proportion of participants with any grade 3 or higher adverse reaction to vaccination up until day 35. Safety at later time points as well as humoral and cellular immunogenicity were assessed in secondary endpoints. This trial is registered with ClinicalTrials.gov, NCT02658253. FINDINGS: Between April 19, 2016, and July 13, 2017, 68 women (18 in France, 50 in Burkina Faso) of 101 assessed for eligibility were included. No serious adverse event related to the vaccine occurred. PRIMVAC antibody titres increased with each dose and seroconversion was observed in all women vaccinated with PRIMVAC (n=57). PRIMVAC antibody titres reached a peak (geometric mean 11 843·0, optical density [OD] 1·0, 95% CI 7559·8-18 552·9 with 100 µg dose and GLA-SE) 1 week after the third vaccination (day 63). Compared with Alhydrogel, GLA-SE tended to improve the PRIMVAC antibody response (geometric mean 2163·5, OD 1·0, 95% CI 1315·7-3557·7 with 100 µg dose and Alhydrogel at day 63). 1 year after the last vaccination, 20 (71%) of 28 women who were vaccinated with PRIMVAC/Alhydrogel and 26 (93%) of 28 women who were vaccinated with PRIMVAC/GLA-SE still had anti-PRIMVAC antibodies, although antibody magnitude was markedly lower (452·4, OD 1·0, 95% CI 321·8-636·1 with 100 µg dose and GLA-SE). These antibodies reacted with native homologous VAR2CSA expressed by NF54-CSA infected erythrocytes (fold change from baseline at day 63 with 100 µg dose and GLA-SE: 10·74, 95% CI 8·36-13·79). Limited cross-recognition, restricted to sera collected from women that received the 100 µg PRIMVAC dose, was observed against heterologous VAR2CSA variants expressed by FCR3-CSA (fold change from baseline at day 63: 1·49, 95% CI 1·19-1·88) and 7G8-CSA infected erythrocytes (1·2, 1·08-1·34). INTERPRETATION: PRIMVAC adjuvanted with Alhydrogel or GLA-SE had an acceptable safety profile, was immunogenic, and induced functional antibodies reacting with the homologous VAR2CSA variant expressed by NF54-CSA infected erythrocytes. Cross-reactivity against heterologous VAR2CSA variants was limited and only observed in the higher dose group. An alternate schedule of immunisation, antigen dose, and combinations with other VAR2CSA-based vaccines are envisaged to improve the cross-reactivity against heterologous VAR2CSA variants. FUNDING: Bundesministerium für Bildung und Forschung, through Kreditanstalt für Wiederaufbau, Germany; Inserm, and Institut National de Transfusion Sanguine, France; Irish Aid, Department of Foreign Affairs and Trade, Ireland.

Social value of a set of proposals for the ideal approach of multiple sclerosis within the Spanish National Health System: a social return on investment study.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease that in many cases produces disability, having a high impact in patients' lives, reducing significantly their quality of life. The aim of this study was to agree on a set of proposals to improve the current management of MS within the Spanish National Health System (SNHS) and apply the Social Return on Investment (SROI) method to measure the potential social impact these proposals would create. METHODS: A Multidisciplinary Working Team of nine experts, with representation from the main stakeholders regarding MS, was set up to agree on a set of proposals to improve the management of MS. A forecast SROI analysis was carried out, with a one-year timeframe. Data sources included an expert consultation, a narrative literature review and a survey to 532 MS patients. We estimated the required investment of a hypothetical implementation, as well as the potential social value that it could create. We calculated outcomes in monetary units and we measured intangible outcomes through financial proxies. RESULTS: The proposed ideal approach revealed that there are still unmet needs related to MS that can be addressed within the SNHS. Investment would amount to 148 million € and social return to 272 million €, so each euro invested could yield almost €2 of social return. CONCLUSIONS: This study could guide health interventions, resulting in money savings for the SNHS and increases in patients' quality of life.

High-resolution mapping of tuberculosis transmission: Whole genome sequencing and phylogenetic modelling of a cohort from Valencia Region, Spain.

BACKGROUND: Whole genome sequencing provides better delineation of transmission clusters in Mycobacterium tuberculosis than traditional methods. However, its ability to reveal individual transmission links within clusters is limited. Here, we used a 2-step approach based on Bayesian transmission reconstruction to (1) identify likely index and missing cases, (2) determine risk factors associated with transmitters, and (3) estimate when transmission happened. METHODS AND FINDINGS: We developed our transmission reconstruction method using genomic and epidemiological data from a population-based study from Valencia Region, Spain. Tuberculosis (TB) incidence during the study period was 8.4 cases per 100,000 people. While the study is ongoing, the sampling frame for this work includes notified TB cases between 1 January 2014 and 31 December 2016. We identified a total of 21 transmission clusters that fulfilled the criteria for analysis. These contained a total of 117 individuals diagnosed with active TB (109 with epidemiological data). Demographic characteristics of the study population were as follows: 80/109 (73%) individuals were Spanish-born, 76/109 (70%) individuals were men, and the mean age was 42.51 years (SD 18.46). We found that 66/109 (61%) TB patients were sputum positive at diagnosis, and 10/109 (9%) were HIV positive. We used the data to reveal individual transmission links, and to identify index cases, missing cases, likely transmitters, and associated transmission risk factors. Our Bayesian inference approach suggests that at least 60% of index cases are likely misidentified by local public health. Our data also suggest that factors associated with likely transmitters are different to those of simply being in a transmission cluster, highlighting the importance of differentiating between these 2 phenomena. Our data suggest that type 2 diabetes mellitus is a risk factor associated with being a transmitter (odds ratio 0.19 [95% CI 0.02-1.10], p < 0.003). Finally, we used the most likely timing for transmission events to study when TB transmission occurred; we identified that 5/14 (35.7%) cases likely transmitted TB well before symptom onset, and these were largely sputum negative at diagnosis. Limited within-cluster diversity does not allow us to extrapolate our findings to the whole TB population in Valencia Region. CONCLUSIONS: In this study, we found that index cases are often misidentified, with downstream consequences for epidemiological investigations because likely transmitters can be missed. Our findings regarding inferred transmission timing suggest that TB transmission can occur before patient symptom onset, suggesting also that TB transmits during sub-clinical disease. This result has direct implications for diagnosing TB and reducing transmission. Overall, we show that a transition to individual-based genomic epidemiology will likely close some of the knowledge gaps in TB transmission and may redirect efforts towards cost-effective contact investigations for improved TB control.