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Abstract Background As the second most populous country in the world, China has a huge demand for health human resources. Over the past decade, the Chinese government has continuously increased investment in the health sector and implemented relevant policies and systems in an attempt to enhance the overall quantity and equity of health human resources. This study aims to analyze the equity and developmental trends in the allocation of health human resources in China from 2012 to 2021, providing reference and theoretical support for the government’s further optimization of health human resources allocation. Methods This study collected health human resources data from 31 provinces, municipalities, and autonomous regions in China from 2012 to 2021. The methods employed included Lorenz curves, Gini coefficients, and agglomeration degree analysis, which examined the developmental trends and equity of health human resources from the perspectives of population and geographical. Results This study found that over the past decade, there has been a significant increase in the total quantity of health human resources in China, accompanied by an improvement in equity, although disparities still exist. There are notable variations in the distribution of health human resources based on geographical area, with disparities between different regions. Relative shortages of health human resources are observed in western regions, while some areas in the eastern and central regions exhibit an abundance or surplus of health human resources. Conclusion Overall, health human resources in China have experienced stable development, with an incremental improvement in allocation equity, yet there remains considerable room for progress. It is imperative to continue strengthening policy guidance and regulation to facilitate the rational flow of health human resources, narrow regional disparities, and achieve the goal of universal health coverage.

Abstract The Qinling water conveyance tunnel has a large buried depth and high in-situ stress level, and rockburst disasters frequently occurred during excavation. In order to find out the mechanical mechanism of rockburst, the research work in this paper is as follows: (1) In-situ three-dimensional hydraulic fracturing method was used to measure the in-situ stress of the deep buried tunnel crossing the ridge. (2) Based on the measured in-situ stress results, the stress distribution characteristics of the tunnel crossing the ridge were obtained by the multiple linear regression method, and the rockburst tendency during construction was predicted. (3) A three-dimensional numerical model of tunnel excavation was established to analyze the dynamic adjustment characteristics of the surrounding rock stress and elastic strain energy during TBM excavation, and to clarify the mechanical mechanism of rockburst. The research results show that the maximum principal stress of the deep-buried tunnel crossing the ridge of Qinling is 40–66 MPa, which belongs to extremely high in-situ stress level, and medium-strong rockburst may occur during excavation. In the process of TBM excavation, the stress of the surrounding rock in the range of 2.6 times the diameter of the tunnel before and after the working face is adjusted violently, and the concentrated zones after the stress redistribution are mainly distributed in the arch roof and arch bottom, and the stress concentration coefficient can reach 2.06. The arch roof, arch waist, and arch bottom are susceptible to immediate rockburst due to stress transient unloading at the moment of excavation. After the elastic strain energy of the surrounding rock at the arch roof and the arch bottom is released and accumulated, it is easy to cause time delayed rockburst, and the depth of the rockburst pit can reach 3.5 m, which is consistent with the rockburst phenomenon in the field.

Abstract In this work, an innovative design model aimed at enhancing the efficacy of ground-state probabilistic logic with a binary energy landscape (GSPL-BEL) is presented. This model enables the direct conversion of conventional CMOS-based logic circuits into corresponding probabilistic graphical representations based on a given truth table. Compared to the conventional approach of solving the configuration of Ising model-basic probabilistic gates through linear programming, our model directly provides configuration parameters with embedded many-body interactions. For larger-scale probabilistic logic circuits, the GSPL-BEL model can fully utilize the dimensions of many-body interactions, achieving minimal node overhead while ensuring the simplest binary energy landscape and circumventing additional logic synthesis steps. To validate its effectiveness, hardware implementations of probabilistic logic gates were conducted. Probabilistic bits were introduced as Ising cells, and cascaded conventional XNOR gates along with passive resistor networks were precisely designed to realize many-body interactions. HSPICE circuit simulation results demonstrate that the probabilistic logic circuits designed based on this model can successfully operate in free, forward, and reverse modes, exhibiting the simplest binary probability distributions. For a 2-bit × 2-bit integer factorizer involving many-body interactions, compared to the logic synthesis approach, the GSPL-BEL model significantly reduces the number of consumed nodes, the solution space (in the free-run mode), and the number of energy levels from 12, 4096, and 9–8, 256, and 2, respectively. Our findings demonstrate the significant potential of the GSPL-BEL model in optimizing the structure and performance of probabilistic logic circuits, offering a new robust tool for the design and implementation of future probabilistic computing systems.

BackgroundThe expansion of higher education and the growing number of college students have led to increased awareness of mental health issues such as stress, anxiety, and eating disorders. In China, the educational system and cultural expectations contribute to the stress experienced by college students. This study aims to clarify the role of anxiety as a mediator in the relationship between stress and eating behaviors among Chinese college students.MethodsThis study utilized data from the 2021 Psychology and Behavior Investigation of Chinese Residents, which included 1,672 college students under the age of 25. The analysis methods comprised descriptive statistics, t-tests, Pearson correlation analyses, and mediation effect analysis.ResultsThe findings indicate that Chinese college students experience high levels of stress, with long-term stress slightly exceeding short-term stress. Both types of stress were positively correlated with increased anxiety and the adoption of unhealthy eating behaviors. Anxiety was identified as a significant mediator, accounting for 28.3% of the relationship between long-term stress and eating behavior (95% CI = 0.058–0.183). The mediation effect of short-term stress on eating behavior through anxiety was also significant, explaining 61.4% of the total effect (95% CI = 0.185–0.327).ConclusionThe study underscores the importance of stress management and mental health services for college students. It recommends a comprehensive approach to reducing external pressures, managing anxiety, and promoting healthy eating behaviors among college students. Suggestions include expanding employment opportunities, providing career guidance, enhancing campus and societal support for holistic development, strengthening mental health services, leveraging artificial intelligence technologies, educating on healthy lifestyles, and implementing targeted health promotion programs.

BackgroundT cell exhaustion is a state in which T cells become dysfunctional and is associated with a decreased efficacy of immune checkpoint inhibitors. Lung cancer has the highest mortality among all cancers. However, the roles of genetic variants of the T cell exhaustion-related genes in the prognosis of non-small cell lung cancer (NSCLC) patients has not been reported.MethodsWe conducted a two-stage multivariable Cox proportional hazards regression analysis with two previous genome-wide association study (GWAS) datasets to explore associations between genetic variants in the T cell exhaustion-related genes and survival of NSCLC patients. We also performed expression quantitative trait loci analysis for functional validation of the identified variants.ResultsOf all the 52,103 single nucleotide polymorphisms (SNPs) in 672 T cell exhaustion-related genes, 1,721 SNPs were found to be associated with overall survival (OS) of 1185 NSCLC patients of the discovery GWAS dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, and 125 of these 1,721 SNPs remained significant after validation in an additional independent replication GWAS dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. In multivariable stepwise Cox model analysis, three independent SNPs (i.e., LRRC8C rs10493829 T>C, OAS2 rs2239193 A>G, and CCL25 rs3136651 T>A) remained significantly associated with OS with hazards ratios (HRs) of 0.86 (95% confidence interval (CI) = 0.77-0.96, P = 0.008), 1.48 (95% CI = 1.18-1.85, P < 0.0001) and 0.78 (95% CI = 0.66-0.91, P = 0.002), respectively. Further combined analysis for these three SNPs suggested that an unfavorable genotype score was associated with a poor OS and disease-specific survival. Expression quantitative trait loci analysis suggested that the LRRC8C rs10493829 C allele was associated with elevated LRRC8C mRNA expression levels in normal lymphoblastoid cells, lung tissue, and whole blood.ConclusionOur findings suggested that these functional SNPs in the T cell exhaustion-related genes may be prognostic predictors for survival of NSCLC patients, possibly via a mechanism of modulating corresponding gene expression.

Abstract To study the fracture instability characteristics and fracture mechanism of overlying strata in steeply dipping and large mining height stope, through the combination of physical simulation experiment, numerical calculation, theoretical analysis and field measurement, the correlation between the evolution of mining stress field and the fracture of overlying strata in large mining height stope under the effect of dip angle is analyzed, and the stress transfer path and the fracture mechanism of overlying strata are revealed. Finally, the influence mechanism of key strata on the evolution of the mining stress field of overlying strata is explained. The research shows that under the influence of gravity dip angle effect and mining height increase, the mining stress is non-equilibrium transferred and evolved in space, and the principal stress field presents the characteristics of partition evolution. The fracture trajectory of rock strata is multi-step and “八” shaped, and the inclined masonry structure and multi-step key strata form a cooperative bearing structure. The key layer of the ladder is the stress transmission structure between the caving zone and the stress arch, and the high stress in the overhanging area under the main roof is transmitted to the advanced roof. With the increase of dip angle, the height of the caving zone decreases, and the fracture range of ladder and principal stress arch decreases. The cracks in the middle and upper broken rock blocks increase, and the instability of the “high ladder rock layer” is easy to induce the simultaneous fracture of the “inclined masonry structure”, resulting in regional unbalanced instability and impact. The research results can provide some reference and guiding significance for the stability control of surrounding rock in longwall stope with steeply dipping.

Abstract Protected surface states arising from non-trivial bandstructure topology in semimetals can potentially enable advanced device functionalities in compute, memory, interconnect, sensing, and communication. This necessitates a fundamental understanding of surface-state transport in nanoscale topological semimetals. Here, we investigate quantum transport in a prototypical topological semimetal NbAs to evaluate the potential of this class of materials for beyond-Cu interconnects in highly-scaled integrated circuits. Using density functional theory (DFT) coupled with non-equilibrium Green’s function (NEGF) calculations, we show that the resistance-area R A product in NbAs films decreases with decreasing thickness at the nanometer scale, in contrast to a nearly constant R A product in ideal Cu films. This anomalous scaling originates from the disproportionately large number of surface conduction states which dominate the ballistic conductance by up to 70% in NbAs thin films. We also show that this favorable R A scaling persists even in the presence of surface defects, in contrast to R A sharply increasing with reducing thickness for films of conventional metals, such as Cu, in the presence of surface defects. These results underscore the potential of topological semimetals as future back-end-of-line (BEOL) interconnect metals.

Abstract Background Intensive longitudinal data (ILD) collected in near real time by mobile health devices provide a new opportunity for monitoring chronic diseases, early disease risk prediction, and disease prevention in health research. Functional data analysis, specifically functional principal component analysis, has great potential to abstract trends in ILD but has not been used extensively in mobile health research. Objective To introduce functional principal component analysis (fPCA) and demonstrate its potential applicability in estimating trends in ILD collected by mobile heath devices, assessing longitudinal association between ILD and health outcomes, and predicting health outcomes. Methods fPCA and scalar-to-function regression models were reviewed. A case study was used to illustrate the process of abstracting trends in intensively self-measured blood glucose using functional principal component analysis and then predicting future HbA1c values in patients with type 2 diabetes using a scalar-to-function regression model. Results Based on the scalar-to-function regression model results, there was a slightly increasing trend between daily blood glucose measures and HbA1c. 61% of variation in HbA1c could be predicted by the three preceding months’ blood glucose values measured before breakfast (P

Metal powders are essential for additive manufacturing (AM), with their morphology significantly impacting the performance of AM components. Gas atomisation (GA) is a common method for producing metal powders due to its efficiency and cost-effectiveness. However, GAed powders often exhibit defects such as alien powders, satellite powders, and hollow powders, which can adversely affect the AM process. To address these challenges, coaxial gas technology has been introduced and analysed through numerical simulation. Our study involved comparing GA processes with and without coaxial gas technology to generate two types of powders. These powders were assessed using Synchrotron X-ray computed tomography (SXCT) and classification algorithms. The pores in AM components manufactured from these powders were examined using SXCT, and their mechanical properties were evaluated through tensile tests. The findings of our research validate the effectiveness of coaxial gas technology in reducing powder defects and enhancing the performance of AM components.

Abstract Background Hypoxia is often involved in tumor microenvironment, and the hypoxia‐induced signaling pathways play a key role in aggressive cancer phenotypes, including angiogenesis, immune evasion, and therapy resistance. However, it is unknown what role genetic variants in the hypoxia‐related genes play in survival of patients with non‐small cell lung cancer (NSCLC). Methods We evaluated the associations between 16,092 single‐nucleotide polymorphisms (SNPs) in 182 hypoxia‐related genes and survival outcomes of NSCLC patients. Data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial were used as the discovery dataset, and the Harvard Lung Cancer Susceptibility (HLCS) Study served as the replication dataset. We also performed additional linkage disequilibrium analysis and a stepwise multivariable Cox proportional hazards regression analysis in the PLCO dataset. Results An independent SNP, ERRFI1 rs28624 A > C, was identified with an adjusted hazards ratio (HR) of 1.31 (95% CI = 1.14–1.51, p = 0.0001) for overall survival (OS). In further analyses, unfavorable genotypes AC and CC, compared with the AA genotype, were associated a worse OS (HR = 1.20, 95% CI = 1.03–1.39, p = 0.014) and disease‐specific survival (HR = 1.21, 95% CI = 1.04–1.42, p = 0.016). Further expression quantitative trait loci analysis indicated that ERRFI1 rs28624C genotypes were significantly associated with higher ERRFI1 mRNA expression levels in the whole blood. Additional analysis showed that high ERRFI1 mRNA expression levels were associated with a worse OS in patients with lung adenocarcinoma. Conclusion Our findings suggest that genetic variants in the hypoxia‐related gene ERRFI1 may modulate NSCLC survival, potentially through their effect on the gene expression.

B cells are adaptive immune cells in the tumor microenvironment and play an important role in tumor development and metastasis. However, the roles of genetic variants of the immunity B cell-related genes in the survival of patients with non-small cell lung cancer (NSCLC) remain unknown. In the present study, we first evaluated associations between 10,776 single nucleotide polymorphisms (SNPs) in 220 immunity B cell-related genes and survival of NSCLC in a discovery dataset of 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We found that 369 SNPs were significantly associated with overall survival (OS) of NSCLC in multivariable Cox proportional hazards regression analysis (P ≤ 0.05, Bayesian false discovery probability ≤ 0.80), of which 18 SNPs were validated in another independent genotyping dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. We then performed linkage disequilibrium (LD) analysis, followed by stepwise analysis with a multivariable Cox regression model. Finally, two independent SNPs, inositol polyphosphate-5-phosphatase D (INPP5D) rs13385922 C>T and exosome component 3 (EXOSC3) rs3208406 A>G, remained significantly associated withNSCLC OS with a combined hazards ratio (HR) of 1.14 (95% confidence interval = 1.06-1.23, P = 2.41×10-4) and 1.20 (95% confidence interval = 1.14-1.28, P = 3.41×10-9), respectively. Furthermore, NSCLC patients with the combination of unfavorable genotypes for these two SNPs were associated with a poor OS (Ptrend = 0.0002) and disease-specific survival (DSS, Ptrend < 0.0001) in the PLCO dataset. Expression quantitative trait loci (eQTL) analysis suggested that the INPP5D rs6782875 T allele was significantly correlated with elevated INPP5D mRNA expression levels in normal lung tissues and whole blood samples, while the EXOSC3 rs3208406 G allele was significantly correlated with increased EXOSC3 mRNA expression levels in normal lung tissues. Our data indicated that genetic variants in these immunity B cell-related genes may predict NSCLC survival possibly by influencing the gene expression.

The present study was conducted to evaluate the effect of dietary Silphium perfoliatum L. on growth performance, immunity, intestinal health, and resistance against Nocardia seriolae of largemouth bass. Four dietary concentrations of S. perfoliatum L. were prepared: 0% (SPL0), 1% (SPL1), 2.5% (SPL2.5), and 5% (SPL5). After 60 d feeding, a challenge test was conducted by injecting N. seriolae intraperitoneally. The results showed that supplementing the diets with S. perfoliatum L. could promote the weight gain rate, specific growth rate, and feed intake. Meantime, S. perfoliatum L. could also enhance the activity of immune-related enzymes and improve the expression of immune-related genes in the liver. Compared to the control group, S. perfoliatum L. improved intestinal morphology and reduced the abundance of harmful bacteria in intestinal microbiota. Importantly, supplementing the diets with S. perfoliatum L. protected largemouth bass from N. seriolae infection, resulting in a relative percent survival (RPS) of 24% (SPL1), 31.99% (SPL2.5), and 43.99% (SPL5). In conclusion, the present study showed that S. perfoliatum L. could boost growth performance, enhance immunity, promote intestinal health, and improve the ability of largemouth bass against N. seriolae infection.

Ivosidenib, an isocitrate dehydrogenase 1 (IDH1) inhibitor, has demonstrated clinical benefits in a pivotal study (AG120-C-001) in patients with IDH1-mutated (mIDH1) acute myeloid leukemia (AML). A registry study (CS3010-101: NCT04176393) was conducted to assess the pharmacokinetic (PK) characteristics, safety, and efficacy of ivosidenib in Chinese patients with relapsed or refractory (R/R) mIDH1 AML. Patients received ivosidenib 500 mg once daily for 28-day cycles until disease progression. Ten subjects underwent intensive PK/progressive disease (PD) assessments. All subjects had the clinical response assessed at screening, every 28 days through month 12, and then every 56 days. Between November 12, 2019, and April 2, 2021, 30 patients were enrolled; 26 (86.7%) had de novo AML and 18 (60.0%) were transfusion-dependent at baseline. Following single and repeated doses of ivosidenib, median time to maximum plasma concentration (Tmax) was 4.0 and 2.0 hours, respectively. The inter-individual variability of pharmacokinetic exposure was moderate to high (coefficient of variation [CV], 25%–53%). No obvious accumulation was observed after repeated doses at cycle 2 day 1. Regarding the clinical response, the CR + CRh rate was 36.7% (95% confidence interval [CI]: 19.9%–56.1%), the median duration of CR + CRh was 19.7 months (95% CI: 2.9 months–not reached [NR]), and median duration of response (DoR) was 14.3 months (95% CI: 6.4 months–NR). Consistent clinical benefits and safety of ivosidenib were consistently observed at the final data cutoff with median follow-up time 26.0 months, as compared with primary data cutoff, and the data from Chinese R/R mIDH1 AML patients were also consistent with results from pivotal study.

Summary: Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with traditional endocrine therapy (ET) are now the recommended first-line treatment for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (MBC). However, the benefits of adding CDK4/6 inhibitors to ET in HER2-low-positive and HER2-0 subgroups remain unclear. We aimed to assess the effectiveness of CDK4/6 inhibitors in combination with ET in patients with HR-positive, HER2-low-positive and HER2-0 MBC. Methods: This secondary analysis assessed progression-free survival (PFS) among HER2-low-positive and HER2-0 patients enrolled in the double-blind, placebo-controlled randomised clinical trials PALOMA-2 and PALOMA-3. The study included 1186 HER2-negative, HR-positive female patients, with available immunohistochemistry (IHC) and/or in situ hybridization (ISH) results, across 17 countries enrolled between February 2013 and August 2014. HER2-low-positive status was defined by IHC 1+ or 2+ with negative ISH, and HER2-zero by IHC 0. Data analyses were conducted between March and May 2023. In the PALOMA-2 trial, patients were randomly assigned to receive either palbociclib or placebo, in combination with letrozole in the first-line treatment for HR-positive MBC. Patients in the PALOMA-3 study, who had progression or relapse during previous ET, were randomly allocated to receive either palbociclib plus fulvestrant or placebo plus fulvestrant. The primary endpoint was investigator-assessed PFS. Kaplan–Meier approach and Cox proportional hazards model were applied to estimate the association of treatment strategies with PFS among HER2-0 and HER2-low-positive populations. The two trials are registered with ClinicalTrials.gov, number NCT01740427 and NCT01942135. Findings: Of the 666 patients with MBC from the PALOMA-2 study, there were 153 HER2-0 and 513 HER2-low-positive patients. In the HER2-0 population, no significant difference in PFS was observed between the palbociclib-letrozole and placebo-letrozole groups (hazard ratio = 0.79, 95% confidence interval [CI] 0.48–1.30, p = 0.34). In the HER2-low-positive population, palbociclib-letrozole demonstrated a significantly lower risk of PFS than placebo-letrozole group (hazard ratio = 0.52, 95% CI 0.41–0.66, p

Abstract The nonlinear Hall effect (NLHE) is a phenomenon which could produce a transverse Hall voltage in a time-reversal-invariant material. Here, we report the real space characterizations of NLHE evaluated through quantum transport in TaIrTe4 nanoribbon without the explicit Berry curvature dipole (BCD) information. We first characterize the NLHE in both transverse confined directions in global-level measurement. The impact of quantum confinement in NLHE is evaluated by adjusting the width of nanoribbons. Then, the probing area is trimmed to the atomic scale to evaluate the local texture, where we discover its patterns differ among the probed neighboring atomic groups. The analysis of charge distribution reveals the connections between NLHE’s local patterns and its non-centrosymmetric nature, rendering nearly an order of Hall voltage enhancement through probe positioning. Our work paves the way to expand the range of NLHE study and unveil its physics in more versatile material systems.

Abstract Background There is a causal link between childhood socioeconomic status and health status in adulthood and beyond. It's vital to comprehend the relationship between childhood socioeconomic status and mental health among older Chinese individuals from the current generation who have undergone significant social changes in China. This understanding is critical to foster healthy demographic and social development in China. Methods Using data from the 2020 China Family Panel Studies, we investigate the relationship between childhood socioeconomic status and depression in older adults. Additionally, we examine the mediating role of adult socioeconomic status and subjective well-being. Results 1) Childhood socioeconomic status of Chinese older adults differences by region of residence, while depression levels differences by gender, region of residence, and marital status. 2) Adult socioeconomic status mediated the relationship between childhood socioeconomic status and depression in older adults. 3) Adult socioeconomic status and subjective well-being had a chain-mediated role in the relationship between childhood socioeconomic status and depression in older adults. Conclusions In terms of childhood socioeconomic status, older adults in urban regions were significantly higher than those in rural regions. As for depression level, female older adults were more depressed than males; married older people have the lowest depression levels, while unmarried and widowed older people have higher depression levels; older adults in rural regions had higher depression levels than those in urban regions. Evidence from our study further suggests that childhood socioeconomic status can suppress the depression level in older adults through adult socioeconomic status; it can also further reduce the depression level in older adults through the chain mediation of adult economic status affecting subjective well-being. As depression is more prevalent among older individuals with a lower childhood socioeconomic status, it is vital to prioritize the extensive impact of childhood socioeconomic status as a distal factor and investigate "upstream" solutions to enhance childhood socioeconomic status and reduce the gap during the early years of life.

Abstract Purpose Previous randomized studies have shown a survival benefit of using regorafenib but a high rate of adverse events in unresectable colorectal cancer patients. To reduce these adverse events and improve the tolerability, we examined the appropriate dose of regorafenib based on body weight. Methods We used a nationwide claims database in Japan and examined the efficacy and safety of regorafenib for patients with metastatic colorectal cancer between groups divided by body weight (60 kg) and median average dose (120 mg) between 2013 and 2018. We also assessed overall survival (OS) and adverse events between these groups. Results We identified 2530 Japanese patients (heavy weight/high dose: 513, light weight/low dose: 921, heavy weight/low dose: 452, and light weight/high dose: 644). There was no significant difference in the adverse events and OS after inverse probability treatment weighting (IPTW) adjustment between heavy weight/high dose group and light weight/low dose group (hazard ratio, HR=0.97). Among the light-weight patients, higher average dose was associated with shorter OS (IPTW adjusted HR=1.21, 95% CI 1.05 – 1.39, Table 3) while among the heavy-weight patients, there was no significant difference in OS between high and low dose groups (IPTW adjusted HR=1.14, 95% CI 0.95 – 1.37). Conclusion The findings suggest that a low dose of regorafenib for light-weight patients may be as safe and effective as high doses for heavy-weight patients. Further studies should be conducted to identify an appropriate dose based on each patient's physique and condition.

Abstract INTRODUCTION Alzheimer's disease (AD) is a neurodegenerative disorder characterized by declines in cognitive and functional severities. This research utilized the Clinical Dementia Rating (CDR) to assess the influence of tilavonemab on these deteriorations. METHODS Longitudinal Item Response Theory (IRT) models were employed to analyze CDR domains in early‐stage AD patients. Both unidimensional and multidimensional models were contrasted to elucidate the trajectories of cognitive and functional severities. RESULTS We observed significant temporal increases in both cognitive and functional severities, with the cognitive severity deteriorating at a quicker rate. Tilavonemab did not demonstrate a statistically significant effect on the progression in either severity. Furthermore, a significant positive association was identified between the baselines and progression rates of both severities. DISCUSSION While tilavonemab failed to mitigate impairment progression, our multidimensional IRT analysis illuminated the interconnected progression of cognitive and functional declines in AD, suggesting a comprehensive perspective on disease trajectories. Highlights Utilized longitudinal Item Response Theory (IRT) models to analyze the Clinical Dementia Rating (CDR) domains in early‐stage Alzheimer's disease (AD) patients, comparing unidimensional and multidimensional models. Observed significant temporal increases in both cognitive and functional severities, with cognitive severity deteriorating at a faster rate, while tilavonemab showed no statistically significant effect on either domain's progression. Found a significant positive association between the baseline severities and their progression rates, indicating interconnected progression patterns of cognitive and functional declines in AD. Introduced the application of multidimensional longitudinal IRT models to provide a comprehensive perspective on the trajectories of cognitive and functional severities in early AD, suggesting new avenues for future research including the inclusion of time‐dependent random effects and data‐driven IRT models.

In large-scale poultry farming, real-time online measurement of egg weight and shape parameters remains a challenge. To address this, we developed FEgg3D, a non-contact dynamic measuring device based on a self-designed laser scanner. The device employed a subset of the point cloud generated to predict the shape parameters and weight of eggs using machine learning algorithms. Different colors and sizes of eggs on various backgrounds were scanned using FEgg3D mounted on a gantry system. Our results demonstrated the following: (1) The Support Vector Regression (SVR) model was optimal for major axis length estimation, with an R2 of 0.932 using six laser lines and eight points per line. (2) The Gaussian Process Regression (GPR) model excelled in minor axis length estimation, achieving an R2 of 0.974 with six laser lines and 16 points per line. (3) SVR was optimal for volume estimation, attaining an R2 of 0.962 with six laser lines and 16 points per line. (4) GPR showed superior performance in weight prediction, with an R2 of 0.964 using five laser lines and 16 points per line. Including density features significantly improved accuracy to an R2 of 0.978. This approach paves the way for advanced online egg measurement in commercial settings.

Abstract Tumor-infiltrating immune cells and fibroblasts are significant components of the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC), and they participate in tumor progression as closely as tumor cells. However, the relationship between the features of the TME and patient outcomes and the interactions among TME components are still unclear. In this study, we evaluated the PDAC TME in terms of the quantity and location of cluster of differentiation (CD)4+ T cells, CD8+ T cells, macrophages, stromal maturity, and tumor-stroma ratio (TSR), as evaluated by immunohistochemical staining of serial whole-tissue sections from 116 patients with PDAC. The density of T cells and macrophages (mainly activated macrophages) was significantly higher at the invasive margins (IMs) than at the tumor center (TC). CD4+ T cells were significantly association with all the other tumor-associated immune cells (TAIs) including CD8, CD68 and CD206 positive cells. Tumors of the non-mature (intermediate and immature) stroma type harbored significantly more CD8+ T cells at the IMs and more CD68+ macrophages at the IMs and the TC. The density of CD4+, CD8+, and CD206+ cells at the TC; CD206+ cells at the IMs; and tumor-node-metastasis (TNM) staging were independent risk factors for patient outcomes, and the c-index of the risk nomogram for predicting the survival probability based on the TME features and TNM staging was 0.772 (95% confidence interval: 0.713–0.832). PDAC harbored a significantly immunosuppressive TME, of which the IMs were the hot zones for TAIs, while cells at the TC were more predictive of prognosis. Our results indicated that the model based on the features of the TME and TNM staging could predict patient outcomes.

Regarding the replacement and maintenance of submarine buried cables, a piece of equipment, i.e., a submarine buried cable detection and hanging device, was specifically designed in this study that can be used to hook and mark a submarine buried cable, with the aim of facilitating underwater operation tools in completing future maintenance and repair. To verify the equipment design, a test bench was prepared for technical testing. During the test, feedback signals of the detection and hanging device were collected through an integrated displacement sensor and a pressure sensor. From the signal data, the operation window diagram corresponding to submarine buried cable detection and hanging information was established. Finally, the operation window diagram was used to guide and judge whether the detection and hanging device successfully marked the hook of submarine buried cable or not. The research results could provide important technical support as well as experimental basis for further design and application of underwater operation tools.

Background and Purpose: The International Movement Disorder Society revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) is widely used in the assessment of the severity of Parkinson’s disease (PD). This study aimed to validate the Kazakh version of the MDS-UPDRS, explore its dimensionality, and compare it to the original English version. Methods: The validation was conducted in three phases: first, the English version of the MDS-UPDRS was translated into Kazakh and thereafter back-translated into English by two independent teams; second, the Kazakh version underwent a cognitive pretesting; third, the Kazakh version was tested in 360 native Kazakh-speaking PD patients. Both confirmatory and exploratory factor analyses were performed to validate the scale. We calculated the comparative fit index (CFI) for confirmatory factor analysis and used unweighted least squares for exploratory factor analysis. Results: The CFI was higher than 0.90 for all parts of the scale, thereby meeting the pre-set threshold for the official designation of a validated translation. Exploratory factor analysis also showed that the Kazakh MDS-UPDRS has the analogous factors structure in each part as the English version. Conclusions: The Kazakh MDS-UPDRS had a consistent overall structure as the English MDS-UPDRS, and it was designated as the official Kazakh MDS-UPDRS, which can reliably be used in the Kazakh-speaking populations. Presently, Kazakhstan stands as the sole country in both Central Asia and Transcaucasia with an MDS-approved translated version of the MDS-UPDRS. We expect that other Central Asian and Transcaucasian countries will embark on the MDS Translation Program for MDS-UPDRS in the near future.

BackgroundThe GABRA1 gene, encoding the GABRAR subunit α1, plays vital roles in inhibitory neurons. Previously, the GABRA1 gene has been identified to be associated with developmental and epileptic encephalopathy (DEE) and idiopathic generalized epilepsy (IGE). This study aims to explore the phenotypic spectrum of GABRA1 and molecular subregional effect analysis.MethodsTrios-based whole-exome sequencing was performed in patients with epilepsy. Previously reported GABRA1 mutations were systematically reviewed to analyze the molecular subregional effects.ResultsDe novo GABRA1 mutations were identified in six unrelated patients with heterogeneous epilepsy, including three missense mutations (p.His83Asn, p.Val207Phe, and p.Arg214Cys) and one frameshift mutation (p.Thr453Hisfs*47). The two missense mutations, p.His83Asn and p.Val207Phe, were predicted to decrease the protein stability but no hydrogen bond alteration, with which the two patients also presented with mild genetic epilepsy with febrile seizures plus and achieved seizure-free status by monotherapy. The missense variant p.Arg214Cys was predicted to decrease protein stability and destroy hydrogen bonds with surrounding residues, which was recurrently identified in three cases with severe DEE. The frameshift variant p.Thr453Hisfs*47 was located in the last fifth residue of the C-terminus and caused an extension of 47 amino acids, with which the patients presented with moderated epilepsy with generalized tonic-clonic seizures alone (GTCA) but achieved seizure-free status by four drugs. The four variants were not presented in gnomAD and were evaluated as “pathogenic/likely pathogenic” according to ACMG criteria. Analysis of all reported cases indicated that patients with mutations in the N-terminal extracellular region presented a significantly higher percentage of FS and DEE, and the patients with variants in the transmembrane region presented earlier seizure onset ages.SignificanceThis study suggested that GABRA1 variants were potentially associated with a spectrum of epilepsies, including EFS+, DEE, and GTCA. Phenotypic severity may be associated with the damaging effect of variants. The molecular subregional effects help in understanding the underlying mechanism of phenotypic variation.

BackgroundThe DLG3 gene encodes disks large membrane-associated guanylate kinase scaffold protein 3, which plays essential roles in the clustering of N-methyl-D-aspartate receptors (NMDARs) at excitatory synapses. Previously, DLG3 has been identified as the causative gene of X-linked intellectual developmental disorder—90 (XLID-90; OMIM# 300850). This study aims to explore the phenotypic spectrum of DLG3 and the genotype-phenotype correlation.MethodsTrios-based whole-exome sequencing was performed in patients with epilepsy of unknown causes. To analyze the genotype-phenotype correlations, previously reported DLG3 variants were systematically reviewed.ResultsDLG3 variants were identified in seven unrelated cases with epilepsy. These variants had no hemizygous frequencies in controls. All variants were predicted to be damaging by silico tools and alter the hydrogen bonds with surrounding residues and/or protein stability. Four cases mainly presented with generalized seizures, including generalized tonic-clonic and myoclonic seizures, and the other three cases exhibited secondary generalized tonic-clonic seizures and focal seizures. Multifocal discharges were recorded in all cases during electroencephalography monitoring, including the four cases with generalized discharges initially but multifocal discharges after drug treating. Protein-protein interaction network analysis revealed that DLG3 interacts with 52 genes with high confidence, in which the majority of disease-causing genes were associated with a wide spectrum of neurodevelopmental disorder (NDD) and epilepsy. Three patients with variants locating outside functional domains all achieved seizure-free, while the four patients with variants locating in functional domains presented poor control of seizures. Analysis of previously reported cases revealed that patients with non-null variants presented higher percentages of epilepsy than those with null variants, suggesting a genotype-phenotype correlation.SignificanceThis study suggested that DLG3 variants were associated with epilepsy with/without NDD, expanding the phenotypic spectrum of DLG3. The observed genotype-phenotype correlation potentially contributes to the understanding of the underlying mechanisms driving phenotypic variation.

Once a fire breaks out in an electric bus, it can easily lead to mass casualties and severe injuries, resulting in significant property damage and social impact. The high-temperature smoke and toxic gases in an electric bus fire are key factors that cause a large number of casualties, both of which are closely related to ventilation conditions. In view of this, this study utilized the Fire Dynamics Simulator (FDS 6) software to establish a three-dimensional experimental model of an electric bus. Numerical simulations of the fire combustion process in the electric bus under different ventilation conditions were conducted. Multiple fire scenes were established based on varying ventilation areas, different wind speeds, and diverse window opening positions. This study specifically analyzed the temperature and CO concentration variations under different fire scenes. By comparing the simulation results under different ventilation conditions, it can be concluded that when an electric bus catches fire, opening 100% of the windows, the wind speed is 8 m/s, and opening the rear window of the electric bus first can minimize the fire risk. Through the numerical simulation of electric bus fires under various conditions, this study analyzed the impact of different ventilation conditions on electric bus fires, providing a theoretical basis for firefighting and rescue efforts as well as personnel evacuation in electric bus fire incidents, with the ultimate goal of maximizing public safety.

Inspired by many-body effects, we propose a novel design for Boltzmann machine (BM)-based invertible logic (IL) using probabilistic bits (p-bits). A CMOS-based XNOR gate is derived to serve as the hardware implementation of many-body interactions, and an IL family is built based on this design. Compared to the conventional two-body-based design framework, the many-body-based design enables compact configuration and provides the simplest binarized energy landscape for fundamental IL gates; furthermore, we demonstrate the composability of the many-body-based IL circuit by merging modular building blocks into large-scale integer factorizers (IFs). To optimize the energy landscape of large-scale combinatorial IL circuits, we introduce degeneracy in energy levels, which enlarges the probabilities for the lowest states. Circuit simulations of our IFs reveal a significant boost in factorization accuracy. An example of a 2- $\times2$ -bit IF demonstrated an increment of factorization accuracy from 64.99% to 91.44% with a reduction in the number of energy levels from 32 to 9. Similarly, our 6- $\times6$ -bit IF increases the accuracy from 4.430% to 83.65% with the many-body design. Overall, the many-body-based design scheme provides promising results for future IL circuit designs.

Background Limited data are available to establish evidence-based management protocols for vestibulodynia (VBD), a chronic vulvar pain condition that affects approximately 14 million women in the U.S. For the purposes of the study, our group subdivided VBD subtypes that may benefit from different types of treatment: 1) VBD peripheral (VBD-p), characterized by pain localized to the vulvar vestibule and 2) VBD central (VBD-c), characterized by VBD alongside one or more other chronic overlapping pain conditions (e.g. irritable bowel syndrome, temporomandibular disorder, and fibromyalgia syndrome) that affect remote body regions. Here, we describe the rationale and design of an NIH-funded multicenter clinical trial comparing the effectiveness of topical and/or systemic medication for alleviating pain and normalizing pain- relevant biomarkers among women with VBD-p and VBD-c.Methods Participants will be randomly assigned to one of four parallel arms: peripheral treatment with 5% lidocaine + 0.5 mg/ml 0.02% oestradiol compound cream + oral placebo pill, 2) central treatment with the tricyclic antidepressant nortriptyline + placebo cream, 3) combined peripheral cream and central pill treatments, or 4) placebo cream and placebo pill. The treatment phase will last 16 weeks, with outcome measures and biomarkers assessed at 4 time points (0, 8, 16, and 24 weeks). First, we will compare the efficacy of treatments in alleviating pain using standardized tampon insertion with a numeric rating scale and self-reported pain on the short form McGill Pain Questionnaire. Next, we will compare the efficacy of treatments in improving perceived physical, mental, and sexual health using standardized questionnaires. Finally, we will measure cytokines and microRNAs in local vaginal and circulating blood samples using multiplex assays and RNA sequencing, and determine the ability of these biomarkers to predict treatment response.Conclusion This is the first multicenter randomized controlled trial to evaluate the efficacy of peripherally and centrally acting medications currently used in clinical practice for treating unique VBD subtypes based on distinct clinical and biological signatures. Administrative information Vestibulodynia UPDATe is a multi-centre, two-by-two factorial designed randomized, double-blind, placebo-controlled trial registered at clinical trials.gov (NCT03844412). This work is supported by the R01 HD096331 awarded to Drs. Nackley, Rapkin, Geller and Carey by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).Key messagesPeripheral lidocaine and oestradiol and centrally-targeted nortriptyline medications are used for the treatment of pain in women with VBD, but there is a lack of data from well-powered RCTs.This two-by-two factorial RCT will test the efficacy of these medications in VBD subtypes characterized by distinct clinical characteristics and biomarker profiles.We hope that results will provide clinicians with scientific evidence of therapeutic efficacy in distinct VBD subtypes in an effort to direct and optimize treatment approaches.

To address the positioning and communication requirements of cable relay buoys connected to manned submersibles working in deep sea for a long time, a technical scheme of an underwater buoy retracting and releasing winch suitable for manned submersibles is proposed in this study. The scheme is based on the working characteristics of winches on manned submersibles that work in underwater environments and are intelligently controlled in manned cabins. We discussed the working principles, structural composition, hydraulic control system of the winch, and calculation of the main parameters. The results show that the scheme can satisfy the demand for retracting and releasing the buoys of manned submersibles, thereby providing a reference for the design of this type of winch.

Abstract The Movement Disorder Society revised version of the Unified Parkinson’s Disease Rating Scale (MDS‐UPDRS) parts 2 and 3 reflect patient‐reported functional impact and clinician‐reported severity of motor signs of Parkinson’s disease (PD), respectively. Total scores are common clinical outcomes but may obscure important time‐based changes in items. We aim to analyze longitudinal disease progression based on MDS‐UPRDS parts 2 and 3 item‐level responses over time and as functions of Hoehn & Yahr (H&Y) stages 1 and 2 for subjects with early PD. The longitudinal item response theory (IRT) modeling is a novel statistical method addressing limitations in traditional linear regression approaches, such as ignoring varying item sensitivities and the sum score balancing out improvements and declines. We utilized a harmonized dataset consisting of six studies with 3573 subjects with early PD and 14,904 visits, and mean follow‐up time of 2.5 years (±1.57). We applied both a unidimensional (each part separately) and multidimensional (both parts combined) longitudinal IRT models. We assessed the progression rates for both parts, anchored to baseline H&Y stages 1 and 2. Both the uni‐ and multidimensional longitudinal IRT models indicate significant worsening time effects in both parts 2 and 3. Baseline H&Y stage 2 was associated with significantly higher baseline severities, but slower progression rates in both parts, as compared with stage 1. Patients with baseline H&Y stage 1 demonstrated slower progression in part 2 severity compared to part 3, whereas patients with baseline H&Y stage 2 progressed faster in part 2 than part 3. The multidimensional model had a superior fit compared to the unidimensional models and it had excellent model performance.

In recent years, multi-bucket foundations have been studied and gradually adopted in engineering practices as a novel foundation for offshore wind turbines within a range of water depth of 30 to 50 m. This study investigated the motion characteristics of air-floating tripod bucket foundation (AFTBF) through a series of experiments during free air-floating. The experimental results show that the surge force appears to be the most important factor influencing pitch moment and motion, whether it is a change in water depth or a draft for AFTBF. The maximum amplitudes of surge acceleration and pitch angle show a trend of increasing with narrower spacing and decreasing with wider spacing, while the heave acceleration shows an opposite trend. The added mass and damping of heave motion for AFTBF increase with shallower water due to the increasing pressure difference between the inside and bottom of bucket foundation. The shallower the water depth and the larger the draft, the longer the resonance period of heave.

BackgroundRecessive SZT2 variants are reported to be associated with developmental and epileptic encephalopathy 18 (DEE-18) and occasionally neurodevelopment abnormalities (NDD) without seizures. This study aims to explore the phenotypic spectrum of SZT2 and the genotype-phenotype correlation.MethodsTrios-based whole-exome sequencing was performed in patients with epilepsy. Previously reported SZT2 mutations were systematically reviewed to analyze the genotype-phenotype correlations.ResultsSZT2 variants were identified in six unrelated cases with heterogeneous epilepsy, including one de novo null variant and five pairs of biallelic variants. These variants had no or low frequencies in controls. All missense variants were predicted to alter the hydrogen bonds with surrounding residues and/or protein stability. The three patients with null variants exhibited DEE. The patients with biallelic null mutations presented severe DEE featured by frequent spasms/tonic seizures and diffuse cortical dysplasia/periventricular nodular heterotopia. The three patients with biallelic missense variants presented mild partial epilepsy with favorable outcomes. Analysis of previously reported cases revealed that patients with biallelic null mutations presented significantly higher frequency of refractory seizures and earlier onset age of seizure than those with biallelic non-null mutations or with biallelic mutations containing one null variant.SignificanceThis study suggested that SZT2 variants were potentially associated with partial epilepsy with favorable outcomes without NDD, expanding the phenotypic spectrum of SZT2. The genotype-phenotype correlation helps in understanding the underlying mechanism of phenotypic variation.

Directed energy deposition (DED) of aluminum with infrared lasers faces many processing issues, e.g., poor formability, pore formation, high reflectivity, all lowering the productivity. In this paper, we developed and applied a 2 kW high-power (450 nm) blue laser directed energy deposition (BL-DED) of a nano-TiB2 decorated AlSi10Mg composite. The single-track experiment reveals that the required power density of blue laser to form fully melted track is lower than that of an infrared laser (1060 nm). Under the laser power of 900 W with a scanning speed of 4 mm/s, the width and depth of molten pool is approximately 2500 µm and 350 µm respectively with blue laser, while the powders are not fully melted with infrared laser, owing to aluminum's higher absorption at blue laser wavelengths. The area fraction of equiaxed grains accounts for as high as 63% at 4 mm/s. To the best of our knowledge, this result is the highest area fraction of equiaxed grains in a single-track molten pool of DED process. Such a high fraction is mainly due to the low thermal gradient (8 × 105 K/m) of the flat-top blue laser and the refining effect of nano TiB2 particles. Our work demonstrates that high-power blue laser has enhanced both efficiency and build quality compared to DED of aluminum alloys and composites using an infrared laser, which also promises to help process other high-reflectivity materials like copper alloys.

Takifugu fasciatus is an anadromous fish widely distributed in East Asia and often experiences fluctuations in temperature and salinity. This study investigated the effects of the interactions between temperature and salinity on apoptosis, antioxidant enzymes, and mitogen-activated protein kinase (MAPK) signaling pathways in the liver of T. fasciatus. The temperature (25, 21, 17, and 13 ℃) and salinity (0, 10, and 20 ppt salinity) were conducted with three replicates for each treatment. Quantitative reverse transcription-PCR (qRT-PCR), western blotting, and TdT-mediated dUTP Nick-End Labeling (Tunel) assays were used to detect mRNA expression, protein levels, and apoptosis levels. The expressions of caspase 3, 7, 9, and the apoptosis index increased in T. fasciatus as the temperature decreased, while the expression of B-cell lymphoma-2 (BCL-2) decreased. The correlation results in this study showed that after the exposure to 10 ppt salinity at 13 and 17 ℃, the glutathione peroxidase (GSH-PX) activity and malondialdehyde (MDA) concentration, caspase3, 7, and 9 expressions, and apoptosis index were decreased as compared with those in the control. In addition, there were no deaths and no significant change in apoptosis in the group at 21 ℃, and there were a small number of deaths in the 20 ppt, 25 ℃ groups. Correspondingly, MDA concentration and total superoxide dismutase (T-SOD) activity, caspase7 and 9 expressions, and apoptosis index in the liver were significantly higher in the 20 ppt, 25 ℃ groups than in the 0 ppt, 25 ℃, and 10 ppt, 25 ℃ groups. In addition, salinity had no significant influence on the expression of p-p38 MAPK and its phosphorylation ratio (p-p38/p38) at low temperatures but significantly affected its downstream transcription factors (ATF2, ElK-1, MEF2, and P53). Our study provides a reference for healthy cultures of T. fasciatus.

Gas atomization (GA) is the main method to produce metal powders for additive manufacturing (AM) because of its low cost and high efficiency. However, the liquid breakup behaviors in high-speed gas flow during GA remains unclear, especially the primary breakup in the near field and the secondary breakup in the far field. Great difficulty exists in in-situ observation of the interactions between high-speed gas and high-temperature molten metal because of the limitations of the enclosed environment. Here, we built a new GA simulation system with a close-coupled atomizer utilizing liquids with low melting temperature, such as water, glycerin, etc. We use a high-speed camera to capture the evolution of liquid behaviors at various parameters. We first reveal that four primary breakup modes and four secondary breakup modes exist in the GA process, and these breakup modes significantly influence the particle size distribution (PSD) and the defects of the powder. Besides, the breakup modes are clarified by the dimensionless analysis. This manuscript provides an effective experimental platform to understand the breakup behaviors of the liquid jet in GA and suggests the optimal breakup mode for powder production.

BackgroundBibliometric analysis is a quantitative method which applies mathematical and statistical tools to evaluate the inter-relationships and impacts of publications, authors, institutions and countries in a specific research area. Systematic reviews and meta-analyses (SRMAs) are summaries of the best available evidence to address a specific research question via comprehensively literature search, in-depth analysis and synthesis of results. To date, there have been several studies summarizing the publication trends of SRMAs in research specialties, however, none has conducted specifically in ophthalmology. The purpose of this study is to establish the scientometric landscape of SRMAs published in the field of ophthalmology over time.MethodsWe retrieved relevant ophthalmological SRMAs and the corresponding bibliometric parameters during 2000 to 2020 from Web of Science Core Collection. Bibliometric analysis was performed using bibliometrix package. Pre-registration and guideline compliance of each article was independently assessed by two investigators.ResultsA total of 2,660 SRMAs were included, and the average annual growth rate was 21.26%. China and the United States were the most productive countries, while Singapore was the country with the highest average citations per document. Wong TY was not only the most productive, but also the most frequently cited author. The most productive affiliation was National University of Singapore (n = 236). Systematic reviews and meta-analyses output in most subspecialties had steadily increased with retina/vitreous (n = 986), glaucoma (n = 411) and cornea/external diseases (n = 303) constantly as the most dominant fields. Rates of pre-registration and guideline compliance had dramatically increased over time, with 20.0 and 63.5% of article being pre-registered and reported guideline in 2020, respectively. However, SRMAs published on ophthalmology journals tended to be less frequently pre-registered and guideline complied than those on non-ophthalmology journals (both p

Objective This study aims to validate the Thai translation of the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). Methods The English version was translated into Thai and then back-translated into English. The translated version underwent 2 rounds of cognitive pretesting to assess the ease of comprehension, ease of use and comfort with the scale. Then, it underwent large clinimetric testing. Results The Thai version was validated in 354 PD patients. The comparative fit index (CFI) for all four parts of the Thai version of the MDS-UPDRS was 0.93 or greater. Exploratory factor analysis identified isolated item differences in factor structure between the Thai and English versions. Conclusion The overall factor structure of the Thai version was consistent with that of the English version based on the high CFIs (all CFI ≥ 0.90). Hence, it can be designated the official Thai version of the MDS-UPDRS.

Abstract This paper applies the wireless powered communication network (WPCN) to an indoor communication system with two energy harvesting (EH) enabled users. Unlike the existing WPCN works designed for outdoor communications, where each user harvests energy only from the signals transmitted by a dedicatedly deployed hybrid access point (H‐AP), due to the short device‐to‐device distance in the indoor scenario, each user additionally harvests a sufficient amount of energy from the information signals transmitted by the H‐AP and the other user. First, the joint downlink and uplink throughput are maximized for the wireless powered indoor communication system. This problem is non‐convex. Thus, the authors manage to transform this problem into a convex one and solve it using convex optimization techniques. The solutions reveal that the total throughput increases largely over a reduced device‐to‐device distance due to the resultant harvested energy from both energy and information signals at each user. However, an unfair downlink versus uplink rate allocation phenomenon is observed. Thus, considering the importance of uplink communication quality for various indoor applications, a new problem is further proposed to maximize the uplink sum‐throughput over both users with an additional constraint to ensure a sufficient downlink rate. This problem is also shown to be non‐convex and is solved optimally by using a method similar to that in the first problem. Numerical results demonstrate the effectiveness of the proposed approach for improving the downlink versus uplink rate allocation fairness in the indoor wireless‐powered communication system.

Rice panicle apical abortion (PAA) is a detrimental agronomic trait resulting in spikelet number reduction and yield loss. To understand its underlying molecular mechanism, we identified one recessive PAA mutant tutou2 from the offspring of tissue cultures. The mutation locus was finely mapped to a 75-kb interval on the long arm of chromosome 10. Sequence analysis revealed a single nucleotide substitution of A to T at the 941 position of LOC_Os10g31910 in tutou2, resulting in an amino acid change from isoleucine to phenylalanine. Complementation analysis showed that the degenerated panicle phenotype in tutou2 was rescued in the transgenic lines. A phenotype similar to tutou2 can also be obtained by LOC_Os10g31910 knockout in wild-type rice. These results suggested that LOC_Os10g31910 is the causative locus TUTOU2 responsible for the tutou2 PAA phenotype and probably also the locus of DEL1, previously documented as a leaf senescence gene. The significant phenotypic differences between del1 and tutou2 suggest that the locus DEL1/TUTOU2 plays roles in both leaf and panicle development which were not considered fully in previous studies.

In this paper, by accounting for the angle constraint (AC) and autopilot lag compensation (ALC), a novel fixed-time convergent guidance law is developed based on a fixed-time state observer and bi-limit homogeneous technique. The newly proposed guidance law exhibits three attractive features: (1) unlike existing guidance laws with AC and ALC which can only guarantee asymptotic stability or finite-time stability, the newly proposed guidance scheme can achieve fixed-time stability. Thus, the newly proposed scheme can drive the guidance error to zero within bounded time which is independent of the initial system conditions. (2) To compensate for autopilot lag, existing guidance schemes need the unmeasurable second derivative of the range along line-of-sight (LOS) and second derivative of LOS angle or the derivative of missile’s acceleration. Without using these unmeasurable states, the newly proposed guidance law still can guarantee the fixed-time stability. (3) By using the bi-limit homogeneous technique to construct an integral sliding-mode surface, the proposed scheme eliminates the singular problem without using the commonly-used approximate method in recent fixed-time convergent guidance schemes. Finally, the simulation results demonstrate the effectiveness of the proposed scheme.

Unmanned aerial vehicles (UAVs) are a promising technology used to provide on-demand wireless energy transfer (WET) and sustain various low-power ground devices (GDs) for the Internet of Everything (IoE) in sixth generation (6G) wireless networks. However, an individual UAV has limited battery energy, which may confine the required wide-range mobility in a complex IoE scenario. Furthermore, the heterogeneous GDs in IoE applications have distinct non-linear energy harvesting (EH) properties and diversified energy and/or communication demands, which poses new requirements on the WET and trajectory design of UAVs. In this article, to reflect the non-linear EH properties of GDs, we propose the UAV’s effective-WET zone (E-zone) above each GD, where a GD is assured to harvest non-zero energy from the UAV only when the UAV transmits into the E-zone. We then introduce the free space optics (FSO) powered UAV with enhanced mobility, and propose its adaptive WET for the GDs with non-linear EH. Considering the time urgency of the different energy demands of the GDs, we propose a new metric called the energy latency time, which is the time duration that a GD can wait before becoming fully charged. By proposing the energy-demand aware UAV trajectory, we further present a novel hierarchical WET scheme to meet the GDs’ diversified energy latency time. Moreover, to efficiently sustain IoE communications, the multi-UAV enabled WET is employed by unleashing their cooperative diversity gain and the joint design with the wireless information transfer (WIT). The numerical results show that our proposed multi-UAV cooperative WET scheme under the energy-aware trajectory design achieves the shortest task completion time as compared to the state-of-the-art benchmarks. Finally, the new directions for future research are also provided.

In this study, we developed a novel method for the detection of Vibrio alginolyticus, utilizing the specific recognition of an aptamer for V. alginolyticus and signal amplification via hybridization chain reaction (HCR) and horseradish-peroxidase-conjugated streptavidin. The proposed HCR-based multivalent aptamer (multi-Apt) amplifier allows for sensitive detection of V. alginolyticus in a linear range from 10 to 107 CFU/mL. The linear equation is y = 747.5x + 126.2, R2 = 0.986, and the limit of detection (LOD) is 3 CFU/mL. Seawater and freshwater samples were utilized in the spike recovery experiment, yieldng a recovery rates ranging from 94.3% to 108.8%. The relative standard deviation (RSD) for all samples is below 6.73%. Taken together, the proposed method has great potential for application in monitoring of V. alginolyticus in aquaculture environments.

Immune-checkpoint inhibitor-based combination immunotherapy has become a first-line treatment for several major types of cancer including hepatocellular carcinoma (HCC), renal cell carcinoma, lung cancer, cervical cancer, and gastric cancer. Combination immunotherapy counters several immunosuppressive elements in the tumor microenvironment and activates multiple steps of the cancer-immunity cycle. The anti-PD-L1 antibody, atezolizumab, plus the anti-vascular endothelial growth factor antibody, bevacizumab, represents a promising class of combination immunotherapy. This combination has produced unprecedented clinical efficacy in unresectable HCC and become a landmark in HCC therapy. Advanced HCC patients treated with atezolizumab plus bevacizumab demonstrated impressive improvements in multiple clinical endpoints including overall survival, progress-free survival, objective response rate, and patient-reported quality of life when compared to current first-line treatment with sorafenib. However, atezolizumab plus bevacizumab first-line therapy has limitations. First, cancer patients falling into the criteria for the combination therapy may need to be further selected to reap benefits while avoiding some potential pitfalls. Second, the treatment regimen of atezolizumab plus bevacizumab at a fixed dose may require adjustment for optimal normalization of the tumor microenvironment to obtain maximum efficacy and reduce adverse events. Third, utilization of predictive biomarkers is urgently needed to guide the entire treatment process. Here we review the current status of clinically approved combination immunotherapies and the underlying immune mechanisms. We further provide a perspective analysis of the limitations for combination immunotherapies and potential approaches to overcome the limitations.

The implementation of the toll free during holidays makes a large number of traffic jams on the expressway. Real-time and accurate holiday traffic flow forecasts can assist the traffic management department to guide the diversion and reduce the expressway's congestion. However, most of the current prediction methods focus on predicting traffic flow on ordinary working days or weekends. There are fewer studies for festivals and holidays traffic flow prediction, it is challenging to predict holiday traffic flow accurately because of its sudden and irregular characteristics. Therefore, we put forward a data-driven expressway traffic flow prediction model based on holidays. Firstly, Electronic Toll Collection (ETC) gantry data and toll data are preprocessed to realize data integrity and accuracy. Secondly, after Complete Ensemble Empirical Mode Decomposition with Adaptive Noise (CEEMDAN) processing, the preprocessed traffic flow is sorted into trend terms and random terms, and the spatial-temporal correlation and heterogeneity of each component are captured simultaneously using the Spatial-Temporal Synchronous Graph Convolutional Networks (STSGCN) model. Finally, the fluctuating traffic flow of holidays is predicted using Fluctuation Coefficient Method (FCM). Through experiments of real ETC gantry data and toll data in Fujian Province, this method is superior to all baseline methods and has achieved good results. It can provide reference for future public travel choices and further road network operation.

The KCNK4 gene, predominantly distributed in neurons, plays an essential role in controlling the resting membrane potential and regulating cellular excitability. Previously, only two variants were identified to be associated with human disease, facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth (FHEIG) syndrome. In this study, we performed trio-based whole exon sequencing (WES) in a cohort of patients with epilepsy. Two de novo likely pathogenic variants were identified in two unrelated cases with heterogeneous phenotypes, including one with Rolandic epilepsy and one with the FHEIG syndrome. The two variants were predicted to be damaged by the majority of in silico algorithms. These variants showed no allele frequencies in controls and presented statistically higher frequencies in the case cohort than that in controls. The FHEIG syndrome-related variants were all located in the region with vital functions in stabilizing the conductive conformation, while the Rolandic epilepsy-related variant was distributed in the area with less impact on the conductive conformation. This study expanded the genetic and phenotypic spectrum of KCNK4. Phenotypic variations of KCNK4 are potentially associated with the molecular sub-regional effects. Carbamazepine/oxcarbazepine and valproate may be effective antiepileptic drugs for patients with KCNK4 variants.

Ghost imaging (GI) retrieves an image from the correlation between a sequence of illumination patterns on the object and their corresponding bucket detections. Traditionally, GI requires the precise information of the illumination patterns, which raises technology barriers on building a high-speed illumination source, limiting the scope of its application. In this study, we propose a high-speed GI system, which implements a self-correlation with a purely optical operation without determining illumination patterns. The light source is an optical phased array (OPA), built of a set of waveguide-type electro-optic phase modulators. The OPA is driven to randomly change the phases in every 200 ns, generating speckle patterns at a rate of 5 MHz. Although the speckle patterns are not predictable or post-determinable, with the help of the naked-eye GI scheme, the system in real time optically generates the images of the object at a frame rate of more than 1 kHz, which can be directly observed by eyes or using a camera. This method avoids acquiring the information of the illumination, thus providing a simple and easy way to realize high-speed GI. It also inspires a different way of applying OPAs to high-speed imaging.

In large-scale laying hen farming, timely detection of dead chickens helps prevent cross-infection, disease transmission, and economic loss. Dead chicken detection is still performed manually and is one of the major labor costs on commercial farms. This study proposed a new method for dead chicken detection using multi-source images and deep learning and evaluated the detection performance with different source images. We first introduced a pixel-level image registration method that used depth information to project the near-infrared (NIR) and depth image into the coordinate of the thermal infrared (TIR) image, resulting in registered images. Then, the registered single-source (TIR, NIR, depth), dual-source (TIR-NIR, TIR-depth, NIR-depth), and multi-source (TIR-NIR-depth) images were separately used to train dead chicken detecting models with object detection networks, including YOLOv8n, Deformable DETR, Cascade R-CNN, and TOOD. The results showed that, at an IoU (Intersection over Union) threshold of 0.5, the performance of these models was not entirely the same. Among them, the model using the NIR-depth image and Deformable DETR achieved the best performance, with an average precision (AP) of 99.7% (IoU = 0.5) and a recall of 99.0% (IoU = 0.5). While the IoU threshold increased, we found the following: The model with the NIR image achieved the best performance among models with single-source images, with an AP of 74.4% (IoU = 0.5:0.95) in Deformable DETR. The performance with dual-source images was higher than that with single-source images. The model with the TIR-NIR or NIR-depth image outperformed the model with the TIR-depth image, achieving an AP of 76.3% (IoU = 0.5:0.95) and 75.9% (IoU = 0.5:0.95) in Deformable DETR, respectively. The model with the multi-source image also achieved higher performance than that with single-source images. However, there was no significant improvement compared to the model with the TIR-NIR or NIR-depth image, and the AP of the model with multi-source image was 76.7% (IoU = 0.5:0.95) in Deformable DETR. By analyzing the detection performance with different source images, this study provided a reference for selecting and using multi-source images for detecting dead laying hens on commercial farms.

Aims: Patient-reported outcome measures have become an important part of routine care. The aim of this study was to determine if Patient-Reported Outcomes Measurement Information System (PROMIS) measures can be used to create patient subgroups for individuals seeking orthopaedic care. Methods: This was a cross-sectional study of patients from Duke University Department of Orthopaedic Surgery clinics (14 ambulatory and four hospital-based). There were two separate cohorts recruited by convenience sampling (i.e. patients were included in the analysis only if they completed PROMIS measures during a new patient visit). Cohort #1 (n = 12,141; December 2017 to December 2018,) included PROMIS short forms for eight domains (Physical Function, Pain Interference, Pain Intensity, Depression, Anxiety, Sleep Quality, Participation in Social Roles, and Fatigue) and Cohort #2 (n = 4,638; January 2019 to August 2019) included PROMIS Computer Adaptive Testing instruments for four domains (Physical Function, Pain Interference, Depression, and Sleep Quality). Cluster analysis (K-means method) empirically derived subgroups and subgroup differences in clinical and sociodemographic factors were identified with one-way analysis of variance. Results: Cluster analysis yielded four subgroups with similar clinical characteristics in Cohort #1 and #2. The subgroups were: 1) Normal Function: within normal limits in Physical Function, Pain Interference, Depression, and Sleep Quality; 2) Mild Impairment: mild deficits in Physical Function, Pain Interference, and Sleep Quality but with Depression within normal limits; 3) Impaired Function, Not Distressed: moderate deficits in Physical Function and Pain Interference, but within normal limits for Depression and Sleep Quality; and 4) Impaired Function, Distressed: moderate (Physical Function, Pain Interference, and Sleep Quality) and mild (Depression) deficits. Conclusion: These findings suggest orthopaedic patient subgroups differing in physical function, pain, and psychosocial distress can be created from as few as four different PROMIS measures. Longitudinal research is necessary to determine whether these subgroups have prognostic validity.

IntroductionPRRT2 is a major causative gene for self-limited familial neonatal-infantile epilepsy, paroxysmal kinesigenic dyskinesia, and paroxysmal kinesigenic dyskinesia with infantile convulsions. Voluntary movement trigger is prominent in adolescence and adulthood, but the triggers are unknown in infants.MethodsA gene panel designed for targeted next-generation sequencing (NGS) was used to screen genetic abnormalities in a cohort of 45 cases with infantile convulsions. The copy number variation was detected by a computational method based on the normalized depth of coverage and validated by a quantitative real-time polymerase chain reaction (RT-qPCR) method. The genotype-phenotype correlation of the PRRT2 mutation gene was analyzed.ResultsA de novo heterozygous PRRT2 deletion was identified in a child who had infantile convulsions induced by vigorous sucking. Seizures happened during the change of feeding behavior from breast to formula, which led to hungry and vigorous sucking. Ictal electroencephalograms recorded seizures with focal origination, which provided direct evidence of epileptic seizures in infants with PRRT2 mutations. Seizures stopped soon after the feeding behavior was changed by reducing feeding interval time and extending feeding duration. Data reanalysis on our previously reported cases with PRRT2 mutations showed that six of 18 (33.3%) patients had infantile convulsions or infantile non-convulsion seizures during feeding. The mutations included two truncating mutations (c.579dupA/p.Glu194Argfs*6, and c.649dupC/p.Arg217Profs*8) that were identified in each of the three affected individuals.ConclusionsThis study suggests that feeding, especially vigorous sucking, is potentially a trigger and highlights the significance of feeding behavior in preventing seizures in infants with PRRT2 mutations. Identification of PRRT2 haploinsufficiency mutations in the patients with infantile convulsions induced by sucking suggested a potential genotype-phenotype correlation.