Global, regional, and national burdens of leukemia from 1990 to 2019: A systematic analysis of the global burden of disease in 2019 based on the APC model.

BACKGROUND: Leukemia is the tenth most common cause of cancer death worldwide and one of the most important causes of disability. To understand the current status and changing trends of the disease burden of leukemia at the global, regional, and national levels, and to provide a scientific basis for the development of leukemia prevention and treatment strategies. METHODS: Based on open data from the Global Burden of Disease Study 2019 (GBD 2019), R software was used to calculate estimated annual percentage changes to estimate trends in the age-standardized incidence (ASIR) and the age-standardized disability-adjusted life years (DALY) rate due to leukemia and its major subtypes from 1990 to 2019. RESULTS: In 2019, globally, the number of incidences and DALYs of leukemia were 643.6 × 103 (587.0 × 103, 699.7 × 103) and 11,657.5 × 103 (10529.1 × 103, 12700.7 × 103), respectively. The ASIR (estimated annual percentage change (EAPC) = -0.37, 95%UI -0.46 to -0.28) and the age-standardized DALY rate (EAPC = -1.72, 95%UI -1.80 to -1.65) of leukemia showed a decreasing trend from 1990 to 2019. The APC model analysis showed that the age effect of leukemia risk was a "U"-shaped distribution of relative risk (RR) with increasing age from 1990 to 2019, globally. The time effect was an increase in incidence rate with increasing years but a decrease in DALY rate with increasing years. The cohort effects of both incidence and DALY rates tended to increase and then decrease with the development of the birth cohort. In 1990 and 2019, smoking, high body-mass index, occupational exposure to benzene, and occupational exposure to formaldehyde were risk factors for DALY in leukemia, especially in areas with high SDI. CONCLUSIONS: From 1990 to 2019, the disease burden of leukemia showed a decreasing trend, but it is worth noting that its overall severity is still very high. The disease burden of leukemia varies greatly from region to region, and exclusive strategies for the prevention and treatment of leukemia should be developed according to the economic and cultural development of each region.

Rapamycin and Hyperoside-Co-loaded Macrophage Delivery System Enhanced Pulmonary Fibrosis Therapy by Autophagy Upregulation and Epithelial-to-Mesenchymal Transition Inhibition.

Pulmonary fibrosis is a lethal interstitial lung disease, for which current treatments are inadequate in halting its progression. A significant factor contributing to the development of fibrosis is insufficient autophagy, which leads to increased fibroblast proliferation and collagen deposition. However, treatments aimed at upregulating autophagy often cause further lung pathology due to the disruption of epithelial cell balance. In response, we have developed a novel macrophage delivery system loaded with an epithelial-to-mesenchymal transition inhibitor, hyperoside (HYP), and an autophagy inducer, rapamycin (RAP). This system targets the fibrotic areas of the lung through chemotaxis, releases liposomes via macrophage extracellular traps, and effectively inhibits fibroblast proliferation while restoring the alveolar structure through the combined effects of RAP and HYP, ultimately reducing lung pathology without causing systemic toxicity. Our findings not only highlight a promising method to enhance autophagy-based treatments for pulmonary fibrosis but also demonstrate the potential of macrophages as effective nanocarriers for drug delivery.

Structure and mechanism of the osmoregulated choline transporter BetT.

The choline-glycine betaine pathway plays an important role in bacterial survival in hyperosmotic environments. Osmotic activation of the choline transporter BetT promotes the uptake of external choline for synthesizing the osmoprotective glycine betaine. Here, we report the cryo-electron microscopy structures of Pseudomonas syringae BetT in the apo and choline-bound states. Our structure shows that BetT forms a domain-swapped trimer with the C-terminal domain (CTD) of one protomer interacting with the transmembrane domain (TMD) of a neighboring protomer. The substrate choline is bound within a tryptophan prism at the central part of TMD. Together with functional characterization, our results suggest that in Pseudomonas species, including the plant pathogen P. syringae and the human pathogen Pseudomonas aeruginosa, BetT is locked at a low-activity state through CTD-mediated autoinhibition in the absence of osmotic stress, and its hyperosmotic activation involves the release of this autoinhibition.

Changes in slow-wave sleep characteristics in Parkinson's disease patients with mild-moderate depression.

INTRODUCTION: Depression and sleep disturbances are commonly seen non-motor symptoms in patients with Parkinson's disease (PD). This study used polysomnography to examine the relationship between mild-moderate depression in PD and sleep characteristics, particularly slow wave activities (SWA). METHODS: 59 PD patients were split into two groups: nd-PD (n = 27) (patients with PD without depression) and d-PD (n = 32) (patients with PD with mild-moderate depression). Their clinical features, polysomnography parameters, and demographics were evaluated. Early and late sleep SWA spectrum densities and overnight SWA decline in different brain regions were particularly analyzed. RESULTS: Non-rapid eye movement 3 (N3) sleep duration and percentage were greater in the d-PD group. N3 percentage was linked to depression (p = 0.014). During late sleep, higher SWA (0.5-4Hz) in the frontal and central regions, higher low-SWA (0.5-2Hz) in the whole brain, central and occipital regions, and higher high-SWA (2-4Hz) in the frontal region was observed in the d-PD group. During early sleep, there was also higher low-SWA (0.5-2Hz) in the occipital region. Patients in d-PD group exhibited reduced overnight high-SWA (2-4Hz) decline (Δhigh-SWA) in the whole brain and occipital regions. Δhigh-SWA(2-4Hz) in the occipital region were associated with depression (p = 0.049). CONCLUSION: PD patients with mild-moderate depression have impaired slow wave sleep, exhibiting as increased N3 sleep, SWA, and reduced overnight SWA decline. This implies that synaptic strength reduction during sleep and impaired synaptic homeostasis regulation may be associated with depression in PD. Reduced overnight high-SWA decline in the occipital region may serve as a novel electrophysiological biomarker for indicating depression in PD.

Survival benefits of postoperative radiotherapy in patients with cT1 - 2N1M0 breast cancer after neoadjuvant chemotherapy: a SEER-based population study.

BACKGROUND: Whether patients with cT1 - 2N1M0 breast cancer can benefit from postoperative radiotherapy (RT) after receiving neoadjuvant chemotherapy (NAC) has been controversial. Therefore, the purpose of this study was to explore whether postoperative RT can benefit this group of patients in terms of survival. METHODS: We used Surveillance, Epidemiology, and End Results (SEER) data to conduct a retrospective review of women with cT1 - 2N1M0 breast cancer diagnosed between 20 and 80 years of age who received NAC between 2010 and 2015. Our study compared the impact of postoperative RT on overall survival (OS) and cancer-specific survival (CSS) in breast cancer patients using propensity score matching (PSM) and performed subgroup analysis. RESULTS: This study finally included 1092 cT1 - 2N1M0 breast cancer patients. Regardless of the patient's PSM status, postoperative RT was significantly associated with OS of cT1-2N1M0 breast cancer patients who received NAC. Specifically, the 10-year OS rate was 78.7% before PSM matching, compared with 71.1% in patients who did not receive postoperative RT, and the difference was more significant after PSM matching, which was 83.1% and 71.1% respectively. However, postoperative RT did not significantly benefit CSS in patients with cT1 - 2N1M0 breast cancer who received NAC. The 10-year CSS rate was 81.4% VS 76.2% (P = 0.085) before PSM matching and 85.8% VS 76.2%(P = 0.076) after matching. Due to the intersection of OS and CSS curves, this restricted mean survival time (RMST) method was chosen as a supplement. After 60 months, the OS difference in RMST between the postoperative RT group and the non-radiotherapy (noRT) group was 7.37 months (95%CI: 0.54-14.21; P = 0.034), and the CSS difference was 5.18 months (95%CI: -1.31-11.68; P = 0.118). Subgroup analysis found that in patients with right-sided breast cancer, postoperative RT improved the patient's OS (HR = 0.45, 95%CI: 0.21-0.95, P = 0.037) and CSS (HR = 0.42, 95%CI: 0.18-0.98, P = 0.045). CONCLUSIONS: Our results showed that additional postoperative RT improved the OS of cT1 - 2N1M0 breast cancer patients who received NAC, but failed to improve their CSS. It is worth noting that in the subgroup analysis of patients with right-sided breast cancer, we observed significant improvements in OS and CSS. And further prospective studies are still needed to verify the effect of postoperative RT in different subgroups.

Neoadjuvant chemotherapy may be the best neoadjuvant therapy modality for non-metastatic pancreatic cancer: a population based study.

Objective: Currently, there are no studies showing which neoadjuvant therapy modality can provide better prognosis for patients after pancreatic cancer surgery. This study explores the optimal neoadjuvant therapy model by comparing the survival differences between patients with non-metastatic pancreatic cancer (cT1-4N0-1M0) who received neoadjuvant chemotherapy (NACT) and neoadjuvant chemoradiotherapy (NARCT). Methods: We retrospectively analyzed the clinical data of 723 patients with cT1-4N0-1M0 pancreatic cancer who received neoadjuvant therapy before surgery from the Surveillance, Epidemiology, and End Results (SEER) database. After propensity score matching (PSM), we compared the effects of NACT and NARCT on overall survival (OS) and cancer-specific survival (CSS) in patients with non-metastatic pancreatic cancer, and then performed subgroup analyze. Finally, we used univariate and multivariate Cox regression analysis to explore potential risk factors for OS and CSS in patients with non-metastatic pancreatic cancer treated with preoperative neoadjuvant therapy. Result: Before PSM, mOS (30.0 months VS 26.0 months, P=0.122) and mCSS (30.0 months VS 26.0 months, P=0.117) were better in patients with non-metastatic pancreatic cancer treated with NACT compared with NARCT, but this was not statistically significant (P>0.05). After PSM, mOS (30.0 months VS 25.0 months, P=0.032) and mCSS (33.0 months VS 26.0 months, P=0.028) were better in patients with non-metastatic pancreatic cancer treated with NACT compared with NARCT, and this difference was statistically significant (P<0.05). Multivariate Cox regression analysis results showed that age, lymph node positivity, and NARCT were independent adverse prognostic factors for OS and CSS in patients with non-metastatic pancreatic cancer. Conclusion: The study results show that compared with NARCT, NACT is the best preoperative neoadjuvant therapy mode for patients with non-metastatic pancreatic cancer. This result still needs to be confirmed by more prospective randomized controlled trials.

Unraveling the interplay between dyskinesia and overactive bladder symptoms in Parkinson's disease: a comprehensive cohort study based on the long-term follow-up database of Parkinson's disease.

OBJECTIVES: Overactive bladder (OAB) and dyskinesia are frequent complications in patients with Parkinson's disease (PD). However, the correlation between OAB and dyskinesia has been insufficiently explored. The purpose of this study was to examine the relationship between dyskinesia, OAB, and clinical characteristics among individuals with PD. METHODS: 1338 PD patients were included in the present study. Demographic features were compared between patients with or without dyskinesia and OAB symptoms. Logistic regression was conducted on dyskinesia to screen clinically relevant factors. Overactive Bladder Symptom Score (OABSS) was further used to stratify the association between the severity of OAB and the occurrence of dyskinesia. RESULTS: This study indicates that both dyskinesia and OAB are significantly related to disease severity and cognitive status. PD patients with dyskinesia and OAB having higher UPDRS scores (p < 0.001), H-Y scores (p < 0.001), NMSQ (p < 0.001) and MoCA scores (p < 0.001), and lower MMSE scores (p < 0.001) are identified. The multivariate logistic regression confirms that disease duration (p = 0.041), LEDD (p < 0.001), UPDRSII (p < 0.001), MoCA (p = 0.024), urgency (p < 0.001), frequency (p < 0.001), and nocturia (p = 0.002) are independent risk factors for dyskinesia. Trend analysis indicates that the risk of dyskinesia significantly increases when patients exhibit moderate to severe OAB symptoms (OABSS > 5) (p < 0.001). No significant interactions were found between OABSS and age, gender, disease duration, LEDD, and NMSQ scores in different subgroups, indicating that dyskinesia is more pronounced in patients with OABSS > 5. DISCUSSION: This study provides compelling evidence supporting the strong correlation between OAB and dyskinesia in PD patients, emphasizing the presence of shared pathogenic mechanisms between these two conditions. Our findings underscore the importance of considering both OAB and dyskinesia in the clinical management of PD, investigating the intricate connections between OAB and dyskinesia could unveil valuable insights into the complex pathophysiology of PD and potentially identify novel therapeutic targets for more effective PD treatment strategies.

The causal effects of genetically predicted alcohol consumption on endometrial cancer risk from a Mendelian randomization study.

Endometrial cancer (EC) is a common gynecological tumor in females with an increasing incidence over the past few decades. Alcohol consumption has been linked to the occurrence of various cancers; However, epidemiological studies have shown inconsistent associations between alcohol consumption and EC risk. In order to avoid the influence of potential confounding factors and reverse causality in traditional epidemiological studies, we used a method based on genetic principles-Mendelian randomization (MR) analysis to test whether there is a causal relationship between alcohol consumption and EC. MR analysis was conducted using publicly available summary-level data from genome-wide association studies (GWAS). Fifty-seven single nucleotide polymorphisms (SNPs) were extracted as instrumental variables for alcohol exposure from the GWAS and Sequencing Consortium of Alcohol and Nicotine GWAS summary data involving 941,287 participants of European ancestry. SNPs for EC were obtained from the Endometrial Cancer Association Consortium, the Endometrial Cancer Epidemiology Consortium, and the UK Biobank, involving 121,885 European participants. The inverse variance weighted (IVW) method was used as the primary method to estimate the causal effect, and the MR-Egger regression and weighted median method were used as supplementary methods. Sensitivity analyses were conducted using the Mendelian Randomization Pleiotropy RESidual Sum and Outlier global test, MR-Egger intercept test, and leave-one-out analysis to evaluate the impact of pleiotropy on causal estimates. An increase of 1 standard deviation of genetically predicted log-transformed alcoholic drinks per day was associated with a 43% reduction in EC risk [odds ratio (OR) = 0.57, 95% confidence interval (CI) 0.41-0.79, P < 0.001]. Subgroup analysis of EC revealed that alcohol consumption was a protective factor for endometrioid endometrial cancer (EEC) (OR = 0.56, 95% CI 0.38-0.83, P = 0.004) but not for non-endometrioid endometrial cancer (NEC) (OR = 1.36, 95% CI 0.40-4.66, P = 0.626). The MR-Egger regression and weighted median method yielded consistent causal effects with the IVW method. The consistent results of sensitivity analyses indicated the reliability of our causal estimates. Additionally, alcohol consumption was associated with decreased human chorionic gonadotropin (HCG) and insulin-like growth factor 1 (IGF1) levels. This MR study suggests that genetically predicted alcohol consumption is a protective factor for EC, particularly for EEC, and this protective effect may be mediated through the reduction of HCG and IGF1.

Small Oversized Stent Graft Is Associated With Increased Patency for the Treatment of Central Venous Disease in Hemodialysis Patients.

PURPOSE: The purpose of this study was to identify the independent predictors of higher patency rates and investigate the selection of specifications of stent graft in the treatment of central venous disease. MATERIALS AND METHODS: This retrospective study included 54 patients who underwent stent-grafts' placement for the treatment of central venous disease between March 2017 and September 2022 at a tertiary hospital. The demographic data for the patients and the clinical data of the treated lesions were collected and analyzed. The patency rates of the treated lesions with different oversizing range were calculated via the Kaplan-Meier and log-rank analyses. The multivariate Cox proportional hazard models were constructed to identify the independent predictor of the target site primary patency. RESULTS: The median follow-up period was 21.5 months. The primary patency rates of the target sites were 90.7%, 72.2%, and 55.1% at 6, 12, and 24 months, respectively. The assisted primary patency rates of the lesions were 96.3%, 92.5%, and 80.3% at 6, 12, and 24 months, respectively. The log-rank analysis showed that the stent-grafts' placement with small oversizing had significantly higher primary patency rates than those with large oversizing (p=0.022). The multivariate analysis revealed that concomitant stenosis and large oversizing stent graft were the independent predictors of target site primary patency. CONCLUSIONS: Stent grafts showed reasonable primary patency for the treatment of central venous disease in hemodialysis patients. A stent graft with small oversizing is associated with better target site primary patency rates than those with large oversizing. CLINICAL IMPACT: Stent grafts showed reasonable primary patency for the treatment of central venous disease in hemodialysis patients. Few studies, however, have explored the efficiency of stent grafts to treat CVD by considering different factors such as sizing considerations, the rate of oversizing percentage, etc. A stent graft with small oversizing is associated with better target site primary patency rates than those with large oversizing. Excessive oversizing should be avoided to prevent infolding or stent collapse.

Slow-wave sleep and REM sleep without atonia predict motor progression in Parkinson's disease.

BACKGROUND: Growing evidence supports the potential role of sleep in the motor progression of Parkinson's disease (PD). Slow-wave sleep (SWS) and rapid eye movement (REM) sleep without atonia (RWA) are important sleep parameters. The association between SWS and RWA with PD motor progression and their predictive value have not yet been elucidated. METHODS: We retro-prospectively analyzed clinical and polysomnographic data of 136 patients with PD. The motor symptoms were assessed using Unified Parkinson's Disease Rating Scale Part III (UPDRS III) at baseline and follow-up to determine its progression. Partial correlation analysis was used to explore the cross-sectional associations between slow-wave energy (SWE), RWA and clinical symptoms. Longitudinal analyses were performed using Cox regression and linear mixed-effects models. RESULTS: Among 136 PD participants, cross-sectional partial correlation analysis showed SWE decreased with the prolongation of the disease course (P = 0.046), RWA density was positively correlated with Hoehn & Yahr (H-Y) stage (tonic RWA, P < 0.001; phasic RWA, P = 0.002). Cox regression analysis confirmed that low SWE (HR = 1.739, 95% CI = 1.038-2.914; P = 0.036; FDR-P = 0.036) and high tonic RWA (HR = 0.575, 95% CI = 0.343-0.963; P = 0.032; FDR-P = 0.036) were predictors of motor symptom progression. Furthermore, we found that lower SWE predicted faster rate of axial motor progression (P < 0.001; FDR-P < 0.001) while higher tonic RWA density was associated with faster rate of rigidity progression (P = 0.006; FDR-P = 0.024) using linear mixed-effects models. CONCLUSIONS: These findings suggest that SWS and RWA might represent markers of different motor subtypes progression in PD.