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Background: By March, 2023, 54 countries, areas, and territories (hereafter CAT) in the WHO European Region had reported more than 2·2 million COVID-19-related deaths to the WHO Regional Office for Europe. Here, we estimated how many lives were directly saved by vaccinating adults in the WHO European Region from December, 2020, to March, 2023., Methods: In this retrospective surveillance study, we estimated the number of lives directly saved by age group, vaccine dose, and circulating variant-of-concern (VOC) period, regionally and nationally, using weekly data on COVID-19 mortality and infection, COVID-19 vaccination uptake, and SARS-CoV-2 virus characterisations by lineage downloaded from The European Surveillance System on June 11, 2023, as well as vaccine effectiveness data from the literature. We included data for six age groups (25-49 years, 50-59 years, ≥60 years, 60-69 years, 70-79 years, and ≥80 years). To be included in the analysis, CAT needed to have reported both COVID-19 vaccination and mortality data for at least one of the four older age groups. Only CAT that reported weekly data for both COVID-19 vaccination and mortality by age group for 90% of study weeks or more in the full study period were included. We calculated the percentage reduction in the number of expected and reported deaths., Findings: Between December, 2020, and March, 2023, in 34 of 54 CAT included in the analysis, COVID-19 vaccines reduced deaths by 59% overall (CAT range 17-82%), representing approximately 1·6 million lives saved (range 1·5-1·7 million) in those aged 25 years or older: 96% of lives saved were aged 60 years or older and 52% were aged 80 years or older; first boosters saved 51% of lives, and 60% were saved during the Omicron period., Interpretation: Over nearly 2·5 years, most lives saved by COVID-19 vaccination were in older adults by first booster dose and during the Omicron period, reinforcing the importance of up-to-date vaccination among the most at-risk individuals. Further modelling work should evaluate indirect effects of vaccination and public health and social measures., Funding: US Centers for Disease Control and Prevention., Competing Interests: Declaration of interests GD reports that the predecessor of the organisation he works for, Public Health England, received an unrestricted grant from GSK to undertake a study on the outcome of patients who received parenteral zanamavir. The funder received data and interim reports from Public Health England but did not influence analysis and reporting of the study. GD had no involvement in the GSK-funded study on parenteral zanamavir. Furthermore, the currently submitted work was part of the public health response activities to COVID-19 and had no relationship to GSK or the study on parenteral zanamivir. EP has received a personal grant from the Finnish Medical Foundation for PhD studies. JM declares that Public Health Scotland received funding from the EU Horizon 2020 programme for work in describing the epidemiology of COVID-19 and its impact on primary and secondary care as a partner in the IMOVE-COVID-19 project. MK declares having received consulting fees from Gilead Sciences for advising on development of a clinical module for collection of patient-reported outcome data from people living with HIV, and having received an honoraria from GESIDA for speaking at an annual conference on patient-reported outcome measures for people with HIV. All other authors declare no competing interests., (Copyright © 2024 World Health Organization. Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background and Aim: Diacylglycerol kinase (DGK) isoforms catalyze an enzymatic reaction that removes diacylglycerol (DAG) and thereby terminates protein kinase C signaling by converting DAG to phosphatidic acid. DGKδ (type II isozyme) downregulation causes insulin resistance, metabolic inflexibility, and obesity. Here we determined whether DGKδ overexpression prevents these metabolic impairments., Methods: We generated a transgenic mouse model overexpressing human DGKδ2 under the myosin light chain promoter (DGKδ TG). We performed deep metabolic phenotyping of DGKδ TG mice and wild-type littermates fed chow or high-fat diet (HFD). Mice were also provided free access to running wheels to examine the effects of DGKδ overexpression on exercise-induced metabolic outcomes., Results: DGKδ TG mice were leaner than wild-type littermates, with improved glucose tolerance and increased skeletal muscle glycogen content. DGKδ TG mice were protected against HFD-induced glucose intolerance and obesity. DGKδ TG mice had reduced epididymal fat and enhanced lipolysis. Strikingly, DGKδ overexpression recapitulated the beneficial effects of exercise on metabolic outcomes. DGKδ overexpression and exercise had a synergistic effect on body weight reduction. Microarray analysis of skeletal muscle revealed common gene ontology signatures of exercise and DGKδ overexpression that were related to lipid storage, extracellular matrix, and glycerophospholipids biosynthesis pathways., Conclusion: Overexpression of DGKδ induces adaptive changes in both skeletal muscle and adipose tissue, resulting in protection against HFD-induced obesity. DGKδ overexpression recapitulates exercise-induced adaptations on energy homeostasis and skeletal muscle gene expression profiles., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We conducted a multicentre test-negative case-control study covering the period from October 2023 to January 2024 among adult patients aged ≥ 18 years hospitalised with severe acute respiratory infection in Europe. We provide early estimates of the effectiveness of the newly adapted XBB.1.5 COVID-19 vaccines against PCR-confirmed SARS-CoV-2 hospitalisation. Vaccine effectiveness was 49% overall, ranging between 69% at 14-29 days and 40% at 60-105 days post vaccination. The adapted XBB.1.5 COVID-19 vaccines conferred protection against COVID-19 hospitalisation in the first 3.5 months post vaccination, with VE > 70% in older adults (≥ 65 years) up to 1 month post vaccination., (© 2024 The Author(s). Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

BackgroundLeptospirosis is a zoonotic disease caused by bacteria of the genus Leptospira . Humans are infected by exposure to animal urine or urine-contaminated environments. Although disease incidence is lower in Europe compared with tropical regions, there have been reports of an increase in leptospirosis cases since the 2000s in some European countries.AimWe aimed to describe the epidemiology of reported cases of leptospirosis in the European Union/European Economic Area (EU/EEA) during 2010-2021 and to identify potential changes in epidemiological patterns.MethodsWe ran a descriptive analysis of leptospirosis cases reported by EU/EEA countries to the European Centre for Disease Prevention and Control with disease during 2010-2021. We also analysed trends at EU/EEA and national level.ResultsDuring 2010-2021, 23 countries reported 12,180 confirmed leptospirosis cases corresponding to a mean annual notification rate of 0.24 cases per 100,000 population. Five countries (France, Germany, the Netherlands, Portugal and Romania) accounted for 79% of all reported cases. The highest notification rate was observed in Slovenia with 0.82 cases per 100,000 population. Overall, the notification rate increased by 5.0% per year from 2010 to 2021 (95% CI: 1.2-8.8%), although trends differed across countries.ConclusionThe notification rate of leptospirosis at EU/EEA level increased during 2010-2021 despite including the first 2 years of the COVID-19 pandemic and associated changes in population behaviours. Studies at (sub)national level would help broaden the understanding of differences at country-level and specificities in terms of exposure to Leptospira , as well as biases in diagnosis and reporting.

We conducted a multicentre hospital-based test-negative case-control study to measure vaccine effectiveness (VE) against PCR-confirmed influenza in adult patients with severe acute respiratory infection (SARI) during the 2022/2023 influenza season in Europe. Among 5547 SARI patients ≥18 years, 2963 (53%) were vaccinated against influenza. Overall VE against influenza A(H1N1)pdm09 was 11% (95% CI: -23-36); 20% (95% CI: -4-39) against A(H3N2) and 56% (95% CI: 22-75) against B. During the 2022/2023 season, while VE against hospitalisation with influenza B was >55%, it was ≤20% for influenza A subtypes. While influenza vaccination should be a priority for future seasons, improved vaccines against influenza are needed., (© 2024 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

We conducted a multicentre hospital-based test-negative case-control study to measure the effectiveness of adapted bivalent COVID-19 mRNA vaccines against PCR-confirmed SARS-CoV-2 infection during the Omicron XBB lineage-predominant period in patients aged ≥ 60 years with severe acute respiratory infection from five countries in Europe. Bivalent vaccines provided short-term additional protection compared with those vaccinated > 6 months before the campaign: from 80% (95% CI: 50 to 94) for 14-89 days post-vaccination, 15% (95% CI: -12 to 35) at 90-179 days, and lower to no effect thereafter.

By December 2021, administration of the third dose of COVID-19 vaccinations coincided with the spread of the Omicron variant in Europe. Questions had been raised on protection against infection conferred by previous vaccination and/or infection. Our study population included 252,433 participants from the COVID-19 vaccination registry in Malta. Data were then matched with the national testing database. We collected vaccination status, vaccine brand, vaccination date, infection history, and age. Using logistic regression, we examined different combinations of vaccine dose, prior infection status and time, and the odds of infection during the period when the Omicron variant was the dominant variant in Malta. Participants infected with Sars-Cov-2 prior to the Omicron wave had a significantly lower odds of being infected with the Omicron variant. Additionally, the more recent the infection and the more recent the vaccination, the lower the odds of infection. Receiving a third dose within 20 weeks of the start of the Omicron wave in Malta offered similar odds of infection as receiving a second dose within the same period. Time since vaccination was a strong determinant against infection, as was previous infection status and the number of doses taken. This finding reinforces the importance of future booster dose provision especially to vulnerable populations.

IntroductionTwo large multicentre European hospital networks have estimated vaccine effectiveness (VE) against COVID-19 since 2021.AimWe aimed to measure VE against PCR-confirmed SARS-CoV-2 in hospitalised severe acute respiratory illness (SARI) patients ≥ 20 years, combining data from these networks during Alpha (March-June)- and Delta (June-December)-dominant periods, 2021.MethodsForty-six participating hospitals across 14 countries follow a similar generic protocol using the test-negative case-control design. We defined complete primary series vaccination (PSV) as two doses of a two-dose or one of a single-dose vaccine ≥ 14 days before onset.ResultsWe included 1,087 cases (538 controls) and 1,669 cases (1,442 controls) in the Alpha- and Delta-dominant periods, respectively. During the Alpha period, VE against hospitalisation with SARS-CoV2 for complete Comirnaty PSV was 85% (95% CI: 69-92) overall and 75% (95% CI: 42-90) in those aged ≥ 80 years. During the Delta period, among SARI patients ≥ 20 years with symptom onset ≥ 150 days from last PSV dose, VE for complete Comirnaty PSV was 54% (95% CI: 18-74). Among those receiving Comirnaty PSV and mRNA booster (any product) ≥ 150 days after last PSV dose, VE was 91% (95% CI: 57-98). In time-since-vaccination analysis, complete all-product PSV VE was > 90% in those with their last dose < 90 days before onset; ≥ 70% in those 90-179 days before onset.ConclusionsOur results from this EU multi-country hospital setting showed that VE for complete PSV alone was higher in the Alpha- than the Delta-dominant period, and addition of a first booster dose during the latter period increased VE to over 90%.

Background: In late 2020, the European Centre for Disease Prevention and Control and Epiconcept started implementing a surveillance system for severe acute respiratory infections (SARI) across Europe., Objective: We sought to describe the process of digitizing and upgrading SARI surveillance in Malta, an island country with a centralized health system, during the COVID-19 pandemic from February to November 2021. We described the characteristics of people included in the surveillance system and compared different SARI case definitions, including their advantages and disadvantages. This study also discusses the process, output, and future for SARI and other public health surveillance opportunities., Methods: Malta has one main public hospital where, on admission, patient data are entered into electronic records as free text. Symptoms and comorbidities are manually extracted from these records, whereas other data are collected from registers. Collected data are formatted to produce weekly and monthly reports to inform public health actions. From October 2020 to February 2021, we established an analogue incidence-based system for SARI surveillance. From February 2021 onward, we mapped key stakeholders and digitized most surveillance processes., Results: By November 30, 2021, 903 SARI cases were reported, with 380 (42.1%) positive for SARS-CoV-2. Of all SARI hospitalizations, 69 (7.6%) were admitted to the intensive care unit, 769 (85.2%) were discharged, 27 (3%) are still being treated, and 107 (11.8%) died. Among the 107 patients who died, 96 (89.7%) had more than one underlying condition, the most common of which were hypertension (n=57, 53.3%) and chronic heart disease (n=49, 45.8%)., Conclusions: The implementation of enhanced SARI surveillance in Malta was completed by the end of May 2021, allowing the monitoring of SARI incidence and patient characteristics. A future shift to register-based surveillance should improve SARI detection through automated processes., (©John Paul Cauchi, Maria-Louise Borg, Aušra Džiugytė, Jessica Attard, Tanya Melillo, Graziella Zahra, Christopher Barbara, Michael Spiteri, Allan Drago, Luke Zammit, Joseph Debono, Jorgen Souness, Steve Agius, Sharon Young, Alan Dimech, Ian Chetcuti, Mark Camenzuli, Ivan Borg, Neville Calleja, Lorraine Tabone, Charmaine Gauci, Pauline Vassallo, Joaquin Baruch. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 05.12.2022.)

Obesity leads to the development of nonalcoholic fatty liver disease (NAFLD) and associated alterations to the plasma proteome. To elucidate the underlying changes associated with obesity, we performed liquid chromatography-tandem mass spectrometry in the liver and plasma of obese leptin-deficient ob/ob mice and integrated these data with publicly available transcriptomic and proteomic datasets of obesity and metabolic diseases in preclinical and clinical cohorts. We quantified 7173 and 555 proteins in the liver and plasma proteomes, respectively. The abundance of proteins related to fatty acid metabolism were increased, alongside peroxisomal proliferation in ob/ob liver. Putatively secreted proteins and the secretory machinery were also dysregulated in the liver, which was mirrored by a substantial alteration of the plasma proteome. Greater than 50% of the plasma proteins were differentially regulated, including NAFLD biomarkers, lipoproteins, the 20S proteasome, and the complement and coagulation cascades of the immune system. Integration of the liver and plasma proteomes identified proteins that were concomitantly regulated in the liver and plasma in obesity, suggesting that the systemic abundance of these plasma proteins is regulated by secretion from the liver. Many of these proteins are systemically regulated during type 2 diabetes and/or NAFLD in humans, indicating the clinical importance of liver-plasma cross talk and the relevance of our investigations in ob/ob mice. Together, these analyses yield a comprehensive insight into obesity and provide an extensive resource for obesity research in a prevailing model organism., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: To investigate the effect of oral consumption of engineered mesoporous silica particles, SiPore15 ® , on long-term blood glucose levels and other metabolic parameters in individuals with prediabetes and newly diagnosed Type 2 diabetes. Method: An open-label, single-arm, multicenter trial was conducted in which SiPore15 was consumed three times daily for 12 weeks. Hemoglobin A1c (HbA1c, primary end point) and an array of metabolic parameters were measured at baseline and throughout the trial. Result: SiPore15 treatment significantly reduced HbA1c by a clinically meaningful degree and improved several disease-associated parameters with minimal side effects. Conclusion: The results from this study demonstrate the potential use of SiPore15 as a treatment for prediabetes that may also delay or prevent the onset of Type 2 diabetes.

Skeletal muscle is an endocrine organ secreting exercise-induced factors (exerkines), which play a pivotal role in interorgan cross talk. Using mass spectrometry (MS)-based proteomics, we characterized the secretome and identified thymosin β4 (TMSB4X) as the most upregulated secreted protein in the media of contracting C2C12 myotubes. TMSB4X was also acutely increased in the plasma of exercising humans irrespective of the insulin resistance condition or exercise mode. Treatment of mice with TMSB4X did not ameliorate the metabolic disruptions associated with diet induced-obesity, nor did it enhance muscle regeneration in vivo. However, TMSB4X increased osteoblast proliferation and neurite outgrowth, consistent with its WADA classification as a prohibited growth factor. Therefore, we report TMSB4X as a human exerkine with a potential role in cellular cross talk.

Background: Type 2 diabetes and obesity are often seen concurrently with skeletal muscle wasting, leading to further derangements in function and metabolism. Muscle wasting remains an unmet need for metabolic disease, and new approaches are warranted. The neuropeptide urocortin 2 (UCN2) and its receptor corticotropin releasing factor receptor 2 (CRHR2) are highly expressed in skeletal muscle and play a role in regulating energy balance, glucose metabolism, and muscle mass. The aim of this study was to investigate the effects of modified UCN2 peptides as a pharmaceutical therapy to counteract the loss of skeletal muscle mass associated with obesity and casting immobilization., Methods: High-fat-fed mice (C57Bl/6J; 26 weeks old) and ob/ob mice (11 weeks old) were injected daily with a PEGylated (Compound A) and non-PEGylated (Compound B) modified human UCN2 at 0.3 mg/kg subcutaneously for 14 days. A separate group of chow-fed C57Bl/6J mice (12 weeks old) was subjected to hindlimb cast immobilization and, after 1 week, received daily injections with Compound A. In vivo functional tests were performed to measure protein synthesis rates and skeletal muscle function. Ex vivo functional and molecular tests were performed to measure contractile force and signal transduction of catabolic and anabolic pathways in skeletal muscle., Results: Skeletal muscles (extensor digitorum longus, soleus, and tibialis anterior) from high-fat-fed mice treated with Compound A were ~14% heavier than muscles from vehicle-treated mice. Chronic treatment with modified UCN2 peptides altered the expression of structural genes and transcription factors in skeletal muscle in high-fat diet-induced obesity including down-regulation of Trim63 and up-regulation of Nr4a2 and Igf1 (P < 0.05 vs. vehicle). Signal transduction via both catabolic and anabolic pathways was increased in tibialis anterior muscle, with increased phosphorylation of ribosomal protein S6 at Ser 235/236 , FOXO1 at Ser 256 , and ULK1 at Ser 317 , suggesting that UCN2 treatment modulates protein synthesis and degradation pathways (P < 0.05 vs. vehicle). Acutely, a single injection of Compound A in drug-naïve mice had no effect on the rate of protein synthesis in skeletal muscle, as measured via the surface sensing of translation method, while the expression of Nr4a3 and Ppargc1a4 was increased (P < 0.05 vs. vehicle). Compound A treatment prevented the loss of force production from disuse due to casting. Compound B treatment increased time to fatigue during ex vivo contractions of fast-twitch extensor digitorum longus muscle. Compound A and B treatment increased lean mass and rates of skeletal muscle protein synthesis in ob/ob mice., Conclusions: Modified human UCN2 is a pharmacological candidate for the prevention of the loss of skeletal muscle mass associated with obesity and immobilization., (© 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

The importation of novel tick species to Europe and the emergence of tick-borne diseases have been of rising concern over the last decades. In May 2019, a total of 349 asylum seekers arrived in Malta by boat. Public health syndromic surveillance was conducted on all migrant boat arrivals. The incidental finding of a tick with anomalous morphology in a newly arrived migrant in Malta prompted an epidemiological investigation. Morphological identification of the tick followed by species identification using keys specific to North Africa was conducted and molecular testing for Crimean Congo haemorrhagic fever virus (CCHFV) was performed. Detailed interview and clinical examination of the case were conducted on arrival and follow-up interviews were undertaken 1- and 4-weeks post-arrival. A Hyalomma rufipes tick was identified on the chest of a 28-year-old male from Sudan. The patient reported malaise and headache on arrival. No further symptoms were reported during follow-up. There was no evidence of previous CCHFV infection or the presence of other ticks or pathogens on the patient. The investigation revealed that the H. rufipes tick had likely been acquired in Libya. This is the first report of the presence of a H. rufipes tick, the main vector for CCHFV, on a recently arrived migrant in Europe. This event highlights the importance of increasing awareness on the risk of tick-borne infections among recently arrived migrants in the Mediterranean countries and the need to consider tick screening as part of the health screening offered in the EU., (Copyright © 2020. Published by Elsevier GmbH.)

Global dissemination of ciprofloxacin-resistant Salmonella Kentucky has been observed over the past decades. In recent years, there have been reports of extended-spectrum β-lactamase (ESBL) producing S . Kentucky. Routine surveillance at the European Centre for Disease Prevention and Control (ECDC) detected cases with a ciprofloxacin-resistant S . Kentucky with the ESBL-gene bla CTX-M-14b . Ensuing research identified 78 cases in 2013-2018 in eight European countries. Compared to other S . Kentucky and non-typhoidal Salmonella infections, reported to the European Surveillance System, these cases were more likely to be elderly and to present urinary-tract infections. Bayesian time-scaled phylogeny on whole genome sequences of isolates from these cases and supplementary isolates from public sequence databases was used to infer the origin and spread of this clone. We dated the origin of the bla CTX-M-14b clone to approximately 2005 in Northern Africa, most likely in Egypt. The geographic origin predicted by the phylogenetic analysis is consistent with the patients' travel history. Next to multiple introductions of the clone to Europe from Egypt, our analysis suggests that in some parts of Europe the clone might have formed a stable population, from which further spread has occurred. Comparative genomics indicated that the bla CTX-M-14b gene is present on the bacterial chromosome, within the type VI secretion system region. The bla CTX-M-14b gene is integrated downstream of the hcp1 gene, on a 2854 bp plasmid fragment containing also IS Ecp1 . This is the first report of a chromosomally integrated CTX-M gene in Salmonella spp. in Europe, previous studies having identified similar genes only on plasmids.

The neuropeptide urocortin 2 (UCN2) and its receptor corticotropin-releasing hormone receptor 2 (CRHR2) are highly expressed in skeletal muscle and play a role in regulating energy balance and glucose metabolism. We investigated a modified UCN2 peptide as a potential therapeutic agent for the treatment of obesity and insulin resistance, with a specific focus on skeletal muscle. High-fat-fed mice (C57BL/6J) were injected daily with a PEGylated UCN2 peptide (compound A) at 0.3 mg/kg subcutaneously for 14 days. Compound A reduced body weight, food intake, whole-body fat mass, and intramuscular triglycerides compared with vehicle-treated controls. Furthermore, whole-body glucose tolerance was improved by compound A treatment, with increased insulin-stimulated Akt phosphorylation at Ser 473 and Thr 308 in skeletal muscle, concomitant with increased glucose transport into extensor digitorum longus and gastrocnemius muscle. Mechanistically, this is linked to a direct effect on skeletal muscle because ex vivo exposure of soleus muscle from chow-fed lean mice to compound A increased glucose transport and insulin signaling. Moreover, exposure of GLUT4-Myc-labeled L6 myoblasts to compound A increased GLUT4 trafficking. Our results demonstrate that modified UCN2 peptides may be efficacious in the treatment of type 2 diabetes by acting as an insulin sensitizer in skeletal muscle., (© 2019 by the American Diabetes Association.)

IntroductionSequence-based typing of hepatitis A virus (HAV) is important for outbreak detection, investigation and surveillance. In 2013, sequencing was central to resolving a large European Union (EU)-wide outbreak related to frozen berries. However, as the sequenced HAV genome regions were only partly comparable between countries, results were not always conclusive.AimThe objective was to gather information on HAV surveillance and sequencing in EU/European Economic Area (EEA) countries to find ways to harmonise their procedures, for improvement of cross-border outbreak responses.MethodsIn 2014, the European Centre for Disease Prevention and Control (ECDC) conducted a survey on HAV surveillance practices in EU/EEA countries. The survey enquired whether a referral system for confirming primary diagnostics of hepatitis A existed as well as a central collection/storage of hepatitis A cases' samples for typing. Questions on HAV sequencing procedures were also asked. Based on the results, an expert consultation proposed harmonised procedures for cross-border outbreak response, in particular regarding sequencing. In 2016, a follow-up survey assessed uptake of suggested methods.ResultsOf 31 EU/EEA countries, 23 (2014) and 27 (2016) participated. Numbers of countries with central collection and storage of HAV positive samples and of those performing sequencing increased from 12 to 15 and 12 to 14 respectively in 2016, with all countries typing an overlapping fragment of 218 nt. However, variation existed in the sequenced genomic regions and their lengths.ConclusionsWhile HAV sequences in EU/EEA countries are comparable for surveillance, collaboration in sharing and comparing these can be further strengthened.

Between 1 June 2016 and 31 May 2017, 17 European Union (EU) and European Economic Area countries reported 4,096 cases associated with a multi-country hepatitis A (HA) outbreak. Molecular analysis identified three co-circulating hepatitis A virus (HAV) strains of genotype IA: VRD&#95;521&#95;2016, V16-25801 and RIVM-HAV16-090. We categorised cases as confirmed, probable or possible, according to the EU outbreak case definitions. Confirmed cases were infected with one of the three outbreak strains. We investigated case characteristics and strain-specific risk factors for transmission. A total of 1,400 (34%) cases were confirmed; VRD&#95;521&#95;2016 and RIVM-HAV16-090 accounted for 92% of these. Among confirmed cases with available epidemiological data, 92% (361/393) were unvaccinated, 43% (83/195) travelled to Spain during the incubation period and 84% (565/676) identified as men who have sex with men (MSM). Results depict an HA outbreak of multiple HAV strains, within a cross-European population, that was particularly driven by transmission between non-immune MSM engaging in high-risk sexual behaviour. The most effective preventive measure to curb this outbreak is HAV vaccination of MSM, supplemented by primary prevention campaigns that target the MSM population and promote protective sexual behaviour.

Salmonella Give is a rare serotype across Europe. In October 2016, a national outbreak of S. Give occurred in Malta. We describe the epidemiological, environmental, microbiological and veterinary investigations. Whole-genome sequencing (WGS) was performed on human, food, environmental and veterinary isolates. Thirty-six human cases were reported between October and November 2016, 10 (28%) of whom required hospitalisation. Twenty-six (72%) cases were linked to four restaurants. S. Give was isolated from ready-to-eat antipasti served by three restaurants which were all supplied by the same local food manufacturer. Food-trace-back investigations identified S. Give in packaged bean dips, ham, pork and an asymptomatic food handler at the manufacturer; inspections found inadequate separation between raw and ready-to-eat food during processing. WGS indicated two genetically distinguishable strains of S. Give with two distinct clusters identified; one cluster linked to the local food manufacturer and a second linked to veterinary samples. Epidemiological, environmental and WGS evidence pointed towards cross-contamination of raw and ready-to-eat foods at the local manufacturer as the likely source of one cluster. Severity of illness indicates a high virulence of this specific serotype. To prevent future cases and outbreaks, adherence to food safety practices at manufacturing level need to be reinforced.

BackgroundTravel to countries with high or intermediate hepatitis A virus (HAV) endemicity is a risk factor for infection in residents of countries with low HAV endemicity. Aim: The objective of this study was to estimate the risk for hepatitis A among European travellers using surveillance and travel denominator data. Methods: We retrieved hepatitis A surveillance data from 13 European Union (EU)/ European Economic Area (EEA) countries with comprehensive surveillance systems and travel denominator data from the Statistical Office of the European Union. A travel-associated case of hepatitis A was defined as any case reported as imported. Results: From 2009 to 2015, the 13 countries reported 18,839 confirmed cases of hepatitis A, of which 5,233 (27.8%) were travel-associated. Of these, 39.8% were among children younger than 15 years. The overall risk associated with travel abroad decreased over the period at an annual rate of 3.7% (95% confidence interval (CI): 0.7-2.7) from 0.70 cases per million nights in 2009 to 0.51 in 2015. The highest risk was observed in travellers to Africa (2.11 cases per million nights). Cases more likely to be reported as travel-associated were male and of younger age (< 25 years). Conclusion: Travel is still a major risk factor for HAV infection in the EU/EEA, although the risk of infection may have slightly decreased in recent years. Children younger than 15 years accounted for a large proportion of cases and should be prioritised for vaccination.

Diacylglycerol kinases (DGKs) regulate the balance between diacylglycerol (DAG) and phosphatidic acid. DGKζ is highly abundant in skeletal muscle and induces fiber hypertrophy. We hypothesized that DGKζ influences functional and metabolic adaptations in skeletal muscle and whole-body fuel utilization. DAG content was increased in skeletal muscle and adipose tissue, but unaltered in liver of DGKζ KO mice. Linear growth, body weight, fat mass, and lean mass were reduced in DGKζ KO versus wild-type mice. Conversely, male DGKζ KO and wild-type mice displayed a similar robust increase in plantaris weight after functional overload, suggesting that DGKζ is dispensable for muscle hypertrophy. Although glucose tolerance was similar, insulin levels were reduced in high-fat diet (HFD)-fed DGKζ KO versus wild-type mice. Submaximal insulin-stimulated glucose transport and p-Akt Ser 473 were increased, suggesting enhanced skeletal muscle insulin sensitivity. Energy homeostasis was altered in DGKζ KO mice, as evidenced by an elevated respiratory exchange ratio, independent of altered physical activity or food intake. In conclusion, DGKζ deficiency increases tissue DAG content and leads to modest growth retardation, reduced adiposity, and protection against insulin resistance. DGKζ plays a role in the control of growth and metabolic processes, further highlighting specialized functions of DGK isoforms in type 2 diabetes pathophysiology., (Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.)

Background/aims: Ciliary neurotrophic factor (CNTF) exerts powerful anorectic effects and has been suggested to regulate long-term energy balance by inducing adult neurogenesis in the arcuate nucleus of the hypothalamus., Methods: The CNTF analogue, Axokine, was infused into the lateral ventricle of high-fat-fed mice for 1 week. Food intake, energy expenditure, body mass, glucose metabolism, and neurogenesis in the arcuate nucleus (ARC) of the hypothalamus were assessed 3 weeks after cessation of Axokine treatment., Results: Short-term administration of Axokine induced an anorexic response but did not promote sustained weight loss. Instead, a rapid rebound in food intake and body mass occurred immediately after cessation of Axokine treatment, and this tended to reduce insulin sensitivity. Immunolabeling of 5-bromo-2'-deoxyuridine revealed limited neurogenesis in the ARC 3 weeks after Axokine treatment., Conclusion: These findings suggest that Axokine/CNTF does not induce substantial or sustained ARC neurogenesis or contribute to the long-term regulation of energy balance in mice., (© 2015 S. Karger AG, Basel.)

Neurons within the hypothalamic arcuate nucleus (ARC) are important regulators of energy balance. Recent studies suggest that neurogenesis in the ARC is an important regulator of body mass in response to pharmacological stressors. Regular exercise training improves insulin action, and is a primary treatment modality for obesity and type 2 diabetes. We examined whether exercise training causes hypothalamic neurogenesis and whether this contributes to exercise-induced improvements in insulin action. Short-term exercise in adult mice induced a proneurogenic transcriptional program involving growth factors, cell proliferation, and neurogenic regulators in the hypothalamus. Daily exercise training for 7 days increased hypothalamic cell proliferation 3.5-fold above that of sedentary mice, and exercise-induced cell proliferation was maintained in diet-induced obese mice. Colocalization studies indicated negligible neurogenesis in the ARC of sedentary or exercise-trained mice. Blocking cell proliferation via administration of the mitotic blocker arabinosylcytosine (AraC) did not affect food intake or body mass in obese mice. While 4 weeks of exercise training improved whole-body insulin sensitivity compared with sedentary mice, insulin action was not affected by AraC administration. These data suggest that regular exercise training induces significant non-neuronal cell proliferation in the hypothalamus of obese mice, but this proliferation is not required for enhanced insulin action., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Impaired coupling of adipose tissue expansion and vascularization is proposed to lead to adipocyte hypoxia and inflammation, which in turn contributes to systemic metabolic derangements. Pigment epithelium-derived factor (PEDF) is a powerful antiangiogenic factor that is secreted by adipocytes, elevated in obesity, and implicated in the development of insulin resistance. We explored the angiogenic and metabolic role of adipose-derived PEDF through in vivo studies of mice with overexpression of PEDF in adipocytes (PEDF-aP2). PEDF expression in white adipocytes and PEDF secretion from adipose tissue was increased in transgenic mice, but circulating levels of PEDF were not increased. Overexpression of PEDF did not alter vascularization, the partial pressure of O2, cellular hypoxia, or gene expression of inflammatory markers in adipose tissue. Energy expenditure and metabolic substrate utilization, body mass, and adiposity were not altered in PEDF-aP2 mice. Whole body glycemic control was normal as assessed by glucose and insulin tolerance tests, and adipocyte-specific glucose uptake was unaffected by PEDF overexpression. Adipocyte lipolysis was increased in PEDF-aP2 mice and associated with increased adipose triglyceride lipase and decreased perilipin 1 expression. Experiments conducted in mice rendered obese by high-fat feeding showed no differences between PEDF-aP2 and wild-type mice for body mass, adiposity, whole body energy expenditure, glucose tolerance, or adipose tissue oxygenation. Together, these data indicate that adipocyte-generated PEDF enhances lipolysis but question the role of PEDF as a major antiangiogenic or proinflammatory mediator in adipose tissue in vivo., (Copyright © 2014 the American Physiological Society.)

The detection of hormone and nutrient signals by the hypothalamus is blunted in obesity and contributes to dysregulated energy homeostasis. We investigated whether aerobic exercise training would improve long-term hypothalamic sensitivity to both leptin and ghrelin, independent of acute exercise-induced signalling. Male C57Bl/6J mice were fed either a chow or high-fat diet for 6 weeks, then remained sedentary on their respective diet, or completed 6 weeks of treadmill exercise training with a progressive increase in exercise volume and intensity. Food intake and hypothalamic signalling were assessed in mice injected with leptin or ghrelin at least 24 h after the last exercise bout. Exercise training reduced body mass, increased daily food intake and improved glucose tolerance. Intraperitoneal leptin administration reduced food intake in lean and obese mice, and this was not enhanced after exercise training. Leptin-mediated activation of phosphorylated signal transducer and activator of transcription 3 in the arcuate nucleus and ventromedial nucleus of the hypothalamus was not enhanced with exercise training. Ghrelin increased food intake and c-Fos positive neurones in the hypothalamus in lean and obese mice, and these physiological and molecular responses were not enhanced with exercise training. This suggests that the previously reported exercise effects on sensitising hypothalamic signalling and food intake responses may be limited to the period immediately after an exercise bout, and are not a result of stable structural or molecular changes that occur with exercise training., (© 2014 British Society for Neuroendocrinology.)

Purpose: Exercise at 50-60 % of peak oxygen consumption (VO2 peak) stimulates maximal fat oxidation rates. Despite a lower estimated work performed; high-intensity intermittent exercise (HIIE) training produces greater fat mass reductions when compared with workload-matched continuous (CON) steady state exercise. No metabolic basis has been documented nor mechanisms offered to explain this anomaly. This study investigated the physiological and metabolic responses of two different workload-matched exercise protocols., Methods: On separate occasions and at least 1 week apart, eight apparently healthy males cycled for 30 min at either 50 % VO2 peak (CON) or performed repeated 20 s bouts of supramaximal exercise at 150 %VO2 peak separated by 40 s rest (HIIE)., Results: The average heart rate, oxygen consumption, plasma glycerol and free fatty acid concentrations were not different during exercise and recovery between the trials. Plasma lactate and hypoxanthine (Hx) concentrations were elevated and urinary excretion rates of Hx and uric acid were greater following HIIE as compared to CON (P < 0.05)., Conclusion: Exercise-induced plasma Hx accumulation and urinary purine excretion are greater following HIIE and indirectly represents a net loss of adenosine triphosphate (ATP) from the muscle. The subsequent restorative processes required for intramuscular de novo replacement of ATP may contribute to a negative energy balance and in part, account for the potential accelerated fat loss observed with HIIE when compared with CON training programs.

Obesity is characterised by increased storage of fatty acids in an expanded adipose tissue mass and in peripheral tissues such as the skeletal muscle and liver, where it is associated with the development of insulin resistance. Insulin resistance also develops in the central nervous system with high-fat feeding. The capacity for hypothalamic cells to accumulate/store lipids, and the effects of obesity remain undefined. The aims of this study were (1) to examine hypothalamic lipid content in mice with increased dietary fat intake and in obese ob/ob mice fed a low-fat diet, and (2) to determine whether endurance exercise training could reduce hypothalamic lipid accumulation in high-fat fed mice. Male C57BL/6 mice were fed a low- (LFD) or high-fat diet (HFD) for 12 weeks; ob/ob mice were maintained on a chow diet. HFD-exercise (HFD-ex) mice underwent 12 weeks of high-fat feeding with 6 weeks of treadmill exercise training (increasing from 30 to 70 min day(-1)). Hypothalamic lipids were assessed by unbiased mass spectrometry. The HFD increased body mass and hepatic lipid accumulation, and induced glucose intolerance, while the HFD-ex mice had reduced body weight and improved glucose tolerance. A total of 335 lipid molecular species were identified and quantified. Lipids known to induce insulin resistance, including ceramide (22%↑), diacylglycerol (25%↑), lysophosphatidylcholine (17%↑), cholesterol esters (60%↑) and dihexosylceramide (33%↑), were increased in the hypothalamus of HFD vs. LFD mice. Hypothalamic lipids were unaltered with exercise training and in the ob/ob mice, suggesting that obesity per se does not alter hypothalamic lipids. Overall, hypothalamic lipid accumulation is regulated by dietary lipid content and is refractory to change with endurance exercise training.

Diagnoses of Shigella flexneri in the United Kingdom (UK) are usually travel-related. However, since 2009, there has been an overall increase in UK-acquired cases. The Health Protection Agency has been investigating a national outbreak of S. flexneri detected in 2011 and which is still ongoing. Cases occurred mostly in men who have sex with men and were of serotype 3a. The investigation aimed at obtaining epidemiological data to inform targeted outbreak management and control.

Objective: Pigment epithelium-derived factor (PEDF) is an adipocyte-secreted factor involved in the development of insulin resistance in obesity. Previous studies have identified PEDF as a regulator of triacylglycerol metabolism in the liver that may act through adipose triglyceride lipase (ATGL). We used ATGL(-/-) mice to determine the role of PEDF in regulating lipid and glucose metabolism., Research Design and Methods: Recombinant PEDF was administered to ATGL(-/-) and wild-type mice, and whole-body energy metabolism was studied by indirect calorimetry. Adipose tissue lipolysis and skeletal muscle fatty acid metabolism was determined in isolated tissue preparations. Muscle lipids were assessed by electrospray ionization-tandem mass spectrometry. Whole-body insulin sensitivity and skeletal muscle glucose uptake were assessed., Results: PEDF impaired the capacity to adjust substrate selection, resulting in a delayed diurnal decline in the respiratory exchange ratio, and suppressed daily fatty acid oxidation. PEDF enhanced adipocyte lipolysis and triacylglycerol lipase activity in skeletal muscle. Muscle fatty acid uptake and storage were unaffected, whereas fatty acid oxidation was impaired. These changes in lipid metabolism were abrogated in ATGL(-/-) mice and were not attributable to hypothalamic actions. ATGL(-/-) mice were also refractory to PEDF-mediated insulin resistance, but this was not related to changes in lipid species in skeletal muscle., Conclusions: The results are the first direct demonstration that 1) PEDF influences systemic fatty acid metabolism by promoting lipolysis in an ATGL-dependent manner and reducing fatty acid oxidation and 2) ATGL is required for the negative effects of PEDF on insulin action.

The aim of this study was to compare the bioavailability and plasma profiles of estradiol and estrone after repeated applications of 2 types of estradiol transdermal systems: a new adhesive matrix system (Menorest®) compared with a reference membrane/reservoir system (Estraderm®) and to evaluate their short term safety. This was an open, randomised, crossover study, with 2 treatment periods of 10.5 days separated by a 10-day washout period and with a 1-week follow-up. Participants were studied at Institut Aster, Paris, and Association de Recherche Thérapeutique (ART), Lyon, France, and included 31 healthy postmenopausal women, all volunteers aged between 49 and 67 years (mean 58 years). Each transdermal system was applied for three successive 3.5 day-wear periods (10.5 days) on the lower abdominal skin. Plasma estradiol and estrone concentrations were measured at steady-state, before and after the third application of each transdermal system at regular intervals over 106 hours. Cutaneous tolerance was assessed after each transdermal system removal. Although the extent of availability [area under the plasma concentration-time curve (AUC) and average plasma concentration (Cav)] was similar with both transdermal systems, their pharmacokinetic profiles were different, with Menorest® producing less fluctuating and more sustained plasma estradiol levels than the reference system. The mean estradiol to estrone Cav ratio was similar with the 2 transdermal systems and in the physiological range of premenopausal status. The incidence of adverse events was similar for both treatments, but a lower incidence of local erythema was observed with Menorest® (8.9%) than with the reference system (18.3%). In conclusion, during the entire wear period, Menorest® produced more sustained plasma estradiol levels with less fluctuations (40 to 72 ng/L) than the reservoir/ membrane system (18 to 102 ng/L). Menorest® gave estradiol plasma levels approximating the concentrations observed during the early to mid-follicular premenopausal stage, with a 2-fold lower incidence of erythema than with the reservoir/membrane system.