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Abstract Background To comprehend the current state of death anxiety among Chinese college students during the COVID-19 pandemic, analyze its influencing factors, and provide recommendations for mitigating death anxiety among these students. Methods From March to May 2023, utilizing a cluster sampling method, students from three universities in Changzhou, Jiangsu, were selected as research participants. The investigation employed a general information questionnaire, the PTSD Checklist for DSM-5 (PCL-5), the Chinese Version Templer-Death Anxiety Scale (CT-DAS), and the brief version of the Big Five Inventory (BFI-10). Multivariate linear regression analysis was performed to examine the factors influencing death anxiety among Chinese college students during the COVID-19 pandemic. Results The total average score of death anxiety among the college students in this study was 44.35 ± 8.21. There was a positive correlation between death anxiety scores and both PTSD symptoms scores and neuroticism (r = 0.134, 0.255, both P

Abstract Background Chronic empyema after total pneumonectomy is a potentially fatal complication.The aim of the study is to explore the treatment strategy and clinical efficacy of chronic empyema after pneumonectomy. Methods A retrospective analysis of 6 patients with chronic empyema after pneumonectomy in our hospital. Utilizing a staged surgical model, the treatment approach involved rib debridement drainage, open-window thoracostomy (OWT), and the application of autologous tissue flaps, including free myocutaneous flap, pedicled muscle flap, and pedicled greater omentum, to effectively eliminate the abscess cavity. Results All patients with empyema were successfully treated after surgery, with follow-up durations ranging from 3 to 29 months and an average of (10.50 ± 9.67) months. Re-examination using chest computed tomography (CT) or magnetic resonance imaging (MRI) revealed that the empyema residual cavity had either completely disappeared or had significantly reduced. Conclusion The treatment of chronic refractory empyema after total pneumonectomy by rib debridement drainage, OWT and autologous tissue flap transplantation has a high cure rate and satisfactory clinical effect.

Abstract Background Chronic empyema is usually considered to be very challenging in clinical management and has a high mortality rate. On this basis, if combined with bronchopleural fistula (BPF) and huge irregular abscess cavity, there are not many treatment options available, and some patients may even develop cachexia due to long-term chronic consumption. The application of pedicled combined muscle flaps to repair and reconstruct according to the region of abscess cavity may improve the quality of life for such complex cases. Case presentation A 59-year-old male patient underwent surgical treatment for lung squamous cell carcinoma 2 years ago. Due to the low differentiation of malignant tumor, empyema complicated with BPF occurred after the fourth cycle of chemotherapy. His past medical history was free of other illnesses. The patient was admitted to our hospital for further treatment because of long-term chest tube drainage and obvious respiratory irritation symptoms such as cough during body position change. Chest computed tomography (CT) scan revealed a left-sided hydropneumothorax. Bronchoscopy revealed BPF. Considering that the volume of the abscess cavity did not shrink significantly after long-term drainage, we chose first-stage surgery to complete the debridement of empyema and the closure of the fistula. In the second-stage surgery, the combined pedicled muscle flaps were used to complete the filling in different areas of the huge irregular residual cavity. This surgical mode of staging and sub-regional treatment of abscess cavity has achieved satisfactory clinical results. Conclusions Utilizing the pedicled combined muscle flaps to address chronic empyema accompanied by a huge irregular abscess cavity shows promise as a treatment method for eliminating residual cavity in various regions.

Abstract Microbial biosynthesis has become the leading commercial approach for large-scale production of terpenoids, a valuable class of natural products. Enhancing terpenoid production, however, requires complex modifications on the host organism. Recently, a two-step isopentenol utilization (IU) pathway relying solely on ATP as the cofactor has been proposed as an alternative to the mevalonate (MVA) pathway, streamlining the synthesis of the common terpenoid precursors. Herein, we find that isopentenol inhibits energy metabolism, leading to reduced efficiency of the IU pathway in Saccharomyces cerevisiae. To overcome this, we engineer an IU pathway-dependent (IUPD) strain, designed for growth-coupled production. The IUPD strain is compelled to enhance the ATP supply, essential for the IU pathway, and incorporates a high-throughput screening method for enzyme evolution. The refined IU pathway surpasses the MVA pathway in synthesizing complex terpenoids. Our work offers valuable insights into developing growth-coupled strains adapted to efficient natural product synthesis.

Multi-objective optimization problems (MOPs) constitute a vital component in the field of mathematical optimization and operations research. The multi-objective evolutionary algorithm based on decomposition (MOEA/D) decomposes a MOP into a set of single-objective subproblems and approximates the true Pareto front (PF) by optimizing these subproblems in a collaborative manner. However, most existing MOEA/Ds maintain population diversity by limiting the replacement region or scale, which come at the cost of decreasing convergence. To better balance convergence and diversity, we introduce auction theory into algorithm design and propose an auction-based matching (ABM) mechanism to coordinate the replacement procedure in MOEA/D. In the ABM mechanism, each subproblem can be associated with its preferred individual in a competitive manner by simulating the auction process in economic activities. The integration of ABM into MOEA/D forms the proposed MOEA/D-ABM. Furthermore, to make the appropriate distribution of weight vectors, a modified adjustment strategy is utilized to adaptively adjust the weight vectors during the evolution process, where the trigger timing is determined by the convergence activity of the population. Finally, MOEA/D-ABM is compared with six state-of-the-art multi-objective evolutionary algorithms (MOEAs) on some benchmark problems with two to ten objectives. The experimental results show the competitiveness of MOEA/D-ABM in the performance of diversity and convergence. They also demonstrate that the use of the ABM mechanism can greatly improve the convergence rate of the algorithm.

Abstract Background Schools are high incidence places for public health emergencies. Good health literacy helps students cope with public health emergencies. Overall, the health literacy of young students is relatively low. Health education can promote health literacy, but the health education related to public health emergencies for Chinese junior middle school students needs to be improved. To design and implement health education courses related to public health emergencies for junior middle school students and examine the impact on their health literacy, emotions, and coping styles. Methods From March to December 2022, 724 students in Grade 7 and Grade 8 of two junior middle schools in Changzhou were randomly divided into a course group (n = 359) and a control group (n = 365). The course group received an age-appropriate health education course that addressed public health emergencies; there were 12 classes, one per week. The control group received general health education. One week before and after the courses, the two groups of students were assessed with the Adolescent Health Literacy Evaluation Scale under Public Health Emergencies (AHLES-PHE), the Depression Self-Rating Scale for Children (DSRSC), the Generalized Anxiety Disorder 7-item scale (GAD-7), and the Simplified Coping Style Questionnaire (SCSQ). Results After the courses were completed, the scores of AHLES-PHE [156.0 (45.0,180.0) vs. 165.0 (54.0,180.0), P 0.05). Conclusion This suggests that the health education courses related to public health emergencies designed in this study has an effect on improving health literacy, depression and anxiety in junior middle school students.

Abstract Objective A thorough examination of the available approaches is crucial to comprehensively understand the variance among the alignment strategies employed in total knee arthroplasty (TKA). In this study, we assessed the functional outcomes during the perioperative and postoperative periods of TKA in patients using generic instruments with varus knee to compare the mechanical alignment (MA) and kinematic alignment (KA) procedures. Methods A total of 127 patients from the First Affiliated Hospital of Wannan Medical College who had undergone unilateral TKA between November 2019 and April 2021 were included. The patients with varus knee deformity were categorized into two groups [type I (n = 64) and type IV (n = 63)] based on the modified coronal plane alignment of the knee (mCPAK) classification. The type I and IV groups were further subdivided into MA (n = 30 and n = 32) and KA subgroups (n = 34 and n = 21), respectively. The clinical information collected included sex, surgical side, age, body mass index, and perioperative data [including operation time, intraoperative blood loss, length of hospital stay, and the American Society of Anesthesiologists (ASA) classification]. All patients were monitored for 12 months post-surgery to evaluate the recovery of knee joint function. During this period, the Knee Disability and Osteoarthritis Outcome Score for Joint Replacement (KOOS JR) and the active range of motion (AROM) and visual analog scale (VAS) pain scores were compared at different time points, i.e., before the operation and 6 weeks, 6 months, and 12 months post-operation. Additionally, the patients’ subjective experiences were assessed at 6 and 12 months post-surgery using Forgotten Joint Score Knee (FJS-12 Knee), while complications were recorded throughout the monitoring period. Results No significant variances were observed in ASA classification, operation duration, blood loss volume during surgery, and hospital stay length between the patients who underwent KA TKA and those who received MA TKA (P > 0.05). During the initial 6 weeks post-operation, the KA group exhibited a significantly reduced average VAS pain score (P 0.05). Furthermore, the KA group had significantly higher scores on the KOOS JR at 6 weeks, 6 months, and 1 year following the surgery (P 0.05). The KA cohort also exhibited a significant increase in FJS-12 Knee at 1 year following the operation (P 0.05). Thus, compared to the MA method, the KA procedure provided pain relief and improved active motion range within 6 weeks after the surgery in patients undergoing TKA. Further, the KOOS JR exhibited significant increases at 6 weeks, 6 months, and 1 year while the FJS-12 Knee demonstrated a significant increase at 1 year after the KA TKA procedure. Conclusion Therefore, our study results suggest that the KA approach can be considered in patients using generic instruments with varus alignment of the knee, particularly those with mCPAK type I and IV varus knees, to help improve patient satisfaction.

Abstract In minimally invasive thoracoscopic surgery, for solitary pulmonary nodules (SPNs) far from the pleura, it is difficult to resected by only relying on imaging data, and effective preoperative localization can significantly improve the success rate of surgery. Therefore, preoperative localization is particularly important for accurate resection. Here, we compare the value of a novel Lung‐pro‐guided localization technique with Hook‐wire localization in video‐assisted thoracoscopic surgery. Method In this study, 70 patients who underwent CT‐guided Hook‐wire localization and Lung‐pro guided surgical marker localization before VATS‐based SPNs resection between May 2020 and March 2021 were analyzed, and the clinical efficacy and complication rate of the two groups were compared. Result Thirty‐five patients underwent Lung‐pro guided surgical marker localization, and 35 patients underwent CT‐guided Hook‐wire localization. The localization success rates were 94.3% and 88.6%, respectively (p = 0.673). Compared with the puncture group, the locating time in the Lung‐pro group was significantly shorter (p = 0.000), and the wedge resection time was slightly shorter than that in the puncture group (P = 0.035). There were no significant differences in the success rate of localization, localization complications, intraoperative blood loss, postoperative hospital stay, and the number of staplers used. Conclusion The above studies show that the Lung‐pro guided surgical marker localization and the CT‐guided Hook‐wire localization have shown good safety and effectiveness. However, the Lung‐pro guided surgical marker localization may show more safety than the Hook‐wire and can improve the patient's perioperative experience.

The weapon-target allocation (WTA) problem is a fundamental subject of defense-related applications research, and previous studies assume that the parameters in the model are determinate. For the real battlefield, asymmetric information usually leads to the failure of the above assumption, and there are uncertain factors whose frequency is hard to pinpoint. Based on uncertainty theory, we study a WTA problem in indeterminate battlefield in this paper. First, we analyze the uncertain factors in indeterminate battlefield and their influence on WTA problem. Then, considering the target threat value, the protected asset value and the extra cost of interception as uncertain variables, the uncertain multi-objective dynamic WTA (UMDWTA) model is established, where three indices including the value of destruction of targets, the value of surviving assets and the cost of operation are regarded as objective functions, and on this basis, an equivalent transformation is presented to convert the UMDWTA model into a determinate multi-objective programming (MOP) problem by expected value and standard deviation principle. To solve the proposed model efficiently, an improved multi-objective evolutionary algorithm based on decomposition (MOEA/D) is designed, which employs three new evolutionary operators and the weight vectors adaptation mechanism to improve the convergence and uniformity of the Pareto front obtained. Finally, a case of the UMDWTA problem is carried out to be solved by the designed algorithm, and the results verify the feasibility of the proposed model.

Lung cancer is the leading cause of cancer death in the world today, and adenocarcinoma is the most common histopathological type of lung cancer. In May 2021, World Health Organization (WHO) released the 5th edition of the WHO classification of thoracic tumors, which classifies invasive non-mucinous adenocarcinoma (INMA) into lepidic adenocarcinoma, acinar adenocarcinoma, papillary adenocarcinoma, solid adenocarcinoma, and micropapillary adenocarcinoma based on its histological characteristics. These five pathological subtypes differ in clinical features, treatment and prognosis. A complete understanding of the characteristics of these subtypes is essential for the clinical diagnosis, treatment options, and prognosis predictions of patients with lung adenocarcinoma, including recurrence and progression. This article will review the grading system, morphology, imaging prediction, lymph node metastasis, surgery, chemotherapy, targeted therapy and immunotherapy of different pathological subtypes of INMA.

IntroductionN-methyl-D-aspartate receptor (NMDAR) is one of the main receptor of the excitatory neurotransmitter glutamate in the brain, which is the key determinant of the excitatory/inhibitory balance of neural network. GluN2A/GRIN2A is one of the subunits of NMDAR and plays an important role in epilepsy. Approximately 78% of patients with GluN2A/Grin2a mutations have epilepsy, and the underlying mechanism of this association is not well characterized.MethodsWe constructed a mouse model of hyperthermic seizure, and conducted in vitro and in vivo electrophysiological and behavioral studies to clarify the pathogenic characteristics and mechanism of GluN2A/GRIN2A-V685G mutation. In addition, the drug efavirenz (EFV), which is used to treat HIV infection, was administrated to mutant animals to assess whether it can restore the loss of function.ResultsMutant mice showed no significant change in the mRNA or protein expressions of NMDAR compared with wild type (WT) mice. Mice with GluN2A/GRIN2A-V685G mutation exhibited shorter latency to seizure, increased frequency of seizure-like events, decreased peak current and current area of NMDAR excitatory postsynaptic current, and decreased event frequency of micro-inhibitory postsynaptic current, compared to WT mice. They also exhibited decreased threshold, increased amplitude, increased input resistance, and increased root number of action potential. EFV administration reversed these changes. The loss-of-function (LoF) mutation of NMDAR changed the excitatory/inhibitory balance of neural network, rendering animal more prone to seizures.DiscussionEFV was indicated to hold its potential in the treatment of inherited epilepsy.

BackgroundChina’s southwestern region, Qujing, harbors a high incidence of non-small cell lung cancer (NSCLC) and related mortality. This study was designed to reveal the impact of an immune-related prognostic signature (IRPS) on advanced NSCLC in the Qujing.MethodsTissue specimens from an independent cohort of 37 patients with advanced NSCLC were retrospectively evaluated to determine the relationship between the IRPS estimated by next-generation sequencing (NGS) and clinical outcome. To compare the IRPS in tissue and the clinical outcomes between Qujing and non-Qujing populations, we analyzed datasets of 23 patients with advanced NSCLC from The Cancer Genome Atlas (TCGA) database. In addition, an independent cohort (n=111) of blood specimens was retrospectively analyzed to determine the relationship between the IRPS and clinical outcome. Finally, we evaluated the utility of the blood IRPS in classifying 24 patients with advanced NSCLC who might benefit from immunotherapy.ResultsIn cohort 1, the Qujing population with tTMB-H (≥ 10 mutations/Mb) or KRAS mutations had shorter progression-free survival (PFS) (hazard ratio [HR] 0.37, 0.14 to 0.97, P = 0.04; HR 0.23, 0.08 to 0.66, P < 0.01) and overall survival (OS) (HR 0.05, 0.01 to 0.35, P < 0.01; HR 0.22, 0.07 to 0.66, P < 0.01). In cohort 2 of the Qujing population, bTMB-H (≥ 6 mutations per Mb) and KRAS mutations were related to PFS (HR 0.59, 0.36 to 0.99, P = 0.04; HR 0.50, 0.26 to 0.98, P = 0.04) and OS (HR 0.58, 0.35 to 0.96, P = 0.03; HR 0.48, 0.25 to 0.93, P = 0.03). Notably, the Qujing population with bTMB-H had superior PFS (HR 0.32, 0.09 to 1.09, P = 0.01), OS (HR 0.33, 0.10 to 1.13, P < 0.01) and objective response rates (ORRs) (83.3% vs. 14.3% vs. 20.0%, P

BackgroundLung adenocarcinoma (LUAD) is the most predominant histological subtype of lung cancer. Abnormal lipid metabolism is closely related to the development of LUAD. LncRNAs are involved in the regulation of various lipid metabolism-related genes in various cancer cells including LUAD. Here, we aimed to identify lipid metabolism-related lncRNAs associated with LUAD prognosis and to propose a new prognostic signature.MethodsFirst, differentially expressed lncRNAs (DE-lncRNAs) from the TCGA-LUAD and the GSE31210 dataset were identified. Then the correlation analysis between DE-lncRNAs and lipid metabolism genes was performed to screen lipid metabolism-related lncRNAs. Cox regression analyses were performed in the training set to establish a prognostic model and the model was validated in the testing set and the validation set. Moreover, The role of this model in the underlying molecular mechanisms, immunotherapy, and chemotherapeutic drug sensitivity analysis was predicted by methods such as Gene Set Enrichment Analysis, immune infiltration, tumor mutational burden (TMB), neoantigen, Tumor Immune Dysfunction and Exclusion, chemosensitivity analysis between the high- and low-risk groups. The diagnostic ability of prognostic lncRNAs has also been validated. Finally, we validated the expression levels of selected prognostic lncRNAs by quantitative real-time polymerase chain reaction (qRT-PCR).ResultsThe prognostic model was constructed based on four prognostic lncRNAs (LINC00857, EP300-AS1, TBX5-AS1, SNHG3) related to lipid metabolism. The receiver operating characteristic curve (ROC) and Kaplan Meier (KM) curves of the risk model showed their validity. The results of Gene Set Enrichment Analysis suggested that differentially expressed genes in high- and low-risk groups were mainly enriched in immune response and cell cycle. There statistical differences in TMB and neoantigen between high- and low-risk groups. Drug sensitivity analysis suggested that patients with low risk scores may have better chemotherapy outcomes. The results of qRT-PCR were suggesting that compared with the normal group, the expressions of EP300-AS1 and TBX5-AS1 were down-regulated in the tumor group, while the expressions of LINC00857 and SNHG3 were up-regulated. The four prognostic lncRNAs had good diagnostic capabilities, and the overall diagnostic model of the four prognostic lncRNAs was more effective.ConclusionA total of 4 prognostic lncRNAs related to lipid metabolism were obtained and an effective risk model was constructed.

Anthocyanins are natural pigments found in various plants. As multifunctional natural compounds, anthocyanins are widely used in food, pharmaceuticals, health products, and cosmetics. At present, the anthocyanins are heterologously biosynthesized in prokaryotes from flavan-3-ols, which is rather expensive. This study aimed to metabolically engineer Saccharomyces cerevisiae for anthocyanin production. Anthocyanin production has been extensively studied to understand the metabolic pathway enzymes in their natural hosts, including CHS (chalcone synthase); FLS (flavonol synthase); CHI (chalcone isomerase); F3H (flavanone 3-hydroxylase); F3′H (flavonoid 3′-hydroxylase); F3′5′H (flavonoid 3′,5′-hydroxylase); DFR (dihydroflavonol 4-reductase); ANS (anthocyanidin synthase); LAR (leucoanthocyanidin reductase); and UFGT (flavonoid 3-O-glucosyltransferase). The anthocyanin transporter MdGSTF6 was first introduced and proven to be indispensable for the biosynthesis of anthocyanins. By expressing MdGSTF6, FaDFR, PhANS0, and Dc3GT and disrupting EXG1 (the main anthocyanin-degrading enzyme), the BA-22 strain produced 261.6 mg/L (254.5 mg/L cyanidin-3-O-glucoside and 7.1 mg/L delphinidin-3-O-glucoside) anthocyanins from 2.0 g/L dihydroflavonols, which was known to be the highest titer in eukaryotes. Finally, 15.1 mg/L anthocyanins was obtained from glucose by expressing the de novo biosynthesis pathway in S. cerevisiae, which is known to be the highest de novo production. It is the first study to show that through the introduction of a plant anthocyanin transporter and knockout of a yeast endogenous anthocyanin degrading enzyme, the anthocyanin titer has been increased by more than 100 times.

BackgroundInherited susceptibility and environmental carcinogens are crucial players in lung cancer etiology. The lung microbiome is getting rising attention in carcinogenesis. The present work sought to investigate the microbiome in lung cancer patients affected by familial lung cancer (FLC) and indoor air pollution (IAP); and further, to compare host gene expression patterns with their microbiome for potential links.MethodsTissue sample pairs (cancer and adjacent nonmalignant tissue) were used for 16S rRNA (microbiome) and RNA-seq (host gene expression). Subgroup microbiome diversities and their matched gene expression patterns were analyzed. Significantly enriched taxa were screened out, based on different clinicopathologic characteristics.ResultsOur FLC microbiome seemed to be smaller, low-diversity, and inactive to change; we noted microbiome differences in gender, age, blood type, anatomy site, histology type, TNM stage as well as IAP and smoking conditions. We also found smoking and IAP dramatically decreased specific-OTU biodiversity, especially in normal lung tissue. Intriguingly, enriched microbes were in three categories: opportunistic pathogens, probiotics, and pollutant-detoxication microbes; this third category involved Sphingomonas, Sphingopyxis, etc. which help degrade pollutants, but may also cause epithelial damage and chronic inflammation. RNA-seq highlighted IL17, Ras, MAPK, and Notch pathways, which are associated with carcinogenesis and compromised immune system.ConclusionsThe lung microbiome can play vital roles in carcinogenesis. FLC and IAP subjects were affected by fragile lung epithelium, vulnerable host-microbes equilibrium, and dysregulated immune surveillance and response. Our findings provided useful information to study the triple interplay among environmental carcinogens, population genetic background, and diversified lung microbiome.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary cerebral small vascular disease caused by a homozygous mutation in the high-temperature requirement A serine peptidase 1 (HTRA1) gene. Cerebral microbleeds (CMBs) are increasingly being recognized as neuroimaging findings occurring with cerebrovascular disease and have different etiologies. Mild to moderate CMBs are not unusual in CARASIL, and they are observed to affect cortical and subcortical structures; in contrast, diffuse CMBs, especially in the cerebellum, are rare. In this case, we report a novel mutation of HTRA1 in a 43-year-old woman whose imaging indicated multiple CMBs in all lobes, brain stem, and cerebellum. The amount and location of CMBs vary in CARASIL cases, and the potential cause is not fully understood. This study revealed that specific imaging findings of this patient may be related to a new genetic mutation.

Thrombus components are dynamically influenced by local blood flow and blood immune cells. After a large-vessel occlusion stroke, changes in the cerebral thrombus are unclear. Here we assessed a total of 206 cerebral thrombi from patients with ischemic stroke undergoing endovascular thrombectomy. The thrombi were categorized by time to reperfusion of 8 h (T8). The cellular compositions in thrombus were analyzed, and relevant clinical features were compared. Both white blood cells and neutrophils were increased and then decreased in thrombus with time to reperfusion, which were positively correlated with those in peripheral blood. The neutrophil extracellular trap (NET) content in thrombus was correlated with the degree of neurological impairment of patients. Moreover, with prolonged time to reperfusion, the patients showed a trend of better collateral grade, which was associated with a lower NET content in the thrombus. In conclusion, the present results reveal the relationship between time-related endovascular immune response and clinical symptoms post-stroke from the perspective of thrombus and peripheral blood. The time-related pathological changes of cerebral thrombus may not be the direct cause for the difficulty in thrombolysis and thrombectomy. A low NET content in thrombi indicates excellent collateral flow, which suggests that treatments targeting NETs in thrombi might be beneficial for early neurological protection.

Background and Purpose: Drug-eluting stents generally have superior performance to bare metal stents in the treatment of vertebral artery stenosis (VAS). This prospective, multicenter, and single-arm clinical trial was initiated to assess in-stent restenosis (ISR) and midterm outcome after rapamycin-eluting stent placement in patients with symptomatic extracranial VAS.Methods: The subjects underwent angiographic follow-up at 6 months and final clinical follow-up at 12 months. The primary efficacy endpoint was ISR at 6 months. Secondary endpoints included technical success, target lesion-related transient ischemic attack (TIA), stroke, or death, and all-cause TIA, stroke, or death during the 12-month follow-up period.Results: A total of 104 stents were implanted in the 101 patients and 83 patients (82.2%) completed angiographic follow-up at 6 months. The technical success rate was 86.1% (87/101); mean in-stent stenosis rate was 25.1 ± 17.1% and ISR rate was 5.9% (95% CI: 0.8–10.9%). All the patients with ISR were completely asymptomatic and no stent fractures were observed during angiographic follow-up. At the 12-month clinical follow-up, target lesion-related TIA, stroke, or death had occurred in two (2.0%) patients and all-cause TIA, stroke, or death had occurred in six (6.1%) patients.Conclusion: The placement of rapamycin-eluting stents in patients with symptomatic extracranial VAS yields favorable ISR results and showed a trend of favorable safety outcomes including low rates of perioperative complications and late stroke. However, further study is needed to establish the long-term clinical benefits of this stent in the treatment of VA disease.

Cerebral small vessel disease (cSVD)—a common cause of stroke and vascular dementia—is a group of clinical syndromes that affects the brain's small vessels, including arterioles, capillaries, and venules. Its pathogenesis is not fully understood, and effective treatments are limited. Increasing evidence indicates that an elevated total serum homocysteine level is directly and indirectly associated with cSVD, and endothelial dysfunction plays an active role in this association. Hyperhomocysteinemia affects endothelial function through oxidative stress, inflammatory pathways, and epigenetic alterations at an early stage, even before the onset of small vessel injuries and the disease. Therefore, hyperhomocysteinemia is potentially an important therapeutic target for cSVD. However, decreasing the homocysteine level is not sufficiently effective, possibly due to delayed treatment, which underlying reason remains unclear. In this review, we examined endothelial dysfunction to understand the close relationship between hyperhomocysteinemia and cSVD and identify the optimal timing for the therapy.

Objectives: We aimed to identify the factors contributing to comorbid anxiety symptoms over a 12-month follow-up period in Chinese adults with newly diagnosed epilepsy.Methods: Adult patients with newly diagnosed epilepsy (PWNDE) were recruited from First Hospital, Jilin University. Anxiety symptoms were assessed using the Generalized Anxiety Disorder-7 questionnaire (GAD-7; Chinese version) at 12 months. Multivariate stepwise logistic regression analysis was employed to identify the predictors for anxiety symptoms at 12 months.Results: A total of 157 PWNDE completed the study and were included in the final analysis. The percentage of participants with anxiety symptoms significantly decreased from 31.2% at baseline to 23.6% at 12 months (p = 0.027). Multivariate stepwise logistic regression analysis indicated that depressive symptoms at baseline [odds ratio (OR) 3.877 (95% confidence interval (CI) 1.683–8.933); P = 0.001] and the number of antiseizure medications (ASMs) during the follow-up period [OR 2.814 (95% CI 1.365–5.803); P = 0.005] were independent factors contributing to comorbid anxiety symptoms at 12 months.Conclusion: Depressive symptoms at baseline and the number of ASMs during the follow-up period were significant predictors of comorbid anxiety symptoms 12 months after a diagnosis of epilepsy.

Background Both genetic and environmental factors contribute to the development of cancer and its mutant spectrum. Lung cancer has familial aggregation. Lung cancer caused by non‐tobacco factors has unique pathological and molecular characteristics. The interaction between genetic lung cancer susceptibility and carcinogens from coal burning remains complex and understudied. Methods We selected 410 non‐small cell lung cancer (NSCLC) patients with a family history of lung cancer (FLC) and exposure to coal combustion between 2014 and 2017. Clinicopathologic parameters were analyzed. Reverse transcription‐PCR was performed to detect ALK, ROS1, RET, and NTRK1 rearrangement. Results Among the 410 NSCLC patients, 192 had FLC and 204 (49.8%) were exposed to occupational or domestic coal combustion. FLC patients had the same characteristics regardless of gender and coal exposure: younger age, high female ratio, adenocarcinoma, increased metastasis, later stage at diagnosis, and higher frequency of gene fusion. Sixty‐seven patients (16.3%) had gene rearrangement: 51 (12.4%) harbored EML4‐ALK fusions and 16 ROS1 fusions (3.9%). The highest gene fusion rate (35.1%, 33/94) occurred in patients with both FLC and high tobacco and coal exposure. ALK fusions and total gene rearrangement were closely associated with women, never smokers, younger age, FLC, and coal exposure. Conclusion FLC and exposure to coal combustion have an important impact on the clinicopathological characteristics and gene fusion mode of NSCLC, particularly in cases of higher levels of carcinogens, and genetic susceptibility has a greater impact. Our findings may help evaluate the effect of FLC and coal exposure on the pathogenesis of lung cancer.

Background:SCN1A and SCN2A genes have been reported to be associated with the efficacy of single and combined antiepileptic therapy, but the results remain contradictory. Previous meta-analyses on this topic mainly focused on the SCN1A rs3812718 polymorphism. However, meta-analyses focused on SCN1A rs2298771, SCN1A rs10188577, SCN2A rs17183814, or SCN2A rs2304016 polymorphisms are scarce or non-existent.Objective: We aimed to conduct a meta-analysis to determine the effects of SCN1A rs2298771, SCN1A rs10188577, SCN2A rs17183814, and SCN2A rs2304016 polymorphisms on resistance to antiepileptic drugs (AEDs).Methods: We searched the PubMed, Embase, Cochrane Library, WANFANG, and CNKI databases up to June 2020 to collect studies on the association of SCN1A and SCN2A polymorphisms with reactivity to AEDs. We calculated the pooled odds ratios (ORs) under the allelic, homozygous, heterozygous, dominant, and recessive genetic models to identify the association between the four single-nucleotide polymorphisms (SNPs) and resistance to AEDs.Results: Our meta-analysis included 19 eligible studies. The results showed that the SCN1A rs2298771 polymorphism was related to AED resistance in the allelic, homozygous, and recessive genetic models (G vs. A: OR = 1.20, 95% CI: 1.012–1.424; GG vs. AA: OR = 1.567, 95% CI: 1.147–2.142; GG vs. AA + AG: OR = 1.408, 95% CI: 1.053–1.882). The homozygous model remained significant after Bonferroni correction (P < 0.0125). Further subgroup analyses demonstrated the significance of the correlation in the dominant model in Caucasians (South Asians) after Bonferroni correction (GG + GA vs. AA: OR = 1.620, 95% CI: 1.165–2.252). However, no association between SCN1A rs2298771 polymorphism and resistance to AEDs was found in Asians or Caucasians (non-South Asians). For SCN1A rs10188577, SCN2A rs17183814, and SCN2A rs2304016 polymorphisms, the correlations with responsiveness to AEDs were not significant in the overall population nor in any subgroup after conducting the Bonferroni correction. The results for SCN1A rs2298771, SCN1A rs10188577, and SCN2A rs2304016 polymorphisms were stable and reliable according to sensitivity analysis and Begg and Egger tests. However, the results for SCN2A rs17183814 polymorphism have to be treated cautiously owing to the significant publication bias revealed by Begg and Egger tests.Conclusions: The present meta-analysis indicated that SCN1A rs2298771 polymorphism significantly affects resistance to AEDs in the overall population and Caucasians (South Asians). There were no significant correlations between SCN1A rs10188577, SCN2A rs17183814, and SCN2A rs2304016 polymorphisms and resistance to AEDs.

In our study, a chronic unpredictable mild stress-induced depression rat model was constructed then the antidepressant effects and mechanisms of Epigallocatechin-3-O-gallate (EGCG) have been evaluaed accordingly. In the study, there were three subgroups of stochastically-selected male Wistar rats, namely, Control, CUMS-induced (chronic unpredictable mild stress) and CUMS with EGCG administration. The outcomes of sucrose preference and open-field tests presented the antidepressant-like effects of EGCG. With EGCG treatment, the levels of IL-6 and NO had significantly declined. Through EGCG administration, the suppressed expression of caspase-3 and caspase-9 mRNA in hippocampus was exhibited in the experiment. The implication of experimental outcomes can be served as preclinical evidences for therapeutic applications in the treatment of depression potentially, because of the antidepressant-like role of EGCG played against inflammation to protect neurons in hippocampus.

Purpose: To examine the mortality rate and causes of death of phenobarbital (PB) monotherapy and sodium valproate (VPA) monotherapy in patients with convulsive epilepsy in rural northeast China and compare the differences in the results between the two antiepileptic drugs.Methods: Patients with convulsive epilepsy were recruited by trained public health workers in a project for epilepsy prevention and treatment. Patients were enrolled between January 2010 and December 2018 and were treated with PB or VPA. Mortality rate (MR), the proportional mortality ratio (PMR) for each cause, standardized mortality ratio, and years of potential life lost (YPLL) for sex, age, and cause were estimated based on the 2018 Chinese rural population.Results: A total of 3,916 patients with convulsive epilepsy enrolled in the study, of whom 3,418 received PB and 498 received VPA. There were 325 reported deaths (300 from the PB group) during the follow-up period. The MRs were 9.96 and 5.73% in the PB and VPA groups, respectively. The overall SMRs were 12.92 (95% confidence intervals [CI]: 11.50–13.93) and 7.39 (95% CI: 4.78–10.91), for the PB and VPA groups, respectively. Cerebrovascular disease and heart disease were the major causes of death in both treatment groups. The average YPLL for the PB group (21.9 years) was higher than that for the VPA group (13.4 years).Conclusion: This is the first epidemiological study to examine the MR of patients with epilepsy in rural northeast China. Our study is somewhat different from previous studies reported in China, and we provide new relevant data from northeast China.

Semantic audiovisual stimuli have a facilitatory effect on behavioral performance and influence the integration of multisensory inputs across sensory modalities. Many neuroimaging and electrophysiological studies investigated the neural mechanisms of multisensory semantic processing and reported that attention modulates the response to multisensory semantic inputs. In the present study, we designed an functional magnetic resonance imaging (fMRI) experiment of semantic discrimination using the unimodal auditory, unimodal visual and bimodal audiovisual stimuli with semantic information. By manipulating the stimuli present on attended and unattended position, we recorded the task-related fMRI data corresponding to the unimodal auditory, unimodal visual and bimodal audiovisual stimuli in attended and unattended conditions. We also recorded the fMRI data in resting state. Then the fMRI method was used together with a graph theoretical analysis to construct the functional brain networks in task-related and resting states and quantitatively characterize the topological network properties. The aim of our present study is to explore the characteristics of functional brain networks that process semantic audiovisual stimuli in attended and unattended conditions, revealing the neural mechanism of multisensory processing and the modulation of attention. The behavioral results showed that the audiovisual stimulus presented simultaneously promoted the performance of semantic discrimination task. And the analyses of network properties showed that compared with the resting-state condition, the functional networks of processing semantic audiovisual stimuli (both in attended and unattended conditions) had greater small-worldness, global efficiency, and lower clustering coefficient, characteristic path length, global efficiency and hierarchy. In addition, the hubs were concentrated in the bilateral temporal lobes, especially in the anterior temporal lobes (ATLs), which were positively correlated to reaction time (RT). Moreover, attention significantly altered the degree of small-worldness and the distribution of hubs in the functional network for processing semantic audiovisual stimuli. Our findings suggest that the topological structure of the functional brain network for processing semantic audiovisual stimulus is modulated by attention, and has the characteristics of high efficiency and low wiring cost, which maintains an optimized balance between functional segregation and integration for multisensory processing efficiently.

Background: Epilepsy is one of the most prevalent chronic brain diseases worldwide and is often accompanied by cognitive impairment. Event-related potentials (ERPs) are an objectively non-invasive approach for studying information processing and cognitive functions in the brain. The P300 is an important and extensively explored late component of ERPs that has been widely applied to assess cognitive function in epilepsy in previous studies. However, consistent conclusions have not yet been reached for various reasons.Objective: We conducted a comprehensive systematic review and meta-analysis of P300-related studies to assess the latency and amplitude of the P300 in epileptic patients.Methods: PubMed, EMBASE, and Cochrane Library databases were systematically searched for eligible studies. The standard mean difference (SMD) and the 95% confidence interval (CI) were calculated as the effect size of the P300 component.Results: The main results of the present meta-analysis indicated that epileptic patients have a longer P300 latency and a lower P300 amplitude than controls. Subgroup analysis based on age group demonstrated that these differences can be observed in both children and adult patients compared with healthy controls. In addition, the P300 latency was longer in patients with the five main types of epileptic seizures than in controls.Conclusion: This study revealed that epileptic patients have abnormalities in the P300 component, which may reflect deficits in cognitive function. Thus, the P300 may be a potential objective approach for evaluating cognitive function in epileptic patients.

Background: Lung cancer has inherited susceptibility and show familial aggregation, the characteristics of familial lung cancer exhibit population heterogeneity. Despite previous studies, familial lung cancer in China's Yunnan-Guizhou plateau remains understudied.Methods: Between 2015 and 2017, 1,023 lung cancer patients (residents of Yunnan-Guizhou plateau) were enrolled with no limitation on other parameters, 152 subjects had familial lung cancer. Clinicopathologic parameters were analyzed and compared, 4,754 lung cancer patients from NCI-GDC were used to represent a general population.Results: Familial lung cancer (FLC) subjects showed unique characters: early-onset; increased rate of female, adenocarcinoma, stage IV and other cancer history; unbalance in anatomic sites; all ruling out significant difference in smoking status. Unbalanced distribution of co-existing diseases or symptoms was also discovered. FLC patients were more likely to develop benign lesions (polyps, nodules, cysts) early in life, especially early-growth of multiple pulmonary nodules at higher frequency. Typical diseases with family history like diabetes and hypertension were also increased in FLC population. Compared to GDC data, our subject population was younger: the age peak of our FLC group was in 50–59; our sporadic group had an age peak around 60; while GDC patients' age peak was in 60–69. Importantly, the biggest difference happened in age 40–49: our FLC group and sporadic group had 3 times and 2 times higher ratio than GDC population, respectively. Moreover, the age peaks of our FLC males and FLC females were both in 50–59; while our sporadic females had the age peak in 50–59, much earlier than sporadic males (around 60–69); reflecting gender-specific or age-specific characters in our subject population.Conclusions: Familial lung cancer in China's Yunnan-Guizhou plateau showed unique clinicopathologic characters, differences were found in gender, age, histologic type, TNM stage and co-existing diseases or symptoms. Identification of hereditary factors which lead to increased lung cancer risk will be a challenge of both scientific and clinical significance.

Background and objective Indoor air pollution induces asthma, leads to chronic obstructive pulmonary disease, and may promote lung cancer. Our previous studies found that the accumulation of inorganic particulate matter that is due to indoor air pollution can lead to damage to alveolar cells and activation of signaling pathway, and ultimately provoke tumorigenesis. The aim of this study is to explore the accumulation of inorganics and activation of nuclear factor κB (NF-κB)-inducible nitric oxide synthase (iNOS) signaling pathway of lung tissue in Xuanwei lung cancer patients. Methods From December 2013 to November 2014, 48 cases Xuanwei patients with lung cancer who underwent surgical treatment from the Third Affiliated Hospital of Kunming Medical University were enrolled in this study and compared with lung cancer patients from other regions. The ultrastructure of postoperative specimens was observed by transmission electron microscopy (TEM) to explore the occurrence of inorganic particles. Serum cytokines were analyzed. Then, the expression levels of NF-κB-p65 protein and iNOS protein in postoperative specimens was explored by immunohistochemistry and Western blot. Finally, 8-OHdG accumulation in lung cancer tissues and urine was measured. Results A large number of nanoscale inorganics were observed in alveolar type II cells and macrophages located in adjacent tissues of lung cancer with Xuanwei patients. Silicon (Si) content was found in inorganic elemental analysis. The serum interleukin (IL)-1β levels (31.50±19.16) pg/mL of Xuanwei lung-cancer patients were remarkably higher than those from other regions (11.33±6.94) pg/mL (P

Background and objective Lung cancer is the type of cancer with the highest incidence and mortality in numerous countries and regions. Establishing an appropriate animal model that can be used to simulate lung cancer etiology, pathogenesis, and similar processes, is urgent. We explore the feasibility of establishing a lung cancer model induced by Xuanwei bituminous coal dust PM10 (particulate matter with diameters of 10 μm or less), which affects bronchial epithelium of tree shrews. Methods The neck skin of adult tree shrews is dissected, and the thyroid cartilage is fully exposed. Subsequently, the weak part at the top of the thyroid cartilage is treated with intratracheal agents by perfusion via a special infusion needle puncture method. Regular X-ray examination and lung tissue biopsy were performed on the sacrificed animals to observe changes in pulmonary imaging and bronchial epithelial cells after perfusion of Xuanwei bituminous coal dust PM 10. Results The tree shrews of the experimental group (exposed to bituminous coal dust) died in a week after perfusion with PM10, whereas no animal died until the end of the experiment in the blank control and the solvent control groups. Sections of lung tissue biopsy of the regularly killed tree shrews were stained with hematoxylin and eosin. The lung tissues of tree shrews in the experimental group showed a serial changes caused by bronchial epithelial hyperplasia, such as squamous metaplasia, dysplasia, and early invasive carcinoma, whereas no significant pathological changes were observed in the blank control and solvent control groups. Conclusion Endotracheal infusion of Xuanwei bituminous coal dust PM10 induces lung cancer in tree shrews. Thus, the lung cancer model was established.

Background and objective The high incidence of lung cancer in Xuanwei, China, has become an important restricting factor for livelihood development, thus exerting local social and economic impacts. Coal is the main fuel of the local community and also the main source of indoor pollution. This study aims to explore the coal combustion inhalable fine particulate matter (PM2.5) and its component output differences in different areas of Xuanwei, Yunnan. Moreover, the aim of this study is to investigate the relationship between inhalation of fine particles and high incidence of local lung cancer. Methods For combustion test, coal mines designated as C1, K7 and M30 were collected from LaoLin Colliery of Laibing Town, Huchang Colliery of Baoshan Town, and Taiping Colliery of Wenxing Town in Xuanwei, respectively. PM2.5 of indoor air was weighed, analyzed for elemental composition, and morphologically compared. The pathological specimen of lung cancer patients in Xuanwei who underwent operation was observed through electron microscope. Results The PM2.5 concentrations in indoor air were (8.244 ±1.460) mg/m3 (C1), (5.066±0.984) mg/m3 (K7), and (5.071±1.460) mg/m3 (M30). The differences among pairwise comparisons were statistically significant (P=0.029). The filter impurities of C1 coal seam primarily include Si- and O-enriched compounds. Moreover, three membranes that comprised other elements, including C, S, and Si, were observed. These membranes were evident from the aggregation of silica and a Ca-Al membrane. Compared with that of other coal seams, C1 coal generated a mass of impurities, in which several particles have irregular shape. We found nanoscale fine particles in some specimens of Xuanwei lung cancer patients. Conclusion The produced combustion of C1 coal was different from that of K7 and M30 coal. PM2.5 composition may be associated with the high local incidence of lung cancer.

Background and objective The mismatch between pleural space and remnant lung after bilobectomy has been considered as the main reason for the high incidence of postoperative complications in non-small cell lung cancer (NSCLC) patients. The aim of this study is to analyze the differences in postoperative complications between bilobectomy and lobectomy in the right lung of NSCLC patients. Method This study included 528 NSCLC patients who underwent right pulmonary lobectomy. A total of 352 cases that underwent upper or lower right lobectomy (108 upper and 244 lower) were the control group, and 176 cases that underwent bilobectomy (57 upper and middle and 119 lower and middle) were the observation group. A retrospective case-control study was performed on a series of matched NSCLC patients. Cases and controls were matched by age, ppoFEV1%, LEVF%, operation method, cardiac comorbidity, type of postoperative management, and pathological type at a ratio of 1:2. The prevalence of 30-day death, occurrence of cardiac-respiratory complications (hospital-acquired pneumonia, low oxygen concentration, pulmonary embolism, cerebral apoplexy, arrhythmia, myocardial ischemia or infarction, and cardiac insufficiency) and occurrence of space-related complications (atelectasis, air leak more than 5 days, and pneumothorax) were compared between the bilobectomy and lobectomy groups. Result The prevalence of 30-day death was 3.4% (6/176) in the bilobectomy group and 2.3% (8/352) in the lobectomy group. No statistical significance was observed between the two groups. The cardiac-respiratory complication rate in bilobectomy group (23.8%; 42/176) was higher than that in lobectomy group (10.7%; 38/352). The cardiac-respiratory complication rate of the lower and middle pulmonary lobectomy patients in the bilobectomy group (26.5%; 31/119) was significantly higher than that in the lower pulmonary lobectomy patients (4.9%; 12/244). The space-related complications in bilobectomy group and lobectomy group were 20.4% (36/176) and 17.3% (61/352), respectively. No statistically significant difference between the two groups was observed. Conclusion The postoperative cardiac-respiratory complications of NSCLC patients with right bilobectomy are higher than those of the right lobectomy patients, but the prevalence of 30-day death and space-related complication was not statistically different between the two groups.

Background and objective Silicon nanoparticles are widely used in daily life. Therefore, they attract increased attention because of their potential biotoxicity to the lungs when inhaled. The aims of this study are to explore the organism distribution and genotoxicity of silica nanoparticles in human bronchial epithelial cells (BEAS-2B). Methods The biodistribution of silica with different particle sizes in human bronchial epithelial cells was observed by transmission electron microscopy (TEM). DNA damage was detected by single-cell gel electrophoresis (comet assay). Results TEM revealed that SiO2 nanoparticles with different sizes can be uptaken by cells and be localized in the cytoplasm and the nucleus. Compared with micro-silica, nano-silica in BEAS-2B cells can inflict more severe DNA damage (P

We investigate opinion dynamics as a stochastic process in social networks. We introduce the stubborn agent in order to determine the impact of network structure on the emergence of consensus. Depending on the fraction of undirected long-range connections, we observe fascinatingly rich dynamical behavior and transitions from disordered to ordered states. In general, we find that the stubborn agent promotes the emergence of consensus due to the so-called “group effect” that facilitates coalescence between separated network components. Agents are also behaviorally constrained Shannon information entropy in networks. However, since agents want to evolve their opinion with Brownian motion, which may in turn impede full consensus, sufficiently frequent long-range links are in such situations crucial for the network to converge into an absorbing phase. Our experimental findings indicate that, for a large range of control parameters, our model yields stable and fluctuating polarized states.

Background and objective China’s Xuan Wei County in Yunnan Province have the world’s highest incidence of lung cancer in nonsmoking women-20 times higher than the rest of China. Previous studies showed, this high lung cancer incidence may be associated with the silica particles embedded in the production combustion from the C1 coal. The aim of this study is to separate the silica particles from production combustion from the C1 bituminous coal in Xuan Wei County of Yunnan Province, and study in vitro toxicity of naturally occurring silica particles on BEAS-2B. Methods ①Separating the silica particles from combustion products of C1 bituminous coal by physical method, observing the morphology by Scanning Electron Microscope, analysis elements by SEM-EDX, observed the single particle morphology by Transmission Electron Microscope, analyed its particle size distribution by Laser particle size analyzer, the surface area of silica particles were determined by BET nitrogen adsorption analysis; ②Cell viability of the experimental group (silica; naturally occurring), control group (silica; industrial produced and crystalline silica) was detected by assay used the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, and the reactive oxygen species (ROS), lactate dehydrogenase (LDH) were determined after 24 h-72 h exposed to these particles. Results ①The physical method can separate silica particles from production combustion from the C1 bituminous coal, which have different size, and from 30 nm to 120 nm particles accounted for 86.8%, different morphology, irregular surface area and containing trace of aluminum, calcium and iron and other elements; ②Under the same concentration, the experiment group have higher toxicity on BEAS-2B than control groups. Conclusion ①Physical method can separate silica particles from production combustion from the C1 bituminous coal and not change the original morphology and containing trace; ②Naturally occurring silica nanoparticles have irregular morphology, surface area, and containing complex trace elements may has greater toxicity than the silica nanoparticle of industrial produced and crystalline silica.

Abstract Background Microwave ablation (MWA) is widely used to eliminate colorectal liver metastases (CRLM). However, the risk of tumor recurrence is difficult to predict due to lack of reliable clinical and biological markers. Elevation of gamma-glutamyl transferase (GGT) and aspartate transaminase (AST) provides signals for liver inflammation and cancer progression. The present study evaluated the association between pre-ablation GGT to AST ratio index (GSR) and hepatic recurrence in patients with CRLM after MWA. Methods A retrospectively analyzed 192 CRLM patients who underwent MWA from January 2013 to December 2017. Pre-ablation GSR was classified into high (≤ 2.34) or low (> 2.34) using the upper quartile value. The prognostic value of GSR and other risk factors for liver progression-free survival (LPFS) and cancer-specific survival (CSS) were evaluated by univariate and multivariate analyses. Results High GSR was significantly associated with males (P = 0.041), the presence of cholelithiasis (P = 0.012), but not pre-ablation chemotherapy (P = 0.355), which caused significantly increased levels of GGT (P = 0.015) and AST (P = 0.008). GSR showed a significant association with LPFS and CSS through univariate analysis (P = 0.002 and 0.006) and multivariate analysis (P = 0.043 and 0.037). The subgroup analysis demonstrated no interaction between GSR and all variables except for distribution in the sub-analysis of LPFS. Conclusions Our findings suggest that the pre-ablation GSR can be considered as a promising prognostic indicator for poor prognosis of patients with CRLM underwent MWA. Trial registration Not applicable.