Net Health System Costs of Parkinson Disease: A Propensity Score-Matched Health Administrative Data Cohort Study in Ontario, Canada.

Background and Objectives: Few estimates of the long-term health system costs of Parkinson disease by phase of disease are available. We estimated 10-year and phase-based net health system costs of Parkinson disease before and after case ascertainment. Methods: Using population-based linked administrative databases from Ontario, Canada, we identified 43,149 community-dwelling persons with incident Parkinson disease aged 40 years and older between 2009 and 2018 using a validated algorithm. These individuals were matched 1:1 to controls without Parkinson disease based on demographics and a propensity score. We calculated phase-based, net health system costs from the provincial government perspective during the preascertainment (3 years before index), initial (1 year after index), early continuing (>1-6 years after index), later continuing (>6-10 years after index), and terminal (1 year before death, if applicable) phases (standardized to 2020 $CAD and calculated on an annual basis). By applying survival probabilities to monthly cost estimates, we also determined 10-year net health system costs, stratified by sex and age. Results: Annual mean net costs of Parkinson disease were lowest in the preascertainment phase ($212 CAD, 95% CI [$20-$404]), intermediate in the initial phase ($4,576 (95% CI [$4,217-$4,935]), and higher in the early continuing phase ($7,078, 95% CI [$6,717-$7,438]). The later continuing phase ($12,500, 95% CI [$12,060-$12,940]) and the terminal phase ($13,933, 95% CI [$13,123-$14,743]) showed the highest costs. The 10-year net cost of Parkinson disease was $82,153 (95% CI [$77,965-$86,341]) and was significantly higher in women ($89,773, 95% CI [$83,306-$96,240]) than in men ($76,469, 95% CI [$70,983-$81,953]) and older individuals ($92,197, 95% CI [$87,087-$97,307]), compared with younger individuals ($62,580, 95% CI [$55,346-$69,814]). Over the 10-year period, hospital, nursing home, and home care were the largest contributors to costs of Parkinson disease. Discussion: Health system costs of Parkinson disease are substantial, particularly in the later phases. Interventions to reduce avoidable use of hospital and nursing home services by persons living with Parkinson disease may provide better quality of life and be cost saving from the health system perspective.

The effect of lipidomes on the risk of endometrioid endometrial cancer: a Mendelian randomization study.

Objective: This study aimed to explore the potential effects between various human plasma lipidomes and endometrioid endometrial cancer (EEC) by using Mendelian randomization (MR) methods. Methods: This study designated a total of 179 human plasma lipidomes from the genome-wide association study (GWAS) database as the exposure variable. An EEC-related dataset from the GWAS (GCST006465) served as the outcome variable. MR analyses used the inverse variance-weighted method (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods for regression calculations, accounting for possible biases induced by linkage disequilibrium and weak instrument variables. Any lipidomes failing to pass heterogeneity and horizontal pleiotropy tests were deemed to lack significant causal impact on the outcome. Results: The results of IVW analysis disclosed that a variety of human plasma lipidomes (n = 15) exhibited a significant causal effect on EEC (p < 0.05). A subset of these lipidomes (n = 13) passed heterogeneity and horizontal pleiotropy tests, which demonstrated consistent and viable causal effects (p < 0.05) including glycerophospholipids, glycerolipids, and sterols. Specifically, phosphatidylcholine (odds ratio [OR]: 1.065-1.129, p < 0.05) exhibited a significant positive causal effect on the occurrence of EEC. Conversely, sterol ester (OR = 0.936, p = 0.007), diacylglycerol (OR = 0.914, p = 0.036), phosphatidylcholine (OR: 0.903-0.927, p < 0.05), phosphatidylethanolamine (OR = 0.907, p = 0.046) and triacylglycerol (OR: 0.880-0.924, p < 0.05) showed a notable negative causal association with EEC, suggesting their inhibitory effects on the EEC occurrence. Conclusions: The study revealed that human plasma lipidomes have complex impacts on EEC through Mendelian randomization. This indicated that the diversity of structural changes in lipidomes could show different effects on subtypes and then affect EEC occurrence. Although these lipids had the potential to be promising biomarkers, they needed to be further clinically validated nevertheless.

Maternal Downward Neighborhood Income Mobility and Newborn Discharge to Child Protective Services.

This cohort study examines whether there is an association between a mother moving into a neighborhood with lower income between births and newborn custody by child protective services at birth.

Marine Staurosporine Analogues: Activity and Target Identification in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high mortality and drug resistance and no targeted drug available at present. Compound 4, a staurosporine alkaloid derived from Streptomyces sp. NBU3142 in a marine sponge, exhibits potent anti-TNBC activity. This research investigated its impact on MDA-MB-231 cells and their drug-resistant variants. The findings highlighted that compound 4 inhibits breast cancer cell migration, induces apoptosis, arrests the cell cycle, and promotes cellular senescence in both regular and paclitaxel-resistant MDA-MB-231 cells. Additionally, this study identified mitogen-activated protein kinase kinase kinase 11 (MAP3K11) as a target of compound 4, implicating its role in breast tumorigenesis by affecting cell proliferation, migration, and cell cycle progression.

The Predatory Properties of Bradymonabacteria, the Representative of Facultative Prey-Dependent Predators.

Bradymonabacteria, as the representative of the facultative prey-dependent predators, were re-classified from the preceding Deltaproteobacteria into the phylum Myxococcota and proposed as a novel class named Bradymonadia. However, it was ambiguous whether their predatory pattern and properties were similar to those of the other myxobacterial predators. Therefore, the physiologic features were compared to determine the similarities and differences during the process of group attack and kin discrimination. Comparative genomic analyses were performed to conclude the core genome encoded commonly by bradymonabacteria, Myxococcia, and Polyangia. In conclusion, we proposed that bradymonabacteria have a predation pattern similar to the that of the representative of opportunistic predators like Myxococcus xanthus but with some subtle differences. Their predation was predicted to be initiated by the needle-less T3SS*, and the S-motility mediated by T4P also participated in the process. Meanwhile, their group attacks relied on cell contact and cell destiny. Inter-species (strains) kin discriminations occurred without the existence of T6SS. However, no extracellular lethal substance was detected in the fermentation liquor culture of bradymonabacteria, and the death of prey cells could only be observed when touched by their cells. Moreover, the prey-selective predation was observed when the predator encountered certain prey from Bacillus (G+), Algoriphagus (G-), and Nocardioides (G+). Bradymonabacteria can be regarded as a potential consumer and decomposer, and preying on many sea-dwelling or human pathogenic bacteria allows this group a broad application prospect in marine culture and clinical disease control. Our study will provide more evidence for its exploitations and applications.

Long term outcomes and risk factors of compensatory hyperhidrosis after thoracoscopic sympathectomy in primary palmar hyperhidrosis patients: a retrospective single-center study.

OBJECTIVE: This study aims to evaluate the long-term outcomes of compensatory hyperhidrosis (CH) after thoracoscopic sympathectomy and explore the risk factors affecting postoperative CH in primary palmar hyperhidrosis(PPH) patients. METHOD: A retrospective analysis was conducted on patients who underwent thoracoscopic sympathectomy in the thoracic surgery department of our hospital from January 2015 to May 2022. Long-term follow-up surveys was conducted to collect data on post-operative satisfaction, PPH recurrence, and CH occurrence. Postoperative CH outcomes were assessed using the HDSS and satisfaction scores scale. Univariate and multivariate logistic regression analyses were used to identify independent risk factors for postoperative CH. RESULT: A total of 152 patients was included in the final study, with 113 cases in the CH group and 39 cases in the nCH group. The incidence of postoperative CH was 74.3% (113/152), within which 33.6% (38/113) were severe CH. The median follow-up time was 3.1 years(2.5-5.5y) and the median interval of CH onset after surgery was 30 days (14-90d). Univariate analysis showed that body mass index(BMI), surgical time, and transected nerve level are correlated with CH, with statistically significant differences. Multivariate logistic regression analysis indicated a higher BMI (OR = 0.864, 95% CI 0.755-0.989, P < 0.05) is the independent risk factor for the occurrence of CH. There was no statistically significant difference in HDSS scores among CH patients at 1 month, 1 year, and 3 years after surgery. CONCLUSION: A higher BMI is the independent risk factor for postoperative CH after thoracoscopic sympathectomy. The incidence and severity of postoperative CH kept stable during a long term follow up.

Configurational Paths of Preconditions to Transformational Leadership Among Core Hospital Leaders: A Fuzzy-Set Qualitative Comparative Analysis.

Purpose: Transformational leadership among core hospital leaders boosts medical organizations' competitiveness, adaptability, and sustainability, which is jointly affected by individual, organizational and environmental factors. This study aims to unpack its configurational framework and propose strategies to strengthen core hospital leaders' transformational leadership. Patients and Methods: Data were collected from an online questionnaire among 31 core hospital leaders. The fuzzy-set qualitative comparative analysis (fsQCA) was used to explore the causal mechanism of high-level transformational leadership. We enrich this mechanism by professional background, critical thinking, initiative spirit, family-work conflict, job satisfaction, subordinates' followership, and work pressure. Results: Result shows initiative spirit is the only necessary condition (consistency=0.911) for the formation of high-level transformational leadership among core hospital leaders. Three configurations are the sufficient conditions that lead to high-level transformational leadership among core hospital leaders with two different professional backgrounds (overall solution consistency= 0.952). Conclusion: Core hospital leaders' initiative spirit is an indispensable condition for improving high-level transformational leadership, emphasizing the necessity for core leaders to be proactive in order to develop such leadership. Besides, the study also uncovered three configurations are the sufficient conditions for core hospital leaders with diverse professional backgrounds to achieve high-level transformational leadership. This finding offers significant insights into hospital management practices, suggesting that core hospital leaders' work should be managed in a personalized manner based on their professional backgrounds, thereby fostering favorable conditions conducive to the development of their high-level transformational leadership capabilities. Furthermore, the central insight of this study is that the formation of high-level transformational leadership contingent upon the collaboration of professional background, critical thinking, initiative spirit, family-work conflict, job satisfaction, subordinates' followership, and work pressure, contributing to a holistic and more rigorous view for the development of transformational leadership.

Assembly Regulates Gamma Radiation Polymerization of Polytelluoxane.

Regulating chemical drug's responsiveness to gamma radiation is crucial for achieving better therapeutic effects in cancer treatment. Most research focused on thermodynamic chemical structure design, while little attention was paid to kinetic regulate strategy, which possesses greater universality and security. In this study, we achieved a kinetic-based regulate strategy of gamma radiation reaction, through the construction of microphase environment during polymerization of polytelluoxane (PTeO). We designed hydrophobic segments forming large compound micelles (LCMs) assembly to create kinetically favorable higher concentration for radiation-induced reaction. It exhibited a > ten times higher responsiveness and, as far as we know, merely required a minimum dosage of 5 Gy for polymerization to occur. What's more, by taking advantages of the assembly change with Te-O hydrophilic segments and gamma radiation, polymerization became milder with lower polydispersity than previous methods. Such kinetic-based regulate strategy could offer a novel perspective on the design of radiation-responsive chemoradiotherapy and other radiation-induced chemical process.

Nomogram using human epididymis protein 4 predicted concurrent endometrial cancer from endometrial atypical hyperplasia before surgery.

Objective: To establish a nomogram based on presurgical predictors of concurrent endometrial cancer (EC) for patients diagnosed with endometrial atypical hyperplasia before definitive surgery (preoperative-EAH) to improve the risk stratification and clinical application. Methods: Preoperative-EAH patients who underwent hysterectomy in a tertiary hospital from January 2020 to December 2022 were retrospectively analyzed. Independent predictors from the multivariate logistic regression model were used to establish a nomogram, and bootstrap resampling was used for internal validation. Results: Of 370 preoperative-EAH patients, 23.4% were diagnosed with EC after definitive surgery (final-EC). Multivariate analyses found three independent predictors of final EC: human epididymis protein 4 (HE4) ≥43.50 pmol/L [odds ratio (OR) = 3.70; 95% confidence intervals (CI) = 2.06-6.67], body mass index (BMI) ≥ 28 kg/m2 (OR = 2.05; 95% CI = 1.14-3.69), and postmenopausal status, particularly at postmenopausal time ≥5 years (OR = 5.84, 95% CI = 2.51-13.55), which were used to establish a nomogram model. The bootstrap-corrected C-index of the nomogram was 0.733 (95% CI = 0.68-0.79), which was significantly higher than that of each individual factor. The calibration curve and decision curve showed good consistency and clinical net benefit of the model. At the maximum Youden index, 49.4% (43/87) of women in the high-risk group defined by nomogram had concurrent EC, versus 16.6% in the low-risk group (P< 0.001). Conclusion: The nomogram based on HE4, menopausal status, and BMI was found with an improved predictive value to stratify preoperative-EAH patients at high risk of concurrent EC for better clinical management.

Emerging role of Jumonji domain-containing protein D3 in inflammatory diseases.

Jumonji domain-containing protein D3 (JMJD3) is a 2-oxoglutarate-dependent dioxygenase that specifically removes transcriptional repression marks di- and tri-methylated groups from lysine 27 on histone 3 (H3K27me2/3). The erasure of these marks leads to the activation of some associated genes, thereby influencing various biological processes, such as development, differentiation, and immune response. However, comprehensive descriptions regarding the relationship between JMJD3 and inflammation are lacking. Here, we provide a comprehensive overview of JMJD3, including its structure, functions, and involvement in inflammatory pathways. In addition, we summarize the evidence supporting JMJD3's role in several inflammatory diseases, as well as the potential therapeutic applications of JMJD3 inhibitors. Additionally, we also discuss the challenges and opportunities associated with investigating the functions of JMJD3 and developing targeted inhibitors and propose feasible solutions to provide valuable insights into the functional exploration and discovery of potential drugs targeting JMJD3 for inflammatory diseases.

Unraveling the role of ubiquitin-conjugating enzyme 5 (UBC5) in disease pathogenesis: A comprehensive review.

While certain members of ubiquitin-coupled enzymes (E2s) have garnered attention as potential therapeutic targets across diverse diseases, research progress on Ubiquitin-Conjugating Enzyme 5 (UBC5)-a pivotal member of the E2s family involved in crucial cellular processes such as apoptosis, DNA repair, and signal transduction-has been relatively sluggish. Previous findings suggest that UBC5 plays a vital role in the ubiquitination of various target proteins implicated in diseases and homeostasis, particularly in various cancer types. This review comprehensively introduces the structure and biological functions of UBC5, with a specific focus on its contributions to the onset and advancement of diverse diseases. It suggests that targeting UBC5 holds promise as a therapeutic approach for disease therapy. Recent discoveries highlighting the high homology between UBC5, UBC1, and UBC4 have provided insight into the mechanism of UBC5 in protein degradation and the regulation of cellular functions. As our comprehension of the structural distinctions among UBC5 and its homologues, namely UBC1 and UBC4, advances, our understanding of UBC5's functional significance also expands.

Large-Area Perovskite Nanocrystal Metasurfaces for Direction-Tunable Lasing.

Perovskite nanocrystals (PNCs) are attractive emissive materials for developing compact lasers. However, manipulation of PNC laser directionality has been difficult, which limits their usage in photonic devices that require on-demand tunability. Here we demonstrate PNC metasurface lasers with engineered emission angles. We fabricated millimeter-scale CsPbBr3 PNC metasurfaces using an all-solution-processing technique based on soft nanoimprinting lithography. By designing band-edge photonic modes at the high-symmetry X point of the reciprocal lattice, we achieved four linearly polarized lasing beams along a polar angle of ∼30° under optical pumping. The device architecture further allows tuning of the lasing emission angles to 0° and ∼50°, respectively, by adjusting the PNC thickness to shift other high-symmetry points (Γ and M) to the PNC emission wavelength range. Our laser design strategies offer prospects for applications in directional optical antennas and detectors, 3D laser projection displays, and multichannel visible light communication.

Discovery of 1,2,4-Triazole-3-thione Derivatives as Potent and Selective DCN1 Inhibitors for Pathological Cardiac Fibrosis and Remodeling.

DCN1, a critical co-E3 ligase during the neddylation process, is overactivated in many diseases, such as cancers, heart failure as well as fibrotic diseases, and has been regarded as a new target for drug development. Herein, we designed and synthesized a new class of 1,2,4-triazole-3-thione-based DCN1 inhibitors based the hit HD1 identified from high-throughput screening and optimized through numerous structure-activity-relationship (SAR) explorations. HD2 (IC50= 2.96 nM) was finally identified and represented a highly potent and selective DCN1 inhibitor with favorable PK properties and low toxicity. Amazingly, HD2 effectively relieved Ang II/TGFß-induced cardiac fibroblast activation in vitro, and reduced ISO-induced cardiac fibrosis as well as remodeling in vivo, which was linked to the inhibition of cullin 3 neddylation and its substrate Nrf2 accumulation. Our findings unveil a novel 1,2,4-triazole-3-thione-based derivative HD2, which can be recognized as a promising lead compound targeting DCN1 for cardiac fibrosis and remodeling.

[Research progress of KCNJ5 gene in aldosterone-producing adenoma].

Aldosterone-producing adenoma is a subtype of primary aldosteronism. Recent advancements in multi-omics research have led to significant progress in understanding primary aldosteronism at the genetic level. Among the various genes associated with the development of aldosterone-producing adenomas, the KCNJ5 (potassium inwardly rectifying channel, subfamily J, member 5) gene has received considerable attention due to its prevalence as the most common somatic mutation gene in primary aldosteronism. This paper aims to integrate the existing evidence on the involvement of KCNJ5 gene in the pathogenesis of aldosterone-producing adenomas, to enhance the understanding of the underlying mechanisms of aldosterone-producing adenomas from the perspective of genetics, and to provide novel insights for the clinical diagnosis and treatment of aldosterone-producing adenomas.

Silane modified Cr2O3/polyimide nanocomposite films with excellent surface insulation performance for space applications.

The exploration of deep space significantly increases the probability of spacecraft failures due to surface electrostatic discharge, which imposes higher vacuum insulation protection requirements on polyimide (PI), the external insulation material of spacecrafts. To address this challenge, this study proposes using silane coupling agent KH550 for organic grafting treatment of Cr2O3nanoparticles, which are then used to dope and modify PI to enhance the vacuum surface insulation of PI films. The KH550 grafting improves the interface strength between the fillers and the matrix, allowing the fillers to be uniformly dispersed in the matrix. Compared to pure PI films, the prepared PI-Cr2O3@KH550 composite films exhibit significantly enhanced vacuum surface flashover voltage, improved surface/volume resistivity, and dielectric properties. The results demonstrate that PI composite films with 0.8% by mass of Cr2O3@KH550 show the most notable performance improvement, with the DC flashover voltage and impulse flashover voltage in vacuum increasing by 20.7% and 27.8%, respectively. The doping of chromium oxide nanoparticles introduces more deep traps into the PI films and reduce the surface resistivity. The higher deep trap density inhibits charge migration, thereby alleviating secondary electron emission and surface electric field distortion. Simultaneously, the lower surface resistivity facilitates dissipating surface charges and improves the surface insulation. These findings are of significant reference value for promoting the enhancement of aerospace insulation performance.

Site-specific photo-crosslinking of Hsc70 with the KFERQ pentapeptide motif in a chaperone-mediated autophagy and microautophagy substrate in mammalian cells.

Heat shock cognate protein 70 (Hsc70/HSPA8) belongs to the Hsp70 family of molecular chaperones. The fundamental functions of Hsp70 family molecular chaperones depend on ATP-dependent allosteric regulation of binding and release of hydrophobic polypeptide substrates. Hsc70 is also involved in various other cellular functions including selective pathways of protein degradation: chaperone-mediated autophagy (CMA) and endosomal microautophagy (eMI), in which Hsc70 recruits substrate proteins containing a KFERQ-like pentapeptide motif from the cytosol to lysosomes and late endosomes, respectively. However, whether the interaction between Hsc70 and the pentapeptide motif is direct or mediated by other molecules has remained unknown. In the present study, we introduced a photo-crosslinker near the KFERQ motif in a CMA/eMI model substrate and successfully detected its crosslinking with Hsc70, revealing the direct interaction between Hsc70 and the KFERQ motif for the first time. In addition, we demonstrated that the loss of the Hsc70 ATPase activity by the D10 N mutation appreciably reduced the crosslinking efficiency. Our present results suggested that the ATP allostery of Hsc70 is involved in the direct interaction of Hsc70 with the KFERQ-like pentapeptide.

Prenatal low-dose Bisphenol A exposure impacts cortical development via cAMP-PKA-CREB pathway in offspring.

Bisphenol A (BPA) is a widely used plasticizer known to cause various disorders. Despite a global reduction in the use of BPA-containing products, prenatal exposure to low-dose BPA, even those below established safety limits, has been linked to neurological and behavioral deficits in childhood. The precise mechanisms underlying these effects remain unclear. In the present study, we observed a significant increase in the number of cortical neurons in offspring born to dams exposed to low-dose BPA during pregnancy. We also found that this prenatal exposure to low-dose BPA led to increased proliferation but reduced migration of cortical neurons. Transcriptomic analysis via RNA sequencing revealed an aberrant activation of the cAMP-PKA-CREB pathway in offspring exposed to BPA. The use of H89, a selective PKA inhibitor, effectively rescued the deficits in both proliferation and migration of cortical neurons. Furthermore, offspring from dams exposed to low-dose BPA exhibited manic-like behaviors, including hyperactivity, anti-depressant-like responses, and reduced anxiety. While H89 normalized hyperactivity, it didn't affect the other behavioral changes. These results suggest that the overactivation of PKA plays a causative role in BPA-induced changes in neuronal development. Our data also indicate that manic-like behaviors induced by prenatal low-dose BPA exposure may be influenced by both altered neuronal development and abnormal PKA signaling in adulthood.

Nonflammable All-Fluorinated Electrolyte Enabling High-Voltage and High-Safety Lithium-Ion Cells.

In this study, a nonflammable all-fluorinated electrolyte for lithium-ion cells with a Li(Ni0.8Mn0.1Co0.1)O2 cathode is investigated under high voltages. This electrolyte, named FT46, consists of fluoroethylene carbonate (FEC) and bis(2,2,2-trifluoroethyl) carbonate (TFEC) in a mass ratio of 4:6. Compared to a commercially available electrolyte and several other fluorinated electrolytes, cells containing FT46 demonstrate significantly better cycling performances under high voltage (3.0-4.5 V). This result may be ascribed to the generation of a stable, smooth, and thin passivation layer and the improved solvation structure formed by FT46. The LiF-rich passivation layer strengthens the electrode/electrolyte interface, inhibits the degradation of the electrode, and suppresses side reactions between the electrodes and electrolytes under high voltage. The solvation structure formed by FT46 is derived from anions, enabling an enhanced Li+ migration rate and inhibiting lithium plating generation. Additionally, due to the nonflammability of the electrolyte and the stable passivation layers, FT46 cells also demonstrate promising safety characteristics when exposed to typical abusive conditions, such as thermal abuse, mechanical abuse, and electrical abuse.

Elevated basophil count is associated with increased risk of endometriosis.

Immunological dysregulation plays a fundamental role in the inflammatory aspects of endometriosis. Circulating blood leukocytes, one of the most abundant immune cell populations in the human body, have been shown diagnostic significance in some diseases. Nevertheless, the association between peripheral blood leukocyte counts and endometriosis remains unexplored to date. We analysed two targeted study cohorts: a tertiary centre cohort (Endometriosis at Oxford University [ENDOX] study, 325 cases/177 controls) and a large-scale population study (UK Biobank [UKBB], 1537 cases/6331 controls). In both datasets, peripheral venous blood sample results were retrieved and counts of leukocyte subpopulations, including neutrophils, lymphocytes, monocytes, eosinophils and basophils analysed. Logistic regression models were used to investigate the association of leukocyte subtype alterations with endometriosis status, adjusting for confounding factors. We demonstrate that higher blood basophil level is associated with increased odds of endometriosis. This association was first discovered in the ENDOX cohort (basophils >0.04 x10^9/L: OR 1.65 [95%CI:1.06-2.57], P trend = 0.025) and replicated in the UKBB dataset (basophils >0.04 x10^9/L: OR 1.26 [95%CI:1.09-1.45], P trend = 0.001). Notably, women with basophil counts in the upper tercile had significantly increased odds of having stage III/IV endometriosis (ENDOX study: OR = 2.30, 95% CI [1.25 to 4.22], P trend = 0.007; UKBB study (OR = 1.40, 95% CI [1.07 to 1.85], P trend = 0.015). None of the other leukocyte subtypes showed an association. Our findings suggest an association between inflammatory responses and the pathogenesis of endometriosis; future studies are warranted to investigate whether the association is causal.