Predictors of persistent opioid use in Australian primary care: A retrospective cohort study, 2018-2022.

OBJECTIVE: To examine the predictors of persistent opioid use ('persistence') in people initiating opioids for non-cancer pain in Australian primary care. DESIGN: A retrospective cohort study. SETTING: Australian primary care. SUBJECTS: People prescribed opioid analgesics between 2018-2022, identified through the Population Level Analysis and Reporting (POLAR) database. METHODS: Persistence was defined as receiving opioid prescriptions for at least 90 days with a gap of less than 60 days between subsequent prescriptions. Multivariable logistic regression was used to examine the predictors of persistent opioid use. RESULTS: The sample consisted of 343,023 people initiating opioids for non-cancer pain; of these, 16,527 (4.8%) developed persistent opioid use. Predictors of persistence included older age (≥75 vs 15-44 years: Adjusted odds ratio: 1.67, 95% CI: 1.58-1.78), concessional beneficiary status (1.78, 1.71-1.86), diagnosis of substance use disorder (1.44, 1.22-1.71) and chronic pain (2.05, 1.85-2.27), initiation of opioid therapy with buprenorphine (1.95, 1.73-2.20) and long-acting opioids (2.07, 1.90-2.25), provision of higher quantity of opioids prescribed at initiation (total OME of ≥ 750mg vs < 100mg: 7.75, 6.89-8.72), provision of repeat/refill opioid prescriptions at initiation (2.94, 2.77-3.12), and prescription of gabapentinoids (1.59, 1.50-1.68), benzodiazepines (1.43, 1.38-1.50) and z-drugs (e.g., zopiclone, zolpidem; 1.61, 1.46-1.78). CONCLUSIONS: These findings add to the limited evidence of individual-level factors associated with persistent opioid use. Further research is needed to understand the clinical outcomes of persistent opioid use in people with these risk factors to support the safe and effective prescribing of opioids.

Intraoperative radiotherapy: An alternative to whole-breast external beam radiotherapy in the management of highly selective breast cancer: A SEER database analysis.

OBJECTIVE: This study aimed to verify if intraoperative radiotherapy (IORT) can achieve the same survival outcome as whole-breast external beam radiotherapy (EBRT) in early breast cancer after breast-conserving surgery (BCS), and to explore the suitable candidates that can safely receive IORT after BCS. METHODS: Eligible post-BCS patients who received IORT or EBRT were included in the Surveillance, Epidemiology and End Results (SEER) database from 2010 to 2018. Risk factors that affected 5-year overall survival (OS) or breast cancer specific survival (BCSS) were identified by Cox proportional hazards regression analysis. Clinical characteristics, OS, and BCSS were comparatively analyzed between the two treatment modalities. RESULTS: The survival analysis after propensity score matching confirmed that patients who received IORT (n = 2200) had a better 5-year OS than those who received EBRT (n = 2200) (p = 0.015). However, the two groups did not differ significantly in 5-year BCSS (p = 0.381). This feature persisted even after multivariate analyses that took into account numerous clinical characteristics. Although there was no significant difference in BCSS between different subgroups of patients treated with IORT or EBRT, patients over 55 years of age, with T1, N0, non-triple negative breast cancers, hormone receptor-positive, and histologic grade II showed a better OS after receiving IORT. CONCLUSION: In low-risk, early-stage breast cancer, IORT was not inferior to EBRT considering 5-year BCSS and OS. Considering the equivalent clinical outcome but less radiotoxicity, IORT might be a reasonable alternative to EBRT in highly selective patients undergoing BCS.

The effects of exoskeleton use on human response to simulated overhead tasks with vibration.

The use of occupational exoskeletons has grown fast in manufacturing industries in recent years. One major scenario of exoskeleton use in manufacturing is to assist overhead, power hand tool operations. This preliminary work aimed to determine the effects of arm-supporting exoskeletons on shoulder muscle activity and human-hand tool coupling in simulated overhead tasks with axially applied vibration. An electromagnetic shaker capable of producing the random vibration spectrum specified in ISO 10819 was hung overhead to deliver vibrations. Two passive, arm-supporting exoskeletons, with one (ExoVest) transferring load to both the shoulder and pelvic region while the second one (ExoStrap) transferring load primarily to the pelvic region, were used in testing. Testing was also done with the shaker placed in front of the body to better understand the posture and exoskeleton engagement effects. The results collected from 6 healthy male subjects demonstrate the dominating effects of the overhead working posture on increased shoulder muscle activities. Vibration led to higher muscle activities in both agonist and antagonist shoulder muscles to a less extent. Exoskeleton use reduced the anterior deltoid and serratus anterior activities by 27% to 43%. However, wearing the ExoStrap increased the upper trapezius activities by 23% to 38% in the overhead posture. Furthermore, an increased human-shaker handle coupling was observed in the OH posture when wearing the ExoVest, indicating a more demanding neuromuscular control.

The current work sought to understand exoskeleton use in overhead tasks with power hand tools. The study findings demonstrate that vibration didn't alter the effects of arm-supporting exoskeletons on shoulder muscle activities in overhead tasks with vibration, though exoskeleton use may complicate human-hand tool coupling and corresponding neuromuscular control.

Faculty standardized patients versus traditional teaching method to improve clinical competence among traditional Chinese medicine students: a prospective randomized controlled trial.

BACKGROUND: Standardized patients (SPs) simulation training models have been widely used in various fields, the study of using SPs in Traditional Chinese medicine (TCM) is still a new filed. Previous studies have demonstrated the effectiveness of occupational SP for TCM (OSP-TCM), which has an increasingly problem of high time and financial costs. The faculty SPs for TCM (FSP-TCM) simulation training model may provide a better alternative. This study aims to test and determine whether FSP-TCM simulations are more cost-effective than OSP-TCM and traditional educational models to improve the clinical competence of TCM students. METHODS: This study was a single-blind, prospective, randomized controlled trial conducted between February 2023 and October 2023. The participants were randomized into FSP-TCM group, OSP-TCM group and traditionally taught group (TT group) in the ratio of 1:1:1. The duration of this training program was 12 weeks (36 credit hours). Formative and summative assessments were integrated to evaluate the effectiveness of teaching and learning. Three distinct questionnaires were utilized to collect feedback from students, SPs, and teachers at the conclusion of the course. Additionally, analysis of cost comparisons between OSP-TCM and FSP-TCM were performed in the study. RESULTS: The study comprised a total of 90 students, with no dropouts during the research. In the formative evaluation, students assigned to both the FSP-TCM and OSP-TCM groups demonstrated higher overall scores compared to those in the TT group. Notably, their performance in "physical examination" (Pa = 0.01, Pb = 0.04, Pc = 0.93) and "comprehensive ability" (Pa = 0.01, Pb = 0.006, Pc = 0.96) significantly exceeded that of the TT group. In the summary evaluation, both SP-TCM groups students outperforms TT group in the online systematic knowledge test (Pa = 0.019, Pb = 0.04, Pc = 0.97), the application of TCM technology (Pa = 0.01, Pb = 0.03, Pc = 0.93) and real-time assessment (Pa= 0.003, Pb = 0.01, Pc = 0.93). The feedback questionnaire demonstrated that both SP-TCM groups showed higher levels of agreement for this course in "satisfaction with the course" (Pa = 0.03; Pb = 0.02) and "enhanced TCM clinical skills" (Pa = 0.02; Pb = 0.03) than TT group. The SP questionnaire showed that more FSPs than OSPs in "provided professional feedback" (FSPs: strongly agree 30%, agree 50% vs. OSPs: strongly agree 20%, agree 40%. P = 0.69), and in "gave hints" during the course (FSPs: strongly agree 10%, agree 30% vs. OSPs: strongly agree 0%, agree 10%. P = 0.42). It is noteworthy that FSP-TCM was significantly lower than the OSP-TCM in overall expense (FSP-TCM $7590.00 vs. OSP-TCM $17415.60), and teachers have a positive attitude towards the FSP-TCM. CONCLUSION: FSP-TCM training mode showed greater effectiveness than traditional teaching method in improving clinical competence among TCM students. It was feasible, practical, and cost-effective, and may serve as an alternative method to OSP-TCM simulation.

Time trends in Alzheimer's disease mortality attributable to metabolic risks and smoking in China from 1990 to 2019: an age-period-cohort analysis.

Background: With the increase in the aging population worldwide, Alzheimer's disease has become a rapidly increasing public health concern. In the Global Burden of Disease Study 2019, there are three risk factors judged to have evidence for a causal link to Alzheimer's disease and other dementias: smoking, high body-mass index (HBMI), and high fasting plasma glucose (HFPG). Objective: This study aimed to analyze trends in AD mortality and the relevant burden across China from 1990 to 2019, as well as their correlation with age, period, and birth cohort. Methods: The data were extracted from the GBD 2019. Trends in AD mortality attributable to metabolic risks (HFPG and HBMI) and smoking were analyzed using Joinpoint regression. The age-period-cohort (APC) model was used to evaluate cohort and period effects. Results: From 1990 to 2019, the overall age-standardized mortality rate of AD increased, especially in women. There was an increase in AD mortality due to smoking in the net drift, and it was more significant in women (0.46, 95%CI = [0.09, 0.82]) than men (-0.03, 95%CI = [-0.11, 0.05]). For the cause of HFPG, the net drift values for men and women were 0.82% and 0.43%. For HBMI, the values were 3.14% and 2.76%, respectively, reflecting substantial increases in AD mortality. Conclusion: Time trends in AD mortality caused by metabolic risks and smoking in China from 1990 to 2019 have consistently increased. Therefore, it is necessary to prevent excessive weight gain and obesity during the later stages of life, especially for females.

Correlates of stocking naloxone: a cross-sectional survey of community pharmacists.

BACKGROUND: Provision of take-home naloxone (THN) and overdose education reduces opioid-related mortality. In Australia, from July 2022, all Australian community pharmacies were eligible to supply naloxone for free through the national THN Program. AIM: This study aimed to identify naloxone stocking rates and correlates of stocking naloxone across Australian pharmacies. METHOD: Data were collected from a representative sample of Australian pharmacists in Victoria, New South Wales, Queensland and Western Australia via an online survey. Data collected included pharmacy and pharmacist characteristics and services offered within the pharmacy, including needle and syringe programs, opioid agonist treatment (OAT) and stocking naloxone. Binary probit regression analysis was used to identify correlates of stocking naloxone after controlling for key covariates. RESULTS: Data from 530 pharmacists were analysed. In total, 321 pharmacies (60.6%) reported stocking naloxone. Chain pharmacies and pharmacies that provided OAT had a greater probability of stocking naloxone (B = 0.307, 95%CI: [0.057, 0.556], and B = 0.543, 95%CI: [0.308, 0.777] respectively). Most (61.7%) pharmacists felt comfortable discussing overdose prevention with patients who use prescription opioids, and this comfort was associated with a higher probability of stocking naloxone (B = 0.392, 95%CI: 0.128, 0.655). Comfort discussing overdose prevention with people who use illicit opioids was lower (49.4%) and was not associated with stocking naloxone. CONCLUSION: There is scope to increase stocking of naloxone and comfort with overdose prevention, particularly through addressing comfort working with higher risk groups such as people who use illicit opioids.

Application of HFO and scaling analysis of neuronal oscillations in the presurgical evaluation of focal epilepsy.

PURPOSE: To explore the utility of high frequency oscillations (HFO) and long-range temporal correlations (LRTCs) in preoperative assessment of epilepsy. METHODS: MEG ripples were detected in 59 drug-resistant epilepsy patients, comprising 5 with parietal lobe epilepsy (PLE), 21 with frontal lobe epilepsy (FLE), 14 with lateral temporal lobe epilepsy (LTLE), and 19 with mesial temporal lobe epilepsy (MTLE) to identify the epileptogenic zone (EZ). The results were compared with clinical MEG reports and resection area. Subsequently, LRTCs were quantified at the source-level by detrended fluctuation analysis (DFA) and life/waiting -time at 5 bands for 90 cerebral cortex regions. The brain regions with larger DFA exponents and standardized life-waiting biomarkers were compared with the resection results. RESULTS: Compared to MEG sensor-level data, ripple sources were more frequently localized within the resection area. Moreover, source-level analysis revealed a higher proportion of DFA exponents and life-waiting biomarkers with relatively higher rankings, primarily distributed within the resection area (p<0.01). Moreover, these two LRCT indices across five distinct frequency bands correlated with EZ. CONCLUSION: HFO and source-level LRTCs are correlated with EZ. Integrating HFO and LRTCs may be an effective approach for presurgical evaluation of epilepsy.

Trends in breast cancer mortality attributable to metabolic risks in Chinese women from 1990 to 2019: an age-period-cohort analysis.

Objective: Metabolic risks (MRs) are the primary determinants of breast cancer (BC) mortality among women. This study aimed to examine the changing trends in BC mortality associated with MRs and explore how they related to age, time period, and birth cohorts in Chinese women aged 25 and above. Methods: Data were sourced from the Global Burden of Disease Study 2019 (GBD2019). The BC mortality trajectories and patterns attributable to MRs were assessed using Joinpoint regression. The age-period-cohort (APC) model was employed to evaluate cohort and time period effects. Results: The age-standardized mortality rate (ASMR) of BC mortality linked to MRs displayed an escalating trend from 1990 to 2019, demonstrating an average annual percentage change (AAPC) of 1.79% (95% CI: 1.69~1.87). AAPCs attributable to high fasting plasma glucose (HFPG) and high body mass index (HBMI) were 0.41% (95% CI: 0.32~0.53) and 2.75% (95% CI: 2.68~2.82), respectively. APC analysis revealed that BC mortality due to HBMI in women aged 50 and above showed a rise with age and mortality associated with HFPG consistently demonstrated a positive correlation with age. The impact of HBMI on BC mortality significantly outweighed that of HFPG. The risk of BC mortality linked to HBMI has steadily increased since 2005, while HFPG demonstrated a trend of initial increase followed by a decrease in the period effect. Regarding the cohort effect, the relative risk of mortality was greater in the birth cohort of women after the 1960s of MRs on BC mortality, whereas those born after 1980 displayed a slight decline in the relative risk (RR) associated with BC mortality due to HBMI. Conclusion: This study suggests that middle-aged and elderly women should be considered as a priority population, and control of HBMI and HFPG should be used as a primary tool to control metabolic risk factors and effectively reduce BC mortality.

Stocking and supplying naloxone: Findings from a representative sample of community pharmacies in Victoria, Australia.

INTRODUCTION: Naloxone is an opioid receptor antagonist, which can rapidly reverse the effects of an opioid overdose. Community pharmacists may experience several barriers to stocking and supplying naloxone including a lack of confidence or knowledge and time constraints. The current study aimed to examine the extent to which Victorian community pharmacies stock and supply naloxone and determine specific characteristics associated with stocking naloxone. METHODS: A representative sample of community pharmacists (n = 558) in Victoria, Australia, were contacted between October and November 2020 and invited to participate in an online survey. Data related to pharmacy- and pharmacist-related characteristics, including stocking and frequency of supplying naloxone in the past year. Multivariate logistic regression analysis was performed to examine the effect of various covariates on stocking naloxone. RESULTS: The sample comprised 265 pharmacists (response rate 47%). Most pharmacies were located in Melbourne (the capital city of Victoria, 59.6%) and were part of a pharmacy chain (61.5%). In total, 100 (38%) pharmacies stocked naloxone, a third of whom did not supply it in the past year. Pharmacies that provided opioid agonist treatment had 2.4 times higher odds of stocking naloxone (95% confidence interval 1.425-4.136; p = 0.001). DISCUSSION AND CONCLUSION: Less than half of Victorian community pharmacies stock naloxone, with even fewer actually supplying it in the past year. Future efforts are needed to increase the number of pharmacies that stock naloxone and the frequency in which it is supplied, while also addressing possible barriers to stocking and supplying naloxone among community pharmacists.

Secular trends in gabapentinoid dispensing by compensated workers with low back pain: a retrospective cohort study.

OBJECTIVES: The increase in gabapentinoid prescribing is paralleling the increase in serious harms. To describe the low back pain workers compensation population whose management included a gabapentinoid between 2010 and 2017, and determine secular trends in, and factors associated with gabapentinoid use. METHODS: We analysed claim-level and service-level data from the Victorian workers' compensation programme between 1 January 2010 and 31 December 2017 for workers with an accepted claim for a low back pain injury and who had programme-funded gabapentinoid dispensing. Secular trends were calculated as a proportion of gabapentinoid dispensings per year. Poisson, negative binomial and Cox hazards models were used to examine changes over time in incidence and time to first dispensing. RESULTS: Of the 17 689 low back pain claimants, one in seven (14.7%) were dispensed at least one gabapentinoid during the first 2 years (n=2608). The proportion of workers who were dispensed a gabapentinoid significantly increased over time (7.9% in 2010 to 18.7% in 2017), despite a reduction in the number of claimants dispensed pain-related medicines. Gabapentinoid dispensing was significantly associated with an opioid analgesic or anti-depressant dispensing claim, but not claimant-level characteristics. The time to first gabapentinoid dispensing significantly decreased over time from 311.9 days (SD 200.7) in 2010 to 148.2 days (SD 183.1) in 2017. CONCLUSIONS: The proportion of claimants dispensed a gabapentinoid more than doubled in the period 2010-2017; and the time to first dispensing halved during this period.

Achyranthes bidentata polysaccharide ameliorates type 2 diabetes mellitus by gut microbiota-derived short-chain fatty acids-induced activation of the GLP-1/GLP-1R/cAMP/PKA/CREB/INS pathway.

Gut microbiota variances reflecting the severity type 2 diabetes mellitus (T2DM). Achyranthes bidentata polysaccharide (ABP) can regulate gut microbiota. However, the hypoglycemic effect and underlying mechanism of ABP remain unclear. Herein, we characterized the structure of ABP and revealed the hypoglycemic effect of ABP in mice with T2DM. ABP repaired the intestinal barrier in T2DM mice and regulated the composition and abundance of gut microbiota, especially increasing bacteria which producing short-chain fatty acids (SCFAs), then increasing glucagon-like peptide-1 (GLP-1) level. The abundance of these bacteria was positively correlated with blood lipid and INS levels, negatively correlated with FBG levels. Colon transcriptome data and immunohistochemistry demonstrated that the alleviating T2DM effect of ABP was related to activation of the GLP-1/GLP-1 receptor (GLP-1R)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-response element binding protein (CREB)/INS pathway. Fecal microbiota transplantation (FMT) confirmed the transmissible efficacy of ABP through gut microbiota. Overall, our research shows that ABP plays a hypoglycemic role by increasing gut microbiota-derived SCFAs levels, and activating the GLP-1/GLP-1R/cAMP/PKA/CREB/INS pathway, emphasizing ABP as promising T2DM therapeutic candidates.

ROS-Induced Gingival Fibroblast Senescence: Implications in Exacerbating Inflammatory Responses in Periodontal Disease.

Periodontal disease is the pathological outcome of the overwhelming inflammation in periodontal tissue. Cellular senescence has been associated with chronic inflammation in several diseases. However, the role of cellular senescence in the pathogenesis of periodontal disease remained unclear. This study aimed to investigate the role and the mechanism of cellular senescence in periodontal disease. Using single-cell RNA sequencing, we first found the upregulated level of cellular senescence in fibroblasts and endothelial cells from inflamed gingival tissue. Subsequently, human gingival fibroblasts isolated from healthy and inflamed gingival tissues were labeled as H-GFs and I-GFs, respectively. Compared to H-GFs, I-GFs exhibited a distinct cellular senescence phenotype, including an increased proportion of senescence-associated ß-galactosidase (SA-ß-gal) positive cells, enlarged cell morphology, and significant upregulation of p16INK4A expression. We further observed increased cellular reactive oxygen species (ROS) activity, mitochondrial ROS, and DNA damage of I-GFs. These phenotypes could be reversed by ROS scavenger NAC, which suggested the cause of cellular senescence in I-GFs. The migration and proliferation assay showed the decreased activity of I-GFs while the gene expression of senescence-associated secretory phenotype (SASP) factors such as IL-1ß, IL-6, TGF-ß, and IL-8 was all significantly increased. Finally, we found that supernatants of I-GF culture induced more neutrophil extracellular trap (NET) formation and drove macrophage polarization toward the CD86-positive M1 pro-inflammatory phenotype. Altogether, our findings implicate that, in the inflamed gingiva, human gingival fibroblasts acquire a senescent phenotype due to oxidative stress-induced DNA and mitochondrial damage, which in turn activate neutrophils and macrophages through the secretion of SASP factors.

Capture, Coding, and Reporting of Health Care and Medicine Information in Australian Workers' Compensation Systems.

OBJECTIVE: This study aims to characterize the approaches to collecting, coding, and reporting health care and medicines data within Australian workers' compensation schemes. METHODS: We conducted a cross-sectional survey of data and information professionals in major Australian workers' compensation jurisdictions. Questionnaires were developed with input from key informants and a review of existing documentation. RESULTS: Twenty-five participants representing regulators (40%) and insurers (60%) with representation from all Australian jurisdictions were included. Health care and medicines data sources, depth, coding standards, and reporting practices exhibited significant variability across the Australian workers' compensation schemes. CONCLUSIONS: Substantial variability exists in the capture, coding, and reporting of health care and medicine data in Australian workers' compensation jurisdictions. There are opportunities to advance understanding of medicines and health service delivery in these schemes through greater harmonization of data collection, data coding, and reporting.

The Critical Role of Pyroptosis in Peri-Implantitis.

Background: Peri-implantitis (PI) is a prevalent complication of implant treatment. Pyroptosis, a distinctive inflammatory programmed cell death, is crucial to the pathophysiology of PI. Despite its importance, the pyroptosis-related genes (PRGs) influencing PI's progression remain largely unexplored. Methods: This study conducted histological staining and transcriptome analyze from three datasets. The intersection of differentially expressed genes (DEGs) and PRGs was identified as pyroptosis-related differentially expressed genes (PRDEGs). Functional enrichment analyses were conducted to shed light on potential underlying mechanisms. Weighted Gene Co-expression Network Analysis (WGCNA) and a pyroptotic macrophage model were utilized to identify and validate hub PRDEGs. Immune cell infiltration in PI and its relationship with hub PRDEGs were also examined. Furthermore, consensus clustering was performed to identify new PI subtypes. Protein-protein interaction (PPI) network, competing endogenous RNA (ceRNA) network, mRNA-mRNA binding protein regulatory (RBP) network, and mRNA-drugs regulatory network of hub PRDEGs were also analyzed. Results: Eight hub PRDEGs were identified: PGF, DPEP1, IL36B, IFIH1, TCEA3, RIPK3, NET7, and TLR3, which are instrumental in the PI's progression. Two PI subtypes were distinguished, with Cluster 1 exhibiting higher immune cell activation. The exploration of regulatory networks provided novel mechanisms and therapeutic targets in PI. Conclusion: Our research highlights the critical role of pyroptosis and identifies eight hub PRDEGs in PI's progression, offering insights into novel immunotherapy targets and laying the foundation for advanced diagnostic and treatment strategies. This contributes to our understanding of PI and underscores the potential for personalized clinical management.

Comparison of the osteogenic potential of fibroblasts from different sources.

OBJECTIVE: With the growing interest in the role of fibroblasts in osteogenesis, this study presents a comparative evaluation of the osteogenic potential of fibroblasts derived from three distinct sources: human gingival fibroblasts (HGFs), mouse embryonic fibroblasts (NIH3T3 cells), and mouse subcutaneous fibroblasts (L929 cells). MC3T3-E1 pre-osteoblast cells were employed as a positive control for osteogenic behavior. DESIGN: Our assessment involved multiple approaches, including vimentin staining for cell origin verification, as well as ALP and ARS staining in conjunction with RT-PCR for osteogenic characterization. RESULTS: Our findings revealed the superior osteogenic differentiation capacity of HGFs compared to MC3T3-E1 and NIH3T3 cells. Analysis of ALP staining confirmed that early osteogenic differentiation was most prominent in MC3T3-E1 cells at 7 days, followed by NIH3T3 and HGFs. However, ARS staining at 21 days demonstrated that HGFs produced the highest number of calcified nodules, indicating their robust potential for late-stage mineralization. This late-stage osteogenic potential of HGFs was further validated through RT-PCR analysis. In contrast, L929 cells displayed no significant osteogenic differentiation potential. CONCLUSIONS: In light of these findings, HGFs emerge as the preferred choice for seed cells in bone tissue engineering applications. This study provides valuable insights into the potential utility of HGFs in the fields of bone tissue engineering and regenerative medicine.

A randomized trial of Bacteroides fragilis 839 on preventing chemotherapy-induced myelosuppression and gastrointestinal adverse effects in breast cancer patients.

BACKGROUND AND OBJECTIVES: To evaluate the potential benefits of Bacteroides fragilis 839 (BF839), a next-generation probiotics, in reducing myelosuppression and gastrointestinal toxicity associated with chemotherapy in breast cancer patient. METHODS AND STUDY DESIGN: 40 women with early breast cancer were randomly assigned to the BF839 (n=20) or placebo (n=20) during the administration of adjuvant chemotherapy (4 cycles of epirubicin 100mg/m2 and cyclophosphamide 600mg/m2). Myelosuppression and gastrointestinal adverse effects were monitored in both groups. RESULTS: Throughout the four treatment cycles, the percentage of patients experiencing myelosuppression was 42.5% in the BF839 group, significantly lower than the 66.3% observed in the control group (p=0.003). Two patients in the BF839 group and three patients in the placebo group received recombinant human granulocyte colony-stimulating factor (rhG-CSF) due to leuko-penia/neutropenia. When considering an ITT analysis, which included all patients regardless of rhG-CSF treatment, the BF839 group exhibited less reduction from baseline in white blood cells (-0.31±1.19 vs -1.15±0.77, p=0.012) and neutrophils (0.06±1.00 vs -0.84±0.85, p=0.004) compared to the placebo group. The difference became even more significant when excluding the patients who received rhG-CSF injections. Throughout the four treatment cycles, compared to the placebo group, the BF839 group had significantly lower rates of 3-4 grade nausea (35.0% vs 71.3%, p=0.001), vomiting (20.0% vs 45.0%, p=0.001), and diarrhea (15.0% vs 30.0%, p=0.023). CONCLUSIONS: These findings suggest that BF839 has the potential to effectively mitigate myelosuppression and gastrointestinal toxicity associated with chemotherapy in breast cancer patients.

Melanoidin-like carbohydrate-containing macromolecules from Shanxi aged vinegar exert immunoenhancing effects on macrophage RAW264.7 cells.

Bioactive macromolecule mining is important for the functional chemome analysis of traditional Chinese vinegar. In this study, we isolated and characterized carbohydrate-containing macromolecules from Shanxi aged vinegar (CCMSAV) and evaluated their immunomodulatory activity. The isolation process involved ethanol precipitation, deproteinization, decolorization, and DEAE-650 M column chromatography, resulting in the acquisition of four sub-fractions. All sub-fractions exhibited a molecular weight range of 6.92 to 16.71 kDa and were composed of 10 types of monosaccharides. Comparative analysis of these sub-fractions with two melanoidins exhibited similarities in elemental composition, spectral signature, and pyrolytic characteristics. Immunological assays confirmed the significantly enhanced cell viability, phagocytic activity, and secretion of nitric oxide, tumor necrosis factor (TNF)-α and interleukin (IL)-6 in RAW264.7 cells by all four sub-fractions. Further investigation of the immunomodulatory mechanism revealed that SAV-RP70-X, the most potent purified sub-fraction, enhanced aerobic glycolysis in macrophages and activated Toll-like receptor 2 (TLR2), TLR4, mannose receptor (MR), scavenger receptor (SR), and the dendritic cell-associated C-type lectin-1 receptor (Dectin-1). Furthermore, the activation of macrophages was associated with the MyD88/PI3K/Akt/NF-κB signaling pathway. Methylation analysis revealed that 1,4-Xylp was the most abundant glycosidic linkage in SAV-RP70-X.

S-nitrosoglutathione reductase-dependent p65 denitrosation promotes osteoclastogenesis by facilitating recruitment of p65 to NFATc1 promoter.

Osteoclasts, the exclusive bone resorptive cells, are indispensable for bone remodeling. Hence, understanding novel signaling modulators regulating osteoclastogenesis is clinically important. Nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) is a master transcription factor in osteoclastogenesis, and binding of NF-κB p65 subunit to NFATc1 promoter is required for its expression. It is well-established that DNA binding activity of p65 can be regulated by various post-translational modifications, including S-nitrosation. Recent studies have demonstrated that S-nitrosoglutathione reductase (GSNOR)-mediated protein denitrosation participated in cell fate commitment by regulating gene transcription. However, the role of GSNOR in osteoclastogenesis remains unexplored and enigmatic. Here, we investigated the effect of GSNOR-mediated denitrosation of p65 on osteoclastogenesis. Our results revealed that GSNOR was up-regulated during osteoclastogenesis in vitro. Moreover, GSNOR inhibition with a chemical inhibitor impaired osteoclast differentiation, podosome belt formation, and bone resorption activity. Furthermore, GSNOR inhibition enhanced the S-nitrosation level of p65, precluded the binding of p65 to NFATc1 promoter, and suppressed NFATc1 expression. In addition, mouse model of lipopolysaccharides (LPS)-induced calvarial osteolysis was employed to evaluate the therapeutic effect of GSNOR inhibitor in vivo. Our results indicated that GSNOR inhibitor treatment alleviated the inflammatory bone loss by impairing osteoclast formation in mice. Taken together, these data have shown that GSNOR activity is required for osteoclastogenesis by facilitating binding of p65 to NFATc1 promoter via promoting p65 denitrosation, suggesting that GSNOR may be a potential therapeutic target in the treatment of osteolytic diseases.

Association of state-level prescription drug monitoring program implementation with opioid prescribing transitions in primary care in Australia.

AIMS: This study aimed to evaluate whether voluntary and mandatory prescription drug monitoring program (PDMP) use in Victoria, Australia, had an impact on prescribing behaviour, focusing on individual patients' prescribed opioid doses and transition to prescribing of nonmonitored medications. METHODS: This was a retrospective cross-sectional study using routinely collected primary healthcare data. A 90-day moving average prescribed opioid dose in oral morphine equivalents was used to estimate opioid dosage. A Markov transition matrix was used to describe how patients prescribed medications transitioned between opioid dose groups and other nonopioid treatment options during 3 transition periods: transition between 2 control periods prior to PDMP implementation (T1 to T2); during the voluntary PDMP implementation (T2 to T3); and during mandatory PDMP implementation (T3 to T4). RESULTS: Among patients prescribed opioids in our study, we noted an increased probability of transitioning to not being prescribed opioids during the mandatory PDMP period (T3 to T4). This increase was attributed mainly to the ceasing of low-dose opioid prescribing. Membership in an opioid dose group remained relatively stable for most patients who were prescribed high opioid doses. For those who were only prescribed nonmonitored medications initially, the probability of being prescribed opioids increased during the mandatory PDMP when compared to other transition periods. CONCLUSION: The introduction of PDMP mandates appeared to have an impact on the prescribing for patients who were prescribed low-dose opioids, while its impact on individuals prescribed higher opioid doses was comparatively limited.