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Abstract Objective The aim of this study was to investigate the relationship between triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) and the risk of cardiovascular disease (CVD) in middle-aged and elderly Chinese population. CVD has high morbidity and mortality in China, with 5.09 million CVD deaths in 2019 and a mortality rate of 364.5 cases per 100,000 people. Existing studies have focused on specific populations and lack studies on the general population. Methods This study used data from the China Health and Aged Care Tracking Survey (CHARLS) to analyse the middle-aged and elderly population between 2011 and 2020. The exposure variable was TG/HDL-C ratio, the outcome variable was the occurrence of heart disease (including myocardial infarction, coronary heart disease, etc.), and the covariates included age, gender, education level, and body mass index. The final sample size was 4,551 participants. Weighted Cox regression models were used to assess the association between TG/HDL-C and CVD risk, and nonlinear associations and stratified analyses were performed. Results The results demonstrated a significant association between TG/HDL-C ratios and cardiac morbidity, with a risk ratio of 0.71 (95% CI: 0.71–0.71) in the adjusted model II. Nonlinear analysis revealed a threshold effect. Within the TG/HDL-C 0.15–1.5 interval (inflection point LnTG/HDL-C 0.41), each 1-unit increase in Ln (TG/HDL-C) was associated with a 17% reduction in the risk. The inflection point was associated with a 0.83-fold reduction in the risk of CVD (95% CI: 0.75, 0.92; p = 0.0003), but beyond this point, the association was no longer significant (1.00-fold reduction in risk; 95% CI: 0.95, 1.05; p = 0.9701). In contrast, stratified analyses demonstrated that the results were more applicable to women and those younger than 65 years. Conclusion In summary, the study found a significant inverse relationship between the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and the risk of cardiovascular disease in the middle-aged and elderly Chinese population, with a nonlinear threshold effect observed at a TG/HDL-C ratio of around 1.5.

Contradiction between ultrafast nucleation and deposition rates of lithium (Li) crystals at high rate and heterogeneity of Li+ flux resulting from concentration polarization has compromised the performance of Li metal anodes especially at high areal capacity and current density. Here, multifunctional protective layer consisting of MoO3 nanobelt films (MoO3-NF) is introduced on the surface of Li by a simple rolling method. The strong binding energy between Li and MoO3 guides the homogeneous nucleation and deposition of Li, while the nanobelt networks provide effective ion channels for uniform distribution of the Li+ flux. Because of the novel multifunctional protective layer, the MoO3-NF@Li anodes demonstrate a remarkable stability for 800 h with ultralow overpotential of 159 mV at extreme harsh conditions of 60 mA·h/cm2 and 60 mA/cm2. MoO3-NF@Li||LiNi0.6Co0.2Mn0.2O2 full-cells can run 100 cycles with a superior capacity retention of 84.2% under practical test conditions, demonstrating great potential for high output and energy-density metal batteries.

Abstract Glutaraldehyde (GTA) crosslinking is commonly used to improve the thermal stability and mechanical strength of collagen casings. The aim of this research was to determine the optimal pH of the crosslinking between GTA and collagen as well as the crosslinking mechanisms. The weakly alkaline environment could facilitate the generation of GTA polymerization through the rapid generation of -C = C-C = O and -N = C-C = C- conjugated structures, and enhance the crosslinking reaction of GTA polymers with collagen amino groups. In the pH range of 8–10, the fibril diameter and d-space value declined significantly in the self-assembled collagen fibril-GTA system. Meanwhile, collagen casing films crosslinked with GTA in weakly alkaline conditions exhibited higher mechanical strength and thermal stability. These results suggest that the crosslinking of collagen casings and GTA can be improved by adjusting the pH. Possible crosslinking mechanisms related to the formation of conjugated long chains have also been proposed. This study could provide guidance on the appropriate use of GTA in the production process of collagen casings. Graphical Abstract

Abstract Natural selection has driven arthropods to evolve fantastic natural compound eyes (NCEs) with a unique anatomical structure, providing a promising blueprint for artificial compound eyes (ACEs) to achieve static and dynamic perceptions in complex environments. Specifically, each NCE utilises an array of ommatidia, the imaging units, distributed on a curved surface to enable abundant merits. This has inspired the development of many ACEs using various microlens arrays, but the reported ACEs have limited performances in static imaging and motion detection. Particularly, it is challenging to mimic the apposition modality to effectively transmit light rays collected by many microlenses on a curved surface to a flat imaging sensor chip while preserving their spatial relationships without interference. In this study, we integrate 271 lensed polymer optical fibres into a dome-like structure to faithfully mimic the structure of NCE. Our ACE has several parameters comparable to the NCEs: 271 ommatidia versus 272 for bark beetles, and 180o field of view (FOV) versus 150–180o FOV for most arthropods. In addition, our ACE outperforms the typical NCEs by ~100 times in dynamic response: 31.3 kHz versus 205 Hz for Glossina morsitans. Compared with other reported ACEs, our ACE enables real-time, 180o panoramic direct imaging and depth estimation within its nearly infinite depth of field. Moreover, our ACE can respond to an angular motion up to 5.6×106 deg/s with the ability to identify translation and rotation, making it suitable for applications to capture high-speed objects, such as surveillance, unmanned aerial/ground vehicles, and virtual reality.

Abstract Background Immune Checkpoint Inhibitors (ICIs) have revolutionized cancer therapy. This study examines the cardiovascular risks of ICIs compared to non-ICI therapies. Methods Utilizing the Chang Gung Research Database (CGRD) of Taiwan, this retrospective study analyzed 188,225 cancer patients, with 1,737 undergoing ICI treatment from January 1, 2008, to June 30, 2021. Through 1:1 propensity score matching (PSM), we compared specific outcomes between patients treated with ICIs and those who were not. The analysis also accounted for the competing risk of mortality in assessing the results after PSM. The observation period spanned from this index date to whichever came first: the date of the specific outcomes, the last follow-up recorded, or the end date of the study on June 30, 2022. Results The study found no significant increase in the risk of cardiac death, non-fatal myocardial infarction, heart failure hospitalization, deep vein thrombosis, or pulmonary embolism in patients treated with ICIs as compared to those receiving non-ICI therapy. Interestingly, ICI treatment was linked to a lower risk of non-fatal stroke (0.27% per year vs. 0.46% per year; subdistribution hazard ratio = 0.59; 95% confidence interval = 0.35–0.98; P = 0.0430). Furthermore, subgroup analysis revealed that the ICI group had a decreased risk of cardiac death in patients with cancers other than head and neck cancer, and a reduced risk of stroke among diabetic patients. Conclusions ICIs do not significantly elevate the risk of cardiovascular events in cancer patients and may lower the stroke risk, underscoring the need for additional prospective studies to clarify these findings.

Abstract The group fuzzy extractor allows group users to extract and reproduce group cryptographic keys from their individual non-uniform random sources. It can be easily used in group-oriented cryptographic applications. However, current group fuzzy extractors are not dynamic, i.e. they spend a large cost when dealing with user revocation. In this work, we propose the formal definition and construction of dynamic group fuzzy extractor (DGFE) to address this issue. For the revocation, DGFE allows unrevoked group users to reproduce updated group keys from the existing group help data. Meanwhile, it prevents any revoked group user from generating new group keys using the previously authorized individual help data. We propose a DGFE construction based on the revocable group signature. Furthermore, we give formal proofs of reusability, anonymity and traceability of our construction.

Abstract Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as ‘DC-like’ (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients’ blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.

Abstract Background Endometriosis is one of the most common gynaecological diseases, yet it lacks efficient biomarkers for early detection and unravels disease mechanisms. Proteomic profiling has revealed diverse patterns of protein changes in various clinical samples. Integrating and systematically analysing proteomics data can facilitate the development of biomarkers, expediting diagnosis and providing insights for potential clinical and therapeutic applications. Hence, this systematic review and meta-analysis aimed to explore potential non-invasive diagnostic biomarkers in various biological samples and therapeutic targets for endometriosis. Methods Online databases, including Scopus, PubMed, Web of Science, MEDLINE, Embase via Ovid, and Google Scholar, were searched using MeSH terms. Two independent authors screened the articles, extracted the data, and assessed the methodological quality of the included studies. GO and KEGG analyses were performed to identify the pathways that were significantly enriched. Protein‑protein interaction and hub gene selection analyses were also conducted to identify biomarker networks for endometriosis. Results Twenty-six observational studies with a total of 2,486 participants were included. A total of 644 differentially expressed proteins (180 upregulated and 464 downregulated) were identified from 9 studies. Proteins in peripheral blood exhibited a sensitivity and specificity of 38-100% and 59-99%, respectively, for detecting endometriosis, while proteins in urine had a sensitivity of 58-91% and specificity of 76-93%. Alpha-1-antitrypsin, albumin, and vitamin D binding proteins were significantly DEPs in both serum and urine. Complement C3 is commonly expressed in serum, menstrual blood, and cervical mucus. Additionally, S100-A8 is commonly expressed in both menstrual blood and cervical mucus. Haptoglobin is commonly detected in both serum and plasma, whereas cathepsin G is found in urine, serum, and plasma. GO and KEGG enrichment analyses revealed that proteoglycans in cancer pathways, which regulate cell-to-cell interactions, modulate the extracellular matrix, and promote the proliferation and invasion of endometrial cells, are commonly enriched in serum and urine. Conclusion This comprehensive study revealed potential proteomes that were significantly differentially expressed in women with endometriosis utilizing various non-invasive clinical samples. Exploring common differentially expressed proteins in various biological samples provides insights into the diagnosis and pathophysiology of endometriosis, as well as potential clinical and therapeutic applications. Graphical abstract

Abstract. Background:. Life's Simple 7, the former construct of cardiovascular health (CVH) has been used to evaluate adverse non-communicable chronic diseases (NCDs). However, some flaws have been recognized in recent years and Life's Essential 8 has been established. In this study, we aimed to analyze the association between CVH defined by Life's Essential 8 and risk of 44 common NCDs and further estimate the population attributable fractions (PAFs) of low-moderate CVH scores in the 44 NCDs. Methods:. In the UK Biobank, 170,726 participants free of 44 common NCDs at baseline were included. The Life's Essential 8 composite measure consists of four health behaviours (diet, physical activity, nicotine exposure, and sleep) and four health factors (body mass index, non-high density lipoprotein cholesterol, blood glucose, and blood pressure), and the maximum CVH score was 100 points. CVH score was categorized into low, moderate, and high groups. Participants were followed up for 44 NCDs diagnosis across 10 human system disorders according to the International Classification of Diseases 10th edition (ICD-10) code using linkage to national health records until 2022. Cox proportional hazard models were used in this study. The hazard ratios (HRs) and PAFs of 44 NCDs associated with CVH score were examined. Results:. During the median follow-up of 10.85 years, 58,889 incident NCD cases were documented. Significant linear dose-response associations were found between higher CVH score and lower risk of 25 (56.8%) of 44 NCDs. Low-moderate CVH (

The current study aimed to investigate the effects of plant-mediated selenium nanoparticles (SeNPs) on plant growth, photosynthetic pigments, antioxidant activity, and the triacylglycerol profile of sesame (Sesamum indicum L.). The green synthesis of SeNPs was achieved using garlic extract, resulting in spherical nanoparticles with an average size range of 70–75 nm. Three SeNP treatments (T3, 30 ppm; T4, 40 ppm; and T5, 50 ppm) were applied through seed and foliar spray on six sesame varieties (V1, TS-5; V2, TH-6; V3, Til-18; V4, Niab Millennium; V5, Niab Pearl; and V6, NS-16). All enzymatic antioxidant parameters showed an increase in the treated groups, such as SOD (74.4% in V1 at T4), POD (43% in V5 at T5), APX (62% in V1 at T3), and GPX (31.56% in V3 at T4). CAT showed the highest percentage improvement in T5 for V1, V2, V4, and V5, while V3 and V4 exhibited the highest values at T4. Likewise, seed antioxidant parameters also showed increase in antioxidant activity, highest total phenolic content (6.06 mg GAE/g) was found at T5 treatment with percent increase of 27.41%, but the highest percent increase was found to be at T4 treatments in V1 with increase of 46.83%. Percent oil yield was also noted to be higher as highest percent (60%) oil yield was obtained at T4 treatment in V3. Ultra High Performance Mass-Spectrometry (UHPLC-MS) analysis and chemometric modeling suggested a total of 10 triacylglycerol (TG) biomarkers separating untreated groups, with higher relative abundance values at T4 and T5 treatments compared to control. PCA and correlation analysis showed clustering of untreated groups from T4 and T5, which suggests that these two treatments result in higher accumulation of oil. A generalized linear model with ANOVA showed a highly significant impact of treatments on all the growth and oil parameters, with significance involvement of varieties. The interaction between variety and treatment showed no significant effect on the growth and oil biomarkers of sesame. However, it can be concluded that the T4 and T5 treatments (40 ppm and 50 ppm) of SeNPs, applied through seed and foliar methods, have a strong influence on the overall growth and oil yield of sesame. This warrants further transcriptomic and molecular analysis to gain deeper insight into the mechanisms of action of SeNPs.

Epidemiological studies have suggested a positive association between environmental cadmium (Cd) exposure and type 2 diabetes mellitus (T2DM). Skeletal muscle insulin resistance (IR) plays a critical role in the pathogenesis of T2DM. This study aimed to investigate the effects of chronic low-level Cd exposure on skeletal muscle IR and its potential mechanism. Rats were exposed to drinking water containing 2 or 10 mg/L Cd for 24 weeks. Differentiated L6 myotubes were treated with Cd for 72 h. Immunofluorescence, flow cytometry assay, RNA-sequencing, and Seahorse analysis were conducted to determine the effects of Cd and its underlying mechanism on relevant parameters, including insulin sensitivity, glucose uptake, oxidative stress, mitophagy, and mitochondrial function in skeletal muscle and L6 myotubes. N-acetyl-cysteine (NAC), a scavenger of reactive oxygen species (ROS), and mitophagy inhibitor Cyclosporin A (CsA) were used to confirm the role of oxidative stress in mitophagy and mitochondrial dysfunction caused by Cd. We found that rats exposed to 10 mg/L Cd exhibited hyperglycemia and skeletal muscle IR. Cd markedly increased IRS-1 phosphorylation at Ser612, while decreased levels of phosphorylated PI3K, Akt, AS160, inhibited GLUT4 translocation and glucose uptake. Mechanistically, Cd increased the intracellular ROS, hydrogen peroxide, and malondialdehyde levels and decreased antioxidase activity in L6 myotubes. Furthermore, Cd upregulated the mRNA and protein levels of LC3II/I, PINK1, and Parkin. In addition, Cd induced the formation of mitophagosomes, reduced the mitochondrial membrane potential, decreased the adenosine triphosphate content, and impaired the mitochondrial respiratory capacity. Strikingly, NAC ameliorated oxidative stress, excessive mitophagy, and the associated reduction in myotube insulin sensitivity, while inhibition of mitophagy by CsA alleviated skeletal muscle IR. In conclusion, this study reveals a previously unrecognized mechanism that chronic low-level Cd exposure may induce mitophagy by activating the PINK1/Parkin signal pathway by increasing ROS, thus causing skeletal muscle IR and elevated blood glucose.

A congenital protein anomaly in the erythrocyte membrane skeleton causes a hereditary haemolytic illness known as hereditary spherocytosis (HS). The primary characteristic of HS is an increase in the number of tiny spherical red blood cells in the peripheral blood. The chief clinical features of HS include anaemia, jaundice, splenomegaly, spherical erythrocytosis in the blood, chronic anaemia with haemolysis, and recurrent acute attacks. Most patients have a family history; some have autosomal recessive inheritance, whereas most have autosomal dominant inheritance. In cases of severe hyperbilirubinemia disproportionate to haemolysis, other causes of hyperbilirubinemia should be considered. Gilbert syndrome (GS) is an autosomal dominant illness caused by the reduced activity of uridine diphosphate-glucuronosyl transferase lAl and is characterised by intermittent hyperbilirubinemia without any other signs or symptoms of liver disease. The possibility of the coexistence of HS and GS is very limited. Here we present the case of an elderly man with yellow skin and sclera recurring anaemia, and a final diagnosis of coexisting HS and GS.

Abstract Drug screening based on in-vitro primary tumor cell culture has demonstrated potential in personalized cancer diagnosis. However, the limited number of tumor cells, especially from patients with early stage cancer, has hindered the widespread application of this technique. Hence, we developed a digital microfluidic system for drug screening using primary tumor cells and established a working protocol for precision medicine. Smart control logic was developed to increase the throughput of the system and decrease its footprint to parallelly screen three drugs on a 4 × 4 cm2 chip in a device measuring 23 × 16 × 3.5 cm3. We validated this method in an MDA-MB-231 breast cancer xenograft mouse model and liver cancer specimens from patients, demonstrating tumor suppression in mice/patients treated with drugs that were screened to be effective on individual primary tumor cells. Mice treated with drugs screened on-chip as ineffective exhibited similar results to those in the control groups. The effective drug identified through on-chip screening demonstrated consistency with the absence of mutations in their related genes determined via exome sequencing of individual tumors, further validating this protocol. Therefore, this technique and system may promote advances in precision medicine for cancer treatment and, eventually, for any disease.

Abstract. Background:. The serum vitamin D level varies widely by population, and studies have linked vitamin D levels with the risk of type 2 diabetes mellitus (T2DM). However, the relationship is inconsistent and the impact of vitamin D on T2DM among East Chinese adults is unclear. The study aimed to investigate the association between serum 25-hydroxyvitamin D (25[OH]D) levels and the risk of T2DM and evaluated whether the association is modified by genetic predisposition. Methods:. In the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors (SPECT-China) cohort, 1862 participants free of T2DM at baseline were included. A weighted genetic risk score was calculated with 28 variants associated with T2DM. Hierarchical logistic models were used to examine the association of serum 25(OH)D and genetic risk with T2DM. Results:. After a 5-year follow-up, 132 cases of T2DM were documented. We observed no significant association between quartiles of serum 25(OH)D and T2DM risk after multivariable adjustment (χ2 = 0.571, Pfor trend = 0.426). Compared to those in the lowest quartile of 25(OH)D, the odds ratios (ORs) (95% confidence interval [CI]) for participants with increased quartiles were 1.29 (0.74–2.25), 1.35 (0.77–2.36), and 1.27 (0.72–2.24), respectively. We observed a positive association of glycated hemoglobin (HbA1c) with 25(OH)D at baseline (β = 1.752, P = 0.001) and after follow-up (β = 1.385, P = 0.003), and a negative association of ln conversion homeostasis model assessment (HOMA)-β with 25(OH)D at baseline (β = -0.982, P = 0.021). There was no significant interaction between 25(OH)D and diabetes genetic predisposition on the risk of T2DM (χ2 = 2.710, Pfor interaction = 0.100). The lowest OR (95% CI) of T2DM was among participants with low genetic risk and the highest quartile of 25(OH)D (0.17 [0.05–0.62]). Conclusion:. Serum 25(OH)D may be irrelevant to the risk of incident T2DM among East Chinese adults regardless of genetic predisposition.

The automatic extraction of inspection points for pylons is essential for intelligent Unmanned Aerial Vehicle (UAV) power inspections, especially in generating inspection route. However, current researches primarily focus on power scene perception and power component fault detection, with little attention paid to the inspection point detection. The primary reason are the lack of public pylon datasets for keypoint detection and the neglect of distinguish the inspection points from the keypoints used in feature extraction. Regarding that, this paper proposes a two-stage unsupervised pylon keypoint detection (UPKD) method to improve the efficiency of power inspections. In the first stage, the UPKD Network processes the point cloud to generate candidate keypoints, which comprises two main components: a data normalization module and an unsupervised keypoint detection network (UKD-Net). The data normalization module compresses information based on the symmetric structure of pylons, thereby reducing instability in inspection point detection. The UKD-Net incorporates a Point Transformer layer that uses self-attention mechanisms to extract features from the point cloud. In the second stage, a convex optimization strategy is applied to filter and acquire inspection points. These inspection points are then interconnected using a shortest-path strategy to generate the UAV inspection route. Our dataset is obtained using the Riegl VUX-1 laser measurement system and comprises 3,296 pylons of 10 types. Each pylon’s point cloud contains up to 25,000 points, with a high point density of 100 pts/m2. Extensive experiments show that the UPKD Network achieved state-of-the-art performance on our dataset, with repeatability achieving 90.39%, effectiveness (the ratio of effective keypoints to annotation points) achieving 69.95%, and completeness (the ratio of detected annotation points to keypoints) achieving 79.55%.

Chemotherapy has been the standard treatment for liver cancer. However, intrinsic or acquired drug resistance remains a major barrier to successful treatment. At present, the underlying molecular mechanisms of chemoresistance in liver cancer have not been elucidated. Dipeptidyl peptidase 9 (DPP9) is a member of the dipeptidyl peptidase IV family that has been found to be highly expressed in a variety of tumors, including liver cancer. It is unclear whether DPP9 affects chemoresistance in liver cancer. In this study, we find that DPP9 weakens the responses of liver cancer cells to chemotherapy drugs by up-regulating NQO1 and inhibiting intracellular ROS levels. In terms of mechanism, DPP9 inhibits ubiquitin-mediated degradation of NRF2 protein by binding to KEAP1, up-regulates NRF2 protein levels, promotes mRNA transcription of NQO1, and inhibits intracellular ROS levels. In addition, the NQO1 inhibitor dicoumarol can enhance the efficacy of chemotherapy drugs in liver cancer cells. Collectively, our findings suggest that inhibiting DPP9/NQO1 signaling can serve as a potential therapeutic strategy for liver cancer.

Background: Medicare Part D plans are required to provide Medication therapy management (MTM) services to eligible beneficiaries to optimize medication utilization. Comprehensive medication review (CMR) is a core element of the MTM program. Despite the availability of advanced medical treatment for patients with chronic obstructive pulmonary disease (COPD), medication adherence to maintenance medications poses a continued challenge for patients with COPD. Objective: To examine the effects of CMR on medication adherence among patients with COPD. Methods: Medicare data for 2016–2017 linked to Area Health Resource Files were analyzed. The study population was Medicare beneficiaries with COPD. The intervention group consisted of beneficiaries who received CMR in 2017 but not in 2016. Patients who were eligible for MTM services but did not receive these services in 2016 or 2017 made up the control group. Propensity score matching was used to select an intervention and control group with balanced characteristics. The study outcome was adherence to COPD medications with the proportion of days covered at or above 80%. A difference-in-differences approach was adopted in the logistic regression analyses with an interaction term between the status of CMR receipt and the year 2017. Results: The study sample included 25,564 patients with COPD. The proportions of adherent patients were similar in the control group in both years but increased significantly from 60.08% in 2016 to 69.38% in 2017 in the intervention group (P

Background Reticulocyte haemoglobin equivalent (RET-He) is a useful tool for evaluating recent iron usage irrespective of inflammatory status. This study aims to establish a reference for RET-He among Hong Kong healthy children under the age of 5 years and to investigate the association between RET-He and various blood parameters.Methods A total of 946 children aged 2–48 months from July 2019 to December 2022 were recruited in this cross-sectional study. The RET-He and other haematological parameters were measured by the haematology analyser from Sysmex XN-9100/XN-1500. The ferritin test was performed with the electrochemiluminescence immunoassay. Interval 2.5th percentile to 97.5th percentile represented the normal RET-He ranges. Linear multiple regression analysis was performed to examine the relation between RET-He and various blood parameters. Receiver-operating characteristic curve analysis revealed the sensitivity and specificity of RET-He in identifying iron deficiency.Results The RET-He in the study population was approximately normally distributed. The age-specific lower limit of RET-He ranges from 25.81 pg (25–36 months) to 27.15 pg (13–24 months). RET-He was found to be lower in the age group 2–6 months (mean=29.47 pg) and 7–12 months (mean=29.41 pg). Changes in RET-He and haemoglobin in relation to age were observed in both sexes (both p

Number Theoretic Transform (NTT) has been widely used in accelerating computations in lattice-based cryptography. However, attackers can potentially launch power analysis targeting the NTT because it is one of the most time-consuming parts of the implementation. This extended time frame provides a natural window of opportunity for attackers. In this paper, we investigate the first CPU frequency leakage (Hertzbleed-like) attacks against NTT in lattice-based KEMs. Our key observation is that different inputs to NTT incur different Hamming weights in its output and intermediate layers. By measuring the CPU frequency during the execution of NTT, we propose a simple yet effective attack idea to find the input to NTT that triggers NTT processing data with significantly low Hamming weight. We further apply our attack idea to real-world applications that are built upon NTT: CPAsecure Kyber without Compression and Decompression functions, and CCA-secure NTTRU. This leads us to extract information or frequency hints about the secret key. Integrating these hints into the LWE-estimator framework, we estimate a minimum of 35% security loss caused by the leakage. The frequency and timing measurements on the Reference and AVX2 implementations of NTT in both Kyber and NTTRU align well with our theoretical analysis, confirming the existence of frequency side-channel leakage in NTT. It is important to emphasize that our observation is not limited to a specific implementation but rather the algorithm on which NTT is based. Therefore, our results call for more attention to the analysis of power leakage against NTT in lattice-based cryptography.

The study presents the Multi-Strategy Learning Fusion Slime Mould Algorithm (MFSMA), a novel method designed to optimize parameters in photovoltaic systems, thereby increasing the efficiency of solar energy conversion. MFSMA employs an advanced technique that incorporates elite opposition-based learning to quickly identify optimal solutions while preserving diversity within the population. Additionally, it integrates a ranking mechanism from the Grey Wolf Algorithm, which categorizes individuals according to their fitness levels, ensuring a balanced approach between exploratory diversity and exploitative precision during the optimization journey. Through rigorous testing on various benchmark functions, MFSMA has demonstrated its exceptional ability to outperform existing algorithms widely used in the sector. The algorithm’s effectiveness is further validated through its application in determining the parameters of single, double, and triple-junction photovoltaic modules. Moreover, the durability and effectiveness of the MFSMA algorithm have been rigorously evaluated using data from manufacturers’ datasheets across different temperature and irradiance conditions. Statistical analysis supports the conclusion that MFSMA offers superior accuracy and dependability in estimating vital parameters for photovoltaic modules, making it an invaluable tool for overcoming the challenges of parameter identification in solar energy technologies.

Abstract Background Adverse childhood experiences (ACE) have been documented to have long-term impacts on sleep disturbances. However, less is known about how ACE co-occurs with positive childhood experiences (PCE) and modulate their effects on adult sleep disturbances, particularly in the context of persistent insomnia. Building on resilience theory, this study aims to examine the interplay between ACE and PCE and their effects on persistent insomnia during emerging adulthood. Methods A total of 2,841 emerging adults were recruited from the Taiwan Youth Project. Persistent insomnia during emerging adulthood was assessed using two adult surveys (mean age = 19.8 and 21.9). The ACE (10 items) and PCE (7 items) were obtained from the baseline survey (mean age = 13.8). A series of logistic regression analyses were conducted. Results Among the emerging adults, 29.22% had persistent insomnia. Consistent with the compensatory model, ACE and PCE exerted opposing effects on persistent insomnia during emerging adulthood. In line with the protective model, the negative effect of ACE is mitigated when individuals have high PCE. However, consistent with the challenge model, the protective effect of PCE on persistent insomnia was inhibited in individuals with four or more ACE. Conclusions PCE serves as a protective factor, shielding emerging adults from the adverse effects of ACE on persistent insomnia. It is essential to prioritize positive experiences during early life to promote lifelong sleep health.

[Introduction] The volatility and intermittency of wind energy pose significant challenges for large-scale wind power integration. An effective approach to address this issue is to provide accurate wind power forecasting. [Method] In response to this challenge, this study proposed a wind power forecasting model for deep learning neural networks based on an improved LSTM (Long Short-Term Memory) architecture. The model incorporated a wind power forecasting approach that included independently developed data anomaly detection and processing, wind speed feature extraction and hyperparameter tuning. To enhance the neural network model's ability to accurately learn the impact of wind speed features on wind power, a feature engineering method combining feature screening and feature augmentation was also defined. [Result] The simulation results demonstrate that the proposed data cleaning and data augmentation algorithm can enhance the accuracy of various machine learning algorithms by approximately 5%. Furthermore, the proposed improved LSTM neural network model, after data cleaning, outperforms traditional algorithms and state-of-the-art neural network algorithms in the industry, achieving a 2.5% increase in accuracy. [Conclusion] The improved approach not only exhibits robust capability in cleaning noisy data but also consistently outperforms other algorithms in terms of forecasting accuracy across all experiments. This model provides valuable guidance for practical applications in the field of wind power forecasting.

Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus. Angiogenesis is a major pathophysiology in endometriosis. Our previous studies have demonstrated that the prodrug of epigallocatechin gallate (ProEGCG) exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate (EGCG). However, their direct binding targets and underlying mechanisms for the differential effects remain unknown. In this study, we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis. Additionally, 1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin (MTDH) and PX domain containing serine/threonine kinase-like (PXK) as novel binding targets of EGCG and ProEGCG, respectively. Computational simulation and BioLayer interferometry were used to confirm their binding affinity. Our results showed that MTDH-EGCG inhibited protein kinase B (Akt)-mediated angiogenesis, while PXK-ProEGCG inhibited epidermal growth factor (EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor (HIF-1a)/vascular endothelial growth factor (VEGF) pathway. In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways. Moreover, our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.

Abstract The microbiome in a specific human organ has been well-studied, but few reports have investigated the multi-organ microbiome as a whole. Here, we aim to analyse the intra-individual inter-organ and intra-organ microbiome in deceased humans. We collected 1608 samples from 53 sites of 7 surface organs (oral cavity, esophagus, stomach, small intestine, appendix, large intestine and skin; n = 33 subjects) and performed microbiome profiling, including 16S full-length sequencing. Microbial diversity varied dramatically among organs, and core microbial species co-existed in different intra-individual organs. We deciphered microbial changes across distinct intra-organ sites, and identified signature microbes, their functional traits, and interactions specific to each site. We revealed significant microbial heterogeneity between paired mucosa-lumen samples of stomach, small intestine, and large intestine. Finally, we established the landscape of inter-organ relationships of microbes along the digestive tract. Therefore, we generate a catalogue of bacterial composition, diversity, interaction, functional traits, and bacterial translocation in human at inter-organ and intra-organ levels.

Introduction Neonatal jaundice is a common and life-threatening health problem in neonates due to overaccumulation of circulating unconjugated bilirubin. Gut flora has a potential influence on bilirubin metabolism. The infant gut microbiome is commonly copied from the maternal gut. During pregnancy, due to changes in dietary habits, hormones and body weight, maternal gut dysbiosis is common, which can be stabilised by probiotics supplementation. However, whether probiotic supplements can reach the baby through the mother and reduce the incidence of neonatal jaundice has not been studied yet. Therefore, we aim to evaluate the effect of prenatal maternal probiotic supplementation on the incidence of neonatal jaundice.Methods and analysis This is a randomised double-blind placebo-controlled clinical trial among 94 pregnant women (47 in each group) in a tertiary hospital in Hong Kong. Voluntary eligible participants will be recruited between 28 and 35 weeks of gestation. Computer-generated randomisation and allocation to either the intervention or control group will be carried out. Participants will take either one sachet of Vivomixx (450 billion colony-forming units per sachet) or a placebo per day until 1 week post partum. Neither the study participants nor researchers will know the randomisation and allocation. The intervention will be initiated at 36 weeks of gestation. Neonatal bilirubin level will be measured to determine the primary outcome (hyperbilirubinaemia) while the metagenomic microbiome profile of breast milk and maternal and infant stool samples as well as pregnancy outcomes will be secondary outcomes. Binary logistic and linear regressions will be carried out to assess the association of the microbiome data with different clinical outcomes.Ethics and dissemination Ethics approval is obtained from the Joint CUHK-NTEC Clinical Research Ethics Committee, Hong Kong (CREC Ref: 2023.100-T). Findings will be published in peer-reviewed journals and presented at international conferences.Trial registration number NCT06087874.

Abstract Preeclampsia (PE) is considered as a disease of placental origin. However, the specific mechanism of placental abnormalities remains elusive. This study identified thrombospondin‐1 (THBS1) is downregulated in preeclamptic placentae and negatively correlated with blood pressure. Functional studies show that THBS1 knockdown inhibits proliferation, migration, and invasion and increases the cycle arrest and apoptosis rate of HTR8/SVneo cells. Importantly, THBS1 silencing induces necroptosis in HTR8/SVneo cells, accompanied by the release of damage‐associated molecular patterns (DAMPs). Necroptosis inhibitors necrostatin‐1 and GSK′872 restore the trophoblast survival while pan‐caspase inhibitor Z‐VAD‐FMK has no effect. Mechanistically, the results show that THBS1 interacts with transforming growth factor B‐activated kinase 1 (TAK1), which is a central modulator of necroptosis quiescence and affects its stability. Moreover, THBS1 silencing up‐regulates the expression of neuronal precursor cell‐expressed developmentally down‐regulated 4 (NEDD4), which acts as an E3 ligase of TAK1 and catalyzes K48‐linked ubiquitination of TAK1 in HTR8/SVneo cells. Besides, THBS1 attenuates PE phenotypes and improves the placental necroptosis in vivo. Taken together, the down‐regulation of THBS1 destabilizes TAK1 by activating NEDD4‐mediated, K48‐linked TAK1 ubiquitination and promotes necroptosis and DAMPs release in trophoblast cells, thus participating in the pathogenesis of PE.

Introduction Pelvic fistulas affect a significant number of patients globally, with a relatively low prevalence in the United States. Virtual education offers an effective, scalable solution to bridge this educational gap and lead to a deeper understanding of more common conditions, such as urinary and fecal incontinence. Methods We developed two virtual cases on rectovaginal and vesicovaginal/ureterovaginal fistulas to enhance medical students’ exposure, knowledge, and confidence regarding assessment of pelvic fistulas. The cases could be completed in approximately 30 minutes, asynchronously, and at students’ own pace. The cases were integrated into an OB/GYN clerkship. We conducted a survey among students receiving the cases to gather feedback on usability, acceptability, and educational value, which guided subsequent improvements. Results Forty medical students, ranging from first to third year, participated in the urogynecology elective; 21 (53%) completed the survey. Ninety-one percent agreed or strongly agreed they were satisfied with the cases. All respondents found the format easy to use and appropriate for their level of learning. Most reported the cases improved their confidence in nonsurgical and surgical management options for pelvic fistulas. Discussion Offering virtual and interactive patient cases on e-learning platforms represents an innovative approach to increasing clinical exposure to urogynecologic disorders. By providing medical students with the opportunity to interact with pelvic fistulas virtually, these cases can help bridge a gap in clinical education. Future exploration is valuable for examining knowledge deficiencies and developing cost-effective, self-paced, easily accessible educational resources to advance medical training and optimize patient care.

With the improvement of the reliability and lifespan of electrical connectors, the traditional single objective design focusing solely on performance or reliability has become inadequate to meet the requirements. This paper analyzes the failure mechanism of a specific electrical connector under the conditions of insertions-extractions. It establishes a contact degradation model and an integrated design model that considers mechanical properties and reliability. By analyzing the integrated design model, the optimization variables have been defined as the radius of the spring wire, the radius of the pin, the inner radius of the inner sleeve, the length of the inner sleeve, and the inclination of the spring wire. Additionally, the objective function of optimization has been determined. The optimal solutions that satisfy the constraints were calculated using the global optimization algorithm. The optimization results not only achieve the goal of high reliability but also the goal of extended mechanical life.

Introduction Pre-eclampsia (PE) affects about 5% of Chinese pregnant women and is a major cause of maternal and perinatal morbidity and mortality. The first trimester screening model developed by the Fetal Medicine Foundation, which uses the Bayes theorem to combine maternal characteristics and medical history together with measurements of biomarkers, has been proven to be effective and has superior screening performance to that of the traditional risk factor-based approach for the prediction of PE. Prophylactic use of low-dose aspirin in women at risk for PE has resulted in a lower incidence of preterm-PE. However, there is no consensus on the preferred aspirin dosage for the prevention of preterm-PE. Evidence has also suggested that metformin has the potential benefit in preventing PE in pregnant women who are at high risk of the disorder.Method and analysis We present a protocol (V.2.0, date 17 March 2022) for the AVERT trial, which is a multicentre, double-blinded, 3-arm randomised controlled trial (RCT) that uses an effective PE screening programme to explore the optimal dosage of aspirin and the role of metformin for the prevention of PE among high-risk pregnant women in China. We intend to recruit 66 000 singleton pregnancies without treatment of low-dose aspirin and metformin at 11–13 weeks’ gestation and all eligible women attending for their first trimester routine scan will be invited to undergo screening for preterm-PE by the combination of maternal factors, mean arterial pressure and placental growth factor. Women found to be at high risk of developing preterm-PE will be invited to take part in the RCT. This study will compare the incidence of preterm-PE with delivery at

The present study aimed to investigate the effect of a blatant activation of age-based stereotype threats (ABST) on time-based prospective memory (TBPM) in older adults. A sample of 74 adults from Hong Kong was randomly assigned to one of the two experimental conditions: the stereotyped condition (n = 36) or the neutral condition (n = 38). Participants were asked to read fictitious news reports related to dementia (stereotyped condition) or the importance of English oral skills (neutral condition). After, all participants performed a TBPM task using the Chinese lexical decision task as an ongoing task block. The results indicate a main effect of ABST on TBPM accuracy. Specifically, older adults under a blatant activation of ABST demonstrated lower TBPM accuracy (p

Systemic lupus erythematosus (SLE) is a complicated multisystem autoimmune disease that carries substantial mortality and morbidity. The development of new therapies is partly hindered by the lack of a flawless instrument to gauge disease activity in different organs for the primary efficacy outcome. Until a global consensus is reached regarding the most preferred assessment tool, application of any of the existing disease activity indices is acceptable in clinical practice and research. However, one should have a more thorough understanding of the strength and limitations of individual disease activity instruments. This article updates the SLE disease activity indices commonly used in clinical trials and their latest stage of development.

Coronavirus disease 2019 (COVID-19) was one of the most important infections in the past few years. Although most cases of COVID-19 are mild, serious complications may arise. The multisystem inflammatory syndrome (MIS) is a rare but severe, yet poorly understood complication of COVID-19. It was first described in childhood patients with COVID-19 (MIS-C) but is increasingly reported in adults. MIS-A may lead to diagnostic and therapeutic dilemma as its manifestations may mimic a flare of the underlying disease and the use of immunosuppressive therapy may further increase the risk of other infective complications in these patients. However, MIS-A has rarely been reported in patients with pre-existing autoimmune conditions. We hereby present a patient with systemic lupus erythematosus who developed severe MIS-A 6 weeks after a recent SARS-CoV-2 infection.

To investigate the synergistic effect of Rosa roxbunghii Tratt. polysaccharide（RRTP）and Rosa roxbunghii Tratt. insoluble dietary fiber（RTIDF）on hypoglycemic function. In this study, RRTP and RTIDF were extracted, isolated and purified, the antioxidant and hypoglycemic activities of polysaccharides were measured by in vitro experiment and the relationship between hypoglycemic function and intestinal microbial community structure in mice was analyzed in vivo intervention experiment of Type Ⅱ diabetes in mice. The results were as follows: (1) RRTP had a good free radical scavenging ability in vitro, and could significantly inhibit α-glucosidase and α-amylase activities with IC50 values of 0.293 and 4.251 mg·mL-1, respectively. RTIDF only showed certain inhibitory activity on α-amylase activity. (2) After the intervention of the extracts in the model mice, the tendency of the obese mice to continue to lose weight was reversed. Compared with CK group (physiological saline), the blood glucose level of RTIDF and RRTP+RTIDF mice were significantly down-regulated, and the activity of CAT enzyme in serum was significantly enhanced. RRTP+RTIDF group was superior to RTIDF group. (3) The extract intervention could reduce the inflammatory factors in the liver, relieve the degree of cell swelling, increase the number of absorbing cells in the cecum, and restore the intestinal wall mucosal layer. (4) Further analysis of intestinal microbial community showed that RTIDF+RRTP could reduce the proportion of Bacteroidetes and Firmicutes, increase the abundance of beneficial bacteria such as Acetobacter, but RTIDF had more significant regulation effect on the population. Therefore, based on in vitro hypoglycemic simulation and in vivo intervention results, RRTP and RTIDF have a certain synergistic effect on glucose intervention in diabetic mice, it may be used together as an intervention to improve Type Ⅱ diabetes.

Cancer is a leading cause of death worldwide. Around one-third of the total global cancer incidence and mortality are related to gastrointestinal (GI) cancers. Over the past few years, rapid developments have been made in patient-derived organoid (PDO) models for gastrointestinal cancers. By closely mimicking the molecular properties of their parent tumors in vitro, PDOs have emerged as powerful tools in personalized medicine and drug discovery. Here, we review the current literature on the application of PDOs of common gastrointestinal cancers in the optimization of drug treatment strategies in the clinic and their rising importance in pre-clinical drug development. We discuss the advantages and limitations of gastrointestinal cancer PDOs and outline the microfluidics-based strategies that improve the throughput of PDO models in order to extract the maximal benefits in the personalized medicine and drug discovery process.

Botulinum neurotoxin-A (BoNT-A) injections are effective for focal spasticity. However, the impact on muscle strength is not established. This study aimed to investigate the effect of BoNT-A injections on muscle strength in adult neurological conditions. Studies were included if they were Randomised Controlled Trials (RCTs), non-RCTs, or cohort studies (n ≥ 10) involving participants ≥18 years old receiving BoNT-A injection for spasticity in their upper and/or lower limbs. Eight databases (CINAHL, Cochrane, EMBASE, Google Scholar, Medline, PEDro, Pubmed, Web of Science) were searched in March 2024. The methodology followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered in the Prospective Register of Systematic Reviews (PROSPERO: CRD42022315241). Quality was assessed using the modified Downs and Black checklist and the PEDro scale. Pre-/post-injection agonist, antagonist, and global strength outcomes at short-, medium-, and long-term time points were extracted for analysis. Following duplicate removal, 8536 studies were identified; 54 met the inclusion criteria (3176 participants) and were rated as fair-quality. Twenty studies were analysed as they reported muscle strength specific to the muscle injected. No change in agonist strength after BoNT-A injection was reported in 74% of the results. Most studies’ outcomes were within six weeks post-injection, with few long-term results (i.e., >three months). Overall, the impact of BoNT-A on muscle strength remains inconclusive.

The global rise in electricity demand necessitates extensive transmission infrastructure, where insulators play a critical role in ensuring the safe operation of power transmission systems. However, insulators are susceptible to burst defects, which can compromise system safety. To address this issue, we propose an insulator defect detection framework, ID-Det, which comprises two main components, i.e., the Insulator Segmentation Network (ISNet) and the Insulator Burst Detector (IBD). (1) ISNet incorporates a novel Insulator Clipping Module (ICM), enhancing insulator segmentation performance. (2) IBD leverages corner extraction methods and the periodic distribution characteristics of corners, facilitating the extraction of key corners on the insulator mask and accurate localization of burst defects. Additionally, we construct an Insulator Defect Dataset (ID Dataset) consisting of 1614 insulator images. Experiments on this dataset demonstrate that ID-Det achieves an accuracy of 97.38%, a precision of 97.38%, and a recall rate of 94.56%, outperforming general defect detection methods with a 4.33% increase in accuracy, a 5.26% increase in precision, and a 2.364% increase in recall. ISNet also shows a 27.2% improvement in Average Precision (AP) compared to the baseline. These results indicate that ID-Det has significant potential for practical application in power inspection.

Successfully, theoretical equations were established to study the effect of solvent polarities on the electron current density, fill factor and efficiencies of Tris (8-hydroxy) quinoline aluminum (Alq3)/ ZnO solar cells. Three different solvents studied in this theoretical works, namely 1-propanol, ethanol and acetonitrile. The quantum model of transition energy in donor–acceptor system was used to derive a current formula. After that, it has been used to calculate the fill factor and the efficiency of the solar cell. The calculations indicated that the efficiency of the solar cell is influenced by the polarity of solvents. The best performance was for the solar cell based on acetonitrile as a solvent with electron current density of (5.078-12.331) mA/cm2between (1-6) V. In addition, the highest efficiency calculated for the (Alq3)/ ZnO solar cell was 2.593% which corresponds to the highest current density. However, the calculated fill-factor values were significantly unchanged with the changing of the current density. Interestingly, the measured values are in a good agreement with previously reported experimental values.

Abstract Background Restrictive spirometry pattern (RSP), defined as reduced forced vital capacity (FVC) in absence of airflow obstruction (AFO), is associated with increased risk of mortality in general population. However, evidence in the patients with silicosis is limited. This study was aimed to investigate the relationship between RSP and the risk of death in a silicotic cohort. Method This retrospective cohort study used data from the Pneumoconiosis Clinic, Hong Kong Department of Health that containing 4315 patients aged 18–80 years and diagnosed with silicosis during 1981–2019, with a follow-up till 31 December 2019. Spirometry was carried out at the diagnostic examination of silicosis. Lung function categories were classified as normal spirometry (FEV1/FVC ≥ 0.7, FVC ≥ 80% predicted), RSP only (FEV1/FVC ≥ 0.7, FVC

Abstract KRAS is an important tumor intrinsic factor driving immune suppression in colorectal cancer (CRC). In this study, we demonstrate that SLC25A22 underlies mutant KRAS-induced immune suppression in CRC. In immunocompetent male mice and humanized male mice models, SLC25A22 knockout inhibits KRAS-mutant CRC tumor growth with reduced myeloid derived suppressor cells (MDSC) but increased CD8+ T-cells, implying the reversion of mutant KRAS-driven immunosuppression. Mechanistically, we find that SLC25A22 plays a central role in promoting asparagine, which binds and activates SRC phosphorylation. Asparagine-mediated SRC promotes ERK/ETS2 signaling, which drives CXCL1 transcription. Secreted CXCL1 functions as a chemoattractant for MDSC via CXCR2, leading to an immunosuppressive microenvironment. Targeting SLC25A22 or asparagine impairs KRAS-induced MDSC infiltration in CRC. Finally, we demonstrate that the targeting of SLC25A22 in combination with anti-PD1 therapy synergizes to inhibit MDSC and activate CD8+ T cells to suppress KRAS-mutant CRC growth in vivo. We thus identify a metabolic pathway that drives immunosuppression in KRAS-mutant CRC.

Abstract Decreasing particle size (like thickness) is a common strategy to enhance the activities of catalysts. In this work, we have synthesized two coppers, which are bismuth‐based metal‐organic framework (CuBi‐MOF) catalysts with different thicknesses (134.8 and 2.0 nm). In contrast to common expectations, large thickness CuBi‐MOF has exhibited superior activities as a comparison to its small‐thickness counterpart in terms of carbon dioxide electroreduction to produce formate, characteristic of high selectivity (Faraday efficiency > 90%), a wide window of potential (−0.6 to −1.6 V vs. reversible hydrogen electrode), and large current densities (up to −380 mA cm−2). The mechanism study has been performed by using density functional theory calculations, which highlight the strong synergic effect between Cu and Bi sites in large‐thickness CuBi‐MOF for activating CO2 molecules. Consequently, large‐thickness CuBi‐MOF could show smaller Gibbs free energies compared to its small counterpart for binding with reaction intermediate (*COOH, 1.1 vs. 1.8 eV). The result of this work could provide new insights into catalyst design toward a number of electrochemical systems.

Objective: To study the predictive value of a positive anti-nuclear antibody (ANA) for a rheumatological diagnosis in an outpatient setting. Methods: Individuals who were referred to the rheumatology outpatient clinics because of a positive ANA between July 2014 and June 2015 were retrospectively reviewed. Presenting symptoms in addition to a positive ANA and whether a final rheumatological diagnosis was made were recorded. The positive predictive value of a positive ANA and its titer for a rheumatological diagnosis, with and without accompanying symptoms was evaluated. Results: A total of 230 patients were included (82% women, age 47.7 ± 14.1 years [range 18-84]). Family medicine and the general outpatient clinic were the main sources of referral (32.2%), followed by ophthalmology (13.0%) and otorhinolaryngology (11.7%). A final rheumatological diagnosis was made in 54 (23.5%) patients, with rheumatoid arthritis being the commonest diagnosis (40.7%). In the absence of any associated symptoms, the predictive value of a positive ANA was 0%. The presence of Raynaud’s phenomenon (100%), joint swelling (59.5%), and joint stiffness (48.9%) predicted a better final rheumatological diagnosis along with a positive ANA. ANA titers of 1:80 or less had a low sensitivity for rheumatic diseases. A receiver operating characteristic (ROC) curve analysis showed that an ANA titer of [Formula: see text]1:128 best predicted a rheumatological diagnosis (AUC 0.78 [0.71–0.85]; sensitivity 0.78; specificity 0.64). Conclusions: To improve the prediction for a rheumatological diagnosis, referral for a positive ANA test should be more appropriately done with compatible symptoms.

Abstract MLK4, a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, has been implicated in cancer progression. However, its role in lung adenocarcinoma has not been characterized. Here, we showed that MLK4 was overexpressed in a significant subset of lung adenocarcinoma, associated with a worse prognosis, and exerted an oncogenic function in vitro and in vivo. Bioinformatics analyses of clinical datasets identified phosphoenolpyruvate carboxykinase 1 (PCK1) as a novel target of MLK4. We validated that MLK4 regulated PCK1 expression at transcriptional level, by phosphorylating the transcription factor CREB, which in turn mediated PCK1 expression. We further demonstrated that PCK1 is an oncogenic factor in lung adenocarcinoma. Given the importance of PCK1 in the regulation of cellular metabolism, we next deciphered the metabolic effects of MLK4. Metabolic and mass spectrometry analyses showed that MLK4 knockdown led to significant reduction of glycolysis and decreased levels of glycolytic pathway metabolites including phosphoenolpyruvate and lactate. Finally, the promoter analysis of MLK4 unravelled a binding site of transcription factor KLF5, which in turn, positively regulated MLK4 expression in lung adenocarcinoma. In summary, we have revealed a KLF5-MLK4-PCK1 signalling pathway involved in lung tumorigenesis and established an unusual link between MAP3K signalling and cancer metabolism.