Fe-O4 Motif Activated Graphitic Carbon via Oxo-Bridge for Highly Selective H2O2 Electrosynthesis.

Carbon-based materials have been utilized as effective catalysts for hydrogen peroxide electrosynthesis via two-electron oxygen reduction reaction (2e ORR), however the insufficient selectivity and productivity still hindered the further industrial applications. In this work, we report the Fe-O4 motif activated graphitic carbon material which enabled highly selective H2O2 electrosynthesis operating at high current density with excellent anti-poisoning property. In the bulk production test, the concentration of H2O2 cumulated to 8.6 % in 24 h and the corresponding production rate of 33.5 mol gcat -1 h-1 outperformed all previously reported materials. Theoretical model backed by in situ characterization verified α-C surrounding the Fe-O4 motif as the actual reaction site in terms of thermodynamics and kinetics aspects. The strategy of activating carbon reaction site by metal center via oxo-bridge provides inspiring insights for the rational design of carbon materials for heterogeneous catalysis.

Natural Coptidis Rhizoma Nanoparticles Improved the Oral Delivery of Docetaxel.

Purpose: Docetaxel (DTX) is a valuable anti-tumor chemotherapy drug with limited oral bioavailability. This study aims to develop an effective oral delivery system for DTX using natural nanoparticles (Nnps) derived from Coptidis Rhizoma extract. Methods: DTX-loaded self-assembled nanoparticles (Nnps-DTX) were created using an optimized heat-induction strategy. Nnps-DTX's shape, size, Zeta potential, and in vitro stability were all carefully examined. Additionally, the study investigated the encapsulation efficiency, loading capacity, crystal form, and intermolecular interactions of DTX in Nnps-DTX. Subsequently, the solubility, release, cellular uptake, metabolic stability, and preclinical pharmacokinetics of DTX in Nnps-DTX were systematically evaluated. Finally, the cytotoxicity of Nnps-DTX was assessed in three tumor cell lines. Results: Nnps-DTX was spherical in shape, 138.6 ± 8.2 nm in size, with a Zeta potential of -20.8 ± 0.6 mV, a DTX encapsulation efficiency of 77.6 ± 8.5%, and a DTX loading capacity of 6.8 ± 1.9%. Hydrogen bonds, hydrophobic interactions, and electrostatic interactions were involved in the formation of Nnps-DTX. DTX within Nnps-DTX was in an amorphous form, resulting in enhanced solubility (23.3 times) and release compared to free DTX. Following oral treatment, the mice in the Nnps-DTX group had DTX peak concentrations 8.8, 23.4, 44.6, and 5.7 times higher in their portal vein, systemic circulation, liver, and lungs than the mice in the DTX group. Experiments performed in Caco-2 cells demonstrated a significant increase in DTX uptake by Nnps-DTX compared to free DTX, which was significantly inhibited by indomethacin, an inhibitor of caveolae-mediated endocytosis. Furthermore, compared to DTX, DTX in Nnps-DTX demonstrated better metabolic stability in liver microsomes. Notably, Nnps-DTX significantly reduced the viability of MCF-7, HCT116, and HepG2 cells. Conclusion: The novel self-assembled nanoparticles considerably enhanced the cellular absorption, solubility, release, metabolic stability, and pharmacokinetics of oral DTX and demonstrated strong cytotoxicity against tumor cell lines.

Chitinase 3-like-1 (CHI3L1) in the pathogenesis of epidermal growth factor receptor mutant non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for 85 % of all lung cancers. In NSCLC, 10-20 % of Caucasian patients and 30-50 % of Asian patients have tumors with activating mutations in the Epidermal Growth Factor Receptor (EGFR). A high percentage of these patients exhibit favorable responses to treatment with tyrosine kinase inhibitors (TKI). Unfortunately, a majority of these patients develop therapeutic resistance with progression free survival lasting 9-18 months. The mechanisms that underlie the tumorigenic effects of EGFR and the ability of NSCLC to develop resistance to TKI therapies, however, are poorly understood. Here we demonstrate that CHI3L1 is produced by EGFR activation of normal epithelial cells, transformed epithelial cells with wild type EGFR and cells with cancer-associated, activating EGFR mutations. We also demonstrate that CHI3L1 auto-induces itself and feeds back to stimulate EGFR and its ligands via a STAT3-dependent mechanism(s). Highly specific antibodies against CHI3L1 (anti-CHI3L1/FRG) and TKI, individually and in combination, abrogated the effects of EGFR activation on CHI3L1 and the ability of CHI3L1 to stimulate the EGFR axis. Anti-CHI3L1 also interacted with osimertinib to reverse TKI therapeutic resistance and induce tumor cell death and inhibit pulmonary metastasis while stimulating tumor suppressor genes including KEAP1. CHI3L1 is a downstream target of EGFR that feeds back to stimulate and activate the EGFR axis. Anti-CHI3L1 is an exciting potential therapeutic for EGFR mutant NSCLC, alone and in combination with osimertinib or other TKIs.

Response of soil moisture to rainfall following deep soil drying in China's hilly loess lands.

Deep soil drying is a physical soil phenomenon that has become increasingly characteristic to artificial afforestation on China's Loess Plateau. Current research is largely short of conclusive reports on soil moisture recovery following deep soil drying in afforested lands. In this study, a 10-m deep underground column was constructed at Pengyang Experimental Station in Ningxia. The CS650-CR1000 automatic soil moisture monitoring system and BLJW-4 small meteorological observation stations were used to respectively monitor soil moisture and meteorological conditions in the study area for the period 2014-2019. The local rainfall was classified and the characteristics of soil infiltration analyzed at both monthly and annual scales. The results showed that: i) Deep soil moisture recovery in the semi-arid Loess Plateau region depended mainly on 25-49.9 mm and >50 mm types of rainfall; together accounting for 35.44 % of the precipitation. ii) Deep soil moisture replenishment occurred mainly for the period from April to October. While this accounted for 30.13 % of the precipitation, evaporation loss accounted for 69.87 % of it. With increasing monthly rainfall (Pm), the variation in monthly infiltration depth (Zm) was quadratic in shape - where Zm = -0.0094 Pm2 + 3.7702 Pm (R2 = 0.9577). iii) At the annual scale, deep soil moisture replenishment was mainly driven by year-on-year infiltration water accumulation. This is because a single year precipitation infiltration was not enough to replenish deep soil moisture. The cumulative infiltration depth for 2014-2019 was 180, 260, 400, 700, 1000 > 1000 cm. It suggested that soil water infiltration and deep dry soil recovery occurred at different times under rainfed conditions in the semi-arid loess hills in China. This is key for in-depth studies of the hydrological process in dry soil regions.

Risks associated with cognitive function and management strategies in the clinical use of ADT: a systematic review from clinical and preclinical studies.

Prostate cancer is one of the most common malignancies and a leading cause of death in men. Owing to its excellent anti-tumor effects, androgen deprivation therapy (ADT) is widely used in the treatment of prostate cancer. However, its use is controversial because of its potential for inducing cognitive decline. In this review, we summarized the findings of preclinical and clinical studies investigating the effects of ADT on cognitive function in prostate cancer. We discussed the methods used to assess cognitive function in these studies, elucidated the mechanisms through which ADT affects cognitive function, and highlighted recent advancements in cognitive assessment methods. The findings of this review serve as a valuable reference for examining the relationship between ADT and cognitive function in future studies. Besides, the findings may help clinicians understand the advantages and disadvantages of ADT and optimize the treatment plan so as to minimize the adverse effects of ADT.

Seasonal variations in soil microbial community co-occurrence network complexity respond differently to field-simulated warming experiments in a northern subtropical forest.

Global warming may reshape seasonal changes in microbial community diversity and co-occurrence network patterns, with significant implications for terrestrial ecosystem function. We conducted a 2-year in situ field simulation of the effects of warming on the seasonal dynamics of soil microbial communities in a northern subtropical Quercus acutissima forest. Our study revealed that warming had no significant effect on the richness or diversity of soil bacteria or fungi in the growing season, whereas different warming gradients had different effects on their diversity in the nongrowing season. Warming also changed the microbial community structure, increasing the abundance of some thermophilic microbial species and decreasing the abundance of some symbiotrophic microorganisms. The co-occurrence network analysis of the microbial community showed that warming decreased the complexity of the intradomain network in the soil bacterial community in the growing and nongrowing seasons but increased it in the fungal community. Moreover, increasing warming temperatures increased the complexity of the interdomain network between bacteria and fungi in the growing season but decreased it in the nongrowing season, and the keystone species in the interdomain network changed with warming. Warming also reduced the proportion of positive microbial community interactions, indicating that warming reduced the mutualism, commensalism, and neutralism of microorganisms as they adapted to soil environmental stress. The factors affecting the fungal community varied considerably across warming gradients, with the bacterial community being significantly affected by soil temperature, MBC, NO3--N and NH4+-N, moreover, SOC and TN significantly affected fungal communities in the 4 °C warming treatment. These results suggest that warming increases seasonal differences in the diversity and complexity of soil microbial communities in the northern subtropical region, significantly influencing soil dynamic processes regulating forest ecosystems under global warming.

Ultrafine Asymmetric Soft/Stiff Nanohybrids with Tunable Patchiness via a Dynamic Surface-Mediated Assembly.

Asymmetric soft-stiff patch nanohybrids with small size, spatially separated organics and inorganics, controllable configuration, and appealing functionality are important in applications, while the synthesis remains a great challenge. Herein, based on polymeric single micelles (the smallest assembly subunit of mesoporous materials), we report a dynamic surface-mediated anisotropic assembly approach to fabricate a new type of small asymmetric organic/inorganic patch nanohybrid for the first time. The size of this asymmetric organic/inorganic nanohybrid is ∼20 nm, which contains dual distinct subunits of a soft organic PS-PVP-PEO single micelle nanosphere (12 nm in size and 632 MPa in Young' modulus) and stiff inorganic SiO2 nanobulge (∼8 nm, 2275 MPa). Moreover, the number of SiO2 nanobulges anchored on each micelle can be quantitatively controlled (from 1 to 6) by dynamically tuning the density (fluffy or dense state) of the surface cap organic groups. This small asymmetric patch nanohybrid also exhibits a dramatically enhanced uptake level of which the total amount of intracellular endocytosis is about three times higher than that of the conventional nanohybrids.

Impact of Lime Saturation Factor on Alite-Ye'Elimite Cement Synthesis and Hydration.

Alite(C3S)-Ye'elimite(C4A3$) cement is a high cementitious material that incorporates a precise proportion of ye'elimite into the ordinary Portland cement. The synthesis and hydration behavior of Alite-Ye'elimite clinker with different lime saturation factors were investigated. The clinkers were synthesized using a secondary thermal treatment process, and their compositions were characterized. The hydrated pastes were analyzed for their hydration products, pore structure, mechanical strength, and microstructure. The clinkers and hydration products were characterized using XRD, TG-DSC, SEM, and MIP analysis. The results showed that the Alite-Ye'elimite cement clinker with a lime saturation factor (KH) of 0.93, prepared through secondary heat treatment, contained 64.88% C3S and 2.06% C4A3$. At this composition, the Alite-Ye'elimite cement clinker demonstrated the highest 28-day strength. The addition of SO3 to the clinkers decreased the content of tricalcium aluminate (C3A) and the ratio of Alite/Belite (C3S/C2S), resulting in a preference for belite formation. The pore structure of the hydrated pastes was also investigated, revealing a distribution of pore sizes ranging from 0.01 to 10 µm, with two peaks on each differential distribution curve corresponding to micron and sub-micron pores. The pore volume decreased from 0.22 ± 0.03 to 0.15 ± 0.18 cm3 g-1, and the main peak of pore distribution shifted towards smaller sizes with increasing hydration time.

Global burden of type 1 diabetes in adults aged 65 years and older, 1990-2019: population based study.

OBJECTIVES: To estimate the burden, trends, and inequalities of type 1 diabetes mellitus (T1DM) among older adults at global, regional, and national level from 1990 to 2019. DESIGN: Population based study. POPULATION: Adults aged ≥65 years from 21 regions and 204 countries and territories (Global Burden of Disease and Risk Factors Study 2019)from 1990 to 2019. MAIN OUTCOME MEASURES: Primary outcomes were T1DM related age standardised prevalence, mortality, disability adjusted life years (DALYs), and average annual percentage change. RESULTS: The global age standardised prevalence of T1DM among adults aged ≥65 years increased from 400 (95% uncertainty interval (UI) 332 to 476) per 100 000 population in 1990 to 514 (417 to 624) per 100 000 population in 2019, with an average annual trend of 0.86% (95% confidence interval (CI) 0.79% to 0.93%); while mortality decreased from 4.74 (95% UI 3.44 to 5.9) per 100 000 population to 3.54 (2.91 to 4.59) per 100 000 population, with an average annual trend of -1.00% (95% CI -1.09% to -0.91%), and age standardised DALYs decreased from 113 (95% UI 89 to 137) per 100 000 population to 103 (85 to 127) per 100 000 population, with an average annual trend of -0.33% (95% CI -0.41% to -0.25%). The most significant decrease in DALYs was observed among those aged <79 years: 65-69 (-0.44% per year (95% CI -0.53% to -0.34%)), 70-74 (-0.34% per year (-0.41% to -0.27%)), and 75-79 years (-0.42% per year (-0.58% to -0.26%)). Mortality fell 13 times faster in countries with a high sociodemographic index versus countries with a low-middle sociodemographic index (-2.17% per year (95% CI -2.31% to -2.02%) v -0.16% per year (-0.45% to 0.12%)). While the highest prevalence remained in high income North America, Australasia, and western Europe, the highest DALY rates were found in southern sub-Saharan Africa, Oceania, and the Caribbean. A high fasting plasma glucose level remained the highest risk factor for DALYs among older adults during 1990-2019. CONCLUSIONS: The life expectancy of older people with T1DM has increased since the 1990s along with a considerable decrease in associated mortality and DALYs. T1DM related mortality and DALYs were lower in women aged ≥65 years, those living in regions with a high sociodemographic index, and those aged <79 years. Management of high fasting plasma glucose remains a major challenge for older people with T1DM, and targeted clinical guidelines are needed.

The Influence of Retreated Lithium Slag with a High Content of Alkali, Sulfate and Fluoride on the Composition and the Microstructure of Autoclaved Aerated Concrete.

In this paper, the possibility of retreated lithium slag (RTLS) with a high content of alkali, sulfate and fluoride as a partial replacement for fly ash (FA) to produce autoclaved aerated concrete (AAC) was investigated. The influence of the RTLS dosage on the AAC performance were examined. The composition and microstructure of hydrates as well as the microstructure of the RTLS-FA-based AAC compositions were determined by XRD, FTIR, TG-DSC and SEM. The results illustrated that the incorporation of RTLS changed the crystal structure and the microstructure of the tobermorite. With increased RTLS contents, the morphology of tobermorite was changed, and the grass-like tobermorite gradually transformed into network-like tobermorite. The newly formed tobermorite improved the mechanical performance of the AAC. Compared with the RTLS10, the content of tobermorite in the RTLS30 increased by 8.6%.

Multi-omics reveals the molecular mechanism of the combined toxic effects of PFOA and 4-HBP exposure in MCF-7 cells and the key player: mTORC1.

With the discovery of evidence that many endocrine-disrupting chemicals (EDCs) in the environment influence human health, their toxic effects and mechanisms have become a hot topic of research. However, investigations into their endocrine-disrupting toxicity under combined binary exposure, especially the molecular mechanism of combined effects, have rarely been documented. In this study, two typical EDCs, perfluorooctanoic acid (PFOA) and 4-hydroxybenzophenone (4-HBP), were selected to examine their combined effects and molecular mechanism on MCF-7 cell proliferation at environmentally relevant exposure concentrations. We have successfully established a model to evaluate the binary combined toxic effects of endocrine disruptors, presenting combined effects in a simple and direct way. Results indicated that the combined effect changed from additive to synergistic from 1.25 × 10-8 M to 4 × 10-7 M. Metabolomics analyses suggested that exposure to PFOA and 4-HBP caused significant alterations in purine metabolism, arginine, and proline metabolism and had superimposed influences on metabolism. Enhanced combined effects were observed in glycine, serine, and threonine metabolic pathways compared to exposure to PFOS and 4-HBP alone. Additionally, the differentially expressed genes (DEGs) are primarily involved in Biological Processes, especially protein targeting the endoplasmic reticulum, and significantly impact the oxidative phosphorylation and thermogenesis-related KEGG pathway. By integrating metabolome and transcriptome analyses, PFOA and 4-HBP regulate purine metabolism, the TCA cycle, and endoplasmic reticulum protein synthesis in MCF-7 cells via mTORC1, which provides genetic material, protein, and energy for cell proliferation. Furthermore, molecular docking confirmed the ability of PFOA and 4-HBP to stably bind the estrogen receptor, indicating that they have different binding pockets. Collectively, these findings will offer new insights into understanding the mechanisms by which EDCs produce combined toxicity.

Enhancing clinical utility: deep learning-based embryo scoring model for non-invasive aneuploidy prediction.

BACKGROUND: The best method for selecting embryos ploidy is preimplantation genetic testing for aneuploidies (PGT-A). However, it takes more labour, money, and experience. As such, more approachable, non- invasive techniques were still needed. Analyses driven by artificial intelligence have been presented recently to automate and objectify picture assessments. METHODS: In present retrospective study, a total of 3448 biopsied blastocysts from 979 Time-lapse (TL)-PGT cycles were retrospectively analyzed. The "intelligent data analysis (iDA) Score" as a deep learning algorithm was used in TL incubators and assigned each blastocyst with a score between 1.0 and 9.9. RESULTS: Significant differences were observed in iDAScore among blastocysts with different ploidy. Additionally, multivariate logistic regression analysis showed that higher scores were significantly correlated with euploidy (p < 0.001). The Area Under the Curve (AUC) of iDAScore alone for predicting euploidy embryo is 0.612, but rose to 0.688 by adding clinical and embryonic characteristics. CONCLUSIONS: This study provided additional information to strengthen the clinical applicability of iDAScore. This may provide a non-invasive and inexpensive alternative for patients who have no available blastocyst for biopsy or who are economically disadvantaged. However, the accuracy of embryo ploidy is still dependent on the results of next-generation sequencing technology (NGS) analysis.

Detection of Cadmium in Human Biospecimens by a Cadmium-Selective Whole-Cell Biosensor Based on Deoxyviolacein.

Cadmium poses a severe health risk, impacting various bodily systems. Monitoring human exposure is vital. Urine and blood cadmium serve as critical biomarkers. However, current urine and blood cadmium detection methods are expensive and complex. Being cost-effective, user-friendly, and efficient, visual biosensing offers a promising complement to existing techniques. Therefore, we constructed a cadmium whole-cell biosensor using CadR10 and deoxyviolacein pigment in this study. We assessed the sensor for time-dose response, specific response to cadmium, sensitivity response to cadmium, and stability response to cadmium. The results showed that (1) the sensor had a preferred signal-to-noise ratio when the incubation time was 4 h; (2) the sensor showed excellent specificity for cadmium compared to the group 12 metals and lead; (3) the sensor was responsive to cadmium down to 1.53 nM under experimental conditions and had good linearity over a wide range from 1.53 nM to 100 µM with good linearity (R2 = 0.979); and (4) the sensor had good stability. Based on the excellent results of the performance tests, we developed a cost-effective, high-throughput method for detecting urinary and blood cadmium. Specifically, this was realized by adding the blood or urine samples into the culture system in a particular proportion. Then, the whole-cell biosensor was subjected to culture, n-butanol extraction, and microplate reading. The results showed that (1) at 20% urine addition ratio, the sensor had an excellent curvilinear relationship (R2 = 0.986) in the range of 3.05 nM to 100 µM, and the detection limit could reach 3.05 nM. (2) At a 10% blood addition ratio, the sensor had an excellent nonlinear relationship (R2 = 0.978) in the range of 0.097-50 µM, and the detection limit reached 0.195 µM. Overall, we developed a sensitive and wide-range method based on a whole-cell biosensor for the detection of cadmium in blood and urine, which has the advantages of being cost-effective, ease of operation, fast response, and low dependence on instrumentation and has the potential to be applied in the monitoring of cadmium exposure in humans as a complementary to the mainstream detection techniques.

Cannabidiol improves the cognitive function of SAMP8 AD model mice involving the microbiota-gut-brain axis.

Cannabidiol (CBD), a natural component extracted from Cannabis sativa L. exerts neuroprotective, antioxidant, and anti-inflammatory effects in Alzheimer's disease (AD), a disease characterized by impaired cognition and accumulation of amyloid-B peptides (Aß). Interactions between the gut and central nervous system (microbiota-gut-brain axis) play a critical role in the pathogenesis of neurodegenerative disorder AD. At present investigations into the mechanisms underlying the neuroprotective action of CBD in AD are not conclusive. The aim of this study was thus to examine the influence of CBD on cognition and involvement of the microbiota-gut-brain axis using a senescence-accelerated mouse prone 8 (SAMP8) model. Data demonstrated that administration of CBD to SAMP8 mice improved cognitive function as evidenced from the Morris water maze test and increased hippocampal activated microglia shift from M1 to M2. In addition, CBD elevated levels of Bacteriodetes associated with a fall in Firmicutes providing morphologically a protective intestinal barrier which subsequently reduced leakage of intestinal toxic metabolites. Further, CBD was found to reduce the levels of hippocampal and colon epithelial cells lipopolysaccharide (LPS), known to be increased in AD leading to impaired gastrointestinal motility, thereby promoting neuroinflammation and subsequent neuronal death. Our findings demonstrated that CBD may be considered a beneficial therapeutic drug to counteract AD-mediated cognitive impairment and restore gut microbial functions associated with the observed neuroprotective mechanisms.

Coupled conversion of polyethylene and carbon dioxide catalyzed by a zeolite-metal oxide system.

Zeolite-catalyzed polyethylene (PE) aromatization achieves reduction of the aromatic yield via hydrogenation and hydrogenolysis reactions. The hydrogen required for CO2 hydrogenation can be provided by H radicals formed during aromatization. In this study, we efficiently convert PE and CO2 into aromatics and CO using a zeolite-metal oxide catalyst (HZSM-5 + CuZnZrOx) at 380°C and under hydrogen- and solvent-free reaction conditions. Hydrogen, derived from the aromatization of PE over HZSM-5, diffuses through the Brønsted acidic sites of the zeolite to the adjacent CuZnZrOx, where it is captured in situ by CO2 to produce bicarbonate and further hydrogenated to CO. This favors aromatization while inhibiting hydrogenation and secondary hydrogenolysis reactions. An aromatic yield of 62.5 wt % is achieved, of which 60% consisted of benzene, toluene, and xylene (BTX). The conversion of CO2 reaches values as high as 0.55 mmol gPE-1. This aromatization-hydrogen capture pathway provides a feasible scheme for the comprehensive utilization of waste plastics and CO2.

Implanting Colloidal Nanoparticles into Single-Crystalline Zeolites for Catalytic Dehydration.

The encapsulation of functional colloidal nanoparticles (100 nm) into single-crystalline ZSM-5 zeolites, aiming to create uniform core-shell structures, is a highly sought-after yet formidable objective due to significant lattice mismatch and distinct crystallization properties. In this study, we demonstrate the fabrication of a core-shell structured single-crystal zeolite encompassing an Fe3O4 colloidal core via a novel confinement stepwise crystallization methodology. By engineering a confined nanocavity, anchoring nucleation sites, and executing stepwise crystallization, we have successfully encapsulated colloidal nanoparticles (CN) within single-crystal zeolites. These grafted sites, alongside the controlled crystallization process, compel the zeolite seed to nucleate and expand along the Fe3O4 colloidal nanoparticle surface, within a meticulously defined volume (1.5×107≤V≤1.3×108 nm3). Our strategy exhibits versatility and adaptability to an array of zeolites, including but not restricted to ZSM-5, NaA, ZSM-11, and TS-1 with polycrystalline zeolite shell. We highlight the uniformly structured magnetic-nucleus single-crystalline zeolite, which displays pronounced superparamagnetism (14 emu/g) and robust acidity (~0.83 mmol/g). This innovative material has been effectively utilized in a magnetically stabilized bed (MSB) reactor for the dehydration of ethanol, delivering an exceptional conversion rate (98 %), supreme ethylene selectivity (98 %), and superior catalytic endurance (in excess of 100 hours).

Global, Regional, and National Burdens of Stroke in Children and Adolescents From 1990 to 2019: A Population-Based Study.

BACKGROUND: Stroke is one of the leading causes of death among children, yet evidence on stroke incidence and prognosis in this population is largely neglected worldwide. The aim of this study was to estimate the latest burden of childhood stroke, as well as trends, risk factors, and inequalities from 1990 to 2019, at the global, regional, and national levels. METHODS: The Global Burden of Disease 2019 study was utilized to evaluate the prevalence, incidence, years lived with disability, years of life lost (YLLs), and average annual percentage changes in stroke among populations aged 0 to 19 years from 1990 to 2019. RESULTS: The global age-standardized incidence of stroke increased (average annual percentage change, 0.15% [95% uncertainty interval, 0.09%-0.21%]), while YLLs decreased substantially (average annual percentage change, -3.33% [95% uncertainty interval, -3.38% to -3.28%]) among children and adolescents between 1990 and 2019. Ischemic stroke accounted for 70% of incident cases, and intracerebral hemorrhage accounted for 63% of YLLs. Children under 5 years of age had the highest incidence of ischemic stroke, while adolescents aged 15 to 19 years had the highest incidence of hemorrhagic stroke. In 2019, low-income and middle-income countries were responsible for 84% of incident cases and 93% of YLLs due to childhood stroke. High-sociodemographic index countries had a reduction in YLLs due to stroke that was more than twice as fast as that of low-income and middle-income. CONCLUSIONS: Globally, the burden of childhood stroke continues to increase, especially among females, children aged <5 years, and low-sociodemographic index countries, such as sub-Saharan Africa. The burden of childhood stroke is likely undergoing a significant transition from being fatal to causing disability. Global public health policies and the deployment of health resources need to respond rapidly and actively to this shift.

Early Immunomodulatory Program Triggered by Protolerogenic Bifidobacterium pseudolongum Drives Cardiac Transplant Outcomes.

BACKGROUND: Despite ongoing improvements to regimens preventing allograft rejection, most cardiac and other organ grafts eventually succumb to chronic vasculopathy, interstitial fibrosis, or endothelial changes, and eventually graft failure. The events leading to chronic rejection are still poorly understood and the gut microbiota is a known driving force in immune dysfunction. We previously showed that gut microbiota dysbiosis profoundly influences the outcome of vascularized cardiac allografts and subsequently identified biomarker species associated with these differential graft outcomes. METHODS: In this study, we further detailed the multifaceted immunomodulatory properties of protolerogenic and proinflammatory bacterial species over time, using our clinically relevant model of allogenic heart transplantation. RESULTS: In addition to tracing longitudinal changes in the recipient gut microbiome over time, we observed that Bifidobacterium pseudolongum induced an early anti-inflammatory phenotype within 7 d, whereas Desulfovibrio desulfuricans resulted in a proinflammatory phenotype, defined by alterations in leukocyte distribution and lymph node (LN) structure. Indeed, in vitro results showed that B pseudolongum and D desulfuricans acted directly on primary innate immune cells. However, by 40 d after treatment, these 2 bacterial strains were associated with mixed effects in their impact on LN architecture and immune cell composition and loss of colonization within gut microbiota, despite protection of allografts from inflammation with B pseudolongum treatment. CONCLUSIONS: These dynamic effects suggest a critical role for early microbiota-triggered immunologic events such as innate immune cell engagement, T-cell differentiation, and LN architectural changes in the subsequent modulation of protolerant versus proinflammatory immune responses in organ transplant recipients.