Fatty Hepatocytes Induce Skeletal Muscle Atrophy In Vitro: A New 3D Platform to Study the Protective Effect of Albumin in Non-Alcoholic Fatty Liver

The liver neutralizes endogenous and exogenous toxins and metabolites, being metabolically interconnected with many organs. Numerous clinical and experimental studies show a strong association between Non-alcoholic fatty liver disease (NAFLD) and loss of skeletal muscle mass known as sarcopenia. Liver transplantation solves the hepatic-related insufficiencies, but it is unable to revert sarcopenia. Knowing the mechanism(s) by which different organs communicate with each other is crucial to improve the drug development that still relies on the two-dimensional models. However, those models fail to mimic the pathological features of the disease. Here, both liver and skeletal muscle cells were encapsulated in gelatin methacryloyl and carboxymethylcellulose to recreate the disease’s phenotype in vitro. The 3D hepatocytes were challenged with non-esterified fatty acids (NEFAs) inducing features of Non-alcoholic fatty liver (NAFL) such as lipid accumulation, metabolic activity impairment and apoptosis. The 3D skeletal muscle tissues incubated with supernatant from fatty hepatocytes displayed loss of maturation and atrophy. This study demonstrates the connection between the liver and the skeletal muscle in NAFL, narrowing down the players for potential treatments. The tool herein presented was employed as a customizable 3D in vitro platform to assess the protective effect of albumin on both hepatocytes and myotubes

Circulating circRNA as biomarkers for dilated cardiomyopathy etiology

Dilated cardiomyopathy (DCM) is the third most common cause of heart failure. The multidisciplinary nature of testing - involving genetics, imaging, or cardiovascular techniques - makes its diagnosis challenging. Novel and reliable biomarkers are needed for early identification and tailored personalized management. Peripheral circular RNAs (circRNAs), a leading research topic, remain mostly unexplored in DCM. We aimed to assess whether peripheral circRNAs are expressed differentially among etiology-based DCM. The study was based on a case-control multicentric study. We enrolled 130 subjects: healthy controls (n = 20), idiopathic DCM (n = 30), ischemic DCM (n = 20), and familial DCM patients which included pathogen variants of (i) LMNA gene (n = 30) and (ii) BCL2-associated athanogene 3 (BAG3) gene (n = 30). Differentially expressed circRNAs were analyzed in plasma samples by quantitative RT-PCR and correlated to relevant systolic and diastolic parameters. The pathophysiological implications were explored through bioinformatics tools. Four circRNAs were overexpressed compared to controls: hsa_circ_0003258, hsa_circ_0051238, and hsa_circ_0051239 in LMNA-related DCM and hsa_circ_0089762 in the ischemic DCM cohort. The obtained areas under the curve confirm the discriminative capacity of circRNAs. The circRNAs correlated with some diastolic and systolic echocardiographic parameters with notable diagnostic potential in DCM. Circulating circRNAs may be helpful for the etiology-based diagnosis of DCM as a non-invasive biomarker. Key messages The limitations of cardiac diagnostic imaging and the absence of a robust biomarker reveal the need for a diagnostic tool for dilated cardiomyopathy (DCM). The circular RNA (circRNA) expression pattern is paramount for categorizing the DCM etiologies. Our peripheral circRNAs fingerprint discriminates between various among etiology-based DCM and correlates with some echocardiographic parameters. We provide a potential non-invasive biomarker for the etiology-based diagnosis of LMNA-related DCM and ischemic DCM.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by grants in the framework of the European Regional Development Fund (ERDF) Integrated Territorial Initiative (ITI PI0048-2017 and ITI0033_2019), a clinical research grant from the Spanish Society of Cardiology for Basic Research in cardiology (PI0012_2019), COST (European Cooperation in Science and Technology) Action EUCardioRNA CA17129, and the Portuguese Foundation for Science and Technology (FCT) under the framework of the research grant PTDC-MED-GEN-29389-2017

Overcoming Ostrea edulis seed production limitations to meet ecosystem restoration demands in the UN decade on restoration

The European flat oyster, Ostrea edulis, is a habitat-forming bivalve which was historically widespread throughout Europe. Following its decline due to overfishing, pollution, sedimentation, invasive species, and disease, O. edulis and its beds are now listed as a threatened and/or declining species and habitat by OSPAR. Increasing recognition of the plight of the oyster, alongside rapidly developing restoration techniques and growing interest in marine restoration, has resulted in a recent and rapid growth in habitat restoration efforts. O. edulis seed supply is currently a major bottleneck in scaling up habitat restoration efforts in Europe. O. edulis has been cultured for centuries, however, research into its culture declined following the introduction of the Pacific oyster, Crassostrea gigas to Europe in the early 1970 s. Recent efforts to renew both hatchery and pond production of O. edulis seed for habitat restoration purposes are hampered by restoration project timelines and funding typically being short, or projects not planning appropriately for the timescales required for investment, research-and-development and delivery of oyster seed by commercial producers. Furthermore, funding for restoration is intermittent, making long-term commitments between producers and restoration practitioners difficult. Long-term, strategic investment in research and production are needed to overcome these bottlenecks and meet current ambitious restoration targets across Europe

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Base de datos de abejas ibéricas

Las abejas son un grupo extremadamente diverso con más de 1000 especies descritas en la península ibérica. Además, son excelentes polinizadores y aportan numerosos servicios ecosistémicos fundamentales para la mayoría de ecosistemas terrestres. Debido a los diversos cambios ambientales inducidos por el ser humano, existen evidencias del declive de algunas de sus poblaciones para ciertas especies. Sin embargo, conocemos muy poco del estado de conservación de la mayoría de especies y de muchas de ellas ignoramos cuál es su distribución en la península ibérica. En este trabajo presentamos un esfuerzo colaborativo para crear una base de datos de ocurrencias de abejas que abarca la península ibérica e islas Baleares que permitirá resolver cuestiones como la distribución de las diferentes especies, preferencia de hábitat, fenología o tendencias históricas. En su versión actual, esta base de datos contiene un total de 87 684 registros de 923 especies recolectados entre 1830 y 2022, de los cuales un 87% presentan información georreferenciada. Para cada registro se incluye información relativa a la localidad de muestreo (89%), identificador y colector de la especie (64%), fecha de captura (54%) y planta donde se recolectó (20%). Creemos que esta base de datos es el punto de partida para conocer y conservar mejor la biodiversidad de abejas en la península ibérica e Islas Baleares. Se puede acceder a estos datos a través del siguiente enlace permanente: https://doi.org/10.5281/zenodo.6354502ABSTRACT: Bees are a diverse group with more than 1000 species known from the Iberian Peninsula. They have increasingly received special attention due to their important role as pollinators and providers of ecosystem services. In addition, various rapid human-induced environmental changes are leading to the decline of some of its populations. However, we know very little about the conservation status of most species and for many species, we hardly know their true distributions across the Iberian Peninsula. Here, we present a collaborative effort to collate and curate a database of Iberian bee occurrences to answer questions about their distribution, habitat preference, phenology, or historical trends. In total we have accumulated 87 684 records from the Iberian Peninsula and the Balearic Islands of 923 different species with 87% of georeferenced records collected between 1830 and 2022. In addition, each record has associated information such as the sampling location (89%), collector and person who identified the species (64%), date of the capture (54%) and plant species where the bees were captured (20%). We believe that this database is the starting point to better understand and conserve bee biodiversity in the Iberian Peninsula. It can be accessed at: https://doi.org/10.5281/zenodo.6354502Esta base de datos se ha realizado con la ayuda de los proyectos EUCLIPO (Fundação para a Ciência e a Tecnologia, LISBOA-01-0145-FEDER-028360/EUCLIPO) y SAFEGUARD (ref. 101003476 H2020 -SFS-2019-2).info:eu-repo/semantics/publishedVersio

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030