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Background: Snake and scorpion envenomation is a common public health problem in many regions of the world. Life-threatening emergencies may occur in patients with snake and scorpion envenomation; therefore, these patients may be required intensive care unit (ICU) follow-up. Our objective was to present the demographic and clinical characteristics, treatment modalities and short term outcomes of patients with snake and scorpion envenomation who followed up in our tertiary hospital ICU. Methods: Patient records were retrospectively searched and snake or scorpion envenomation patients with ICU stay were identified with relevant keywords and ICD-10 codes between January 2010 and September 2019. All cases with ICU stay were included for study analysis, regardless of patient age. Scorpion and snake envenomation managed in outpatient clinic were excluded from our data. Poisoning severity score (PSS) system was used to present signs and symptoms and PSS was calculated. Primary and critical care treatment modalities were identified and analyzed. Results: Forty patients (25 with snake bites [62.5%] and 15 with scorpion sting [37.5%]) were included in this retrospective study. Local and systemic effects have been reported in 33 (82.5%) and in 27 patients (67.5%), respectively. Majority of patients suffered from pain or disturbances in sensory neural, hematological, cardiovascular or metabolic systems. Median PSS was 2 (0-4) and median length of stay in ICU was 2 days (1-12). Mortality rate was 2.5%. Antivenom immunoglobulins (n=32, %80.0), systemic antibacterial agents (n=24, 60%), and paracetamol (n=21, 52.5%) were the most common systemically administered treatments. Surgical interventions were performed in 4 patients (10%) Conclusions: We reported that snake and scorpion envenomation were mostly admitted to the ICU with local and/or systemic symptoms for advanced monitoring and observation. Although life treating emergencies and mortality was uncommon in our study, we think that these patients should be closely followed up in ICU.

Objective: We aimed to evaluate the safety of nivolumab + ipilimumab (nivo + ipi) in advanced melanoma patients who had relapsed after ≥1 line of systemic treatment in a real-world setting. Methods: Adult patients with advanced melanoma who had progressed after ≥1 line of systemic treatment were eligible for nivo 1 mg/kg + ipi 3 mg/kg Q3W × 4, followed by nivo 3 mg/kg Q2W until progression, or unacceptable toxicity for up to 24 months in the Early Access Program (EAP) in Turkey. Treatment-related adverse events (TRAEs) were recorded and analyzed. Results: Forty patients who received at least one dose of nivo + ipi were included. Median number of doses (Nivo + ipi and nivo alone) were 4 with a median follow-up of 19 weeks. Thirty patients (75%) were alive and 24 patients (60%) were on treatment. TRAEs of any grade and grade 3–4 occurred in 53% and 20% of the patients, respectively. One patient died due to TRAEs (colitis and diarrhea) after the second dose of nivo + ipi. Median times to onset and resolution of TRAEs were 6 and 3 weeks, respectively. Eleven patients (28%) discontinued treatment for reasons other than TRAEs. TRAEs of any grade led to discontinuation in 5 patients (13%). Most of the TRAEs were reversible when managed with available guidelines. Discussion: Safety profile of N + I was found to be consistent with early reports. Increased experience with the management of TRAEs of immunotherapies, short follow-up and ≥2 line real-world setting may account for lower TRAEs rates. Long-term follow is needed. Keywords: Nivolumab, Ipilimumab, Immunotherapy, Melanoma

Abstract To ensure optimal coordination of the EU-funded COVID-19 platform trials, a double coordination mechanism was established. It included the Trial Coordination Board (TCB) to promote the dialogue between investigators and relevant public health stakeholders and the Joint Access Advisory Mechanism (JAAM) to streamline access of new intervention arms to the platform trials. Both the TCB and the JAAM emerged as efficient instruments to promote cooperation and optimise the use of resources within EU-funded adaptive platform trials. In addition, an adaptive platform trial toolbox was developed to collect information and literature on challenges and solutions identified to date. The recently funded ‘Coordination MEchanism for Cohorts and Trials’ (CoMeCT) project will endeavour to make this model sustainable, with a further expansion to other emerging infectious diseases, as part of the governance of the current and future platform trials for pandemic preparedness. This example could serve as a model for platform trial coordination in other disease areas.

Summary: Platform trials bring the promise of making clinical research more efficient and more patient centric. While their use has become more widespread, including their prominent role during the COVID-19 pandemic response, broader adoption of platform trials has been limited by the lack of experience and tools to navigate the critical upfront planning required to launch such collaborative studies. The European Union-Patient-cEntric clinicAl tRial pLatform (EU-PEARL) initiative has produced new methodologies to expand the use of platform trials with an overarching infrastructure and services embedded into Integrated Research Platforms (IRPs), in collaboration with patient representatives and through consultation with U.S. Food and Drug Administration and European Medicines Agency stakeholders. In this narrative review, we discuss the outlook for platform trials in Europe, including challenges related to infrastructure, design, adaptations, data sharing and regulation. Documents derived from the EU-PEARL project, alongside a literature search including PubMed and relevant grey literature (e.g., guidance from regulatory agencies and health technology agencies) were used as sources for a multi-stage collaborative process through which the 10 more important points based on lessons drawn from the EU-PEARL project were developed and summarised as guidance for the setup of platform trials. We conclude that early involvement of critical stakeholder such as regulatory agencies or patients are critical steps in the implementation and later acceptance of platform trials. Addressing these gaps will be critical for attaining the full potential of platform trials for patients. Funding: Innovative Medicines Initiative 2 Joint Undertaking with support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

Abstract Background Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI − 0.1% [− 8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (− 3.2% [− 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 ).

Background: Amitriptyline is an important cause of mortality due to its cardiovascular toxicity. Aims: To investigate the changes in levels of cardiac S100b protein on amitriptyline-induced cardiotoxicity and also to examine the correlation between amitriptyline-induced cardiotoxic effects and cardiac S100b protein in an isolated rat heart model. Study Design: Animal experimentation, isolated heart model. Methods: After a stabilization period, isolated hearts were randomized to two groups (n=5 and n=7). In the control group, isolated hearts were subjected to an infusion of 5% dextrose for 60 minutes. In the amitriptyline group, 5.5×10-5 M amitriptyline was infused for 60 minutes to achieve amitriptyline toxicity. After the infusion period, heart tissues were removed for histological examination. Results: In comparison to control treatment, amitriptyline infusion decreased left ventricular developed pressure (LVDP), dp/dtmax and heart rate (HR) and significantly prolonged QRS duration (p