Molecular characterisation defines clinically-actionable heterogeneity within Group 4 medulloblastoma and improves disease risk-stratification.

Group 4 tumours (MBGrp4) represent the majority of non-WNT/non-SHH medulloblastomas. Their clinical course is poorly predicted by current risk-factors. MBGrp4 molecular substructures have been identified (e.g. subgroups/cytogenetics/mutations), however their inter-relationships and potential to improve clinical sub-classification and risk-stratification remain undefined. We comprehensively characterised the paediatric MBGrp4 molecular landscape and determined its utility to improve clinical management. A clinically-annotated discovery cohort (n = 362 MBGrp4) was assembled from UK-CCLG institutions and SIOP-UKCCSG-PNET3, HIT-SIOP-PNET4 and PNET HR + 5 clinical trials. Molecular profiling was undertaken, integrating driver mutations, second-generation non-WNT/non-SHH subgroups (1-8) and whole-chromosome aberrations (WCAs). Survival models were derived for patients ≥ 3 years of age who received contemporary multi-modal therapies (n = 323). We first independently derived and validated a favourable-risk WCA group (WCA-FR) characterised by ≥ 2 features from chromosome 7 gain, 8 loss, and 11 loss. Remaining patients were high-risk (WCA-HR). Subgroups 6 and 7 were enriched for WCA-FR (p < 0·0001) and aneuploidy. Subgroup 8 was defined by predominantly balanced genomes with isolated isochromosome 17q (p < 0·0001). While no mutations were associated with outcome and overall mutational burden was low, WCA-HR harboured recurrent chromatin remodelling mutations (p = 0·007). Integration of methylation and WCA groups improved risk-stratification models and outperformed established prognostication schemes. Our MBGrp4 risk-stratification scheme defines: favourable-risk (non-metastatic disease and (i) subgroup 7 or (ii) WCA-FR (21% of patients, 5-year PFS 97%)), very-high-risk (metastatic disease with WCA-HR (36%, 5-year PFS 49%)) and high-risk (remaining patients; 43%, 5-year PFS 67%). These findings validated in an independent MBGrp4 cohort (n = 668). Importantly, our findings demonstrate that previously established disease-wide risk-features (i.e. LCA histology and MYC(N) amplification) have little prognostic relevance in MBGrp4 disease. Novel validated survival models, integrating clinical features, methylation and WCA groups, improve outcome prediction and re-define risk-status for ~ 80% of MBGrp4. Our MBGrp4 favourable-risk group has MBWNT-like excellent outcomes, thereby doubling the proportion of medulloblastoma patients who could benefit from therapy de-escalation approaches, aimed at reducing treatment induced late-effects while sustaining survival outcomes. Novel approaches are urgently required for the very-high-risk patients.

Thermodynamic Entropy as a Noether Invariant from Contact Geometry.

We use a formulation of Noether's theorem for contact Hamiltonian systems to derive a relation between the thermodynamic entropy and the Noether invariant associated with time-translational symmetry. In the particular case of thermostatted systems at equilibrium, we show that the total entropy of the system plus the reservoir are conserved as a consequence thereof. Our results contribute to understanding thermodynamic entropy from a geometric point of view.

Bronchoscopist's perception of the quality of the single-use bronchoscope (Ambu aScope4™) in selected bronchoscopies: a multicenter study in 21 Spanish pulmonology services.

BACKGROUND: The disposable bronchoscope is an excellent alternative to face the problem of SARS-CoV-2 and other cross infections, but the bronchoscopist's perception of its quality has not been evaluated. METHODS: To evaluate the quality of the Ambu-aScope4 disposable bronchoscope, we carried out a cross-sectional study in 21 Spanish pulmonology services. We use a standardized questionnaire completed by the bronchoscopists at the end of each bronchoscopy. The variables were described with absolute and relative frequencies, measures of central tendency and dispersion depending on their nature. The existence of learning curves was evaluated by CUSUM analysis. RESULTS: The most frequent indications in 300 included bronchoscopies was bronchial aspiration in 69.3% and the median duration of these was 9.1 min. The route of entry was nasal in 47.2% and oral in 34.1%. The average score for ease of use, image, and aspiration quality was 80/100. All the planned techniques were performed in 94.9% and the bronchoscopist was satisfied in 96.6% of the bronchoscopies. They highlighted the portability and immediacy of the aScope4TM to start the procedure in 99.3%, the possibility of taking and storing images in 99.3%. The CUSUM analysis showed average scores > 70/100 from the first procedure and from the 9th procedure more than 80% of the scores exceeded the 80/100 score. CONCLUSIONS: The aScope4™ scored well for ease of use, imaging, and aspiration. We found a learning curve with excellent scores from the 9th procedure. Bronchoscopists highlighted its portability, immediacy of use and the possibility of taking and storing images.

Management and outcome of children and adolescents with non-medulloblastoma CNS embryonal tumors in Spain: room for improvement in standards of care.

Non-medulloblastoma CNS embryonal tumors (former PNET/Pineoblastomas) are aggressive malignancies with poor outcome that have been historically treated with medulloblastoma protocols. The purpose of this study is to present a tumor-specific, real-world data cohort of patients with CNS-PNET/PB to analyze quality indicators that can be implemented to improve the outcome of these patients. Patients 0-21 years with CNS-PNET treated in eight large institutions were included. Baseline characteristics, treatment and outcome [progression-free and overall survival (PFS and OS respectively)] were analyzed. From 2005 to 2014, 43 patients fulfilled entry criteria. Median age at diagnosis was 3.6 years (range 0.0-14.7). Histology was pineoblastoma (9%), ependymoblastoma (5%), ETANTR (7%) and PNET (77%). Median duration of the main symptom was 2 weeks (range 0-12). At diagnosis, 28% presented with metastatic disease. Seventeen different protocols were used on frontline treatment; 44% had gross total resection, 42% craniospinal radiotherapy, 86% chemotherapy, and 33% autologous hematopoietic stem cell transplantation (aHSCT). Median follow-up for survivors was 3.5 years (range 1.7-9.3). 3-year PFS was 31.9% (95% CI 17-47%) and OS 35.1% (95% CI 20-50%). Age, extent of resection and radiotherapy were prognostic of PFS and OS in univariate analysis (p < 0.05). Our series shows a dismal outcome for CNS-PNET, especially when compared to patients included in clinical trials. Establishing a common national strategy, implementing referral circuits and collaboration networks, and incorporating new molecular knowledge into routine clinical practice are accessible measures that can improve the outcome of these patients.

Impact of environmental air pollutants on disease control in asmathic patients.

PURPOSE: Asthmatics are adversely affected by the presence of air pollutants, the concentrations of which can nowadays be measured. However, the utility of this information in clinical practice has not been defined in a group of asthmatics in stable condition. Our objective was to determine what impact the level of air pollutants had on the control of their asthma and the degree of airway inflammation. METHODS: We performed a cross-sectional study of adult asthmatics in stable condition. From the regional environmental authority, we obtained the concentrations of ambient nitric oxide (NO2), ozone (O3), suspended particulate matter up to 10 micrometers in diameter (PM10) and sulphur dioxide (SO2) at fixed geographical points. Disease control was assessed using asthma control test (ACT) scores, and airway inflammation using fraction of exhaled nitric oxide (FeNO) values. Correlation and linear regression studies were performed using ACT scores as the dependent variable. RESULTS: The study included 99 asthmatics, aged 39 years (SD 8), 55% women. Mean ACT value was 17.2 (SD 6.5), and FeNO 33.7 (SD 16). Of the pollutants studied, only NO2 was correlated with ACT scores (CC = 0.45, p < 0.001). We found no relationship between pollutants and airway inflammation. Multivariate analysis showed that ACT score was predicted by ambient air NO2 concentration and, to a lesser extent, mean FeNO. CONCLUSIONS: Information on the concentration of ambient NO2 in our environment can help the clinician to interpret the evolution of asthmatic patients.

Molecular investigation of tularemia outbreaks, Spain, 1997-2008.

Tularemia outbreaks occurred in northwestern Spain in 1997-1998 and 2007-2008 and affected >1,000 persons. We assessed isolates involved in these outbreaks by using pulsed-field gel electrophoresis with 2 restriction enzymes and multilocus variable number tandem repeat analysis of 16 genomic loci of Francisella tularensis, the cause of this disease. Isolates were divided into 3 pulsotypes by pulsed-field gel electrophoresis and 8 allelic profiles by multilocus variable number tandem repeat analysis. Isolates obtained from the second tularemia outbreak had the same genotypes as isolates obtained from the first outbreak. Both outbreaks were caused by genotypes of genetic subclade B.Br:FTNF002-00, which is widely distributed in countries in central and western Europe. Thus, reemergence of tularemia in Spain was not caused by the reintroduction of exotic strains, but probably by persistence of local reservoirs of infection.

Methicillin-resistant Staphylococcus aureus harboring mecC in livestock in Spain.

We report for the first time mecC-positive methicillin-resistant Staphylococcus aureus (mecC-MRSA) in livestock in Spain. One isolate (sequence type 130) was found in milk samples among 601 S. aureus isolates obtained from 229 dairy sheep farms. This finding highlights the potential for zoonotic transmission of mecC-positive MRSA and the need for surveillance programs to monitor its presence and clonal evolution.

ECLIM-SEHOP: how to develop a platform to conduct academic trials for childhood cancer.

INTRODUCTION: ECLIM-SEHOP platform was created in 2017. Its main objective is to establish the infrastructure to allow Spanish participation into international academic collaborative clinical trials, observational studies, and registries in pediatric oncology. The aim of this manuscript is to describe the activity conducted by ECLIM-SEHOP since its creation. METHODS: The platform's database was queried to provide an overview of the studies integrally and partially supported by the organization. Data on trial recruitment and set-up/conduct metrics since its creation until November 2023 were extracted. RESULTS: ECLIM-SEHOP has supported 47 studies: 29 clinical trials and 18 observational studies/registries that have recruited a total of 5250 patients. Integral support has been given to 25 studies: 16 trials recruiting 584 patients and nine observational studies/registries recruiting 278 patients. The trials include front-line studies for leukemia, lymphoma, brain and solid extracranial tumors, and other key transversal topics such as off-label use of targeted therapies and survivorship. The mean time from regulatory authority submission to first patient recruited was 12.2 months and from first international site open to first Spanish site open was 31.3 months. DISCUSSION: ECLIM-SEHOP platform has remarkably improved the availability and accessibility of international academic clinical trials and has facilitated the centralization of resources in childhood cancer treatment. Despite the progressive improvement on clinical trial set-up metrics, timings should still be improved. The program has contributed to leveling survival rates in Spain with those of other European countries that presented major differences in the past.

Molecular characterization of Mycoplasma agalactiae reveals the presence of an endemic clone in Spain.

Mycoplasma agalactiae isolates from Spain were genetically characterized to investigate their genomic diversity and to better understand their relationship to isolates from other countries. Molecular typing revealed a high genomic homogeneity in Spanish M. agalactiae isolates, which clearly shows the circulation of one endemic clonal population.

A survey of Mycoplasma agalactiae in dairy sheep farms in Spain.

BACKGROUND: Contagious Agalactia (CA) is one of the major animal health problems in small ruminants because of its economic significance. Currently, four Mycoplasma spp. have been associated with this syndrome: M. agalactiae, M. mycoides subsp. capri, M. capricolum subsp. capricolum and M. putrefaciens. Their presence has been evaluated in several studies conducted in CA-endemic countries. However, previous Spanish studies have been focused on caprine CA, and there is a knowledge gap regarding which Mycoplasma species are present in sheep flocks from Spain, which has the second highest number of sheep amongst the 27 European Union member states. Consequently, we investigated the presence and geographic distribution of the four CA-causing mycoplasmas in Spanish dairy sheep farms. This is the first time such an investigation has been performed. RESULTS: Three hundred thirty nine out of 922 sheep flocks were positive for M. agalactiae by real time PCR (36.8%) and 85 by microbiological identification (9.2%). Interestingly, all 597 milk samples assessed for the presence of M. mycoides subsp. capri, M. capricolum subsp. capricolum and M. putrefaciens tested negative. To evaluate the intermittent excretion of the pathogen in milk, we sampled 391 additional farms from 2 to 5 times, resulting that in 26.3% of the cases a previously positive farm tested negative in a later sampling. CONCLUSIONS: M. agalactiae was the only Mycoplasma species detected in the study area showing a high frequency of presence and wide distribution. Therefore, the establishment of a permanent surveillance network is advantageous, as well as the implementation of control and prevention measures to hinder the dissemination of M. agalactiae and to prevent the entrance of other Mycoplasma species.

Adiabatic lapse rate of real gases.

We derive a formula for the dry adiabatic lapse rate of atmospheres composed of real gases. We restrict our study to those described by a family of two-parameter cubic equations of state and the recent Guevara-Rodríguez noncubic equation. Since our formula depends on the adiabatic curves, we compute them all at once, considering molecules that can move, rotate, and vibrate, for any equation of state. To illustrate our results, we estimate the lapse rate of the troposphere of Titan, obtaining a better approximation to the observed data in some instances, when compared to the estimation provided by the virial expansion up to the third order.

Clinical management of the acute complications of sickle cell anemia: 11 years of experience in a tertiary hospital.

INTRODUCTION: Sickle cell disease is an emerging anemia in Europe leading to high morbidity with severe acute complications requiring hospital admission and chronic consequences. The management of these patients is complex and needs interdisciplinary care. The objective is to analyze clinical characteristics and management of patients with sickle cell disease admitted for acute complications. METHODS: Retrospective descriptive study of admissions for acute complications of patients with sickle cell disease under 16 years of age in a tertiary hospital between 2010 and 2020. Clinical, laboratory and radiological data were reviewed. RESULTS: We included 71 admissions corresponding to 25 patients, 40% diagnosed by neonatal screening. Admissions increased during this period. The most frequent diagnoses were vaso-occlusive crisis (35.2%), febrile syndrome (33.8%) and acute chest syndrome (32.3%). Nine patients required critical care at PICU. Positive microbiological results were confirmed in 20 cases, bacterial in 60%. Antibiotic therapy was administered in 86% of cases and the vaccination schedule of asplenia was adequately fulfilled by 89%. Opioid analgesia was required in 28%. Chronic therapy with hydroxyurea prior to admission was used in 41%. CONCLUSIONS: Acute complications requiring hospital admission are frequent in patients with sickle cell disease, being vaso-occlusive crisis and febrile syndrome the most common. These patients need a high use of antibiotics and opioid analgesia. Prior diagnosis facilitates the recognition of life-threatening complications such as acute chest syndrome and splenic sequestration. Despite the prophylactic and therapeutic measures currently provided to these patients, many patients suffer acute complications that require hospital management.

Identification and Functional Analysis of a Novel CTNNB1 Mutation in Pediatric Medulloblastoma.

Medulloblastoma is the primary malignant tumor of the Central Nervous System (CNS) most common in pediatrics. We present here, the histological, molecular, and functional analysis of a cohort of 88 pediatric medulloblastoma tumor samples. The WNT-activated subgroup comprised 10% of our cohort, and all WNT-activated patients had exon 3 CTNNB1 mutations and were immunostained for nuclear ß-catenin. One novel heterozygous CTNNB1 mutation was found, which resulted in the deletion of ß-catenin Ser37 residue (ΔS37). The ΔS37 ß-catenin variant ectopically expressed in U2OS human osteosarcoma cells displayed higher protein expression levels than wild-type ß-catenin, and functional analysis disclosed gain-of-function properties in terms of elevated TCF/LEF transcriptional activity in cells. Our results suggest that the stabilization and nuclear accumulation of ΔS37 ß-catenin contributed to early medulloblastoma tumorigenesis.

Structural changes associated to orthokeratology: A systematic review.

PURPOSE: To summarize the peer-reviewed literature on corneal structural changes after orthokeratology (OK) and to analyze the quality of the studies published. METHODS: An exhaustive search was carried out in the databases Pubmed MEDLINE, Web of Science and Scopus. Original studies in English, with a cohort or experimental design and analyzing the cellular and structural changes of the cornea after OK fitting for myopia correction were selected. The NewCastle-Ottawa Assessment Scale (NOS) tool was used to analyze the quality of the studies selected. RESULTS: The search provided a total of 1837 articles, of which 12 were selected following the inclusion and exclusion criteria. All studies had good quality according to the NOS tool (mean 7.58 ± 1.31). The mean ± standard deviation follow-up period of lens wear in the studies evaluated was 19.27 ± 33.97 months. The following reversible changes after OK have been reported: reduction in central epithelial basal cells, an increase in height and especially in width of superficial epithelial cells, as well as an increase in central stromal thickness and in the number of active keratocytes. Concerning corneal endothelium, only changes in terms of polymegathism were reported that were compatible with those observed for other types of contact lens wear. In relation to corneal sensitivity, there was a reduction during the use of OK, as well as in the nervous density of the sub-basal plexus at the central level, with some contradictory outcomes concerning the reversibility of these changes. CONCLUSION: OK produces reversible structural changes in the central epithelium and central anterior corneal stroma, as well as a decrease in the nerve density of the sub-basal plexus and corneal sensitivity. The quality of published studies evaluating these aspects is good, although more studies are needed to evaluate longer follow-up changes.

The economic consequences of diabetes and cardiovascular disease in the United States.

Diabetes-related care and complications constitute a significant proportion of the United States' (US) health care expenditure. Of these complications, cardiovascular disease (CVD) is a major component. Higher morbidity and mortality rates translate to higher costs of care in patients with diabetes compared to those who do not have the disease. Minorities bear a disproportionate burden of diabetes and CVD. We review this disparity and examine potential etiologies for it in Hispanics and African-Americans, the two largest minority groups in the US. We examine strategies in these populations that may improve outcomes in diabetes and CVD, potentially decreasing health care costs.

Quadrivalent Influenza Vaccine Prevents Illness and Reduces Healthcare Utilization Across Diverse Geographic Regions During Five Influenza Seasons: A Randomized Clinical Trial.

BACKGROUND: We evaluated an inactivated quadrivalent influenza vaccine (IIV4) in children 6-35 months of age in a phase III, observer-blind trial. METHODS: The aim of this analysis was to estimate vaccine efficacy (VE) in preventing laboratory-confirmed influenza in each of 5 independent seasonal cohorts (2011-2014), as well as vaccine impact on healthcare utilization in 3 study regions (Europe/Mediterranean, Asia-Pacific and Central America). Healthy children were randomized 1:1 to IIV4 or control vaccines. VE was estimated against influenza confirmed by reverse transcription polymerase chain reaction on nasal swabs. Cultured isolates were characterized as antigenically matched/mismatched to vaccine strains. RESULTS: The total vaccinated cohort included 12,018 children (N = 1777, 2526, 1564, 1501 and 4650 in cohorts 1-5, respectively). For reverse transcription polymerase chain reaction confirmed influenza of any severity (all strains combined), VE in cohorts 1-5 was 57.8%, 52.9%, 73.4%, 30.3% and 41.4%, respectively, with the lower limit of the 95% confidence interval >0 for all estimates. The proportion of vaccine match for all strains combined in each cohort was 0.9%, 79.3%, 72.5%, 24.1% and 28.6%, respectively. Antibiotic use associated with influenza illness was reduced with IIV4 by 71% in Europe, 36% in Asia Pacific and 59% in Central America. CONCLUSIONS: IIV4 prevented influenza in children 6-35 months of age in each of 5 separate influenza seasons in diverse geographical regions. A possible interaction between VE, degree of vaccine match and socioeconomic status was observed. The IIV4 attenuated the severity of breakthrough influenza illness and reduced healthcare utilization, particularly antibiotic use.

[Utility of urokinase in percutaneous drainage treatment of intra-abdominal abscesses]. / Utilidad de la urocinasa en el tratamiento de los abscesos intraabdominales mediante drenaje percutáneo.

BACKGROUND AND OBJECTIVE: The aim of the study was to analyze the usefulness of the treatment with Urokinase (UK) in percutaneous drainage of intra-abdominal abscesses (IAA). PATIENTS AND METHODS: Prospective, observational study of 50 patients treated in the Interventional Radiology Unit from University Hospital Lozano Blesa .Zaragoza. Spain. All procedures were performed under local anesthesia and ultrasound control, using Pigtail catheters (12-14 F). PH , D-dimer determination and microbiological studies were done from the initial aspirated sample. Subsequently, we injected 10 cc of UK (100,000 IU) 3 times a day for 3 days at least. Variables study: RESOLUTION (Principal variable). Other variables included epidemiological, specific prognostic indexes (Mannheim, Altona); types of abscesses (location/origin), pH, D-Dímer and microbiology. Technical success, days of treatment, stay and mortality were also analyzed. RESOLUTION: 86%; technical success: 100%; subsequent surgery: 3 cases. Mean treatment days: 7. Mean stay: 12 days. Death rate: 8% (PMI=or>13 and PIA II=or<-3,76). CONCLUSIONS: The treatment of IAA through percutaneous drainage and washed with urokinase, is a safe, feasible and reproducible technique. The outcomes are similar to those reported previously.

[Role of low molecular weight heparins in prophylaxis of thromboembolic events on oncological patients with indwelling central venous catheter]. / Heparinas de bajo peso molecular en la profilaxis de episodios tromboembólicos en pacientes con cáncer portadores de catéter venoso central.

BACKGROUND AND OBJECTIVE: Our study was designed to assess the incidence of thrombosis in the upper limbs and of pulmonary embolism in oncological patients with indwelling central venous catheters, and to evaluate, also, the potential role of LMWH to prevent these events. PATIENTS AND METHODS: Oncological patients undergoing placement of a central venous acccess (port-a-cath type) were treated with or without bemiparin in a non-randomized fashion. Assessment included clinical and radiological follow-up. A phlebography on the first day and ecodoppler on days 1th, 45th and 90th were performed. Patients received or not prophylactic bemiparin (3500UI/day) in a non-randomized way. The incidence of thrombosis in both groups was assessed as well as its relation with some risk factors. RESULTS: One hundred and forty eight patients were eligible; 19 thrombotic events were found. The incidence of symptomatic upper extremity thrombosis was 5.41%, asymptomatic thrombosis in 2.03% ; there was one case of pulmonary embolism ( 0,68%); catheter failure occurred in 2.70%; incidence of lower extremities deep venous thrombosis was 2.03%. There was a higher percentage of events in the group of patients treated with bemiparin than in the not treated individuals (9.4%), although the difference did not reach statistical significance (p=0.27). The only risk factors reaching statistical significance were the prothrombin time, high blood pressure and overweight. CONCLUSIONS: Central venous catheters are very useful in oncology. The procedure was related with a low percentage of thrombotic complications. Sodic bemiparin does not reduce the thrombotic risk in these patients.

Biliary spills and collections: causes, diagnosis, and multidisciplinary management.

PURPOSE: To evaluate the role of image-guided percutaneous interventions in patients with bile leaks and bile collections managed by a multidisciplinary team. MATERIAL & METHODS: Selection criteria included those patients from February 1999 to August 2007 who had bile leaks and bile collections in whom an image-guided procedure was performed. Ultrasound (US), computed tomography (CT), and nuclear medicine studies were used for diagnostic imaging. Patients were evaluated and managed in a multidisciplinary fashion by gastroenterologists, surgeons, and interventionists. Parameters measured in the study were drainage indications, cause and location of the biliary injury, location and size of bile collections, volume of fluid drained, fluid microbiology results, duration of catheterization, and patient outcome. Patients were followed up by the interventionist on daily rounds while inpatients and at the interventional clinic as outpatients. RESULTS: There were 31 patients who underwent image-guided percutaneous interventions as part of the management of bile leaks and bile collections. Causes of biliary injuries were surgical procedures, 18 patients (laparoscopic cholecystectomy, 11 patients; hepatectomy, 7 patients); abdominal trauma, 8 patients; percutaneous biliary procedures, 3 patients; liver abscess, 1 patient; gallbladder rupture, 1 patient. Bile collections were localized in 23 patients and diffuse in 8 patients. Localized collections were extrahepatic in 17 patients and intrahepatic in 6 patients. The size of the bile collections ranged from 4 to 12 cm (mean, 8 cm) in maximum diameter. The volume of fluid drained ranged from 25 mL to 4300 mL (mean, 915 mL). Microbiology studies showed sterile bile in 24 patients and bacterial infections in 7 patients. Duration of catheterization ranged from 3 days to 202 days (mean, 36 days). Of the 31 patients, 28 (90%) were cured from their condition and 3 (10%) patients died. Image-guided percutaneous interventions were able to resolve bile leaks and bile collections in 24 (86%) patients while 4 (14%) required additional procedures (endoscopic, 3 patients; surgery, 1 patient). CONCLUSION: Under multidisciplinary management, image-guided interventions are effective for resolution of most bile spills and collections. Additional endoscopic and surgical procedures are necessary when the percutaneous approach fails.

Efficacy, immunogenicity, and safety of a quadrivalent inactivated influenza vaccine in children aged 6-35 months: A multi-season randomised placebo-controlled trial in the Northern and Southern Hemispheres.

BACKGROUND: A quadrivalent split-virion inactivated influenza vaccine (VaxigripTetra™, Sanofi Pasteur; IIV4) containing two A strains (H1N1 and H3N2) and B strains from both lineages (Victoria and Yamagata) was approved in Europe in 2016 for individuals aged ≥ 3 years. This study examined the efficacy and safety of IIV4 in children aged 6-35 months. METHODS: This was a phase III randomised controlled trial conducted in Latin America, Asia, Africa, and Europe during the Northern Hemisphere 2014/2015 and 2015/2016 and Southern Hemisphere 2014 and 2015 influenza seasons. Healthy children aged 6-35 months not previously vaccinated against influenza were randomised to receive two full doses 28 days apart of IIV4, placebo, the licensed trivalent split-virion inactivated vaccine (IIV3), an investigational IIV3 containing a B strain from the alternate lineage. The primary objective was to demonstrate efficacy against influenza illness caused by any strain or vaccine-similar strains. RESULTS: The study enrolled 5806 participants. Efficacy, assessed in 4980 participants completing the study according to protocol, was demonstrated for IIV4. Vaccine efficacy was 50.98% (97% CI, 37.36-61.86%) against influenza caused by any A or B type and 68.40% (97% CI, 47.07-81.92%) against influenza caused by vaccine-like strains. Safety profiles were similar for IIV4, placebo, and the IIV3s, although injection-site reactions were slightly more frequent for IIV4 than placebo. CONCLUSIONS: IIV4 was safe and effective for protecting children aged 6-35 months against influenza illness caused by vaccine-similar or any circulating strains. CLINICAL TRIAL REGISTRATION: EudraCT no. 2013-001231-51.