ObjectiveTo investigate the risk factors for pyogenic liver abscess （PLA） comorbid with sepsis by analyzing clinical features， and to construct a predictive model. MethodsA retrospective analysis was performed for 489 patients who were hospitalized and diagnosed with PLA in The Affiliated Hospital of Xuzhou Medical University from January 2019 to December 2023， and according to the presence or absence of sepsis， they were divided into sepsis group with 306 patients and non-sepsis group with 183 patients. Related data were collected， including general information， laboratory markers， and outcome measures. The patients were further divided into a training set of 342 patients and a validation set of 147 patients at a ratio of 7∶3， and the training set was used for screening of variables and construction of a predictive model， while the validation set was used to test the performance of the model. An LASSO regression analysis was used for the screening of variables， and a multivariate Logistic regression analysis was used to construct the predictive model and plot a nomogram. The calibration curve， the receiver operating characteristic （ROC） curve， and the decision curve analysis were used for the validation of the model， and internal validation was performed for assessment. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups； the chi-square test was used for comparison of categorical variables between groups. ResultsThere were significant differences between the sepsis group and the non-sepsis group in pulse rate， mean arterial pressure， duration pf symptoms， comorbidity of liver cirrhosis or malignant tumor， leukocyte count， neutrophil count， lymphocyte count， platelet count （PLT）， activated partial thromboplastin time， fibrinogen， C-reactive protein， aspartate aminotransferase， alanine aminotransferase， albumin， total bilirubin （TBil）， creatinine， potassium， and prognostic nutritional index （PNI） （all P<0.05）. In the training set， the LASSO regression analysis identified four predictive factors of pulse rate， PLT， TBil and PNI， and the multivariate Logistic regression analysis showed that pulse rate （odds ratio ［OR］=1.033， 95% confidence interval ［CI］： 1.006‍ ‍—‍ ‍1.061， P=0.018）， PLT （OR=0.981， 95%CI： 0.975‍ ‍—‍ ‍0.987， P<0.001）， TBil （OR=1.086， 95%CI： 1.053‍ ‍—‍ ‍1.125， P<0.001）， and PNI （OR=0.935， 95%CI： 0.882‍ ‍—‍ ‍0.988， P=0.019） were independent influencing factors for the risk of sepsis in patients with PLA. The model constructed based on these factors showed a good predictive ability， with an area under the ROC curve of 0.948 （95%CI： 0.923‍ ‍—‍ ‍0.973） in the training set and 0.912 （95%CI： 0.848‍ ‍—‍ ‍0.976） in the validation set. The decision curve analysis showed that the model has a good net benefit within the range of 0.3‍ ‍—‍ ‍0.9 for threshold probability. ConclusionThe nomogram prediction model constructed based on pulse rate， PLT， TBil， and PNI has a certain clinical value and can well predict the risk of sepsis in patients with PLA.

[摘 要] 尽管基于T细胞的免疫检查点阻断（ICB）和过继性T细胞治疗已在临床上取得了显著疗效，但大多数实体瘤患者仍无法实现对免疫疗法的长期应答。其中一个重要原因是肿瘤微环境（TME）中复杂的代谢模式和抑制性信号会引发免疫细胞的代谢重编程，从而削弱其抗肿瘤效应。本文回顾不同分化状态的CD8+ T细胞的代谢偏好性，探讨CD8+ T细胞在与肿瘤细胞和TME相互作用过程中发生的代谢变化，讨论这些代谢变化如何影响CD8+ T细胞分化、功能和干性，以及如何利用代谢分子或者代谢通路来增强CD8+ T细胞的抗肿瘤能力，从而实现嵌合抗原受体基因修饰T淋巴细胞（CAR-T细胞）疗法和ICB疗法增效。

BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

BACKGROUND: Spatiotemporal disparities exist in the disease burden of non-communicable diseases (NCDs) attributable to kidney dysfunction, which has been poorly assessed. The present study aimed to evaluate the spatiotemporal trends of the global burden of NCDs attributable to kidney dysfunction and to predict future trends. METHODS: Data on NCDs attributable to kidney dysfunction, quantified using deaths and disability-adjusted life-years (DALYs), were extracted from the Global Burden of Diseases Injuries, and Risk Factors (GBD) Study in 2019. Estimated annual percentage change (EAPC) of age-standardized rate (ASR) was calculated with linear regression to assess the changing trend. Pearson's correlation analysis was used to determine the association between ASR and sociodemographic index (SDI) for 21 GBD regions. A Bayesian age-period-cohort (BAPC) model was used to predict future trends up to 2040. RESULTS: Between 1990 and 2019, the absolute number of deaths and DALYs from NCDs attributable to kidney dysfunction increased globally. The death cases increased from 1,571,720 (95% uncertainty interval [UI]: 1,344,420-1,805,598) in 1990 to 3,161,552 (95% UI: 2,723,363-3,623,814) in 2019 for both sexes combined. Both the ASR of death and DALYs increased in Andean Latin America, the Caribbean, Central Latin America, Southeast Asia, Oceania, and Southern Sub-Saharan Africa. In contrast, the age-standardized metrics decreased in the high-income Asia Pacific region. The relationship between SDI and ASR of death and DALYs was negatively correlated. The BAPC model indicated that there would be approximately 5,806,780 death cases and 119,013,659 DALY cases in 2040 that could be attributed to kidney dysfunction. Age-standardized death of cardiovascular diseases (CVDs) and CKD attributable to kidney dysfunction were predicted to decrease and increase from 2020 to 2040, respectively. CONCLUSION NCDs attributable to kidney dysfunction remain a major public health concern worldwide. Efforts are required to attenuate the death and disability burden, particularly in low and low-to-middle SDI regions.
Humans ; Noncommunicable Diseases/epidemiology* ; Global Burden of Disease ; Disability-Adjusted Life Years ; Male ; Female ; Risk Factors ; Middle Aged ; Kidney Diseases/epidemiology* ; Bayes Theorem ; Adult ; Aged ; Global Health ; Quality-Adjusted Life Years

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Purpose To investigate the protective effect and mechanism of A-485 on renal tubular injury in diabetic mice.Methods Eighteen male C57BL/6J mice were randomly divided into three groups:Control group,diabetic kidney dis-ease(DKD)group and A-485 treatment group.The DKD mice model was established by feeding high-fat diet for 8 weeks and intraperitoneal injection of streptozotocin for 5 days.Subsequent-ly,the A-485 treatment group was given A-485(10 mg/kg/day)by intraperitoneal injection every other day for 4 weeks.After treatment,the renal function,P300 enzyme activity and lipid deposition in renal tissue were measured.Western blot a-nalysis was performed to detect SREBP-1,FASN,ACC,ChREBP,P300,CBP,H3K18ac and H3K27ac protein levels.Results Compared with control mice,the levels of FBG,BUN,Scr and UAE were significantly increased in diabetic mice(FBG:2.52 times,BUN:2.89 times,Scr:2.13 times,UAE:4.21 times),while diabetic mice treatment with A-485 exhibi-ted a remarkable decrease on BUN,Scr and UAE(BUN:0.511 times,Scr:0.636 times,UAE:0.574 times,P＜0.01).The results of the transmission electron microscopy and oil red O stai-ning showed that A-485 treatment prevents lipid droplets forma-tion and up-regulation of SREBP-1,FASN,ACC and ChREBP in renal tubular cells of diabetic mice(SREBP-1:0.544 times,FASN:0.449 times,ACC:0.306 times,ChREBP:0.317 times,P＜0.01).Furthermore,A-485 intervention downregu-lated the enzyme activity of P300(0.546 times)and suppressed the expression of H3K18ac(0.337 times)and H3K27ac(0.308 times,P＜0.01).Conclusion A-485 can significant-ly improve renal lipid metabolic disorder in diabetic mice,which may be achieved by inhibiting p300-induced H3K18ac and H3K27ac.

Cerebral small vascular disease (CSVD) is an important risk factor for stroke, cognitive impairment, and death, but its exact pathogenesis is not yet fully understood. Recent studies have shown that as an important part of pathophysiological mechanisms of CSVD, immunoinflammation may affect the progression and prognosis of CSVD. This article reviews the role of immunoinflammation in CSVD.

Objective:To conduct the genetic analysis of a family with one patient suffering from juvenile Parkinson's disease(JP)and discuss the clinical manifestations,genetic mutation characteristics,and treatment plans prompted by PRKN gene compound heterozygous mutations,and to enhance the clinicians'awareness of this disease.Methods:The clinical data of one patient with JP caused by PRKN gene mutations was analyzed,the clinical manifestations and genetic mutation features of the patient were summarized,and the related literatures were reviewed.Results:The patient,a 16-year-old male,was admitted to the hospital due to unstable gait,trembling limbs with rigidity in both lower limbs for three years.The examination results revealed a panic gait,clear consciousness,fluent speech,normal muscle strength in limbs,increased"gear-like"muscle tone in both upper limbs,and"lead-pipe"rigidity in both lower limbs;the sensory functions and tendon reflexes were normal.The head,neck,and thoracic magnetic resonance imaging(MRI)results showed no abnormalities.18F-fluorodeoxyglucose(18F-FDG)positron emission tomography/computed tomography(PET/CT)results showed that the head size and shape were normal,the glucose metabolism in the left cerebellum and middle temporal gyrus was slightly decreased,and the glucose metabolism in bilateral thalami,right frontal lobe,parietotemporal lobe,and left medial frontal lobe was increased.The dopamine transporter(DAT)PET/CT results showed that there was no radioactive distribution in the brain cortex and the DAT distribution in the posterior part of both striata was decreased.The whole-exome sequencing results showed the patient had two PRKN gene mutations,such as codons c.8T>A and c.850G>C compound heterozygous mutations,and each mutation was from one parent;the patient's father carried the c.8T>A mutation,the patient's mother carried the c.850G>C mutation,and the patient's sister had the same genetic mutation site as the patient's father.Conclusion:PRKN gene compound heterozygous mutations may be the basis of the disease in this family.Identification of the mutation c.8T>A expands the mutation spectrum of the PRKN gene,and provides the valuable information for the research on the pathogenic genetic mutations of the JP patients.

Dura mater is a tough collagen connective tissue attached to inner surface of skull and wrapped around brain.As a buffer bridge between brain tissue and skull,its physiological function and role in skull development and repair have always been a focus of research.Recent studies have found that dura mater not only directly participates in skull development during skull growth,but also secretes a variety of cytokines that control the development of central nervous system.There are abundant material exchange and cell communication between the two.This article reviews the role of dura in development and repair of skull,and provides clues for further discovery of the relevant mechanisms of dura in development and repair of skull.