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Introduction The identification of type 1 diabetes at an early presymptomatic stage has clinical benefits. These include a reduced risk of diabetic ketoacidosis (DKA) at the clinical manifestation of the disease and a significant reduction in clinical symptoms. The European action for the Diagnosis of Early Non-clinical Type 1 diabetes For disease Interception (EDENT1FI) represents a pioneering effort to advance early detection of type 1 diabetes through public health screening. With the EDENT1FI Master Protocol, the project aims to harmonise and standardise screening for early-stage type 1 diabetes and care.Methods and analysis Public health islet autoantibody screening is conducted in the Czech Republic, Denmark, Germany, Italy, Poland, Portugal, Sweden and the UK. Between November 2023 (start date) and October 2028 (planned end date), an estimated number of 200 000 children and adolescents aged 1–17 years are expected to be screened. Screening is performed in capillary blood, examining different islet autoantibodies (autoantibodies against insulin, glutamic acid decarboxylase-65, insulinoma-associated antigen-2 and/or zinc transporter-8). Positive screening results undergo confirmation through a second antibody method. A second (venous) blood sample is requested if at least two autoantibodies are detected, to confirm the autoantibody status. Children and adolescents with confirmed two or more autoantibodies are invited to metabolic staging (oral glucose tolerance test, haemoglobin A1c (HbA1c), random glucose, optionally continuous glucose monitoring); an educational programme and recommendations for monitoring are provided. The feasibility and acceptability of screening are evaluated by feedback questionnaires. Pseudonymised data is collated in the EDENT1FI Registry. Study outcomes include country-specific screening rates, prevalences of stage 1 and stage 2 type 1 diabetes, number in EDENT1FI Registry, proportion with DKA and symptoms at clinical diagnosis and median HbA1c.Ethics and dissemination Following the EDENT1FI Master Protocol, site-specific protocols are developed and approved by local ethics committees (Technical University of Munich, Medical Faculty, Nr. 70/14; Medizinische Hochschule Hannover, Nr. 9588_BO_S_2021; Technische Universität Dresden, Nr. BO-EK-356082020; Center for Sundhed Region Hovedstaden, Nr. H-22053116; Swedish Ethical Review Authority, Nr. 2023-00312-01; National Health Service Health Research Authority and Health Care Research Wales, IRAS (Integrated Research Application System) project ID 309252; Italian National Institute of Health, National ethics committee for clinical trials of public research bodies (EPR) and other national public institutions, Prot. PRE BIO CE Nr. 0059835; Charles University in Prague, Ethics Committee for Multi-Centric Clinical Trials of the University Hopital Motol and 2nd Faculty of Medicine, Nr. 1271/23; Bioethics Committee at the Medical University of Warsaw, Nr. 21/2024 and KB/6/R/2024; Associação Protectora dos Diabéticos de Portugal, Nr. 211/2024). Results are disseminated through peer-reviewed journals and conference presentations and will be shared openly.

Abstract Subthalamic deep brain stimulation (STN-DBS) is an effective therapy for alleviating motor symptoms in people with Parkinson’s disease (PwP), although some may not receive optimal clinical benefits. One potential mechanism of STN-DBS involves antidromic activation of the hyperdirect pathway (HDP), thus suppressing cortical beta synchrony to improve motor function, albeit the precise mechanisms underlying optimal DBS parameters are not well understood. To address this, 18 PwP with STN-DBS completed a 2 Hz monopolar stimulation of the left STN during MEG. MEG data were imaged in the time-frequency domain using minimum norm estimation. Peak vertex time series data were extracted to interrogate the directional specificity and magnitude of DBS current on evoked and induced cortical responses and accelerometer metrics of finger tapping using linear mixed-effects models and mediation analyses. We observed increases in evoked responses (HDP ~ 3–10 ms) and synchronization of beta oscillatory power (14–30 Hz, 10–100 ms) following DBS pulse onset in the primary sensorimotor cortex (SM1), supplementary motor area (SMA) and middle frontal gyrus (MFG) ipsilateral to the site of stimulation. DBS parameters significantly modulated neural and behavioral outcomes, with clinically effective contacts eliciting significant increases in medium-latency evoked responses, reductions in induced SM1 beta power, and better movement profiles compared to suboptimal contacts, often regardless of the magnitude of current applied. Finally, HDP-related improvements in motor function were mediated by the degree of SM1 beta suppression in a setting-dependent manner. Together, these data suggest that DBS-evoked brain-behavior dynamics are influenced by the level of beta power in key hubs of the basal ganglia-cortical loop, and this effect is exacerbated by the clinical efficacy of DBS parameters. Such data provides novel mechanistic and clinical insight, which may prove useful for characterizing DBS programming strategies to optimize motor symptom improvement in the future.

Submarine canyons enhance shelf–slope sediment exchange and influence hydrodynamic processes, with consequences for biogeochemical cycles. This work documents variations in the vertical export of biogenic matter on the northern shore of the lower St. Lawrence Estuary (LSLE, Quebec, eastern Canada), which is characterized by the presence of an active submarine canyon system. A total of three moorings were deployed from November 2020 to September 2021. One nearshore mooring (PDMc) was deployed in the main axis of the Pointe-des-Monts (PDM) canyon system and was equipped with an acoustic Doppler current profiler (ADCP), and two moorings equipped with sediment traps were deployed in the distal PDM canyon system (PDM-154, PDM-224) and offshore Baie-Comeau (BC-133). The ADCP data revealed the occurrence of a minor sediment remobilization event (December 2020) and a small turbidity current (February 2021) in the canyon. Concurrent elevated fluxes of total particulate matter, particulate organic carbon, particulate nitrogen, and chloropigments showed that these events left a signature in sediment traps PDM-154 and PDM-224 located > 2.6 km further offshore by enhancing lateral dispersion of resuspended sediments. The composition of diatom and dinoflagellate assemblages was similar in the canyon system and offshore BC, but the diatom bloom occurred 2 weeks earlier (in mid-April) at the PDM site. A bloom of the potentially toxic diatom Pseudo-nitzschia seriata was also observed during the second half of September 2021 at the BC site. Annual diatom and dinoflagellate fluxes were almost 2 times lower at the PDM site than at the BC site, possibly due to differences in riverine input and the structure of the water column, as well as increased sediment input and resuspension at the PDM site, leading to limited light availability. This study notably helps identify the relationship between near-bed canyon processes and biogenic matter export in the water column, thereby directly influencing the ecosystem offshore PDM. The study period further covered an anomalously nearly ice-free winter, and thus, in the context of climate change, it provides valuable insight into future trends of biogenic matter export in the LSLE.

Introduction Neurofilmology is a young and evolving research field, at the intersection between neuroscience and movie experiences, that explores how the brain processes and responds to visual storytelling. It involves examining the cognitive and emotional effects of movies on viewers, including social cognition and perspective-taking aspects. However, up to date, these studies have focused only on the neurotypical population, hence constituting a considerable gap in the literature with respect to individuals with neuroatypical functioning. Objectives Aim of this study was to investigate the experience of film viewing and its correlates in individuals with a diagnosis of Autism Spectrum Disorders (ASD). Methods 30 neurotypical individuals and 30 individuals with ASD without intellectual disabilities were asked to observe 12 short video clips of 3 seconds length, showing an agent grasping an object from a table, and filmed with three different camera techniques: Still, Steadycam, Zoom; for each clip, they were asked to respond to six question on a Visual Analogue Scale (0-100) designed to investigate participants’ potential feeling of involvement with the observed scene, their comfort with the different filming conditions, and their estimation of the ecological plausibility of the different types of camera movements. Results Participants felt more involved watching videos filmed with a Steadycam, with respect to the Zoom and Still condition. Within the neurotypical group participants felt more comfortable when the camera was in motion (both Steadycam and Zoom condition) compared to the Still condition; no differences were found between conditions in the ASD group, as if they felt equally comfortable in every condition administered, regardless the filming technique. Conclusions First, our results reinforce prior findings regarding the influence of different camera techniques on neurotypical individuals. Second, they add to the existing literature suggesting that individuals with ASD may exhibit differences in their subjective experiences related to empathizing with characters and immersing themselves as actors when the camera replicates naturalistic movements, resulting in a diminished overall fulfillment in the movie-watching process. Disclosure of Interest None Declared

Objective: In primary hypercholesterolemia many people treated with statins do not reach their plasma LDL-C goals and are at increased risk of cardiovascular disease (CVD). This study aimed to evaluate efficacy and safety of a new fixed-dose combination (FDC) formulation of rosuvastatin/ezetimibe (R/E) in this population. Methods: This was a multicenter, multinational, randomized, double-blind, double-dummy, active-controlled, parallel-arm study of FDC R/E in people with primary hypercholesterolemia at very high risk (VHR) or high risk (HR) of CVD, inadequately controlled with 20 mg or 10 mg stable daily dose of rosuvastatin or equipotent dose of another statin. The primary objective was to demonstrate superiority of FDC R/E versus rosuvastatin monotherapy uptitrated to 40 mg (R40) or 20 mg (R20) in reduction of LDL-C after 6 weeks. Results: Randomized VHR participants (n = 244) were treated with R40, R40/E10, or R20/E10; randomized HR participants (n = 208) received R10/E10 or R20. In VHR participants, superiority of R40/E10 and R20/E10 versus R40 was demonstrated on LDL-C percent change from baseline to Week 6 with least squares mean differences (LSMD) of −19.66% (95% CI: −29.48% to −9.84%; P < .001) and −12.28% (95% CI: −22.12% to −2.44%; P = .015), respectively. In HR participants, superiority of R10/E10 over R20 was not demonstrated (LSMD −5.20%; 95% CI: −15.18% to 4.78%; P = .306), despite clinically relevant LDL-C reduction with R10/E10. No unexpected safety findings were reported. Conclusions: The results from this study suggest that R/E FDCs improve LDL-C reduction and goal achievement in people with primary hypercholesterolemia inadequately controlled with statins and at VHR/HR of CVD.

Background/Aims Efficacy and safety data of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), is not yet well established in the Korean population. We assessed them in ODYSSEY-KT through the pre-specified Korean subanalysis. Methods In the ODYSSEY-KT study, South Korean and Taiwanese patients with hypercholesterolemia and high cardiovascular risks were randomized (1:1) to alirocumab or placebo. Alirocumab was self-administered subcutaneously at 75 mg every 2 weeks with a maximally tolerated statin dose with or without other lipid-modifying therapies. Alirocumab dose was increased to 150 mg every 2 weeks at week 12 if low density lipoprotein cholesterol (LDL-C) ≥ 70 mg/dL at week 8. Primary endpoint was percent change in LDL-C from baseline to week 24. Results from Korean cohort (n = 83: 40 for alirocumab and 43 for placebo, respectively) analyses are reported here. Results In alirocumab group, the least square of mean change percent in LDL-C levels was –65.7% (placebo: 11.1%; p < 0.0001) and 92.0% of them achieved LDL-C < 70 mg/dL (placebo: 12.7%; p < 0.0001) at week 24. Alirocumab also showed significantly greater improvements in high density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol, lipoprotein(a), and apolipoprotein B than placebo (p < 0.05). Two consecutive calculated LDL-C values < 25 mg/dL were observed in 37.5% of alirocumab-treated patients. Overall, 45.0% alirocumab-treated and 51.2% placebo-treated patients experienced treatment-emergent adverse events (TEAEs) without discontinuation of treatment due to TEAEs. Conclusions Alirocumab has demonstrated to be effective in improvement of LDL-C and related lipid profiles in Korean cohort. Alirocumab was generally well tolerated with no significant safety signals.

Abstract Background Statins are generally well-tolerated and serious side effects are infrequent, but some patients experience adverse events and reduce their statin dose or discontinue treatment altogether. Alirocumab is a highly specific, fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), which can produce substantial and sustained reductions of low-density lipoprotein cholesterol (LDL-C). Methods The randomized, double-blind, placebo-controlled, parallel-group, phase 3 ODYSSEY NIPPON study will explore alirocumab 150 mg every 4 weeks (Q4W) in 163 Japanese patients with hypercholesterolemia who are on the lowest-strength dose of atorvastatin (5 mg/day) or are receiving a non-statin lipid-lowering therapy (LLT) (fenofibrate, bezafibrate, ezetimibe, or diet therapy alone). Hypercholesterolemia is defined as LDL-C ≥ 100 mg/dL (2.6 mmol/L) in patients with heterozygous familial hypercholesterolemia or non-familial hypercholesterolemia with a history of documented coronary heart disease, or ≥120 mg/dL (3.1 mmol/L) in patients with non-familial hypercholesterolemia classified as primary prevention category III (i.e. high-risk patients). During the 12-week double-blind treatment period, patients will be randomized (1:1:1) to receive alirocumab subcutaneously (SC) 150 mg Q4W alternating with placebo for alirocumab Q4W, or alirocumab 150 mg SC every 2 weeks (Q2W), or SC placebo Q2W. The primary efficacy endpoint is the percentage change in calculated LDL-C from baseline to week 12. The long-term safety and tolerability of alirocumab will also be investigated. Discussion The ODYSSEY NIPPON study will provide insights into the efficacy and safety of alirocumab 150 mg Q4W or 150 mg Q2W among Japanese patients with hypercholesterolemia who are on the lowest-strength dose of atorvastatin, or are receiving a non-statin LLT (including diet therapy alone). Trial registration ClinicalTrials.gov number: NCT02584504

Background The PCSK9 antibody alirocumab (75 mg every 2 weeks; Q2W) as monotherapy reduced low‐density lipoprotein‐cholesterol (LDL‐C) levels by 47%. Because the option of a monthly dosing regimen is convenient, ODYSSEY CHOICE II evaluated alirocumab 150 mg Q4W in patients with inadequately controlled hypercholesterolemia and not on statin (majority with statin‐associated muscle symptoms), receiving treatment with fenofibrate, ezetimibe, or diet alone. Methods and Results Patients were randomly assigned to placebo, alirocumab 150 mg Q4W or 75 mg Q2W (calibrator arm), with dose adjustment to 150 mg Q2W at week (W) 12 if W8 predefined LDL‐C target levels were not met. The primary efficacy endpoint was LDL‐C percentage change from baseline to W24. Mean baseline LDL‐C levels were 163.9 mg/dL (alirocumab 150 mg Q4W, n=59), 154.5 mg/dL (alirocumab 75 mg Q2W, n=116), and 158.5 mg/dL (placebo, n=58). In the alirocumab 150 mg Q4W and 75 mg Q2W groups (49.1% and 36.0% of patients received dose adjustment, respectively), least‐squares mean LDL‐C changes from baseline to W24 were −51.7% and −53.5%, respectively (placebo [+4.7%]; both groups P

A utilização dos produtos do sangue como medicamentos essenciais e o reconhecimento das dimensões dos riscos transfusionais demandam dos países uma ação regulatória com foco em qualidade e segurança. Nesse campo, os órgãos reguladores têm papel fundamental em imprimir socialmente a garantia de que os componentes do sangue serão produzidos e utilizados de acordo com as normas técnicas vigentes. Assim, na busca para gerenciar os riscos sanitários envolvidos no processamento e uso do sangue, o modelo regulatório brasileiro, baseado na construção de uma política nacional de sangue, sob gestão do Estado, vem passando por aprimoramento conceitual e inovação de seus instrumentos. Com a inserção das boas práticas de fabricação preconizadas pela Organização Munidal da Saúde nas normativas brasileiras, o país avança na visão dos estabelecimentos de sangue como centros produtores de produtos biológicos originados do sangue para fins terapêuticos e fortalece a necessidade de desenvolvimento de mecanismos para a segurança no atendimento a doadores e receptores. O desenvolvimento de uma política nacional de sangue coordenada pelo Estado e a instituição de um sistema nacional de vigilância sanitária com poder fiscalizatório legitimado são elementos essenciais utilizados no Brasil para garantia de sangue em quantidade, qualidade, segurança e em tempo oportuno à população. Este artigo tem por objetivo discutir o contexto atual do modelo regulatório de sangue no Brasil na perspectiva de apontar desafios para o aperfeiçoamento desse modelo.