The Human Ganglioside Interactome in Live Cells Revealed Using Clickable Photoaffinity Ganglioside Probes.

Gangliosides, sialic acid bearing glycosphingolipids, are components of the outer leaflet of plasma membranes of all vertebrate cells. They contribute to cell regulation by interacting with proteins in their own membranes (cis) or their extracellular milieu (trans). As amphipathic membrane constituents, gangliosides present challenges for identifying their ganglioside protein interactome. To meet these challenges, we synthesized bifunctional clickable photoaffinity gangliosides, delivered them to plasma membranes of cultured cells, then captured and identified their interactomes using proteomic mass spectrometry. Installing probes on ganglioside lipid and glycan moieties, we captured cis and trans ganglioside-protein interactions. Ganglioside interactomes varied with the ganglioside structure, cell type, and site of the probe (lipid or glycan). Gene ontology revealed that gangliosides engage with transmembrane transporters and cell adhesion proteins including integrins, cadherins, and laminins. The approach developed is applicable to other gangliosides and cell types, promising to provide insights into molecular and cellular regulation by gangliosides.

Exploring the Comparability Between EQ-5D and the EQ Health and Wellbeing in the General Australian Population.

OBJECTIVES: The EQ Health and Wellbeing (EQ-HWB) is a novel measure that conceptually overlaps with the 5-level EQ-5D (EQ-5D-5L) while capturing broader dimensions of health and well-being. This study aimed to explore the extent to which the EQ-HWB and EQ-5D-5L capture overlapping or complementary constructs and to explore the discriminative ability of the EQ-HWB Short version (EQ-HWB-S) as a multiattribute utility instrument in the Australian setting. METHODS: A secondary analysis of data from a nationally representative cross-sectional survey of 2002 Australian adults was performed. The survey included socioeconomic questions and health characteristics and the EQ-HWB and EQ-5D-5L instruments. Convergent and known-group validity were evaluated through Spearman rank correlation and multivariable regression analyses, respectively. An exploratory factor analysis was also performed to explore the underlying constructs of the 2 measures. RESULTS: Correlation coefficients varied from moderate to strong (rs ≥ 0.40) between the EQ-5D-5L and the corresponding EQ-HWB dimensions (all P < .001). Based on the exploratory factor analysis, both instruments measure similar underlying constructs, with the EQ-HWB capturing broader aspects of well-being. The known-group analysis demonstrated the relative discriminative ability of the EQ-HWB-S in capturing broader aspects of health and well-being. CONCLUSIONS: The EQ-HWB was at least moderately correlated with the EQ-5D-5L in overlapping domains/dimensions and demonstrated greater sensitivity in participants with mental health problems versus the EQ-5D-5L. Our findings support future research exploring the value of the EQ-HWB-S as a multiattribute utility instrument for the general Australian population.

Co-inoculation of rhizobia and AMF improves growth, nutrient uptake, and cadmium resistance of black locust grown in sand culture.

Rhizobia and arbuscular mycorrhizal fungi (AMF) are symbiotic microorganisms important for plants grown in nutrient-deficient and heavy metal-contaminated soils. However, it remains unclear how plants respond to the coupled stress by heavy metal and nitrogen (N) deficiency under co-inoculation. Here, we investigated the synergistic effect of Mesorhizobium huakuii QD9 and Funneliformis mosseae on the response of black locust (Robinia pseudoacacia L.) grown in sand culture to cadmium (Cd) under N deficiency conditions. The results showed that single inoculation of AMF improved the growth and Cd resistance of black locust, co-inoculation improved the most. Compared to non-inoculated controls, co-inoculation mediated higher biomass and antioxidant enzyme activity, reduced oxidative stress, and promoted nodulation, mycorrhizal colonization, photosynthetic capacity, and N, P, Fe and Mg acquisition when exposed to Cd. This increase was significantly higher under N deficiency compared to N sufficiency. In addition, the uptake of Cd by co-inoculated black locust roots increased, but Cd translocation to the above-ground decreased under both N deficiency and sufficiency. Thus, in the tripartite symbiotic system, not merely metabolic processes but also Cd uptake increased under N deficiency. However, enhanced Cd detoxification in the roots and reduced allocation to the shoot likely prevent Cd toxicity and rather stimulated growth under these conditions.

Quantifying Methane Influx from Sewer into Wastewater Treatment Processes.

Wastewater treatment contributes substantially to methane (CH4) emissions, yet monitoring and tracing face challenges because the treatment processes are often treated as a "black box". Particularly, despite growing interest, the amount of CH4 carryover and influx from the sewer and its impacts on overall emissions remain unclear. This study quantified CH4 emissions from six wastewater treatment plants (WWTPs) across China, utilizing existing multizonal odor control systems, with a focus on Beijing and Guiyang WWTPs. In the Beijing WWTP, almost 90% of CH4 emissions from the wastewater treatment process were conveyed through sewer pipes, affecting emissions even in the aerobic zone of biological treatment. In the Guiyang WWTP, where most CH4 from the sewer was released at the inlet well, a 24 h online monitoring revealed CH4 fluctuations linked to neighborhood water consumption and a strong correlation to influent COD inputs. CH4 emission factors monitored in six WWTPs range from 1.5 to 13.4 gCH4/kgCODrem, higher than those observed in previous studies using A2O technology. This underscores the importance of considering CH4 influx from sewer systems to avoid underestimation. The odor control system in WWTPs demonstrates its potential as a cost-effective approach for tracing, monitoring, and mitigating CH4.

A regimen based on the combination of trimethoprim/sulfamethoxazole with caspofungin and corticosteroids as a first-line therapy for patients with severe non-HIV-related pneumocystis jirovecii pneumonia: a retrospective study in a tertiary hospital.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is a life-threatening and severe disease in immunocompromised hosts. A synergistic regimen based on the combination of sulfamethoxazole-trimethoprim (SMX-TMP) with caspofungin and glucocorticosteroids (GCSs) may be a potential first-line therapy for PJP. Therefore, it is important to explore the efficacy and safety of this synergistic therapy for treating non-HIV-related PJP patients. METHODS: We retrospectively analysed the data of 38 patients with non-HIV-related PJP at the First Affiliated Hospital of Xi'an Jiaotong University. Patients were divided into two groups: the synergistic therapy group (ST group, n = 20) and the monotherapy group (MT group, n = 18). All patients were from the ICU and were diagnosed with severe PJP. In the ST group, all patients were treated with SMX-TMP (TMP 15-20 mg/kg per day) combined with caspofungin (70 mg as the loading dose and 50 mg/day as the maintenance dose) and a GCS (methylprednisolone 40-80 mg/day). Patients in the MT group were treated only with SMX-TMP (TMP 15-20 mg/kg per day). The clinical response, adverse events and mortality were compared between the two groups. RESULTS: The percentage of patients with a positive clinical response in the ST group was significantly greater than that in the MT group (100.00% vs. 66.70%, P = 0.005). The incidence of adverse events in the MT group was greater than that in the ST group (50.00% vs. 15.00%, P = 0.022). Furthermore, the dose of TMP and duration of fever in the ST group were markedly lower than those in the MT group (15.71 mg/kg/day vs. 18.35 mg/kg/day (P = 0.001) and 7.00 days vs. 11.50 days (P = 0.029), respectively). However, there were no significant differences in all-cause mortality or duration of hospital stay between the MT group and the ST group. CONCLUSIONS: Compared with SMZ/TMP monotherapy, synergistic therapy (SMZ-TMP combined with caspofungin and a GCS) for the treatment of non-HIV-related PJP can increase the clinical response rate, decrease the incidence of adverse events and shorten the duration of fever. These results indicate that synergistic therapy is effective and safe for treating severe non-HIV-related PJP.

Colchicine disrupts bile acid metabolic homeostasis by affecting the enterohepatic circulation in mice.

Although the medicinal properties of colchicine (COL) have been widely known for centuries, its toxicity has been the subject of controversy. The narrow therapeutic window causes COL to induce gastrointestinal adverse effects even when taken at recommended doses, mainly manifested as nausea, vomiting, and diarrhea. However, the mechanism of COL-induced gastrointestinal toxic reactions remains obscure. In the present study, the mice were dosed with COL (2.5 mg/kg b.w./day) for a week to explore the effect of COL on bile acid metabolism and the mechanism of COL-induced diarrhea. The results showed that COL treatment affected liver biochemistry in mice, resulting in a significant down-regulation of the mRNA expression levels of bile acid biosynthesis regulators Cyp7a1, Cyp8b1, Cyp7b1, and Cyp27a1 in liver tissues. The mRNA expression levels of bile acid transporters Ntcp, Oatp1, Mrp2, Ibabp, Mrp3, Osta, and Ostb in liver and ileum tissues were also significantly down-regulated. In addition, COL treatment significantly inhibited the mRNA expression levels of Fxr and its downstream target genes Shp, Lrh1, and Fgf15 in liver and ileum tissues, affecting the feedback regulation of bile acid biosynthesis. More importantly, the inhibition of COL on bile acid transporters in ileal and hepatic tissues affected bile acid recycling in the ileum as well as their reuptake in the liver, leading to a significantly increased accumulation of bile acids in the colon, which may be an important cause of diarrhea. In conclusion, our study revealed that COL treatment affected bile acid biosynthesis and enterohepatic circulation, thereby disrupting bile acid metabolic homeostasis in mice.

Simulating the healthcare workforce impact and capacity for pancreatic cancer care in Victoria: a model-based analysis.

BACKGROUND: The incidence of pancreatic cancer is rising. With improvements in knowledge for screening and early detection, earlier detection of pancreatic cancer will continue to be more common. To support workforce planning, our aim is to perform a model-based analysis that simulates the potential impact on the healthcare workforce, assuming an earlier diagnosis of pancreatic cancer. METHODS: We developed a simulation model to estimate the demand (i.e. new cases of pancreatic cancer) and supply (i.e. the healthcare workforce including general surgeons, medical oncologists, radiation oncologists, pain medicine physicians, and palliative care physicians) between 2023 and 2027 in Victoria, Australia. The model compares the current scenario to one in which pancreatic cancer is diagnosed at an earlier stage. The incidence of pancreatic cancer in Victoria, five-year survival rates, and Victoria's population size were obtained from Victorian Cancer Registry, Cancer Council NSW, and Australian Bureau of Statistics respectively. The healthcare workforce data were sourced from the Australian Government Department of Health and Aged Care's Health Workforce Data. The model was constructed at the remoteness level. We analysed the new cases and the number of healthcare workforce by profession together to assess the impact on the healthcare workforce. RESULTS: In the status quo, over the next five years, there will be 198 to 220 stages I-II, 297 to 330 stage III, and 495 to 550 stage IV pancreatic cancer cases diagnosed annually, respectively. Assuming 20-70% of the shift towards pancreatic cancer's earlier diagnosis (shifting from stage IV to stages I-II pancreatic cancer within one year), the stages I-II cases could increase to 351 to 390 or 598 to 665 per year. The shift to early diagnosis led to substantial survival gains, translating into an additional 284 or 795 out of 5246 patients with pancreatic cancer remaining alive up to year 5 post-diagnosis. Workforce supply decreases significantly by the remoteness levels, and remote areas face a shortage of key medical professionals registered in delivering pancreatic cancer care, suggesting travel necessities by patients or clinicians. CONCLUSION: Improving the early detection and diagnosis of pancreatic cancer is expected to bring significant survival benefits, although there are workforce distribution imbalances in Victoria that may affect the ability to achieve the anticipated survival gain.

Pubertal exposure to Microcystin-LR arrests spermatogonia proliferation by inducing DSB and inhibiting SIRT6 dependent DNA repair in vivo and in vitro.

The reproduction toxicity of pubertal exposure to Microcystin-LR (MC-LR) and the underlying mechanism needs to be further investigated. In the current study, pubertal male ICR mice were intraperitoneally injected with 2 µg/kg MC-LR for four weeks. Pubertal exposure to MC-LR decreased epididymal sperm concentration and blocked spermatogonia proliferation. In-vitro studies found MC-LR inhibited cell proliferation of GC-1 cells and arrested cell cycle in G2/M phase. Mechanistically, MC-LR exposure evoked excessive reactive oxygen species (ROS) and induced DNA double-strand break in GC-1 cells. Besides, MC-LR inhibited DNA repair by reducing PolyADP-ribosylation (PARylation) activity of PARP1. Further study found MC-LR caused proteasomal degradation of SIRT6, a monoADP-ribosylation enzyme which is essential for PARP1 PARylation activity, due to destruction of SIRT6-USP10 interaction. Additionally, MG132 pretreatment alleviated MC-LR-induced SIRT6 degradation and promoted DNA repair, leading to the restoration of cell proliferation inhibition. Correspondingly, N-Acetylcysteine (NAC) pre-treatment mitigated the disturbed SIRT6-USP10 interaction and SIRT6 degradation, causing recovered DNA repair and subsequently restoration of cell proliferation inhibition in MC-LR treated GC-1 cells. Together, pubertal exposure to MC-LR induced spermatogonia cell cycle arrest and sperm count reduction by oxidative DNA damage and simultaneous SIRT6-mediated DNA repair failing. This study reports the effect of pubertal exposure to MC-LR on spermatogenesis and complex mechanism how MC-LR induces spermatogonia cell proliferation inhibition.

Prevalence and associated factors of chemotherapy-related cognitive impairment in older breast cancer survivors.

AIMS: To examine the prevalence and associated factors of chemotherapy-related cognitive impairment (CRCI) in older breast cancer survivors (BCS). DESIGN: Systematic review. DATA SOURCES: We searched EMBASE, PubMed, PsychInfo, CINAHL, Cochrance Library, Web of Science, CNKI and SinoMed, without language restrictions, for studies published from the establishment of the database to September 2022. REVIEW METHODS: Two researchers independently examined the full texts, data extraction and quality assessment, and any discrepancies were resolved through discussion with a third reviewer. Quality of evidence was assessed using the Newcastle-Ottawa Scale and the Agency for Healthcare Research and Quality Scale. RESULTS: The seven included studies showed that the estimated prevalence of CRCI in older BCS ranged from 18.6% to 27% on objective neuropsychological tests and from 7.6% to 49% on subjective cognitive assessments. The areas most affected were attention, memory, executive functioning and processing speed. CRCI was associated with 10 factors in six categories, including sociodemographic (e.g. age, education level), physiological (e.g. sleep disorders, fatigue and comorbidities), psychological (e.g. anxiety, depression), treatment modalities (e.g. chemotherapy cycles, chemotherapy regimens), genetic (e.g. APOE2, APOE4) and lifestyle factor (e.g. physical inactivity). CONCLUSION: CRCI is multifactorial and has a relatively high prevalence. However, the results of subjective and objective cognitive examinations were inconsistent, possibly due to variations in tools used to evaluate different definitions of CRCI. Nevertheless, as there are few published studies of older BCS, this conclusion still require verification by well-designed studies in the future. IMPACT: We found that the prevalence of CRCI in older adults is relatively high and multifactorial, providing evidence for further health care for this population. NO PATIENT OR PUBLIC CONTRIBUTION: There was no patient or public involvement.

Transport and retention of ciprofloxacin with presence of multi-walled carbon nanotubes in the saturated porous media: impacts of ionic strength and cation types.

The environmental fate and risks of ciprofloxacin (CIP) in the subsurface have raised intensive concerns. Herein, the transport behaviors of CIP in both saturated quartz sand and sand/multi-walled carbon nanotubes (MWCNTs) mixtures under different solution ionic strength of the solution and coexisting cation types were investigated. Batch adsorption experiments highlighted growing adsorptive capacity for CIP with the increasing content of MWCNTs in the MWCNTs-quartz sand mixtures (from 0.5% to 1.5%, w/w). Breakthrough curves (BTCs) of CIP in the MWCNTs-quartz sand mixtures were well fitted by the two-site chemical nonequilibrium model (R2 > 0.833). The estimated retardation factors for CIP increased from 9.68 to 282 with growing content of MWCNTs in the sand column, suggesting the presence of MWCNTs significantly inhibited the transport of CIP in saturated porous media. Moreover, the values of retardation factors are negatively correlated with the ionic strength and higher ionic strength could facilitate the transport of CIP in the saturated porous media. Compared with monovalent cations (Na+), the presence of divalent cations (Ca2+) significantly facilitated the transport of CIP in the columns due to the complexation between CIP and Ca2+ as well as deposition of MWCNTs aggregates on the sand surface. Results regarding CIP retention in columns indicated that MWCNTs could enhance the accumulation of CIP in the layers close to the influent of sand columns, while they could hinder upward transport of CIP to the effluent. This study improves our understanding for transport behaviors and environmental risk assessments of CIP in the saturated porous media with MWCNTs.

Rugby Fans in Training New Zealand (RUFIT NZ): a randomized controlled trial to assess the effectiveness of a healthy lifestyle program for overweight men delivered through professional rugby clubs.

BACKGROUND: A healthy lifestyle program that appeals to, and supports, overweight and obese New Zealand (NZ) European, Maori (indigenous) and Pasifika men to achieve weight loss is urgently needed. A pilot program inspired by the successful Football Fans in Training program but delivered via professional rugby clubs in NZ (n = 96) was shown to be effective in weight loss, adherence to healthy lifestyle behaviors, and cardiorespiratory fitness in overweight and obese men. A full effectiveness trial is now needed. AIMS: To determine the effectiveness and cost effectiveness of Rugby Fans In Training-NZ (RUFIT-NZ) on weight loss, fitness, blood pressure, lifestyle change, and health related quality of life (HRQoL) at 12- and 52-weeks. METHODS: We conducted a pragmatic, two-arm, multi-center, randomized controlled trial in NZ with 378 (target 308) overweight and obese men aged 30-65 years, randomized to an intervention group or wait-list control group. The 12-week RUFIT-NZ program was a gender-sensitised, healthy lifestyle intervention delivered through professional rugby clubs. Each intervention session included: i) a 1-h workshop-based education component focused on nutrition, physical activity, sleep, sedentary behavior, and learning evidence-based behavior change strategies for sustaining a healthier lifestyle; and 2) a 1-h group-based, but individually tailored, exercise training session. The control group were offered RUFIT-NZ after 52-weeks. The primary outcome was change in body weight from baseline to 52-weeks. Secondary outcomes included change in body weight at 12-weeks, waist circumference, blood pressure, fitness (cardiorespiratory and musculoskeletal), lifestyle behaviors (leisure-time physical activity, sleep, smoking status, and alcohol and dietary quality), and health-related quality of life at 12- and 52-weeks. RESULTS: Our final analysis included 200 participants (intervention n = 103; control n = 97) who were able to complete the RUFIT-NZ intervention prior to COVID-19 restrictions. At 52-weeks, the adjusted mean group difference in weight change (primary outcome) was -2.77 kg (95% CI -4.92 to -0.61), which favored the intervention group. The intervention also resulted in favorable significant differences in weight change and fruit and vegetable consumption at 12-weeks; and waist circumference, fitness outcomes, physical activity levels, and health-related quality of life at both 12 and 52 weeks. No significant intervention effects were observed for blood pressure, or sleep. Incremental cost-effective ratios estimated were $259 per kg lost, or $40,269 per quality adjusted life year (QALY) gained. CONCLUSION: RUFIT-NZ resulted in sustained positive changes in weight, waist circumference, physical fitness, self-reported physical activity, selected dietary outcomes, and health-related quality of life in overweight/obese men. As such, the program should be recommended for sustained delivery beyond this trial, involving other rugby clubs across NZ. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry, ACTRN12619000069156. Registered 18 January 2019, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376740 Universal Trial Number, U1111-1245-0645.

Modelling the Long-Term Health Outcome and Costs of Thrombectomy in Treating Stroke Patients with Large Ischaemic Core: Comparison between Clinical Trials and Real-World Data.

INTRODUCTION: We aimed to assess the long-term health outcomes and costs of endovascular thrombectomy (EVT) using clinical trials and real-world evidence in patients with large ischaemic core. METHODS: Both clinical trials and the INternational Stroke Perfusion Imaging REgistry (INSPIRE) were used. Patients with acute computed tomography perfusion scan with an ischaemic core of ≥70 mL were included. A Markov model was constructed to simulate the long-term costs and health outcomes (quality-adjusted life year) post-index stroke. Effectiveness of EVT (modified Rankin scale score at 3 months) was derived from the trials and INSPIRE registry (compared to matched patients not treated with EVT), respectively. RESULTS: Based on the trial and real-world data, the overall results revealed varied health benefits and costs due to EVT, with reduced health benefits and increased costs from EVT treatment in everyday practice. The long-term simulation estimated that offering EVT to large vessel occlusion stroke patients with large ischaemic core was associated with greater benefits (1.12 vs. 0.25 quality-adjusted life year gains) and lower (-A$19,320) or higher costs (A$11,278), using trial and real-world data, respectively. The incremental cost of the EVT procedure (i.e., A$14,356) could be primarily offset to a different extent by the reduction in costs related to the nursing home care (-$31,986 vs. -A$1,874) in the clinical trial and real-world practice. CONCLUSIONS: Our results highlight the potential gaps when implementing an effective intervention in the real world and the importance of the rigorous selection of large infarct core patients for EVT.

Cost-Effectiveness of Endovascular Thrombectomy in M2 Occlusion Stroke: Real-World Experience Versus Clinical Trials.

OBJECTIVES: This study sought to establish the cost-effectiveness of endovascular thrombectomy (EVT) in M2 occlusions compared with patients who did not have EVT using both real-world and clinical trial evidence. METHODS: The effectiveness of EVT in M2 occlusions was informed by the International Stroke Perfusion Imaging Registry (INSPIRE, real-world data for a wide range of strokes) and HERMES collaboration, trial data. Patients who received EVT and non-EVT treatment from INSPIRE were matched according to baseline characteristics. A Markov model with 7 health states defined by the 3-month modified Rankin scale (mRS) was constructed. Endovascular thrombectomy and non-EVT-treated patients in real-world, and clinical trials were run through the Markov model separately to generate the results from a limited societal perspective. National statistics and published literature informed the long-term probability of recurrent stroke, mortality, costs of management post-stroke, non-medical care, and nursing home care. RESULTS: A total of 83 (42 EVT and 41 non-EVT) patients were matched of 278 (45 EVT and 233 non-EVT) patients in INSPIRE who had M2 occlusion stroke at presentation. The long-term simulation estimated that offering EVT to M2 occlusion stroke patients was associated with greater benefits (5.48 EVT vs 5.24 non-EVT quality-adjusted life year [QALY]) and higher costs (A$133 457 EVT vs A$126 127 non-EVT) compared with non-EVT treatment in real-world from a limited societal perspective. The incremental cost-effectiveness ratio (ICER) of EVT in real-world was A$29 981 (€19 488)/QALY. The analysis using the data from HERMES collaboration yielded consistent results for the EVT patients. Comparison with real-world cost-effectiveness analyses of EVT in internal carotid artery/middle cerebral artery-M1 (ICA/MCA-M1) occlusion suggested a potential reduced QALY gains and increased ICER in M2 occlusions. CONCLUSIONS: Our study suggested that the benefits gained from EVT in M2 occlusion stroke in the real-world were similar to that derived from the clinical trials. The clinical and cost benefits from EVT appeared to be reduced in M2 compared with that from the ICA/MCA-M1 occlusions. CLINICAL IMPACT: Our study has provided valuable insights into the clinical significance of endovascular therapy (EVT) in the context of M2 occlusion stroke within a real-world setting. It is noteworthy that our findings indicate that the benefits obtained from EVT in M2 occlusion stroke closely align with those observed in controlled clinical trials. However, it is essential to recognize that there is a reduction in the clinical and cost-related advantages when comparing M2 occlusions to more proximal ICA/MCA-M1 occlusions.

An Intersectional Approach to Quantifying the Impact of Geographic Remoteness and Health Disparities on Quality-Adjusted Life Expectancy: Application to Australia.

OBJECTIVES: An intersectional multilevel analysis of individual heterogeneity and discriminatory accuracy (MAIHDA) is a novel method for exploring the interaction between sociodemographic characteristics that affect health outcomes. This study explores the interaction between geographic remoteness and socioeconomic status on health outcomes in Australia from an intersectional perspective. METHODS: Data from a cross-sectional survey were matched with data from the Australian Bureau of Statistics and the Australian Institute of Health and Welfare. To explore the effect of health-related quality of life on life expectancy, quality-adjusted life expectancy (QALE) was estimated through applying utility values derived from the EQ-5D-5L to life table data from the Australian Bureau of Statistics. The effect of geographic remoteness on QALE was quantified using multivariable linear regression. An intersectional MAIHDA was performed to explore differences in mean QALE across strata formed by intersections of age, sex, and Socioeconomic Indexes for Areas score. RESULTS: Based on multivariable linear modeling, QALE declined significantly with increasing remoteness (inner regional, -1.0 years [undiscounted]; remote/very remote, -3.3 years [undiscounted]) (P < .001). In contrast, life expectancy was only significantly different between participants in remote/very remote areas and major cities (ß-coefficient, -2.4; 95% CI -4.4 to -0.4; P = .016). No intersectional interaction effects between strata on QALE were found in the MAIHDA. CONCLUSIONS: QALE has considerable value as a metric for exploring disparities in health outcomes. Given that no intersectional interactions were identified, our findings support broad interventions that target the underlying social determinants of health appropriately reduce disparities versus interventions targeting intersectional interactions.

Body mass index affects the association between plasma lipids and peripheral eosinophils in a general chinese population: a cross-sectional survey.

BACKGROUND: Lipid metabolism affects type 2 immunity; however, the association between plasma lipids and eosinophilic inflammation in humans is uncertain. This study analysed the relationship between plasma lipids and peripheral eosinophils and whether patterns differ with different body mass indexes (BMI). METHODS: A cross-sectional survey including 62,441 healthy participants recruited from a regular health screening programme was conducted. Participants were divided into normal weight, overweight and obese subgroups according to BMI. RESULTS: Multiple linear regression analysis revealed that elevated logarithmic-transformed eosinophil counts (log(EOS)) significantly correlated with high total cholesterol(TC), triglyceride(TG), low-density lipoprotein-cholesterol (LDL-C), and low high-density lipoprotein-cholesterol (HDL-C)levels in the overall population, as well as in men and women, while certain associations between peripheral blood eosinophil percentage and serum lipids varied by gender. These correlations existed across almost all BMI subgroups, and standardised ß values decreased sequentially with increasing BMI. HDL-C had the most significant effect on eosinophils in obese women. Two-factor analysis of variance showed log(EOS) increased with higher BMI and hyperlipidemia whether in male or female and a synergistic effect exists of lipid levels (TG and LDL-C) and BMI in men. CONCLUSIONS: Blood eosinophil counts were correlated with blood lipid levels and modified by body mass index status. The effects of lipid levels and body mass index on blood eosinophil counts were synergistic. Therefore, lipid metabolism may be involved in systemic eosinophil inflammation.

Characteristics and prognostic implications of peripheral blood lymphocyte subsets in patients with anti-MDA5 antibody positive dermatomyositis-interstitial lung disease.

OBJECTIVES: To examine the characteristics of blood lymphocyte subsets in dermatomyositis-interstitial lung disease (DM-ILD) inflicted patients with positive anti-melanoma differentiation-associated gene 5 (anti-MDA5), as well as its prognosis value in this set of patients. METHODS: Data were retrospectively collected from 253 DM-ILD patients from three hospitals in China between January 2016 to January 2021. Patients were grouped into anti-MDA5 antibody positive group (MDA5+ DM-ILD) and anti-MDA5 antibody negative group (MDA5- DM-ILD) based on myositis-specific autoantibody test results. Demographic characteristics, lymphocyte subsets patterns and other clinical features were compared between the two groups. The association of lymphocyte subsets with 180-day mortality was investigated using survival analysis in MDA5+ DM-ILD. RESULTS: Out of 253 eligible patients with DM-ILD, 59 patients were anti-MDA5+ and 194 were anti-MDA5-. Peripheral blood lymphocyte count, CD3+ count, percentage of CD3+, CD3+CD4+ count, and CD3+CD8+ count was lower in MDA5+ DM-ILD than in MDA5- DM-ILD- (all P < 0.001) as well as CD3-CD19+ count (P = 0.04). In MDA5+ DM-ILD, CD3+CD8+ count ≤ 49.22 cell/µL (HR = 3.81, 95%CI [1.20,12.14]) and CD3-CD19+ count ≤ 137.64 cell/µL (HR = 3.43, 95%CI [1.15,10.24]) were independent predictors of mortality. CD3+CD8+ count ≤ 31.38 cell/µL was associated with a higher mortality risk in all DM-ILD patients (HR = 8.6, 95%CI [2.12,31.44]) after adjusting for anti-MDA5 and other clinical characteristics. CONCLUSION: Significant lymphocytes decrease was observed in MDA5+ DM-ILD patients. CD3+CD8+ cell count was associated with worse prognosis in both MDA5+ DM-ILD and all DM-ILD patients.

Social frailty as a predictor of adverse outcomes among older adults: a systematic review and meta-analysis.

BACKGROUND: With the aging of the population, frailty has attracted much attention, and the social dimension of frailty, namely social frailty, has also attracted attention. Studies have shown that social frailty can bring some adverse effects to the elderly, such as physical and cognitive function. AIMS: To explore the risk of adverse health outcomes in older adults with social frailty compared with older adults with non-social frailty. METHODS: Five databases were systematically searched from inception to February 28, 2023. Screening, data extraction and quality assessment were conducted independently by two researchers. The included studies were longitudinal studies of adverse outcomes in community-dwelling socially frail older adults, and the quality of each study was assessed using the Newcastle‒Ottawa Scale. RESULTS: A total of 15 studies were included based on the inclusion criteria, of which 4 were subjected to meta-analysis. The mean age of the included population ranged from 66.3 to 86.5 years. According to existing research, social frailty was predictive of some adverse outcomes, such as incident disability, depressive symptoms, and reduced neuropsychological function. The meta-analysis showed that social frailty had a significant predictive effect on mortality among older adults [HR = 2.27, (95% CI = 1.03-5.00)]. CONCLUSION: In community-dwelling older adults, social frailty was a predictor of mortality, incident disability, depressive symptoms and other adverse outcomes. Social frailty had a negative impact on older adults, so it was necessary to strengthen the screening of social frailty to reduce the incidence of adverse outcomes.

Use of General Practitioner Telehealth Services During the COVID-19 Pandemic in Regional Victoria, Australia: Retrospective Analysis.

BACKGROUND: In March 2020, the Australian Government expanded general practitioner (GP) telehealth services in response to the COVID-19 pandemic. OBJECTIVE: This study sought to assess use patterns of GP telehealth services in response to changing circumstances (before and during the COVID-19 pandemic and with or without a lockdown) in regional Victoria, Australia. METHODS: We conducted a secondary analysis of monthly Medicare claims data from July 2019 to June 2021 from 140 regional GP practices in Western Victoria. The longitudinal patterns of proportion of GP telehealth consultations stratified by type of consultation (ie, videoconference vs telephone) and by geographical, consumer, and consultation characteristics were analyzed. RESULTS: Telehealth comprised 25.8% (522,932/2,025,615) of GP consultations over the 2-year period. After the introduction of the Australian telehealth expansion policy in March 2020, there was a rapid uptake in GP telehealth services (including telephone and video services), from 0% before COVID-19 to 15% (11,854/80,922) of all consultations in March 2020, peaking at 55% (50,828/92,139) in August 2020. Thereafter, the use of telehealth declined steadily to 31% (23,941/77,344) in January 2021 and tapered off to 28% (29,263/103,798) in June 2021. Telephone services and shorter consultations were the most dominant form, and those aged 15-64 years had higher telehealth use rates than younger or older age groups. The proportion of video consultations was higher during periods with government-imposed lockdowns and higher in the most socioeconomically advantaged areas compared to less socioeconomically advantaged areas. CONCLUSIONS: Our findings support the continuation of telehealth use in rural and regional Australia post pandemic. Future policy must identify mechanisms to reduce existing equity gaps in video consultations and consider patient- and system-level implications of the dominant use of short telephone consultations.

1-Nitropyrene disrupts testicular steroidogenesis via oxidative stress-evoked PERK-eIF2α pathway.

Our previous study showed 1-Nitropyrene (1-NP) exposure disrupted testicular testosterone synthesis in mouse, but the exact mechanism needs further investigation. The present research found 4-phenylbutyric acid (4-PBA), an endoplasmic reticulum (ER) stress inhibitor, recovered 1-NP-induced ER stress and testosterone synthases reduction in TM3 cells. GSK2606414, a protein kinase-like ER kinase (PERK) kinase inhibitor, attenuated 1-NP-induced PERK-eukaryotic translation initiation factor 2α (eIF2α) signaling activation and downregulation of steroidogenic proteins in TM3 cells. Both 4-PBA and GSK2606414 attenuated 1-NP-induced steroidogenesis disruption in TM3 cells. Further studies used N-Acetyl-L-cysteine (NAC) as a classical antioxidant to explore whether oxidative stress-activated ER stress mediated 1-NP-induced testosterone synthases reduction and steroidogenesis disruption in TM3 cells and mouse testes. The results showed NAC pretreatment mitigated oxidative stress, and subsequently attenuated ER stress, particularly PERK-eIF2α signaling activation, and downregulation of testosterone synthases in 1-NP-treated TM3 cells. More importantly, NAC extenuated 1-NP-induced testosterone synthesis in vitro and in vivo. The current work indicated that oxidative stress-caused ER stress, particularly PERK-eIF2α pathway activation, mediates 1-NP-downregulated steroidogenic proteins and steroidogenesis disruption in TM3 cells and mouse testes. Significantly, the current study provides a theoretical basis and demonstrates the experimental evidence for the potential application of antioxidant, such as NAC, in public health prevention, particularly in 1-NP-induced endocrine disorder.

Burden of Hypertensive Heart Disease and High Systolic Blood Pressure in Australia from 1990 to 2019: Results From the Global Burden of Diseases Study.

BACKGROUND: There is a dearth of comprehensive studies examining the burden and trends of hypertensive heart disease (HHD) and high systolic blood pressure (SBP) among the Australian population. We aimed to explore the burden of HHD and high SBP, and how they changed over time from 1990 to 2019 in Australia. METHODS: We analysed data from the Global Burden of Disease study in Australia. We assessed the prevalence, mortality, disability-adjusted life-years (DALY), years lived with disability (YLD) and years of life lost (YLL) attributable to HHD and high SBP. Data were presented as point estimates with 95% uncertainty intervals (UI). We compared the burden of HHD and high SBP in Australia with World Bank defined high-income countries and six other comparator countries with similar sociodemographic characteristics and economies. RESULTS: From 1990 to 2019, the burden of HHD and high SBP in Australia reduced. Age standardised prevalence rate of HHD was 119.3 cases per 100,000 people (95% UI 86.6-161.0) in 1990, compared to 80.1 cases (95% UI 57.4-108.1) in 2019. Deaths due to HDD were 3.4 cases per 100,000 population (95% UI 2.6-3.8) in 1990, compared to 2.5 (95% UI 1.9-3.0) in 2019. HHD contributed to 57.2 (95% UI 46.6-64.7) DALYs per 100,000 population in 1990 compared to 38.4 (95% UI 32.0-45.2) in 2019. Death rates per 100,000 population attributable to high SBP declined significantly over time for both sexes from 1990 (155.6 cases; 95% UI 131.2-177.0) to approximately one third in 2019 (53.8 cases; 95% UI 43.4-64.4). Compared to six other countries in 2019, the prevalence of HHD was highest in the USA (274.3%) and lowest in the UK (52.6%), with Australia displaying the third highest prevalence. Australia ranked second in term of lowest rates of deaths and third for lowest DALYs respectively due to high SBP. From 1990-2019, Australia ranked third best for reductions in deaths and DALYs due to HHD and first for reductions in deaths and DALYs due to high SBP. CONCLUSION: Over the past three decades, the burden of HHD in Australia has reduced, but its prevalence remains relatively high. The contribution of high SBP to deaths, DALYs and YLLs also reduced over the three decades.