Search

Archaea are a group of single-celled microorganisms with distinct characteristics, and constitute 1 of the 3 domains of life, along with bacteria and eukarya. Although they were thought to live [...]

Abstract Background Invasive blood pressure measurement is the in-hospital gold standard to guide hemodynamic management and consecutively cerebral perfusion pressure in patients with traumatic brain injury (TBI). Its prehospital use is controversial since it may delay further care. The primary aim of this study was to test the hypothesis that patients with severe traumatic brain injury who receive prehospital arterial cannulation, compared to those with in-hospital cannulation, do not have a prolonged time between on-scene arrival and first computed tomography (CT) of the head by more than ten minutes. Methods This retrospective study included patients 18 years and older with isolated severe TBI and prehospital induction of emergency anaesthesia who received treatment in the resuscitation room of the University Hospital of Graz between January 1st, 2015, and December 31st, 2022. A Wilcoxon rank-sum test was used to test for non-inferiority (margin = ten minutes) of the time interval between on-scene arrival and first head CT. Results We included data of 181 patients in the final analysis. Prehospital arterial line insertion was performed in 87 patients (48%). Median (25–75th percentile) durations between on-scene arrival and first head CT were 73 (61–92) min for prehospital arterial cannulation and 75 (60–93) min for arterial cannulation in the resuscitation room. Prehospital arterial line insertion was significantly non-inferior within a margin of ten minutes with a median difference of 1 min (95% CI − 6 to 7, p = 0.003). Conclusion Time-interval between on-scene arrival and first head CT in patients with isolated severe traumatic brain injury who received prehospital arterial cannulation was not prolonged compared to those with in-hospital cannulation. This supports early out-of-hospital arterial cannulation performed by experienced providers.

Abstract Archaea are vital components of the human microbiome, yet their study within the gastrointestinal tract (GIT) is limited by the scarcity of cultured representatives. Our study presents a method for the targeted enrichment and isolation of methanogenic archaea from human fecal samples. The procedure combines methane breath testing, in silico metabolic modeling, media optimization, FACS, dilution series, and genomic sequencing through Nanopore technology. Additional analyzes include the co-cultured bacteriome, comparative genomics of archaeal genomes, functional comparisons, and structure-based protein function prediction of unknown differential traits. Successful establishment of stable archaeal cultures from 14 out of 16 fecal samples yielded nine previously uncultivated strains, eight of which are absent from a recent archaeome genome catalog. Comparative genomic and functional assessments of Methanobrevibacter smithii and Candidatus Methanobrevibacter intestini strains from individual donors revealed features potentially associated with gastrointestinal diseases. Our work broadens available archaeal representatives for GIT studies, and offers insights into Candidatus Methanobrevibacter intestini genomes’ adaptability in critical microbiome contexts.

Archaea represent a separate domain of life, next to bacteria and eukarya. As components of the human microbiome, archaea have been associated with various diseases, including periodontitis, endodontic infections, small intestinal bacterial overgrowth, and urogenital tract infections. Archaea are generally considered nonpathogenic; the reasons are speculative because of limited knowledge and gene annotation challenges. Nevertheless, archaeal syntrophic principles that shape global microbial networks aid both archaea and potentially pathogenic bacteria. Evaluating archaea interactions remains challenging, requiring clinical studies on inflammatory potential and the effects of archaeal metabolism. Establishing a culture collection is crucial for investigating archaea functions within the human microbiome, which could improve health outcomes in infectious diseases. We summarize potential reasons for archaeal nonpathogenicity, assess the association with infectious diseases in humans, and discuss the necessary experimental steps to enable mechanistic studies involving archaea.

Plastics are ubiquitous materials in our daily lives, but their inadequate disposal has led to the widespread distribution of their micro- and nanoparticles in various ecosystems. Their detection in feed and food, as well as in livestock and human stool samples, strongly suggests a continuous circulation in the feed and food chain. The ability of plastic particles to penetrate the intestinal barrier determines their accumulation in the body and in food of animal origin. The gastrointestinal (GI) microbiome, whose fermentation activity can influence the particle size distribution of certain plastic materials and which is known to modulate the permeability of the intestinal barrier, may be a critical hub in this transfer. This review attempts to summarise research efforts to date on the interaction between microplastics (MPs) and the GI microbiome of humans, mice, chickens and aquatic animals. We have analysed the state of knowledge and identified future avenues for targeted research approaches to answer open questions regarding the interaction of plastic particles with the GI microbiome, which may help to develop predictive models for the accumulation of plastic particles from feed and food in the body and animal products, respectively.HIGHLIGHTS Microplastics (MPs) influence the gastrointestinal (GI) microbiome. The microbiome may facilitate microplastic breakdown. This may influence the size distribution of plastic particles and their potential to penetrate the intestinal barrier.

The stratospheric polar vortex (SPV) comprises strong westerly winds during winter in each hemisphere. Despite ample knowledge on the SPV's high variability and its frequent disruptions by sudden stratospheric warmings (SSWs) in the Northern Hemisphere (NH), questions on how well current climate models can simulate these dynamics remain open. Specifically the accuracy in reproducing SPV morphology and the differentiation between split and displacement SSW events are crucial to assess the models in this regard. In this study, we evaluate the capability of climate models to simulate the NH SPV by comparing large ensembles of historical simulations to ERA5 reanalysis data. For this, we analyze geometric-based diagnostics at three pressure levels that describe SPV morphology. Our analysis reveals that no model exactly reproduces SPV morphology of ERA5 in all diagnostics at all altitudes. Concerning the SPV morphology as stretching (aspect ratio) and location (centroid latitude) parameters, most models are biased to some extent, but the strongest deviations can be found for the vortex-splitting parameter (excess kurtosis). Moreover, some models underestimate the variability of SPV strength. Assessing the reliability of the ensembles in distinguishing SSWs subdivided into SPV displacement and split events, we find large differences between the model ensembles. In general, SPV displacements are represented better than splits in the simulation ensembles, and high-top models and models with finer vertical resolution perform better. A good performance in representing the morphological diagnostics does not necessarily imply reliability and therefore a good performance in simulating displacements and splits. Assessing the model biases and their representation of SPV dynamics is needed to improve credibility of climate model projections, for example, by giving stronger weightings to better performing models.

Yun Liu,1,2 Timo Hamm,3 Thomas Ralf Eichinger,3 Walter Kamm,3 Heike Andrea Wieland,3 Brigitta Loretz,1 Anna KH Hirsch,2,4 Sangeun Lee,1,2 Claus-Michael Lehr1,2 1Department of Drug Delivery Across Biological Barriers, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany; 2Department of Pharmacy, Saarland University, Saarbrücken, Germany; 3Department of Research and Development, Sanofi-Aventis Deutschland GmbH, Frankfurt Am Main, Germany; 4Department of Drug Design and Optimisation, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, GermanyCorrespondence: Claus-Michael Lehr, Department of Drug Delivery Across Biological Barriers, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany, Tel +49 681 98806-1000, Fax +49 681 98806 1009, Email Claus-Michael.Lehr@helmholtz-hips.de Sangeun Lee, Department of Pharmacy, Saarland University, Saarbrücken, Germany, Tel +49 681 302 4764, Fax +49 681 302 2028, Email Sangeun.Lee@uni-saarland.deBackground: Therapeutic proteins and peptides offer great advantages compared to traditional synthetic molecular drugs. However, stable protein loading and precise control of protein release pose significant challenges due to the extensive range of physicochemical properties inherent to proteins. The development of a comprehensive protein delivery strategy becomes imperative accounting for the diverse nature of therapeutic proteins.Methods: Biodynamers are amphiphilic proteoid dynamic polymers consisting of amino acid derivatives connected through pH-responsive dynamic covalent chemistry. Taking advantage of the amphiphilic nature of the biodynamers, PNCs and DEs were possible to be prepared and investigated to compare the delivery efficiency in drug loading, stability, and cell uptake.Results: As a result, the optimized PNCs showed 3-fold encapsulation (< 90%) and 5-fold loading capacity (30%) compared to DE-NPs. PNCs enhanced the delivery efficiency into the cells but aggregated easily on the cell membrane due to the limited stability. Although DE-NPs were limited in loading capacity compared to PNCs, they exhibit superior adaptability in stability and capacity for delivering a wider range of proteins compared to PNCs.Conclusion: Our study highlights the potential of formulating both PNCs and DE-NPs using the same biodynamers, providing a comparative view on protein delivery efficacy using formulation methods. Keywords: amphiphilic polymer, nanocomplex, double emulsion, pH-responsive, protein delivery, dynamic covalent chemistry

ABSTRACT Hospitals are subject to strict microbial control. Stringent cleaning and confinement measures in hospitals lead to a decrease in microbial diversity, but an increase in resistance genes. Given the rise of antimicrobial resistances and healthcare-associated infections, understanding the hospital microbiome and its resistome is crucial. This study compared the microbiome and resistome at different levels of confinement (CL) within a single hospital. Using amplicon sequencing, shotgun metagenomics, and genome/plasmid reconstruction, we demonstrate that microbial composition differs in a stable way between the CLs and that the most restrictive confinement level CL1 had the lowest microbial but the highest functional diversity. This CL also exhibited a greater abundance of functions related to virulence, disease, defense, and stress response. Comparison of antibiotic resistance also showed differences among CLs in terms of the selection process and specific mechanisms for antimicrobial/antibiotic resistance. The resistances found in the samples of CL1 were mostly mediated via antibiotic efflux pumps and were mainly located on chromosomes, whereas in the other, less restrictive CL antibiotic resistances were more present on plasmids. This could be of particular importance for patient-related areas (CL2), as the potential spread of antibiotic resistances could be a major concern in this area. Our results show that there are differences in the microbiome and resistome even within a single hospital, reflecting room utilization and confinement. Since restrictive confinement selects for resistant microorganisms, strategies are required to deepen our understanding of dynamic processes of microbiome and resistome within hospital environments.IMPORTANCEEffective measures to combat antibiotic resistances and healthcare-associated infections are urgently needed, including optimization of microbial control. However, previous studies have indicated that stringent control can lead to an increase in the resistance capacities of microbiomes on surfaces. This study adds to previous knowledge by focusing on the conditions in a single hospital, resolving the microbiomes and their resistomes in three different confinement levels (CL): operating room, patient-related areas, and non-patient-related areas. We were able to identify stable key taxa; profiled the capacities of taxa, functions, and antimicrobial resistances (AMR); and reconstruct genomes and plasmids in each CL. Our results show that the most restrictive CL indeed had the highest functional diversity, but that resistances were mostly encoded on chromosomes, indicating a lower possibility of resistance spread. However, clever strategies are still required to strike a balance between microbial control and selective pressures in environments where patients need protection.

ABSTRACT The microbial ecosystem of women undergoes enormous changes during pregnancy and the perinatal period. Little is known about the extent of changes in the maternal microbiome beyond the vaginal cavity and its recovery after birth. In this study, we followed pregnant women [maternal prepartum (mpre), n = 30] into the postpartum period [1 month postpartum, maternal postpartum (mpost), n = 30]. We profiled their oral, urinary, and vaginal microbiome; archaeome; mycobiome; and urinary metabolome and compared them with those of nonpregnant (np) women (n = 29). Overall, pregnancy status (np, mpre, and mpost) had a smaller effect on the microbiomes than body site, but massive transitions were observed for the oral and urogenital (vaginal and urinary) microbiomes. While the oral microbiome fluctuates during pregnancy but stabilizes rapidly within the first month postpartum, the urogenital microbiome is characterized by a major remodeling caused by a massive loss of Lactobacillus and thus a shift from Vaginal Community State Type (CST) I (40% of women) to CST IV (85% of women). The urinary metabolome rapidly reached an np-like composition after delivery, apart from lactose and oxaloacetic acid, which were elevated during active lactation. Fungal and archaeal profiles were indicative of pregnancy status. Methanobacterium signatures were found mainly in np women, and Methanobrevibacter showed an opposite behavior in the oral cavity (increased) and vagina (decreased) during pregnancy. Our findings suggest that the massive remodeling of the maternal microbiome and metabolome needs more attention and that potential interventions could be envisioned to optimize recovery and avoid long-term effects on maternal health and subsequent pregnancies.IMPORTANCEThe perinatal microbiome is of specific interest for the health of the mother and infant. We therefore investigate the dynamics of the female microbiome from nonpregnant over prepartum to the postpartum period in urine and the oral and vaginal cavities. A specific focus of this study is put not only on the bacterial part of the microbiome but also on the underinvestigated contribution of fungi and archaea. To our knowledge, we present the first study highlighting those aspects. Our findings suggest that the massive remodeling of the maternal microbiome and metabolome needs more attention and that potential interventions could be envisioned to optimize recovery and avoid long-term effects on maternal health and subsequent pregnancies.

Observational monitoring of the stratospheric transport circulation, the Brewer–Dobson circulation (BDC), is crucial to estimate any decadal to long-term changes therein, a prerequisite to interpret trends in stratospheric composition and to constrain the consequential impacts on climate. The transport time along the BDC (i.e. the mean stratospheric age of air, AoA) can best be deduced from trace gas measurements of tracers which increase linearly with time and are chemically passive. The gas sulfur hexafluoride (SF6) is often used to deduce AoA because it has been increasing monotonically since the ∼1950s, and previously its chemical sinks in the mesosphere have been assumed to be negligible for AoA estimates. However, recent studies have shown that the chemical sinks of SF6 are stronger than assumed and become increasingly relevant with rising SF6 concentrations. To adjust biases in AoA that result from the chemical SF6 sinks, we here propose a simple correction scheme for SF6-based AoA estimates accounting for the time-dependent effects of chemical sinks. The correction scheme is based on theoretical considerations with idealized assumptions, resulting in a relation between ideal AoA and apparent AoA which is a function of the tropospheric reference time series of SF6 and of the AoA-dependent effective lifetime of SF6. The correction method is thoroughly tested within a self-consistent data set from a climate model that includes explicit calculation of chemical SF6 sinks. It is shown within the model that the correction successfully reduces biases in SF6-based AoA to less than 5 % for mean ages below 5 years. Tests using only subsampled data for deriving the fit coefficients show that applying the correction scheme even with imperfect knowledge of the sink is far superior to not applying a sink correction. Furthermore, we show that based on currently available measurements, we are not able to constrain the fit parameters of the correction scheme based on observational data alone. However, the model-based correction curve lies within the observational uncertainty, and we thus recommend using the model-derived fit coefficients until more high-quality measurements are able to further constrain the correction scheme. The application of the correction scheme to AoA from satellites and in situ data suggests that it is highly beneficial to reconcile different observational estimates of mean AoA.

Abstract Background Metachromatic leukodystrophy (MLD; OMIM 250100 and 249900) is a rare lysosomal storage disease caused by deficient arylsulfatase A activity, leading to accumulation of sulfatides in the nervous system. This systematic literature review aimed to explore the effect of MLD on the lives of patients. Methods The Ovid platform was used to search Embase, MEDLINE, and the Cochrane Library for articles related to the natural history, clinical outcomes, and burden of illness of MLD; congress and hand searches were performed using ‘metachromatic leukodystrophy’ as a keyword. Of the 531 publications identified, 120 were included for data extraction following screening. A subset of findings from studies relating to MLD natural history and burden of illness (n = 108) are presented here. Results The mean age at symptom onset was generally 16–18 months for late-infantile MLD and 6–10 years for juvenile MLD. Age at diagnosis and time to diagnosis varied widely. Typically, patients with late-infantile MLD presented predominantly with motor symptoms and developmental delay; patients with juvenile MLD presented with motor, cognitive, and behavioral symptoms; and patients with adult MLD presented with cognitive symptoms and psychiatric and mood disorders. Patients with late-infantile MLD had more rapid decline of motor function over time and lower survival than patients with juvenile MLD. Commonly reported comorbidities/complications included ataxia, epilepsy, gallbladder abnormalities, incontinence, neuropathy, and seizures. Conclusions Epidemiology of MLD by geographic regions, quantitative cognitive data, data on the differences between early- and late-juvenile MLD, and humanistic or economic outcomes were limited. Further studies on clinical, humanistic (i.e., quality of life), and economic outcomes are needed to help inform healthcare decisions for patients with MLD.

Abstract Background The assessment of illness severity in the prehospital setting is essential for guiding appropriate medical interventions. The National Advisory Committee for Aeronautics (NACA) score is a validated tool commonly used for this purpose. However, the potential benefits of using bitemporal documentation of NACA scores to capture the dynamic changes in emergency situations remain uncertain. The objective of this study was to evaluate the potential benefit of bitemporal NACA score documentation in the prehospital setting, specifically in assessing the dynamic changes of emergencies and facilitating quality improvement through enhanced documentation practices. Methods In this retrospective study, data from prehospital emergency patients were analyzed who received care from the physician response unit between January 1, 2018, and May 31, 2021. Patient demographics, NACA scores, indications for emergency care, and changes in NACA scores were extracted from medical records. Statistical analyses were performed to examine the associations between NACA scores, emergency categories, indications, and changes in NACA scores. Results The study included 4005 patients, predominantly categorized as NACA III (33.7% at initial assessment, 41.8% at subsequent assessment) and NACA IV (31.6% at initial assessment, 22.4% at subsequent assessment). There was a significant improvement in NACA scores during the provision of prehospital care (p

Abstract Background Aronia melanocarpa is a berry rich in polyphenols known for health benefits. However, the bioavailability of polyphenols has been questioned, and the individual taste acceptance of the fruit with its specific flavor varies. We recently observed substantial differences in the tolerability of aronia juice among healthy females, with half of the individuals tolerating aronia juice without complaints. Given the importance of the gut microbiome in food digestion, we investigated in this secondary analysis of the randomized placebo-controlled parallel intervention study (ClinicalTrials.gov registration: NCT05432362) if aronia juice tolerability was associated with changes in intestinal microbiota and bacterial metabolites, seeking for potential mechanistic insights into the impact on aronia polyphenol tolerance and metabolic outcomes. Results Forty females were enrolled for this 6-week trial, receiving either 100 ml natural aronia juice (verum, V) twice daily or a polyphenol-free placebo (P) with a similar nutritional profile, followed by a 6-week washout. Within V, individuals were categorized into those who tolerated the juice well (Vt) or reported complaints (Vc). The gut microbiome diversity, as analyzed by 16S rRNA gene-based next-generation sequencing, remained unaltered in Vc but changed significantly in Vt. A MICOM-based flux balance analysis revealed pronounced differences in the 40 most predictive metabolites post-intervention. In Vc carbon-dioxide, ammonium and nine O-glycans were predicted due to a shift in microbial composition, while in Vt six bile acids were the most likely microbiota-derived metabolites. NMR metabolomics of plasma confirmed increased lipoprotein subclasses (LDL, VLDL) post-intervention, reverting after wash out. Stool samples maintained a stable metabolic profile. Conclusion In linking aronia polyphenol tolerance to gut microbiota-derived metabolites, our study explores adaptive processes affecting lipoprotein profiles during high polyphenol ingestion in Vt and examines effects on mucosal gut health in response to intolerance to high polyphenol intake in Vc. Our results underpin the importance of individualized hormetic dosing for beneficial polyphenol effects, demonstrate dynamic gut microbiome responses to aronia juice, and emphasize personalized responses in polyphenol interventions. Graphical Abstract Video Abstract

The gut microbiota has been implicated as a driver of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Recently we described, mucosal biofilms, signifying alterations in microbiota composition and bile acid (BA) metabolism in IBS and ulcerative colitis (UC). Luminal oxygen concentration is a key factor in the gastrointestinal (GI) ecosystem and might be increased in IBS and UC. Here we analyzed the role of archaea as a marker for hypoxia in mucosal biofilms and GI homeostasis. The effects of archaea on microbiome composition and metabolites were analyzed via amplicon sequencing and untargeted metabolomics in 154 stool samples of IBS-, UC-patients and controls. Mucosal biofilms were collected in a subset of patients and examined for their bacterial, fungal and archaeal composition. Absence of archaea, specifically Methanobrevibacter, correlated with disrupted GI homeostasis including decreased microbial diversity, overgrowth of facultative anaerobes and conjugated secondary BA. IBS-D/-M was associated with absence of archaea. Presence of Methanobrevibacter correlated with Oscillospiraceae and epithelial short chain fatty acid metabolism and decreased levels of Ruminococcus gnavus. Absence of fecal Methanobrevibacter may indicate a less hypoxic GI environment, reduced fatty acid oxidation, overgrowth of facultative anaerobes and disrupted BA deconjugation. Archaea and Ruminococcus gnavus could distinguish distinct subtypes of mucosal biofilms. Further research on the connection between archaea, mucosal biofilms and small intestinal bacterial overgrowth should be performed.

Abstract Climate models robustly project acceleration of the Brewer‐Dobson circulation (BDC) in response to climate change. However, the BDC trends simulated by comprehensive models are poorly constrained by observations, which cannot even determine the sign of potential trends. Additionally, the changing structure of the troposphere and stratosphere has received increasing attention in recent years. The extent to which vertical shifts of the circulation are driving the acceleration is under debate. In this study, we present a novel method that enables the attribution of advective BDC changes to structural changes of the circulation and of the stratosphere itself. Using this method allows studying the advective BDC trends in unprecedented detail and sheds new light into discrepancies between different data sets (reanalyses and models) at the tropopause and in the lower stratosphere. Our findings provide insights into the reliability of model projections of BDC changes and offer new possibilities for observational constraints.

ABSTRACT STW 5, a blend of nine medicinal plant extracts, exhibits promising efficacy in treating functional gastrointestinal disorders, notably irritable bowel syndrome (IBS). Nonetheless, its effects on the gastrointestinal microbiome and the role of microbiota on the conversion of its constituents are still largely unexplored. This study employed an experimental ex vivo model to investigate STW 5’s differential effects on fecal microbial communities and metabolite production in samples from individuals with and without IBS. Using 560 fecal microcosms (IBS patients, n = 6; healthy controls, n = 10), we evaluated the influence of pre-digested STW 5 and controls on microbial and metabolite composition at time points 0, 0.5, 4, and 24 h. Our findings demonstrate the potential of this ex vivo platform to analyze herbal medicine turnover within 4 h with minimal microbiome shifts due to abiotic factors. While only minor taxonomic disparities were noted between IBS- and non-IBS samples and upon treatment with STW 5, rapid metabolic turnover of STW 5 components into specific degradation products, such as 18β-glycyrrhetinic acid, davidigenin, herniarin, 3-(3-hydroxyphenyl)propanoic acid, and 3-(2-hydroxy-4-methoxyphenyl)propanoic acid occurred. For davidigenin, 3-(3-hydroxyphenyl)propanoic acid and 18β-glycyrrhetinic acid, anti-inflammatory, cytoprotective, or spasmolytic activities have been previously described. Notably, the microbiome-driven metabolic transformation did not induce a global microbiome shift, and the detected metabolites were minimally linked to specific taxa. Observed biotransformations were independent of IBS diagnosis, suggesting potential benefits for IBS patients from biotransformation products of STW 5.IMPORTANCESTW 5 is an herbal medicinal product with proven clinical efficacy in the treatment of functional gastrointestinal disorders, like functional dyspepsia and irritable bowel syndrome (IBS). The effects of STW 5 on fecal microbial communities and metabolite production effects have been studied in an experimental model with fecal samples from individuals with and without IBS. While only minor taxonomic disparities were noted between IBS- and non-IBS samples and upon treatment with STW 5, rapid metabolic turnover of STW 5 components into specific degradation products with reported anti-inflammatory, cytoprotective, or spasmolytic activities was observed, which may be relevant for the pharmacological activity of STW 5.

Activated lung ILC2s produce large quantities of IL-5 and IL-13 that contribute to eosinophilic inflammation and mucus production following respiratory syncytial virus infection (RSV). The current understanding of ILC2 activation during RSV infection, is that ILC2s are activated by alarmins, including IL-33, released from airway epithelial cells in response to viral-mediated damage. Thus, high levels of RSV neutralizing maternal antibody generated from maternal immunization would be expected to reduce IL-33 production and mitigate ILC2 activation. Here we report that lung ILC2s from mice born to RSV-immunized dams become activated despite undetectable RSV replication. We also report, for the first time, expression of activating and inhibitory Fcgamma receptors on ILC2s that are differentially expressed in offspring born to immunized versus unimmunized dams. Alternatively, ex vivo IL-33-mediated activation of ILC2s was mitigated following the addition of antibody: antigen immune complexes. Further studies are needed to confirm the role of Fcgamma receptor ligation by immune complexes as an alternative mechanism of ILC2 regulation in RSV-associated eosinophilic lung inflammation.

Background: Hyperkalaemia is a common electrolyte abnormality seen in critically ill patients. In haemorrhagic shock, it may contribute to cardiac arrest and has been identified as a potential marker for tissue hypoxia. However, the significance of its role in haemorrhagic shock and its contribution to mortality remains unclear. This study aimed to examine the potential underlying pathophysiology and evaluate the incidence and characteristics of patients with hyperkalaemia on hospital arrival in bleeding trauma patients before transfusions and its mortality. Methods: A retrospective cohort study was conducted on adult patients with traumatic bleeding admitted to a European Major Trauma Centre between January 2016 and December 2021. Patients were classified according to their serum potassium levels on arrival, and relevant clinical parameters between non-hyperkalaemic and hyperkalaemic patients were compared. Results: Among the 83 patients in this study, 8 (9.6 %) presented with hyperkalaemia on arrival. The median shock index showed a higher tendency in the hyperkalaemic group. Hyperkalaemia was found to be more common among younger patients who sustained penetrating trauma. Mortality rates were higher in the hyperkalaemic group, but the difference was not statistically significant. Conclusion: Our results suggest that hyperkalaemia occurs frequently in bleeding trauma patients on hospital arrival pre-transfusions, indicating a more severe illness. Our findings provide insights into the pathophysiology and characteristics of hyperkalaemia in bleeding trauma patients. Further studies are required to investigate the mechanisms by which hyperkalaemia contributes to mortality in haemorrhagic shock patients.

ObjectiveTo determine whether locally acting ACE-083 is safe, well tolerated, and increases muscle volume, motor function, and quality of life (QoL) in adults with Charcot-Marie-Tooth disease (CMT) type 1.MethodsThis phase 2 study enrolled adults with CMT1 or CMTX (N=63). Part 1 was open-label and evaluated safety and tolerability of different dose levels of ACE-083 for use in Part 2. Part 2 was a randomized, placebo-controlled, 6-month study of 240 mg/muscle ACE-083 injected bilaterally in the tibialis anterior muscle, followed by a 6-month, open-label extension in which all patients received ACE-083. Pharmacodynamic endpoints included total muscle volume (TMV; primary endpoint), contractile muscle volume (CMV), and fat fraction. Additional secondary endpoints included 6-minute walk test, 10-meter walk/run, muscle strength, and QoL. Safety was assessed with treatment-emergent adverse events (TEAEs) and clinical laboratory tests.ResultsIn Part 1 (n=18), ACE-083 was generally safe and well tolerated at all dose levels, with no serious AEs, TEAEs ≥Grade 3, or death reported. In Part 2 (n=45 enrolled, n=44 treated), there was significantly greater change in TMV with ACE-083 compared with placebo (LS mean difference: 13.5%; p = 0.0096). There was significant difference between ACE-083 and placebo for CMV and change in ankle dorsiflexion strength. Fat fraction and all other functional outcomes were not significantly improved by ACE-083. Moderate-to-mild injection-site reactions were the most common TEAEs.ConclusionsDespite significantly increased TMV and CMV, patients with CMT receiving ACE-083 in tibialis anterior muscles did not demonstrate greater functional improvement compared with those receiving placebo.Classification of evidenceThis study provides Class II evidence that intramuscular ACE-083 is safe, well tolerated, and increases total muscle volume after 6 months of treatment in adults with CMT1 or CMTX.