Autism-related dietary preferences mediate autism-gut microbiome associations.

There is increasing interest in the potential contribution of the gut microbiome to autism spectrum disorder (ASD). However, previous studies have been underpowered and have not been designed to address potential confounding factors in a comprehensive way. We performed a large autism stool metagenomics study (n = 247) based on participants from the Australian Autism Biobank and the Queensland Twin Adolescent Brain project. We found negligible direct associations between ASD diagnosis and the gut microbiome. Instead, our data support a model whereby ASD-related restricted interests are associated with less-diverse diet, and in turn reduced microbial taxonomic diversity and looser stool consistency. In contrast to ASD diagnosis, our dataset was well powered to detect microbiome associations with traits such as age, dietary intake, and stool consistency. Overall, microbiome differences in ASD may reflect dietary preferences that relate to diagnostic features, and we caution against claims that the microbiome has a driving role in ASD.

Self-Expanding or Balloon-Expandable TAVR in Patients with a Small Aortic Annulus.

BACKGROUND: Patients with severe aortic stenosis and a small aortic annulus are at risk for impaired valvular hemodynamic performance and associated adverse cardiovascular clinical outcomes after transcatheter aortic-valve replacement (TAVR). METHODS: We randomly assigned patients with symptomatic severe aortic stenosis and an aortic-valve annulus area of 430 mm2 or less in a 1:1 ratio to undergo TAVR with either a self-expanding supraannular valve or a balloon-expandable valve. The coprimary end points, each assessed through 12 months, were a composite of death, disabling stroke, or rehospitalization for heart failure (tested for noninferiority) and a composite end point measuring bioprosthetic-valve dysfunction (tested for superiority). RESULTS: A total of 716 patients were treated at 83 sites in 13 countries (mean age, 80 years; 87% women; mean Society of Thoracic Surgeons Predicted Risk of Mortality, 3.3%). The Kaplan-Meier estimate of the percentage of patients who died, had a disabling stroke, or were rehospitalized for heart failure through 12 months was 9.4% with the self-expanding valve and 10.6% with the balloon-expandable valve (difference, -1.2 percentage points; 90% confidence interval [CI], -4.9 to 2.5; P<0.001 for noninferiority). The Kaplan-Meier estimate of the percentage of patients with bioprosthetic-valve dysfunction through 12 months was 9.4% with the self-expanding valve and 41.6% with the balloon-expandable valve (difference, -32.2 percentage points; 95% CI, -38.7 to -25.6; P<0.001 for superiority). The aortic-valve mean gradient at 12 months was 7.7 mm Hg with the self-expanding valve and 15.7 mm Hg with the balloon-expandable valve, and the corresponding values for additional secondary end points through 12 months were as follows: mean effective orifice area, 1.99 cm2 and 1.50 cm2; percentage of patients with hemodynamic structural valve dysfunction, 3.5% and 32.8%; and percentage of women with bioprosthetic-valve dysfunction, 10.2% and 43.3% (all P<0.001). Moderate or severe prosthesis-patient mismatch at 30 days was found in 11.2% of the patients in the self-expanding valve group and 35.3% of those in the balloon-expandable valve group (P<0.001). Major safety end points appeared to be similar in the two groups. CONCLUSIONS: Among patients with severe aortic stenosis and a small aortic annulus who underwent TAVR, a self-expanding supraannular valve was noninferior to a balloon-expandable valve with respect to clinical outcomes and was superior with respect to bioprosthetic-valve dysfunction through 12 months. (Funded by Medtronic; SMART ClinicalTrials.gov number, NCT04722250.).

Less Deformable Erythrocyte Subpopulations Biomechanically Induce Endothelial Inflammation in Sickle Cell Disease.

Sickle cell disease (SCD) is canonically characterized by reduced red blood cell (RBC) deformability leading to microvascular obstruction and inflammation. While the biophysical properties of sickle RBCs are known to influence SCD vasculopathy, the contribution of poor RBC deformability to endothelial dysfunction has yet to be fully explored. Leveraging interrelated in vitro and in silico approaches, we introduce a new paradigm of SCD vasculopathy in which poorly deformable sickle RBCs directly cause endothelial dysfunction via mechanotransduction, where endothelial cells sense and pathophysiologically respond to aberrant physical forces independently of microvascular obstruction, adhesion, or hemolysis. We demonstrate that perfusion of sickle RBCs or pharmacologically-dehydrated healthy RBCs into small venule-sized "endothelialized" microfluidics leads to pathologic physical interactions with endothelial cells that directly induce inflammatory pathways. Using a combination of computational simulations and large venule-sized endothelialized microfluidics, we observed that perfusion of heterogeneous sickle RBC subpopulations of varying deformability, as well as suspensions of dehydrated normal RBCs admixed with normal RBCs leads to aberrant margination of the less-deformable RBC subpopulations towards the vessel walls, causing localized, increased shear stress. Increased wall stress is dependent on the degree of subpopulation heterogeneity and oxygen tension and leads to inflammatory endothelial gene expression via mechanotransductive pathways. Our multifaceted approach demonstrates that the presence of sickle RBCs with reduced deformability leads directly to pathological physical (i.e., direct collisions and/or compressive forces) and shear-mediated interactions with endothelial cells and induces an inflammatory response, thereby elucidating the ubiquity of vascular dysfunction in SCD.

High-throughput quantification of red blood cell deformability and oxygen saturation to probe mechanisms of sickle cell disease.

The complex, systemic pathology of sickle cell disease is driven by multiple mechanisms including red blood cells (RBCs) stiffened by polymerized fibers of deoxygenated sickle hemoglobin. A critical step toward understanding the pathologic role of polymer-containing RBCs is quantifying the biophysical changes in these cells in physiologically relevant oxygen environments. We have developed a microfluidic platform capable of simultaneously measuring single RBC deformability and oxygen saturation under controlled oxygen and shear stress. We found that RBCs with detectable amounts of polymer have decreased oxygen affinity and decreased deformability. Surprisingly, the deformability of the polymer-containing cells is oxygen-independent, while the fraction of these cells increases as oxygen decreases. We also find that some fraction of these cells is present at most physiologic oxygen tensions, suggesting a role for these cells in the systemic pathologies. Additionally, the ability to measure these pathological cells should provide clearer targets for evaluating therapies.

Complete vs. Culprit-Only Revascularization in Older Patients with ST-segment Elevation Myocardial Infarction: An Individual Patient Meta-Analysis.

Background: Complete revascularization is the standard treatment for patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease. The Functional Assessment in Elderly MI Patients with Multivessel Disease (FIRE) trial confirmed the benefit of complete revascularization in a population of older patients, but the follow-up is limited to 1 year. Therefore, the long-term benefit ( > 1-year) of this strategy in older patients is debated. To address this, an individual patient data meta-analysis was conducted in STEMI patients aged 75 years or older enrolled in randomized clinical trials investigating complete vs. culprit-only revascularization strategies. Methods: PubMed, Embase, and the Cochrane database, were systematically searched to identify randomized clinical trials comparing complete vs. culprit-only revascularization. Individual patient-level data were collected from the relevant trials. The primary endpoint was death, myocardial infarction (MI), or ischemia-driven revascularization. The secondary endpoint was cardiovascular death or myocardial infarction. Results: Data from seven RCTs, encompassing 1733 patients (917 randomized to culprit-only and 816 to complete revascularization), were analyzed. The median age was 79 [77-83] years. Females were 595 (34%). Follow-up ranged from a minimum of six months to a maximum of 6.2 years (median 2.5 [1-3.8] years). Complete revascularization reduced the primary endpoint up to four years (HR 0.78, 95%CI 0.63-0.96), but not at the longest available follow-up (HR 0.83, 95%CI 0.69-1.01). Complete revascularization significantly reduced the occurrence of cardiovascular death or MI at the longest available follow-up (HR 0.76, 95%CI 0.58-0.99). This was observed even when censoring the follow-up at each year. Long-term rate of death did not differ between complete and culprit-only revascularization arms. Conclusions: In this individual patient data meta-analysis of older STEMI patients with multivessel disease, complete revascularization reduced the primary endpoint of death, MI or ischemia-driven revascularization up to 4-year. At the longest follow-up, complete revascularization reduced the composite of cardiovascular death or MI, but not the primary endpoint. Clinical Study Registration: PROSPERO CRD42022367898.

Great debate: pre-diabetes is not an evidence-based treatment target for cardiovascular risk reduction.

With the increasing burden of diabetes as a cause of macro- and microvascular disease linked to the epidemics of obesity, attention is being paid to dysglycaemic states that predict and precede the development of type 2 diabetes. Such conditions, termed pre-diabetes, are characterized by fasting plasma glucose, or plasma glucose levels on an oral glucose tolerance test, or values of glycated haemoglobin intermediate between 'normal' values and those characterizing diabetes. These last are by definition associated, in epidemiological terms, with a higher incidence of microvascular disease-mostly retinopathy. Pre-diabetes overlaps with the components of the 'metabolic syndrome'-among which are excess visceral adiposity; hypertension; hypertriglyceridaemia; high levels of small, dense low-density lipoproteins; and metabolic-associated fatty liver disease. There is little doubt that pre-diabetes has important prognostic implications, especially for the occurrence of myocardial infarction, ischaemic stroke, and peripheral arterial disease. It is disputed, however, whether pre-diabetes is itself an actionable disease entity, in addition to the risk factors characterizing it. Because of this uncertainty, the latest European Society of Cardiology guidelines chose not to include pre-diabetes as a treatment target for atherosclerotic cardiovascular disease, at variance from the three previous editions of such guidelines. This is spurring a debate, the Pro and Contra arguments featured in the present debate article.

A streamlined pathway for transcatheter aortic valve implantation: the BENCHMARK study.

BACKGROUND AND AIMS: There is significant potential to streamline the clinical pathway for patients undergoing transcatheter aortic valve implantation (TAVI). The purpose of this study was to evaluate the effect of implementing BENCHMARK best practices on the efficiency and safety of TAVI in 28 sites in 7 European countries. METHODS: This was a study of patients with severe symptomatic aortic stenosis (AS) undergoing TAVI with balloon-expandable valves before and after implementation of BENCHMARK best practices. Principal objectives were to reduce hospital length of stay (LoS) and duration of intensive care stay. Secondary objective was to document patient safety. RESULTS: Between January 2020 and March 2023, 897 patients were documented prior to and 1491 patients after the implementation of BENCHMARK practices. Patient characteristics were consistent with a known older TAVI population and only minor differences. Mean LoS was reduced from 7.7 ± 7.0 to 5.8 ± 5.6 days (median 6 vs. 4 days; P < .001). Duration of intensive care was reduced from 1.8 to 1.3 days (median 1.1 vs. 0.9 days; P < .001). Adoption of peri-procedure best practices led to increased use of local anaesthesia (96.1% vs. 84.3%; P < .001) and decreased procedure (median 47 vs. 60 min; P < .001) and intervention times (85 vs. 95 min; P < .001). Thirty-day patient safety did not appear to be compromised with no differences in all-cause mortality (0.6% in both groups combined), stroke/transient ischaemic attack (1.4%), life-threatening bleeding (1.3%), stage 2/3 acute kidney injury (0.7%), and valve-related readmission (1.2%). CONCLUSIONS: Broad implementation of BENCHMARK practices contributes to improving efficiency of TAVI pathway reducing LoS and costs without compromising patient safety.

Variation in secondary prevention of coronary heart disease: the INTERASPIRE study.

BACKGROUND AND AIMS: INTERASPIRE is an international study of coronary heart disease (CHD) patients, designed to measure if guideline standards for secondary prevention and cardiac rehabilitation are being achieved in a timely manner. METHODS: Between 2020 and 2023, adults hospitalized in the preceding 6-24 months with incident or recurrent CHD were sampled in 14 countries from all 6 World Health Organization regions and invited for a standardized interview and examination. Direct age and sex standardization was used for country-level prevalence estimation. RESULTS: Overall, 4548 (21.1% female) CHD patients were interviewed a median of 1.05 (interquartile range .76-1.45) years after index hospitalization. Among all participants, 24.6% were obese (40.7% centrally). Only 38.6% achieved a blood pressure (BP) < 130/80 mmHg and 16.6% a LDL cholesterol (LDL-C) of <1.4 mmol/L. Of those smoking at hospitalization, 48% persisted at interview. Of those with known diabetes, 55.2% achieved glycated haemoglobin (HbA1c) of <7.0%. A further 9.8% had undetected diabetes and 26.9% impaired glucose tolerance. Females were less likely to achieve the targets: BP (females 36.8%, males 38.9%), LDL-C (females 12.0%, males 17.9%), and HbA1c in diabetes (females 47.7%, males 57.5%). Overall, just 9.0% (inter-country range 3.8%-20.0%) reported attending cardiac rehabilitation and 1.0% (inter-country range .0%-2.4%) achieved the study definition of optimal guideline adherence. CONCLUSIONS: INTERASPIRE demonstrates inadequate and heterogeneous international implementation of guideline standards for secondary prevention in the first year after CHD hospitalization, with geographic and sex disparity. Investment aimed at reducing between-country and between-individual variability in secondary prevention will promote equity in global efforts to reduce the burden of CHD.

Faecal microbial transfer and complex carbohydrates mediate protection against COPD.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a major cause of global illness and death, most commonly caused by cigarette smoke. The mechanisms of pathogenesis remain poorly understood, limiting the development of effective therapies. The gastrointestinal microbiome has been implicated in chronic lung diseases via the gut-lung axis, but its role is unclear. DESIGN: Using an in vivo mouse model of cigarette smoke (CS)-induced COPD and faecal microbial transfer (FMT), we characterised the faecal microbiota using metagenomics, proteomics and metabolomics. Findings were correlated with airway and systemic inflammation, lung and gut histopathology and lung function. Complex carbohydrates were assessed in mice using a high resistant starch diet, and in 16 patients with COPD using a randomised, double-blind, placebo-controlled pilot study of inulin supplementation. RESULTS: FMT alleviated hallmark features of COPD (inflammation, alveolar destruction, impaired lung function), gastrointestinal pathology and systemic immune changes. Protective effects were additive to smoking cessation, and transfer of CS-associated microbiota after antibiotic-induced microbiome depletion was sufficient to increase lung inflammation while suppressing colonic immunity in the absence of CS exposure. Disease features correlated with the relative abundance of Muribaculaceae, Desulfovibrionaceae and Lachnospiraceae family members. Proteomics and metabolomics identified downregulation of glucose and starch metabolism in CS-associated microbiota, and supplementation of mice or human patients with complex carbohydrates improved disease outcomes. CONCLUSION: The gut microbiome contributes to COPD pathogenesis and can be targeted therapeutically.

Optimising brain age estimation through transfer learning: A suite of pre-trained foundation models for improved performance and generalisability in a clinical setting.

Estimated age from brain MRI data has emerged as a promising biomarker of neurological health. However, the absence of large, diverse, and clinically representative training datasets, along with the complexity of managing heterogeneous MRI data, presents significant barriers to the development of accurate and generalisable models appropriate for clinical use. Here, we present a deep learning framework trained on routine clinical data (N up to 18,890, age range 18-96 years). We trained five separate models for accurate brain age prediction (all with mean absolute error ≤4.0 years, R2 ≥ .86) across five different MRI sequences (T2 -weighted, T2 -FLAIR, T1 -weighted, diffusion-weighted, and gradient-recalled echo T2 *-weighted). Our trained models offer dual functionality. First, they have the potential to be directly employed on clinical data. Second, they can be used as foundation models for further refinement to accommodate a range of other MRI sequences (and therefore a range of clinical scenarios which employ such sequences). This adaptation process, enabled by transfer learning, proved effective in our study across a range of MRI sequences and scan orientations, including those which differed considerably from the original training datasets. Crucially, our findings suggest that this approach remains viable even with limited data availability (as low as N = 25 for fine-tuning), thus broadening the application of brain age estimation to more diverse clinical contexts and patient populations. By making these models publicly available, we aim to provide the scientific community with a versatile toolkit, promoting further research in brain age prediction and related areas.

Effects of complete revascularization according to age in patients with ST-segment elevation myocardial infarction and multivessel disease (COMPLETE-AGE).

BACKGROUND: In ST-segment elevation myocardial infarction (STEMI), complete revascularization with percutaneous coronary intervention (PCI) reduces major cardiovascular events compared with culprit-lesion-only PCI. Whether age influences these results remains unknown. METHODS: COMPLETE was a multinational, randomized trial evaluating a strategy of staged complete revascularization, consisting of angiography-guided PCI of all suitable nonculprit lesions, versus a strategy of culprit-lesion-only PCI. In this prespecified subgroup analysis, treatment effect according to age (≥65 years vs <65 years) was determined for the first coprimary outcome of cardiovascular (CV) death or new myocardial infarction (MI) and the second coprimary outcome of CV death, new MI, or ischemia-driven revascularization (IDR). Median follow-up was 35.8 months (interquartile range [IQR]: 27.6-44.3 months). RESULTS: Of 4,041 patients randomized in COMPLETE, 1,613 were aged ≥ 65 years (39.9%). Higher event rates were observed for both coprimary outcomes in patients aged ≥ 65 years comparted with those aged < 65 years (11.2% vs 7.9%, HR 1.49, 95% CI 1.22-1.83; 14.4% vs 11.8%, HR 1.28, 95% CI 1.07-1.52, respectively). Complete revascularization reduced the first coprimary outcome in patients ≥ 65 years (9.7% vs 12.5%, HR 0.77; 95% CI, 0.58-1.04) and < 65 years (6.7% vs 9.1%, HR 0.72; 95% CI, 0.54-0.96)(interaction P = .74). The second coprimary outcome was reduced in those ≥ 65 years (HR 0.56, 95% CI, 0.43-0.74) and < 65 years (HR 0.48, 95% CI, 0.37-0.61 (interaction P = .37). A sensitivity analysis was performed with consistent results demonstrated using a 75-year threshold (albeit attenuated). CONCLUSIONS: In patients with STEMI and multivessel CAD, complete revascularization compared with culprit-lesion-only PCI reduced major cardiovascular events regardless of patient age and could be considered as a revascularization strategy in older adults.

Bicuspid valve CT registry of balloon-expandable TAVR: BETTER TAVR registry.

BACKGROUND: The anatomic substrate of bicuspid valves may lead to suboptimal TAVR stent expansion and geometry. AIM: We evaluated determinants of stent geometry in bicuspid valves treated with Sapien transcatheter aortic valve replacement (TAVR) valves. METHODS: A multicenter retrospective registry of patients (February 2019 to August 2022) who underwent post-TAVR computed tomography to determine stent area (vs. nominal valve area) and stent ellipticity (maximum diameter/minimum diameter). Predictors of relative stent expansion (minimum area/average of inflow + outflow area) and stent ellipticity were evaluated in a multivariable regression model, including valve calcium volume (indexed by annular area), presence of raphe calcium, sinus diameters indexed by area-derived annular diameter, and performance of pre-dilation and post-dilation. RESULTS: The registry enrolled 101 patients from four centers. The minimum stent area (vs. nominal area) was 88.1%, and the maximum ellipticity was 1.10, with both observed near the midframe of the valve in all cases. Relative stent expansion ≥90% was observed in 64/101 patients. The only significant predictor of relative stent expansion ≥90% was the performance of post-dilation (OR: 4.79, p = 0.018). Relative stent expansion ≥90% was seen in 86% of patients with post-dilation compared to 57% without (p < 0.001). The stent ellipticity ≥1.1 was observed in 47/101 patients. The significant predictors of stent ellipticity ≥1.1 were the indexed maximum sinus diameter (OR: 0.582, p = 0.021) and indexed intercommisural diameter at 4 mm (OR: 2.42, p = 0.001). Stent expansion has a weak negative correlation with post-TAVR mean gradient (r = -0.324, p < 0.001). CONCLUSION: Relative stent expansion ≥90% was associated with the performance of post-dilation, and stent ellipticity ≥1.1 was associated with indexed intercommisural diameter and indexed maximum sinus diameter. Further studies to determine optimal deployment strategies in bicuspid valves are needed.

Scalable dual column cation exchange affinity chromatography based platform process for recombinant protein purification.

A novel tandem affinity tag is presented that enables the use of cation exchange resins for initial affinity purification, followed by an additional column step for enhanced purity and affinity tag self-removal. In this method, the highly charged heparin-binding tag binds strongly and selectively to either a strong or weak cation exchange resin based on electrostatic interactions, effectively acting as an initial affinity tag. Combining the heparin-binding tag (HB-tag) with the self-removing iCapTag™ provides a means for removing both tags in a subsequent self-cleaving step. The result is a convenient platform for the purification of diverse tagless proteins with a range of isoelectric points and molecular weights. In this work, we demonstrate a dual column process in which the tagged protein of interest is first captured from an E. coli cell lysate using a cation exchange column via a fused heparin-binding affinity tag. The partially purified protein is then diluted and loaded onto an iCapTag™ split-intein column, washed, and then incubated overnight to release the tagless target protein from the bound tag. Case studies are provided for enhanced green fluorescent protein (eGFP), beta galactosidase (ßgal), maltose binding protein (MBP) and beta lactamase (ßlac), where overall purity and host cell DNA clearance is provided. Overall, the proposed dual column process is shown to be a scalable platform technology capable of accessing both the high dynamic binding capacity of ion exchange resins and the high selectivity of affinity tags for the purification of recombinant proteins.

Improved self-cleaving precipitation tags for efficient column free bioseparations.

Current biological research requires simple protein bioseparation methods capable of purifying target proteins in a single step with high yields and purities. Conventional affinity tag-based approaches require specific affinity resins and expensive proteolytic enzymes for tag removal. Purification strategies based on self-cleaving aggregating tags have been previously developed to address these problems. However, these methods often utilize C-terminal cleaving contiguous inteins which suffer from premature cleavage, resulting in significant product loss during protein expression. In this work, we evaluate two novel mutants of the Mtu RecA ΔI-CM mini-intein obtained through yeast surface display for improved protein purification. When used with the elastin-like-polypeptide (ELP) precipitation tag, the novel mutants - ΔI-12 and ΔI-29 resulted in significantly higher precursor content, product purity and process yield compared to the original Mtu RecA ΔI-CM mini-intein. Product purities ranging from 68 % to 94 % were obtained in a single step for three model proteins - green fluorescent protein (GFP), maltose binding protein (MBP) and beta-galactosidase (beta-gal). Further, high cleaving efficiency was achieved after 5 h under most conditions. Overall, we have developed improved self-cleaving precipitation tags which can be used for purifying a wide range of proteins cheaply at laboratory scale.

Artificial intelligence in clinical pharmacology: A case study and scoping review of large language models and bioweapon potential.

This paper aims to explore the possibility of employing large language models (LLMs) - a type of artificial intelligence (AI) - in clinical pharmacology, with a focus on its possible misuse in bioweapon development. Additionally, ethical considerations, legislation and potential risk reduction measures are analysed. The existing literature is reviewed to investigate the potential misuse of AI and LLMs in bioweapon creation. The search includes articles from PubMed, Scopus and Web of Science Core Collection that were identified using a specific protocol. To explore the regulatory landscape, the OECD.ai platform was used. The review highlights the dual-use vulnerability of AI and LLMs, with a focus on bioweapon development. Subsequently, a case study is used to illustrate the potential of AI manipulation resulting in harmful substance synthesis. Existing regulations inadequately address the ethical concerns tied to AI and LLMs. Mitigation measures are proposed, including technical solutions (explainable AI), establishing ethical guidelines through collaborative efforts, and implementing policy changes to create a comprehensive regulatory framework. The integration of AI and LLMs into clinical pharmacology presents invaluable opportunities, while also introducing significant ethical and safety considerations. Addressing the dual-use nature of AI requires robust regulations, as well as adopting a strategic approach grounded in technical solutions and ethical values following the principles of transparency, accountability and safety. Additionally, AI's potential role in developing countermeasures against novel hazardous substances is underscored. By adopting a proactive approach, the potential benefits of AI and LLMs can be fully harnessed while minimizing the associated risks.

The INTOXICATE study: methodology and preliminary results of a prospective observational study.

BACKGROUND: There is currently no practice-based, multicenter database of poisoned patients admitted to intensive care units (ICUs). The INTOXICATE study, endorsed by the ESICM and EAPCCT, aimed to determine the rate of eventful admissions among acutely intoxicated adult ICU patients. METHODS: Ethical approval was obtained for this multicenter, prospective observational study, and data-sharing agreements were signed with each participating center. An electronic case report form was used to collect data on patient demographics, exposure, clinical characteristics, investigations, treatment, and in-hospital mortality data. The primary outcome, 'eventful admission', was a composite outcome defined as the rate of patients who received any of the following treatments in the first 24 h after the ICU admission: oxygen supplementation with a FiO2 > 40%, mechanical ventilation, vasopressors, renal replacement therapy (RRT), cardiopulmonary resuscitation, antidotes, active cooling, fluid resuscitation (> 1.5 L of intravenous fluid of any kind), sedation, or who died in the hospital. RESULTS: Seventy-eight ICUs, mainly from Europe, but also from Australia and the Eastern Mediterranean, participated. A total of 2,273 patients were enrolled between November 2020 and June 2023. The median age of the patients was 41 years, 72% were exposed to intoxicating drugs. The observed rate of patients with an eventful ICU admission was 68% (n = 1546/2273 patients). The hospital mortality was 4.5% (n = 103/2273). CONCLUSIONS: The vast majority of patients survive, and approximately one third of patients do not receive any ICU-specific interventions after admission in an intensive care unit for acute intoxication. High-quality detailed clinical data have been collected from a large cohort of acutely intoxicated ICU patients, providing information on the pattern of severe acute poisoning requiring intensive care admission and the outcomes of these patients. TRIAL REGISTRATION: OSF registration ID: osf.io/7e5uy.

Joint RCEM and NPIS best practice guideline: assessment and management of acute opioid toxicity in adults in the emergency department.

The Royal College of Emergency Medicine Toxicology Special Interest Group in collaboration with the UK National Poisons Information Service and the Clinical Toxicology Department at Guy's and St Thomas' NHS Foundation Trust has produced guidance to support clinicians working in the ED with the assessment and management of adults with acute opioid toxicity.Considerations regarding identification of acute opioid toxicity are discussed and recommendations regarding treatment options and secondary prevention are made. There is a focus on making recommendations on the best available evidence.

Trend-attribute forecasting of hourly PM2.5 trends in fifteen cities of Central England applying optimized machine learning feature selection.

Recorded particulate matter (PM2.5) hourly trends are compared for fifteen urban recording sites distributed across central England for the period 2018 to 2022. They include 10 urban-background and five urban-traffic (roadside) sites with some located within the same urban area. The sites all show consistent background and peak distributions with mean annual values and standard deviations higher for 2018 and 2019 than for 2020 to 2022. The objective of this study is to demonstrate that trend attributes extracted from hourly recorded univariate PM2.5 trends at these sites can be used to provide reliable short-term hourly predictions and provide valuable insight into the regional variations in the recorded trends. Fifteen trend attributes extracted from the prior 12 h (t-1 to t-12) of recorded PM2.5 data were compiled and used as input to four supervised machine learning models (SML) to forecast PM2.5 concentrations up to 13 h ahead (t0 to t+12). All recording sites delivered forecasts with similar ranges of error levels for specific hours ahead which are consistent with their PM2.5 recorded ranges. Forecasting results for four representative sites are presented in detail using models trained and cross-validated with 2020 and 2021 hourly data to forecast 2021 and 2022 hourly data, respectively. A novel optimized feature selection procedure using a suite of five optimizers is used to improve the efficiency of the forecasting models. The LASSO and support vector regression models generate the best and most generalizable hourly PM2.5 forecasts from trained and validated SML models with mean average error (MAE) of between ∼1 and ∼3 µg/m3 for t0 to t+3 h ahead. A novel overfitting indicator, exploiting the cross-validation mean values, demonstrates that these two models are not affected by overfitting. Forecasts for t+6 to t+12 h forward generate higher MAE values between ∼3 and ∼4 µg/m3 due to their tendency to underestimate some of the extreme PM2.5 peaks. These findings indicate that further model refinements are required to generate more reliable short-term predictions for the t+6 to t+24 h ahead.

Osteohematology: To be or Notch to be.

Osteohematology is an emerging research field that studies the crosstalk between hematopoietic and bone stromal cells, to elucidate the mechanisms of hematological and skeletal malignancies and diseases. The Notch is an evolutionary conserved developmental signaling pathway, with critical roles in embryonic development by controlling cell proliferation and differentiation. However, the Notch pathway is also critically involved in cancer initiation and progression, such as osteosarcoma, leukemia, and multiple myeloma. The Notch-mediated malignant cells dysregulate bone and bone marrow cells in the tumour microenvironment, resulting in disorders ranging from osteoporosis to bone marrow dysfunction. To date, the complex interplay of Notch signaling molecules in hematopoietic and bone stromal cells is still poorly understood. In this mini-review, we summarize the crosstalk between cells in bone and bone marrow and their influence under the Notch signaling pathway in physiological conditions and in tumour microenvironment.