A Rare Complication in the Oral Local Infiltration Anesthesia.

The present report describes a rare complication named Kuhn anemia, which happened during local infiltration anesthesia of maxillary wisdom tooth. A 24-year-old male was referred for residual crown of left maxillary wisdom tooth and therefore required extraction. Oral examination revealed a buccal impacted left maxillary wisdom tooth (28), severe caries affecting the dental pulp, and pain with percussion. This case was diagnosed as impacted wisdom tooth 28 and pulpitis. Thus, the authors performed an extraction of the 28. After injection of articaine hydrochloride (68 mg:1.7 mL) containing epinephrine (1:100,000) as local anesthetic, the patient felt pain and heat in the left cheek, and an irregularly shaped pale area appeared on the left cheek. The authors stopped the surgery and comforted him. After a 30-minute break, the cheek turned normal, and abnormal sensation was no longer felt.

Association Between Cognitive Function and Risk of Chronic Kidney Disease: A Longitudinal Cohort and Mendelian Randomization Study.

OBJECTIVE: To investigate the causal dose-response association between cognitive function and the risk of chronic kidney disease (CKD) by a longitudinal cohort and mendelian randomization study. METHODS: The longitudinal cohort study included 396,600 participants without prior dementia and CKD from the UK Biobank. Cognitive function (including prospective memory, numeric memory, visuospatial memory, reaction time, and reasoning ability) was assessed by computerized touchscreen tests. Global cognitive function was defined as a composite score of those specific cognitive domains. A 2-stage mendelian randomization analysis was conducted with 12,979 cases of CKD and 379,424 controls. Genetically predicted global cognitive function was instrumented with 91 confirmed genome-wide significant variants. The study outcome was new-onset CKD. The study was conducted from March 13, 2006, to September 30, 2021. RESULTS: During a median follow-up of 12.5 years, new-onset CKD developed in 13,090 participants. Per 1 SD score increments in reaction time (adjusted hazard ratio [HR], 0.97; 95% CI, 0.95 to 0.99), reasoning ability (adjusted HR, 0.91; 95% CI, 0.88 to 0.94), and global cognitive function (adjusted HR, 0.96; 95% CI, 0.95 to 0.98) were associated with a significantly lower risk of new-onset CKD. Compared with an incorrect answer in the prospective memory test, a correct answer was associated with a lower risk of new-onset CKD (adjusted HR, 0.82; 95% CI, 0.76 to 0.88). Mendelian randomization analyses found that per 1 SD score increments in genetically predicted global cognitive function resulted in a significantly (7%; 95% CI, 2% to 12%) lower risk of new-onset CKD. CONCLUSION: A better cognitive function is causally associated with a lower risk of CKD in participants without prior dementia.

Characterization of a novel multi-resistant Pseudomonas juntendi strain from China with chromosomal blaVIM-2 and a megaplasmid coharboring blaIMP-1-like and blaOXA-1.

BACKGROUND: Pseudomonas juntendi is a newly identified opportunistic pathogen, of which we have limited understanding. P. juntendi strains are often multidrug resistant, which complicates clinical management of infection. METHODS: A strain of Pseudomonas juntendi (strain L4326) isolated from feces was characterized by MALDI-TOF-MS and Average Nucleotide Identity BLAST. This strain was further subject to whole-genome sequencing and Maximum Likelihood phylogenetic analysis. The strain was phenotypically characterized by antimicrobial susceptibility testing and conjugation assays. RESULTS: We have isolated the novel P. juntendi strain L4236, which was multidrug resistant, but retained sensitivity to amikacin. L4236 harbored a megaplasmid that encoded blaOXA-1 and a novel blaIMP-1 resistance gene variant. P. juntendi strain L4236 was phylogenetically related to P. juntendi strain SAMN30525517. CONCLUSION: A rare P. juntendi strain was isolated from human feces in southern China with a megaplasmid coharboring blaIMP-1-like and blaOXA-1. Antimicrobial selection pressures may have driven acquisition of drug-resistance gene mutations and carriage of the megaplasmid.

Inverse association between lung function and nonalcoholic fatty liver disease: An observational and mendelian randomization study.

BACKGROUND AND AIM: The association between lung function with non-alcoholic fatty liver disease (NAFLD) in the general population remains unknown. We aimed to examine the association between lung function and NAFLD among the general population in an observational and Mendelian randomization (MR) study. METHODS AND RESULTS: 340, 253 participants without prior liver diseases were included from the UK Biobank. Of these, 30,397 participants had liver proton density fat fraction (PDFF) measurements by magnetic resonance image (MRI). Lung function parameters included forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). The primary outcome was the presence of NAFLD, defined as a PDFF greater than 5.5%. The secondary outcome included incident severe NAFLD and severe liver diseases (including liver cirrhosis, liver failure, hepatocellular carcinoma and liver-related death), defined by the International Classification of Disease codes with different data sources. During a media follow-up duration of 9.3 years, 7335 (24.1%) the presence of NAFLD cases were documented. There was an inverse association of FEV1 (% predicted) (Per SD increment, adjusted OR = 0.91, 95%CI: 0.88-0.94) and FVC (% predicted) (Per SD increment, adjusted OR = 0.90, 95%CI: 0.87-0.92) with the presence of NAFLD. Similar results were found for incident severe NAFLD, severe liver disease, liver cirrhosis, liver failure and liver-related death. MR analyses showed that the genetically predicted FEV1 (adjusted OR = 0.63, 95%CI: 0.46-0.87) and FVC (adjusted OR = 0.69, 95%CI: 0.51-0.95) were both inversely associated with the presence of NAFLD. CONCLUSIONS: There was an inverse causal relationship between lung function and NAFLD in the general population.

Sweetened beverages and atrial fibrillation in people with prediabetes or diabetes.

AIM: To assess the association of intake of sugar-sweetened beverages (SSBs), artificially sweetened beverages (ASBs) and natural juices (NJs) with new-onset atrial fibrillation (AF) in people with prediabetes or diabetes. METHODS: A total of 31 433 participants with prediabetes and diabetes from the UK Biobank were included. Information on the intake of SSBs, ASBs and NJs was accessed by 24-hour dietary recalls from 2009 to 2012. The study outcome was new-onset AF. RESULTS: During a median follow-up of 12.0 years, 2470 (7.9%) AF cases were documented. Both the intake of SSBs (per 1 unit/day increment; adjusted hazard ratio [HR] = 1.11; 95% confidence interval [CI]: 1.04-1.18) and ASBs (per 1 unit/day increment; adjusted HR = 1.08; 95% CI: 1.02-1.14) were linearly and positively associated with new-onset AF, while NJ intake was not significantly associated with new-onset AF (per 1 unit/day increment; adjusted HR = 1.00; 95% CI: 0.93-1.08). Accordingly, compared with non-consumers, participants who consumed more than one unit per day of SSBs (adjusted HR = 1.30; 95% CI: 1.11-1.53) or ASBs (adjusted HR = 1.21; 95% CI:1.05-1.40) had an increased risk of AF. Substituting 1 unit/day of NJs for SSBs was associated with a 9% (adjusted HR = 0.91; 95% CI: 0.83-0.99) lower risk of new-onset AF, while replacing SSBs with ASBs was not significantly associated with new-onset AF (adjusted HR = 0.97; 95% CI: 0.89-1.06). CONCLUSIONS: Both the intake of SSBs and ASBs were linearly and positively associated with new-onset AF, while NJ intake did not show a significant association with AF in people with prediabetes or diabetes. Replacing an equivalent amount of SSB intake with NJs, but not ASBs, was associated with a lower risk of AF.

Association of Quantity and Diversity of Different Types of Fruit Intake with New-Onset Kidney Stones.

SCOPE: This study aims to assess the association between intake of different types of fruit (citrus, pomes, tropical fruits, berries, gourds, drupes, dried fruits, and other fruits), the intake diversity of fruit types, and risk of new-onset kidney stones in general population. METHODS AND RESULTS: A total of 205 896 participants with at least one completed 24-h dietary recall from the UK Biobank are included. During a median follow-up of 11.6 years, 2074 cases of kidney stones are documented. Compared with nonconsumers, participants with higher intake of citrus (50-<100 g day-1; hazards ratio [HR] = 0.78; 95% confidence interval [CI], 0.66-0.91; ≥100 g day-1; HR = 0.75; 95%CI, 0.63-0.89), pomes (≥100 g day-1; HR = 0.86; 95%CI, 0.77-0.96), or tropical fruits (50-<100 g day-1; HR = 0.86; 95%CI, 0.75-0.99; ≥100 g day-1; HR = 0.88; 95%CI, 0.79-0.99) have a lower risk of new-onset kidney stones. However, there is no significant association of intake of berries, gourds, drupes, dried fruits, and other fruits with kidney stones. A higher fruit variety score is significantly associated with a lower risk of new-onset kidney stones (per 1-score increment, HR = 0.86; 95%CI, 0.81-0.91). CONCLUSIONS: Higher intake of citruses (≥50 g day-1), pomes (≥100 g day-1), and tropical fruits (≥50 g day-1), as well as increasing diversity of intake of these three fruits, are associated with a lower risk of new-onset kidney stones.

Association of accelerometer-derived "weekend warrior" moderate to vigorous physical activity, chronic kidney disease and acute kidney injury.

OBJECTIVE: To examine the relationship between an accelerometer-derived "weekend warrior" pattern, characterized by achieving the most moderate to vigorous physical activity (MVPA) over 1-2 days, as opposed to more evenly distributed patterns, with risk of chronic kidney disease (CKD) and acute kidney injury (AKI). METHODS: 77,977 participants without prior kidney diseases and with usable accelerometer data (collected between 2013 and 2015) were included from the UK Biobank. Three physical activity patterns were compared: active weekend warrior pattern (achieving ≥150 min MVPA per week and accumulating ≥50 % of total MVPA in 1-2 days), active regular pattern (achieving ≥150 min MVPA but not meeting active weekend warrior criteria per week), and inactive pattern (<150 min MVPA per week). The study outcomes included incident CKD and AKI, ascertained through self-report data and data linkage with primary care, hospital admissions, and death registry records. RESULTS: During a median follow-up of 6.8 years, 1324 participants developed CKD and 1515 developed AKI. In multivariable-adjusted models, when compared with inactive participants, individuals with active weekend warrior pattern (CKD: hazard ratio [HR], 0.79, 95 % confidence interval [CI], 0.69-0.89; AKI: HR, 0.70, 95 %CI, 0.62-0.79) and those with active regular pattern (CKD: HR, 0.81, 95 %CI, 0.69-0.95; AKI: HR, 0.79, 95 %CI, 0.68-0.91) exhibited a similar and significantly lower risk of incident CKD and AKI. Similar findings were observed at the median threshold of ≥230.4 min of MVPA per week. CONCLUSION: Concentrated MVPA within 1 to 2 days is as effective as distributed ones in decreasing the risk of renal outcomes.

Macrophage α7nAChR alleviates the inflammation of neonatal necrotizing enterocolitis through mTOR/NLRP3/IL-1ß pathway.

BACKGROUND: Neonatal necrotizing enterocolitis (NEC) is one of the most prevalent and severe intestinal emergencies in newborns. The inflammatory activation of macrophages is associated with the intestinal injury of NEC. The neuroimmune regulation mediated by α7 nicotinic acetylcholine receptor (α7nAChR) plays an important role in regulating macrophage activation and inflammation progression, but in NEC remains unclear. This study aims to explore the effect of macrophage α7nAChR on NEC. METHODS: Mice NEC model were conducted with high-osmolarity formula feeding, hypoxia, and cold stimulation. The α7nAChR agonist PNU-282987 and mTOR inhibitor rapamycin were treated by intraperitoneal injections in mice. The expression and distribution of macrophages, α7nAChR, and phospho-mammalian target of rapamycin (p-mTOR) in the intestines of NEC patients and mice was assessed using immunohistochemistry, immunofluorescence, and flow cytometry. The expression of NLRP3, activated caspase-1 and IL-1ß in mice intestines was detected by flow cytometry, western blot or ELISA. In vitro, the mouse RAW264.7 macrophage cell line was also cultured followed by various treatments. Expression of p-mTOR, NLRP3, activated caspase-1, and IL-1ß in macrophages was determined. RESULTS: Macrophages accumulated in the intestines and the expression of α7nAChR in the mucosal and submucosal layers of the intestines was increased in both the NEC patients and mice. The p-mTOR and CD68 were increased and co-localized in intestines of NEC patients. In vitro, α7nAChR agonist PNU-282987 significantly reduced the increase of NLRP3, activated caspase-1, and IL-1ß in macrophages. PNU-282987 also significantly reduced the increase of p-mTOR. The effect was blocked by AMPK inhibitor compound C. The expression of NLRP3, activated caspase-1, and IL-1ß was inhibited after mTOR inhibitor rapamycin treatment. In NEC model mice, PNU-282987 reduced the expression of p-mTOR, NLRP3, activated caspase-1, and IL-1ß in the intestine. Meanwhile, rapamycin significantly attenuated NLRP3 activation and the release of IL-1ß. Moreover, the proportion of intestinal macrophages and intestinal injury decreased after PNU-282987 treatment. CONCLUSION: Macrophage α7nAChR activation mitigates NLRP3 inflammasome activation by modulating mTOR phosphorylation, and subsequently alleviates intestinal inflammation and injury in NEC.

Retrospective assessment of short-term outcomes of robotic- versus laparoscopic-assisted duodenal diamond anastomosis in neonates.

OBJECTIVE: The purpose of this study was to retrospectively compare the short-term outcomes of robotic- (RAD) and laparoscopic-assisted duodenal diamond-shaped anastomosis (LAD) in neonates. METHODS: Neonates who underwent RAD (n = 30) or LAD (n = 38) between January 2019 and December 2022 were analyzed retrospectively. Major patient data were collected, including preoperative, intraoperative, and postoperative information. RESULTS: All patients were neonates below the age of 30 days weighing 4 kg. Thirty (44.1%) neonates underwent RAD and 38 neonates (55.9%) underwent LAD. Compared to the LAD group, the RAD group had a shorter intra-abdominal operation time (RAD, 60.0(50.0 ~ 70.0) min; LAD, 79.9(69.0 ~ 95.3) min; p < 0.001). There were no significant differences in immediate and 30-day complications between the two groups. CONCLUSIONS: RAD is safe and effective in neonates. Compared to traditional LAD, RAD showed comparable results.

RNF31-mediated IKKα ubiquitination aggravates inflammation and intestinal injury through regulating NF-κB activation in human and mouse neonates.

AIMS: Neonatal necrotizing enterocolitis (NEC) is a leading cause of intestine inflammatory disease, and macrophage is significantly activated during NEC development. Posttranslational modifications (PTMs) of proteins, particularly ubiquitination, play critical roles in immune response. This study aimed to investigate the effects of ubiquitin-modified proteins on macrophage activation and NEC, and discover novel NEC-related inflammatory proteins. MATERIALS AND METHODS: Proteomic and ubiquitin proteomic analyses of intestinal macrophages in NEC/healthy mouse pups were carried out. In vitro macrophage inflammation model and in vivo NEC mouse model, as well as clinical human samples were used for further verification the inhibitor of nuclear factor-κB kinase α (IKKα) ubiquitination on NEC development through Western blot, immunofluorescence, quantitative real-time polymerase chain reaction (qRT-PCR) and flow cytometry. KEY FINDINGS: We report here that IKKα was a new ubiquitin-modified protein during NEC through ubiquitin proteomics, and RING finger protein 31 (RNF31) acted as an E3 ligase to be involved in IKKα degradation. Inhibition of IKKα ubiquitination and degradation with siRNF31 or proteasome inhibitor decreased nuclear factor-κB (NF-κB) activation, thereby decreasing the expression of pro-inflammatory factors and M1 macrophage polarization, resulting in reliving the severity of NEC. SIGNIFICANCE: Our study suggests the activation of RNF31-IKKα-NF-κB axis triggering NEC development and suppressing RNF31-mediated IKKα degradation may be therapeutic strategies to be developed for NEC treatment.

Large-Scale Proteomics Improve Prediction of Chronic Kidney Disease in People With Diabetes.

OBJECTIVE: To develop and validate a protein risk score for predicting chronic kidney disease (CKD) in patients with diabetes and compare its predictive performance with a validated clinical risk model (CKD Prediction Consortium [CKD-PC]) and CKD polygenic risk score. RESEARCH DESIGN AND METHODS: This cohort study included 2,094 patients with diabetes who had proteomics and genetic information and no history of CKD at baseline from the UK Biobank Pharma Proteomics Project. Based on nearly 3,000 plasma proteins, a CKD protein risk score including 11 proteins was constructed in the training set (including 1,047 participants; 117 CKD events). RESULTS: The median follow-up duration was 12.1 years. In the test set (including 1,047 participants; 112 CKD events), the CKD protein risk score was positively associated with incident CKD (per SD increment; hazard ratio 1.78; 95% CI 1.44, 2.20). Compared with the basic model (age + sex + race, C-index, 0.627; 95% CI 0.578, 0.675), the CKD protein risk score (C-index increase 0.122; 95% CI 0.071, 0.177), and the CKD-PC risk factors (C-index increase 0.175; 95% CI 0.126, 0.217) significantly improved the prediction performance of incident CKD, but the CKD polygenic risk score (C-index increase 0.007; 95% CI -0.016, 0.025) had no significant improvement. Adding the CKD protein risk score into the CKD-PC risk factors had the largest C-index of 0.825 (C-index from 0.802 to 0.825; difference 0.023; 95% CI 0.006, 0.044), and significantly improved the continuous 10-year net reclassification (0.199; 95% CI 0.059, 0.299) and 10-year integrated discrimination index (0.041; 95% CI 0.007, 0.083). CONCLUSIONS: Adding the CKD protein risk score to a validated clinical risk model significantly improved the discrimination and reclassification of CKD risk in patients with diabetes.

A Particle Gel Assay for Detection of Intracellular Hepatitis B Virus Subviral Particles in Cultured Cells.

Chronic hepatitis B virus (HBV) infection is due to the failure of host immune system to resolve the viral infection. Accordingly, restoration or reconstitution of a functional antiviral immune response to HBV is essential to achieve durable control of HBV replication leading to a functional cure of chronic hepatitis B (CHB). Noninfectious subviral particles (SVPs), comprised of HBV surface antigen (HBsAg), are the predominant viral products secreted by HBV-infected hepatocytes. The high levels of SVPs in the circulation induce immune tolerance and contribute to the establishment of chronic HBV infection. The current standard-of-care medications for CHB efficiently suppress HBV replication but fail to reduce the levels of HBsAg in majority of treated patients. Further understanding the mechanisms underlying SVP morphogenesis, secretion and regulation by viral and host cellular factors are critical for the discovery of therapeutics that can inhibit SVP production and/or induce the degradation of HBV envelope proteins. We describe herein a protocol for intracellular SVP detection by a native agarose gel electrophoresis-based particle gel assy. The method is suitable for quantitative detection of intracellular HBV SVPs and can be applied in dissecting the molecular mechanism of SVP morphogenesis and the discovery of antiviral agents targeting SVP formation in hepatocytes.

Discovery of hepatitis B virus subviral particle biogenesis inhibitors from a bioactive compound library.

High levels of hepatitis B virus (HBV) surface antigen (HBsAg) in the blood of chronic HBV carriers are considered to drive the exhaustion of antigen-specific T and B lymphocytes and thus responsible for the persistence of infection. Accordingly, therapeutic elimination of HBsAg may facilitate the activation of adaptive antiviral immune responses against HBV and achieve a functional cure of chronic hepatitis B. We discovered recently that an amphipathic alpha helix spanning W156 to R169 of HBV small envelope (S) protein plays an essential role in the morphogenesis of subviral particles (SVPs) and metabolism of S protein. We thus hypothesized that pharmacological disruption of SVP morphogenesis may induce intracellular degradation of S protein and reduce HBsAg secretion. To identify inhibitors of SVP biogenesis, we screened 4417 bioactive compounds with a HepG2-derived cell line expressing HBV S protein and efficiently secreting small spherical SVPs. The screen identified 24 compounds that reduced intracellular SVPs and secreted HBsAg in a concentration-dependent manner. However, 18 of those compounds inhibited the secretion of HBsAg and HBeAg in HBV replicon transfected HepG2 cells at similar efficiency, suggesting each of those compounds may disrupt a common cellular function required for the synthesis and/or secretion of these viral proteins. Interestingly, lycorine more efficiently inhibited the secretion of HBsAg in HepG2 cells transfected with HBV replicons, HepG2.2.15 cells and HBV infected - HepG2 cells expressing sodium taurocholate cotransporting polypeptide (NTCP). The structure activity relationship and antiviral mechanism of lycorine against HBV have been determined.

Unraveling the nexus of NAD+ metabolism and diabetic kidney disease: insights from murine models and human data.

Background: Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme involved in kidney disease, yet its regulation in diabetic kidney disease (DKD) remains inadequately understood. Objective: Therefore, we investigated the changes of NAD+ levels in DKD and the underlying mechanism. Methods: Alternations of NAD+ levels and its biosynthesis enzymes were detected in kidneys from streptozotocin-induced diabetic mouse model by real-time PCR and immunoblot. The distribution of NAD+ de novo synthetic enzymes was explored via immunohistochemical study. NAD+ de novo synthetic metabolite was measured by LC-MS. Human data from NephroSeq were analyzed to verify our findings. Results: The study showed that NAD+ levels were decreased in diabetic kidneys. Both mRNA and protein levels of kynurenine 3-monooxygenase (KMO) in NAD+ de novo synthesis pathway were decreased, while NAD+ synthetic enzymes in salvage pathway and NAD+ consuming enzymes remained unchanged. Further analysis of human data suggested KMO, primarily expressed in the proximal tubules shown by our immunohistochemical staining, was consistently downregulated in human diabetic kidneys. Conclusion: Our study demonstrated KMO of NAD+ de novo synthesis pathway was decreased in diabetic kidney and might be responsible for NAD+ reduction in diabetic kidneys, offering valuable insights into complex regulatory mechanisms of NAD+ in DKD.

Association between Life's Essential 8 and estimated pulse wave velocity among adults in the US: a cross-sectional study of NHANES 2011-2018.

Background: Arterial stiffness, typically evaluated via estimated pulse wave velocity (ePWV), is believed to have a significant association with cardiovascular diseases. The objective of this study was to investigate the correlation between Life's Essential 8 (LE8), a newly revised metric of cardiovascular health, and ePWV among adult population in the United States. Methods: This research employed a cross-sectional methodology, drawing upon data from the National Health and Nutrition Examination Survey (NHANES) spanning from 2011 to 2018. To explore the relationship between LE8 and ePWV among adults in the US, both univariate and multivariate linear regression analyses were carried out. Additionally, the restricted cubic splines method was utilized to examine any non-linear correlation. Results: The study comprised 6,742 participants with an average age of 48.30 ± 0.35 years. Among these, 3,236 were males, representing a weighted percentage of 48%. The population's weighted average LE8 score was 68.68 ± 0.37, while the average ePWV was 8.18 ± 0.04. An entirely adjusted model revealed a negative correlation between ePWV and LE8 scores [in the moderate LE8 group, coefficient - 0.17, 95% CI -0.28 to -0.06, p = 0.004; in the high LE8 group, coefficient - 0.44, 95% CI -0.56 to -0.32, p < 0.0001]. This negative correlation was consistent with the findings in demographic subgroup analysis, with the effect size being more pronounced among adults under the age of 60, and individuals without hypertension, cardiovascular disease, or diabetes. Conclusion: Our study reveals a negative correlation between LE8 and ePWV in the adult population of the US, suggesting that LE8 could potentially serve as an indicative marker for evaluating the risk of vascular stiffness. This inverse relationship is markedly stronger in adults below 60 years and those without diagnosed vascular diseases. This implies that lifestyle upgrades and risk factor management could be especially advantageous in curbing arterial stiffness within these groups. These conclusions underscore the importance of primary prevention in mitigating the risk of vascular aging in a relatively healthy group, emphasizing the significance of early intervention and risk factor management in cardiovascular disease.

Association between lung function and risk of microvascular diseases in patients with diabetes: A prospective cohort and Mendelian randomization study.

BACKGROUND AND AIMS: To investigate causal relationships of lung function with risks microvascular diseases among participants with diabetes, type 2 diabetes mellitus (T2DM) and type 1 diabetes mellitus (T1DM), respectively, in prospective and Mendelian randomization (MR) study. METHODS AND RESULTS: 14,617 participants with diabetes and without microvascular diseases at baseline from the UK Biobank were included in the prospective analysis. Of these, 13,421 had T2DM and 1196 had T1DM. The linear MR analyses were conducted in the UK Biobank with 6838 cases of microvascular diseases and 10,755 controls. Lung function measurements included forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). The study outcome was microvascular diseases, a composite outcome including chronic kidney diseases, retinopathy and peripheral neuropathy. During a median follow-up of 12.1 years, 2668 new-onset microvascular diseases were recorded. FVC (%predicted) was inversely associated with the risk of new-onset microvascular diseases in participants with diabetes (Per SD increment, adjusted HR = 0.86; 95%CI:0.83-0.89), T2DM (Per SD increment, adjusted HR = 0.86; 95%CI:0.82-0.90) and T1DM (Per SD increment, adjusted HR = 0.87; 95%CI: 0.79-0.97), respectively. Similar results were found for FEV1 (%predicted). In MR analyses, genetically predicted FVC (adjusted RR = 0.55, 95%CI:0.39-0.77) and FEV1 (adjusted RR = 0.48, 95%CI:0.28-0.83) were both inversely associated with microvascular diseases in participants with T1DM. No significant association was found in those with T2DM. Similar findings were found for each component of microvascular diseases. CONCLUSION: There was a causal inverse association between lung function and risks of microvascular diseases in participants with T1DM, but not in those with T2DM.

A nomogram for predicting hemorrhagic shock in pediatric patients with multiple trauma.

The timely detection and management of hemorrhagic shock hold paramount importance in clinical practice. This study was designed to establish a nomogram that may facilitate early identification of hemorrhagic shock in pediatric patients with multiple-trauma. A retrospective study was conducted utilizing a cohort comprising 325 pediatric patients diagnosed with multiple-trauma, who received treatment at the Children's Hospital, Zhejiang University School of Medicine, Zhejiang, China. For external validation, an additional cohort of 144 patients from a children's hospital in Taizhou was included. The model's predictor selection was optimized through the application of the Least Absolute Shrinkage and Selection Operator (LASSO) regression. Subsequently, a prediction nomogram was constructed using multivariable logistic regression analysis. The performance and clinical utility of the developed model were comprehensively assessed utilizing various statistical metrics, including Harrell's Concordance Index (C-index), receiver operating characteristic (ROC) curve analysis, calibration curve analysis, and decision curve analysis (DCA). Multivariate logistic regression analysis identified systolic blood pressure (ΔSBP), platelet count, activated partial thromboplastin time (APTT), and injury severity score (ISS) as independent predictors for hemorrhagic shock. The nomogram constructed using these predictors demonstrated robust predictive capabilities, as evidenced by an impressive area under the curve (AUC) value of 0.963. The model's goodness-of-fit was assessed using the Hosmer-Lemeshow test (χ2 = 10.023, P = 0.209). Furthermore, decision curve analysis revealed significantly improved net benefits with the model. External validation further confirmed the reliability of the proposed predictive nomogram. This study successfully developed a nomogram for predicting the occurrence of hemorrhagic shock in pediatric patients with multiple trauma. This nomogram may serve as an accurate and effective tool for timely and efficient management of children with multiple trauma.

Tea Consumption, Milk or Sweeteners Addition, Genetic Variation in Caffeine Metabolism, and Incident Venous Thromboembolism.

OBJECTIVE: The association between tea consumption and venous thromboembolism (VTE) remains unknown. We aimed to evaluate the association between tea consumption with different additives (milk and/or sweeteners) and incident VTE, and the modifying effects of genetic variation in caffeine metabolism on the association. METHODS: A total of 190,189 participants with complete dietary information and free of VTE at baseline in the UK Biobank were included. The primary outcome was incident VTE, including incident deep vein thrombosis and pulmonary embolism. RESULTS: During a median follow-up of 12.1 years, 4,485 (2.4%) participants developed incident VTE. Compared with non-tea drinkers, tea drinkers who added neither milk nor sweeteners (hazard ratio [HR]: 0.85; 95% confidence interval [95% CI]: 0.76-0.94), only milk (HR: 0.86; 95% CI: 0.80-0.93), and both milk and sweeteners to their tea (HR: 0.90; 95% CI: 0.81-0.99) had a lower risk of VTE, while those who added only sweeteners to their tea did not (HR: 0.94; 95% CI: 0.75-1.17). Moreover, there was an L-shaped relationship between tea consumption and incident VTE among tea drinkers who added neither milk nor sweeteners, only milk, and both milk and sweeteners to their tea, respectively. However, a nonsignificant association was found among tea drinkers who added only sweeteners to their tea. Genetic variation in caffeine metabolism did not significantly modify the association (p-interaction = 0.659). CONCLUSION: Drinking unsweetened tea, with or without added milk, was associated with a lower risk of VTE. However, there was no significant association between drinking tea with sweeteners and incident VTE.

circ_JMJD1C expedites breast cancer progression by regulating miR-182-5p/JMJD1C/SOX4 axis.

Circular RNAs (circRNAs) are engaged in various types of cancers. This study aimed to investigate the roles of circ_0006743 (circ_JMJD1C) in breast cancer. The downstream of circ_JMJD1C and their interaction network was determined by bioinformatic analyses. Gene expression were analyzed through western blot and qRT-PCR assays. Functional assays were conducted in vitro and in vivo to verify circ_JMJD1C role in BC. FISH and confocal analysis indicated the cellular distribution of circ_JMJD1C. Luciferase reporter, RNA immune-precipitation (RIP) assays, as well as Pearson's correlation analysis, were implemented to test the relation of miR-182-5p, JMJD1C and circ_JMJD1C. Circ_JMJD1C and JMJD1C expression were both elevated, and their expression was positively correlated in BC. Circ_ JMJD1C knockdown hindered BC cell proliferation, invasion, and migration, along with epithelial-mesenchymal transition (EMT) in vitro and in vivo. Circ_JMJD1C facilitated BC progression by the miR-182-5p-JMJD1C axis. Circ_JMJD1C epigenetically upregulated SOX4. Circ_JMJD1C promotes the aggressiveness of BC via regulating miR-182-5p/JMJD1C/SOX4 axis. This may provide a novel and promising therapy targeting BC.

ATP-Responsive Manganese-Based Bacterial Materials Synergistically Activate the cGAS-STING Pathway for Tumor Immunotherapy.

Stimulating the cyclic guanosine monophophate(GMP)-adenosine monophosphate (AMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial strategy by which bacteria activate the tumor immune system. However, the limited stimulation capability poses significant challenges in advancing bacterial immunotherapy. Here, an adenosine 5'-triphosphate (ATP)-responsive manganese (Mn)-based bacterial material (E. coli@PDMC-PEG (polyethylene glycol)) is engineered successfully, which exhibits an exceptional ability to synergistically activate the cGAS-STING pathway. In the tumor microenvironment, which is characterized by elevated ATP levels, this biohybrid material degrades, resulting in the release of divalent manganese ions (Mn2+) and subsequent bacteria exposure. This combination synergistically activates the cGAS-STING pathway, as Mn2+ enhances the sensitivity of cGAS to the extracellular DNA (eDNA) secreted by the bacteria. The results of the in vivo experiments demonstrate that the biohybrid materials E. coli@PDMC-PEG and VNP20009@PDMC-PEG effectively inhibit the growth of subcutaneous melanoma in mice and in situ liver cancer in rabbits. Valuable insights for the development of bacteria-based tumor immunotherapy are provided here.