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Abstract Background Studies have suggested that blood circulating phytosterols, plant-derived sterols analogous to cholesterol, were associated with blood lipid levels and the risk of Alzheimer’s disease (AD) and Parkinson’s disease (PD). This Mendelian randomization (MR) study is performed to determine the causal effect of circulating phytosterols on AD and PD and evaluate the mediation effect of blood lipids. Methods Leveraging genome-wide association studies summary-level data for phytosterols, blood lipids, AD, and PD, univariable and multivariable MR (MVMR) analyses were conducted. Four types of phytosterols (brassicasterol, campesterol, sitosterol, and stigmasterol), three blood lipids parameters (high-density lipoprotein cholesterol [HDL-C], non-HDL-C, and triglyceride), two datasets for AD and PD were used. Inverse-variance weighted method was applied as the primary analysis, and false discovery rate method was used for adjustment of multiple comparisons. Results Using the largest AD dataset, genetically proxied higher levels of stigmasterol (OR = 0.593, 95%CI = 0.431–0.817, P = 0.004) and sitosterol (OR = 0.864, 95%CI = 0.791–0.943, P = 0.004) significantly correlated with a lower risk of AD. No significant associations were observed between all four types of phytosterols levels and PD. MVMR estimates showed that the above causal associations were missing after integrating the blood lipids as exposures. Sensitivity analyses confirmed the robustness of these associations, with no evidence of pleiotropy and heterogeneity. Conclusion The study supports a potential beneficial role of blood stigmasterol and sitosterol in reducing the risk of AD, but not PD, which is dependent on modulating blood lipids. These insights highlight circulating stigmasterol and sitosterol as possible biomarkers and therapeutic targets for AD.

Abstract Chronic diseases often lead to metabolic disorders, causing anabolic resistance and increased energy consumption, which result in cachexia. Cachexia, in turn, can lead to major clinical consequences such as impaired quality of life, shortened life expectancy, and increased healthcare expenditure. Existing international diagnostic criteria for cachexia employ thresholds derived from Western populations, which may not apply to Asians due to differing body compositions. To address this issue, the Asian Working Group for Cachexia (AWGC) was initiated. The AWGC comprises experts in cachexia research and clinical practice from various Asian countries and aims to develop a consensus on diagnostic criteria and significant clinical outcomes for cachexia in Asia. The AWGC, composed of experts in cachexia research and clinical practice from several Asian countries, undertook three‐round Delphi surveys and five meetings to reach a consensus. Discussions were held on etiological diseases, essential diagnostic items for cachexia, including subjective and objective symptoms and biomarkers, and significant clinical outcomes. The consensus highlighted the importance of multiple diagnostic factors for cachexia, including chronic diseases, either or both weight loss or low body mass index, and at least one of the following: anorexia, decreased grip strength (5 mg/L [0.5 mg/dL]). The AWGC proposed a significant weight change of 2% or more over a 3–6 month period and suggested a tentative cut‐off value of 21 kg/m2 for low body mass index in diagnosing cachexia. Critical clinical outcomes were determined to be mortality, quality of life as assessed by tools such as EQ‐5D or the Functional Assessment of Anorexia/Cachexia Therapy, and functional status as measured by the Clinical Frailty Scale or Barthel Index, with significant emphasis on patient‐reported outcomes. The AWGC consensus offers a comprehensive definition and user‐friendly diagnostic criteria for cachexia, tailored specifically for Asian populations. This consensus is set to stimulate future research and enhance the multidisciplinary approach to managing cachexia. With plans to develop further guidelines for the optimal treatment, prevention, and care of cachexia in Asians, the AWGC criteria are expected to drive research across chronic co‐morbidities and cancer in Asia, leading to future refinement of diagnostic criteria.

A longstanding quest in material science has been the development of superhydrophobic coating based on a single material, without the requirement of fluorination or silane treatment. In this work, the micro-arc oxidation (MAO) coating as transition layer can effectively enhance the bonding force of the superhydrophobic coating. The semiconductor@metal organic frameworks (MOFs) core-shell structure was synthesized by a simple self-templating method, and obtained ZnO@2-methylimidazole zinc salt (ZIF-8) nanorods array on magnesium (Mg) alloy. ZnO nanorods not only act as the template but also provide Zn2+ for ZIF-8. In addition, we proved that the ligand concentration, synthesis time and temperature are the keys to the preparation of ZnO@ZIF-8 nanorods. As we expect, the ZnO@ZIF-8 nanorods array can trap air in the gaps to form an air layer, and the coating exhibits superhydrophobic properties (154.81°). Excitingly, ZnO@ZIF-8 nanorods array shown a superhydrophobic property, without the requirement of fluorination or silane treatment. The results shown that the coating has good chemical stability and self-cleaning performance. Meanwhile, the corrosion resistance has been significantly improved, Rct was increased from 1.044×103 to 1.414×106 Ω/cm2 and Icorr was reduced from 4.275×10−5 to 5.611×10−9 A/cm2. Therefore, the semiconductor@MOFs core-shell structure has broad application prospects in anti-corrosion.

Objective To study the effect of triptolide(TPL)combined with chemotherapy drug doxorubicin(DOX)on apoptosis of human breast cancer cell line MCF-7 and its molecular mechanism. Methods MCF-7 cells were treated with triptolide and different concentrations of doxorubicin alone or in combination. Cell viability was analyzed by CCK-8 method with the combination index calculated. Cell proliferation was detected by plate cloning formation assay. Cell apoptosis and cell cycle were detected by flow cytometry. The expressions of apoptosis-related proteins Bcl-2, Bax, cleaved caspase-3 and proteins in PI3K/AKT signaling pathway were analyzed by Western blot. Results Triptolide combined with different concentrations of doxorubicin significantly inhibited cell proliferation as compared with the doxorubicin group alone after incubation for 24, 48 and 72 hours(P＜0.05). The clone formation was restrained and the cell apoptosis rate was significantly higher(P＜0.01). The expressions of Bax and cleaved caspase-3 was up-regulated, and the expressions of Bcl-2, p-PI3K, p-AKT was down-regulated(P＜0.05). The cells were blocked in S phase after combination treatment of the two drugs(P＜0.05). Conclusions The combination of triptolide and doxorubicin significantly increases the sensitivity of MCF-7 cells to doxorubicin and promotes the apoptosis of cells, which might be related to the inhibition of PI3K/AKT signaling pathway.

The Three-River Headwaters (TRH) region in the Tibetan Plateau is vulnerable to climate change; changes in summer (June–August) precipitation have a significant impact on water security and sustainability in both local and downstream areas. However, the changes in summer precipitation of different intensities over the TRH region, along with their influencing factors, remain unclear. In this study, we used observational and ERA5 reanalysis data and employed a precipitation categorization and water vapor budget analysis to quantify the categorized precipitation variations and investigate their possible linkages with the water vapor budget. Our results showed an increasing trend in summer precipitation at a rate of 0.9 mm per year (p

Mg alloys are considered the most promising engineering materials because of their unique properties. However, the uncontrolled corrosion rate of these alloys limits their applications. Therefore, in this study, a micro-arc oxidation layer was used as a transition layer to “directly” grow a zinc-based metal-organic framework (MOF) composite coating on the surface of a Mg alloy (AZ91D). Herein, the two zeolitic imidazolate framework (ZIF-8) coatings with different morphologies were separately prepared by homologous metal oxide induction and a one-step in-situ growth method. The superhydrophobic composite coating showed strong hydrophobicity and self-cleaning properties, which could prevent the penetration of water and corrosive ions (Cl−) into the surface of AZ91D. Electrochemical tests demonstrated that the super-hydrophobic composite coatings greatly enhanced the corrosion resistance of AZ91D, and the corrosion current density decreased from 10−5 to 10−9 A/cm2. These results indicate that the ZIF-8 coatings are beneficial for improving the hydrophobicity and enhancing the corrosion resistance of Mg alloys. Therefore, MOF composite coatings provide a new strategy that can be used to prepare multifunctional anticorrosion coatings on metal substrates.

To improve estimating accuracy in the traditional mean rank or median rank estimation method, an improved mean rank is proposed in the correction principle of rank estimation function as the cumulative distribution function of samples by adjusting the applicable points of natural mean rank. Then a least squares estimation is performed by directly fitting the cumulative distribution function. Based on the hypothesis of Weibull distribution under small sample, the parameter estimations under different ranks are calculated by Monte Carlo simulation. The results indicate that the relative error on calculating scale parameter using the improved mean rank method for the Weibull distribution with different parameters is less than 9.5% under the condition of sample size not less than 4. Furthermore, the relative error on calculating mean time between failures using the improved mean rank method is less than 8.7%, while the relative errors using traditional methods are higher than 16%. From calculated results, proposed method can effectively improve the parameter estimation accuracy for Weibull distribution.

To solve the problems of complex calculation and weak applicability of the traditional interval estimation methods such as Weibull distribution with the different parameters, a simple interval estimation method suitable to the conditions of multi-parameters was proposed. Through the expression of Weibull distribution, the pivotal-variable obeying chi-square distribution was obtained and the degrees of freedom were modified. Combined with the point estimation results from maximum likelihood estimation and the empirical estimation shape parameter in the Weibull distribution, the interval estimation method of two parameters in Weibull distribution was established. The confidence of proposed interval estimation method was verified by Monte Carlo simulation, and the applicability of the method on different parameters was also analyzed. Furthermore, comparisons with the results computed from traditional least square and maximum likelihood estimation methods were carried out by using simulation. Simulation results indicated that the modified pivotal-variable method has simple calculation process and small deviation from predefined nominal confidence with the different parameters. Therefore, it can be concluded that proposed method executes the more effective estimation than the traditional methods.

(1) Background: Lower back pain is often caused by lumbar facet joint syndrome. This study investigated the effectiveness of three different injection methods under ultrasound guidance in treating elderly patients with lumbar facet joint syndrome. The difficulty in performing these injections was also evaluated; (2) Methods: A total of 60 elderly patients with facet joint syndrome as the cause of lower back pain were recruited and divided into 3 groups. Group 1 received medial branch block (MBB). Group 2 received intra-articular facet joint injections. Group 3 received injection into the multifidus muscle portion that covers the facet joint. Five percent dextrose water (D5W) was used as the injectant. The visual analog scale (VAS) was used to measure the degree of lower back pain; (3) Results: Before the injection treatments, the VAS score averaged about 7.5. After three consecutive injection treatments (two weeks interval), the VAS score decreased significantly to an average of about 1 in all 3 groups, representing mild to no pain. Between group analyses also did not reveal significant statistical differences, suggesting that these procedures are equally effective; (4) Conclusions: Ultrasound-guided injection of the multifidus muscle may be a feasible option in treating elderly patients with lower back pain caused by facet joint syndrome as it is easier to perform as compared to MBB and intra-articular facet joint injection.

BackgroundDementia development is a complex process in which the occurrence and sequential relationships of different diseases or conditions may construct specific patterns leading to incident dementia. ObjectiveThis study aimed to identify patterns of disease or symptom clusters and their sequences prior to incident dementia using a novel approach incorporating machine learning methods. MethodsUsing Taiwan’s National Health Insurance Research Database, data from 15,700 older people with dementia and 15,700 nondementia controls matched on age, sex, and index year (n=10,466, 67% for the training data set and n=5234, 33% for the testing data set) were retrieved for analysis. Using machine learning methods to capture specific hierarchical disease triplet clusters prior to dementia, we designed a study algorithm with four steps: (1) data preprocessing, (2) disease or symptom pathway selection, (3) model construction and optimization, and (4) data visualization. ResultsAmong 15,700 identified older people with dementia, 10,466 and 5234 subjects were randomly assigned to the training and testing data sets, and 6215 hierarchical disease triplet clusters with positive correlations with dementia onset were identified. We subsequently generated 19,438 features to construct prediction models, and the model with the best performance was support vector machine (SVM) with the by-group LASSO (least absolute shrinkage and selection operator) regression method (total corresponding features=2513; accuracy=0.615; sensitivity=0.607; specificity=0.622; positive predictive value=0.612; negative predictive value=0.619; area under the curve=0.639). In total, this study captured 49 hierarchical disease triplet clusters related to dementia development, and the most characteristic patterns leading to incident dementia started with cardiovascular conditions (mainly hypertension), cerebrovascular disease, mobility disorders, or infections, followed by neuropsychiatric conditions. ConclusionsDementia development in the real world is an intricate process involving various diseases or conditions, their co-occurrence, and sequential relationships. Using a machine learning approach, we identified 49 hierarchical disease triplet clusters with leading roles (cardio- or cerebrovascular disease) and supporting roles (mental conditions, locomotion difficulties, infections, and nonspecific neurological conditions) in dementia development. Further studies using data from other countries are needed to validate the prediction algorithms for dementia development, allowing the development of comprehensive strategies to prevent or care for dementia in the real world.

Abstract Purpose The purpose was to explore the effect of drug-eluting beads transarterial chemoembolization (DEB-TACE) on down-staging in unresectable liver cancer patients. Methods A total of 180 patients with PHC treated by TACE were retrospectively analyzed. These included 80 cases in the DEB-TACE group and 100 cases in the cTACE group. Of these, 56 had complete clinical data (DEB-TACE: 24, cTACE: 32), and 23 patients received hepatectomy after TACE as a down-staging therapy (DEB-TACE: 15, cTACE: 8). Data (including clinical characteristics, clinical efficacy, tumor response, tumor diameters, residual liver volume, and liver function indexes before and after TACE, RFS, OS, and complications were collected and compared. Treatment response was evaluated at 1 month after TACE. Tumor diameter was evaluated by abdominal computed tomography scan. The residual liver volume was evaluated by IQQA liver system, and relapse-free survival (RFS) and overall survival (OS) were calculated by Kaplan–Meier curves. Results The conversion rate in DEB-TACE group was higher than cTACE group (18.8% vs 8%, p = 0.032). In DEB-TACE group, 17 patients achieved objective response rate (ORR) which was higher than cTACE group (70.8% vs 34.4%, p = 0.007). The tumor necrosis rate was higher in DEB-TACE group, but there was no significant difference between the two groups (p = 0.053). Tumor diameter was decreased after TACE compared to before TACE (DEB-TACE: 9.4 ± 3.3 vs. 5.4 ± 3.5 cm, p = 0.003; cTACE: 9.7 ± 2.6 vs. 6.9 ± 2.2, p = 0.036). As to residual liver volume, it was increased after TACE compared to before TACE (1066.2 cm3 vs. 1180.3 cm3, p = 0.007) in DEB-TACE group, while there was no significant difference in cTACE group (1046.4 cm3 vs. 1170 cm3, p = 0.339) compared by paired-sample t-test, but there was no significant difference before and after TACE when compared by unpaired-sample t-test (p > 0.05). After TACE at 1 month, the AFP level in the DEB-TACE group was significantly lower than that in the cTACE group (p = 0.003). For survival, the median RFS was 26.0 months in DEB-TACE group and 15 months in cTACE group; there was significant difference between the two groups (p = 0.0465). As to OS, the median OS in DEB-TACE group was higher than that in cTACE group, but there was no significant difference between the two groups (p = 0.165). For safety profiles, in terms of liver function and adverse events, there was no significant difference between the two groups. Conclusion Compared with cTACE, DEB-TACE might be a more efficient and safety down-staging treatment in unresectable liver cancer patients.

Abstract Hyoscine-N-butylbromide (HBB) is the most used antiperistaltic agent during esophagogastroduodenoscopy (EGD). However, almost half of the elderly have a contraindication to HBB. We aimed to evaluate l-menthol’s antiperistaltic effect and safety for EGD in the elderly with contraindication to HBB. This prospective, randomized, double-blind, placebo-controlled study screened 86 elderly patients (≥ 65 years old) scheduled to undergo EGD, and 52 of them with contraindication to HBB were enrolled. The participants were randomized to receive l-menthol (n = 26) or a placebo (n = 26), which was locally sprayed on the gastric antrum endoscopically. The proportion of patients with no or mild peristalsis after medication and at the end of EGD was significantly higher in the l-menthol group (76.9%) than in the placebo group (11.5%, p

Tumor necrosis factor (TNF)-α is a proinflammatory cytokine involved in the pathogenesis of sarcopenia, but its short half-life and inconsistent reproducibility limit the potential of TNF-α to be an ideal sarcopenia biomarker. Anti-TNF-α, a natural consequent autoantibody to TNF-α, is an indicator of relatively prolonged TNF-α exposure, has more stable concentrations than TNF-α and should be a better alternative as a biomarker of sarcopenia. Data from 484 participants from the I-Lan Longitudinal Aging Study were used for this study, and sarcopenia was defined by the Asian Working Group for Sarcopenia 2019 consensus. Plasma levels of anti-TNF-α were determined by a sandwich ELISA approach, and levels of TNF-α were determined by an immunoassay. Compared to nonsarcopenic participants, 43 sarcopenic participants had higher levels of anti-TNF-α (0.73 ± 0.19 vs. 0.79 ± 0.25 OD, p = 0.045). Plasma levels of anti-TNF-α were positively correlated with TNF-α (r = 0.24, p

Abstract Background Sarcopenic obesity aims to capture the risk of functional decline and cardiometabolic diseases, but its operational definition and associated clinical outcomes remain unclear. Using data from the Longitudinal Aging Study of Taipei, this study explored the roles of the muscle‐to‐fat ratio (MFR) with different definitions and its associations with clinical characteristics, functional performance, cardiometabolic risk and outcomes. Methods (1) Appendicular muscle mass divided by total body fat mass (aMFR), (2) total body muscle mass divided by total body fat mass (tMFR) and (3) relative appendicular skeletal muscle mass (RASM) were measured. Each measurement was categorized by the sex‐specific lowest quintiles for all study participants. Clinical outcomes included all‐cause mortality and fracture. Results Data from 1060 community‐dwelling older adults (mean age: 71.0 ± 4.8 years) were retrieved for the study. Overall, 196 (34.2% male participants) participants had low RASM, but none was sarcopenic. Compared with those with high aMFR, participants with low aMFR were older (72 ± 5.6 vs. 70.7 ± 4.6 years, P = 0.005); used more medications (2.9 ± 3.3 vs. 2.1 ± 2.5, P = 0.002); had a higher body fat percentage (38 ± 4.8% vs. 28 ± 6.4%, P

A major unmet need in the cystic fibrosis (CF) therapeutic landscape is the lack of effective treatments for nonsense CFTR mutations, which affect approximately 10% of CF patients. Correction of nonsense CFTR mutations via genomic editing represents a promising therapeutic approach. In this study, we tested whether prime editing, a novel CRISPR-based genomic editing method, can be a potential therapeutic modality to correct nonsense CFTR mutations. We generated iPSCs from a CF patient homozygous for the CFTR W1282X mutation. We demonstrated that prime editing corrected one mutant allele in iPSCs, which effectively restored CFTR function in iPSC-derived airway epithelial cells and organoids. We further demonstrated that prime editing may directly repair mutations in iPSC-derived airway epithelial cells when the prime editing machinery is efficiently delivered by helper-dependent adenovirus (HDAd). Together, our data demonstrated that prime editing may potentially be applied to correct CFTR mutations such as W1282X.

Abstract Background Few studies have made longitudinal comparisons between frailty phenotype (FP) and frailty index (FI) changes. We aimed to investigate frailty status changes defined by FP and FI concurrently, and to compare the associated factors and incident disability among different combination of FI and FP trajectory groups. Methods Data on respondents aged over 50 who completed the 1999, 2003 and 2007 Taiwan Longitudinal Study on Aging (TLSA) surveys (n = 2807) were excerpted. Changes of FI, FP and major time-dependent variables were constructed by group-based trajectory modeling. Logistic regression was used to investigate the associated factors and relationships with incident disability among different frailty trajectories. Results We identified four FP trajectories – stably robust, worsened frailty, improved frailty, and stably frail and three FI trajectories – stable FI, moderate increase FI and rapid increase FI. Lower self-rated health, mobility impairment, and depressed mood were associated with unfavorable FP and FI changes (all p