Development of the Clinical pHysical rEsilience assEssment Scale (CHEES) in Chinese Older Adults.

BACKGROUND: Physical resilience is an emerging concept that describes an individual's capacity to recover from stressors. However, few instruments are currently available for assessing physical resilience. OBJECTIVE: To develop a scale to assess physical resilience in older adults. DESIGN: Development of a clinical scale. SETTING AND PARTICIPANTS: A total of 172 hospitalized older adults were recruited. MEASUREMENTS: This study comprised two stages. First, a pool of physical resilience scale items was created through a literature review, and the Delphi method was used to establish an initial scale. Second, the initial physical resilience scale was tested on hospitalized older adults. RESULTS: Five primary and 19 secondary items were identified after reviewing the literature. After two rounds of expert consultations, three primary and 16 secondary items were determined. The overall Cronbach's alpha for the scale was 0.760. Except for items N2, N4, N5, N8, and N14, Pearson's correlation between the scores of the remaining items and the total score ranged from 0.407 to 0.672. Except for items N2, N4, and N5, the corrected item-total correlation results ranged from 0.301 to 0.580, indicating good consistency between each item and the overall scale. Factor analysis showed that except for N7, the factor loadings of the remaining items were between 0.584 and 0.844. After expert discussions, items N2, N4, N7, and N14 were included in the scale, and items N5 and N8 were removed. CONCLUSION: A 14-item physical resilience scale, CHEES, was developed to assess physical resilience levels in older adults.

Is polyethylene glycol loxenatide 100 µg the preferred glucagon-like peptide-1 receptor agonist for type 2 diabetes mellitus? A meta-analysis and trial sequential analysis.

OBJECTIVE: This study aimed to systematically evaluate the efficacy, safety and optimal dose of polyethylene glycol loxenatide (PEX168) for treating type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Clinical trials of PEX168 for T2DM were identified in 8 databases, with a build time limit of January 2023. Included studies were subjected to meta-analysis and trial sequential analysis (TSA). RESULTS: On the efficacy endpoint, the meta-analysis showed that PEX168 100 µg significantly reduced 0.86% glycated hemoglobin type A1c (HbA1c) (MD -0.86, 95% CI -1.02 - -0.70,  p<0.00001), 1.11 mmol/L fasting plasma glucose (FPG) (MD -1.11, 95% CI -1.49 - -0.74, p<0.00001) and 1.91 mmol/L 2h postprandial glucose (PPG) (MD -1.91, 95% CI -3.35 - -0.46, p=0.01) compared with placebo. The TSA showed that all these benefits were conclusive. On safety endpoints, total adverse events (AEs), gastrointestinal (GI) AEs, serious AEs, and hypoglycemia were comparable to placebo for PEX168 100 µg (p>0.05). In the dose comparison, the HbA1c, FPG, and 2h PPG of PEX168 200 µg were comparable to 100 µg (p>0.05), while GI AEs were significantly higher than 100 µg (RR=2.84, 95% CI 1.64-4.93,  p=0.0002). CONCLUSIONS: PEX168 100 µg can significantly lower blood glucose and does not increase the risk of total AEs, GI AEs, and hypoglycemia, which may be a preferred glucagon-like peptide-1 receptor agonist for type 2 diabetes mellitus.

Spiritual Interventions Among Pediatric Patients With Cancer: A Systematic Review And Meta-Analysis.

CONTEXT: Although spiritual intervention is crucial in the care of childhood cancer patients (CCPs), its effectiveness has not yet been systematically evaluated. OBJECTIVES: To determine the effectiveness of existing spiritual interventions on psychological, spiritual outcomes, and quality of life (QoL) in CCPs. METHODS: We searched eight databases to identify relevant randomized controlled trials and quasi-experimental studies. Risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials. Results were either synthesized in a systematic narrative synthesis or a meta-analysis using a random effects model, where appropriate. The pooled treatment effect was estimated using the standardized mean difference (SMD) and 95% confidence interval (CI). RESULTS: Twelve studies with 576 CCPs were included. Eight studies showed a high risk of bias. The overall effect of existing spiritual interventions on QoL (Z = 1.05, SMD = 0.64, 95%CI = -0.15 to 1.83, P = 0.29), anxiety (Z = 1.11, SMD = -0.83, 95%CI = -2.30 to 0.64, P = 0.28) and depressive symptoms (Z = 1.06, SMD = -0.49, 95%CI = -1.40 to 0.42, P = 0.12) were statistically nonsignificant. The nonsignificant findings could be attributed to the high heterogeneity among the included studies (QoL: I2 = 85%; anxiety: I2 = 90%; depressive symptoms: I2 = 58%). CONCLUSION: Evidence to support the positive effects of existing spiritual interventions on psychological and spiritual outcomes and QoL in CCPs is insufficient. Future studies should adopt a more rigorous design and unify the outcome measures to reduce the risk of bias and heterogeneity, respectively.

[Cost-effectiveness of HCV testing strategies for hepatitis C elimination in general population in China].

Objective: To evaluate the cost-effectiveness of hepatitis C screening in general population in China, and find the age group in which hepatitis C screening can achieve the best cost-effectiveness. Methods: A decision-Markov model was constructed by using software TreeAge pro 2019 to simulate the outcomes of hepatitis C disease pregression of 100 000 persons aged 20-59 years. The cost-effectiveness of the strategies were evaluated from societal perspectives by using incremental cost-effectiveness ratio (ICER) and net monetary benefit (NMB). One-way sensitivity analysis and probability sensitivity analysis were used to evaluate the uncertainty of parameters and model. Results: Hepatitis C screening was cost-effective in people aged 20- 59 years and the cost effectiveness was best in age group 40-49 years. Compared with non-screening strategy of hepatitis C in people aged 20-59 years, the incremental cost was 161.24 yuan, the incremental utility was 0.003 6 quality adjusted life years (QALYs)/per person, ICER was 45 197.26 yuan/QALY, ICER was less than the willing payment threshold. The ICER and NMB in all age groups were 42 055.06-53 249.43 yuan/QALY and 96.52-169.86 yuan/per person. Hepatitis C screening in people aged 40-49 years had the best cost-effectiveness. The results of one-way sensitivity analysis showed that the discount rate, anti-HCV detection cost, anti-HCV infection rate and the cost of direct antiviral agents were the main factors influencing economic evaluation. The results of the probability sensitivity analysis indicated that the model analysis was stable. Conclusions: Implementing hepatitis C screening based on medical institutions is cost-effective in people aged 20- 59 years, especially in those aged 40-49 years. Implementing the HCV screening strategy of be willing to test as far as possible in general population can reduce hepatitis C disease burden in China.

Saturation of Fishbone Instability by Self-Generated Zonal Flows in Tokamak Plasmas.

Gyrokinetic simulations of the fishbone instability in DIII-D tokamak plasmas find that self-generated zonal flows can dominate the nonlinear saturation by preventing coherent structures from persisting or drifting in the energetic particle phase space when the mode frequency down-chirps. Results from the simulation with zonal flows agree quantitatively, for the first time, with experimental measurements of the fishbone saturation amplitude and energetic particle transport. Moreover, the fishbone-induced zonal flows are likely responsible for the formation of an internal transport barrier that was observed after fishbone bursts in this DIII-D experiment. Finally, gyrokinetic simulations of a related ITER baseline scenario show that the fishbone induces insignificant energetic particle redistribution and may enable high performance scenarios in ITER burning plasma experiments.

[Study on transcriptome characteristics of respiratory syncytial virus bronchiolitis in children by RNA sequencing].

To explore the biological characteristics related to the pathogenesis and severity of respiratory syncytial virus (RSV) bronchiolitis by RNA sequencing of white blood cells in children with RSV bronchiolitis. This study is a case-control study. A total of 87 children diagnosed with bronchiolitis and RSV antigen positive and/or RSV nucleic acid positive in the pediatric respiratory department of the Second Affiliated Hospital of Wenzhou Medical University from October 2019 to April 2022 were selected as the case group. The case group was divided into three groups based on the condition: mild, moderate, and severe, and there were two groups according to the presence or absence of atopic symptoms: the atopic group and the non-atopic group, forty healthy children in the same period were selected as the control group. The whole blood leukocyte RNA of the children in the case group and the control group was extracted for RNA sequencing, and the data were analyzed to obtain differentially expressed genes (DEGs). Then, the immunobiological pathways and genes related to the pathogenesis, disease condition, and atopy were screened through Gene Ontology (GO) annotation, Kyoto Gene and Genome Encyclopedia (KEGG) annotation, and protein interaction network (PPI) construction methods. Construct the weighted gene co-expression network analysis (WGCNA) module to identify potential biological indicators related to disease severity.Compared with the control group, the case group had a total of 1 782 DEGs, including 1 586 upregulated genes and 196 downregulated genes. The GO pathway enrichment of DEGs is mainly enriched in molecular functions such as peroxidase activity and oxidoreductase activity. In the cytological components, it is mainly enriched in cytoplasmic vesicle lumen and secretory granule lumen. In biological processes, it is mainly enriched in processes such as neutrophil activation involved in immune responses, neutrophil degranulation, and neutrophil activation. KEGG analysis is mainly concentrated in the signal pathway of the viral protein interaction with cytokine and cytokine receptor. A PPI network was constructed to screen four genes at the core position, including CCL2, IL-10, MMP9 and JUN. The DEGs obtained by comparing different disease groups with the control group are mainly enriched in retrograde endocannabinoid signaling and cell apoptosis pathways. WGCNA analysis showed that the brown module related to oxygen saturation was most closely related to the disease, and its gene was mainly enriched in the RNA helicase retinoic acid inducible gene-I (RIG-I) like receptor signal pathway. There are 230 specific DEGs in the atopic group and 444 in the non-atopic group. KEGG enrichment analysis results show that both groups are enriched to NF-κB signaling pathway, the characteristic does not cause significant changes in immune response and transcriptome characteristics in children with RSV bronchiolitis. In conclusion, neutrophil activation, degranulation pathway and signal pathway of interaction between viral protein and cytokine and cytokine receptor are involved in the immune response of RSV bronchiolitis host. CCL2, IL-10, MMP9 and JUN genes may be associated with the pathogenesis. They might be potential biomarkers related to disease severity in RIG-I like receptors, cell apoptosis, and endogenous cannabinoid related signaling pathways.

Asthma and clinical outcomes of COVID-19 in a community setting.

OBJECTIVES: The association between asthma and COVID-19 mortality remains inconclusive. We examined the association between asthma and clinical outcomes of patients with COVID-19. STUDY DESIGN: A case-control study based on a surveillance cohort in Harris County, Texas. METHODS: Using the data of 21,765 patients who reported having at least one chronic health condition, we investigated the association between asthma and COVID-19 severity, characterized primarily by hospitalization and death. Unconditional logistic regression models were used to estimate the multivariable odds ratio (mOR) and its 95 % confidence interval (CI) of COVID-19 severity associated with asthma and other chronic lung diseases, adjusting for demographic and other comorbidities. A P-value < 0.005 was considered statistically significant after correcting multiple testing. RESULTS: In total, 3034 patients (13.9 %) had asthma, and 774 (3.56 %) had other chronic lung diseases. The case death rate among patients with asthma and other chronic lung diseases was 0.75 % and 19.0 %, respectively. Compared to patients without the respective conditions, patients with asthma had lower odds of death (mOR = 0.44, 95 % CI: 0.27-0.69), while patients with other chronic lung diseases had higher odds of hospitalization (mOR = 2.02, 95 % CI: 1.68-2.42) and death (mOR = 1.95, 95 % CI: 1.52-2.49) (P-values < 0.005). Risk factors for COVID-19 mortality included older age, male gender, diabetes, obesity, hypertension, cardiovascular disease, active cancer, and chronic kidney disease. CONCLUSIONS: The public health surveillance data suggested that preexisting asthma was inversely associated with COVID-19 mortality.

Effect of Taiwan's Diabetes Shared Care Program on the risk of periprosthetic joint infection after total joint arthroplasty in patients with type 2 diabetes mellitus: an eight-year population-based study.

BACKGROUND: Periprosthetic joint infection (PJI) is a significant post-arthroplasty complication for diabetic patients, with uncontrolled diabetes identified as a PJI risk factor. Taiwan's Diabetes Shared Care Program (DSCP) was established for holistic diabetes care. AIM: To evaluate the DSCP's impact on PJI incidence and patients' medical costs. METHODS: Data were analysed from Taiwan's National Health Insurance Research Database from 2010 to 2020, focusing on type 2 diabetes mellitus (DM) patients who had undergone arthroplasty. The study group involved DSCP participants, while a comparison group comprised non-participants with matched propensity scores for age, sex, and comorbidities. The primary outcome was the PJI incidence difference between the groups; the secondary outcome was the medical expense difference. FINDINGS: The study group consisted of 11,908 type 2 DM patients who had arthroplasty and joined the DSCP; PJI occurred in 128 patients. Among non-participants, 184 patients had PJI. The PJI incidence difference between the groups was statistically significant (1.07% vs 1.55%). The study group's medical costs were notably lower, regardless of PJI incidence. Multivariate regression showed higher PJI risk in patients in comparison group, aged >70 years, male, or who had obesity, anaemia. CONCLUSION: The study indicates that DSCP involvement reduces PJI risks and decreases annual medical costs for diabetic patients after arthroplasty. Consequently, the DSCP is a recommendable option for such patients who are preparing for total joint arthroplasty.

Clinical research advances of CFHR5 nephropathy: a recent review.

CFHR5 nephropathy is a type of clinical C3 glomerulopathy, which is a monogenic genetic disease caused by the internal replication of CFHR5 gene, a protein related to the complement regulatory factor H family. The disease seems to be prevalent only in people of Greek Cypriot descent. Because of the special variation of the internal replication of exon 2 and exon 3 of CFHR5 protein in the occurrence of disease, it has had a serious impact on local residents. At present, the mechanism of glomerular damage caused by CFHR5 protein mutations is still unclear. The purpose of this article is to review the clinical research advances of this disease in the past 10 years, including the study of mutant genes, the analysis of mutant proteins and the role of alternative pathways in glomerular injury. It covers the progress in diagnosis and clinical treatment of the disease and looks forward to the future development prospects of its treatment. It is hoped that the recent results will be summarized for the follow-up in-depth study of CFHR5 nephropathy.

Ultra-early electroacupuncture rehabilitation for intravenous thrombolysis-induced cerebral infarction.

OBJECTIVE: The purpose of this research was to investigate whether it is possible to perform ultra-early interventional electroacupuncture on individuals who had experienced intravenous thrombolysis prior to receiving therapy for acute cerebral infarction. PATIENTS AND METHODS: Patients who have undergone intravenous thrombolysis between July 2019 and March 2021 were eligible for participation in this study. The participants were divided into two groups; one group received electroacupuncture therapy 24 hours after their condition became stable, while the other group received treatment 48 hours after their condition became stable. Both groups received the same therapy for their respective forms of rehabilitation. The Fugl-Meyer Motion Assessment Scale (FMA) was used to assess the patients' motor function before and after therapy, as well as two weeks and one month after treatment. The scores of the FMA were recorded before and after treatment. RESULTS: After therapy, the FMI scores were higher in both groups (p<0.05), and the researchers found that the ultra-early electroacupuncture intervention was related to higher FMI ratings 2 weeks and 1 month after treatment (p<0.05). In neither of the two study groups was there any sign of a major adverse response or consequence (p>0.05). CONCLUSIONS: This research offers evidence that ultra-early interventional electroacupuncture rehabilitation therapy may be an effective and safe method of treatment for individuals who have had a cerebral infarction after receiving intravenous thrombolysis. The results lend credence to the notion that this kind of therapy should be taken into consideration as an adjunctive model for rehabilitation in patients of this type.

Concurrent Chemotherapy and Pelvic Radiation Therapy Compared With Pelvic Radiation Therapy Alone as Adjuvant Therapy After Radical Surgery in High-Risk Early-Stage Cancer of the Cervix.

PURPOSE: To determine whether the addition of cisplatin-based chemotherapy (CT) to pelvic radiation therapy (RT) will improve the survival of early-stage, high-risk patients with cervical carcinoma. PATIENTS AND METHODS: Patients with clinical stage IA2, IB, and IIA carcinoma of the cervix, initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic lymph nodes and/or positive margins and/or microscopic involvement of the parametrium were eligible for this study. Patients were randomized to receive RT or RT + CT. Patients in each group received 49.3 GY RT in 29 fractions to a standard pelvic field. Chemotherapy consisted of bolus cisplatin 70 mg/m2 and a 96-hour infusion of fluorouracil 1,000 mg/m2/d every 3 weeks for four cycles, with the first and second cycles given concurrent to RT. RESULTS: Between 1991 and 1996, 268 patients were entered onto the study. Two hundred forty-three patients were assessable (127 RT + CT patients and 116 RT patients). Progression-free and overall survival are significantly improved in the patients receiving CT. The hazard ratios for progression-free survival and overall survival in the RT only arm versus the RT + CT arm are 2.01 (P = .003) and 1.96 (P = .007), respectively. The projected progression-free survivals at 4 years is 63% with RT and 80% with RT + CT. The projected overall survival rate at 4 years is 71% with RT and 81% with RT + CT. Grades 3 and 4 hematologic and gastrointestinal toxicity were more frequent in the RT + CT group. CONCLUSION: The addition of concurrent cisplatin-based CT to RT significantly improves progression-free and overall survival for high-risk, early-stage patients who undergo radical hysterectomy and pelvic lymphadenectomy for carcinoma of the cervix.

[Comparative analysis of intestinal microbiota distribution characteristics based on metagenomics in patients with hepatitis B cirrhosis with or without ascites].

Objective: To use metagenomic sequencing to compare the differences in intestinal microbiota species and metabolic pathways in patients with hepatitis B cirrhosis with or without ascites and further explore the correlation between the differential microbiota and clinical indicators and metabolic pathways. Methods: 20 hepatitis B cirrhosis cases [10 without ascites (HBLC-WOA), 10 with ascites (HBLC-WA), and 5 healthy controls (HC)] were selected from the previously studied 16S rRNA samples. Metagenome sequencing was performed on the intestinal microbiota samples. The Kruskal-Wallis rank sum test and Spearman test were used to identify and analyse differential intestinal microbiota populations, metabolic pathways, and their correlations. Results: (1) The overall structure of the intestinal microbiota differed significantly among the three groups (R = 0.19, P = 0.018). The HC group had the largest abundance of Firmicutes and the lowest abundance of Proteobacteria at the genus level. Firmicutes abundance was significantly decreased (P(fdr) < 0.01), while Proteobacteria abundance was significantly increased (P(fdr) < 0.01) in patients with cirrhosis accompanied by ascites; (2) LEfSe analysis revealed that 29 intestinal microbiota (18 in the HBLC-WA group and 11 in the HBLC-WOA group) played a significant role in the disease group. The unclassified Enterobacteriaceae and Klebsiella species in the HBLC-WA group and Enterobacteriaceae in the HBLC-WOA group were positively correlated with the Child-Turcotte-Pugh (CTP) score, prothrombin time, and international normalized ratio score and negatively correlated with albumin and hemoglobin levels (P < 0.05). Escherichia and Shigella in the HBLC-WA group were positively correlated with CTP scores (P < 0.05); (3) The correlation analysis results between the KEGG pathway and 29 specific intestinal microbiota revealed that Enterobacteriaceae and arachidonic acid, α-linolenic acid, glycerolipid metabolism, and fatty acid degradation were positively correlated in the lipid metabolism pathway, while most Enterobacteriaceae were positively correlated with branched-chain amino acid degradation and negatively correlated with aromatic amino acid biosynthesis in the amino acid metabolic pathway. Conclusion: A significant increment of Enterobacteriaceae in the intestines of HBLC-WA patients influenced hepatic reserve function and was associated with amino acid and lipid metabolic pathways. Therefore, attention should be paid to controlling the intestinal microbiota to prevent complications and improve the prognosis in patients with hepatitis B cirrhosis, especially in those with ascites.

Clinical application of laparoscopic continuous interposition jejunostomy with double-tract anastomosis and esophagogastric anastomosis: a retrospective study.

OBJECTIVE: The aim of this study was to compare the early clinical outcomes of laparoscopic-assisted proximal gastrectomy with continuous interposition of jejunal cis-peristaltic dual-channel anastomosis and esophagogastric anastomosis. PATIENTS AND METHODS: A retrospective analysis of 130 patients who underwent laparoscopic-assisted radical resection of proximal gastric cancer in the Department of Gastrointestinal Surgery at the Affiliated Hospital of Chengde Medical College between June 2018 and October 2022 was conducted. Continuous interposition jejunal double-channel anastomosis (double-tract anastomosis) was used in 71 patients and esophagogastric anastomosis (esophagogastrostomy) in 59 patients. The basic clinical data, preoperative and postoperative clinical test indexes, postoperative complications and improvement of symptoms compared to preoperative ones, basic nutritional status and Visick classification of esophageal reflux symptoms at 6 months after surgery were compared between the two groups. Postoperative contrast images of patients in the continuous interposition jejunal double-tract group were collected and analyzed for the ratio of contrast agent remaining in the stomach to that remaining in the small intestinal channel. RESULTS: A total of 130 cases meeting the criteria were included in this study, including 71 cases involving the double-tract (DT) anastomosis method and 59 cases involving the esophagogastrostomy (EG) anastomosis method. There was no significant difference in preoperative information and perioperative safety between the two groups. Visick score of the DT group was significantly better than that of the EG group. CONCLUSIONS: Double-tract jejunal anastomosis can effectively improve esophageal reflux symptoms after proximal gastrectomy. At the same time, its anastomotic method also improves the nutritional status in the short term compared to the esophagogastric anastomosis and is a more ideal procedure for reconstructing the digestive tract after proximal gastrectomy.

Role of interferon alpha-inducible protein 6 in modulating the proliferation, apoptosis and senescence of oesophageal squamous cell carcinoma cells.

Oesophageal cancer is one of the most malignant tumors worldwide. Dysfunction of interferon alpha-inducible protein 6 (IFI6) has been implicated in numerous human diseases, including cancer. We performed the study to investigate the function and potential molecular pathways of IFI6 in oesophageal squamous cell carcinoma (ESCC) cells. IFI6 expression was analysed using databases-derived data and paraffin-embedded tissue samples. CCK-8-based analyses and EdU staining, colony formation, ß-galactosidase staining and Annexin V/PI double-staining assays were used to determine the influence of IFI6 on cell growth, senescence and apoptosis. Tumor growth in vivo was investigated in mouse xenograft models. RNA sequencing (RNA-seq) was performed to identify the transcripts and pathways affected by IFI6. The results showed that IFI6 expression was elevated in ESCC and correlated with poor clinical prognosis (P<0.05). IFI6 was overexpressed and silenced in TE-1 and TE-10 cells using lentiviruses. Upregulation of IFI6 promoted cell growth both in vitro and in vivo, whereas downregulation induced opposite effects. IFI6 overexpression inhibited cell senescence and apoptosis but did not influence cell cycle progression, while IFI6 downregulation increased cell senescence and apoptosis. RNA-seq revealed that 3 mRNAs (EPHA5, CLIP1 and GTF2F2) were consistently associated with both IFI6 overexpression and silencing. IFI6 appeared to modulate TE-1 cells via complex mechanisms. In conclusion, IFI6 plays a positive role in the proliferation of ESCC cells both in vitro and in vivo, which could be a novel therapeutic target for treating ESCC.

Genome-wide association study identifies variants associated with semen volume in white-feathered broilers.

Semen is a measure of the reproductive efficiency of roosters, which affects the economic benefits of white-feathered broilers. Over the years, research in this field has mainly focused on hens, while there have been fewer studies on the reproductive traits of roosters. To identify the genes related to the semen traits of roosters, we used a chicken 55 K SNP chip to genetically type the white-feathered population (220) and performed imputation with resequencing data from 97 roosters. In total, 1 048 576 SNPs were obtained and used for genome-wide association analysis of semen volume, from which 197 genome-wide significant markers were identified, all within the interval of 13.82-16.12 Mb on chromosome 7. By combining our results with the biological functions of genes in the interval, four candidate genes were identified that potentially relate to semen volume: FAPP1, OSBPL6, SESTD1 and SSFA2. Our findings may provide a basis for further research on the genetic mechanism and marker-assisted selection of semen volume in white-feathered broilers.

Osseointegration of photodynamic active biomaterials for bone regeneration in an animal bone model over a period of 12 months.

OBJECTIVES: Previous efforts led to the development of two different polymeric biomaterials for periodontal regeneration with antibacterial photodynamic surface activity. The present study aimed to investigate osseointegration and bone formation of both materials in an ovine model. METHODS: Both biomaterials: 1) urethane dimethacrylate-based Biomaterial 1 (BioM1) and 2) tri-armed oligoester-urethane methacrylate-based Biomaterial 2 (BioM2) are enriched with beta-tri-calcium phosphate and the photosensitizer meso-tetra(hydroxyphenyl)chlorin (mTHPC). These materials were implanted in non-critical size bone defects in the sheep femur (n = 16) and tibia (n = 8). Empty defects served as controls (n = 16). Polyfluorochrome sequential bone labeling was carried out at baseline and after 3, 6, and 12 months. Animals were sacrificed after 12 months. Bone specimens (n = 40) were fixed and subjected to microtomographic analysis (µCT) for the evaluation of the bone-volume-fraction (BV/TV), trabecular number and trabecular thickness. Subsequently, histological sections were arranged and polyfluorochrome sequential bone labeling was analyzed by confocal laser scanning microscopy (cLSM). RESULTS: cLSM analysis revealed that highest remodeling and bone formation activity occurred during the second half of the study period (6-12 months). Bone formation in the tibia was significantly lower for the control (2.71 ± 1.26%) as compared to BioM1 (6.01 ± 2.99%) and BioM2 (6.45 ± 2.12%); (p = 0.006, p = 0004). Micro-computed tomography revealed a BV/TV volume fraction of 44.72 ± 9.01% in femur defects filled with BioM1 which was significantly higher compared to the control (32.27 ± 7.02%; p = 0.01). Bone architecture (trabecular number, trabecular thickness) did not significantly differ from the self-healed defects. SIGNIFICANCE: Both biomaterials, especially BioM1 showed good osseointegration and bone formation characteristics and can be recommended for further examination in periodontal regeneration studies.

Immune-mediated hematological disease in dogs is associated with alterations of the fecal microbiota: a pilot study.

BACKGROUND: The dog is the most popular companion animal and is a valuable large animal model for several human diseases. Canine immune-mediated hematological diseases, including immune-mediated hemolytic anemia (IMHA) and immune thrombocytopenia (ITP), share many features in common with autoimmune hematological diseases of humans. The gut microbiome has been linked to systemic illness, but few studies have evaluated its association with immune-mediated hematological disease. To address this knowledge gap, 16S rRNA gene sequencing was used to profile the fecal microbiota of dogs with spontaneous IMHA and ITP at presentation and following successful treatment. In total, 21 affected and 13 healthy control dogs were included in the study. RESULTS: IMHA/ITP is associated with remodeling of fecal microbiota, marked by decreased relative abundance of the spirochete Treponema spp., increased relative abundance of the pathobionts Clostridium septicum and Escherichia coli, and increased overall microbial diversity. Logistic regression analysis demonstrated that Treponema spp. were associated with decreased risk of IMHA/ITP (odds ratio [OR] 0.24-0.34), while Ruminococcaceae UCG-009 and Christensenellaceae R-7 group were associated with increased risk of disease (OR = 6.84 [95% CI 2-32.74] and 8.36 [95% CI 1.85-71.88] respectively). CONCLUSIONS: This study demonstrates an association of immune-mediated hematological diseases in dogs with fecal dysbiosis, and points to specific bacterial genera as biomarkers of disease. Microbes identified as positive or negative risk factors for IMHA/ITP represent an area for future research as potential targets for new diagnostic assays and/or therapeutic applications.

Runx1-R188Q germ line mutation induces inflammation and predisposition to hematologic malignancies in mice.

Germ line mutations in the RUNX1 gene cause familial platelet disorder (FPD), an inherited disease associated with lifetime risk to hematopoietic malignancies (HM). Patients with FPD frequently show clonal expansion of premalignant cells preceding HM onset. Despite the extensive studies on the role of RUNX1 in hematopoiesis, its function in the premalignant bone marrow (BM) is not well-understood. Here, we characterized the hematopoietic progenitor compartments using a mouse strain carrying an FPD-associated mutation, Runx1R188Q. Immunophenotypic analysis showed an increase in the number of hematopoietic stem and progenitor cells (HSPCs) in the Runx1R188Q/+ mice. However, the comparison of Sca-1 and CD86 markers suggested that Sca-1 expression may result from systemic inflammation. Cytokine profiling confirmed the dysregulation of interferon-response cytokines in the BM. Furthermore, the expression of CD48, another inflammation-response protein, was also increased in Runx1R188Q/+ HSPCs. The DNA-damage response activity of Runx1R188Q/+ hematopoietic progenitor cells was defective in vitro, suggesting that Runx1R188Q may promote genomic instability. The differentiation of long-term repopulating HSCs was reduced in Runx1R188Q/+ recipient mice. Furthermore, we found that Runx1R188Q/+ HSPCs outcompete their wild-type counterparts in bidirectional repopulation assays, and that the genetic makeup of recipient mice did not significantly affect the clonal dynamics under this setting. Finally, we demonstrate that Runx1R188Q predisposes to HM in cooperation with somatic mutations found in FPDHM, using 3 mouse models. These studies establish a novel murine FPDHM model and demonstrate that germ line Runx1 mutations induce a premalignant phenotype marked by BM inflammation, selective expansion capacity, defective DNA-damage response, and predisposition to HM.

Is tirzepatide 15 mg the preferred treatment strategy for type 2 diabetes? A meta-analysis and trial-sequence-analysis.

OBJECTIVE: The study aims to evaluate tirzepatide's efficacy and safety in treating type 2 diabetes by meta-analysis and trial-sequential-analysis (TSA). MATERIALS AND METHODS: Eight databases were searched for clinical trials on tirzepatide for type 2 diabetes with a time limit of November 2022. Revman5.3 and TSA 0.9.5.10 Beta were selected for meta-analysis and TSA. RESULTS: Compared with placebo, the meta-analysis demonstrated that tirzepatide 15 mg reduced hemoglobin-type-A1C (HbA1c) (p<0.00001), fasting-serum-glucose (FSG) (p<0.00001), and weight (p<0.00001). Compared with insulin, tirzepatide 15 mg reduced HbA1c (p<0.00001), FSG (p<0.00007), and weight (p<0.00001). Compared with glucagon-like-peptide-1 receptor-agonist (GLP-1 RA), tirzepatide 15 mg reduced HbA1c (p=0.00004), FSG (p=0.001), and weight (p<0.00001). In safety endpoints, the meta-analysis revealed that adverse events (AEs) of placebo, insulin and GLP-1 RA were comparable to tirzepatide 15 mg. The total AEs (p=0.02) and gastrointestinal (GI) AEs (p=0.03) were higher in tirzepatide 15 mg than in the placebo, while hypoglycemia (<54 mg/dl) was comparable. The major adverse cardiovascular events-4 (MACE-4) (p=0.03) and hypoglycemia (<54 mg/dl) (p<0.00001) of tirzepatide 15 mg were lower when compared to insulin, while total AEs (p=0.03) were increased. Compared with GLP-1 RA, tirzepatide 15 mg was comparable in safety endpoints in total AEs and GI AEs, while hypoglycemia (<54 mg/dl) (p=0.04) was higher. TSA indicated that HgA1c, FSG, and weight benefits were conclusive. In safety endpoints, only MACE-4 and hypoglycemia (<54 mg/dl) of Tirzepatide 15 mg vs. Insulin were conclusive. Harbord regression of AEs suggested no evident publication bias (p=0.618). CONCLUSIONS: Tirzepatide 15 mg reduced HbA1c and weight more effectively than placebo, insulin, and GLP-1 RA. Total AEs were higher than placebo and insulin but comparable to GLP-1 RA. Tirzepatide 15 mg is a kind of optimal strategy to treat type 2 diabetes. However, there is a need to focus on GI AEs.

[Regulative effects of endogenous sulfur dioxide on oxidant stress in myocardium of rat with sepsis].

OBJECTIVE: To explore the modulating effect of endogenous sulfur dioxide (SO2) on the ba-lance of oxidation/reduction in the cecal-ligation-and-puncture-induced septic rat myocardium. METHODS: Forty male Sprague Dawley rats were randomized into control group, SO2group, sepsis group and sepsis + SO2group. The levels of procalcitonin (PCT), creatine kinase isoenzyme (CK-MB), cardiac troponin Ⅰ (cTn Ⅰ) and fatty acid binding protein (FABP) in plasma in each group of the rats were measured; The level of hydrogen peroxide (H2O2), level of nitric oxide (NO), activity of myeloperoxidase (MPO), activity of hydroxyl free radical (·OH) and level of malondialdehyde (MDA) in myocardial tissue were measured; Total antioxidant capacity (T-AOC), activity of catalase (CAT), level of cytochrome oxidase (CO), level of glutathione (GSH), level of glutathione oxidase (GSH-px) and activity of superoxide dismutase (SOD) in myocardial tissue were measured. RESULTS: The level of PCT in plasma in the rats with sepsis increased from (0.93±0.26) µg/L to (2.45±0.52) µg/L (P < 0.01), and decreased to (1.58±0.36) µg/L after the intervention of sulfur dioxide donor (P < 0.01). In sepsis, the plasma CK-MB, cTn Ⅰ and FABP levels in the rats increased respectively from (14.46±6.48) µg/L, (151.25±30.14) ng/L and (2.72±0.65) µg/L to (23.72±7.72) µg/L, (272.78±52.70) ng/L and (5.22±1.01) µg/L (P all < 0.01), and decreased to (16.74±3.63) µg/L, (184.86±37.72) µg/L and (3.31±0.84) µg/L (all P < 0.05) after the intervention of sulfur dioxide donor. The level of H2O2, level of NO, activity of MPO, activity of ·OH and level of MDA in myocardial tissue in the rats with sepsis increased respectively from (67.26±8.77) mmol/g, (38.39±6.93) µmol/g, (358.25±68.12) U/g, (648.42±93.69) U/ mg and (4.55±0.96) µmol/g to (111.45±17.35) mmol/g, (51.04±5.91) µmol/g, (465.88±76.76) U/g, (873.75±123.47) U/mg and (7.25±0.86) µmol/g (all P < 0.01), and decreased respectively to (75.99±10.52) mmol/g, (39.39±7.80) µmol/g, (393.17±51.5) U/g, (710.54±106.33) U/mg and (5.16±0.65) µmol/g after the intervention of the sulfur dioxide donor (all P < 0.05). The activity of T-AOC, activity of CAT, level of CO, level of GSH, level of GSH-px and activity of SOD in myocardial tissue in the rats with sepsis increased respectively from (2.07±0.37) U/mg, (169.25±36.86) U/g, (1.35±0.32) µmol/g, (103.51±16.62) µmol/g, (38.40±7.97) µmol/g and (38.50±8.30) U/mg to (1.42±0.39) U/mg, (98.44±26.56) U/g, (0.96±0.21) µmol/g, (68.05±7.35) µmol/ g, (23.83±5.04) µmol/g and (23.11±4.63) U/mg (P all < 0.01), and increased respectively to (1.83±0.37) U/mg, (146.14±31.63) U/g, (1.28±0.20) µmol/g, (92.10±11.84) µmol/g, (37.16±3.01) µmol/g and (37.29±2.62) U/mg (P all < 0.05) after the intervention of the sulfur dioxide donor. CONCLUSION: Endogenous SO2 can protect rat myocardium in sepsis by modulating the ba-lance of oxidation and reduction.