DKK1 Activates the PI3K/AKT Pathway via CKAP4 to Balance the Inhibitory Effect on Wnt/ß-Catenin Signaling and Regulates Wnt3a-Induced MSC Migration.

Wnt/ß-catenin signaling plays a crucial role in the migration of mesenchymal stem cells (MSCs). However, our study has revealed an intriguing phenomenon where Dickkopf-1 (DKK1), an inhibitor of Wnt/ß-catenin signaling, promotes MSC migration at certain concentrations ranging from 25 to 100 ng/mL while inhibiting Wnt3a-induced MSC migration at a higher concentration (400 ng/mL). Interestingly, DKK1 consistently inhibited Wnt3a-induced phosphorylation of LRP6 at all concentrations. We further identified cytoskeleton-associated protein 4 (CKAP4), another DKK1 receptor, to be localized on the cell membrane of MSCs. Overexpressing the CRD2 deletion mutant of DKK1 (ΔCRD2), which selectively binds to CKAP4, promoted the accumulation of active ß-catenin (ABC), the phosphorylation of AKT (Ser473) and the migration of MSCs, suggesting that DKK1 may activate Wnt/ß-catenin signaling via the CKAP4/PI3K/AKT cascade. We also investigated the effect of the CKAP4 intracellular domain mutant (CKAP4-P/A) that failed to activate the PI3K/AKT pathway and found that CKAP4-P/A suppressed DKK1 (100 ng/mL)-induced AKT activation, ABC accumulation, and MSC migration. Moreover, CKAP4-P/A significantly weakened the inhibitory effects of DKK1 (400 ng/mL) on Wnt3a-induced MSC migration and Wnt/ß-catenin signaling. Based on these findings, we propose that DKK1 may activate the PI3K/AKT pathway via CKAP4 to balance the inhibitory effect on Wnt/ß-catenin signaling and thus regulate Wnt3a-induced migration of MSCs. Our study reveals a previously unrecognized role of DKK1 in regulating MSC migration, highlighting the importance of CKAP4 and PI3K/AKT pathways in this process.

Likelihood of primary cesarean section following induction of labor in singleton cephalic pregnancies at term, compared with expectant management: An Australian population-based, historical cohort study.

INTRODUCTION: There has been increased use of both induction of labor (IOL) and cesarean section for women with term pregnancies in many high-income countries, and a trend toward birth at earlier gestational ages. Existing evidence regarding the association between IOL and cesarean section for term pregnancies is mixed and conflicting, and little evidence is available on the differential effect at each week of gestation, stratified by parity. MATERIAL AND METHODS: To explore the association between IOL and primary cesarean section for singleton cephalic pregnancies at term, compared with two definitions of expectant management (first: at or beyond the week of gestation at birth following IOL; and secondary: only beyond the week of gestation at birth following IOL), we performed analyses of population-based historical cohort data on women who gave birth in one Australian state (Queensland), between July 1, 2012 and June 30, 2018. Women who gave birth before 37+0 or after 41+6 weeks of gestation, had stillbirths, no-labor, multiple births (twins or triplets), non-cephalic presentation at birth, a previous cesarean section, or missing data on included variables were excluded. Four sub-datasets were created for each week at birth (37-40). Unadjusted relative risk, adjusted relative risk using modified Poisson regression, and their 95% confidence intervals were calculated in each sub-dataset. Analyses were stratified by parity (nulliparas vs. parous women with a previous vaginal birth). Sensitivity analyses were conducted by limiting to women with low-risk pregnancies. RESULTS: A total of 239 094 women were included in the analysis, 36.7% of whom gave birth following IOL. The likelihood of primary cesarean section following IOL in a Queensland population-based cohort was significantly higher at 38 and 39 weeks, compared with expectant management up to 41+6 weeks, for both nulliparas and paras with singleton cephalic pregnancies, regardless of risk status of pregnancy and definition of expectant management. No significant difference was found for nulliparas at 37 and 40 weeks; and for paras at 40 weeks. CONCLUSIONS: Future studies are suggested to investigate further the association between IOL and other maternal and neonatal outcomes at each week of gestation in different maternal populations, before making any recommendation.

Operationalizing the Consolidated Framework for Implementation Research to build and support the lived experience workforce in direct health service provision.

BACKGROUND: The involvement of people with lived experience (LEX) workers in the development, design, and delivery of integrated health services seeks to improve service user engagement and health outcomes and reduce healthcare gaps. Yet, LEX workers report feeling undervalued and having limited influence on service delivery. There is a need for systematic improvements in how LEX workforces are engaged and supported to ensure the LEX workforce can fully contribute to integrated systems of care. OBJECTIVE: This study aimed to operationalize the Consolidated Framework for Implementation Research (CFIR) using a rigorous scoping review methodology and co-creation process, so it could be used by health services seeking to build and strengthen their LEX workforce. SEARCH STRATEGY: A systematic literature search of four databases was undertaken to identify peer-reviewed studies published between 2016 and 2022 providing evidence of the inclusion of LEX workers in direct health service provision. DATA EXTRACTION AND SYNTHESIS: A descriptive-analytical method was used to map current evidence of LEX workers onto the CFIR. Then, co-creation sessions with LEX workers (n = 4) and their counterparts-nonpeer workers (n = 2)-further clarified the structural policies and strategies that allow people with LEX to actively participate in the provision and enhancement of integrated health service delivery. MAIN RESULTS: Essential components underpinning the successful integration of LEX roles included: the capacity to engage in a co-creation process with individuals with LEX before the implementation of the role or intervention; and enhanced representation of LEX across organizational structures. DISCUSSION AND CONCLUSION: The adapted CFIR for LEX workers (CFIR-LEX) that was developed as a result of this work clarifies contextual components that support the successful integration of LEX roles into the development, design, and delivery of integrated health services. Further work must be done to operationalize the framework in a local context and to better understand the ongoing application of the framework in a health setting. PATIENT OR PUBLIC CONTRIBUTION: People with LEX were involved in the operationalization of the CFIR, including contributing their expertise to the domain adaptations that were relevant to the LEX workforce.

Long-Term Effect of Having a Child at Risk of Developmental Delays on Parental Labor Force Participation.

OBJECTIVE: This study aimed to examine the long-term influence of having a child at risk of different developmental delays (communication, mobility, self-care, relating, learning, coping, or behaving) on parental labor force participation as the child grows. METHOD: A retrospective cohort was conducted using data from the Longitudinal Study of Australian Children survey, Waves 1-8 covering birth to 15 years of age of children. Multivariable logistic regressions were used to explore the odds ratio of mothers being out of the labor force at different children's ages. Cox proportional hazards models were utilized to identify the 'risk' of mothers returning to the workforce after leaving. All models were adjusted for the mother's age, education attainment, and employment status at time of birth, as well as marital status at the current wave. RESULTS: There were 5,107 records of children, and 266 of them were at risk of any developmental delays at age 4-5 years. This sample represents 243, 026 children born in Australia in 2003/04. After adjusting for potential confounders, mothers of children at risk of each type of developmental delay (except mobility and self-care) had greater odds of being out of, and not returning to the labor force from children aged 2-3 to 14-15 years, when compared to mothers of children who are not at risk of developmental delays. Similar differences were found for fathers but were distinctly small and with narrower fluctuations, compared to mothers. CONCLUSION: Policies and programs funded by the government are greatly needed to support the mothers of children at risk of developmental delays.

Alleviatory Role of Panax Notoginseng Saponins in Modulating Inflammation and Pulmonary Vascular Remodeling in Chronic Obstructive Pulmonary Disease: mechanisms and Implications.

COPD is an inflammatory lung disease that limits airflow and remodels the pulmonary vascular system. This study delves into the therapeutic potential and mechanistic underpinnings of Panax notoginseng Saponins (PNS) in alleviating inflammation and pulmonary vascular remodeling in a COPD rat model. Symmap and ETCM databases provided Panax notoginseng-related target genes, and the CTD and DisGeNET databases provided COPD-related genes. Intersection genes were subjected to protein-protein interaction analysis and pathway enrichment to identify downstream pathways. A COPD rat model was established, with groups receiving varying doses of PNS and a Roxithromycin control. The pathological changes in lung tissue and vasculature were examined using histological staining, while molecular alterations were explored through ELISA, RT-PCR, and Western blot. Network pharmacology research suggested PNS may affect the TLR4/NF-κB pathway linked to COPD development. The study revealed that, in contrast to the control group, the COPD model exhibited a significant increase in inflammatory markers and pathway components such as TLR4, NF-κB, HIF-1α, VEGF, ICAM-1, SELE mRNA, and serum TNF-α, IL-8, and IL-1ß. Treatment with PNS notably decreased these markers and mitigated inflammation around the bronchi and vessels. Taken together, the study underscores the potential of PNS in reducing lung inflammation and vascular remodeling in COPD rats, primarily via modulation of the TLR4/NF-κB/HIF-1α/VEGF pathway. This research offers valuable insights for developing new therapeutic strategies for managing and preventing COPD.

Acetylation of FOXO1 activates Bim expression involved in CVB3 induced cardiomyocyte apoptosis.

Viral myocarditis (VMC) is the major reason for sudden cardiac death among both children and young adults. Of these, coxsackievirus B3 (CVB3) is the most common causative agent of myocarditis. Recently, the role of signaling pathways in the pathogenesis of VMC has been evaluated in several studies, which has provided a new perspective on identifying potential therapeutic targets for this hitherto incurable disease. In the present study, in vivo and in vitro experiments showed that CVB3 infection leads to increased Bim expression and triggers apoptosis. In addition, by knocking down Bim using RNAi, we further confirmed the biological function of Bim in apoptosis induced by CVB3 infection. We additionally found that Bim and forkhead box O1 class (FOXO1) inhibition significantly increased the viability of CVB3-infected cells while blocking viral replication and viral release. Moreover, CVB3-induced Bim expression was directly dependent on FOXO1 acetylation, which is catalyzed by the co-regulation of CBP and SirTs. Furthermore, the acetylation of FOXO1 was an important step in Bim activation and apoptosis induced by CVB3 infection. The findings of this study suggest that CVB3 infection induces apoptosis through the FOXO1 acetylation-Bim pathway, thus providing new insights for developing potential therapeutic targets for enteroviral myocarditis.

Continuously Flow Photothermal Catalysis Efficiently CO2 Reduction Over S-Scheme 2D/0D Bi5 O7 I-OVs/Cd0.5 Zn0.5 S Heterojunction with Strong Interfacial Electric Field.

Using CO2 , water, and sunlight to produce solar fuel is a very attractive process, which can synchronously reduce carbon and convert solar energy into hydrocarbons. However, photocatalytic CO2 reduction is often limited by the low selectivity of reduction products and poor photocatalytic activity. In this study, S-scheme Bi5 O7 I-OVs/Cd0.5 Zn0.5 S (Bi5 O7 I-OVs/CZS-0.5) heterojunction with strong interfacial electric field (IEF) is prepared by in situ growth method. The performance of reduction CO2 to CO is studied by continuous flow photothermal catalytic (PTC) CO2 reduction platform. 12.5% Bi5 O7 I-OVs/CZS-0.5 shows excellent CO yield of 58.6 µmol g-1  h-1 and selectivity of 98.4%, which are 35.1 times than that of CZS-0.5 under visible light. The charge transfer path of the S-scheme through theoretical calculation (DFT), in situ irradiation Kelvin probe force microscope (ISI-KPFM) and in situ irradiation X-ray photoelectron spectroscopy (ISI-XPS) analysis, is verified. The study can provide useful guidance and reference for improving activity by oxygen vacancy induced strong IEF and the development of a continuous flow PTC CO2 reduction system.

Ethylene response factor MdERF4 and histone deacetylase MdHDA19 suppress apple fruit ripening through histone deacetylation of ripening-related genes.

Histone deacetylase enzymes participate in the regulation of many aspects of plant development. However, the genome-level targets of histone deacetylation during apple (Malus domestica) fruit development have not been resolved in detail, and the mechanisms of regulation of such a process are unknown. We previously showed that the complex of ethylene response factor 4 (MdERF4) and the TOPLESS co-repressor (MdTPL4; MdERF4-MdTPL4) is constitutively active during apple fruit development (Hu et al., 2020), but whether this transcriptional repression complex is coupled to chromatin modification is unknown. Here, we show that a histone deacetylase (MdHDA19) is recruited to the MdERF4-MdTPL4 complex, thereby impacting fruit ethylene biosynthesis. Transient suppression of MdHDA19 expression promoted fruit ripening and ethylene production. To identify potential downstream target genes regulated by MdHDA19, we conducted chromatin immunoprecipitation (ChIP) sequencing of H3K9 and ChIP-quantitative polymerase chain reaction assays. We found that MdHDA19 affects ethylene production by facilitating H3K9 deacetylation and forms a complex with MdERF4-MdTPL4 to directly repress MdACS3a expression by decreasing the degree of acetylation. We demonstrate that an early-maturing-specific acetylation H3K9ac peak in MdACS3a and expression of MdACS3a were specifically up-regulated in fruit of an early-maturing, but not a late-maturing, cultivar. We provide evidence that a C-to-G mutation in the ethylene-responsive element binding factor-associated amphiphilic repression motif of MdERF4 reduces the repression of MdACS3a by the MdERF4-MdTPL4-MdHDA19 complex. Taken together, our results reveal that the MdERF4-MdTPL-MdHDA19 repressor complex participates in the epigenetic regulation of apple fruit ripening.

Tuftelin1 drives experimental pulmonary fibrosis progression by facilitating stress fiber assembly.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) with unknown etiology, characterized by sustained damage repair of epithelial cells and abnormal activation of fibroblasts, the underlying mechanism of the disease remains elusive. METHODS: To evaluate the role of Tuftelin1 (TUFT1) in IPF and elucidate its molecular mechanism. We investigated the level of TUFT1 in the IPF and bleomycin-induced mouse models and explored the influence of TUFT1 deficiency on pulmonary fibrosis. Additionally, we explored the effect of TUFT1 on the cytoskeleton and illustrated the relationship between stress fiber and pulmonary fibrosis. RESULTS: Our results demonstrated a significant upregulation of TUFT1 in IPF and the bleomycin (BLM)-induced fibrosis model. Disruption of TUFT1 exerted inhibitory effects on pulmonary fibrosis in both in vivo and in vitro. TUFT1 facilitated the assembly of microfilaments in A549 and MRC-5 cells, with a pronounced association between TUFT1 and Neuronal Wiskott-Aldrich syndrome protein (N-WASP) observed during microfilament formation. TUFT1 can promote the phosphorylation of tyrosine residue 256 (Y256) of the N-WASP (pY256N-WASP). Furthermore, TUFT1 promoted transforming growth factor-ß1 (TGF-ß1) induced fibroblast activation by increasing nuclear translocation of pY256N-WASP in fibroblasts, while wiskostatin (Wis), an N-WASP inhibitor, suppressed these processes. CONCLUSIONS: Our findings suggested that TUFT1 plays a critical role in pulmonary fibrosis via its influence on stress fiber, and blockade of TUFT1 effectively reduces pro-fibrotic phenotypes. Pharmacological targeting of the TUFT1-N-WASP axis may represent a promising therapeutic approach for pulmonary fibrosis.

Identification and characterization of two SERPINC1 mutations causing congenital antithrombin deficiency.

BACKGROUND: Antithrombin (AT) is the main physiological anticoagulant involved in hemostasis. Hereditary AT deficiency is a rare autosomal dominant thrombotic disease mainly caused by mutations in SERPINC1, which was usually manifested as venous thrombosis and pulmonary embolism. In this study, we analyzed the clinical characteristics and screened for mutant genes in two pedigrees with hereditary AT deficiency, and the functional effects of the pathogenic mutations were evaluated. METHODS: Candidate gene variants were analyzed by next-generation sequencing to screen pathogenic mutations in probands, followed by segregation analysis in families by Sanger sequencing. Mutant and wild-type plasmids were constructed and transfected into HEK293T cells to observe protein expression and cellular localization of SERPINC1. The structure and function of the mutations were analyzed by bioinformatic analyses. RESULTS: The proband of pedigree A with AT deficiency carried a heterozygous frameshift mutation c.1377delC (p.Asn460Thrfs*20) in SERPINC1 (NM000488.3), a 1377C base deletion in exon 7 resulting in a backward shift of the open reading frame, with termination after translation of 20 residues, and a different residue sequence translated after the frameshift. Bioinformatics analysis suggests that the missing amino acid sequence caused by the frameshift mutation might disrupt the disulfide bond between Cys279 and Cys462 and affect the structural function of the protein. This newly discovered variant is not currently included in the ClinVar and HGMD databases. p.Arg229* resulted in a premature stop codon in exon 4, and bioinformatics analysis suggests that the truncated protein structure lost its domain of interaction with factor IX (Ala414 site) after the deletion of nonsense mutations. However, considering the AT truncation protein resulting from the p.Arg229* variant loss a great proportion of the molecule, we speculate the variant may affect two functional domains HBS and RCL and lack of the corresponding function. The thrombophilia and decreased-AT-activity phenotypes of the two pedigrees were separated from their genetic variants. After lentiviral plasmid transfection into HEK293T cells, the expression level of AT protein decreased in the constructed c.1377delC mutant cells compared to that in the wild-type, which was not only reduced in c.685C > T mutant cells but also showed a significant band at 35 kDa, suggesting a truncated protein. Immunofluorescence localization showed no significant differences in protein localization before and after the mutation. CONCLUSIONS: The p.Asn460Thrfs*20 and p.Arg229* variants of SERPINC1 were responsible for the two hereditary AT deficiency pedigrees, which led to AT deficiency by different mechanisms. The p.Asn460Thrfs*20 variant is reported for the first time.

Brain-targeted nanoreactors prevent the development of organophosphate-induced delayed neurological damage.

BACKGROUND: Organophosphate (OP)-induced delayed neurological damage is attributed to permanent neuropathological lesions caused by irreversible OP-neurocyte interactions, without potent brain-targeted etiological antidotes to date. The development of alternative therapies to achieve intracerebral OP detoxification is urgently needed. METHODS: We designed a brain-targeted nanoreactor by integrating enzyme immobilization and biomimetic membrane camouflaging protocols with careful characterization, and then examined its blood-brain barrier (BBB) permeability both in vitro and in vivo. Subsequently, the oxidative stress parameters, neuroinflammatory factors, apoptotic proteins and histopathological changes were measured and neurobehavioral tests were performed. RESULTS: The well-characterized nanoreactors exerted favourable BBB penetration capability both in vitro and in vivo, significantly inhibiting OP-induced intracerebral damage. At the cellular and tissue levels, nanoreactors obviously blocked oxidative stress, cellular apoptosis, inflammatory reactions and brain histopathological damage. Furthermore, nanoreactors radically prevented the occurrence of OP-induced delayed cognitive deficits and psychiatric abnormality. CONCLUSION: The nanoreactors significantly prevented the development of OP-induced delayed neurological damage, suggesting a potential brain-targeted etiological strategy to attenuate OP-related delayed neurological and neurobehavioral disorders.

Han family with essential tremor caused by the P421L variant of the TENM4 gene in China.

BACKGROUND: Essential tremor (ET) is an autosomal dominant inheritance disorder. Mutations in fusion sarcoma (FUS), mitochondrial serine peptidase 2 (HTRA2), teneurin transmembrane protein 4 (TENM4), sortilin1 (SORT1), SCN11A, and notch2N-terminal-like (NOTCH2NLC) genes are associated with familial ET. METHODS: A proband with ET was tested using whole-exome sequencing and repeat-primed polymerase chain reaction. Subsequently, the family members were screened for the suspected mutation, and the results were verified using Sanger sequencing. The relationship between pedigree and phenotype was also analyzed, and structural and functional changes in the variants were predicted using bioinformatics analysis. RESULTS: In a family with ET, the proband (III4) and the proband's father (II1), grandfather (I1), uncle (II2), and cousin (III5) all presented with involuntary tremors of both upper limbs. The responsible mutation was identified as TENM4 c.1262C > T (p.P421L), which showed genetic co-segregation in the family survey. AlphaFold predicted a change in the spatial position of TENM4 after the P421L mutation, which may have affected its stability. AlphaFold also predicted P421L to be a deleterious variation, which would lead to lower degrees of freedom of the TENM4 protein, thereby affecting the protein's structure and stability. According to the bioinformatics analysis, TENM4 (p.P421L) may reduce the signal reaching the nucleus by affecting the expression of TENM4 messenger RNA (mRNA), thereby impairing the normal oligodendrocyte differentiation process and leading to impaired myelination. CONCLUSION: This study revealed that the TENM4 (p.P421L) pathogenic missense variation was responsible for ET in the proband.

Unlocking big data to understand health services usage and government funding during pregnancy and early childhood, evidence in Australia.

BACKGROUND: Maternity care is a high-volume and high-cost area of health care, which entails various types of service use throughout the course of the pregnancy. Thus, the aim of this study was to explore the most common reasons and related costs of health services used by women and babies from pregnancy to 12-month postbirth. METHODS: We used linked administrative data from one state of Australia, which contained all births in Queensland between 01/07/2017 and 30/06/2018. Descriptive analyses were used to identify the 10 most frequent reasons and related costs for accessing inpatient, outpatient, emergency department, and Medicare services. These are reported separately for women and babies in different periods. RESULTS: We included 58,394 births in our data set. The results have highlighted that there was relatively uniform use of inpatient, outpatient, and Medicare services by women and babies, with the 10 most common services accounting for more than half of the total services accessed. However, the emergency department service use was more diverse. Medicare services accounted for the greatest volume (79.21%) of service events but only 10.21% of the overall funding, compared with inpatient services, which accounted for less volume (3.62%) but the highest amount of overall funding (75.19%). CONCLUSION: Study findings provide empirical evidence about the full spectrum of services used by birthing families and their babies, and could assist health providers and managers to understand the services women and infants actually access during pregnancy, birth, and postbirth.

Pan-Cancer Analysis of the Cuproptosis-Related Gene DLD.

Background: Cancer affects millions of people each year and imposes a huge economic and social burden worldwide. Cuproptosis is a recently discovered novel mode of cell death. The exact function of the cuproptosis-related gene dihydrolipoamide dehydrogenase (DLD) and its role in pan-cancer is unknown. Methods: Data were retrieved from the GTEx, TCGA, and multiple online websites. These data were used to assess the expression, prognosis, and diagnostic value of DLD in various tumors. The relationship of DLD with immune microenvironment immunomodulators, immune checkpoints, tumor mutational load (TMB), microsatellite instability (MSI), and oncology drug sensitivity was explored by correlation analysis. Results: The mRNA and protein expression of DLD differs in most cancers. Survival analysis showed that DLD was associated with prognosis with KIRC, KIRP, KICH, and UCS. DLD had a strong diagnostic value in KIRC, GBM, PAAD, and LGG (AUC > 0.9). DLD promoter methylation affects the aberrant expression of LIHC, LUSC, PAAD, READ, and THCA. DLD was negatively correlated with stromal score, immune score, and ESTIMATE score in UCEC, TGCT, LUSC, and SARC. In UCS, resting memory CD4 T cells and activated NK cells were significantly correlated with DLD expression. Significant correlations were also observed between DLD expression and immunomodulators, immune checkpoints, TMB, and MSI in various cancers. Importantly, we also identified a number of potential drugs that may target DLD. Conclusion: DLD expression is associated with a variety of tumor prognoses and plays an integral role in tumorigenesis, tumor metabolism, and immunity.

A Case of Maternal Uniparental Disomy of Chromosome 6 with Intrauterine Growth Restriction.

Background: Uniparental disomy (UPD) is a well-known epigenomic anomaly characterized by the inheritance of both copies of a homologous pair of chromosomes (or part thereof) from the same parent. This genetic condition can have significant implications for prenatal diagnosis and management. Case Presentation: We present a case of a 29-year-old gravida 1 para 0 female who underwent amniocentesis at pregnancy Week 19 due to a high possibility of trisomy chromosome 6, as indicated by noninvasive prenatal testing (NIPT). However, fluorescence in situ hybridization (FISH) and whole-exome sequencing (WES) revealed no abnormalities. Subsequently, chromosomal microarray analysis (CMA) detected uniparental disomy of chromosome 6. Additionally, an ultrasound examination at 28 weeks of gestation revealed intrauterine growth restriction (IUGR). Given these findings, the parents made the decision to terminate the pregnancy. Conclusions: The combination of genetic counseling, FISH, karyotype analysis, WES, CMA, NIPT, and prenatal ultrasound can provide valuable insights for the prenatal diagnosis of UPD. These diagnostic approaches play a crucial role in identifying and managing cases of UPD, primarily when associated with intrauterine growth restrictions.

Constitutions in Traditional Chinese Medicine and Factors Influencing Them in Jilin Province of China.

Context: The identification of a patient's constitution in Traditional Chinese Medicine (TCM) allows physicians to understand his or her risk for different diseases, forecast the mechanism of disease development, and direct treatment strategies, such as herbs and/or acupuncture. However, very few large-scale clinical trials have occurred on the relationships of the TCM constitution to lifestyles and diseases. Objective: The study intended investigate the complex and systematic relationship between the TCM constitution and lifestyles to provide solutions for adjusting unbalanced constitutions and maintaining a balanced constitution and health state among people of various lifestyles in Jilin, China. Design: The research team conducted a randomized cross-sectional survey. Setting: The study took place in Jilin Province in China. Participants: Participants were 1755 residents of Jilin Province in China, 794 men and 961 women, between September 2006 and February 2013. Outcome Measures: The research team: (1) collected participants' data using a basic informational and lifestyle questionnaire and the Constitution in Chinese Medicine Questionnaire (CCMQ); (2) used descriptive analysis to illustrate demographic characteristics and the distribution of TCM constitutions; (3) conducted multivariate logistic regressions to explore potential factors influencing the Deficiency, Excess, Gentleness, and Special-diathesis constitutions. Results: Approximately one-half of participants in Jilin, China had an unbalanced constitution and one-third had Deficiency constitutions. Lifestyles and disease histories were significant influencing factors for the unbalanced constitutions. Of the 1755 participants, 757 had the Gentleness constitution (43.1%); the remaining participants had unbalanced constitutions, including 501 with a Deficiency constitution (28.6%), 423 with an Excess constitution (24.1%), and 74 with a Special-Diathesis constitution (4.2%). Regarding the influencing factors, the Deficiency constitutions were significantly related to lifestyle factors-especially gender, age, exercise, and diet: (21) the Qi-deficiency constitution was significantly related to excessive exercise and chronic bronchia; (2) the Yang-deficiency constitution was significantly related to female gender and prefer to hot food; and (3) the Yin-deficiency constitution was significantly related to age, from 46 to ≥66, and the barbecue diet. The Excess constitutions were related to medical histories: (1) the Phlegm-dampness and Blood-stasis constitutions were both significantly related to cardio-cerebrovascular disease and hyperlipidemia; (2) the Dampness-heat constitution was significantly related to liver disease and osteoporosis; (3) the Qi-depression constitution was significantly related to liver disease and chronic bronchia. The Gentleness constitution was significantly related to a greasy diet, and the Special-diathesis constitution was significantly related to allergies. Conclusions: The identification of TCM constitutions would be beneficial to early identification of potential risk factors and could contribute to the creation of more comprehensive guidelines for health organizations. Controlling the factors influencing the TCM constitutions and using health management plans based on the TCM constitution could help people with unbalanced constitutions to adjust their lifestyles and improve their health.

Long-Term Outcomes After Stenting in Extracranial vs. Intracranial Stenosis.

Objective: The purpose of this pilot study is to explore the difference in safety and effectiveness after stenting in patients with extracranial or intracranial vertebral artery stenosis. Methods: The study involved 26 patients treated with stents for ≥70% stenosis between January 1, 2017, and September 8, 2020. The patients were divided into intracranial and extracranial groups based on the location of the target vessel stenosis. The incidence of stroke or death within 30 days, long-term recurrence of ischemic symptoms, and restenosis during follow-up were monitored. Results: Within 30 days, no stroke or death was observed in the 26 patients, During the follow-up period, the risk of recurrence of posterior circulation stroke or transient ischemic attack was 23.1% (6/26). Vascular-related complications were 5.6% vs. 12.5% (P = .529) in the intracranial vs. extracranial stenosis group. After 1 year, stroke or transient ischemic attack of posterior circulation was observed in 12.5% (1/8) vs. 16.7% (3/18) in the intracranial and extracranial stenosis group, respectively. The restenosis rate in the intracranial stenosis group was higher than the extracranial stenosis group (37.5% vs. 28.6%, P > .05). This trend was also found in the asymptomatic restenosis rate (25% vs. 7.1%, P = .527). Conclusions: The study results showed that there was no significant difference in the safety and effectiveness after stenting in extracranial and intracranial vertebral artery stenosis, but intracranial vertebral artery stenosis has a low rate of symptomatic restenosis. Symptomatic restenosis may be an important problem that limits the efficacy of extracranial vertebral artery stenting.

Intravascular Intervention Combined with Standard Drug Therapy in Patients with Severe Intracranial Atherosclerotic Stenosis and Plaque Enhancement.

Objective: The purpose of this retrospective cohort study was to evaluate clinical outcomes in high-risk patients with symptomatic intracranial atherosclerotic stenosis (sICAS) resulting from plaque enhancement who underwent balloon dilation or stent implantation. Plaque features were identified based on high-resolution magnetic resonance vessel wall imaging (HRMR-VWI). Methods: A total of 37 patients with sICAS (degree of stenosis ≥70%) were enrolled between January 2018 and March 2022 at a single center. All patients underwent HRMR-VWI and received standard drug treatment after hospital admission. The patients were divided into 2 groups based on whether they underwent interventional treatment (n = 18) or non-interventional treatment (n = 19). The grade of enhancement and enhancement rate (ER) of culprit plaque were evaluated using 3D-HRMR-VWI. The risk of symptom recurrence was compared between the 2 groups during follow-up. Results: There was no statistical difference between the intervention and non-intervention groups in the rate and type of enhancement. Median clinical follow-up time was 17.8 (10.0 to 26.0) months and median follow-up time was 3.6 (3.1 to 6.2) months. In the intervention group, 2 patients had stent restenosis, but no stroke or transient ischemia attacks (TIAs) occurred. In contrast, 1 patient in the non-intervention group had an ischemic stroke and 4 patients had TIAs. The incidence of the primary outcome was lower in the intervention group than in the non-intervention group (0 vs 26.3%; P = .046). Conclusions: High-resolution magnetic resonance intracranial vessel wall imaging (HR MR-IVWI) can be used to identify vulnerable plaque features. It is safe and effective in high-risk patients with sICAS with responsible plaque enhancement to undergo intravascular intervention combined with standard drug therapy. Further studies are needed to analyze the link between plaque enhancement and symptom recurrence in the medication group at baseline.

VOC emission caps constrained by air quality targets based on response surface model: A case study in the Pearl River Delta Region, China.

Because of the recent growth in ground-level ozone and increased emission of volatile organic compounds (VOCs), VOC emission control has become a major concern in China. In response, emission caps to control VOC have been stipulated in recent policies, but few of them were constrained by the co-control target of PM2.5 and ozone, and discussed the factor that influence the emission cap formulation. Herein, we proposed a framework for quantification of VOC emission caps constrained by targets for PM2.5 and ozone via a new response surface modeling (RSM) technique, achieving 50% computational cost savings of the quantification. In the Pearl River Delta (PRD) region, the VOC emission caps constrained by air quality targets varied greatly with the NOx emission reduction level. If control measures in the surrounding areas of the PRD region were not considered, there could be two feasible strategies for VOC emission caps to meet air quality targets (160 µg/m3 for the maximum 8-hr-average 90th-percentile (MDA8-90%) ozone and 25 µg/m3 for the annual average of PM2.5): a moderate VOC emission cap with <20% NOx emission reductions or a notable VOC emission cap with >60% NOx emission reductions. If the ozone concentration target were reduced to 155 µg/m3, deep NOx emission reductions is the only feasible ozone control measure in PRD. Optimization of seasonal VOC emission caps based on the Monte Carlo simulation could allow us to gain higher ozone benefits or greater VOC emission reductions. If VOC emissions were further reduced in autumn, MDA8-90% ozone could be lowered by 0.3-1.5 µg/m3, equaling the ozone benefits of 10% VOC emission reduction measures. The method for VOC emission cap quantification and optimization proposed in this study could provide scientific guidance for coordinated control of regional PM2.5 and O3 pollution in China.

A novel compound heterozygous variant linked to hematuria in a family with hereditary factor VII deficiency.

BACKGROUND: Hereditary factor VII deficiency (FVIID) is a rare congenital autosomal recessive bleeding disorder. In clinical manifestations, its onset is caused by variant of the F7 gene (NM_019616) with strong heterogeneity. We identified a family with hematuria caused by a novel F7 compound heterozygous variant and investigated the FVIID-dependent mechanism impacted by these variants. METHODS: Coagulation factors in the proband were functionally verified. We located pathogenic variants in relevant genes using next-generation sequencing after target enrichment and verified them by Sanger sequencing. We examined the coagulation activity and secretion pattern of recombinant FVII variants expressed in cells and observed their location and stability by immunofluorescence. RESULTS: We found a missense variant c.1207G>A (p.Gly403Ser) and a frameshift variant c.154_155del (p.Arg53fs) in the F7 gene of the proband. FVII activity tests showed that the variants significantly decreased its presence in the cell culture supernatant. Moreover, the R53fs mutant lacked the FVII functional domain and had no detectable activity. Immunofluorescence indicated that the p.Gly403Ser variant was distributed to the cell membrane and cytoplasm, whereas the FVII R53fs variant was not detected. Deficient FVII protein function and severe coagulation disorder are the likely causes of hematuria and other bleeding symptoms in the proband. CONCLUSIONS: The newly discovered F7 gene variants enrich the spectrum of hereditary FVII deficiency and provide a new foundation for the diagnosis and treatment of this type of coagulation disorder.