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Abstract Automated test case generation for path coverage (ATCG-PC) is a major challenge in search-based software engineering due to its complexity as a large-scale black-box optimization problem. However, existing search-based approaches often fail to achieve high path coverage in large-scale unit programs. This is due to their expansive decision space and the presence of hundreds of feasible paths. In this paper, we present a microscale (small-size subsets of the decomposed decision set) search-based algorithm with time-space transfer (MISA-TST). This algorithm aims to identify more accurate subspaces consisting of optimal solutions based on two strategies. The dimension partition strategy employs a relationship matrix to track subspaces corresponding to the target paths. Additionally, the specific value strategy allows MISA-TST to focus the search on the neighborhood of specific dimension values rather than the entire dimension space. Experiments conducted on nine normal-scale and six large-scale benchmarks demonstrate the effectiveness of MISA-TST. The large-scale unit programs encompass hundreds of feasible paths or more than 1.00E+50 test cases. The results show that MISA-TST achieves significantly higher path coverage than other state-of-the-art algorithms in most benchmarks. Furthermore, the combination of the two time-space transfer strategies significantly enhances the performance of search-based algorithms like MISA, especially in large-scale unit programs.

Abstract Loeffler's endocarditis (LE) is the cardiac manifestation of hypereosinophilic syndrome. We present a case of LE in a 45‐year‐old female, resulting in diffuse endothelial fibrosis and severe right‐sided heart failure. The patient was admitted with dyspnoea and oedema, with haematology revealing an absolute eosinophil count of 20.9 × 109. Imaging showed near‐complete obliteration of the right ventricular apical and formation of thromboses. Endomyocardial biopsy indicated diffuse fibrous hyperplasia of the endocardium with fibrinous thrombi rich in eosinophils. Molecular and cytogenetic analyses of bone marrow cells showed no signs of FIP1L1‐PDGFRA fusion, PDGFRB mutation, abnormal myeloid maturation, or a lymphoproliferative disorder. Flow cytometry indicated no clonality, ruling out chronic eosinophilic leukaemia. Gene mutation screening discovered a p.L583_A586delinesS mutation in the JAK2 gene. Following treatment with ruxolitinib, the patient's eosinophil levels normalized, but unfortunately, the damage to the heart was irreversible. The patient was hospitalized multiple times due to right heart failure and resistance to diuretics. After thorough discussions with the medical team, it was determined that a heart transplantation would be the most effective treatment. Following the surgery, the patient successfully navigated the postoperative critical period with the support of an intra‐aortic balloon pump (IABP), continuous renal replacement therapy (CRRT), and ventilator‐assisted ventilation but subsequently developed an acquired Intensive care unit‐acquired weakness (ICU‐AW) and a depressive state. Fortunately, the patient gradually recovered from these complications.

Hirschsprung-associated enterocolitis (HAEC) stands as most common and serious complication of Hirschsprung's disease. Variations in the microbiota composition may account for the differences observed between HAEC and healthy individuals, offering crucial insights into the disease's pathogenesis. Here, we performed a study to changes in the gut microbiome using 16sRNA amplicon sequencing in a cohort of HAEC patients (n = 16) and healthy controls (n = 14). Our result revealed a significant disparity in beta diversity between the two groups. Following correction for false discovery rate, a rank–sum test at the genus level indicated a notable decrease in the relative abundance of Bifidobacterium, Lactobacillus, and Veillonella, whereas the Enterococcus genus exhibited a substantial increase in HAEC, a finding further supported by additional linear discriminant analysis effect size analysis. Functional analysis showed that putative transport and catabolism, digestive system, and metabolism of cofactors and vitamins were proved to be some abundant KOs (Kyoto Encyclopedia of Genes and Genomes [KEGG] orthologs) in healthy group, whereas infectious disease, membrane transport, and carbohydrate metabolism were the three KOs with the higher abundance in the HAEC group. Our data increased our insight into the HAEC, which may shed further light on HAEC pathogenesis. Our study firstly demonstrated the difference between fecal microbiota of HAEC patients and healthy individuals, which made a step forward in the understanding of the pathophysiology of HAEC.

Abstract Background Diabetic retinopathy (DR), a prevalent complication in patients with type 2 diabetes, has attracted increasing attention. Recent studies have explored a plausible association between retinopathy and significant liver fibrosis. The aim of this investigation was to develop a sophisticated machine learning (ML) model, leveraging comprehensive clinical datasets, to forecast the likelihood of significant liver fibrosis in patients with retinopathy and to interpret the ML model by applying the SHapley Additive exPlanations (SHAP) method. Methods This inquiry was based on data from the National Health and Nutrition Examination Survey 2005–2008 cohort. Utilizing the Fibrosis-4 index (FIB-4), liver fibrosis was stratified across a spectrum of grades (F0-F4). The severity of retinopathy was determined using retinal imaging and segmented into four discrete gradations. A ten-fold cross-validation approach was used to gauge the propensity towards liver fibrosis. Eight ML methodologies were used: Extreme Gradient Boosting, Random Forest, multilayer perceptron, Support Vector Machines, Logistic Regression (LR), Plain Bayes, Decision Tree, and k-nearest neighbors. The efficacy of these models was gauged using metrics, such as the area under the curve (AUC). The SHAP method was deployed to unravel the intricacies of feature importance and explicate the inner workings of the ML model. Results The analysis included 5,364 participants, of whom 2,116 (39.45%) exhibited notable liver fibrosis. Following random allocation, 3,754 individuals were assigned to the training set and 1,610 were allocated to the validation cohort. Nine variables were curated for integration into the ML model. Among the eight ML models scrutinized, the LR model attained zenith in both AUC (0.867, 95% CI: 0.855–0.878) and F1 score (0.749, 95% CI: 0.732–0.767). In internal validation, this model sustained its superiority, with an AUC of 0.850 and an F1 score of 0.736, surpassing all other ML models. The SHAP methodology unveils the foremost factors through importance ranking. Conclusion Sophisticated ML models were crafted using clinical data to discern the propensity for significant liver fibrosis in patients with retinopathy and to intervene early. Practice implications Improved early detection of liver fibrosis risk in retinopathy patients enhances clinical intervention outcomes.

Abstract Objective This study aims to evaluate the efficacy and safety of 3D printing technology in brachytherapy for cervical cancer, comparing its outcomes with conventional free hand implantation brachytherapy. Methods A total of 50 cervical cancer patients treated at the First Affiliated Hospital of Gannan Medical College from January 2019 to July 2023 were included in this study. Patients were divided into two groups: 25 patients received intensity-modulated radiotherapy (IMRT) combined with 3D-printed brachytherapy, and 25 patients underwent IMRT combined with free hand brachytherapy implantation. Key indicators analyzed included short-term therapeutic effects, survival outcomes, operation times, the number of CT scans, the number of needles inserted, dosimetric parameters, and complications. Results The use of 3D-printed brachytherapy significantly improved the safety of radiation therapy operations, especially for large tumors (≥ 30 mm), by providing more precise dose distribution and reducing the radiation doses received by critical organs such as the bladder and rectum. Compared to the artificial implant group (88% prevalence), the 3D-printed brachytherapy group showed a significantly lower incidence of radiation enteritis (29.2% prevalence, p

Recent studies have identified that metabolic reprogramming in lung adenocarcinoma cells, particularly lactate metabolism disorders, plays a crucial role in tumor development and immune therapy response. The accumulation of lactic acid not only provides energy support for the proliferation of tumor cells but also affects the function of immune cells by changing the tumor microenvironment, thereby promoting immune escape. Immunotherapy, especially the application of immune checkpoint inhibitors, has become an important strategy for treating lung adenocarcinoma. However, lactate metabolism disorders might affect the efficacy of immunotherapy, leading to resistance in some patients. Therefore, a thorough understanding of the mechanisms of lactic acid metabolism in lung adenocarcinoma and its impact on the response to immunotherapy is essential for developing new therapeutic strategies and improving the efficacy of immunotherapy. This review summarizes the role of lactate metabolism disorders in the development and immunotherapy of lung adenocarcinoma, discusses the potential role of lactic acid metabolism-related genes and pathways in lung adenocarcinoma, and explores the progress in therapeutic strategies targeting lactic acid metabolism regulation. This work aims to provide new insights for the treatment of lung adenocarcinoma.

Abstract Background Existing evidence suggests that children and adolescents who had experienced childhood maltreatment (CM) are at higher suicidal risk. However, the mediation role of resilience in this association remains unclear. We aim to investigate the mediation via resilience in the associations between CM and three suicidal risk indicators (suicidal ideation, SI; suicidal plan, SP; suicidal attempt, SA) among a large sample of Chinese children and adolescents. Methods A population-based cross-sectional survey was conducted in southwestern China Yunnan province. A total of 9723 children and adolescents were included and analyzed by using a multi-stage stratified cluster sampling design. Univariate and multivariate logistic regression models were fitted to explore the associations between CM, resilience, and the three suicidal risk indicators, dose-response trends further elucidated by using the restricted cubic splines. Path models were adopted to estimate the mediation of resilience. Results The estimated prevalence rates for one-year SI, SP and SA were 32.86% (95% CI: 31.93–33.80%), 19.36% (95% CI: 18.57–20.16%) and 9.07% (95% CI: 8.51–9.66%). After adjustment, CM significantly associated with all 3 suicidal risk indicators, and the odds ratios (ORs) were 2.13 (95% CI: 1.91–2.37), 2.45 (95% CI: 2.13–2.81), and 3.61 (95% CI: 2.90–4.52) for one-year SI, SP, and SA, respectively. Path models revealed that resilience significantly mediated the associations between CM and the three suicidal risk indicators, and among all dimensions of resilience, family support presented the strongest mediation consistently. Conclusions Our study results suggest that intervention measures which focusing on improving psychological resilience might be effective in reducing suicidal risk for children and adolescents who had experienced maltreatment. Prospective studies should be done to corroborate our findings.

Abstract Wildlife crossing structures and road calming measures are frequently implemented to improve habitat connectivity and mitigate the risks of wildlife–vehicle collisions on roads. Although Southeast Asia is a known biodiversity hotspot, majority of studies assessing effectiveness of such structures were conducted outside the region. Existing studies also tended to be non‐comparative and focused on crossing structures in silo. We addressed this gap by simultaneously surveying and comparing the usage frequency of mammals across three crossing types—culverts, roads and rope bridges—along a road surrounded by forests in Singapore. This allowed us to evaluate the preferences of mammals, assess usage patterns and investigate factors influencing the use of different crossing types. Using camera traps and closed‐circuit televisions, we documented 1133 independent crossing events across a 9‐month study period from March to November 2021. Fourteen mammal species were detected across all crossing types, with wild boar (Sus scrofa) being the most prevalent species (68.2%). Locally critically endangered species such as the Malayan porcupine (Hystrix brachyura), Sunda pangolin (Manis javanica), and Raffles' banded langur (Presbytis femoralis femoralis) were also recorded to use culverts, roads, and rope bridges for crossings, respectively. Although many species used multiple crossing types, most species had a preferred crossing method. Between culverts and roads, factors that influenced crossing preferences included group size for wild boars and time of day and presence of fences for other mammals. Even though such culverts were intended for drainage, they were still widely used by mammals. Overall, all three crossing methods were crucial in facilitating the movement of animals between habitats. Thus, a variety of infrastructure and measures to accommodate the diversity of wildlife moving across forest patches in a fragmented landscape is recommended.

Background: Homeostatic dysregulation (HD), the measure of aging-related physiological dysregulation, serves as an essential intervenable indicator of aging. Objective: To explore the associations of three healthy dietary patterns with HD, investigate the most recommended dietary patterns, and identify the significant beneficial and harmful food groups Methods: This prospective cohort study included 8,288 participants aged 30–79 years from the China Multi-Ethnic Cohort (CMEC), with a female majority (61.6%). Dietary information was obtained through the baseline food frequency questionnaire (FFQ). Three dietary patterns were constructed: Dietary Approaches to Stop Hypertension (DASH), alternative Mediterranean diets (aMED), and Healthy Diet Score (HDS). HD was constructed based on clinical biomarkers and anthropometric measurements. Follow-up analyses adjusted for baseline data were employed to assess the longitudinal associations of three dietary patterns at baseline with HD at follow-up. Additionally, quantile G-computation was utilized to evaluate the relative contribution of each food group to the association with HD. Results: Over a follow-up period of 2.0 years, all healthy dietary patterns exhibited negative associations with HD, with βQ5/Q1 = −0.112, 95%CI (−0.172, −0.051) for HDS, with βQ5/Q1 = −0.073, 95%CI (−0.134, −0.012) for aMED, with βQ5/Q1 = −0.047, 95%CI (−0.107,0.014) for DASH. The results of the component analyses revealed that soybean products were the most significant beneficial food group (relative contribution of 24.0%), while alcohol was identified as the major harmful food group (relative contribution of 76.9%). Conclusion: Healthy dietary patterns, especially HDS, are negatively associated with HD. Additionally, soybean products and alcohol are the most significant beneficial and detrimental food groups respectively. Developing appropriate nutritional strategies may help reduce the burden of disease and promote healthy aging.

Long noncoding RNAs (lncRNAs) regulate the progression of type 2 diabetes mellitus complicated with obstructive sleep apnoea (T2DM-OSA). However, the role of the lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) in T2DM-OSA remains unknown. This study aimed to reveal the function of NEAT1 in T2DM-OSA and the underlying mechanism. KKAy mice were exposed to intermittent hypoxia (IH) or intermittent normoxia to generate a T2DM-OSA mouse model. HMEC-1 cells were treated with high glucose (HG) and IH to construct a T2DM-OSA cell model. RNA expression was detected by qRT-PCR. The protein expression of Apelin, NF-E2-related factor 2 (Nrf2), haem oxygenase-1 (HO-1), and up-frameshift suppressor 1 (UPF1) was assessed using western blot. Cell injury was evaluated using flow cytometry, enzyme-linked immunosorbent assay, and oxidative stress kit assays. RIP, RNA pull-down, and actinomycin D assays were performed to determine the associations between NEAT1, UPF1, and Apelin. NEAT1 expression was upregulated in the aortic vascular tissues of mice with T2DM exposed to IH and HMEC-1 cells stimulated with HG and IH, whereas Apelin expression was downregulated. The absence of NEAT1 protected HMEC-1 cells from HG- and IH-induced damage. Furthermore, NEAT1 destabilized Apelin mRNA by recruiting UPF1. Apelin overexpression decreased HG- and IH-induced injury to HMEC-1 cells by activating the Nrf2/HO-1 pathway. Moreover, NEAT1 knockdown reduced HG- and IH-induced injury to HMEC-1 cells through Apelin. NEAT1 silencing reduced HMEC-1 cell injury through the Apelin/Nrf2/HO-1 signalling pathway in T2DM-OSA.Abbreviations: LncRNAs, long non-coding RNAs; T2DM, type 2 diabetes mellitus; OSA, obstructive sleep apnoea; NEAT1, nuclear paraspeckle assembly transcript 1; IH, intermittent hypoxia; HMEC-1, human microvascular endothelial cells; HG, high glucose; Nrf2, NF-E2-related factor 2; UPF1, up-frameshift suppressor 1; HO-1, haem oxygenase-1; qRT-PCR, quantitative real-time polymerase chain reaction; ELISA, enzyme-linked immunosorbent assay; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; TNF-α, tumour necrosis factor-α; CCK-8, Cell Counting Kit-8; IL-1β, interleukin-1β; ROS, reactive oxygen species; MDA, malondialdehyde; SOD, superoxide dismutase; RIP, RNA immunoprecipitation; SD, standard deviations; GSH, glutathione; AIS, acute ischaemic stroke; HMGB1, high mobility group box-1 protein; TLR4, toll-like receptor 4.

Background A commercial three-dimensional optical (3DO) scanning system was reported to be used in body composition assessment. However, the applicability in Chinese adults has yet to be well-studied.Methods This secondary analysis was based on a 16-week weight-loss clinical trial with an optional extension to 24 weeks. Waist and hip circumference and body composition were measured by 3DO scanning at each follow-up visit during the study. Bioelectrical impedance analysis (BIA) was also performed to confirm the reliability of 3DO scanning at each visit. We used Lin’s concordance correlation coefficients (CCC) to evaluate the correlation between the two methods above-mentioned. Bland-Altman analysis was also performed to evaluate the agreement and potential bias between different methods.Results A total number of 70 Chinese adults overweight and obese (23 men and 47 women, aged 31.8 ± 5.8 years) were included in the analysis, which resulted in 350 3DO scans and corresponding 350 BIA measurements. The percent body fat, fat mass, and fat-free mass were 33.9 ± 5.4%, 26.7 ± 4.6 kg, and 50.3 ± 8.7 kg before the trial by 3DO scanning. And they were 30.5 ± 5.8%, 22.5 ± 4.7 kg, and 49.4 ± 8.3 kg after 16 weeks of the trial. Compared with BIA, 3DO scanning performed best in the assessment of fat-free mass (CCC = 0.89, 95%CI: 0.86, 0.90), then followed by fat mass (CCC = 0.76, 95%CI: 0.71, 0.80) and percent body fat (CCC = 0.70, 95%CI: 0.64, 0.75). Subgroup analysis showed that 3DO scanning and BIA correlated better in women than that in men, and correlated better in measuring fat-free mass in participants with larger body weight (BMI ≥28.0 kg/m2) than those with smaller body weight (

Daphne genkwa (D. genkwa) is the dried flower buds of a Chinese medicinal plant with multiple biological activities. Response surface methodology (RSM) combined with artificial neural network (ANN) techniques were utilized to optimize ultrasound-assisted extraction conditions for D. genkwa. Antioxidant activity and anti-inflammatory and analgesic properties of total flavonoids from D. genkwa (TFDG) were assessed. Optimal conditions involving ultrasonic power of 225 W, 30 min extraction time, 30 mL/g liquid–solid ratio, 60 °C extraction temperature, and 70% ethanol concentration yielded a maximum total flavonoids content (TFC) of 5.41 mg/g. After microporous resin purification, four specific flavonoids in D. genkwa were identified and quantified using high-performance liquid chromatography (HPLC). The TFDG demonstrated potent antioxidant activity, with a 94% rate of scavenging the 2, 2-diphenyl-1-picrylhydrazyl (DPPH). Furthermore, TFDG exhibited pain-alleviating properties in hot plate and acetic acid-induced writhing tests and noteworthy inhibitory effects on xylene-induced ear swelling in mice. The total flavonoids extracted by ultrasound had excellent biological activity. This establishes a foundation for further investigation into the potential medical value of D. genkwa.

Objectives: There is a lack of clear and consistent cost reporting for cost-effectiveness analysis in radiology. Estimates are often obtained using costing derived from hospital charge records. This study aims to evaluate the accuracy of hospital charge records compared to a Singapore hospital's true diagnostic imaging costs. Methods: A seven-step process involving a bottom-up micro-costing approach was devised and followed to calculate the cost of imaging using actual data from a clinical setting. We retrieved electronic data from a random sample of 96 emergency department patients who had CT brain, CT and X-ray cervical spine, and X-ray lumbar spine performed to calculate the parameters required for cost estimation. We adjusted imaging duration and number of performing personnel to account for variations. Results: Our approach determined the average cost for the following imaging procedures: CT brain (€154.00), CT and X-ray cervical spine (€177.14 and €68.22), and X-ray lumbar spine (€79.85). We found that the true cost of both conventional radiography procedures was marginally higher than the subsidized patient charge, and all costs were slightly lower than the private patient charge except for X-ray lumbar spine (€73.49 vs.€79.85). We identified larger differences in cost for both CT procedures and smaller differences in cost for conventional radiography procedures, depending on the patient's private or subsidized status. For private status, the differences were: CT brain (Min: €194.20; Max: €264.40), CT cervical spine (Min: €219.54; Max: €399.05), X-ray cervical spine (Min: €5.27; Max: €61.94), and X-ray lumbar spine (Min: €6.36; Max: €108.04), while for subsidized status, the differences were: CT brain (Min: €7.56; Max: €62.64), CT cervical spine (Min: €47.02; Max: €132.49), X-ray cervical spine (Min: €15.88; Max: €103.44), and X-ray lumbar spine (Min: €13.66; Max: €149.44). Considering examination duration and the number of personnel engaged in a procedure, there were significant variations in the minimum, average, and maximum imaging costs. Conclusion: There is a modest gap between hospital charges and actual costs, and we must therefore exercise caution and recognize the limitations of utilizing hospital charge records as absolute metrics for cost-effectiveness analysis. Our detailed approach can potentially enable more accurate imaging cost determination for future studies.

IntroductionCervical cancer remains a significant challenge in oncology with an escalating demand for novel therapeutic strategies that can navigate the complexities of its pathophysiology. This study elucidated the antineoplastic effects of cryptotanshinone, a derivative of danshen (Salvia miltiorrhiza), a herb widely utilized in traditional Chinese medicine practices.MethodsEmploying a comprehensive multi-omics approach, including transcriptomic, proteomic, and bioinformatics analyses, we investigated the potential effects of cryptotanshinone on cervical cancer through data mining and computational analysis.Results and DiscussionOur results demonstrated that the potential of cryptotanshinone to disrupted cancer cell proliferation and induced apoptosis may be ascribed to its modulation of gene expression and interaction with specific protein networks. Furthermore, network pharmacology and pathway enrichment analyses identified critical hubs and signaling pathways, suggesting a multi-targeted mechanism of action. Furthermore, the establishment of a prognostic model, which is founded upon differentially expressed genes linked to cryptotanshinone treatment, underscores its promising role as both a prognostic biomarker and a therapeutic agent. These insights pave the way for the integration of cryptotanshinone into therapeutic regimens, offering a promising avenue for enhancing the efficacy of cervical cancer treatment and patient outcomes.

IntroductionAn interspecific interaction is an important reason for the yield advantage of interspecific cropping compared with sole cropping, and the relative sowing time of species is an important factor affecting interspecific competitiveness. Our purpose was to explore the effects of different relative sowing times on the interspecific competition-recovery phenomenon in wheat and maize intercropping systems.MethodsThree planting methods (wheat/maize intercropping, wheat and maize sole cropping) and different relative sowing times of wheat were used to carry out field experiments over two years. Sequential harvest of subplots was performed between 3 and 6 times, and the biomass data were fitted to logistic growth model.ResultsDelaying the sowing time of wheat reduced the wheat yield, biomass and nutrient acquisition and increased those of maize, but wheat still had an intercropping advantage during the co-growth period. At the same time, the nutrient acquisition of maize was still inhibited, but its recovery growth advanced. Changing the relative sowing time of wheat significantly changed the maximum instantaneous growth rates of wheat and maize. Delaying the relative sowing time of wheat significantly reduced its maximum instantaneous growth rate, while enhancing that of maize, leading to a balanced mutual benefit.ConclusionsDelaying the sowing time of wheat to the same sowing time as maize will change wheat/maize intercropping from asymmetrical interspecific facilitation to symmetrical interspecific facilitation. However, in this case, intercropped wheat still had an interspecific competitive advantage in the co-growth stage, and intercropped maize still underwent a competition-recovery process.

C16H14Cl2O5, orthorhombic, P212121 (no. 19), a = 8.6429 (4) Å, b = 11.3361 (6) Å, c = 33.9029 (11) Å, V = 3321.7 (3) Å3, Z = 8, R gt(F) = 0.0635, wR ref(F 2) = 0.1630, T = 293(2) K.