Associations between new obesity indices and abnormal bone density in type 2 diabetes mellitus patients.

The clinical data analysis found that, compared with the traditional obesity index, the waist-weight ratio (WWR) has more advantages in predicting abnormal bone mineral density in subjects with type 2 diabetes. WWR may serve as a new predictive indicator for osteoporosis in T2DM patients. PURPOSE: This study was designed to explore the correlation between obesity-related indices and bone mineral density (BMD) and its influencing factors in type 2 diabetes mellitus (T2DM) patients. METHODS: A total of 528 patients with type 2 diabetes were recruited. Glucose tolerance, insulin stimulation, and blood biochemical tests were conducted on all participants. All subjects underwent dual-energy X-ray bone density testing and were grouped based on the bone density results. RESULTS: Compared with those in the normal BMD group, the waist-to-body weight ratio (WWR) and weight-adjusted-waist index (WWI) in the osteopenia and osteoporosis groups were significantly greater, while body mass index (BMI) was significantly lower (P < 0.05). The logistic regression results showed that the WWR, WWI, and BMI were independently correlated with abnormal BMD in T2DM patients (P < 0.05). WWR and the WWI were negatively correlated with the T-value of bone density in various parts of the body, while BMI was positively correlated with the T-value of bone density (P < 0.05). The area under the working characteristic curve (AUC) for T2DM patients with abnormal bone mass predicted by the WWR [0.806, 95% CI = (0.770-0.843), P < 0.001] was greater than that for patients with other obesity indicators, such as the WWI and BMI. CONCLUSION: We found a positive correlation between the WWR and bone density in T2DM patients. Compared with other obesity indicators, such as BMI and WWI, the WWR has a stronger discriminative ability for T2DM patients with abnormal bone density. Therefore, more attention should be given to the WWR in T2DM patients.

Gut Microbiota-Derived Butyrate Induces Epigenetic and Metabolic Reprogramming in Myeloid-Derived Suppressor Cells to Alleviate Primary Biliary Cholangitis.

BACKGROUND & AIMS: Gut dysbiosis and myeloid-derived suppressor cells (MDSCs) are implicated in primary biliary cholangitis (PBC) pathogenesis. However, it remains unknown whether gut microbiota or their metabolites can modulate MDSCs homeostasis to rectify immune dysregulation in PBC. METHODS: We measured fecal short-chain fatty acids levels using targeted gas chromatography-mass spectrometry and analyzed circulating MDSCs using flow cytometry in 2 independent PBC cohorts. Human and murine MDSCs were differentiated in vitro in the presence of butyrate, followed by transcriptomic, epigenetic (CUT&Tag-seq and chromatin immunoprecipitation-quantitative polymerase chain reaction), and metabolic (untargeted liquid chromatography-mass spectrometry, mitochondrial stress test, and isotope tracing) analyses. The in vivo role of butyrate-MDSCs was evaluated in a 2-octynoic acid-bovine serum albumin-induced cholangitis murine model. RESULTS: Decreased butyrate levels and defective MDSC function were found in patients with incomplete response to ursodeoxycholic acid, compared with those with adequate response. Butyrate induced expansion and suppressive activity of MDSCs in a manner dependent on PPARD-driven fatty acid ß-oxidation (FAO). Pharmaceutical inhibition or genetic knockdown of the FAO rate-limiting gene CPT1A abolished the effect of butyrate. Furthermore, butyrate inhibited HDAC3 function, leading to enhanced acetylation of lysine 27 on histone H3 at promoter regions of PPARD and FAO genes in MDSCs. Therapeutically, butyrate administration alleviated immune-mediated cholangitis in mice via MDSCs, and adoptive transfer of butyrate-treated MDSCs also displayed protective efficacy. Importantly, reduced expression of FAO genes and impaired mitochondrial physiology were detected in MDSCs from ursodeoxycholic acid nonresponders, and their impaired suppressive function was restored by butyrate. CONCLUSIONS: We identify a critical role for butyrate in modulation of MDSC homeostasis by orchestrating epigenetic and metabolic crosstalk, proposing a novel therapeutic strategy for treating PBC.

Osteoporosis and Primary Biliary Cholangitis: A Trans-ethnic Mendelian Randomization Analysis.

Osteoporosis is a major clinical problem in many autoimmune diseases, including primary biliary cholangitis (PBC), the most common autoimmune liver disease. Osteoporosis is a major cause of fracture and related mortality. However, it remains unclear whether PBC confers a causally risk-increasing effect on osteoporosis. Herein, we aimed to investigate the causal relationship between PBC and osteoporosis and whether the relationship is independent of potential confounders. We performed bidirectional Mendelian randomization (MR) analyses to investigate the association between PBC (8021 cases and 16,489 controls) and osteoporosis in Europeans (the UK Biobank and FinnGen Consortium: 12,787 cases and 726,996 controls). The direct effect of PBC on osteoporosis was estimated using multivariable MR analyses. An independent replication was conducted in East Asians (PBC: 2495 cases and 4283 controls; osteoporosis: 9794 cases and 168,932 controls). Trans-ethnic meta-analysis was performed by pooling the MR estimates of Europeans and East Asians. Inverse-variance weighted analyses revealed that genetic liability to PBC was associated with a higher risk of osteoporosis in Europeans (OR, 1.040; 95% CI, 1.016-1.064; P = 0.001). Furthermore, the causal effect of PBC on osteoporosis persisted after adjusting for BMI, calcium, lipidemic traits, and sex hormones. The causal relationship was further validated in the East Asians (OR, 1.059; 95% CI, 1.023-1.096; P = 0.001). Trans-ethnic meta-analysis confirmed that PBC conferred increased risk on osteoporosis (OR, 1.045; 95% CI, 1.025-1.067; P = 8.17 × 10-6). Our data supports a causal effect of PBC on osteoporosis, and the causality is independent of BMI, calcium, triglycerides, and several sex hormones.

Antidepressant effects of dexmedetomidine compared with ECT in patients with treatment-resistant depression.

OBJECTIVE: This pilot study was designed to investigate the antidepressant effects of dexmedetomidine (DEX), a selective α2-adrenergic receptor agonist, in patients with treatment-resistant depression (TRD). The antidepressant effects of dexmedetomidine was compared with ECT, which is widely used in clinical practice for treatment of patients with TRD. METHODS: Seventy six patients with TRD were randomly assigned to receive 10 sessions of DEX infusions or electroconvulsive therapy (ECT) treatment. The primary outcome was the changes of depression severity determined by the improvement of 24-item Hamilton Depression Rating Scale (HDRS-24). The second outcomes were the rates of therapeutic response (reduction in HDRS-24 ≥ 50 %) and remission (HDRS-24 ≤ 10 and reduction in HDRS-24 ≥ 60 %) at posttreatment and after 3 months of follow-up visits. RESULTS: We found that 10 sessions of DEX infusions or ECT treatments significantly improved HDRS-24 scores at posttreatment and after 3 months of follow-up visits compared with the baseline. In addition, there was no significant difference between DEX infusions and ECT treatments regarding HDRS-24 at these evaluating points. Furthermore, the depression severity dropped to mild after 2 sessions of DEX infusion. In contrast, at least 6 sessions of ECT treatment were needed to achieve a same level. Finally, the rates of therapeutic response and remission were comparable between the two groups. No serious adverse events were observed. CONCLUSIONS: Based on current published evidence, we conclude that DEX exhibits rapid and durable antidepressant properties similar to ECT but with fewer side effects.

Research progress on the anticancer activity of plant polysaccharides.

Tumor is a serious threat to human health, with extremely high morbidity and mortality rates. However, tumor treatment is challenging, and the development of antitumor drugs has always been a significant research focus. Plant polysaccharides are known to possess various biological activities. They have many pharmacological properties such as immunomodulation, antitumor, antiviral, antioxidative, antithrombotic, and antiradiation effects, reduction of blood pressure and blood sugar levels, and protection from liver injury. Among these effects, the antitumor effect of plant polysaccharides has been widely studied. Plant polysaccharides can inhibit tumor proliferation and growth by inhibiting tumor cell invasion and metastasis, inducing cell apoptosis, affecting the cell cycle, and regulating the tumor microenvironment. They also have the characteristics of safety, high efficiency, and low toxicity, which can alleviate, to a certain extent, the adverse reactions caused by traditional tumor treatment methods such as surgery, radiotherapy, and chemotherapy. Therefore, this paper systematically summarizes the direct antitumor effects of plant polysaccharides, their regulatory effects on the tumor microenvironment, and intervening many common high-incidence tumors in other ways. It also provides data support for the administration of plant polysaccharides in modern tumor drug therapy, enabling the identification of new targets and development of new drugs for tumor therapy.

Real-world data of pyrotinib-based therapy for patients with brain metastases of HER2-positive advanced breast cancer: a single-center retrospective analysis and molecular portraits.

Introduction: Pyrotinib is a novel irreversible pan-HER tyrosine kinase inhibitor (TKI). However, real-world data of pyrotinib-containing therapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and developing brain metastases (BMs) are limited, and the genomic profile of this subpopulation is almost undefined. Methods and materials: Patients with BM of HER2-positive MBC (n = 35) treated with pyrotinib-containing therapy were enrolled in this analysis. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and toxicity profiles were evaluated. Hazard ratios (HRs) and 95% confidence intervals (CIs) for disease progression were estimated using the Cox proportional hazards models. Targeted next-generation sequencing of 618 cancer-relevant genes was performed on plasma and primary breast tumors from patients with BM and without BM. Results: The median PFS time was 8.00 (95% CI, 5.98-10.017) months, and the median OS time was 23 (95% CI, 10.412-35.588) months. The ORR was 45.7%, and the DCR was 74.3%. In the Cox multivariate analysis, prior exposure to brain radiotherapy (HR = 3.268), received pyrotinib as third- or higher-line treatment (HR = 4.949), subtentorial brain metastasis (HR = 6.222), and both supratentorial and subtentorial brain metastases (HR = 5.863) were independently associated with increased risk of progression. The frequent grade 3-4 adverse event was increased direct bilirubin (14.3%), and two patients suffered from grade 3-4 diarrhea. In the exploratory genomic analysis, altered frequencies of FGFR3, CD276, CDC73, and EPHX1 were higher in the BM group. The consistency of mutated profiles of plasma and primary lesion in the BM group was significantly lower (30.4% vs. 65.5%; p = 0.0038). Conclusions: Pyrotinib-containing therapy shows favorable effectiveness and tolerable safety in patients with BM of HER2-positive MBC, particularly in a population that is brain radiotherapy-naïve, received pyrotinib as first- or second-line treatment, and developed supratentorial brain metastasis. In the exploratory genomic analysis, patients with BM showed distinct genomic features from patients without BM.

Effects of Sepsis Serum on the Fate of Adipose Tissue-Derived Stem Cells.

BACKGROUND: Adipose tissue-derived stem cells (ADSCs), a type of mesenchymal stem cell, have been used extensively in clinical trials for the treatment of multiple conditions, including sepsis. However, increasing evidence indicates that ADSCs vanish from tissues within days of administration. Consequently, it would be desirable to establish the mechanisms underlying the fate of ADSCs following transplantation. METHODS: In this study, sepsis serum from mouse models was used to mimic microenvironmental effects. Healthy donor-derived human ADSCs were cultured in vitro in the presence of mouse serum from normal or lipopolysaccharide (LPS)-induced sepsis models for the purposes of discriminant analysis. The effects of sepsis serum on ADSC surface markers and cell differentiation were analyzed by flow cytometry, and the proliferation of ADSCs was assessed using a Cell Counting Kit-8 (CCK-8) assay. Quantitative real-time PCR (qRT-PCR) was applied to assess the degree of ADSC differentiation. The effects of sepsis serum on the cytokine release and migration of ADSCs were determined based on ELISA and Transwell assays, respectively, and ADSC senescence was assessed by ß-galactosidase staining and western blotting. Furthermore, we performed metabolic profiling to determine the rates of extracellular acidification and oxidative phosphorylation and the production of adenosine triphosphate and reactive oxygen species. RESULTS: We found that sepsis serum enhanced the cytokine and growth factor secretion and migratory capacities of ADSCs. Moreover, the metabolic pattern of these cells was reprogrammed to a more activated oxidative phosphorylation stage, leading to an increase in osteoblastic differentiation capacity and reductions in adipogenesis and chondrogenesis. CONCLUSIONS: Our findings in this study reveal that a septic microenvironment can regulate the fate of ADSCs.

Effects of dexmedetomidine on postoperative sleep quality: a systematic review and meta-analysis of randomized controlled trials.

STUDY OBJECTIVES: To assess the effect of dexmedetomidine (DEX) on postoperative sleep quality using polysomnography (PSG) to identify possible interventions for postoperative sleep disturbances. METHODS: An electronic search of PubMed/MEDLINE, EMBASE, Cochrane Library and Web of Science was conducted from database inception to November 20, 2022. Randomized controlled trials (RCTs) on the effect of DEX administration on postoperative sleep quality using PSG or its derivatives were included. No language restrictions were applied. The sleep efficiency index (SEI), arousal index (AI), percentages of stage N1, N2 and N3 of non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep were measured in our meta-analysis. RESULTS: Five studies, involving 381 participants were included. Administration of DEX significantly improved SEI, lowered AI, decreased the duration of stage N1 sleep and increased the duration of stage N2 sleep compared to placebo groups. There were no significant differences in the duration of stage N3 sleep and REM sleep. DEX administration lowered the postoperative Visual Analogue Scale (VAS) score and improved the Ramsay sedation score with no adverse effect on postoperative delirium (POD). However, high heterogeneity was observed in most of the primary and secondary outcomes. CONCLUSIONS: Our study provides support for the perioperative administration of DEX to improve postoperative sleep quality. The optimal dosage and overall effect of DEX on postoperative sleep quality require further investigation using large-scale randomized controlled trials.

A regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression.

Genome-wide association studies have identified 19p13.3 locus associated with primary biliary cholangitis (PBC). Here we aim to identify causative variant(s) and initiate efforts to define the mechanism by which the 19p13.3 locus variant(s) contributes to the pathogenesis of PBC. A genome-wide meta-analysis of 1931 PBC subjects and 7852 controls in two Han Chinese cohorts confirms the strong association between 19p13.3 locus and PBC. By integrating functional annotations, luciferase reporter assay and allele-specific chromatin immunoprecipitation, we prioritize rs2238574, an AT-Rich Interaction Domain 3A (ARID3A) intronic variant, as a potential causal variant at 19p13.3 locus. The risk allele of rs2238574 shows higher binding affinity of transcription factors, leading to an increased enhancer activity in myeloid cells. Genome-editing demonstrates the regulatory effect of rs2238574 on ARID3A expression through allele-specific enhancer activity. Furthermore, knock-down of ARID3A inhibits myeloid differentiation and activation pathway, and overexpression of the gene has the opposite effect. Finally, we find ARID3A expression and rs2238574 genotypes linked to disease severity in PBC. Our work provides several lines of evidence that a non-coding variant regulates ARID3A expression, presenting a mechanistic basis for association of 19p13.3 locus with the susceptibility to PBC.

Intestinal microbiota in biliary diseases.

PURPOSE OF REVIEW: Biliary diseases are a group of disease affecting biliary tract, including immune-mediated primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). With limited treatment options, PBC and PSC may lead to liver cirrhosis. RECENT FINDINGS: Emerging evidence has shown the participation of gut microbiota in the etiology of PBC and PSC. Patients with PBC and PSC exhibit alterations in gut microbiota composition. Dysfunctional gut barrier facilitates the translocation of possible pathogenic bacteria and derived metabolites. Along with molecular mimicry between host and bacterial antigen, these factors result in aberrant auto-immune activation, and subsequently lead to liver injury. Though the precise mechanism has not been fully elucidated, studies investigating the role of gut microbiota in pathogenesis of PBC and PSC have inspired novel biomarkers and therapeutic strategies. SUMMARY: In this review, recent evidence on the alteration of intestinal microbiota and possible mechanistic and therapeutic applications are discussed, predominantly focusing on PSC and PBC.

Nanomaterials Respond to Lysosomal Function for Tumor Treatment.

The safety and efficacy of tumor treatment are difficult problems to address. Recently, lysosomes have become an important target for tumor treatment because of their special environment and function. Nanoparticles have unique physicochemical properties which have great advantages in tumor research. Therefore, in recent years, researchers have designed various types of nanoparticles to treat tumors based on lysosomal function and environment. In this review, we summarize and analyze different perspectives of tumor treatment, including direct destruction of lysosomes or lysosomal escape, drug delivery by nanoparticles, response to endogenous or exogenous stimuli, and the targeting of tumor cells or other cells. We describe the advantages and disadvantages of these approaches as well as the developmental prospects in this field. We hope to provide new ideas for better tumor treatment.

Recent advances of the nanocomposite hydrogel as a local drug delivery for diabetic ulcers.

Diabetic ulcer is a serious complication of diabetes. Compared with that of healthy people, the skin of patients with a diabetic ulcer is more easily damaged and difficult to heal. Without early intervention, the disease will become increasingly serious, often leading to amputation or even death. Most current treatment methods cannot achieve a good wound healing effect. Numerous studies have shown that a nanocomposite hydrogel serves as an ideal drug delivery method to promote the healing of a diabetic ulcer because of its better drug loading capacity and stability. Nanocomposite hydrogels can be loaded with one or more drugs for application to chronic ulcer wounds to promote rapid wound healing. Therefore, this paper reviews the latest progress of delivery systems based on nanocomposite hydrogels in promoting diabetic ulcer healing. Through a review of the recent literature, we put forward the shortcomings and improvement strategies of nanocomposite hydrogels in the treatment of diabetic ulcers.

Intestinal homeostasis in autoimmune liver diseases.

ABSTRACT: Intestinal homeostasis depends on complex interactions between the gut microbiota and host immune system. Emerging evidence indicates that the intestinal microbiota is a key player in autoimmune liver disease (AILD). Autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and IgG4-related sclerosing cholangitis have been linked to gut dysbiosis. Diverse mechanisms contribute to disturbances in intestinal homeostasis in AILD. Bacterial translocation and molecular mimicry can lead to hepatic inflammation and immune activation. Additionally, the gut and liver are continuously exposed to microbial metabolic products, mediating variable effects on liver immune pathologies. Importantly, microbiota-specific or associated immune responses, either hepatic or systemic, are abnormal in AILD. Comprehensive knowledge about host-microbiota interactions, included but not limited to this review, facilitates novel clinical practice from a microbiome-based perspective. However, many challenges and controversies remain in the microbiota field of AILD, and there is an urgent need for future investigations.

[Application of 20% glucose solution in the treatment of diabetic patients with hypoglycemia].

OBJECTIVE: To explore the safety and efficacy of 20% glucose solution in the treatment of adult diabetic patients with hypoglycemia. METHODS: A non-randomized controlled paired design trial was conducted. The diabetes patients with hypoglycemia (blood glucose < 3.9 mmol/L) who were admitted to the department of endocrinology and metabolism of Affiliated Hospital of Jiangsu University from December 2020 to May 2021 were enrolled. When the patients developed hypoglycemia for the first time, 75 mL of 20% glucose solution was pumped intravenously at a constant speed within 15 minutes, which was named the 20% glucose solution group. When the patients had hypoglycemia again, 30 mL of 50% glucose solution was pumped intravenously at a constant speed within 3 minutes, which was named the 50% glucose solution group. If the blood glucose was still ≤ 3.9 mmol/L at 15 minutes of hypoglycemia treatment, or the patients were uncomfortable due to too fast drip speed, it should be terminated immediately. The hypoglycemia treatment should be handled according to the Chinese guidelines for the prevention and treatment of type 2 diabetes (2020 edition). The peripheral blood glucose level and the range of increase at 15 minutes of treatment, the success rate of one treatment, the peripheral blood glucose values at 60 minutes after successful hypoglycemia treatment, the incidence of phlebitis and exudation after hypoglycemia treatment, and the pain of local blood vessels in patients with hypoglycemia treatment were analyzed and compared between the two groups. RESULTS: A total of 65 patients completed the treatment of hypoglycemia with 20% glucose solution and the success rate of one treatment was 100%. The peripheral blood glucose value at 15 minutes of hypoglycemia treatment was (8.30±1.37) mmol/L, and the increased range was (4.86±1.30) mmol/L. The peripheral blood glucose value at 60 minutes after successful hypoglycemia treatment was (6.96±1.48) mmol/L, which indicated that 20% glucose solution could effectively increase blood glucose. Among 65 patients, 32 patients had hypoglycemia again, who were treated with 50% glucose solution, and the success rate of one treatment was 100%. When patients who received 50% glucose solution for hypoglycemia formed a paired design with the first 20% glucose solution treatment, the results showed that there was no significant difference in the peripheral blood glucose value and the increased range in blood glucose at 15 minutes of hypoglycemia treatment between the 20% glucose solution and the 50% glucose solution groups [peripheral blood glucose (mmol/L): 8.20 (7.70, 9.70) vs. 8.30 (7.80, 8.80), increase in blood glucose (mmol/L): 4.96±1.39 vs. 4.70±1.32, both P > 0.05], indicating that the glucose changing at 15 minutes of hypoglycemia treatment with 20% glucose solution was similar to that with 50% glucose solution. The peripheral blood glucose value at 60 minutes after successful hypoglycemia treatment of 20% glucose solution group was significantly lower than that of 50% glucose solution group (mmol/L: 6.37±1.04 vs. 7.20±1.36, P < 0.01), which meant that the blood glucose tended to be more stable. There was no phlebitis and exudation after hypoglycemia treatment in both groups. The pain score of 20% glucose solution group was 0, however, 3 patients in 50% glucose solution group complained of local vascular pain, and the pain score was 1. CONCLUSIONS: 20% glucose solution can effectively treat hypoglycemia in diabetic patients, which has the same curative effect as 50% glucose solution and much safer. It can be used in patients with severe hypoglycemia.

Intrahepatic activated leukocyte cell adhesion molecule induces CD6highCD4+ T cell infiltration in autoimmune hepatitis.

Background and objectives: Autoimmune hepatitis (AIH) is characterized by the expansion and accumulation of pathogenic T cells in liver. Although CD6 and its ligand activated leukocyte cell adhesion molecule (ALCAM) are involved in the evolution of multiple inflammatory diseases, their roles in the pathogenesis of AIH remain unknown. Herein, we aimed to investigate ALCAM-CD6 axis in AIH development. Methods: Immunohistochemistry was performed to examine hepatic expression of CD6 and ALCAM. The concentration of serum ALCAM was evaluated by ELISA. The phenotypes of liver infiltrating T cells were determined by flow cytometry. Primary human CD4+ T cells were used for functional studies. Results: Our data showed that patients with AIH exhibited significantly higher expression of CD6 in the liver as compared to primary biliary cholangitis (PBC), chronic hepatitis B (CHB), non-alcoholic liver disease (NAFLD), and healthy controls (HC). In addition, hepatic CD6 expression was strongly correlated with disease severity of AIH. CD6 was mainly expressed on CD4+ T cells in the liver and intrahepatic CD6highCD4+ T cells demonstrated stronger proinflammatory response and proliferation features than CD6low counterparts in both AIH and HC. ALCAM, the ligand of CD6, was highly expressed in the hepatocytes of AIH and serum ALCAM was strongly associated with clinical indices of AIH. Interestingly, close spatial location between CD6+CD4+ T cells and ALCAM+ hepatocytes was observed. Finally, we found that CD6highCD4+ T cells showed enhanced capacity of trans-endothelial migration in vitro, which could be promoted by recombinant ALCAM. Conclusions: Our study found that ALCAM-CD6 axis was upregulated in the AIH liver, suggesting a potential target for alleviating AIH.

Serum Biomarkers for Autoimmune Hepatitis Type 1: the Case for CD48 and a Review of the Literature.

In autoimmune hepatitis (AIH), the persisting inflammation contributes to fibrosis progression, for which conventional biochemical markers manifest relatively unsatisfactory prediction. Herein, we assessed the value of serum CD48 (sCD48) as an indicator for inflammation and fibrosis in AIH type 1. The levels of sCD48 were detected first in an exploratory cohort using ELISA. In this cohort, compared with healthy controls (4.90 ng/mL, P < 0.0001), primary biliary cholangitis (7.32 ng/mL, P < 0.0001), and non-alcoholic fatty liver disease (7.76 ng/mL, P < 0.0001), sCD48 levels were elevated in AIH (12.81 ng/mL) and correlated with histological inflammation and fibrosis. Further using multivariate logistic regression analysis, sCD48 was identified as an independent predictor for both significant inflammation (G3-4) and advanced fibrosis (S3-4). Two predictive scores, based on sCD48, were constructed for diagnosing significant inflammation and advanced fibrosis (sCD48-AIH-SI and sCD48-AIH-AF, respectively). Using these data as a premise, predictive abilities were subsequently evaluated and verified in a validation cohort. In the exploratory cohort, the area under the receiver operating characteristic curve of sCD48 and sCD48-AIH-SI, for significant inflammation, were 0.748 and 0.813, respectively. Besides, during treatment follow-up, sCD48 levels gradually decreased from immunosuppression initiation to re-evaluation biopsy, in parallel with aspartate transaminase, total sera IgG, and fibrosis-4 score. For AIH patients in a re-evaluation biopsy cohort, sCD48 could predict significant fibrosis (S2-4). Further using immunohistochemistry, hepatic CD48 expression was elevated in AIH patients and decreased after treatment. In conclusion, sCD48 and sCD48-based predictive scores predict histological inflammation and fibrosis in AIH-1. Detecting sCD48 might help in the clinical management of AIH.

NUDT1 promotes the accumulation and longevity of CD103+ TRM cells in primary biliary cholangitis.

BACKGROUND & AIMS: Pyruvate dehydrogenase (PDC)-E2 specific CD8+ T cells play a leading role in biliary destruction in PBC. However, there are limited data on the characterization of these autoantigen-specific CD8+ T cells, particularly in the liver. Herein, we aimed to identify pathogenic intrahepatic CD8+ T-cell subpopulations and investigate their immunobiology in PBC. METHODS: Phenotypic and functional analysis of intrahepatic T-cell subsets were performed by flow cytometry. CD103+ TRM cell frequency was evaluated by histological staining. The transcriptome and metabolome were analyzed by RNA-seq and liquid chromatography-mass spectrometry, respectively. Cytotoxicity of TRM cells against cholangiocytes was assayed in a 3D organoid co-culture system. Moreover, the longevity (long-term survival) of TRM cells in vivo was studied by 2-octynoic acid-BSA (2OA-BSA) immunization, Nudt1 conditional knock-out and adoptive co-transfer in a murine model. RESULTS: Intrahepatic CD103+ TRM (CD69+CD103+CD8+) cells were significantly expanded, hyperactivated, and potentially specifically reactive to PDC-E2 in patients with PBC. CD103+ TRM cell frequencies correlated with clinical and histological indices of PBC and predicted poor ursodeoxycholic acid response. NUDT1 blockade suppressed the cytotoxic effector functions of CD103+ TRM cells upon PDC-E2 re-stimulation. NUDT1 overexpression in CD8+ T cells promoted tissue-residence programming in vitro; inhibition or knockdown of NUDT1 had the opposite effect. Pharmacological blockade or genetic deletion of NUDT1 eliminated CD103+ TRM cells and alleviated cholangitis in mice immunized with 2OA-BSA. Significantly, NUDT1-dependent DNA damage resistance potentiates CD8+ T-cell tissue-residency via the PARP1-TGFßR axis in vitro. Consistently, PARP1 inhibition restored NUDT1-deficient CD103+ TRM cell durable survival and TGFß-Smad signaling. CONCLUSIONS: CD103+ TRM cells are the dominant population of PDC-E2-specific CD8+ T lymphocytes in the livers of patients with PBC. The role of NUDT1 in promoting pathogenic CD103+ TRM cell accumulation and longevity represents a novel therapeutic target in PBC. LAY SUMMARY: Primary biliary cholangitis (PBC) is a rare inflammatory condition of the bile ducts. It can be treated with ursodeoxycholic acid, but a large percentage of patients respond poorly to this treatment. Liver-infiltrating memory CD8+ T cells recognizing the PDC-E2 immunodominant epitope are critical in the pathogenesis of PBC. We identifed the key pathogenic CD8+ T cell subset, and worked out the mechanisms of its hyperactivation and longevity, which could be exploited therapeutically.

Common Sense Model program on illness perceptions in patients with impaired awareness of hypoglycemia.

Background: Illness perceptions are important for patients with insulin-treated type 2 diabetes mellitus (T2DM) and impaired awareness of hypoglycemia (IAH), as they determine health-related behaviors and motivations. Patients with IAH in many countries have poor illness perception, and there is a paucity of research exploring the effectiveness of Common Sense Model (CSM)-based interventions in this population.Objective: To investigate the effects of a CSM-based intervention program on perceptions of illness in patients with insulin-treated T2DM and IAH.Design: Quasi-randomized controlled trial.Methods: 78 patients with IAH receiving routine care were included. The intervention group (n = 39) participated in a CSM-based program, whereas the control group (n = 39) did not. Illness perceptions, coping styles, hypoglycemia fear, and awareness of hypoglycemia at baseline, 1, and 3 months were analyzed and compared between the two groups.Results: The intervention group exhibited significant improvements in consequences (ß = -1.615, P = 0.032); personal control (ß = -1.897, P = 0.006); treatment control (ß = -1.274, P = 0.046); and positive coping style (ß = 4.872, P = 0.002) at the 3-month follow-up, and timeline (ß = 2.769, P = 0.004) at the 1-month follow-up. Hypoglycemia fear and awareness were not significantly improved in the intervention group compared with the control group. No intervention-related adverse events were observed.Conclusions: A CSM-based intervention program can modify illness perceptions to an extent and improve the positive coping style in patients with IAH.Impact statementNurses should conduct a CSM-based intervention program to help patients with IAH improve illness perceptions.

Altered faecal microbiome and metabolome in IgG4-related sclerosing cholangitis and primary sclerosing cholangitis.

OBJECTIVE: Multiple clinical similarities exist between IgG4-related sclerosing cholangitis (IgG4-SC) and primary sclerosing cholangitis (PSC), and while gut dysbiosis has been extensively studied in PSC, the role of the gut microbiota in IgG4-SC remains unknown. Herein, we aimed to evaluate alterations of the gut microbiome and metabolome in IgG4-SC and PSC. DESIGN: We performed 16S rRNA gene amplicon sequencing of faecal samples from 135 subjects with IgG4-SC (n=34), PSC (n=37) and healthy controls (n=64). A subset of the samples (31 IgG4-SC, 37 PSC and 45 controls) also underwent untargeted metabolomic profiling. RESULTS: Compared with controls, reduced alpha-diversity and shifted microbial community were observed in IgG4-SC and PSC. These changes were accompanied by differences in stool metabolomes. Importantly, despite some common variations in the microbiota composition and metabolic activity, integrative analyses identified distinct host-microbe associations in IgG4-SC and PSC. The disease-associated genera and metabolites tended to associate with the transaminases in IgG4-SC. Notable depletion of Blautia and elevated succinic acid may underlie hepatic inflammation in IgG4-SC. In comparison, potential links between the microbial or metabolic signatures and cholestatic parameters were detected in PSC. Particularly, concordant decrease of Eubacterium and microbiota-derived metabolites, including secondary bile acids, implicated novel host-microbial metabolic pathways involving cholestasis of PSC. Interestingly, the predictive models based on metabolites were more effective in discriminating disease status than those based on microbes. CONCLUSIONS: Our data reveal that IgG4-SC and PSC possess divergent host-microbe interplays that may be involved in disease pathogenesis. These data emphasise the uniqueness of IgG4-SC.