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BackgroundBlended learning, which combines face-to-face learning and e-learning, has grown rapidly to be commonly used in education. Nevertheless, the effectiveness of this learning approach has not been completely quantitatively synthesized and evaluated using knowledge outcomes in health education. ObjectiveThe aim of this study was to assess the effectiveness of blended learning compared to that of traditional learning in health education. MethodsWe performed a systematic review of blended learning in health education in MEDLINE from January 1990 to July 2019. We independently selected studies, extracted data, assessed risk of bias, and compared overall blended learning versus traditional learning, offline blended learning versus traditional learning, online blended learning versus traditional learning, digital blended learning versus traditional learning, computer-aided instruction blended learning versus traditional learning, and virtual patient blended learning versus traditional learning. All pooled analyses were based on random-effect models, and the I2 statistic was used to quantify heterogeneity across studies. ResultsA total of 56 studies (N=9943 participants) assessing several types of learning support in blended learning met our inclusion criteria; 3 studies investigated offline support, 7 studies investigated digital support, 34 studies investigated online support, 8 studies investigated computer-assisted instruction support, and 5 studies used virtual patient support for blended learning. The pooled analysis comparing all blended learning to traditional learning showed significantly better knowledge outcomes for blended learning (standardized mean difference 1.07, 95% CI 0.85 to 1.28, I2=94.3%). Similar results were observed for online (standardized mean difference 0.73, 95% CI 0.60 to 0.86, I2=94.9%), computer-assisted instruction (standardized mean difference 1.13, 95% CI 0.47 to 1.79, I2=78.0%), and virtual patient (standardized mean difference 0.62, 95% CI 0.18 to 1.06, I2=78.4%) learning support, but results for offline learning support (standardized mean difference 0.08, 95% CI –0.63 to 0.79, I2=87.9%) and digital learning support (standardized mean difference 0.04, 95% CI –0.45 to 0.52, I2=93.4%) were not significant. ConclusionsFrom this review, blended learning demonstrated consistently better effects on knowledge outcomes when compared with traditional learning in health education. Further studies are needed to confirm these results and to explore the utility of different design variants of blended learning.

Abstract Background Cardiac arrest remains a global health issue with limited data on long-term outcomes, particularly regarding recurrent cardiovascular events in patients surviving out-of-hospital cardiac arrest. (OHCA). We aimed to describe the long-term occurrence of major cardiac event defined by hospital admission for cardiovascular events or death in OHCA hospital survivors, whichever came first. Our secondary objective were to assess separately occurrence of hospital admission and death, and to identify the factors associated with major event occurrence. We hypothesized that patients surviving an OHCA has a protracted increased risk of cardiovascular events, due to both presence of the baseline conditions that lead to OHCA, and to the cardiovascular consequences of OHCA induced acute ischemia-reperfusion. Methods Consecutive OHCA patients from three hospitals of Sudden Death Expertise Center (SDEC) Registry, discharged alive from 2011 to 2015 were included. Long-term follow-up data were obtained using national inter-regime health insurance information system (SNIIRAM) database and the national French death registry. The primary endpoint was occurrence of a major event defined by hospital admission for cardiovascular events and death, whichever came first during the follow-up. The starting point of the time-to-event analysis was the date of hospital discharge. The follow-up was censored on the date of the first event. For patients without event, follow-up was censored on the date of December, 29th, 2016. Results A total of 306 patients (mean age 57; 77% male) were analyzed and followed over a median follow-up of 3 years for hospital admission for cardiovascular event and 6 years for survival. During this period, 38% patients presented a major event. Hospital admission for cardiovascular events mostly occurred during the first year after the OHCA whereas death occurred more linearly during the all period. A previous history of chronic heart failure and coronary artery disease were independently associated with the occurrence of major event (HR 1.75, 95%CI[1.06-2.88] and HR 1.70, 95%CI[1.11-2.61], respectively), whereas post-resuscitation myocardial dysfunction, cardiogenic shock and cardiologic cause of cardiac arrest did not. Conclusion Survivors from OHCA must to be considered at high risk of cardiovascular event occurrence whatever the etiology, mainly during the first year following the cardiac arrest and should require closed monitoring.

Abstract Background Virtual patients (VPs) are widely used in health professions education. When they are well integrated into curricula, they are considered to be more effective than loosely coupled add-ons. However, it is unclear what constitutes their successful integration. The aim of this study was to identify and synthesise the themes found in the literature that stakeholders perceive as important for successful implementation of VPs in curricula. Methods We searched five databases from 2000 to September 25, 2023. We included qualitative, quantitative, mixed-methods and descriptive case studies that defined, identified, explored, or evaluated a set of factors that, in the perception of students, teachers, course directors and researchers, were crucial for VP implementation. We excluded effectiveness studies that did not consider implementation characteristics, and studies that focused on VP design factors. We included English-language full-text reports and excluded conference abstracts, short opinion papers and editorials. Synthesis of results was performed using the framework synthesis method with Kern’s six-step model as the initial framework. We appraised the quality of the studies using the QuADS tool. Results Our search yielded a total of 4808 items, from which 21 studies met the inclusion criteria. We identified 14 themes that formed an integration framework. The themes were: goal in the curriculum; phase of the curriculum when to implement VPs; effective use of resources; VP alignment with curricular learning objectives; prioritisation of use; relation to other learning modalities; learning activities around VPs; time allocation; group setting; presence mode; VPs orientation for students and faculty; technical infrastructure; quality assurance, maintenance, and sustainability; assessment of VP learning outcomes and learning analytics. We investigated the occurrence of themes across studies to demonstrate the relevance of the framework. The quality of the studies did not influence the coverage of the themes. Conclusions The resulting framework can be used to structure plans and discussions around implementation of VPs in curricula. It has already been used to organise the curriculum implementation guidelines of a European project. We expect it will direct further research to deepen our knowledge on individual integration themes.

# Background The February 2023 earthquakes in Turkey and Syria exposed significant gaps in healthcare information systems, which severely hampered communication, coordination, and the overall public health response. These disruptions were primarily due to the lack of real-time, accessible data on healthcare facilities. # Methods In response, an interactive Geographic Information System (GIS) tool, coupled with an integrated WhatsApp chatbot, was developed under the platform Afetsaglikharitasi.org. This system enabled real-time mapping and updates on the status of healthcare services, even in areas with limited internet connectivity, facilitating more efficient resource coordination during the disaster response. # Results By March 30, 2023, the disaster health map included data from 537 health centers and had reached over 800,000 individuals via social media platforms such as Instagram, Facebook, and Twitter. The platform attracted over 3,500 unique users, with most accessing it via mobile devices to locate healthcare services. Additionally, shortcomings in the Turkey National Disaster Response Plan (Türkiye Afet Müdahale Planı -- TAMP) were identified, particularly the lack of integration of digital health technologies, which hindered resource allocation during the earthquake response and underscored the need for their inclusion in disaster management strategies. # Conclusions This study demonstrates the effectiveness of digital health tools in enhancing disaster response and underscores the importance of integrating user-centered, deployable technologies to improve healthcare delivery in emergency settings.

Abstract Global temperatures were exceptionally high in 2023/24. Every month from June 2023 to June 2024 set a new record, and September shattered the previous record by 0.5°C. The 2023 annual average approached 1.5°C above pre‐industrial levels. This results from both long‐term warming and internal variability, with the occurrence of an El Niño episode. However the amplitude of the 2023/24 anomalies was remarkable and surprised the scientific community. Here we analyze the rarity of 2023/24 global temperatures from a climate perspective. We show that a ‘normal’ year 2023 would have roughly equaled the previous annual record, and that the most extreme events of 2023/24 rank among the most extreme since 1940. Our analysis suggests that the 2023/24 event can be reconciled with the long‐term trend and an intense, but not implausible, peak of internal variability.

IMPORTANCE:. Ventilator-associated pneumonia (VAP) frequently occurs in patients with cardiac arrest. Diagnosis of VAP after cardiac arrest remains challenging, while the use of current biomarkers such as C-reactive protein (CRP) or procalcitonin (PCT) is debated. OBJECTIVES:. To evaluate biomarkers’ impact in helping VAP diagnosis after cardiac arrest. DESIGN, SETTING, AND PARTICIPANTS:. This is a prospective ancillary study of the randomized, multicenter, double-blind placebo-controlled ANtibiotherapy during Therapeutic HypothermiA to pRevenT Infectious Complications (ANTHARTIC) trial evaluating the impact of antibiotic prophylaxis to prevent VAP in out-of-hospital patients with cardiac arrest secondary to shockable rhythm and treated with therapeutic hypothermia. An adjudication committee blindly evaluated VAP according to predefined clinical, radiologic, and microbiological criteria. All patients with available biomarker(s), sample(s), and consent approval were included. MAIN OUTCOMES AND MEASURES:. The main endpoint was to evaluate the ability of biomarkers to correctly diagnose and predict VAP within 48 hours after sampling. The secondary endpoint was to study the combination of two biomarkers in discriminating VAP. Blood samples were collected at baseline on day 3. Routine and exploratory panel of inflammatory biomarkers measurements were blindly performed. Analyses were adjusted on the randomization group. RESULTS:. Among 161 patients of the ANTHARTIC trial with available biological sample(s), patients with VAP (n = 33) had higher body mass index and Acute Physiology and Chronic Health Evaluation II score, more unwitnessed cardiac arrest, more catecholamines, and experienced more prolonged therapeutic hypothermia duration than patients without VAP (n = 121). In univariate analyses, biomarkers significantly associated with VAP and showing an area under the curve (AUC) greater than 0.70 were CRP (AUC = 0.76), interleukin (IL) 17A and 17C (IL17C) (0.74), macrophage colony-stimulating factor 1 (0.73), PCT (0.72), and vascular endothelial growth factor A (VEGF-A) (0.71). Multivariate analysis combining novel biomarkers revealed several pairs with p value of less than 0.001 and odds ratio greater than 1: VEGF-A + IL12 subunit beta (IL12B), Fms-related tyrosine kinase 3 ligands (Flt3L) + C–C chemokine 20 (CCL20), Flt3L + IL17A, Flt3L + IL6, STAM-binding protein (STAMBP) + CCL20, STAMBP + IL6, CCL20 + 4EBP1, CCL20 + caspase-8 (CASP8), IL6 + 4EBP1, and IL6 + CASP8. Best AUCs were observed for CRP + IL6 (0.79), CRP + CCL20 (0.78), CRP + IL17A, and CRP + IL17C. CONCLUSIONS AND RELEVANCE:. Our exploratory study shows that specific biomarkers, especially CRP combined with IL6, could help to better diagnose or predict early VAP occurrence in cardiac arrest patients.

Abstract Objective To investigate autonomic nervous system activity measured by brain–heart interactions in comatose patients after cardiac arrest in relation to the severity and prognosis of hypoxic–ischemic brain injury. Methods Strength and complexity of bidirectional interactions between EEG frequency bands (delta, theta, and alpha) and ECG heart rate variability frequency bands (low frequency, LF and high frequency, HF) were computed using a synthetic data generation model. Primary outcome was the severity of brain injury, assessed by (i) standardized qualitative EEG classification, (ii) somatosensory evoked potentials (N20), and (iii) neuron‐specific enolase levels. Secondary outcome was the 3‐month neurological status, assessed by the Cerebral Performance Category score [good (1–2) vs. poor outcome (3–4–5)]. Results Between January 2007 and July 2021, 181 patients were admitted to ICU for a resuscitated cardiac arrest. Poor neurological outcome was observed in 134 patients (74%). Qualitative EEG patterns suggesting high severity were associated with decreased LF/HF. Severity of EEG changes were proportional to higher absolute values of brain‐to‐heart coupling strength (p

BackgroundOrgan shortage is a major public health issue, and patients who die after out-of-hospital cardiac arrest (OHCA) could be a valuable source of organs. Here, our objective was to identify factors associated with organ donation after brain death complicating OHCA, in unselected patients entered into a comprehensive real-life registry covering a well-defined geographic area.MethodsWe prospectively analyzed consecutive adults with OHCA who were successfully resuscitated, but died in intensive care units in the Paris region in 2011-2018. The primary outcome was organ donation after brain death. Independent risk factors were identified using logistic regression analysis. One-year graft survival was assessed using Cox and log-rank tests.ResultsOf the 3061 included patients, 136 (4.4%) became organ donors after brain death, i.e., 28% of the patients with brain death. An interaction between admission pH and post-resuscitation shock was identified. By multivariate analysis, in patients with post-resuscitation shock, factors associated with organ donation were neurological cause of OHCA (odds ratio [OR], 14.5 [7.6-27.4], P

Background Brain injury is one of the most serious complications after cardiac arrest (CA). To prevent this phenomenon, rapid cooling with total liquid ventilation (TLV) has been proposed in small animal models of CA (rabbits and piglets). Here, we aimed to determine whether hypothermic TLV can also offer neuroprotection and mitigate cerebral inflammatory response in large animals. Methods and Results Anesthetized pigs were subjected to 14 minutes of ventricular fibrillation followed by cardiopulmonary resuscitation. After return of spontaneous circulation, animals were randomly subjected to normothermia (control group, n=8) or ultrafast cooling with TLV (TLV group, n=8). In the latter group, TLV was initiated within a window of 15 minutes after return of spontaneous circulation and allowed to reduce tympanic, esophageal, and bladder temperature to the 32 to 34 °C range within 30 minutes. After 45 minutes of TLV, gas ventilation was resumed, and hypothermia was maintained externally until 3 hours after CA, before rewarming using heat pads (0.5 °C–1 °C/h). After an additional period of progressive rewarming for 3 hours, animals were euthanized for brain withdrawal and histological analysis. At the end of the follow‐up (ie, 6 hours after CA), histology showed reduced brain injury as witnessed by the reduced number of Fluroro‐Jade C‐positive cerebral degenerating neurons in TLV versus control. IL (interleukin)‐1ra and IL‐8 levels were also significantly reduced in the cerebrospinal fluid in TLV versus control along with cerebral infiltration by CD3+ cells. Conversely, circulating levels of cytokines were not different among groups, suggesting a discrepancy between local and systemic inflammatory levels. Conclusions Ultrafast cooling with TLV mitigates neuroinflammation and attenuates acute brain lesions in the early phase following resuscitation in large animals subjected to CA.

Abstract The EFSA Panel on Food Contact Materials (FCM) assessed the safety of the substances ‘wax, rice bran, oxidised’ and ‘wax, rice bran, oxidised, calcium salt’, used as additives up to 0.3% in polyethylene terephthalate (PET), polyamide (PA), thermoplastic polyurethane (TPU), polylactic acid (PLA) and poly(vinyl chloride) (PVC) in contact with all food types for long‐term storage at room temperature and below, after hot‐fill and/or heating. The substances consist of the chemical classes wax esters, carboxylic acids, alcohols and calcium salts of acids, along with an unidentified organic fraction up to ■■■■■ w/w. Migration into 10% ethanol and 4% acetic acid was below 0.012 mg/kg for each chemical class, and about 0.001 mg/kg for the unidentified fraction. In isooctane, migration was up to 0.297 mg/kg food for wax esters, below 0.01 mg/kg food for the other chemical classes and about 0.02 mg/kg food for the unidentified fraction. The contact with dry food and food simulated by 20% ethanol were considered covered by the migration tests with aqueous simulants. Based on genotoxicity assays and compositional analyses, the constituents of the chemical classes did not raise a concern for genotoxicity. The potential migration of individual constituents or groups of chemically‐related compounds of the unidentified fraction would result in exposures below (for aqueous food) and above (for fatty food) the threshold of toxicological concern for genotoxic carcinogens. Therefore, the FCM Panel concluded that the substances are not of safety concern for the consumer, if used as additives up to 0.3% w/w in PET, PLA and rigid PVC materials and articles intended for contact with all food types except for fatty foods, for long‐term storage at room temperature and below, including hot‐fill and/or heating up to 100°C for up to 2 h.

Background: Wild-type transthyretin amyloidosis (ATTRwt amyloidosis) is primarily diagnosed in elderly men but diagnoses in younger patients and women have recently increased. Objectives: The purpose of this study was to examine age- and sex-related differences in patients with ATTRwt amyloidosis enrolled in the THAOS (Transthyretin Amyloidosis Outcomes Survey). Methods: THAOS was a global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic transthyretin gene variants. Patient characteristics at enrollment were analyzed by age at enrollment and sex (data cutoff date: August 1, 2022). Results: Of 1,251 patients with ATTRwt amyloidosis, 13.7%, 49.1%, 34.5%, and 2.8% were aged

Abstract The liver plays a key role in the metabolism of lipoproteins, controlling both production and catabolism. To accelerate the development of new lipid‐lowering therapies in humans, it is essential to have a relevant in vitro study model available. The current hepatocyte‐like cells (HLCs) models derived from hiPSC can be used to model many genetically driven diseases but require further improvement to better recapitulate the complexity of liver functions. Here, we aimed to improve the maturation of HLCs using a three‐dimensional (3D) approach using Biomimesys®, a hyaluronic acid‐based hydroscaffold in which hiPSCs may directly form aggregates and differentiate toward a functional liver organoid model. After a 28‐day differentiation 3D protocol, we showed that many hepatic genes were upregulated in the 3D model (liver organoids) in comparison with the 2D model (HLCs). Liver organoids, grown on Biomimesys®, exhibited an autonomous cell organization, were composed of different cell types and displayed enhanced cytochromes P450 activities compared to HLCs. Regarding the functional capacities of these organoids, we showed that they were able to accumulate lipids (hepatic steatosis), internalize low‐density lipoprotein and secrete apolipoprotein B. Interestingly, we showed for the first time that this model was also able to produce apolipoprotein (a), the apolipoprotein (a) specific of Lp(a). This innovative hiPSC‐derived liver organoid model may serve as a relevant model for studying human lipopoprotein metabolism, including Lp(a).

BACKGROUND: It is not clear whether pre-existing macrovascular complications (ischemic heart disease, stroke or peripheral artery disease) are associated with health outcomes in people with diabetes mellitus hospitalized for COVID-19. METHODS: We conducted cohort studies of adults with pre-existing diabetes hospitalized for COVID-19 infection in the UK, France, and Spain during the early phase of the pandemic (between March 2020-October 2020). Logistic regression models adjusted for demographic factors and other comorbidities were used to determine associations between previous macrovascular disease and relevant clinical outcomes: mortality, intensive care unit (ICU) admission and use of invasive mechanical ventilation (IMV) during the hospitalization. Output from individual logistic regression models for each cohort was combined in a meta-analysis. RESULTS: Complete data were available for 4,106 (60.4%) individuals. Of these, 1,652 (40.2%) had any prior macrovascular disease of whom 28.5% of patients died. Mortality was higher for people with compared to those without previous macrovascular disease (37.7% vs 22.4%). The combined crude odds ratio (OR) for previous macrovascular disease and mortality for all four cohorts was 2.12 (95% CI 1.83-2.45 with an I2 of 60%, reduced after adjustments for age, sex, type of diabetes, hypertension, microvascular disease, ethnicity, and BMI to adjusted OR 1.53 [95% CI 1.29-1.81]) for the three cohorts. Further analysis revealed that ischemic heart disease and cerebrovascular disease were the main contributors of adverse outcomes. However, proportions of people admitted to ICU (adjOR 0.48 [95% CI 0.31-0.75], I2 60%) and the use of IMV during hospitalization (adjOR 0.52 [95% CI 0.40-0.68], I2 37%) were significantly lower for people with previous macrovascular disease. CONCLUSIONS: This large multinational study of people with diabetes mellitus hospitalized for COVID-19 demonstrates that previous macrovascular disease is associated with higher mortality and lower proportions admitted to ICU and treated with IMV during hospitalization suggesting selective admission criteria. Our findings highlight the importance correctly assess the prognosis and intensive monitoring in this high-risk group of patients and emphasize the need to design specific public health programs aimed to prevent SARS-CoV-2 infection in this subgroup.

Abstract Background Although it has been reported that patients with pneumococcal pneumonia may develop meningitis, lumbar puncture is not systematically recommended in these patients, even in patients with associated bacteremia or invasive pneumococcal disease. The aim of this study was to determine the characteristics and outcomes of patients admitted to intensive care unit (ICU) for pneumococcal community-acquired pneumonia who developed meningitis. Methods We retrospectively included all consecutive patients admitted to our ICU from January 2006 to December 2020 for severe pneumococcal community-acquired pneumonia according to American Thoracic Society criteria. Meningitis was defined as pleocytosis > 5 cells/mm3 or a positive culture of cerebrospinal fluid for Streptococcus pneumoniae in lumbar puncture. The primary endpoint was the proportion of patients with meningitis during their ICU stay. Results Overall, 262 patients [64(52–75) years old] were included: 154(59%) were male, 80(30%) had chronic respiratory disease, 105(39%) were immunocompromised and 6(2%) were vaccinated against S. pneumoniae. A lumbar puncture was performed in 88(34%) patients with a delay from ICU admission to puncture lumbar of 10.5 (2.8–24.1) h and after the initiation of pneumococcal antibiotherapy in 81(92%) patients. Meningitis was diagnosed in 14 patients: 16% of patients with lumbar puncture and 5% of patients in the whole population. Patients with meningitis had more frequently human immunodeficiency virus positive status (29 vs. 5%, p = 0.02), neurological deficits on ICU admission (43 vs. 16%, p = 0.03) and pneumococcal bacteremia (71 vs. 30%, p

Background: L. Australis is one of the most prevalent Leptospira strains infecting dogs, leading, in natural conditions, to severe life-threatening cases. Objective: The objective was to evaluate the onset and duration of immunity (OOI and DOI) induced by a new licensed quadrivalent antileptospiral vaccine (EURICAN® L4) including four Leptospira components (Canicola, Icterohaemorrhagiae, Grippotyphosa and Australis) against L. Australis. To this end, a severe L. Australis challenge model was developed, using a canine strain recently isolated from the field. Material and Methods: Seven- to ten-week-old puppies received two doses of the vaccine four weeks apart and were challenged with an L. Australis isolate two weeks (OOI) and 12 months (DOI) later. Mortality, clinical signs, leptospiremia, leptospiruria, renal carriage, and renal lesions were assessed after challenge. Results: The challenge induced multiple severe clinical signs in controls, leading to the death or euthanasia of 83% of puppies and 57% of adults. In controls, leptospiremia was detected in all dogs, leptospiruria in 67% of puppies and 86% of adults, kidneys tested positive for Leptospira in 83% of puppies and 71% of adults, and kidney lesions were observed in 100% of puppies and 86% of adults. In addition, thrombocytopenia associated with increased concentrations of urea, creatinine, and aspartate aminotransferase was recorded in controls displaying severe clinical signs. In both OOI and DOI studies, none of the vaccinates had clinical signs, no Leptospira was detected in blood, urine, and kidney samples, and no kidney lesions were observed in vaccinates. No significant changes in hematological and biochemical parameters in vaccinates were recorded. Conclusion: EURICAN® L4 was shown to induce quick and long-lasting protection against a severe L. Australis infectious challenge, preventing mortality, clinical signs, infection, bacterial excretion, renal lesions, and renal carriage.

Abstract The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of amines, di‐C14‐C18‐alkyl, oxidised, renamed by the Panel as amines, di‐C14‐C20‐alkyl, oxidised, from hydrogenated vegetable oil. The substance amines, bis(hydrogenated tallow alkyl) oxidised, consisting of the same components, but originating from tallow, is currently authorised as FCM substance No 768. The vegetable‐sourced substance is intended to be used at up to 0.1% w/w as antioxidant and/or stabiliser in the manufacture of polyolefin food contact materials (FCM) and articles intended for contact with dry, aqueous and acidic foods. The substance is a mixture consisting of linear N,N‐dialkyl hydroxylamines and their corresponding amine, nitrone and oxime derivatives, as well as further components: tert‐N‐oxides, secondary amides and carboxylic acids. Specific migration was tested from polyethylene samples in 10% ethanol and 3% acetic acid for 2 h at 100°C followed by 10 days at 60°C. None of the non‐authorised components were detected to migrate at detection limits (LoD) in the range 0.003–0.029 mg/kg. The LoD of authorised carboxylic acids was 0.35 mg/kg. The Panel reassessed the genotoxicity studies carried out on FCM No 768 and evaluated two new bacterial reverse mutation tests on the nitrone and oxime derivatives as well as new (qualitative/quantitative) structure–activity relationship (Q)SAR analyses on other components. The Panel concluded that the substance did not raise a concern for genotoxicity. The Panel concluded that the substance is not of safety concern for the consumers if it is used as an additive at 0.1% w/w in the manufacture of polyolefin FCM intended to be in contact with foods simulated by food simulants A, B, C and E, except for infant formula and human milk, for storage above 6 months at room temperature and below, including hot‐fill conditions and heating up to 100°C for 2 h.

Abstract The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids assessed the safety of calcium tert‐butylphosphonate, which is intended to be used as a nucleating agent up to 0.15% w/w for the manufacture of polyolefin food contact materials (FCM) and articles for single and repeated use, in contact with all types of food, including infant formula and human milk. Specific migration was tested using polyethylene samples in 10% ethanol, 3% acetic acid and 95% ethanol for 2 h at 100°C, followed by 238 h at 40°C. Results for all three simulants were near or below the limit of detection of 10 μg/kg. As the solubility of the substance is far above the reported migration and above 60 mg/kg food, no assessment of the particle fraction was needed, and the conventional risk assessment was followed. The substance did not induce gene mutations in bacterial cells and structural chromosomal aberrations in mammalian cells, thus, did not raise concern for genotoxicity. The Panel considered that the use of the substance did not give rise to safety concern related to neurotoxicity for the general population, but this conclusion could not be applied to infants below 16 weeks of age, due to their specific sensitivity and the absence of dedicated data. The Panel concluded that calcium tert‐butylphosphonate does not raise a safety concern for the consumer if it is used as a nucleating agent up to 0.15% w/w in the manufacture of polyolefin FCM that are intended to be in contact with all types of food for storage above 6 months at room temperature and below, including temperatures up to 100°C for maximum 2 h and up to 130°C for short durations. The Panel could not evaluate the safety of use to manufacture FCM for contact with infant formula and human milk.

Abstract The EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) assessed the safety of mixtures of 1,9‐nonanediamine (NMDA) and 2‐methyl‐1,8‐octanediamine (MODA) when used to produce polyamide food contact materials for contact with all food types for long‐term storage at room temperature and below, including heating up to 121°C for up to 2 h. The polyamide material is also intended to be used for repeated use up to 121°C with short contact (up to 30 min). The polymer typically contains ■■■■■ of a low molecular weight fraction (LMWF,

Introduction Physical restraint (PR) is prescribed in patients receiving invasive mechanical ventilation in the intensive care unit (ICU) to avoid unplanned removal of medical devices. However, it is associated with an increased risk of delirium. We hypothesise that a restrictive use of PR, as compared with a systematic use, could reduce the duration of delirium in ICU patients receiving invasive mechanical ventilation.Methods and analysis The Restrictive use of Restraints and Delirium Duration in ICU (R2D2-ICU) study is a national multicentric, parallel-group, randomised (1:1) open-label, controlled, superiority trial, which will be conducted in 10 ICUs. A total of 422 adult patients requiring invasive mechanical ventilation for an expected duration of at least 48 hours and eligible for prescription of PR will be randomly allocated within 6 hours from intubation to either the restrictive PR use group or the systematic PR use group, until day 14, ICU discharge or death, whichever comes first. In both groups, PR will consist of the use of wrist straps. The primary endpoint will be delirium or coma-free days, defined as the number of days spent alive in the ICU without coma or delirium within the first 14 days after randomisation. Delirium will be assessed using the Confusion Assessment Method-ICU twice daily. Key secondary endpoints will encompass agitation episodes, opioid, propofol, benzodiazepine and antipsychotic drug exposure during the 14-day intervention period, along with a core outcome set of measures evaluated 90 days postrandomisation.Ethics and dissemination The R2D2-ICU study has been approved by the Comité de Protection des Personnes (CPP) ILE DE FRANCE III—PARIS (CPP19.09.06.37521) on June 10th, 2019). Participant recruitment started on 25 January 2021. Results will be published in international peer-reviewed medical journals and presented at conferences.Trial registration number NCT04273360.

Abstract Background Transthyretin amyloidosis (ATTR amyloidosis) is a progressive, multisystemic, life-threatening disease resulting from the deposition of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in various tissues and organs. Methods Established in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal, observational study of patients with ATTR amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This analysis describes the baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2022), providing a consolidated overview of 15-year data from the THAOS registry. Results This analysis included 4428 symptomatic patients and 1707 asymptomatic gene carriers. The majority of symptomatic patients were male (70.8%) with a mean (standard deviation [SD]) age at symptom onset of 56.6 (17.9) years. Compared with the 14-year analysis, V30M remained the most prevalent genotype in Europe (62.2%), South America (78.6%), and Japan (74.2%) and ATTRwt remained most common in North America (56.2%). Relative to the 14-year analysis, there was an increase of mixed phenotype (from 16.6 to 24.5%) and a reduction of predominantly cardiac phenotype (from 40.7 to 31.9%). The proportion of patients with predominantly neurologic phenotype remained stable (from 40.1 to 38.7%). Asymptomatic gene carriers were 58.5% female with a mean age at enrollment of 41.9 years (SD 15.5). Conclusions This overview of > 6000 patients enrolled over 15 years in THAOS represents the largest registry analysis of ATTR amyloidosis to date and continues to emphasize the genotypic and phenotypic heterogeneity of the disease. Nearly a quarter of the symptomatic population within THAOS was mixed phenotype, underscoring the need for multidisciplinary management of ATTR amyloidosis. Trial registration ClinicalTrials.gov Identifier: NCT00628745.

Abstract Background COVID-19 infections are associated with accrued inflammatory responses which may result in cardiac injury. Immune response to infection appears different between men and women, suggesting that COVID-19 patients’ outcomes may differ according to biological sex. However, the impact of biological sex on the occurrence of cardiac injury during intensive care unit (ICU) stay in COVID-19 patients remain unclear. Methods In this multicenter and prospective study, we included consecutive patients admitted to ICU for severe COVID-19 pneumonia, during the first two pandemic waves. Biological, electrocardiogram (ECG) and echocardiographic variables were collected on ICU admission. Cardiac injury was defined by increased troponin above 99th percentile of upper norm value and newly diagnosed ECG and/or echocardiographic abnormalities. The primary endpoint was the proportion of patients with cardiac injury during ICU stay according to biological sex. The impact of biological sex on other subsequent clinical outcomes was also evaluated. Results We included 198 patients with a median age of 66 (56–73) years, 147 (74%) patients were men and 51 (26%) were women. Overall, 119 (60%) patients had cardiac injury during ICU stay and the proportion of patients with cardiac injury during ICU stay was not different between men and women (60% vs. 61%, p = 1.00). Patients with cardiac injury during ICU stay showed more cardiovascular risk factors and chronic cardiac disease and had a higher ICU mortality rate. On ICU admission, they had a more marked lymphopenia (0.70 (0.40–0.80) vs. 0.80 (0.50–1.10) × 109/L, p

Abstract Background Out-of-hospital cardiac arrest (OHCA) is a heterogeneous entity with multiple origins and prognoses. An early, reliable assessment of the prognosis is useful to adapt therapeutic strategy, tailor intensity of care, and inform relatives. We aimed primarily to undertake a prospective multicentric study to evaluate predictive performance of the Cardiac Arrest Prognosis (CAHP) Score as compare to historical dataset systematically collected after OHCA (Utstein style criteria). Our secondary aim was to evaluate other dedicated scores for predicting outcome after OHCA and to compare them to Utstein style criteria. Methods We prospectively collected data from 24 French and Belgium Intensive Care Units (ICUs) between August 2020 and June 2022. All cases of non-traumatic OHCA (cardiac and non-cardiac causes) patients with stable return of spontaneous circulation (ROSC) and comatose at ICU admission (defined by Glasgow coma score ≤ 8) on ICU admission were included. The primary outcome was the modified Rankin scale (mRS) at day 90 after cardiac arrest, assessed by phone interviews. A wide range of developed scores (CAHP, OHCA, CREST, C-Graph, TTM, CAST, NULL-PLEASE, and MIRACLE2) were included, and their accuracies in predicting poor outcome at 90 days after OHCA (defined as mRS ≥ 4) were determined using the area under the receiving operating characteristic curve (AUROC) and the calibration belt. Results During the study period, 907 patients were screened, and 658 were included in the study. Patients were predominantly male (72%), with a mean age of 61 ± 15, most having collapsed from a supposed cardiac cause (64%). The mortality rate at day 90 was 63% and unfavorable neurological outcomes were observed in 66%. The performance (AUROC) of Utstein criteria for poor outcome prediction was moderate at 0.79 [0.76–0.83], whereas AUROCs from other scores varied from 0.79 [0.75–0.83] to 0.88 [0.86–0.91]. For each score, the proportion of patients for whom individual values could not be calculated varied from 1.4% to 17.4%. Conclusions In patients admitted to ICUs after a successfully resuscitated OHCA, most of the scores available for the evaluation of the subsequent prognosis are more efficient than the usual Utstein criteria but calibration is unacceptable for some of them. Our results show that some scores (CAHP, sCAHP, mCAHP, OHCA, rCAST) have superior performance, and that their ease and speed of determination should encourage their use. Trial registration https://clinicaltrials.gov/ct2/show/NCT04167891

This study generated bioactive hydrolysates using the enzyme Alcalase and autolysis from mesopelagic fish, including Maurolicus muelleri and Benthosema glaciale. Generated hydrolysates were investigated for their bioactivities using in vitro bioassays, and bioactive peptides were identified using mass spectrometry in active hydrolysates with cyclooxygenase, dipeptidyl peptidase IV and antioxidant activities. In silico analysis was employed to rank identified peptide sequences in terms of overall bioactivity using programmes including Peptide Ranker, PrepAIP, Umami-MRNN and AntiDMPpred. Seven peptides predicted to have anti-inflammatory, anti-type 2 diabetes or Umami potential using in silico strategies were chemically synthesised, and their anti-inflammatory activities were confirmed using in vitro bioassays with COX-1 and COX-2 enzymes. The peptide QCPLHRPWAL inhibited COX-1 and COX-2 by 82.90% (+/−0.54) and 53.84%, respectively, and had a selectivity index greater than 10. This peptide warrants further research as a novel anti-inflammatory/pain relief peptide. Other peptides with DPP-IV inhibitory and Umami flavours were identified. These offer potential for use as functional foods or topical agents to prevent pain and inflammation.

Maurolicus muelleri is an important component of mesopelagic ecosystems; nevertheless, we possess only limited knowledge about its biological features. We collected samples of M. muelleri from six scientific surveys between 2019 and 2021 in three geographical areas in the Northeast Atlantic waters (from South to North): the Bay of Biscay, the Celtic Sea, and the Norwegian Sea. Geographical variations in otolith growth, fish age, length, weight, and condition, as well as length–weight relationships and von Bertalanffy growth models (VBGMs), were investigated. Length-weight relationships revealed differences associated with the fish’s origin, paralleling the annual and daily otolith growth. VBGM parameters increased progressively northwards, in accordance with Bergmann’s rules. Fish length was positively related to the otolith radio, and Lee’s phenomenon was undetected. The impact of environmental variables, such as temperature and food availability, is debated, with these considered potential drivers of this variability. Populations may belong to separated units, either genetically or morphologically, representing differences in biological parameters as a signal of geographical divergence.

Abstract Background Out-of-hospital cardiac arrest (OHCA) is a common cause of death. Early circulatory failure is the most common reason for death within the first 48 h. This study in intensive care unit (ICU) patients with OHCA was designed to identify and characterize clusters based on clinical features and to determine the frequency of death from refractory postresuscitation shock (RPRS) in each cluster. Methods We retrospectively identified adults admitted alive to ICUs after OHCA in 2011–2018 and recorded in a prospective registry for the Paris region (France). We identified patient clusters by performing an unsupervised hierarchical cluster analysis (without mode of death among the variables) based on Utstein clinical and laboratory variables. For each cluster, we estimated the hazard ratio (HRs) for RPRS. Results Of the 4445 included patients, 1468 (33%) were discharged alive from the ICU and 2977 (67%) died in the ICU. We identified four clusters: initial shockable rhythm with short low-flow time (cluster 1), initial non-shockable rhythm with usual absence of ST-segment elevation (cluster 2), initial non-shockable rhythm with long no-flow time (cluster 3), and long low-flow time with high epinephrine dose (cluster 4). RPRS was significantly associated with this last cluster (HR, 5.51; 95% confidence interval 4.51–6.74). Conclusions We identified patient clusters based on Utstein criteria, and one cluster was strongly associated with RPRS. This result may help to make decisions about using specific treatments after OHCA.

BackgroundAtrial arrhythmias (AA) commonly affect patients with cardiac amyloidosis (CA) and are a contributing risk factor for the development of heart failure (HF). This study sought to investigate the long-term efficacy and impact of catheter ablation on HF progression in patients with CA and AA.MethodsThirty-one patients with CA and AA undergoing catheter ablation were retrospectively included (transthyretin-ATTR CA 61% and light chain-AL CA 39%). AA subtypes included atrial fibrillation (AFib) in 22 (paroxysmal in 10 and persistent in 12), atrial flutter (AFl) in 17 and atrial tachycardia (AT) in 11 patients. Long-term AA recurrence rates were evaluated along with the impact of sinus rhythm (SR) maintenance on HF and mortality.ResultsAA recurrence was observed in 14 patients (45%) at a median of 3.5 months (AFib n = 8, AT n = 6, AFl = 0). Post-cardioversion, medical therapy or catheter ablation, 10 patients (32%) remained in permanent AA. Over a median follow-up of 19 months, all-cause mortality was 39% (n = 12): 3 with end-stage HF, 5 due to late complications of CA, 1 sudden cardiac death, 1 stroke, 1 COVID 19 (and one unknown). With maintenance of SR following catheter ablation, significant reductions in serum creatinine and natriuretic peptide levels were observed with improvements in NYHA class. Two patients required hospitalization for HF in the SR maintenance cohort compared to 5 patients in the AA recurrence cohort (p = 0.1). All 3 patients with deaths secondary to HF had AA recurrence compared to 11 out of the 28 patients whom were long-term survivors or deaths not related to HF (p = 0.04). All-cause mortality was not associated with AA recurrence.ConclusionThis study demonstrates moderate long-term efficacy of SR maintenance with catheter ablation for AA in patients with CA. Improvements in clinical and biological status with positive trends in HF mortality are observed if SR can be maintained.

Background: While the short-term prognosis of cardiac arrest patients - nearly 250,000 new cases per year in Europe - has been extensively studied, less is known regarding the mid and long-term outcome of survivors. Objective: The aim of the DESAC study is to describe mid- and long-term survival rate and functional status of cardiac arrest survivors, and to assess the influence of pre and intra hospital therapeutic strategies on these two outcomes. Methods: Between Jul 2015 and Oct 2018, adult patients over 18 years who were discharged alive from any intensive care units (public and private hospitals) in the Ile-de-France area (Paris and suburbs, France) after a non-traumatic cardiac arrest were screened for participation in this multicentric study. Survivors were included after they signed (or the proxies) an informed consent before discharge during initial hospitalisation. We calculated that including 600 patients in total would allow an 80% power to demonstrate a 2 years survival rate difference of 10% between patients who did and those who did not receive therapeutic hypothermia after resuscitation. Pre- and in-hospital data related to the circumstances surrounding the event and to the therapeutic interventions (such as cardio-pulmonary resuscitation, defibrillation, emergent coronary revascularization, neuroprotective therapeutics) were collected. After discharge, patients were interviewed at 3 months, 6 months and every year thereafter for a minimum follow-up of 26 months and a maximum follow-up of 48 months. Information on vital status, occurrence of cardiovascular events, medications and a comprehensive assessment of the functional status (qualitive of life as assessed by the Short-Form General Health Survey (SF36) scale, activities of daily living (ADL) scale, neurological Cerebral Performance Categories (CPC) and Overall Performance Categories (OPC) scales, socio-professional activities) were collected at follow-up interviews. Discussion: The DESAC study should provide important information regarding several dimensions of the mid and long-term prognosis of cardiac arrest survivors and on the benefit (and potentially harm) of early therapeutic strategies.