Chemical Constituents of Primulina eburnea (Gesneriaceae) and Their Cytotoxic Activities.

Two new ursane-type triterpenes, eburnealactones A and B (1 and 2), one new flavonoid, eburneatin A (6), and one new phenylethanoid glycoside, chiritoside D (7), along with 9 known compounds (3-5, 8-13) were isolated from the whole plant of Primulina eburnea. Their structures were elucidated by comprehensive spectroscopic data analysis (IR, UV, NMR, and HR-ESI-MS). All the compounds were evaluated for their cytotoxic activities. Compound 1 showed significant cytotoxic activities against MKN-45 cell lines and 5637 cell lines with the IC50 values of 9.57 µM and 8.30 µM, respectively. Compound 1 exhibited moderate cytotoxic activities against A549 and PATU8988T cell lines with the IC50 values of 30.70 µM and 38.22 µM, respectively. Compound 6 exhibited moderate cytotoxic activities against MKN-45, HCT116, PATU8988T, 5637 and A-673 cell lines with the IC50 values of 19.69 µM, 16.44 µM, 18.07 µM, 11.51 µM and 18.15 µM, respectively. Compound 5 showed moderate cytotoxic activities against A549 cell lines with the IC50 values of 24.06 µM.

Resistance traits and molecular characterization of multidrug-resistant Acinetobacter baumannii isolates from an intensive care unit of a tertiary hospital in Guangdong, southern China.

PURPOSE: This study aims to characterize antimicrobial resistance (AMR) of all the non-duplicated Acinetobacter baumannii strains isolated from an intensive care unit in a tertiary hospital during the period of January 1 to December 31, 2015. METHODS: A. baumannii (n = 95 strains) isolated from patients was subjected to antimicrobial susceptibility test (AST) by Vitek 2 Compact system to determine minimum inhibitory concentrations, followed by genotyping by enterobacterial repetitive intergenic consensus-PCR (ERIC-PCR). Resistance genes of interest were PCR amplified and sequenced. RESULTS: All isolates were qualified as MDR, with a resistance rate of > 80% to 8 antimicrobials tested. In terms of beta-lactamase detection, the blaOXA23, blaTEM-1, and armA genes were detected frequently at 92.63%, 9 1.58%, and 88.42%, respectively. The metallo-ß-lactamase genes blaIMP and blaVIM were undetected. Aph (3')-I was detected in 82 isolates (86.32%), making it the most prevalent aminoglycoside-modifying enzyme (AMEs) encoding gene. In addition, ant (3″)-I was detected at 30.53%, while 26.32% of the strains harbored an aac (6')-Ib gene. ERIC-PCR typing suggested moderate genetic diversity among the isolates, which might be organized into 10 distinct clusters, with cluster A (n = 86 isolates or 90.53%) being the dominant cluster. CONCLUSIONS: All of the A. baumannii strains detected in the ICU were MDR clones exhibiting extremely high resistance to carbapenems and aminoglycosides as monitored throughout the study period. They principally belonged to a single cluster of isolates carrying blaOXA23 and armA co-producing different AMEs genes.

Discovery of PHGDH inhibitors by virtual screening and preliminary structure-activity relationship study.

Phosphoglycerate dehydrogenase (PHGDH) is abnormally expressed in numerous malignant tumor cells and catalyzes the first step of serine biosynthesis, thus becoming a key drug target for antitumor treatment. In this study, compound B2 bearing a benzene-1,3-diamine scaffold was identified by structure-based virtual screening as a novel PHGDH inhibitor with moderate enzymatic activity. The structure-activity relationship study led to the discovery of compound C25 possessing improved enzymatic inhibitory activity and potent inhibitory activity on the proliferation of cells overexpressing PHGDH. The enzyme kinetic assay confirmed that C25 inhibited PHGDH in a nicotinamide adenine dinucleotide (NAD+) competitive manner. Molecular docking and mutagenesis experiment on PHGDH collectively revealed the binding site and key interaction residues of C25 in the PHGDH catalytic site. Taken together, this study provides information on the structural diversity for a further development of potent PHGDH inhibitors.

Heterozygosity for a Pathogenic Variant in SLC12A3 That Causes Autosomal Recessive Gitelman Syndrome Is Associated with Lower Serum Potassium.

BACKGROUND: Potassium levels regulate multiple physiologic processes. The heritability of serum potassium level is moderate, with published estimates varying from 17% to 60%, suggesting genetic influences. However, the genetic determinants of potassium levels are not generally known. METHODS: A whole-exome sequencing association study of serum potassium levels in 5812 subjects of the Old Order Amish was performed. A dietary salt intervention in 533 Amish subjects estimated interaction between p.R642G and sodium intake. RESULTS: A cluster of variants, spanning approximately 537 kb on chromosome 16q13, was significantly associated with serum potassium levels. Among the associated variants, a known pathogenic variant of autosomal recessive Gitelman syndrome (p.R642G SLC12A3) was most likely causal; there were no homozygotes in our sample. Heterozygosity for p.R642G was also associated with lower chloride levels, but not with sodium levels. Notably, p.R642G showed a novel association with lower serum BUN levels. Heterozygotes for p.R642G had a two-fold higher rate of self-reported bone fractures and had higher resting heart rates on a low-salt diet compared with noncarriers. CONCLUSIONS: This study provides evidence that heterozygosity for a pathogenic variant in SLC12A3 causing Gitelman syndrome, a canonically recessive disorder, contributes to serum potassium concentration. The findings provide insights into SLC12A3 biology and the effects of heterozygosity on electrolyte homeostasis and related subclinical phenotypes that may have implications for personalized medicine and nutrition.

Stable Zr-Based Metal-Organic Framework Nanoporous Membrane for Efficient Desalination of Hypersaline Water.

Treatment of hypersaline waters is a critical environmental challenge. Pervaporation (PV) desalination is a promising technique to address this challenge, but current PV membranes still suffer from challenging issues such as low flux and insufficient stability. Herein, we propose in situ nanoseeding followed by a secondary growth strategy to fabricate a high-quality stable metal-organic framework (MOF) thin membrane (UiO-66) for high-performance pervaporation desalination of hypersaline waters. To address the issue of membrane quality, a TiO2 nano-interlayer was introduced on coarse mullite substrates to favor the growth of a UiO-66 nanoseed layer, on which a well-intergrown UiO-66 selective membrane layer with thickness as low as 1 µm was finally produced via subsequent secondary growth. The PV separation performance for hypersaline waters was systematically investigated at different salt concentrations, feed temperatures, and long-term operation in different extreme chemical environments. Besides having nearly complete rejection (99.9%), the UiO-66 membrane exhibited high flux (37.4 L·m-2·h-1) for hypersaline waters, outperforming current existing zeolite and MOF membranes. The membrane also demonstrated superior long-term operational stability under various harsh environments (hypersaline, hot, and acidic/alkaline feed water) and mild fouling behavior. The rational design proposed in this study is not only applicable for the development of a high-quality UiO-66 membrane enabling harsh hypersaline water treatment but can also be potentially extended to other next-generation nanoporous MOF membranes for more environmental applications.

Changes in whole metabolites after exenatide treatment in overweight/obese polycystic ovary syndrome patients.

OBJECTIVE: Exenatide is a new agent for diabetes therapy, and its use in polycystic ovary syndrome (PCOS) has gradually increased; however, the clinical benefit and metabolic improvement need further evidence. This research aimed to study the changes in whole metabolites before and after exenatide treatment in overweight/obese PCOS patients to gain a better understanding of exenatide for the treatment of PCOS. METHODS: Sixty-seven women, including 32 with PCOS and 35 age-matched controls, were recruited. The metabolite changes were detected with nontargeted gas chromatography-tandem mass spectrometry (NTGC-MS) before and after exenatide treatment, and changes in clinical biochemical characteristics were also observed. RESULTS: A total of 62 metabolites were differentially expressed between the healthy and PCOS groups, and 31 differentially expressed metabolites were detected before and after exenatide treatment. Abnormal lipid metabolism and amino acid metabolism were the main metabolic disorders. Exenatide improved lipid and amino acid metabolism, especially amino acid metabolites. Three types of branched-chain amino acids (valine, leucine and isoleucine), two types of aromatic amino acids (phenylalanine and tyrosine) and lysine are important potential metabolites for the therapeutic efficacy of exenatide. Many abnormal metabolic disorders are related to insulin resistance, oxidative stress and even ovulatory dysfunction. Moreover, in this small sample clinical study, we also found that exenatide improved insulin sensitivity, reduced body weight and improved glycolipid metabolism in PCOS. CONCLUSIONS: NTGC-MS-based metabolic pathway analysis revealed that exenatide has a beneficial effect on overweight/obese PCOS patients by regulating metabolic disorders, especially amino acid disorders.

Longitudinal analysis of cardiac structure and function in incident-automated peritoneal dialysis: comparison between icodextrin solution and glucose-based solution.

BACKGROUND: This study aimed to evaluate the longitudinal changes in cardiac structure and function in incident-automated peritoneal dialysis (APD) patients. METHODS: We conducted a 2-year prospective, randomized, open-label, parallel-group study to compare the efficacy of icodextrin solution versus glucose-based solution. Echocardiography was performed at baseline, 1 and 2 years. Echocardiographic parameters over 2 years were evaluated for each group, using the Friedman test. Generalized linear regression analysis was used to test the associations between baseline clinical variables and echocardiographic changes, and a multivariate model was used to analyze cardiac function between the two groups. RESULTS: A total of 43 APD patients were enrolled in the beginning of this study. Twenty patients in the icodextrin group (ICO) and 18 patients in the glucose group (GLU) completed the study. In left ventricular (LV) systolic function measurements, ejection fraction (EF) increased significantly in the GLU group. Measurements of LV diastolic function and septal early mitral annulus velocity (EMV) increased significantly from baseline to 24-months in the ICO group (5.43-5.51 ms). The GLU group showed a significant decrease in peak early diastolic velocity (EDV) (70.67-68.25 cm/s), but a significant increase in septal EMV (5.94-7.57 ms) from baseline to 24-months. No significant association was found between the baseline clinical variables and echocardiographic changes within 24 months in the generalized linear regression analysis. Multivariate models were used to investigate changes in the four primary endpoints, namely, myocardial performance index (MPI), left ventricular ejection fraction (LVEF), deceleration time (DT), and E/e' ratio. These primary endpoints show no significant association with the baseline values in both the ICO and GLU groups. CONCLUSION: The present study demonstrates that long-dwell icodextrin solution can maintain reasonable cardiac structure and function in incident-APD patients. TRIAL REGISTRATION: ISRCTN14931270 (retrospectively registered on 23/03/2018).

Evidence for several independent genetic variants affecting lipoprotein (a) cholesterol levels.

Lipoprotein (a) [Lp(a)] is an independent risk factor for atherosclerosis-related events that is under strong genetic control (heritability = 0.68-0.98). However, causal mutations and functional validation of biological pathways modulating Lp(a) metabolism are lacking. We performed a genome-wide association scan to identify genetic variants associated with Lp(a)-cholesterol levels in the Old Order Amish. We confirmed a previously known locus on chromosome 6q25-26 and found Lp(a) levels also to be significantly associated with a SNP near the APOA5-APOA4-APOC3-APOA1 gene cluster on chromosome 11q23 linked in the Amish to the APOC3 R19X null mutation. On 6q locus, we detected associations of Lp(a)-cholesterol with 118 common variants (P = 5 × 10(-8) to 3.91 × 10(-19)) spanning a ∼5.3 Mb region that included the LPA gene. To further elucidate variation within LPA, we sequenced LPA and identified two variants most strongly associated with Lp(a)-cholesterol, rs3798220 (P = 1.07 × 10(-14)) and rs10455872 (P = 1.85 × 10(-12)). We also measured copy numbers of kringle IV-2 (KIV-2) in LPA using qPCR. KIV-2 numbers were significantly associated with Lp(a)-cholesterol (P = 2.28 × 10(-9)). Conditional analyses revealed that rs3798220 and rs10455872 were associated with Lp(a)-cholesterol levels independent of each other and KIV-2 copy number. Furthermore, we determined for the first time that levels of LPA mRNA were higher in the carriers than non-carriers of rs10455872 (P = 0.0001) and were not different between carriers and non-carriers of rs3798220. Protein levels of apo(a) were higher in the carriers than non-carriers of both rs10455872 and rs3798220. In summary, we identified multiple independent genetic determinants for Lp(a)-cholesterol. These findings provide new insights into Lp(a) regulation.

Synthesis of Pentafluoroethyl Ethers by Silver-Mediated Oxidative Pentafluoroethylation of Alcohols and Phenols.

A silver triflate (AgOTf)-mediated oxidative pentafluoroethylation of alcohols and phenols with nucleophilic (pentafluoroethyl)trimethylsilane (TMSCF2CF3) using selectfluor as oxidant under mild reaction conditions was developed. This oxidative coupling protocol utilizes broadly available substrates and easily handled reagents to afford various pentafluoroethyl ethers in moderate to excellent yields. Furthermore, this method was extended to the oxidative heptafluoropropylation and ethoxycarbonyldifluoromethylation of alcohols and phenols for preparation of the corresponding fluoroalkyl ethers.

The common genetic influence over processing speed and white matter microstructure: Evidence from the Old Order Amish and Human Connectome Projects.

Speed with which brain performs information processing influences overall cognition and is dependent on the white matter fibers. To understand genetic influences on processing speed and white matter FA, we assessed processing speed and diffusion imaging fractional anisotropy (FA) in related individuals from two populations. Discovery analyses were performed in 146 individuals from large Old Order Amish (OOA) families and findings were replicated in 485 twins and siblings of the Human Connectome Project (HCP). The heritability of processing speed was h(2)=43% and 49% (both p<0.005), while the heritability of whole brain FA was h(2)=87% and 88% (both p<0.001), in the OOA and HCP, respectively. Whole brain FA was significantly correlated with processing speed in the two cohorts. Quantitative genetic analysis demonstrated a significant degree to which common genes influenced joint variation in FA and brain processing speed. These estimates suggested common sets of genes influencing variation in both phenotypes, consistent with the idea that common genetic variations contributing to white matter may also support their associated cognitive behavior.

Heritability of complex white matter diffusion traits assessed in a population isolate.

INTRODUCTION: Diffusion weighted imaging (DWI) methods can noninvasively ascertain cerebral microstructure by examining pattern and directions of water diffusion in the brain. We calculated heritability for DWI parameters in cerebral white (WM) and gray matter (GM) to study the genetic contribution to the diffusion signals across tissue boundaries. METHODS: Using Old Order Amish (OOA) population isolate with large family pedigrees and high environmental homogeneity, we compared the heritability of measures derived from three representative DWI methods targeting the corpus callosum WM and cingulate gyrus GM: diffusion tensor imaging (DTI), the permeability-diffusivity (PD) model, and the neurite orientation dispersion and density imaging (NODDI) model. These successively more complex models represent the diffusion signal modeling using one, two, and three diffusion compartments, respectively. RESULTS: We replicated the high heritability of the DTI-based fractional anisotropy (h(2) = 0.67) and radial diffusivity (h(2) = 0.72) in WM. High heritability in both WM and GM tissues were observed for the permeability-diffusivity index from the PD model (h(2) = 0.64 and 0.84), and the neurite density from the NODDI model (h(2) = 0.70 and 0.55). The orientation dispersion index from the NODDI model was only significantly heritable in GM (h(2) = 0.68). CONCLUSION: DWI measures from multicompartmental models were significantly heritable in WM and GM. DWI can offer valuable phenotypes for genetic research; and genes thus identified may reveal mechanisms contributing to mental and neurological disorders in which diffusion imaging anomalies are consistently found. Hum Brain Mapp 37:525-535, 2016. © 2015 Wiley Periodicals, Inc.

Effect of zinc supplementation on insulin secretion: interaction between zinc and SLC30A8 genotype in Old Order Amish.

AIMS/HYPOTHESIS: SLC30A8 encodes a zinc transporter in the beta cell; individuals with a common missense variant (rs13266634; R325W) in SLC30A8 demonstrate a lower early insulin response to glucose and an increased risk of type 2 diabetes. We hypothesised that zinc supplementation may improve insulin secretion in a genotype-dependent manner. METHODS: We evaluated the early insulin response to glucose (using frequently sampled intravenous glucose tolerance testing) by R325W genotype before and after 14 days of supplementation with oral zinc acetate (50 mg elemental zinc) twice daily in healthy non-diabetic Amish individuals (N = 55). RESULTS: Individuals with RW/WW genotypes (n = 32) had the lowest insulin response to glucose at 5 and 10 min at baseline (vs RR homozygotes [n = 23]). After zinc supplementation, the RW/WW group experienced 15% and 14% increases in the insulin response to glucose at 5 and 10 min, respectively (p ≤ 0.04), and, compared with RR homozygotes, experienced a 26% (p = 0.04) increase in insulin at 5 min. We observed reciprocal decreases in proinsulin:insulin in the RW/WW (p = 0.002) vs RR group (p = 0.048), suggesting a genotype-specific improvement in insulin processing. CONCLUSIONS/INTERPRETATION: Zinc supplementation appears to affect the early insulin response to glucose differentially by rs13266634 genotype and could be beneficial for diabetes prevention and/or treatment for some individuals based on SLC30A8 variation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00981448.

UPLC-ESI-MS/MS-Based Analysis of Various Edible Rosa Fruits Concerning Secondary Metabolites and Evaluation of Their Antioxidant Activities.

The genus Rosa is globally popular with well-established applications since it has a high edible and medicinal value. However, relatively limited research has been conducted on the composition and quality of wild Rosa fruits. The present study aimed to compare the properties and chemical components of five wild edible Rosa fruits, Rosa roxburghii, Rosa sterilis, Rosa laevigata, Rosa davurica, and Rosa sericea. The UPLC-ESI-MS/MS approach identified the key metabolites among the five Rosa fruits as flavonoids, phenolic acids, and organic acids. The main differential metabolites among the five fruits are flavonoids (22.29-45.13%), phenolic acids (17-22.27%), and terpenoids (7.7-24%), respectively. In total, 125 compounds served as potential markers for the five Rosa species. Differential metabolic pathways of five Rosa fruits were analyzed using the KEGG approach. Rosa laevigata fruits showed the highest total polysaccharide (TPS) content of 64.48 g/100 g. All the five Rosa extracts effectively decreased the levels of malondialdehyde while increasing the activities of superoxide dismutase and glutathione peroxidase in the H2O2-induced HaCaT cell model, demonstrating high potential for antioxidant development. Our findings suggest that the five studied Rosa fruits exhibit biological activity and edible value worth further exploration.

Preoperative CT radiomics of esophageal squamous cell carcinoma and lymph node to predict nodal disease with a high diagnostic capability.

PURPOSE: To develop CT radiomics models of resectable esophageal squamous cell carcinoma (ESCC) and lymph node (LN) to preoperatively identify LN+. MATERIALS AND METHODS: 299 consecutive patients with ESCC were enrolled in the study, 140 of whom were LN+ and 159 were LN-. Of the 299 patients, 249 (from the same hospital) were randomly divided into a training cohort (n = 174) and a test cohort (n = 75). The remaining 50 patients, from a second hospital, were assigned to an external validation cohort. In the training cohort, preoperative contrast-enhanced CT radiomics features of ESCC and LN were extracted, then integrated with clinical features to develop three models: ESCC, LN and combined. The performance of these models was assessed using area under receiver operating characteristic curve (AUC), and F-1 score, which were validated in both the test cohort and external validation cohort. RESULTS: An ESCC model was developed for the training cohort utilizing the 8 tumor radiomics features, and an LN model was constructed using 9 nodal radiomics features. A combined model was constructed using both ESCC and LN extracted features, in addition to cT stage and LN+ distribution. This combined model had the highest predictive ability among the three models in the training cohort (AUC = 0.948, F1-score = 0.878). The predictive ability was validated in both the test and external validation cohorts (AUC = 0.885 and 0.867, F1-score = 0.816 and 0.773, respectively). CONCLUSION: To preoperatively determine LN+, the combined model is superior to models of ESCC and LN alone.

High COL4A3 expression correlates with poor prognosis after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer.

In this study, we investigated whether COL4A3 mRNA expression levels were associated with clinical outcomes after treatment with a combination of gemcitabine (Gem)/cis-diamminedichloroplatinum(II) (CDDP) regimen for patients with advanced stage non-small cell lung cancer (NSCLC). Response and survival were correlated with the level of COL4A3 expression in 58 patients with advanced (stage IIIb or IV) NSCLC treated as part of a multicenter randomized trial with Gem 1,250 mg/m(2) on days 1 and 8 plus CDDP 100 mg/m(2) on day 1 every 3 weeks. mRNA was isolated from paraffin-embedded pretreatment primary tumor specimens, and relative expression levels of COL4A3/ß-actin were measured using a quantitative reverse transcription-PCR (Taqman) system. COL4A3 expression was detectable in all tumors. There were no significant differences in COL4A3 levels by gender, age, performance status, weight loss, or tumor stage. The overall response rate was 45.8 %. There were no significant associations between COL4A3 expression and response. Median overall survival was significantly longer in patients with low COL4A3 expression tumors compared to patients with high expression tumors. COL4A3 expression, Eastern Cooperative Oncology Group performance status, and presence of weight loss were significant prognostic factors for survival in a Cox proportional hazards multivariable analysis. These data suggest that COL4A3 expression is a predictive factor for survival after CDDP/Gem therapy in advanced NSCLC. Although there was a trend toward decreased response with high COL4A3 mRNA levels, this difference failed to reach statistical significance. This result may reflect the impact of Gem and the requirement for COL4A3 expression for CDDP/Gem synergism or may be attributable to the relatively small patient sample size in this study. Prospective studies of COL4A3 as a predictive marker for activity of CDDP-based regimens in NSCLC are warranted.

Overexpression of ECRG4 enhances chemosensitivity to 5-fluorouracil in the human gastric cancer SGC-7901 cell line.

The aim of this study was to examine the effects of esophageal cancer-related gene 4 (ECRG4) expression levels on chemotherapeutic sensitivity of gastric cancer cells. A SGC-7901 cell system with tetracycline-inducible ECRG4 expression (SGC-7901/ECRG4) was successfully established. ECRG4 mRNA and protein expression levels were detected using quantitative reverse transcription polymerase chain reaction and Western blotting, respectively. Chemosensitivity to 5-fluorouracil (5-FU) was examined by cell proliferation assay and cell apoptosis assay. ECRG4 mRNA and protein expression levels were significantly upregulated in SGC-7901/ECRG4 cells induced with tetracycline. Compared with control cells, the growth inhibition rate of cells with ECRG4 overexpression was significantly increased when treated with 5-FU. Treatment with 5 µmol/l 5-FU resulted in 15.2 % apoptotic cells, whereas such treatment after overexpression of ECRG4 resulted in 44.5 % apoptotic cells. In conclusion, overexpression of ECRG4 enhanced the chemosensitivity of gastric cancer SGC-7901 cells to 5-FU through induction of apoptosis.

Image-based visualization of stents in mechanical thrombectomy for acute ischemic stroke: Preliminary findings from a series of cases.

BACKGROUND: Mechanical thrombectomy is the most effective treatment for great cerebral artery embolization within a set time window. Typically, an arteriogram does not show the localization of the stent after release and whether a thrombus is captured or not. Thus, improving the visualization of a stent in interventional therapy will be helpful for clinicians. AIM: To analyze stent imaging findings to enhance clinicians' understanding of a special circumstance, wherein a Solitaire AB retrievable stent was visible during the imaging of a thrombus capture that improved the success rate of stent-based mechanical thrombectomy. METHODS: This was a retrospective study with four acute ischemic stroke (AIS) patients who underwent stent-based mechanical thrombectomy. RESULTS: Patient 1 was a 64-year-old man admitted after 5 h of confusion; angiography revealed basilar artery occlusion. We inserted a stent into the left posterior cerebral artery-P2 segment and visualized the expanded stent that successfully captured a thrombus. Patient 2 was a 74-year-old man admitted with confusion, which lasted approximately 3 h. Angiography revealed a left middle cerebral artery (MCA)-M1 segment occlusion. A stent was deployed in the distal M2 segment, and we could visualize the stent by capturing the thrombus. Patient 3 was a 74-year-old woman admitted after experiencing left hemiplegia for 3 h. We deployed a stent at the distal right MCA-M2 segment, and the developing stent captured a large thrombus. Patient 4 was an 82-year-old man who presented with confusion for 3 h. A developing stent was placed in the distal left MCA-M1 segment, which captured a large thrombus and several fragmented thrombi. CONCLUSION: To the best of our knowledge, this is the first report of stent imaging in patients with AIS. We demonstrated the usefulness and substantial potential of stent imaging in stent-based mechanical thrombectomy for AIS.

Development of a vaccine hesitancy scale for childhood immunization in China.

OBJECTIVE: Vaccine hesitancy is a primary factor that influences vaccine uptake; however, no specific measurement tool to accurately assess vaccine hesitancy is available in China. This study aimed to develop a general vaccine hesitancy scale for childhood immunization. METHODS: We adopted a three-phase process with nine steps to develop and finalize our scale. The scale framework and initial item pool were determined by a literature review. Expert consultation and cognitive interviews with parents were conducted to evaluate content validity. Questionnaire surveys involving parents of children aged <6 years were conducted to select items. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were employed to identify and validate the scale factor structure. The scale's reliability and validity were assessed using multiple indicators. RESULTS: Of the initial 38 items, 21 were retained after expert consultation and cognitive interviews. In survey 1, the number of scale items decreased to 16 following item analysis and EFA. In survey 2, four items were added and EFA identified four factors. In survey 3, CFA confirmed the four-factor structure and the reliability indicators were satisfactory for the total scale. The level of vaccine hesitancy assessed by our scale was positively associated with vaccination refusal behavior and the Vaccine Hesitancy Scale score. The final scale comprised four dimensions (confidence, complacency, convenience, and calculation) with 17 items. CONCLUSIONS: We developed a validated and reliable measurement to assess vaccine hesitancy among parents of children, which promises to be suitable for wide use in China.

A CT-based novel model to predict pathological complete response of locally advanced esophageal squamous cell carcinoma to neoadjuvant PD-1 blockade in combination with chemotherapy.

PURPOSE: To develop a novel CT-based model to predict pathological complete response (pCR) of locally advanced esophageal squamous cell carcinoma (ESCC) to neoadjuvant PD-1 blockade in combination with chemotherapy. METHODS: 117 consecutive patients with locally advanced ESCC were stratified into training cohort (n = 82) and validation cohort (n = 35). All patients underwent non-contrast and contrast-enhanced thoracic and upper abdominal CT before neoadjuvant PD-1 blockade in combination with chemotherapy (CTpre), and after two cycles of the therapy before esophagectomy (CTpost), respectively. Univariate analyses and binary logistic regression analyses of ESCC quantitative and qualitative CT features were performed to determine independent predictors of pCR. Prediction performance of the model developed with independent predictors from training cohort was evaluated by receiver operating characteristic (ROC) analysis, and validated by Kappa test in validation cohort. RESULTS: In training cohort, the difference in CT attenuation between tumor and background normal esophageal wall obtained from CTpre (ΔTNpre), tumoral increased CT attenuation after contrast-enhanced scan from CTpost images (ΔTpost) and gross tumor volume (GTV) from CTpre were independent predictors of pCR (odds ratio = 1.128 (95% confidence interval (CI): 0.997-1.277), 1.113 (95%CI: 0.965-1.239) and 1.133 (95%CI: 1.043-1.231), respectively, all P-values < 0.05). Logistic regression model equation (0.121 × ΔTNpre + 0.107 × ΔTpost + 0.125 × GTV - 9.856) to predict pCR showed the best performance with an area under the ROC of 0.876, compared with each independent predictor. The good performance was confirmed by the Kappa test (K-value = 0.796) in validation cohort. CONCLUSIONS: This novel model can be reliable to predict pCR to neoadjuvant PD-1 blockade in combination with chemotherapy in locally advanced ESCC.

Successful therapy using high-dose furmonertinib for non-small cell lung cancer with leptomeningeal metastasis: a case report and literature review.

Background: Lung cancer is the second most common form of malignant tumor and has the highest mortality rate worldwide. Among its subtypes, lung adenocarcinoma is the most prevalent. Leptomeningeal metastasis (LM) is rare and is characterized by a dismal prognosis, with overall survival periods typically spanning 4 to 6 weeks without treatment. However, in specific cases, survival can be extended to 4 to 6 months with appropriate therapy. The recent approval of third-generation tyrosine kinase inhibitors (TKIs), such as osimertinib, aumolertinib, and furmonertinib, has introduced promising treatment options for individuals with non-small cell lung cancer (NSCLC) who develop LM after developing resistance to first- and second-generation TKIs. These third-generation TKIs exhibit an enhanced ability to penetrate the blood-brain barrier (BBB), opening up new avenues for managing this challenging condition. Case summary: We report the case of a 48-year-old Chinese man diagnosed with advanced NSCLC harboring an epidermal growth factor receptor (EGFR) mutation. Following a pulmonary lobectomy and postoperative adjuvant therapy with gefitinib, the patient was diagnosed with LM, which was confirmed by his neurologic symptoms, cerebrospinal fluid cytologic analysis, and cranial enhancement magnetic resonance imaging. Subsequently, he received oral treatment in the form of 160 mg of furmonertinib daily. After 5 days of furmonertinib therapy, the patient recovered from lethargy, with an obvious improvement in cognitive function. Follow-up visits revealed a 6-month survival period following the LM diagnosis. Patients with NSCLC and LM typically present with severe symptoms, and the efficacy of systemic treatment, intrathecal chemotherapy, and radiotherapy remains unsatisfactory. We hope that this specific case provide valuable insights into the management of patients with EGFR mutation-associated NSCLC with LM. Conclusion: Furmonertinib, a third-generation EGFR TKI with notable BBB penetration, shows promise in LM control and the rapid alleviation of intracranial symptoms. Further investigations into appropriate dosage and toxicity management are imperative.