Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas.

Bruton's tyrosine kinase (BTK) has emerged as a therapeutic target for B-cell malignancies, which is substantiated by the efficacy of various irreversible or reversible BTK inhibitors. However, on-target BTK mutations facilitating evasion from BTK inhibition lead to resistance that limits the therapeutic efficacy of BTK inhibitors. In this study we employed structure-based drug design strategies based on established BTK inhibitors and yielded a series of BTK targeting compounds. Among them, compound S-016 bearing a unique tricyclic structure exhibited potent BTK kinase inhibitory activity with an IC50 value of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC50 = 0.4 nM). S-016, as a novel irreversible BTK inhibitor, displayed superior kinase selectivity compared to ibrutinib and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. Furthermore, we generated BTK inhibitor-resistant lymphoma cells harboring BTK C481F or A428D to explore strategies for overcoming resistance. Co-culture of these DLBCL cells with M0 macrophages led to the polarization of M0 macrophages toward the M2 phenotype, a process known to support tumor progression. Intriguingly, we demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment (TME) and significantly overcame the acquired resistance to BTK inhibitors in both BTK-mutated and wild-type BTK DLBCL models by inhibiting angiogenesis and modulating macrophage polarization. Overall, this study not only promotes the development of new BTK inhibitors but also offers innovative treatment strategies for B-cell lymphomas, including those with BTK mutations.

Outcome of infants with acute lymphoblastic leukemia treated with the Chinese Children's Cancer Group Acute Lymphoblastic Leukemia 2015 study protocol.

Not available.

Bufotalin attenuates pulmonary fibrosis via inhibiting Akt/GSK-3ß/ß-catenin signaling pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with no cure. Bufotalin (BT), an active component extracted from Venenum Bufonis, has been prescribed as a treatment for chronic inflammatory diseases. However, whether BT has antifibrotic properties has never been investigated. In this study, we report on the potential therapeutic effect and mechanism of BT on IPF. BT was shown to attenuate lung injury, inflammation, and fibrosis as well as preserve pulmonary function in bleomycin (BLM)-induced pulmonary fibrosis model. We next confirmed BT's ability to inhibit TGF-ß1-induced epithelial-mesenchymal transition (EMT) and myofibroblast activation (including differentiation, proliferation, migration, and extracellular matrix production) in vitro. Furthermore, transcriptional profile analysis indicated the Wnt signaling pathway as a potential target of BT. Mechanistically, BT effectively prevented ß-catenin from translocating into the nucleus to activate transcription of profibrotic genes. This was achieved by blunting TGF-ß1-induced increases in phosphorylated Akt Ser437 (p-Akt S437) and phosphorylated glycogen synthase kinase (GSK)-3ß Ser9 (p-GSK-3ß S9), thereby reactivating GSK-3ß. Additionally, the antifibrotic effects of BT were further validated in another in vivo model of radiation-induced pulmonary fibrosis. Collectively, these data demonstrated the potent antifibrotic actions of BT through inhibition of Akt/GSK-3ß/ß-catenin axis downstream of TGF-ß1. Thus, BT could be a potential option to be further explored in IPF treatment.

Multi-system diseases and death trajectory of metabolic dysfunction-associated fatty liver disease: findings from the UK Biobank.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a newly defined condition encompassing hepatic steatosis and metabolic dysfunction. However, the relationship between MAFLD and multi-system diseases remains unclear, and the time-dependent sequence of these diseases requires further clarification. METHODS: After propensity score matching, 163,303 MAFLD subjects and 163,303 matched subjects were included in the community-based UK Biobank study. The International Classification of Diseases, Tenth Revision (ICD-10), was used to reclassify medical conditions into 490 and 16 specific causes of death. We conducted a disease trajectory analysis to map the key pathways linking MAFLD to various health conditions, providing an overview of their interconnections. RESULTS: Participants aged 59 (51-64) years, predominantly males (62.5%), were included in the study. During the 12.9-year follow-up period, MAFLD participants were found to have a higher risk of 113 medical conditions and eight causes of death, determined through phenome-wide association analysis using Cox regression models. Temporal disease trajectories of MAFLD were established using disease pairing, revealing intermediary diseases such as asthma, diabetes, hypertension, hypothyroid conditions, tobacco abuse, diverticulosis, chronic ischemic heart disease, obesity, benign tumors, and inflammatory arthritis. These trajectories primarily resulted in acute myocardial infarction, disorders of fluid, electrolyte, and acid-base balance, infectious gastroenteritis and colitis, and functional intestinal disorders. Regarding death trajectories of MAFLD, malignant neoplasms, cardiovascular diseases, and respiratory system deaths were the main causes, and organ failure, infective disease, and internal environment disorder were the primary end-stage conditions. Disease trajectory analysis based on the level of genetic susceptibility to MAFLD yielded consistent results. CONCLUSIONS: Individuals with MAFLD have a risk of a number of different medical conditions and causes of death. Notably, these diseases and potential causes of death constitute many pathways that may be promising targets for preventing general health decline in patients with MAFLD.

"Sandwich" protocol based on modified SMILE regimen for children with newly extranodal NK/T cell lymphoma, nasal type: a single-arm, single-center clinical study.

Extranodal NK/T-cell lymphoma, nasal type (ENKTL), which is a rare form of mature T/NK cell lymphoma in children, currently lacks a standardized first-line treatment approach. However, a treatment protocol known as the "sandwich" regimen has been used in children newly diagnosed with ENKTL. This protocol combines the administration of methotrexate, ifosfamide, etoposide, pegaspargase, and dexamethasone (referred to as SMILE) with the addition of radiotherapy (RT). From September 2017 to December 2020, a total of five patients were included in the study, consisting of three males and two females. The median age of onset was 10.6 years (range, 9.8 to 14.0 years). Among the patients, four had nasal/nasopharyngeal disease at stage II, while one patient had extra nasal disease involving the skin at stage IV. The median EBV-DNA level in plasma was 1.68 × 103 copies/ml (range, 0.44 to 21.1 × 103copies/ml). All the patients had good overall response after 2 cycles of chemotherapy and radiotherapy, including 4 of the patients who had a complete response and 1 of the patients with partial remission. The patient with stage IV received allogeneic hematopoietic stem cell transplantation after the EBV-DNA level was elevated again during treatment. One patient in the low-risk group experienced grade 4 oral mucositis, while no other severe complications or treatment-related deaths were observed. The median follow-up period was 22 months (range, 5 to 57 months). All five patients successfully completed their treatment, with four patients achieving event-free survival, and one patient was lost to follow-up. The median OS time and EFS time was 33 months (range: 18-57 months) and 20 months (range: 5-47 months), respectively. The sandwich protocol has demonstrated a high response rate, good tolerance to chemotherapy, and no treatment-related fatalities. However, further confirmation is necessary through additional clinical studies involving larger sample sizes. Clinical trial registration number: Due to modified SMILE regimens with sandwiched radiotherapy yielded promising outcomes in children ENKTL, we have carried out a phase II multicenter clinical trial (ChiCTR220005954) for children ENKTL in China to further verify the efficacy and safety.

Usability of the Surprise Question by Nurses and Patients' Families for Risk Stratification in Emergency Patients: A Prospective Cohort Study.

The Surprise Question is an effective tool to identify patients in need of palliative care. But it is unknown whether the Surprise Question can effectively predict adverse outcomes in Emergency patients. Therefor this study is to determine the utility of the modified Surprise Question for risk stratification in emergency patients. And assessed if the modified Surprise Question could be used by different healthcare personnel. Nurses and patients' families were asked to respond as "Yes" or "No" to the modified Surprise Question for each patient. The outcome was resuscitation unit admission. Logistic regression was used to determine covariant significantly associated with resuscitation unit admission. The area under the curve for the second Surprise Question response by nurses was 0.620, which improved to 0.704 when the responses of nurses and patients' families were in agreement. The clinical impression of nurses is a valuable tool to predict altered conditions for medium-acuity patients, and the diagnostic accuracy improves when responses of patients' families and nurses agreed. The clinical impression of nurses is a valuable tool to predict altered conditions for medium-acuity patients, and the diagnostic accuracy improves when responses of patients' families and nurses agreed.

Polyphenol-Enriched Protein Oleogels as Potential Delivery Systems of Omega-3 Fatty Acids.

Omega-3 polyunsaturated fatty acids (n-3 FAs) are essential nutrients and are considered effective in improving human health. Recent studies highlight the importance of the combination of n-3 FAs and polyphenols for limiting the oxidation of n-3 FAs and exhibiting synergistic beneficial effects. Herein, we developed a novel formulation technology to prepare oleogels that could be used for the codelivery of n-3 FAs and polyphenols with high loading efficacy and oxidative stability. These oleogels are made from algal oil with polyphenol-enriched whey protein microgel (WPM) particles as gelling agents via simple and scalable ball milling technology. The oxidative status, fatty acid composition, and volatiles of protein oleogels during accelerated storage were systematically assessed by stoichiometry and gas chromatography-mass spectrometry. These results showed that protein oleogels could overcome several challenges associated with the formulation of n-3 oils, including long-term oxidative stability and improved sensory and textural properties. The protein oleogel system could provide an excellent convenience for formulating multiple nutrients and nutraceuticals with integrating health effects, which are expected to be used in the care of highly vulnerable populations, including children, the elderly, and patients.

Dynamic molecular choreography of circadian rhythm disorders (DMCRD): a prospective cohort study protocol.

BACKGROUND: Circadian rhythm disorders (CRDs) are closely associated with the occurrence and development of various diseases, such as inflammatory and cardiovascular diseases, as well as tumors. The impact of a CRD on bodily health is a complex and comprehensive process, and its molecular mechanisms and signaling pathways are still unclear. We therefore aimed to investigate the molecular mechanism variation and adverse outcomes associated with CRDs in a prospective cohort of CRD cases and controls at term using multiomics data. The study has been tasked with developing a precise health promotion model for the prevention and management of CRDs. METHODS: This will be a 5-year prospective cohort study centered on the health management of individuals with CRDs. One hundred volunteers were recruited and had undergone baseline specimen collection, health examination, and health assessment. All of them will be followed up every year using the same protocol, and their biological specimens will be subjected to multiomics analysis after standardized processing. DISCUSSION: Longitudinal health examination, health assessment, and multiomics data will be analyzed to study the impact of CRDs on the volunteers' health status. The results of this study will promote the development of targeted health management programs based on precision medicine. TRIAL REGISTRATION: The clinical study registration has been completed (Trial Registration No. ChiCTR2100047242 ).

Paediatric Erdheim-Chester Disease in the Lateral Ventricle: A Case Report and Review of the Literature.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis caused by the expression of CD68-positive and CD1a-negative foam tissue cells, which is polar in pediatric patients. The study reports a case of an 8-year-old Chinese boy who presented with polydipsia and polyuria for 4 years, followed by central nervous system symptoms. Magnetic resonance imaging (MRI) showed a large lesion in the lateral ventricle. The histiocytes stained positively for CD68, CD163 and negatively for CD1a, glial fibrillary acidic protein (GFAP) and langerin, and were partially positive for S100 by immunohistochemical assay. More importantly, BRAFV 600E staining was positive in tissue, and the BRAF V600E mutations was also detected by real-time quantitative PCR (RT-qPCR) in the intracranial lesion tissue. According to our review of the literature, this is a rare case of ECD in the ventricle, with a younger age.

[Mechanism of microRNA-100-5p on mammalian target of rapamycin in temporomandibular arthritis].

PURPOSE: To investigate the mechanism of microRNA-100-5p (miR-100-5p) on mammalian target (mTOR) of rapamycin in temporomandibular arthritis. METHODS: Sixty SD rats were randomly divided into group A, group B, group C, group D, and group E, with 12 rats in each group. Rat models of temporomandibular arthritis were prepared by injecting sodium iodoacetate solution into the bilateral spaces of temporomandibular joint. After establishment, group C was injected pcDNA3.1-miR-100-5p recombinant plasmid, group D was injected mTOR inhibitor rapamycin, group E was injected with pcDNA3.1-miR-100-5p recombinant plasmid and rapamycin, and group A was injected same amount of normal saline in the same way. Various indexes were observed in each group, including morphological changes of temporomandibular joint tissues, matrix metalloproteinase-3 (MMP-3), MMP-1, MMP-13, interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), miR-100-5p, mTOR expression. The data were processed using SPSS 22.0 software package. RESULTS: In group B, the structure of temporomandibular joint was fuzzy, with synovial hyperplasia, vascular dilatation, clustered cells and a large amount of inflammatory infiltration. Histopathological changes of temporomandibular joint in each interventional group were improved to different degrees compared with group B, among which group E showed the most obvious improvement. The levels of MMP-3, MMP-1, MMP-13, IL-6, IL-1ß and TNF-α in group B were significantly higher than those in group A(P＜0.05). The levels of MMP-3, MMP-1, MMP-13, IL-6, IL-1ß and TNF-α in group C, group D and group E were significantly lower than those in group B(P＜0.05). The levels of MMP-3, MMP-1, MMP-13, IL-6, IL-1ß and TNF-α in group D were not significantly different from those in group C (P＜0.05). The levels of MMP-3, MMP-1, MMP-13, IL-6, IL-1ß and TNF-α in group E were significantly lower than those in group D (P＜0.05). The expression level of miR-100-5p in group E was significantly higher than that in group B (P＜0.05). The expression level of mTOR protein in group E was significantly lower than that in group B (P＜0.05). CONCLUSIONS: MicroRNA-100-5p may alleviate temporomandibular arthritis by down-regulating the expression of mTOR.

Structuring of Edible Liquid Oil into Smart Thermo-Triggered Soft Matters for Controlled Bioactive Delivery.

Growing interest is being dedicated to smart soft matters because of their potential in controlling bioactives upon exposure to an appropriate stimulus. Herein, structuring of edible liquid oil into oleogels and emulgels as smart thermo-triggered soft vehicles for controllable release of diverse nutrients was developed. Edible liquid oil was trapped inside the crystal network structure of phytosterols and monoglycerides resulting in bicomponent solidlike oleogels. Subsequently, both water-in-oleogel (W/O) emulgels and glycerol-in-oleogel (G/O) emulgels were further fabricated by spatial distribution of the stabilizing interfacial crystals around dispersed droplets as well as the network crystals in the continuous phase. Rheological measurements showed that the gel strength of the oleogel-based emulgels depends on the fraction of the aqueous phase and is greater than that of corresponding oleogels due to a filler effect of dispersed aqueous droplets within the crystal network, offering an additional strategy to tune the structure and rheology. Comparatively, introducing glycerol endowed a higher gel strength for the oleogel-based emulgels than water, particularly at increased filler loads. In addition, these soft matters exhibited interesting thermoresponsive nature, which exhibit the flexibility for programmed release of coencapsulated bioactive components upon exposure to an appropriate thermal triggered switchable. The resulted smart thermo-triggered soft matters have emerging opportunities for application in functional active ingredient delivery by on-demand strategies.

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Series and Literature Review.

Langerhans cell histiocytosis (LCH) is characterized pathologically by langerin-positive (CD207+) dendritic cell proliferation and is considered by some as a myeloid neoplastic disorder. Hemophagocytic lymphohistiocytosis (HLH) is associated with immune dysregulation characterized by the accumulation of activated macrophages and hypercytokinemia. However, these 2 histiocytosis rarely coexist. Currently, the etiology, risk factors, optimal therapy, and outcomes of LCH-HLH remain unclear. We reviewed the medical records of 7 LCH-HLH patients from our hospital and analyzed 50 LCH-HLH patients reported in scientific literature. The median age of LCH onset of these 57 LCH-HLH patients was 1 year, and 91% (52/57) of patients diagnosed as LCH were less than 2 years old. Fifty-six LCH-HLH patients belonged to the multisystem LCH category and 84% (47/56) patients had risk-organ involvement. Twenty-three LCH-HLH patients were complicated with infection and 3 patients had a primary pathogenic mutation of HLH. Overall, 90% of LCH patients developed HLH at the diagnosis or during chemotherapy. Of the 57 LCH-HLH patients, 15 died. Multisystem LCH patients with risk-organ involvement under 2 years old were most likely to develop HLH when complicated with infection at diagnosis or during chemotherapy. Identifying LCH-HLH patients during early stages and treating them with prompt chemotherapy, hematopoietic stem cell transplantation, or supportive therapies are important for better survival.

Prognostic value of interleukin-33, sST2, myeloperoxidase, and matrix metalloproteinase-9 in acute aortic dissection.

Background and purpose: Acute aortic dissection (AAD) is a life-threatening cardiovascular emergency. Both neutrophil granzyme and interleukin (IL)-33/ST2 systems have proven to be effective diagnostic markers for AAD. This study aimed to investigate the relationship between plasma IL-33, soluble suppression of tumorigenesis-2 (sST2), myeloperoxidase (MPO), and matrix metalloproteinase (MMP)-9 levels at admission and all-cause mortality in patients with AAD. Methods: A total of 155 patients with AAD were enrolled from the Prospective Evaluation of Acute Chest Pain (PEACP) study. Plasma concentrations of IL-33, sST2, and MMP-9 were measured using an enzyme-linked immunosorbent assay, and MPO was detected using a chemiluminescence immunoassay. Aortic anatomical parameters were measured using CT radiography. The primary endpoint was all-cause mortality rate. Results: The median age of the patients was 55 years, and 96 (61.9%) were diagnosed with type A-AAD. After adjusting for confounding factors, the highest tertiles of IL-33, sST2, MPO, and MMP-9 had hazard risks of 0.870 (95% CI: 0.412-1.836, P = 0.714), 3.769 (95% CI: 1.504-9.446, P = 0.005), 4.689 (95% CI: 1.985-11.076, P < 0.001), and 4.748 (95% CI: 1.763-12.784, P = 0.002), respectively, compared to the lowest tertile. Pearson's correlation analysis revealed a significant correlation between these markers (P < 0.001). Moreover, sST2, MPO, and MMP-9 levels had a significant positive correlation with aortic diameter and pseudolumen area (P < 0.001). Conclusion: The biomarkers sST2, MPO, and MMP-9 were independently associated with mortality in patients with AAD. The significant correlation between these biomarkers suggests a pathogenic role for the IL-33/ST2/neutrophil granzyme system in patients with AAD.

One-pot ultrasonic cavitational emulsification of phytosterols oleogel-based flavor emulsions and oil powder stabilized by natural saponin.

Phytosterols oleogel-based flavor emulsions were successfully fabricated for the first time using natural tea saponin as emulsifier and one-pot ultrasonic technique. The effects of ultrasonic time and power, surfactant concentration, and type of flavor oils (e.g., orange, lemon and peppermint) on the emulsion droplet size were investigated. Submicron emulsions with a dispersed phase made by flavor oil (20 wt%) + phytosterol (4 wt%) were stabilized with 3 wt% saponin were obtained by applying an ultrasonic time of 5 min and ultrasonic power of 280 W. The natural tea saponin emulsions exhibited a superior stability and encapsulation efficiency of phytosterol, compared to traditional emulsifiers. Flavor oil-phytosterol enriched powders were prepared by spray-drying and characterized by SEM, XRD and repose angle. The natural saponin encapsulated oil + phytosterol powders had excellent fluidity, redispersion behavior and low phytosterol crystallinity. It was demonstrated that ultrasound is an effective and suitable technique for fabricating fortified flavor emulsions and microcapsules, which may be used for developing functional lipids-based applications in the food, beverage and cosmetic industries.

Clinical and prognostic characteristics of 95 cases of Langerhans cell histiocytosis in children: a single-institute experience from 2013 to 2020.

BACKGROUND: This study aimed to understand the clinical characteristics and outcomes of children with Langerhans cell histiocytosis (LCH) in China. METHODS: We conducted a retrospective study of 95 paediatric patients with LCH in West China Second University Hospital of Sichuan University between July 2013 and August 2020. RESULTS: The onset age of multisystem LCH (MS-LCH) patients with risk organ (RO) involvement was younger than that of MS-LCH without RO involvement (p = .002) and single system LCH (p < .001) patients; bone was the most frequently involved organ, followed by the skin. Of all, the BRAF-V600E mutation was detected in 48 out of 84 patients who underwent gene analysis. Additionally, in our study, BRAF p.N486_T491 > K, BRAF p.L485_P490delinsF, BRAF p.R506_K507insLLR, ARAF p.Q349_F351delinsL and MAP2K1 p.Q58_E62del were known mutations in the mitogen-activated protein kinase (MAPK) pathway. The BRAF-V600E genotype in the tissue and plasma prior to therapy were detected in 16 patients, and the concordance was only 37.5% (6/16). According to the modified LCH-III-based-protocol, JLSG-02 protocol chemotherapy, and vemurafenib, the estimated five-year overall survival, event-free survival (EFS) and cumulative reactivation rates of 95 patients were 98.8%, 74.6% and 24.5%, respectively. The EFS rate in good responders was better than that in poor responders at 12-week (HR = 0.022, 95%CI 0.002-0.231, p = .002), and EFS was not affected by age, RO involvement or BRAF-V600E mutation. Regarding sequelae, nine patients had central diabetes insipidus and two had growth retardation. CONCLUSIONS: In this study, LCH was a highly heterogeneous disease characterized molecularly by MAPK-pathway activating mutations. Vincristine, prednisone and cytarabine-based chemotherapy combined with vemurafenib improved the prognosis of childhood LCH. In future, prospective clinical trials and novel therapeutic strategies should be developed to improve outcomes in paediatric patients with LCH.KEY MESSAGEChildren with Langerhans cell histiocytosis in China present highly heterogeneous clinical characteristics, with up to 60% of cases harbouring mutations in MAPK pathway.Treatment response at 12-week is associated with EFS in our study.Vincristine, prednisone and cytarabine-based chemotherapy combined with vemurafenib improved the prognosis of Chinese childhood LCH, but the reactivation rate is still high.

Adherence to Healthy Lifestyle and the Risk of Function Limitations in Late Life: The Atherosclerosis Risk in Communities Study.

Background: Physiological function impairment is the main precursor of assisted living, movement disorder, and disability in the elderly. The relationship between a combination of healthy lifestyle factors and functional limitations is unclear. We investigated the association between healthy lifestyle scores and the risk of functional impairment in community residents. Methods: A total of 10,602 participants (aged 40-64 years) of the Atherosclerosis Risk in Communities (ARIC) study with no history of cardiovascular events and tumors and who came for their fourth visit (1997-1999) were included in the final analysis. Primary outcomes were recorded during the fourth visit; these included impaired lower extremity function, activities of daily living, and instrumental activities of daily living. A logistic regression model was used to test the associations between healthy lifestyle scores and functional impairment. The lifestyle score comprised six factors: healthy diet, moderate alcohol consumption, coffee consumption, physical activity, normal body weight, and no smoking. Results: Among the 10,602 participants with a median follow-up of 9 years, the prevalence rates of impaired lower extremity function, activities of daily living, and instrumental activities of daily living were 50.6%, 14.7%, and 21.6%, respectively. In the adjusted Cox regression model, participants with a healthy lifestyle score of 5 plus 6 had a significant lower risk of impaired lower extremity function (odds ratio = 0.252, 95% confidence interval: 0.184-0.344, P < 0.001), activities of daily living (odds ratio = 0.201, 95% confidence interval: 0.106-0.380, P < 0.001), and instrumental activities of daily living (odds ratio = 0.274, 95% confidence interval: 0.168-0.449, P < 0.001) than did participants with a score of 0. The association of healthy lifestyle scores with impaired activities of daily living and instrumental activities of daily living was stronger for individuals without diabetes than for those with it (P for interaction < 0.05). This can be partly explained by the fact that the lowest risk of functional impairment among the participants with diabetes was associated with being overweight. Conclusion: Adherence to an overall healthy lifestyle was associated with a lower risk of physiological function limitation. This study highlights the importance of behavioral interventions in the prevention of disabilities. Clinical Trial Registration: www.ClinicalTrials.gov; Unique identifier: NCT00005131.

Adherence to a Healthy Lifestyle and the Risk of All-Cause Mortality and Cardiovascular Events in Individuals With Diabetes: The ARIC Study.

Objective: The relationship between combined healthy lifestyle and cardiovascular (CV) events in diabetes is unclear. We aim to investigate the association between a healthy lifestyle score (HLS) and the risk of mortality and CV events in diabetes. Methods: We examined the associations of six lifestyle factors scores (including healthy diet, moderate alcohol and regular coffee intakes, never smoking, physical activity, and normal weight) with diabetes in the Atherosclerosis Risk in Communities (ARIC) study of 3,804 participants with diabetes from the United States at baseline. Primary outcomes included all-cause mortality, CV mortality, and composite CV events (heart failure hospitalizations, myocardial infarction, fatal coronary heart disease, and stroke). Results: Among these diabetic participants, 1,881 (49.4%), 683 (18.0%), and 1,600 (42.0%) cases of all-cause mortality, CV mortality, and CV events were documented, respectively, during the 26 years of follow-up. Further, the prevalence of these adverse events became lower with the increase of HLS (all P < 0.001). In the risk-factors adjusted Cox regression model, compared to participants with HLS of 0, participants with HLS of 2 had significant lower risk of all-cause mortality (HR = 0.811, 95% CI: 0.687-0.957, P = 0.013), CV mortality (HR = 0.744, 95% CI: 0.576-0.962, P = 0.024), and CV events (HR = 0.789, 95% CI: 0.661-0.943, P = 0.009). The association of HLS with CV events was stronger for women than men (P for interaction <0.05). Conclusion: Adherence to a healthy lifestyle was associated with a lower risk of CV events and mortality in diabetics. Our findings suggest that the promotion of a healthy lifestyle would help reduce the increasing healthcare burden of diabetes. Clinical Trial Registration: https://clinicaltrials.gov, Identifier: NCT00005131.

[Effect of Huangqin Decoction on pyroptosis pathway of NLRP3/caspase-1 in mice with ulcerative colitis].

To explore the effect of Huangqin Decoction on ulcerative colitis(UC) pyroptosis, and to explain the mechanism of pyroptosis based on NOD-like receptor thermoprotein domain 3(NLRP3)/cysteine proteinase 1(caspase-1) pathway. The animal model of UC induced with 3% dextran sodium sulfate(DSS) was established. The experimental animals were divided into control group, model group, low-dose(4.55 g·kg~(-1)), medium-dose(9.1 g·kg~(-1)) and high-dose(18.2 g·kg~(-1)) Huangqin Decoction groups and salazosulfapyridine group(0.45 g·kg~(-1)). While modeling, intragastric administration was given for 7 consecutive days. On the 8 th day, the mice were euthanized, the colon length was collected, and the histopathological changes were observed by HE staining. The content of interleukin-18(IL-18) was observed by ELISA. The content of lactatedehydrogenase(LDH)was determined by microplate method. TUNEL assay kit was used to detect the cell death. The immunohistochemical staining was used to detect the expressions of NLRP3 and apoptosis-associated speck-like protein containing a CARD(ASC). Western blot was used to detect the expressions of interleukin-1ß(IL-1ß), caspase-1 and gasdermin D(GSDMD).The experimental study showed that compared with normal group, the LDH content, TUNEL positive staining, inflammatory factors(IL-18, IL-1ß), and proteins associated with pyroptosis were significantly increased(P<0.05). Compared with model control group, the LDH content, TUNEL positive staining, inflammatory factors(IL-18, IL-1ß), and proteins associated with pyroptosis were decreased, and these results were more significant in high-dose groups(P<0.05). The results of HE staining showed that Huangqin Decoction could improve the pathological changes of colon. Huangqin Decoction could inhibit UC cell pyroptosis, and the mechanism may be closely related to NLRP3/caspase-1 signaling pathway.

[The Value of Umbilical Cord Blood Erythrocyte Index in the Screening of Neonatal Thalassemia].

OBJECTIVE: To investigate the relationship between umbilical cord blood erythrocyte index and thalasse-mia, and reveal its clinical value in the screening of thalassemia in neonates. METHODS: 2 919 cases of umbilical cord blood from neonatal who were born in Boai Hospital of Zhongshan Affiliated with Southern Medical University from July 2017 to December 2018 were collected, the routine blood tests were preformed to detect the umbilical cord blood. Thalassemia gene in peripheral blood of neonates was collected. The cut-off values of cord blood indexes were determined, and the sensitivity, specificity and other evaluation indexs were calculated. RESULTS: Among the cord blood in 2 919 neonates, 314 cases were detected out as thalassemia(positive rate: 10.76%). The average level of RBC and RDW in 2 605 children with non-thalassemia was lower than those with 314 children with thalassemia. The levels of Hb, MCV, MCH, MCHC, HCT, Hb/RBC and MCV/RBC in children with non-thalassemia were higher than those with thalassemia, and there were significant differences in the neonates between the two groups. The RBC and RDW levels of neonates in the α-thalassemia group were higher than those in the non-thalassemia group, while the levels of Hb, MCV, MCH, MCHC, HCT, Hb/RBC and MCV/RBC of neonates were lower than those in the non-thalassemia group. The levels of MCV, MCH and Hb/RBC of neonates in the ß-thalassaemia group were lower than those in the non-thalassaemia group. The levels of MCV, MCH, Hb/RBC, and MCV/RBC of neonates in the complex thalassemia group were lower than those in the non-thalassemia group. When the cut-off value of MCV was set to 106.05 fl, the sensitivity was 0.548, and the specificity was 0.907, the specificity was the highest among all indexes. The area under the ROC curve of the combined diagnosis of MCH+MCV/RBC was the largest(0.807), the sensitivity was 0.710, the specificity was 0.841, the positive predictive value was 0.348, and the negative predictive value was 0.960. CONCLUSION: The single indicator of umbilical cord blood red blood cells has advantages and disadvantages for the screening of thalassemia, but the combination of MCH+MCV/RBC can improve the accuracy of the screening or diagnosis of thalassemia, it also has a positive effect to the reduction of the birth rate of children with thalassemia major, which showed a high popularization value in primary hospitals.