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BACKGROUND: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established. METHODS: This study is a multi-center randomized, response-adaptive, duration (dose) finding, comparative effectiveness clinical trial with blinded outcome assessment. We investigate two populations of adult comatose survivors of cardiac arrest to ascertain the shortest duration of cooling that provides the maximum treatment effect. The design is based on a statistical model of response as defined by the primary endpoint, a weighted 90-day mRS (modified Rankin Scale, a measure of neurologic disability), across the treatment arms. Subjects will initially be equally randomized between 12, 24, and 48 h of therapeutic cooling. After the first 200 subjects have been randomized, additional treatment arms between 12 and 48 h will be opened and patients will be allocated, within each initial cardiac rhythm type (shockable or non-shockable), by response adaptive randomization. As the trial continues, shorter and longer duration arms may be opened. A maximum sample size of 1800 subjects is proposed. Secondary objectives are to characterize: the overall safety and adverse events associated with duration of cooling, the effect on neuropsychological outcomes, and the effect on patient-reported quality of life measures. DISCUSSION: In vitro and in vivo studies have shown the neuroprotective effects of therapeutic hypothermia for cardiac arrest. We hypothesize that longer durations of cooling may improve either the proportion of patients that attain a good neurological recovery or may result in better recovery among the proportion already categorized as having a good outcome. If the treatment effect of cooling is increasing across duration, for at least some set of durations, then this provides evidence of the efficacy of cooling itself versus normothermia, even in the absence of a normothermia control arm, confirming previous RCTs for OHCA survivors of shockable rhythms and provides the first prospective controlled evidence of efficacy in those without initial shockable rhythms. TRIAL REGISTRATION: ClinicalTrials.gov NCT04217551. Registered on 30 December 2019.

Variovorax species catabolize a wide range of natural and industrial products and have been shown to be integral rhizosphere inhabitants. Here, we report the complete genomes of V. paradoxus 2u118 and V. sp. SPNA7, which were isolated from alfalfa root nodules and possess plant growth-promoting properties.

BackgroundSecuring the representativeness of study populations is crucial in biomedical research to ensure high generalizability. In this regard, using multi-institutional data have advantages in medicine. However, combining data physically is difficult as the confidential nature of biomedical data causes privacy issues. Therefore, a methodological approach is necessary when using multi-institution medical data for research to develop a model without sharing data between institutions. ObjectiveThis study aims to develop a weight-based integrated predictive model of multi-institutional data, which does not require iterative communication between institutions, to improve average predictive performance by increasing the generalizability of the model under privacy-preserving conditions without sharing patient-level data. MethodsThe weight-based integrated model generates a weight for each institutional model and builds an integrated model for multi-institutional data based on these weights. We performed 3 simulations to show the weight characteristics and to determine the number of repetitions of the weight required to obtain stable values. We also conducted an experiment using real multi-institutional data to verify the developed weight-based integrated model. We selected 10 hospitals (2845 intensive care unit [ICU] stays in total) from the electronic intensive care unit Collaborative Research Database to predict ICU mortality with 11 features. To evaluate the validity of our model, compared with a centralized model, which was developed by combining all the data of 10 hospitals, we used proportional overlap (ie, 0.5 or less indicates a significant difference at a level of .05; and 2 indicates 2 CIs overlapping completely). Standard and firth logistic regression models were applied for the 2 simulations and the experiment. ResultsThe results of these simulations indicate that the weight of each institution is determined by 2 factors (ie, the data size of each institution and how well each institutional model fits into the overall institutional data) and that repeatedly generating 200 weights is necessary per institution. In the experiment, the estimated area under the receiver operating characteristic curve (AUC) and 95% CIs were 81.36% (79.37%-83.36%) and 81.95% (80.03%-83.87%) in the centralized model and weight-based integrated model, respectively. The proportional overlap of the CIs for AUC in both the weight-based integrated model and the centralized model was approximately 1.70, and that of overlap of the 11 estimated odds ratios was over 1, except for 1 case. ConclusionsIn the experiment where real multi-institutional data were used, our model showed similar results to the centralized model without iterative communication between institutions. In addition, our weight-based integrated model provided a weighted average model by integrating 10 models overfitted or underfitted, compared with the centralized model. The proposed weight-based integrated model is expected to provide an efficient distributed research approach as it increases the generalizability of the model and does not require iterative communication.

Brown and brown-like adipose tissues have attracted significant attention for their role in metabolism and therapeutic potential in diabetes and obesity. Despite compelling evidence of an interplay between adipocytes and lymphocytes, the involvement of these tissues in immune responses remains largely unexplored. This study explicates a newfound connection between neuroinflammation and brown- and bone marrow adipose tissue. Leveraging the use of [18F]F-AraG, a mitochondrial metabolic tracer capable of tracking activated lymphocytes and adipocytes simultaneously, we demonstrate, in models of glioblastoma and multiple sclerosis, the correlation between intracerebral immune infiltration and changes in brown- and bone marrow adipose tissue. Significantly, we show initial evidence that a neuroinflammation-adipose tissue link may also exist in humans. This study proposes the concept of an intricate immuno-neuro-adipose circuit, and highlights brown- and bone marrow adipose tissue as an intermediary in the communication between the immune and nervous systems. Understanding the interconnectedness within this circuitry may lead to advancements in the treatment and management of various conditions, including cancer, neurodegenerative diseases and metabolic disorders.

The role of gut microbe-derived metabolites in the development of metabolic syndrome (MetS) remains unclear. This study aimed to evaluate the associations of gut microbe-derived metabolites and MetS traits in the cross-sectional Metabolic Syndrome In Men (METSIM) study. The sample included 10,194 randomly related men (age 57.65 ± 7.12 years) from Eastern Finland. Levels of 35 metabolites were tested for associations with 13 MetS traits using lasso and stepwise regression. Significant associations were observed between multiple MetS traits and 32 metabolites, three of which exhibited particularly robust associations. N-acetyltryptophan was positively associated with Homeostatic Model Assessment for Insulin Resistant (HOMA-IR) (β = 0.02, p = 0.033), body mass index (BMI) (β = 0.025, p = 1.3 × 10-16), low-density lipoprotein cholesterol (LDL-C) (β = 0.034, p = 5.8 × 10-10), triglyceride (0.087, p = 1.3 × 10-16), systolic (β = 0.012, p = 2.5 × 10-6) and diastolic blood pressure (β = 0.011, p = 3.4 × 10-6). In addition, 3-(4-hydroxyphenyl) lactate yielded the strongest positive associations among all metabolites, for example, with HOMA-IR (β = 0.23, p = 4.4 × 10-33), and BMI (β = 0.097, p = 5.1 × 10-52). By comparison, 3-aminoisobutyrate was inversely associated with HOMA-IR (β = -0.19, p = 3.8 × 10-51) and triglycerides (β = -0.12, p = 5.9 × 10-36). Mendelian randomization analyses did not provide evidence that the observed associations with these three metabolites represented causal relationships. We identified significant associations between several gut microbiota-derived metabolites and MetS traits, consistent with the notion that gut microbes influence metabolic homeostasis, beyond traditional risk factors.

Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity.

The National Institute of Ecology in Seocheon, Chungcheongnam-do, exhibits and studies Korea’s diverse ecosystems to communicate the importance of biodiversity conservation to the general public. The site faces the challenge of preserving the natural environment while ensuring visitor convenience. This requires systematic data collection to quickly detect and respond to threats from pests and natural disasters. In this study, high-resolution orthoimages were acquired to monitor ecological changes using unmanned aerial vehicles. Images were captured through flights monthly from March to July 2024. Digital elevation models and orthoimages were generated to identify dead trees and assess areas of damage caused by heavy rainfall. The study covered an area of 998,655 m2, and the image resolution was 3.6 cm/pixel. The orthophotos were useful in identifying plant pest damage. They also helped evaluate damage caused by rain, showing that the total area of damage was 29,384 m2, mainly due to soil erosion. Furthermore, it is expected that the accumulation of such unmanned remote sensing image data can also be applied to the safety management of various natural conservation areas and public facilities.

Abstract While waveguide-based light concentrators offer significant advantages, their application has not been considered an interesting option for assisting multijunction or other two-terminal tandem solar cells. In this study, we present a simple yet effective approach to enhancing the output power of transfer-printed multijunction InGaP/GaAs solar cells. By utilizing a simply combinable waveguide concentrator featuring a coplanar waveguide with BaSO4 Mie scattering elements, we enable the simultaneous absorption of directly illuminated solar flux and indirectly waveguided flux. The deployment of cells is optimized for front-surface photon collection in monofacial cells. Through systematic comparisons across various waveguide parameters, supported by both experimental and theoretical quantifications, we demonstrate a remarkable improvement in the maximum output power of a 26%-efficient cell, achieving an enhancement of ~93% with the integration of the optimal scattering waveguide. Additionally, a series of supplementary tests are conducted to explore the effective waveguide size, validate enhancements in arrayed cell module performance, and assess the drawbacks associated with rear illumination. These findings provide a comprehensive understanding of our proposed approach towards advancing multi-junction photovoltaics.

Abstract Backrground Akkermansia muciniphila, a next-generation probiotic, is known as a cornerstone regulating the gut-organ axis in various diseases, but the underlying mechanism remains poorly understood. Here, we revealed the neuronal and antifibrotic effects of A. muciniphila on the gut-liver-brain axis in liver injury. Results To investigate neurologic dysfunction and characteristic gut microbiotas, we performed a cirrhosis cohort (154 patients with or without hepatic encephalopathy) and a community cognition cohort (80 participants in one region for three years) and validated the existence of cognitive impairment in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced hepatic injury mouse model. The effects of the candidate strain on cognition were evaluated in animal models of liver injury. The expression of brain-derived neurotrophic factor (BDNF) and serotonin receptors was accessed in patients with fibrosis (100 patients) according to the fibrosis grade and hepatic venous pressure gradient. The proportion of A. muciniphila decreased in populations with hepatic encephalopathy and cognitive dysfunction. Tissue staining techniques confirmed gut-liver-brain damage in liver injury, with drastic expression of BDNF and serotonin in the gut and brain. The administration of A. muciniphila significantly reduced tissue damage and improved cognitive dysfunction and the expression of BDNF and serotonin. Isolated vagus nerve staining showed a recovery of serotonin expression without affecting the dopamine pathway. Conversely, in liver tissue, the inhibition of injury through the suppression of serotonin receptor (5-hydroxytryptamine 2A and 2B) expression was confirmed. The severity of liver injury was correlated with the abundance of serotonin, BDNF, and A. muciniphila. Conclusions A. muciniphila, a next-generation probiotic, is a therapeutic candidate for alleviating the symptoms of liver fibrosis and cognitive impairment. Graphical Abstract

Abstract The prevalence and dynamics of circulating tumor DNA (ctDNA) in patients with breast cancer recurrence or de novo metastatic cancer were examined in a retrospective analysis of a prospective observational cohort. Twenty-three recurrent/metastatic breast cancer cases (8 locoregional, 15 distant metastasis) were enrolled, and sequential plasma samples were obtained. Anchor mutations were selected from the target sequencing of each patient’s primary and/or metastatic tumor. An in-house developed assay (UHS assay) was employed for a tumor-informed ctDNA assay during treatment and follow-up. A median of three (range 1–5) anchor mutations per case were applied for ctDNA detection. ctDNA was detected in 14 (63.6%, 14/22) cases at the time of enrollment and 18 (78.5%, 18/23) cases during follow-up. More anchor mutations and higher tumor burden were significantly related to higher ctDNA positive rates (p-value 0.036, 0.043, respectively). The mean enriched variant allele frequency (eVAF) at each time point was significantly higher for stable or progressive disease responses (ANOVA test p-value

Abstract Objective The effect of body composition change on the risk of dementia is not clear. This study analyzed the associations of changes in predicted lean body mass index (pLBMI), predicted appendicular skeletal muscle mass index (pASMI), and predicted body fat mass index (pBFMI) with the risk of dementia. Methods In this nationwide cohort study, data were obtained from the Korean National Health Insurance Service database. The exposure was defined as changes in pLBMI, pASMI, and pBFMI derived from validated prediction equations. The outcome was dementia, defined based on the dementia diagnosis with prescription of anti‐dementia medication. Cox proportional hazards regression analyses were performed to obtain the hazard ratio with a 95% confidence interval for risk of dementia according to changes in predicted body composition. Results A total of 13,215,208 individuals with no prior record of dementia who underwent health screenings twice between 2009–2010 and 2011–2012 were included. A 1‐kg/m2 increase in pLBMI and pASMI had an association with reduced risk of dementia (aHR: 0.85, 95% CI 0.84–0.87; aHR: 0.70, 95% CI 0.69–0.72, respectively for men, and aHR: 0.69, 95% CI 0.67–0.71; aHR: 0.59, 95% CI 0.57–0.61, respectively for women). A 1‐kg/m2 increase in pBFMI had an association with a raised risk of dementia (aHR: 1.19, 95% CI 1.17–1.21 for men and aHR: 1.53, 95% CI 1.48–1.57 for women). These results remained consistent regardless of sex or weight change. Interpretation Increase in pLBMI or pASMI, or reduction in pBFMI was linked to lower risk of dementia.

Objective: We aimed to determine if machine learning can predict acute brain injury and to identify modifiable risk factors for acute brain injury in patients receiving venoarterial extracorporeal membrane oxygenation. Methods: We included adults (age ≥18 years) receiving venoarterial extracorporeal membrane oxygenation or extracorporeal cardiopulmonary resuscitation in the Extracorporeal Life Support Organization Registry (2009-2021). Our primary outcome was acute brain injury: central nervous system ischemia, intracranial hemorrhage, brain death, and seizures. We used Random Forest, CatBoost, LightGBM, and XGBoost machine learning algorithms (10-fold leave-1-out cross-validation) to predict and identify features most important for acute brain injury. We extracted 65 total features: demographics, pre-extracorporeal membrane oxygenation/on-extracorporeal membrane oxygenation laboratory values, and pre-extracorporeal membrane oxygenation/on-extracorporeal membrane oxygenation settings. Results: Of 35,855 patients receiving venoarterial extracorporeal membrane oxygenation (nonextracorporeal cardiopulmonary resuscitation) (median age of 57.8 years, 66% were male), 7.7% (n = 2769) experienced acute brain injury. In venoarterial extracorporeal membrane oxygenation (nonextracorporeal cardiopulmonary resuscitation), the area under the receiver operator characteristic curves to predict acute brain injury, central nervous system ischemia, and intracranial hemorrhage were 0.67, 0.67, and 0.62, respectively. The true-positive, true-negative, false-positive, false-negative, positive, and negative predictive values were 33%, 88%, 12%, 67%, 18%, and 94%, respectively, for acute brain injury. Longer extracorporeal membrane oxygenation duration, higher 24-hour extracorporeal membrane oxygenation pump flow, and higher on-extracorporeal membrane oxygenation partial pressure of oxygen were associated with acute brain injury. Of 10,775 patients receiving extracorporeal cardiopulmonary resuscitation (median age of 57.1 years, 68% were male), 16.5% (n = 1787) experienced acute brain injury. The area under the receiver operator characteristic curves for acute brain injury, central nervous system ischemia, and intracranial hemorrhage were 0.72, 0.73, and 0.69, respectively. Longer extracorporeal membrane oxygenation duration, older age, and higher 24-hour extracorporeal membrane oxygenation pump flow were associated with acute brain injury. Conclusions: In the largest study predicting neurological complications with machine learning in extracorporeal membrane oxygenation, longer extracorporeal membrane oxygenation duration and higher 24-hour pump flow were associated with acute brain injury in nonextracorporeal cardiopulmonary resuscitation and extracorporeal cardiopulmonary resuscitation venoarterial extracorporeal membrane oxygenation.

OBJECTIVES:. Anemia has been associated with an increased risk of both cardiac arrest and stroke, frequent complications of COVID-19. The effect of hemoglobin level at ICU admission on a composite outcome of cardiac arrest or stroke in an international cohort of COVID-19 patients was investigated. DESIGN:. Retrospective analysis of prospectively collected database. SETTING:. A registry of COVID-19 patients admitted to ICUs at over 370 international sites was reviewed for patients diagnosed with cardiac arrest or stroke up to 30 days after ICU admission. Anemia was defined as: normal (hemoglobin ≥ 12.0 g/dL for women, ≥ 13.5 g/dL for men), mild (hemoglobin 10.0–11.9 g/dL for women, 10.0–13.4 g/dL for men), moderate (hemoglobin ≥ 8.0 and < 10.0 g/dL for women and men), and severe (hemoglobin < 8.0 g/dL for women and men). PATIENTS:. Patients older than 18 years with acute COVID-19 infection in the ICU. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Of 6926 patients (median age = 59 yr, male = 65%), 760 patients (11.0%) experienced stroke (2.0%) and/or cardiac arrest (9.4%). Cardiac arrest or stroke was more common in patients with low hemoglobin, occurring in 12.8% of patients with normal hemoglobin, 13.3% of patients with mild anemia, and 16.7% of patients with moderate/severe anemia. Time to stroke or cardiac arrest by anemia status was analyzed using Cox proportional hazards regression with death as a competing risk. Covariates selected through clinical knowledge were age, sex, comorbidities (diabetes, hypertension, obesity, and cardiac or neurologic conditions), pandemic era, country income, mechanical ventilation, and extracorporeal membrane oxygenation. Moderate/severe anemia was associated with a higher risk of cardiac arrest or stroke (hazard ratio, 1.32; 95% CI, 1.05–1.67). CONCLUSIONS:. In an international registry of ICU patients with COVID-19, moderate/severe anemia was associated with increased hazard of cardiac arrest or stroke.

In obesity, CD11c+ innate immune cells are recruited to adipose tissue and create an inflammatory state that causes both insulin and catecholamine resistance. We found that ablation of Gnas, the gene that encodes Gαs, in CD11c expressing cells protects mice from obesity, glucose intolerance, and insulin resistance. Transplantation studies showed that the lean phenotype was conferred by bone marrow-derived cells and did not require adaptive immunity. Loss of cAMP signaling was associated with increased adipose tissue norepinephrine and cAMP signaling, and prevention of catecholamine resistance. The adipose tissue had reduced expression of catecholamine transport and degradation enzymes, suggesting that the elevated norepinephrine resulted from decreased catabolism. Collectively, our results identified an important role for cAMP signaling in CD11c+ innate immune cells in whole-body metabolism by controlling norepinephrine levels in white adipose tissue, modulating catecholamine-induced lipolysis and increasing thermogenesis, which, together, created a lean phenotype.Article highlightsWe undertook this study to understand how immune cells communicate with adipocytes, specifically, whether cAMP signaling in the immune cell and the adipocyte are connected. We identified a reciprocal interaction between CD11c+ innate immune cells and adipocytes in which high cAMP signaling in the immune cell compartment induces low cAMP signaling in adipocytes and vice versa. This interaction regulates lipolysis in adipocytes and inflammation in immune cells, resulting in either a lean, obesity-resistant, and insulin-sensitive phenotype, or an obese, insulin-resistant phenotype.

Despite many recent studies on non-alcoholic fatty liver disease (NAFLD) therapeutics, the optimal treatment has yet to be determined. In this unfinished project, we combined secondary metabolites (SMs) from the gut microbiota (GM) and Hordeum vulgare (HV) to investigate their combinatorial effects via network pharmacology (NP). Additionally, we analyzed GM or barley – signalling pathways – targets – metabolites (GBSTMs) in combinatorial perspectives (HV, and GM). A total of 31 key targets were analysed via a protein-protein interaction (PPI) network, and JUN was identified as the uppermost target in NAFLD. On a bubble plot, we revealed that apelin signalling pathway, which had the lowest enrichment factor antagonize NAFLD. Holistically, we scrutinized GBSTM to identify key components (GM, signalling pathways, targets, and metabolites) associated with the Apelin signalling pathway. Consequently, we found that the primary GMs (Eubacterium limosum, Eggerthella sp. SDG-2, Alistipes indistinctus YIT 12060, Odoribacter laneus YIT 12061, Paraprevotella clara YIT 11840, Paraprevotella xylaniphila YIT 11841) to ameliorate NAFLD. The molecular docking test (MDT) suggested that tryptanthrin-JUN is an agonist, conversely, dihydroglycitein-HDAC5, 1,3-diphenylpropan-2-ol-NOS1, and (10[(Acetyloxy)methyl]-9-anthryl)methyl acetate-NOS2, which are antagonistic conformers in the apelin signalling pathway. Overall, these results suggest that combination therapy could be an effective strategy for treating NAFLD.