Objective: To investigate the clinical and genetic mutation characteristics of patients with primary hemophagocytic lymphohistiocytosis (HLH) and their impact on prognosis. Methods: Sixty-three primary HLH patients with complete medical records admitted and diagnosed at Beijing Friendship Hospital of Capital Medical University from January 2013 to December 2022 were selected. The patients' clinical and laboratory features, genetic and rapid immunological indicator characteristics, treatment outcomes and prognosis were retrospectively analyzed. Follow-up was up to June 30, 2023, with a median follow-up time [M (Q1, Q3)] of 47 (21, 76) months. Overall survival was analyzed using Kaplan-Meier survival curve, and prognostic factors were analyzed using Cox proportional hazards regression model. Results: Sixty-three primary HLH patients included 35 males and 28 females, with a median age [M (Q1, Q3)] of 17 (7, 27) years. Clinical manifestations at the initial diagnosis mainly included fever (93.7%, 59/63), splenomegaly (87.3%, 55/63), hemophagocytosis (65.1%, 41/63), hepatomegaly (52.4%, 33/63) and central nervous system (CNS) involvement (38.1%, 24/63). A total of 39 patients (61.9%) were diagnosed with EB virus (EBV) infection at initial diagnosis.PRF1 and UNC13D gene mutations were the most common mutations, and the highest frequency mutation site in the PRF1 gene was c.1349C>T, and that of UNC13D gene was c.2588G>A. A total of 76.2% (48/63) of patients had reduced activity of natural killer (NK) cells. Cytotoxic cell degranulation function was impaired or absent in 52.7% (29/55) of patients, of which 79.2% (19/24) of patients with primary HLH with defects in degranulation-related genes had impaired degranulation function. The 1-year and 3-year overall survival rates were 74.8% and 66.7%, respectively. Cox multivariate analysis suggested that peripheral blood EBV≥10 000 copies/ml (HR=3.523, 95%CI: 1.418-8.757, P=0.007) was the risk factor for prognosis. Conclusions: The main clinical manifestations of primary HLH patients at the initial diagnosis include fever, splenomegaly, hemophagocytosis, hepatomegaly, and CNS involvement. PRF1 and UNC13D are the most commonly mutated genes. High copy number EBV infection in peripheral blood is the risk factor for prognosis.

T-cell dysfunction has been shown to play an important role in the pathogenesis of Sjögren’s syndrome (SS). In recent studies, the increased expression of BMP6 has been reported to be related to SS. However, the roles that BMP6 plays in immune homeostasis in the development of SS as well as the downstream signals activated by BMP6 remain unclear. In this study, we investigated the effects and molecular mechanisms of BMP6 on naive CD4 + T cells, showing that BMP6 could upregulate interferon (IFN)–γ secretion from CD4 + T cells through a ceramide/nuclear factor–κB pathway, with no effect on T-cell activation or proliferation. Moreover, an in vivo study showed that anticeramide treatment (myriocin) for an SS animal model (NOD/LtJ mice) could significantly decrease the IFN-γ expression and Th1 frequency in the salivary glands and suppress the inflammation infiltration in salivary glands and maintain the salivary flow rates, both of which reflect SS-like symptoms. This study identifies a promising target that could effectively attenuate the abnormal state of CD4 + T cells and reverse the progression of SS.

Objective: This study aimed to investigate the clinical characteristics of patients diagnosed with primary hemophagocytic lymphohistiocytosis (pHLH) associated with perforin gene deficiency. Methods: We retrospectively analyzed the clinical data of 16 pHLH patients associated with perforin gene deficiency at Beijing Friendship Hospital, Capital Medical University, from April 2014 to August 2021. The mutation sites, mutation types, family history, clinical characteristics, and prognosis of the patients were assessed. Results: A total of 16 patients, including ten males and six females, with a median onset age of 17.5 years (range: 4-42 years), were enrolled in this study. Sixteen different mutations were identified, consisting of 11 missense mutations, one nonsense mutation, two frameshift mutations, and two in-frame mutations. All patients harbored at least one deleterious missense mutation, with the most common mutation sites being c.1349C>T (p.T450M) and c.503G>A (p.S168N). Decreased natural killer (NK) cell activity was observed in 11 patients, reduced perforin protein expression in ten patients, concurrent Epstein-Barr virus (EBV) infection at onset in eight patients, a family history in two patients, and central nervous system involvement in four patients. Eleven cases underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), with eight cases surviving. The median survival time of non-transplanted patients was eight months (range: 4-18 months), while that of transplanted patients was reported as "not reached". Conclusions: Emphasizing the diagnosis of pHLH in adults with perforin gene deficiency. In addition, it should be noted that EBV infection can potentially act as a triggering factor in such disease, and allo-HSCT exerts a substantial effect on the prognosis of patients.

Dendritic cells (DCs) can mediate inflammation-related bone resorption that is crucial in the development of periodontitis. Butyrate is a critical by-product of microbes with antibacterial and anti-inflammatory properties. Here, we found that butyrate inhibited the activation of lipopolysaccharide (LPS)–induced DCs and generation of inflammatory cytokines by DCs. Moreover, butyrate regulated glycolysis in LPS-induced DCs via the G-protein-coupled receptor/hypoxia-inducible factor–1α pathway. In addition, butyrate inhibited the maturation of CD11c + MHC-II + DCs in vivo, suppressing local inflammatory infiltration and ultimately alleviating bone resorption in a periodontitis model. Our results imply that butyrate suppresses the activation of LPS-induced DCs by modulating their metabolism, highlighting its potential as a therapeutic agent for inflammatory diseases.

BACKGROUND The effects and risks of endovascular thrombectomy 6 to 24 hours after stroke onset due to basilar-artery occlusion have not been extensively studied. METHODS In a trial conducted over a 5-year period in China, we randomly assigned, in a 1:1 ratio, patients with basilar-artery stroke who presented between 6 to 24 hours after symptom onset to receive either medical therapy plus thrombectomy or medical therapy only (control). The original primary outcome, a score of 0 to 4 on the modified Rankin scale (range, 0 to 6, with a score of 0 indicating no disability, 4 moderately severe disability, and 6 death) at 90 days, was changed to a good functional status (a modified Rankin scale score of 0 to 3, with a score of 3 indicating moderate disability). Primary safety outcomes were symptomatic intracranial hemorrhage at 24 hours and 90-day mortality. RESULTS A total of 217 patients (110 in the thrombectomy group and 107 in the control group) were included in the analysis; randomization occurred at a median of 663 minutes after symptom onset. Enrollment was halted at a prespecified interim analysis because of the superiority of thrombectomy. Thrombolysis was used in 14% of the patients in the thrombectomy group and in 21% of those in the control group. A modified Rankin scale score of 0 to 3 (primary outcome) occurred in 51 patients (46%) in the thrombectomy group and in 26 (24%) in the control group (adjusted rate ratio, 1.81; 95% confidence interval [CI], 1.26 to 2.60; P<0.001). The results for the original primary outcome of a modified Rankin scale score of 0 to 4 were 55% and 43%, respectively (adjusted rate ratio, 1.21; 95% CI, 0.95 to 1.54). Symptomatic intracranial hemorrhage occurred in 6 of 102 patients (6%) in the thrombectomy group and in 1 of 88 (1%) in the control group (risk ratio, 5.18; 95% CI, 0.64 to 42.18). Mortality at 90 days was 31% in the thrombectomy group and 42% in the control group (adjusted risk ratio, 0.75; 95% CI, 0.54 to 1.04). Procedural complications occurred in 11% of the patients who underwent thrombectomy. CONCLUSIONS Among patients with stroke due to basilar-artery occlusion who presented 6 to 24 hours after symptom onset, thrombectomy led to a higher percentage with good functional status at 90 days than medical therapy but was associated with procedural complications and more cerebral hemorrhages. (Funded by the Chinese National Ministry of Science and Technology; BAOCHE ClinicalTrials.gov number, NCT02737189.).

Objective: To explore the diagnostic efficacy of metagenomicnext-generation sequencing (mNGS) technique for pathogen diagnosis of intracranial infection after neurosurgery. Methods: Patients with suspected intracranial infection after neurosurgery who were treated in Beijing Tiantan Hospital of Capital Medical University from May 2017 to October 2018 were selected. Cerebrospinal fluid samples were collected for mNGS detection and bacterial culture. The sensitivity, specificity, positive predictive value and negative predictive value of these two methods were calculated, and their differences were compared. Results: A total of 80 cerebrospinal fluid samples from patient with suspected intracranial infection after neurosurgery were included, including 53 males and 27 females, with a mean age of (41±19) years old(age range: 2-80 years).After clinical review, a clinical diagnosis was made by two neurosurgery specialists through comprehensively interpretation of the patient's clinical data, laboratory tests and imaging examinations. Finally, 42 cases of intracranial infection and 38 cases of non-infection were clinically diagnosed. The sensitivity and specificity of mNGS detection were 83.33%(35/42) and 76.32%(29/38), and the positive predictive value and negative predictive value were 79.55%(35/44) and 80.56%(29/36). Meanwhile, the sensitivity and specificity of bacterial culture were 59.52%(28/42) and 68.42%(26/38), the positive predictive value and negative predictive value were 68.00% (28/40) and 60.47%(26/40). The sensitivity of mNGS detection washigher than that of bacterial culture, and the difference was statistically significant(χ2=5.83, P=0.015).Compared with bacterial culture, there was no statistically significant difference in the specificity of mNGS detection(χ2=0.59, P=0.441). Conclusion: mNGS detection technique can improve the detection rate of intracranial infection pathogens after neurosurgery, and may become a promising auxiliary diagnostic tool for pathogen detection.

Objective: To evaluate the efficacy of rapid immunological indicator-degranulation function (CD107a) and perforin expression in the diagnosis of primary hemophagocytic lymphohistiocytosis (pHLH). Methods: The clinical data of 295 HLH patients who underwent genetic screening from April 2015 to June 2020 in Beijing Friendship Hospital, Capital Medical University, Beijing Jingdu Children's Hospital and Beijing Children's Hospital, Capital Medical University was collected and analyzed. The fitness of CD107a and Perforin expression with genetic screening was compared to evaluate the sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) of the two indicators, and the receiver operating characteristic (ROC) curves were generated and used to determine the optimal threshold (cut-off values) of CD107a and Perforin expression assays that would identify pHLH patients with a maximum sensitivity and specificity (Youden index). Results: In all 295 patients included, there were 156 males and 139 females, aged from 2 months to 70 years, with a median age of 18 years. In terms of distinguishing the type of pHLH associated with degranulation gene defect from all other genetic screening results, in the CD107a testing, the ROC curve was generated and showed an area under the curve (AUC) of 0.920 (P<0.001), and the optimal cut-off value was determined to be 7.15% with a sensitivity of 83.3% and specificity of 89.2% when the corresponding Youden index was maximized. The PPV and NPV were 33.3% and 98.8%, respectively. CD107a>10% had an accuracy of 81.6% in judging patients without degranulation-related gene defect and negative genetic screening results. In addition, in terms of distinguishing the type of familial hemophagocytic lymphohistiocytosis type 2 (FHL2) from all other genetic screening results, the sensitivity, specificity, PPV and NPV of the Perforin expression testing were 88.2%, 64.2%, 20.3% and 98.1%, respectively, based on the normal laboratory test value (≥ 81%). The ROC curve was established to further optimize the cut-off value. The AUC was 0.933 (P<0.001). The cut-off value corresponding to the maximum Youden index was 62.34%, and the sensitivity remained at 88.2%. While the specificity, PPV and NPV rose to 91.5%, 51.7% and 98.7%, respectively. Conclusions: CD107a and Perforin assays have good significance of early prediction for pHLH involved in impaired cytotoxic function. Selecting appropriate cut-off values can provide basis for accurate clinical diagnosis.

Background: Current post-resuscitation guidelines recommend oxygen titration in adults with the return of spontaneous circulation after cardiac arrest. However, the optimal peripheral oxygen saturation (SpO(2)) is still unclear for post-cardiac arrest care. Methods: We conducted a retrospective observational study of prospectively collected data of all cardiac arrest patients admitted to the intensive care units between 2014 and 2015. The main exposure was SpO(2), which were interfaced from bedside vital signs monitors as 1-min averages, and archived as 5-min median values. The proportion of time spent in different SpO(2) categories was included in separate multivariable regression models along with covariates. The primary outcome measure was hospital mortality and the proportion of discharged home as the secondary outcome was reported. Results: 2836 post-cardiac arrest patients in ICUs of 156 hospitals were included. 1235 (44%) patients died during hospitalization and 818 (29%) patients discharged home. With multivariate regression analysis, the proportion of time spent in SpO(2) of <= 89%, 90%, 91%, and 92% were associated with higher hospital mortality. The proportion of time spent in SpO(2) of 95%, 96%, and 97% were associated with a higher proportion of discharged home outcome, but not associated with hospital mortality. Conclusions: In this retrospective observational study, the optimal SpO(2) for patients admitted to the intensive care unit after cardiac arrest may be 95-97%. Further investigation is warranted to determine if targeting SpO(2) of 95-97% would improve patient-centered outcomes after cardiac arrest. (c) 2020 Elsevier Inc. All rights reserved.

Recent studies have shown that hyperlipidemia is closely related to the progression of kidney disease and glomerulosclerosis has similar pathophysiological mechanisms with atherosclerosis. Atherosclerosis is essentially a chronic inflammatory process and various kidney diseases are characterized by a micro-inflammatory state. Hyperlipidemia levels are not parallel to the degree of glomerulosclerosis, inflammatory factors together with lipids may contribute to the pathogenesis of glomerulosclerosis. Therefore, it is key to clarify lipid-mediated renal injury through studying the mechanism by which inflammation affects cholesterol homeostasis at the cellular level. Intracellular lipid homeostasis involves both lipid uptake and excretion, therefore in this study, we aimed to explore whether interleukin-1β (IL-1β) promotes the uptake of oxidized low-density lipoprotein (Ox-LDL) to increase in intracellular lipid levels, and to clarify the effect of IL-1β on the expression of lectin-like oxidized LDL receptor 1 (LOX-1) and ATP-binding cassette transporter A1 (ABCA1), which may regulate cholesterol homeostasis in human mesangial cells (HMCs). The effect of IL-1β on uptake of Ox-LDL labeled with fluorescent Dil (Dil-Ox-LDL) by HMCs was observed using laser confocal microscopy. The effect of IL-1β on LOX-1 and ABCA1 expression in HMCs was detected by polymerase chain reaction and western blotting. Laser confocal microscopy revealed that HMCs took up Dil-Ox-LDL. Treatment of HMCs with 5 ng/ml IL-1β for 24 h significantly increased uptake of Dil-Ox-LDL. IL-1β also promoted LOX-1 mRNA and protein expression in a dose-dependent manner. Moreover, ABCA1 mRNA and protein expression were reduced by IL-1β in lipid-loaded HMCs in a dose-dependent manner. IL-1β promotes the uptake of Ox-LDL and expression of LOX-1 in HMCs, whereas it inhibits expression of ABCA1 under lipid load. The imbalance in intracellular cholesterol resulted by IL-1β can in turn transform HMCs into foam cells and aggravate glomerulosclerosis.

Data sharing is not applicable to this article as no datasets were generated or analysed during the study.

Background and purposeElevated C‐reactive protein (CRP) is associated with an increased risk of ischaemic stroke (IS). However, the causality of this association is uncertain. The aim is to investigate whether genetically raised plasma CRP concentration levels are associated with IS on the basis of the Mendelian randomization method.MethodsBased on the National Center for Biotechnology Information single nucleotide polymorphism (SNP) database, the Chinese online genetic database as well as previously published studies, four CRP‐associated SNP alleles (rs1130864, rs1205, rs876537 and rs3093059) with minor allele frequency ≥0.15 were selected and the concentration levels of CRP were measured in 378 first‐ever IS patients and 613 healthy controls.ResultsThree SNPs were chosen and used as instrumental variables. The adjusted odds ratios (ORs) [95% confidence interval (95% CI)] of IS per addition of the modelled allele were 1.07 (0.79–1.45) for rs876537, 0.99 (0.73–1.35) for rs1205 and 1.08 (0.71–1.65) for rs3093059. The OR (95% CI) of IS for plasma CRP ≥2.0 mg/l was 2.19 (1.06–4.53) compared with <2.0 mg/l. The adjusted OR (95% CI) of IS per genetically predicted 10% higher CRP concentration, based on the three SNPs as the instruments, was 1.02 (0.94–1.11). Furthermore, similar results were obtained with adjusted ORs (95% CI) of 1.00 (0.88–1.13) and 1.04 (0.93–1.16), respectively, for large‐artery atherosclerosis and small‐artery occlusion per genetically predicted 10% higher CRP concentration.ConclusionsThis Mendelian randomization study provides no clear support that elevated CRP concentration is causally associated with the risk of IS.

Objectives: To identify the difference between the current newborn birth weight standard and the previous standard in China, and to evaluate the diagnostic value of newborn birth weight in small for gestational age (SGA) infants.Methods: A retrospective analysis was conducted of 112441 delivery cases in 2011, from 39 hospitals at different levels in 14 provinces and autonomous regions. Cases with incomplete data, gestational age<24 weeks, or severe fetal malformations or fetal death were excluded. Data were recorded and entered on hard paper copies and into an online database. SPSS 18.0 and SAS 9.2 statistical software were used for data analysis.Results: This study included 109004 valid cases with an average birth weight of 3226.02 +/- 525.82g. Birth weight changed significantly from 1988 for all gestational ages. In preterm infants with gestational age<37 weeks, birth weight for each gestational week was lower than that in the birth weight standard from 15 cities in China in 1988 (p<0.001). Full-term infants with gestational ages from 37 to 41(+6) weeks showed significantly higher average birth weights compared with the previous birth weight standards (p<0.001). The birth weight standard in this study exhibited better correlations than did the previous standard with regard to the diagnoses of adverse pregnancy outcomes, including SGA infants, stillbirth, neonatal asphyxia, neonatal death and neonatal complications; with RR values of 18.843 (9.656-36.774; 95% CI), 33.125 (14.576-75.275), 24.254 (10.630-56.256) and 2.492 (0.328-18.909), respectively.Conclusions: The current birth weight standard used in Chinese medical institutions was enacted in 1988. This is not suitable for today's socioeconomic and clinical requirements, and needs to be updated. Diagnosis of preterm infants with SGA based upon the updated demographic birth weight standard manifested higher accuracy and avoided unnecessary medical interventions. However, the updated demographic birth weight standards were no better diagnostically than the previous standard for full-term infants. Customized birth weight standards from larger sample sizes and multi-center studies will be necessary to determine the appropriate birth weight standards in developing countries.