Creation of memory-memory entanglement in a metropolitan quantum network.

Towards realizing the future quantum internet1,2, a pivotal milestone entails the transition from two-node proof-of-principle experiments conducted in laboratories to comprehensive multi-node set-ups on large scales. Here we report the creation of memory-memory entanglement in a multi-node quantum network over a metropolitan area. We use three independent memory nodes, each of which is equipped with an atomic ensemble quantum memory3 that has telecom conversion, together with a photonic server where detection of a single photon heralds the success of entanglement generation. The memory nodes are maximally separated apart for 12.5 kilometres. We actively stabilize the phase variance owing to fibre links and control lasers. We demonstrate concurrent entanglement generation between any two memory nodes. The memory lifetime is longer than the round-trip communication time. Our work provides a metropolitan-scale testbed for the evaluation and exploration of multi-node quantum network protocols and starts a stage of quantum internet research.

Tailoring the selective generation of oxidative organic radicals for toxic-by-product-free water decontamination.

Peracetic acid (PAA) is emerging as a versatile agent for generating long-lived and selectively oxidative organic radicals (R-O•). Currently, the conventional transition metal-based activation strategies still suffer from metal ion leaching, undesirable by-products formation, and uncontrolled reactive species production. To address these challenges, we present a method employing BiOI with a unique electron structure as a PAA activator, thereby predominantly generating CH3C(O)O• radicals. The specificity of CH3C(O)O• generation ensured the superior performance of the BiOI/PAA system across a wide pH range (2.0 to 11.0), even in the presence of complex interfering substances such as humic acids, chloride ions, bicarbonate ions, and real-world water matrices. Unlike conventional catalytic oxidative methods, the BiOI/PAA system degrades sulfonamides without producing any toxic by-products. Our findings demonstrate the advantages of CH3C(O)O• in water decontamination and pave the way for the development of eco-friendly water decontaminations based on organic peroxides.

α-Ketoglutarate plays an inflammatory inhibitory role by regulating scavenger receptor class a expression through N6-methyladenine methylation during sepsis.

Sepsis arises from an uncontrolled inflammatory response triggered by infection or stress, accompanied by alteration in cellular energy metabolism, and a strong correlation exists between these factors. Alpha-ketoglutarate (α-KG), an intermediate product of the TCA cycle, has the potential to modulate the inflammatory response and is considered a crucial link between energy metabolism and inflammation. The scavenger receptor (SR-A5), a significant pattern recognition receptor, assumes a vital function in anti-inflammatory reactions. In the current investigation, we have successfully illustrated the ability of α-KG to mitigate inflammatory factors in the serum of septic mice and ameliorate tissue damage. Additionally, α-KG has been shown to modulate metabolic reprogramming and macrophage polarization. Moreover, our findings indicate that the regulatory influence of α-KG on sepsis is mediated through SR-A5. We also elucidated the mechanism by which α-KG regulates SR-A5 expression and found that α-KG reduced the N6-methyladenosine level of macrophages by up-regulating the m6A demethylase ALKBH5. α-KG plays a crucial role in inhibiting inflammation by regulating SR-A5 expression through m6A demethylation during sepsis. The outcomes of this research provide valuable insights into the relationship between energy metabolism and inflammation regulation, as well as the underlying molecular regulatory mechanism.

Metallothionein Alleviates Glutathione Depletion-Induced Oxidative Cardiomyopathy through CISD1-Dependent Regulation of Ferroptosis in Murine Hearts.

This study was designed to discern the effect of heavy scavenger metallothionein on glutathione (GSH) deprivation-evoked cardiac anomalies and mechanisms involved with an emphasis on ferroptosis. Wild-type and cardiac metallothionein transgenic mice received GSH synthase inhibitor buthionine sulfoximine (BSO; 30 mmol/L in drinking water) for 14 days before assessment of myocardial morphology and function. BSO evoked cardiac remodeling and contractile anomalies, including cardiac hypertrophy, interstitial fibrosis, enlarged left ventricular chambers, deranged ejection fraction, fraction shortening, cardiomyocyte contractile capacity, intracellular Ca2+ handling, sarcoplasmic reticulum Ca2+ reuptake, loss of mitochondrial integrity (mitochondrial swelling, loss of aconitase activity), mitochondrial energy deficit, carbonyl damage, lipid peroxidation, ferroptosis, and apoptosis. Metallothionein itself did not affect myocardial morphology and function, although it mitigated BSO-provoked myocardial anomalies, loss of mitochondrial integrity and energy, and ferroptosis. Immunoblotting revealed down-regulated sarco(endo)plasmic reticulum Ca2+-ATPase 2a, glutathione peroxidase 4, ferroptosis-suppressing CDGSH iron-sulfur domain 1 (CISD1), and mitochondrial regulating glycogen synthase kinase-3ß phosphorylation with elevated p53, myosin heavy chain-ß isozyme, IκB phosphorylation, and solute carrier family 7 member 11 (SLC7A11) as well as unchanged SLC39A1, SLC1A5, and ferroptosis-suppressing protein 1 following BSO challenge, all of which, except glutamine transporter SLC7A11 and p53, were abrogated by metallothionein. Inhibition of CISD1 using pioglitazone nullified GSH-offered benefit against BSO-induced cardiomyocyte ferroptosis and contractile and intracellular Ca2+ derangement. Taken together, these findings support a regulatory modality for CISD1 in the impedance of ferroptosis in metallothionein-offered protection against GSH depletion-evoked cardiac aberration.

Mediating and moderating effects of plasma proteomic biomarkers on the association between poor oral health problems and brain white matter microstructural integrity: the UK Biobank study.

The plasma proteome can mediate associations between periodontal disease (Pd) and brain white matter integrity (WMI). We screened 5089 UK Biobank participants aged 40-70 years for poor oral health problems (POHP). We examined the association between POHP and WMI (fractional anisotropy (FA), mean diffusivity (MD), Intracellular Volume Fraction (ICVF), Isotropic Volume Fraction (ISOVF) and Orientation Diffusion (OD)), decomposing the total effect through the plasma proteome of 1463 proteins into pure mediation, pure interaction, neither, while adjusting for socio-demographic and cardiovascular health factors. Similarly, structural equations modeling (SEM) was conducted. POHP was more prevalent among men (12.3% vs. 9.6%), and was associated with lower WMI on most metrics, in a sex-specific manner. Of 15 proteins strongly associated with POHP, growth differentiation factor 15 (GDF15) and WAP four-disulfide core domain 2 (WFDC2; also known as human epididymis protein 4; HE4) were consistent mediators. Both proteins mediated 7-8% of total POHP effect on FAmean. SEM yielded significant total effects for FAmean, MDmean and ISOVFmean in full models, with %mediated by common latent factor (GDF15 and WFDC2) ranging between 13% (FAmean) and 19% (ISOVFmean). For FA, mediation by this common factor was found for 16 of 49 tract-specific and global mean metrics. Protein metabolism, immune system, and signal transduction were the most common pathways for mediational effects. POHP was associated with poorer WMI, which was partially mediated by GDF15 and WFDC2.

Hematopoietic stem cell gene editing rescues B-cell development in X-linked agammaglobulinemia.

BACKGROUND: X-linked agammaglobulinemia (XLA) is an inborn error of immunity that renders boys susceptible to life-threatening infections due to loss of mature B cells and circulating immunoglobulins. It is caused by defects in the gene encoding the Bruton tyrosine kinase (BTK) that mediates the maturation of B cells in the bone marrow and their activation in the periphery. This paper reports on a gene editing protocol to achieve "knock-in" of a therapeutic BTK cassette in hematopoietic stem and progenitor cells (HSPCs) as a treatment for XLA. METHODS: To rescue BTK expression, this study employed a clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 system that creates a DNA double-strand break in an early exon of the BTK locus and an adeno-associated virus 6 virus that carries the donor template for homology-directed repair. The investigators evaluated the efficacy of the gene editing approach in HSPCs from patients with XLA that were cultured in vitro under B-cell differentiation conditions or that were transplanted in immunodeficient mice to study B-cell output in vivo. RESULTS: A (feeder-free) B-cell differentiation protocol was successfully applied to blood-mobilized HSPCs to reproduce in vitro the defects in B-cell maturation observed in patients with XLA. Using this system, the investigators could show the rescue of B-cell maturation by gene editing. Transplantation of edited XLA HSPCs into immunodeficient mice led to restoration of the human B-cell lineage compartment in the bone marrow and immunoglobulin production in the periphery. CONCLUSIONS: Gene editing efficiencies above 30% could be consistently achieved in human HSPCs. Given the potential selective advantage of corrected cells, as suggested by skewed X-linked inactivation in carrier females and by competitive repopulating experiments in mouse models, this work demonstrates the potential of this strategy as a future definitive therapy for XLA.

Drug Exposure and Treatment Outcomes in Patients With Multidrug-Resistant Tuberculosis and Diabetes Mellitus: A Multicenter Prospective Cohort Study From China.

BACKGROUND: The management of multidrug-resistant tuberculosis (MDR-TB) remains challenging. Treatment outcome is influenced by multiple factors; the specific roles of diabetes and glycemic control remain uncertain. This study aims to assess the impact of glycemic control on drug exposure, to investigate the association between drug exposure and treatment outcomes, and to identify clinically significant thresholds predictive of treatment outcome, among patients with diabetes. METHODS: This multicenter prospective cohort study involved patients with confirmed MDR-TB and diabetes. Drug exposure level was estimated by noncompartmental analysis. The minimum inhibitory concentrations (MICs) were determined for the individual Mycobacterium tuberculosis isolates. The influence of poor glycemic control (glycated hemoglobin ≥7%) on drug exposure and the associations between drug exposure and treatment outcome were evaluated by univariate and multivariate analysis. Classification and regression tree analysis was used to identify the drug exposure/susceptibility thresholds. RESULTS: Among the 131 diabetic participants, 43 (32.8%) exhibited poor glycemic control. Poor glycemic control was independently associated with decreased exposure to moxifloxacin, linezolid, bedaquiline, and cycloserine, but not clofazimine. Additionally, a higher ratio of drug exposure to susceptibility was found to be associated with a favorable MDR-TB treatment outcome. Thresholds predictive of 6-month culture conversion and favorable outcome were bedaquiline area under the concentration-time curve (AUC)/MIC ≥245 and moxifloxacin AUC/MIC ≥67, demonstrating predictive accuracy in patients, regardless of their glycemic control status. CONCLUSIONS: Glycemic control and optimal TB drug exposure are associated with improved treatment outcomes. This dual management strategy should be further validated in randomized controlled trials of patients with MDR-TB and diabetes.

The acquired dyad inclination and decreased interpersonal brain communication in the pursuit of collective benefit.

People perform better collectively than individually, a phenomenon known as the collective benefit. To pursue the benefit, they may learn from previous behaviors, come to know whose initial opinion should be valued, and develop the inclination to take it as the collective one. Such learning may affect interpersonal brain communication. To test these hypotheses, this study recruited participant dyads to conduct a perceptual task on which they made individual decisions first and then the collective one. The enhanced interpersonal brain synchronization (IBS) between participants was explored when individual decisions were in disagreement vs. agreement. Computational modeling revealed that participant dyads developed the dyad inclination of taking the higher-able participants', not the lower-able ones' decisions as their collective ones. Brain analyses unveiled the enhanced IBS at frontopolar areas, premotor areas, supramarginal gyri, and right temporal-parietal junctions. The premotor IBS correlated negatively with dyad inclination and collective benefit in the absence of correction. The Granger causality analyses further supported the negative relation of dyad inclination with inter-brain communication. This study highlights that dyads learn to weigh individuals' decisions, resulting in dyad inclinations, and explores associated inter-brain communication, offering insights into the dynamics of collective decision-making.

Copper Ion-Inspired Dual Controllable Drug Release Hydrogels for Wound Management: Driven by Hydrogen Bonds.

Bacterial infections and inflammation progression yield huge trouble for the management of serious skin wounds and burns. However, some hydrogel dressing exhibit poor wound-healing capabilities. Additionally, little information is given on the molecular theory of hydrogel gelation mechanisms and drug release performance from drug-polymer network in the water environment. Herein, cationic guar gum (CG) is first mixed with dipotassium glycyrrhizinate (DG), and then crosslinked Cu2+ to strengthen the mechanical strength followed by encapsulating mussel adhesive protein (MAP) as composite dressings. Intriguingly, CG-Cu2+ 0.5-DG10 possessed proper rheological properties and mechanical strength predominantly driven by strong CG-H2O-Cu2+ and Cu2+-CG hydrogen bonding interaction. Weak DG-CG hydrogen bonding only controlled DG release in the initial 4 h, while strong hydrogen bonding is the main force regulating the sustained release of Cu2+ within 48 h. The incorporation of MAP further loosened the tight crosslinking of CG-Cu2+ 0.5-DG10. The screened CG-Cu2+ 0.5-DG10/MAP possessed excellent self-healing, injectability, antibacterial, anti-inflammatory, cell proliferation-promotion activities with high biocompatibility. Therefore, CG-Cu2+ 0.5-DG10/MAP hydrogel expedited wound closure on S. aureus-infected full-thickness skin wound model and lowered necrosis progression to the unburned interspaces on a rat burn model. The results highlight the promising translational potential of Cu2+-inspired hydrogels for the management of burns and infected wounds.

Metal-Organic Framework Based Mucoadhesive Nanodrugs for Multifunction Helicobacter Pylori Targeted Eradication, Inflammation Regulation and Gut Flora Protection.

The prevalence of drug-resistant bacteria presents a significant challenge to the antibiotic treatment of Helicobacter pylori (H. pylori), while traditional antimicrobial agents often suffer from shortcomings such as poor gastric retention, inadequate alleviation of inflammation, and significant adverse effects on the gut microbiota. Here, a selenized chitosan (CS-Se) modified bismuth-based metal-organic framework (Bi-MOF@CS-Se) nanodrug is reported that can target mucin through the charge interaction of the outer CS-Se layer to achieve mucosal adhesion and gastric retention. Additionally, the Bi-MOF@CS-Se can respond to gastric acid and pepsin degradation, and the exposed Bi-MOF exhibits excellent antibacterial properties against standard H. pylori as well as clinical antibiotic-resistant strains. Remarkably, the Bi-MOF@CS-Se effectively alleviates inflammation and excessive oxidative stress by regulating the expression of inflammatory factors and the production of reactive oxygen species (ROS), thereby exerting therapeutic effects against H. pylori infection. Importantly, this Bi-MOF@CS-Se nanodrug does not affect the homeostasis of gut microbiota, providing a promising strategy for efficient and safe treatment of H. pylori infection.

Domestication and evolutionary histories of specialized gut symbionts across cephalotine ants.

The evolution of animals and their gut symbionts is a complex phenomenon, obscured by lability and diversity. In social organisms, transmission of symbionts among relatives may yield systems with more stable associations. Here, we study the history of a social insect symbiosis involving cephalotine ants and their extracellular gut bacteria, which come predominantly from host-specialized lineages. We perform multi-locus phylogenetics for symbionts from nine bacterial orders, and map prior amplicon sequence data to lineage-assigned symbiont genomes, studying distributions of rigorously defined symbionts across 20 host species. Based on monophyly and additional hypothesis testing, we estimate that these specialized gut bacteria belong to 18 distinct lineages, of which 15 have been successfully isolated and cultured. Several symbiont lineages showed evidence for domestication events that occurred later in cephalotine evolutionary history, and only one lineage was ubiquitously detected in all 20 host species and 48 colonies sampled with amplicon 16S rRNA sequencing. We found evidence for phylogenetically constrained distributions in four symbionts, suggesting historical or genetic impacts on community composition. Two lineages showed evidence for frequent intra-lineage co-infections, highlighting the potential for niche divergence after initial domestication. Nearly all symbionts showed evidence for occasional host switching, but four may, more often, co-diversify with their hosts. Through our further assessment of symbiont localization and genomic functional profiles, we demonstrate distinct niches for symbionts with shared evolutionary histories, prompting further questions on the forces underlying the evolution of hosts and their gut microbiomes.

Comparison of Postoperative Outcomes Between Near-Infrared Fluorescent Imaging-Guided Mediastinal Lymphadenectomy and Conventional Surgery for Esophageal Cancer.

BACKGROUND: The study aimed to evaluate the efficacy of using near-infrared fluorescent imaging (NIRF) imaging with indocyanine green as an intraoperative tool for achieving complete mediastinal lymph node (LN) resection. PATIENTS AND METHODS: Between September 2019 and July 2021, patients with potential for esophagectomy due to middle and lower thoracic esophageal cancer were enrolled in this study. All patients were scheduled for NIRF-guided mediastinal lymphadenectomy during esophageal cancer surgery and were appropriately assigned to the NIRF group. Patients who underwent esophagectomy between September 2017 and September 2019 were assigned to the historical control group upon satisfying the inclusion/exclusion criteria. Surgical outcomes and the number of removed LNs were compared between the two groups using 1:1 propensity score matching. RESULTS: Of 67 eligible patients, 59 patients were included in the NIRF group after postsurgical exclusions. The operative time was significantly shorter in the NIRF group than in the historical control group [180 (140-420) min versus 202 (137-338) min; P < 0.001]. The incidence of postoperative chylothorax and hoarseness were significantly lower in the NIRF group than in the historical control group (0% versus 10.2 %; P = 0.036, 3.4% versus 13.6%; P = 0.047). The number of dissected total LNs, mediastinal LNs, and negative LNs was significantly larger in the NIRF group than in the historical control group. The number of overall metastatic LNs and abdominal LNs was comparable between the two groups. CONCLUSIONS: NIRF imaging can assist in the thorough and complete mediastinal LNs dissections without increasing complications in patients undergoing esophagectomy.

The association between triglyceride glucose-body mass index and all-cause mortality in critically ill patients with atrial fibrillation: a retrospective study from MIMIC-IV database.

BACKGROUND: The TyG-BMI index, which is a reliable indicator of insulin resistance (IR), has been found to have a significant correlation with the occurrence of cardiovascular events. However, there still lacks study on the TyG-BMI index and prognosis in patients with atrial fibrillation (AF). The objective of the present study was to evaluate the relationship between TyG-BMI index at admission to ICU and all-cause mortality in critically ill patients with AF. METHODS: The patient's data were extracted from Medical Information Mart for Intensive Care IV(MIMIC-IV) database. All patients were divided into four groups according to TyG-BMI index. Outcomes include primary and secondary endpoints, with the primary endpoint being the 30-day and 365-day all-cause mortality and the secondary endpoint being the 90-day and 180-day all-cause mortality. TyG-BMI index was quartile and Kaplan-Meier curve was used to compare the outcome of each group. Cox proportional-hazards regression model and restricted cubic splines (RCS) were conducted to assess the relationship between TyG-BMI index and outcomes. RESULTS: Out of a total of 2509 participants, the average age was 73.26 ± 11.87 years, with 1555 (62.0%) being males. Patients with lower level of TyG-BMI had higher risk of 30-day, 90-day, 180-day and 365-day all-cause mortality, according to the Kaplan-Meier curves (log-rank P < 0.001). In addition, cox proportional-hazards regression analysis revealed that the risk of 30-day, 90-day, 180-day and 365-day all-cause mortality was significantly higher in the lowest quartile of TyG-BMI. Meanwhile, the RCS analysis indicated that L-typed relationships between TyG-BMI index and all-cause mortality, with inflection points at 223.60 for 30-day and 255.02 for 365-day all-cause mortality, respectively. Compared to patients with TyG-BMI levels below the inflection points, those with higher levels had a 1.8% lower risk for 30-day all-cause mortality (hazard ratio [HR] 0.982, 95% confidence interval [CI] 0.9676-0.988) and 1.1% lower risk for 365-day all-cause mortality (HR 0.989, 95% CI 0.986-0.991). CONCLUSION: In critically ill patients with AF, a lower TyG-BMI level is significantly associated with a higher risk of 30-day, 90-day, 180-day and 365-day all-cause mortality. TyG-BMI index could be used as a valid indicator for grading and treating patients with AF in the ICU.

Mycoplasma genitalium Membrane Lipoprotein Induces GAPDH Malonylation in Urethral Epithelial Cells to Regulate Cytokine Response.

Membrane lipoproteins serve as primary pro-inflammatory virulence factors in Mycoplasma genitalium. Membrane lipoproteins primarily induce inflammatory responses by activating Toll-like Receptor 2 (TLR2); however, the role of the metabolic status of urethral epithelial cells in inflammatory response remains unclear. In this study, we found that treatment of uroepithelial cell lines with M. genitalium membrane lipoprotein induced metabolic reprogramming, characterized by increased aerobic glycolysis, decreased oxidative phosphorylation, and increased production of the metabolic intermediates acetyl-CoA and malonyl-CoA. The metabolic shift induced by membrane lipoproteins is reversible upon blocking MyD88 and TRAM. Malonyl-CoA induces malonylation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and malonylated GAPDH could dissociate from the 3' untranslated region of TNF-α and IFN-γ mRNA. This dissociation greatly reduces the inhibitory effect on the translation of TNF-α and IFN-γ mRNA, thus achieving fine-tuning control over cytokine secretion. These findings suggest that GAPDH malonylation following M. genitalium infection is an important inflammatory signal that plays a crucial role in urogenital inflammatory diseases.

Plant community diversity alters the response of ecosystem multifunctionality to multiple global change factors.

Biodiversity is considered important to the mitigation of global change impacts on ecosystem multifunctionality in terrestrial ecosystems. However, potential mechanisms through which biodiversity maintains ecosystem multifunctionality under global change remain unclear. We grew 132 plant communities with two levels of plant diversity, crossed with treatments based on 10 global change factors (nitrogen deposition, soil salinity, drought, plant invasion, simulated grazing, oil pollution, plastics pollution, antibiotics pollution, heavy metal pollution, and pesticide pollution). All global change factors negatively impacted ecosystem multifunctionality, but negative impacts were stronger in high compared with low diversity plant communities. We explored potential mechanisms for this unexpected result, finding that the inhibition of selection effects (i.e., selection for plant species associated with high ecosystem functioning) contributed to sensitivity of ecosystem multifunctionality to global change. Specifically, global change factors decreased the abundance of novel functional plants (i.e., legumes) in high but not low diversity plant communities. The negative impacts of global change on ecosystem multifunctionality were also mediated by increased relative abundance of fungal plant pathogens (identified from metabarcoding of soil samples) and their negative relationship with the abundance of novel functional plants. Taken together, our experiment highlights the importance of protecting high diversity plant communities and legumes, and managing fungal pathogens, to the maintenance of ecosystem multifunctionality in the face of complex global change.

TRIM34 suppresses non-small-cell lung carcinoma via inducing mTORC1-dependent glucose utilization and promoting cellular death.

Non-small-cell lung carcinoma (NSCLC) is a type of pernicious tumor, which owns high morbidity and mortality. TRIM34 has a stimulative role in cell apoptosis and a suppressive role in inflammation. However, no studies were focused on the regulatory impacts of TRIM34 in NSCLC. This study aimed to examine the underlying regulatory effects of TRIM34 in NSCLC. TRIM34 exhibited lower expression in NSCLC. TRIM34 facilitated mitochondrial damage and apoptosis in NSCLC. TRIM34 induced the increased activity of mTORC1 and accelerated glycolysis in NSCLC. Enhanced mitochondrial damage induced by TRIM34 overexpression was reversed after rapamycin (mTORC1 inhibitor) treatment in NSCLC. The strengthened cell apoptosis stimulated by TRIM34 overexpression was rescued after rapamycin treatment. TRIM34 activated mTORC1 to suppress NSCLC progression in vivo. TRIM34 suppressed NSCLC via inducing mTORC1-dependent glucose utilization and promoting cellular death. The results suggest that TRIM34 can be a useful therapeutic biomarker for NSCLC patients.

Efficacy and safety of anti-PD-1 inhibitor versus anti-PD-L1 inhibitor in first-line treatment of extensive-stage small cell lung cancer: a multicenter retrospective study.

BACKGROUND: Immunotherapy targeting PD-1/PD-L1 has revolutionized the treatment of extensive-stage small cell lung cancer (ES-SCLC). However, clinical trials suggest differential efficacy of anti-PD-1 agents and anti-PD-L1 agents in first-line treatment of ES-SCLC. This retrospective multicenter study aimed to compare the efficacy and safety of anti-PD-1 agents versus anti-PD-L1 agents in first-line treatment of ES-SCLC in real-world practice. METHODS: Patients with pathologically or cytologically confirmed ES-SCLC treated with platinum plus etoposide combined with anti-PD-1 or PD-L1 agents as first-line treatment in different centers of PLA General Hospital between January 2017 and October 2021 were included for this study. Survival outcomes and safety were compared between patients receiving anti-PD-1 and PD-L1 agents. RESULTS: Of the total 154 included patients, 68 received anti-PD-1 agents plus chemotherapy (PD-1 group), and 86 received anti-PD-L1 agents plus chemotherapy (PD-L1 group). Progression-free survival (PFS) and overall survival (OS) in the entire cohort were 7.6 months (95% confidence interval [CI]: 6.5-8.2 months) and 17.4 months (95% CI: 15.3-19.3 months), respectively. Median PFS and OS were comparable between the PD-1 group and PD-L1 group (PFS: 7.6 months vs. 8.3 months, HR = 1.13, 95% CI: 0.79-1.62, p = 0.415; OS: 26.9 months vs. 25.6 months, HR = 0.96, 95% CI: 0.63-1.47, p = 0.859. The objective response rate and disease control rate were comparable between the two groups: 79.4% vs. 79.1% and 92.6% vs. 94.2%, respectively. The 6-month, 12-month, and 18-month PFS and OS rates were slightly higher in the PD-L1 group than in the PD-1 group, while the 24-month PFS rate was slightly higher in the PD-1 group than in the PD-L1 group. Stratified analysis showed that locoregional thoracic radiotherapy and normal lactate dehydrogenase level were independent predictors of better OS in ES-SCLC patients treated with first-line chemotherapy plus ICI. Adverse events were not significantly different between the two groups. CONCLUSIONS: Anti-PD-1 agents and anti-PD-L1 agents combined with chemotherapy as first-line treatment for ES-SCLC are comparably effective and well tolerated.

Infection burden and its association with neurite orientation dispersion and density imaging markers in the UK Biobank.

BACKGROUND: Infection burden (IB), although linked to neurodegeneration, including Alzheimer's Disease (AD), has not been examined against neurite orientation, dispersion, and density imaging (NODDI) measures. METHODS: Among 38,803 UK Biobank adults (Age:40-70 years), we tested associations of total IB (IBtotal, 47.5 %) and hospital-treated IB (IBhosp, 9.7 %) with NODDI measures (5-15 years later), including volume fraction of Gaussian isotropic diffusion (ISOVF), intra-cellular volume fraction (ICVF) and orientation dispersion (OD) indices, using multiple linear regression models. RESULTS: Total and hospital-treated infection burdens (IBtotal and IBhosp) were associated with increased ISOVF, indicating increased free-water component. IBtotal was positively associated with OD, indicating that at higher IBtotal there was greater fanning of neurites. This was more evident in the lower cardiovascular health group. IBhosp was associated with higher OD, and lower ICVF at higher AD polygenic risk. Together, these findings indicate that both total and hospital-treated infections have effects on NODDI outcomes in the direction of poor brain health. These effects were largely homogeneous across cardiovascular health and AD polygenic risk groups, with some effects shown to be stronger at poor cardiovascular health and/or higher AD risk. CONCLUSIONS: Total and hospital-treated infections were associated with poorer white matter microstructure (higher ISOVF or OD or lower ICVF), with some heterogeneity across cardiovascular health and AD risk. Longitudinal studies with multiple repeats on neuroimaging markers in comparable samples are needed.

Plasma proteomic biomarkers and the association between poor cardiovascular health and incident dementia: The UK Biobank study.

BACKGROUND: The study examined how plasma proteome indicators may explain the link between poor cardiovascular health (CVH) and dementia risk. METHODS: The present study involved 28,974 UK Biobank participants aged 50-74y at baseline (2006-2010) who were followed-up for ≤ 15 y for incidence of dementia. CVH was calculated using Life's Essential 8 (LE8) total scores. The scores were standardized and reverse coded to reflect poor CVH (LE8z_rev). OLINK proteomics was available on this sample (k = 1,463 plasma proteins). The study primarily tested the mediating effects of the plasma proteome in LE8z_rev-dementia effect. The total effect was decomposed into "mediation only" or pure indirect effect (PIE), "interaction only" or interaction referent (INTREF), "neither mediation nor interaction" or controlled direct effect (CDE), and "both mediation and interaction" or mediated interaction (INTMED). RESULTS: The study found poorer CVH assessed by LE8z_rev increased the risk of all-cause dementia by 11 % [per 1 SD, hazard ratio, (HR) = 1.11, 95 % CI: 1.03-1.20, p = 0.005). The study identified 11 plasma proteins with strong mediating effects, with GDF15 having the strongest association with dementia risk (per 1 SD, HR = 1.24, 95 % CI: 1.16, 1.33, P < 0.001 when LE8z_rev is set at its mean value) and the largest proportion mediated combining PIE and INTMED (62.6 %; 48 % of TE is PIE), followed by adrenomedullin or ADM. A first principal component with 10 top mediators (TNFRSF1A, GDF15, FSTL3, COL6A3, PLAUR, ADM, GFRAL, ACVRL1, TNFRSF6B, TGFA) mediated 53.6 % of the LE8z_rev-dementia effect. Using all the significant PIE (k = 526) proteins, we used OLINK Insight pathway analysis to identify key pathways, which revealed the involvement of the immune system, signal transduction, metabolism, disease, protein metabolism, hemostasis, membrane trafficking, extracellular matrix organization, developmental biology, and gene expression among others. STRING analysis revealed that five top consistent proteomic mediators were represented in two larger clusters reflecting numerous interconnected biological gene ontology pathways, most notably cytokine-mediated signaling pathway for GDF15 cluster (GO:0019221) and regulation of peptidyl-tyrosine phosphorylation for the ADM cluster (GO:0050730). CONCLUSION: Dementia is linked to poor CVH mediated by GDF15 and ADM among several key proteomic markers which collectively explained âˆ¼ 54 % of the total effect.

Development and validation of a prognostic model for assessing long COVID risk following Omicron wave-a large population-based cohort study.

BACKGROUND: Long coronavirus disease (COVID) after COVID-19 infection is continuously threatening the health of people all over the world. Early prediction of the risk of Long COVID in hospitalized patients will help clinical management of COVID-19, but there is still no reliable and effective prediction model. METHODS: A total of 1905 hospitalized patients with COVID-19 infection were included in this study, and their Long COVID status was followed up 4-8 weeks after discharge. Univariable and multivariable logistic regression analysis were used to determine the risk factors for Long COVID. Patients were randomly divided into a training cohort (70%) and a validation cohort (30%), and factors for constructing the model were screened using Lasso regression in the training cohort. Visualize the Long COVID risk prediction model using nomogram. Evaluate the performance of the model in the training and validation cohort using the area under the curve (AUC), calibration curve, and decision curve analysis (DCA). RESULTS: A total of 657 patients (34.5%) reported that they had symptoms of long COVID. The most common symptoms were fatigue or muscle weakness (16.8%), followed by sleep difficulties (11.1%) and cough (9.5%). The risk prediction nomogram of age, diabetes, chronic kidney disease, vaccination status, procalcitonin, leukocytes, lymphocytes, interleukin-6 and D-dimer were included for early identification of high-risk patients with Long COVID. AUCs of the model in the training cohort and validation cohort are 0.762 and 0.713, respectively, demonstrating relatively high discrimination of the model. The calibration curve further substantiated the proximity of the nomogram's predicted outcomes to the ideal curve, the consistency between the predicted outcomes and the actual outcomes, and the potential benefits for all patients as indicated by DCA. This observation was further validated in the validation cohort. CONCLUSIONS: We established a nomogram model to predict the long COVID risk of hospitalized patients with COVID-19, and proved its relatively good predictive performance. This model is helpful for the clinical management of long COVID.