Investigating Linguistic Alignment in Collaborative Dialogue: A Study of Syntactic and Lexical Patterns in Middle School Students.

Linguistic alignment, the tendency of speakers to share common linguistic features during conversations, has emerged as a key area of research in computer-supported collaborative learning. While previous studies have shown that linguistic alignment can have a significant impact on collaborative outcomes, there is limited research exploring its role in K-12 learning contexts. This study investigates syntactic and lexical linguistic alignments in a collaborative computer science-learning corpus from 24 pairs (48 individuals) of middle school students (aged 11-13). The results show stronger effects of self-alignment than partner alignment on both syntactic and lexical levels, with students often diverging from their partners on task-relevant words. Furthermore, student self-alignment on the syntactic level is negatively correlated with partner satisfaction ratings, while self-alignment on lexical level is positively correlated with their partner's satisfaction.

Novel indel variation of LTBP4 gene associates with risk of sudden cardiac death in Chinese populations with coronary artery disease.

The objective of this study is to investigate whether common genetic variants of the LTBP4 gene are linked to the susceptibility of sudden cardiac death in individuals who have atherosclerotic coronary artery disease (SCD-CAD) in Chinese populations. A total of 208 SCD-CAD cases and 638 controls were included in the analysis, and logistic regression was employed to assess the association between a 4-bp insertion/deletion polymorphism (rs34005443) within LTBP4 and the susceptibility to SCD-CAD among Chinese individuals. Logistic regression analysis demonstrated a notable association between the insertion allele of rs34005443 and an escalated susceptibility to SCD-CAD [odds ratio (OR) = 1.434; 95 % confidence interval:1.14-1.80; P = 1.79 × 10-3]. Genotype-phenotype correlation analysis was performed using Genotype-Tissue expression (GTEx) database and further validated by human myocardium using qPCR. Correlation analysis revealed that LTBP4 expression level was lower in samples with the insertion allele. Furthermore, the dual-luciferase activity assays indicated that rs34005443 may play a regulatory role. Additionally, we predicted 30 transcription factors that are likely to bind to rs34005443 and its highly linked genetic variants via 3DSNP database. Subsequent GO and KEGG analysis indicated that these transcription factors have a significant function in regulating gene expression. Finally, PPI network analysis suggested a tight connection between LTBP4 proteins and TGFßs, highlighting these genes as potential hub genes in the context of SCD-CAD. In summary, our study revealed that rs34005443 might contribute to SCD-CAD susceptibility by regulating LTBP4 expression. These findings revealed that this indel could be a potentially functional marker for molecular diagnosis and risk stratification of SCD-CAD.

Use of chemotherapy in patients with oesophageal, stomach, colon, rectal, liver, pancreatic, lung, and ovarian cancer: an International Cancer Benchmarking Partnership (ICBP) population-based study.

BACKGROUND: There are few data on international variation in chemotherapy use, despite it being a key treatment type for some patients with cancer. Here, we aimed to examine the presence and size of such variation. METHODS: This population-based study used data from Norway, the four UK nations (England, Northern Ireland, Scotland, and Wales), eight Canadian provinces (Alberta, British Columbia, Manitoba, Newfoundland and Labrador, Nova Scotia, Ontario, Prince Edward Island, and Saskatchewan), and two Australian states (New South Wales and Victoria). Patients aged 15-99 years diagnosed with cancer in eight different sites (oesophageal, stomach, colon, rectal, liver, pancreatic, lung, or ovarian cancer), with no other primary cancer diagnosis occurring from within the 5 years before to 1 year after the index cancer diagnosis or during the study period were included in the study. We examined variation in chemotherapy use from 31 days before to 365 days after diagnosis and time to its initiation, alongside related variation in patient group differences. Information was obtained from cancer registry records linked to clinical or patient management system data or hospital administration data. Random-effects meta-analyses quantified interjurisdictional variation using 95% prediction intervals (95% PIs). FINDINGS: Between Jan 1, 2012, and Dec 31, 2017, of 893 461 patients with a new diagnosis of one of the studied cancers, 111 569 (12·5%) did not meet the inclusion criteria, and 781 892 were included in the analysis. There was large interjurisdictional variation in chemotherapy use for all studied cancers, with wide 95% PIs: 47·5 to 81·2 (pooled estimate 66·4%) for ovarian cancer, 34·9 to 59·8 (47·2%) for oesophageal cancer, 22·3 to 62·3 (40·8%) for rectal cancer, 25·7 to 55·5 (39·6%) for stomach cancer, 17·2 to 56·3 (34·1%) for pancreatic cancer, 17·9 to 49·0 (31·4%) for lung cancer, 18·6 to 43·8 (29·7%) for colon cancer, and 3·5 to 50·7 (16·1%) for liver cancer. For patients with stage 3 colon cancer, the interjurisdictional variation was greater than that for all patients with colon cancer (95% PI 38·5 to 78·4; 60·1%). Patients aged 85-99 years had 20-times lower odds of chemotherapy use than those aged 65-74 years, with very large interjurisdictional variation in this age difference (odds ratio 0·05; 95% PI 0·01 to 0·19). There was large variation in median time to first chemotherapy (from diagnosis date) by cancer site, with substantial interjurisdictional variation, particularly for rectal cancer (95% PI -15·5 to 193·9 days; pooled estimate 89·2 days). Patients aged 85-99 years had slightly shorter median time to first chemotherapy compared with those aged 65-74 years, consistently between jurisdictions (-3·7 days, 95% PI -7·6 to 0·1). INTERPRETATION: Large variation in use and time to chemotherapy initiation were observed between the participating jurisdictions, alongside large and variable age group differences in chemotherapy use. To guide efforts to improve patient outcomes, the underlying reasons for these patterns need to be established. FUNDING: International Cancer Benchmarking Partnership (funded by the Canadian Partnership Against Cancer, Cancer Council Victoria, Cancer Institute New South Wales, Cancer Research UK, Danish Cancer Society, National Cancer Registry Ireland, The Cancer Society of New Zealand, National Health Service England, Norwegian Cancer Society, Public Health Agency Northern Ireland on behalf of the Northern Ireland Cancer Registry, DG Health and Social Care Scottish Government, Western Australia Department of Health, and Public Health Wales NHS Trust).

Use of radiotherapy in patients with oesophageal, stomach, colon, rectal, liver, pancreatic, lung, and ovarian cancer: an International Cancer Benchmarking Partnership (ICBP) population-based study.

BACKGROUND: There is little evidence on variation in radiotherapy use in different countries, although it is a key treatment modality for some patients with cancer. Here we aimed to examine such variation. METHODS: This population-based study used data from Norway, the four UK nations (England, Northern Ireland, Scotland, and Wales), nine Canadian provinces (Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Nova Scotia, Ontario, Prince Edward Island, and Saskatchewan), and two Australian states (New South Wales and Victoria). Patients aged 15-99 years diagnosed with cancer in eight different sites (oesophageal, stomach, colon, rectal, liver, pancreatic, lung, or ovarian cancer), with no other primary cancer diagnosis occurring within the 5 years before to 1 year after the index cancer diagnosis or during the study period were included in the study. We examined variation in radiotherapy use from 31 days before to 365 days after diagnosis and time to its initiation, alongside related variation in patient group differences. Information was obtained from cancer registry records linked to clinical or patient management system data, or hospital administration data. Random-effects meta-analyses quantified interjurisdictional variation using 95% prediction intervals (95% PIs). FINDINGS: Between Jan 1, 2012, and Dec 31, 2017, of 902 312 patients with a new diagnosis of one of the studied cancers, 115 357 (12·8%) did not meet inclusion criteria, and 786,955 were included in the analysis. There was large interjurisdictional variation in radiotherapy use, with wide 95% PIs: 17·8 to 82·4 (pooled estimate 50·2%) for oesophageal cancer, 35·5 to 55·2 (45·2%) for rectal cancer, 28·6 to 54·0 (40·6%) for lung cancer, and 4·6 to 53·6 (19·0%) for stomach cancer. For patients with stage 2-3 rectal cancer, interjurisdictional variation was greater than that for all patients with rectal cancer (95% PI 37·0 to 84·6; pooled estimate 64·2%). Radiotherapy use was infrequent but variable in patients with pancreatic (95% PI 1·7 to 16·5%), liver (1·8 to 11·2%), colon (1·6 to 5·0%), and ovarian (0·8 to 7·6%) cancer. Patients aged 85-99 years had three-times lower odds of radiotherapy use than those aged 65-74 years, with substantial interjurisdictional variation in this age difference (odds ratio [OR] 0·38; 95% PI 0·20-0·73). Women had slightly lower odds of radiotherapy use than men (OR 0·88, 95% PI 0·77-1·01). There was large variation in median time to first radiotherapy (from diagnosis date) by cancer site, with substantial interjurisdictional variation (eg, oesophageal 95% PI 11·3 days to 112·8 days; pooled estimate 62·0 days; rectal 95% PI 34·7 days to 77·3 days; pooled estimate 56·0 days). Older patients had shorter median time to radiotherapy with appreciable interjurisdictional variation (-9·5 days in patients aged 85-99 years vs 65-74 years, 95% PI -26·4 to 7·4). INTERPRETATION: Large interjurisdictional variation in both use and time to radiotherapy initiation were observed, alongside large and variable age differences. To guide efforts to improve patient outcomes, underlying reasons for these differences need to be established. FUNDING: International Cancer Benchmarking Partnership (funded by the Canadian Partnership Against Cancer, Cancer Council Victoria, Cancer Institute New South Wales, Cancer Research UK, Danish Cancer Society, National Cancer Registry Ireland, The Cancer Society of New Zealand, National Health Service England, Norwegian Cancer Society, Public Health Agency Northern Ireland on behalf of the Northern Ireland Cancer Registry, DG Health and Social Care Scottish Government, Western Australia Department of Health, and Public Health Wales NHS Trust).

Revisiting the Calculation for a Novel Measure of Average Lifespan Shortened: Real-World Examples From Cervical and Ovarian Cancers in Alberta, Canada, 2000 - 2020.

In this technical note, we primarily demonstrate the computation of confidence limits for a novel measure of average lifespan shortened (ALSS). We identified women who had died from cervical and ovarian cancer between 2000 and 2020 from the Alberta cancer registry. Years of life lost (YLL) was calculated using the national life tables of Canada. We estimated the ALSS as a ratio of YLL in relation to the expected lifespan. We computed the confidence limits of the measure using various approaches, including the normal distribution, gamma distribution, and bootstrap method. The new ALSS measure shows a modest gain in lifespan of women, particularly women with ovarian cancer, over the study period.

Two Conserved Amino Acids Characterized in the Island Domain Are Essential for the Biological Functions of Brassinolide Receptors.

Brassinosteroids (BRs) play important roles in plant growth and development, and BR perception is the pivotal process required to trigger BR signaling. In angiosperms, BR insensitive 1 (BRI1) is the essential BR receptor, because its mutants exhibit an extremely dwarf phenotype in Arabidopsis. Two other BR receptors, BRI1-like 1 (BRL1) and BRI1-like 3 (BRL3), are shown to be not indispensable. All BR receptors require an island domain (ID) responsible for BR perception. However, the biological functional significance of residues in the ID remains unknown. Based on the crystal structure and sequence alignments analysis of BR receptors, we identified two residues 597 and 599 of AtBRI1 that were highly conserved within a BR receptor but diversified among different BR receptors. Both of these residues are tyrosine in BRI1, while BRL1/BRL3 fixes two phenylalanines. The experimental findings revealed that, except BRI1Y597F and BRI1Y599F, substitutions of residues 597 and 599 with the remaining 18 amino acids differently impaired BR signaling and, surprisingly, BRI1Y599F showed a weaker phenotype than BRI1Y599 did, implying that these residues were the key sites to differentiate BR receptors from a non-BR receptor, and the essential BR receptor BRI1 from BRL1/3, which possibly results from positive selection via gain of function during evolution.

Urinary Metabolomic Study in a Healthy Children Population and Metabolic Biomarker Discovery of Attention-Deficit/Hyperactivity Disorder (ADHD).

Objectives: Knowledge of the urinary metabolomic profiles of healthy children and adolescents plays a promising role in the field of pediatrics. Metabolomics has also been used to diagnose disease, discover novel biomarkers, and elucidate pathophysiological pathways. Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in childhood. However, large-sample urinary metabolomic studies in children with ADHD are relatively rare. In this study, we aimed to identify specific biomarkers for ADHD diagnosis in children and adolescents by urinary metabolomic profiling. Methods: We explored the urine metabolome in 363 healthy children aged 1-18 years and 76 patients with ADHD using high-resolution mass spectrometry. Results: Metabolic pathways, such as arachidonic acid metabolism, steroid hormone biosynthesis, and catecholamine biosynthesis, were found to be related to sex and age in healthy children. The urinary metabolites displaying the largest differences between patients with ADHD and healthy controls belonged to the tyrosine, leucine, and fatty acid metabolic pathways. A metabolite panel consisting of FAPy-adenine, 3-methylazelaic acid, and phenylacetylglutamine was discovered to have good predictive ability for ADHD, with a receiver operating characteristic area under the curve (ROC-AUC) of 0.918. A panel of FAPy-adenine, N-acetylaspartylglutamic acid, dopamine 4-sulfate, aminocaproic acid, and asparaginyl-leucine was used to establish a robust model for ADHD comorbid tic disorders and controls with an AUC of 0.918.

Characterization of LC-MS based urine metabolomics in healthy children and adults.

Previous studies reported that sex and age could influence urine metabolomics, which should be considered in biomarker discovery. As a consequence, for the baseline of urine metabolomics characteristics, it becomes critical to avoid confounding effects in clinical cohort studies. In this study, we provided a comprehensive lifespan characterization of urine metabolomics in a cohort of 348 healthy children and 315 adults, aged 1 to 78 years, using liquid chromatography coupled with high resolution mass spectrometry. Our results suggest that sex-dependent urine metabolites are much greater in adults than in children. The pantothenate and CoA biosynthesis and alanine metabolism pathways were enriched in early life. Androgen and estrogen metabolism showed high activity during adolescence and youth stages. Pyrimidine metabolism was enriched in the geriatric stage. Based on the above analysis, metabolomic characteristics of each age stage were provided. This work could help us understand the baseline of urine metabolism characteristics and contribute to further studies of clinical disease biomarker discovery.

In Vitro Degradation and Photoactivated Antibacterial Activity of a Hemin-CaP Microsphere-Loaded Coating on Pure Magnesium.

Photoactivated sterilization has received more attention in dealing with implant-associated infections due to its advantages of rapid and effective bacteriostasis and broad-spectrum antibacterial activity. Herein, a micro-arc oxidation (MAO)/polymethyltrimethoxysilane (PMTMS)@hemin-induced calcium-bearing phosphate microsphere (Hemin-CaP) coating was prepared on pure magnesium (Mg) via MAO processing and dipping treatments. The morphology and composition of the coating were characterized via scanning electron microscopy, Fourier transform infrared spectrometer, X-ray diffractometer and X-ray photoelectron spectrometer. Corrosion behavior was evaluated through electrochemical and hydrogen evolution tests. The release of Fe3+ ions at different immersion times was measured with an atomic absorption spectrophotometer. Antibacterial performance and cytotoxicity were assessed using the spread plate method, MTT assay and live/dead staining experiment. The results showed that the corrosion current density of the MAO/PMTMS@(Hemin-CaP) coating (4.41 × 10-8 A·cm-2) was decreased by two orders of magnitude compared to that of pure Mg (3.12 × 10-6 A·cm-2). Photoactivated antibacterial efficiencies of the Hemin-CaP microspheres and MAO/PMTMS@(Hemin-CaP) coating reached about 99% and 92%, respectively, which we attributed to the photothermal and photodynamic properties of hemin with a porphyrin ring. Moreover, based on the release of Fe3+ ions, the MC3T3-E1 pre-osteoblasts' viability reached up to 125% after a 72 h culture, indicating a positive effect of the coating in promoting cell growth. Thus, this novel composite coating holds a promising application as bone implants.

Soluble cytotoxic T-lymphocyte-associated antigen 4 (sCTLA-4) as a potential biomarker for diagnosis and evaluation of the prognosis in Glioma.

BACKGROUND: The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is widely considered as a pivotal immune checkpoint molecule to suppress antitumor immunity. However, the significance of soluble CTLA-4 (sCTLA-4) remains unclear in the patients with brain glioma. Here we aimed to investigate the significance of serum sCTLA-4 levels as a noninvasive biomarker for diagnosis and evaluation of the prognosis in glioma patients. METHODS: In this study, the levels of sCTLA-4 in serum from 50 patients diagnosed with different grade gliomas including preoperative and postoperative, and 50 healthy individuals were measured by an enzyme-linked immunosorbent assay (ELISA). And then ROC curve analysis and survival analyses were performed to explore the clinical significance of sCTLA-4. RESULTS: Serum sCTLA-4 levels were significantly increased in patients with glioma compared to that of healthy individuals, and which was also positively correlated with the tumor grade. ROC curve analysis showed that the best cutoff value for sCTLA-4 for glioma is 112.1 pg/ml, as well as the sensitivity and specificity with 82.0 and 78.0%, respectively, and a cut-off value of 220.43 pg/ml was best distinguished in patients between low-grade glioma group and high-grade glioma group with sensitivity 73.1% and specificity 79.2%. Survival analysis revealed that the patients with high sCTLA-4 levels (> 189.64 pg/ml) had shorter progression-free survival (PFS) compared to those with low sCTLA-4 levels (≤189.64 pg/ml). In the univariate analysis, elder, high-grade tumor, high sCTLA-4 levels and high Ki-67 index were significantly associated with shorter PFS. In the multivariate analysis, sCTLA-4 levels and tumor grade remained an independent prognostic factor. CONCLUSION: These findings indicated that serum sCTLA-4 levels play a critical role in the pathogenesis and development of glioma, which might become a valuable predictive biomarker for supplementary diagnosis and evaluation of the progress and prognosis in glioma.

A proteomic analysis of urine biomarkers in autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by early-onset social-communication challenges, restricted and repetitive behaviors, or unusual sensory-motor behaviors. A lack of specific biomarkers hinders the early diagnosis and treatment of this disease in many children. This study analyzes and validates potential urinary biomarkers using mass spectrometry proteomics. Global proteomics profiles of urine from 19 ASD patients and 19 healthy control subjects were compared to identify significantly changed proteins. These proteins were validated with targeted proteomics using parallel reaction monitoring (PRM) in an independent validation set consisting of samples from 40 ASD patients and 38 healthy controls. A total of 34 significantly changed proteins were found in the discovery set, among which seven proteins were identified as potential biomarkers for ASD through PRM assays in the validation set. Of these seven proteins, immunoglobulin kappa variable 4-1, immunoglobulin kappa variable 3-20, and immunoglobulin lambda variable 1-51 were up-regulated, while ATP synthase F1 subunit alpha, 10 kDa heat shock protein, apolipoprotein C-III, and arylsulfatase F were down-regulated. Six of these seven proteins support previous findings that ASD is accompanied by altered immune response and lipid metabolism, as well as mitochondrial dysfunction. This study lays the groundwork for additional research using biomarkers to clinically diagnose ASD. The proteomics and PRM raw data of this study have been deposited under the accession number IPX0002592000 at iProX. SIGNIFICANCE: This study identified 34 proteins in urine of ASD patients that were significantly changed from the urinary proteins of healthy subjects using LC-MS/MS-based proteomics in a discovery set. Seven of these proteins were validated by PRM analysis in an independent validation set. This report represents the first description of combined label-free quantitative proteomics and PRM analysis of targeted proteins for discovery of ASD urinary biomarkers. The results will be helpful for early diagnosis and can provide additional insight into the molecular mechanisms of ASD.

Lipolysis by downregulating miR-92a activates the Wnt/ß-catenin signaling pathway in hypoxic rats.

The aim of the present study was to investigate the role of miR-92a in lipid metabolism in hypoxic rats. Microarray analysis and reverse transcription-quantitative (RT-q)PCR were used to detect changes in the mRNA expression levels of miR-92a in the epididymal fat of hypoxic and normoxic rats. The downstream target mRNA of miR-92a was predicted using bioinformatics analysis and verified using a dual luciferase reporter assay. Changes in the expression of frizzled (Fzd)10 and c-Myc in the epididymal fat were detected using RT-qPCR and western blotting. Microarray analysis and RT-qPCR results showed that the expression of miR-92a was significantly lower in the fat tissues of the hypoxic rats compared with the normoxic rats. The results of the dual luciferase reporter assay showed that the target gene of miR-92a was Fzd10, which is an acceptor in the Wnt pathway. Fzd10 expression was upregulated in the hypoxic rats. The mRNA expression levels of c-Myc, which is located downstream of the Wnt pathway, was increased significantly. The increase in the mRNA and protein expression levels of Fzd10 and c-Myc may be associated with miR-92a downregulation. Downregulation of miR-92a in-turn may result in lipolysis through the regulation of the Wnt/ß-catenin signaling pathway, and thus weight loss in the rats.

Bromide impairs the circadian clock and glycolytic homeostasis via disruption of autophagy in rat H9C2 cardiomyocytes.

BACKGROUND: Trace elements function as essential cofactors that are involved in various biochemical processes in mammals. Autophagy is vital for nutrient supplement, which is an important Zeitegber for the circadian homeostasis in heart. Here, we considered the possibility that autophagy, as well as the cardiomyocyte clock and glycolysis are interlinked. Detrimental effects were observed when cardiac system is exposed to bromine containing drugs. This study investigated the effects and mechanisms of bromide on the circadian clock and glycolytic metabolism of H9C2 cardiomyocytes. RESULTS: In the present study, bromide does not affect cell viability and apoptosis of H9C2 cardiomyocytes. Bromide dampens the clock and glycolytic (Hk2 and Pkm2) gene expression rhythmicity in a dose-dependent manner. Additionally, bromide inhibits autophagic process in H9C2 cardiomyocytes. In contrast, rapamycin (an autophagy inducer) dramatically restores the inhibitory effect of NaBr on the mRNA expression levels of clock genes (Bmal1, Cry1 and Rorα) and glycolytic genes (Hk2 and Pkm2). CONCLUSIONS: Our results reveal that bromide represses the clock and glycolytic gene expression patterns, partially through inhibition of autophagy.

Establishment of rapid risk assessment model for cigarette smoke extract exposure in chronic obstructive pulmonary disease.

Rapid risk assessment models for different types of cigarette smoke extract (CSE) exposure are critical to understanding the etiology of chronic obstructive pulmonary disease. The present study investigated inflammation of cultured tracheal tissues with CSE exposure. Rat trachea rings were isolated, cultured, then exposed to various concentrations of CSE from 3R4 F reference cigarettes for 4 h. Tissue/cellular morphology, ultrastructure, viability and damage, inflammatory cell infiltration, and inflammatory protein levels were measured and compared to untreated controls. Human bronchial epithelial cells (BEAS-2B) exposed to 0 or 300 µg/mL CSE were cocultured with macrophages to assess extent of mobilization and phagocytosis. Endotracheal epithelium cilia densities were significantly reduced with increasing CSE concentrations, while mucous membranes became increasingly disordered; both eventually disappeared. Macrophages became larger as the CSE concentration increased, with microvilli and extended pseudopodium covering their surface, and many primary and secondary lysosomes present in the cytoplasm. Inflammatory cell infiltration also increased with increasing CSE dose, as did intracellular adhesion molecule-1(ICAM-1), interleukin-6(IL-6). The method described here may be useful to qualitatively characterized the effects of the compound under study. Then, we use BEAS-2B cell line system to strength the observation made in the cultured tissues. Probably, an approach to integrate results from both experiments will facilitate its application. These results demonstrate that cultured rat tracheal rings have a whole-tissue structure that undergoes inflammatory processes similar to in vivo tissues upon CSE exposure.

Establishment of a Han Chinese-specific pharmacogenetic-guided warfarin dosing algorithm.

Warfarin is the most common oral anticoagulant. Because of a narrow therapeutic range, interindividual differences in drug responses, and the risk of bleeding, there are many challenges in using warfarin. We need to predict the warfarin maintenance dose. However, ethnic-specific algorithms may be required, and some Chinese algorithms do not perform adequately. Therefore, we aimed to establish a Han Chinese appropriate algorithm.We recruited a study group consisting of 361 Han Chinese patients receiving warfarin treatment who had heart valve replacements. Genotyping of 38 single nucleotide polymorphisms (SNPs) in 13 candidate genes was carried out using the MassARRAY. In the derivation cohort, a multiple linear regression model was constructed to predict the warfarin dosage. We evaluated the accuracy of our algorithm in the validation cohort and compared it with the other 5 algorithms based on Han Chinese and other races.We established a Han Chinese-specific pharmacogenetic-guided warfarin dosing algorithm. Warfarin maintenance dosage (mg/day) = 1.787 - 0.023 × (Age) + 1.151 × (BSA [m]) + 0.917 × (VKORC1 AG) + 4.619 × (VKORC1 GG) + 0.595 × (CYP4F2 TT) + 0.707 × (CYP2C19 CC). It explained 58.3% of the variance in warfarin doses in Han Chinese patients and was superior to the other 5 algorithms. The ability of the 6 algorithms which estimate the required dose correctly was tested. Our model had a mean absolute error of 0.74 mg/day, the other 5 models have mean absolute error of 0.81 mg/day,1.05 mg/day, 1.24 mg/day, 1.18 mg/day, and 0.85 mg/day, respectively. Our model had a mean percentage error of 26.9%, the other 5 models have the mean percentage error of 27.7%, 27.2%, 52.3%, 45.7%, and 29.3%, respectively.Physicians can not adopt algorithm from other race directly to predict warfarin dose in patients with heart valve replacements, they should establish a new algorithm or adjust another algorithm to fit their patients. The algorithm established in this study has the potential to assist physicians in determining warfarin doses that are close to the appropriate doses.

Antithrombotic therapy strategies for atrial fibrillation patients undergoing percutaneous coronary intervention: A systematic review and network meta-analysis.

OBJECTIVE: The aim of this systematic review and network meta-analysis was to evaluate the comparative efficacy and safety of antiplatelet agents, vitamin K antagonist (VKA) and non-VKA oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). METHODS: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched to identify clinical trials comparing antiplatelet drugs with VKA and NOACs or their combination in AF patients undergoing PCI with a mean/median follow-up of at least 12 months. A network meta-analysis was conducted to directly and indirectly compare the efficacy and safety of competitive antithrombotic regimens with a Bayesian random-effects model. Results were presented as relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: A total of 15 studies enrolling 13,104 patients were included. Among 5 regimens, rivaroxaban 15 mg daily plus P2Y12 inhibitor treatment demonstrated significant superiority over dual- and triple-antiplatelet therapies (DAPT, TT) in reducing thromboembolic events (0.64 [0.38, 0.95] and 0.68 [0.43, 0.98], respectively) but showed the maximum possibility of major bleeding risk, while VKA plus single antiplatelet therapy (SAPT) seemed the safest. Significantly less risk of major bleeding was seen in DAPT group than that in TT group (0.63 [0.39, 0.99]). CONCLUSIONS: The present study suggests that combination of VKA and SAPT is the best choice for AF patients undergoing PCI considering both efficacy and safety. Rivaroxaban 2.5 mg twice daily plus DAPT treatment owns the highest probability to be the optimal alternative to VKA plus SAPT for these patients.

High-Throughput, Multiplex Genotyping Directly from Blood or Dried Blood Spot without DNA Extraction for the Screening of Multiple G6PD Gene Variants at Risk for Drug-Induced Hemolysis.

Clinical or epidemiologic screening of single-nucleotide polymorphism markers requires large-scale multiplexed genotyping. Available genotyping tools require DNA extraction and multiplex PCR, which may limit throughput and suffer amplification bias. Herein, a novel genotyping approach has been developed, multiplex extension and ligation-based probe amplification (MELPA), which eliminates DNA extraction and achieves uniform PCR amplification. MELPA lyses blood or dried blood spot and directly captures specific target DNA to 96-well plates using tailed probes. Subsequent enzymatic extension and ligation form target single-nucleotide polymorphism-spanning single-stranded templates, which are PCR-amplified using universal primers. Multiplexed genotyping by single-base primer extension is analyzed by mass spectrometry, with a call rate >97%. MELPA was compared with a commercial assay (iPLEX) for detecting 24 G6PD variants known to be at risk for primaquine-induced hemolysis. MELPA provided results that were more reliable than iPLEX, with higher throughput and lower cost. Genotyping archival blood from 106 malaria patients taking primaquine found 10 G6PD-deficient variants, including 1 patient with a hemizygous Mahidol mutation who had hemolysis. Preemptive G6PD genotyping of 438 dried blood spots from a malaria-endemic area identified three variants. MELPA also enabled pooled genotyping without diluting rare alleles, in which undesired common-allele background increased by sample pooling can be repressed by adding specific common allele blockers. Thus, MELPA represents a high-throughput, cost-effective approach to targeted genotyping at the population level.

Jatrorrhizine hydrochloride attenuates hyperlipidemia in a high-fat diet-induced obesity mouse model.

Jatrorrhizine hydrochloride (JH) is an active component of the traditional Chinese herb Coptis chinensis, which has been used to prevent and treat metabolic disorders. Hyperlipidemia is one of the principal factors underlying numerous metabolic diseases, including diabetes and obesity. Therefore, the aim of the present study was to investigate the lipid lowering effects of JH treatment in vivo in an obesity mouse model. JH-treated hyperlipidemic mice exhibited a reduction in body weight, as well as improved glucose tolerance and insulin sensitivity. In addition, JH­treated hyperlipidemic mice exhibited reduced serum triglyceride, total cholesterol and low­density lipoprotein cholesterol levels, as well as increased high­density lipoprotein cholesterol levels compared with untreated mice fed a high­fat diet. Notably, JH treatment ameliorated the pathophysiological changes observed in the livers of hyperlipidemic mice. At the molecular level, JH downregulated the hepatic mRNA expression levels of SREBP­1c and FAS, and induced PPAR­α and CPT1A mRNA expression in hyperlipidemic mice. These findings suggest that JH ameliorates hyperlipidemia via the suppression of lipogenesis and the enhancement of lipid oxidation in the liver.

Capture and Ligation Probe-PCR (CLIP-PCR) for Molecular Screening, with Application to Active Malaria Surveillance for Elimination.

BACKGROUND: Malaria control programs have achieved remarkable success during the past decade. Nonetheless, sensitive and affordable methods for active screening of malaria parasites in low-transmission settings remain urgently needed. METHODS: We developed a molecular screening method, capture and ligation probe-PCR (CLIP-PCR), which achieved the sensitivity of reverse-transcription PCR but eliminated the reliance on RNA purification and reverse transcription. In this method, 18S rRNA of genus Plasmodium is released from blood, captured onto 96-well plates, and quantified by the amount of ligated probes that bind continuously to it. We first used laboratory-prepared samples to test the method across a range of parasite densities and pool sizes, then applied the method to an active screening of 3358 dried blood spot samples collected from 3 low-endemic areas in China. RESULTS: Plasmodium falciparum diluted in whole blood lysate could be detected at a concentration as low as 0.01 parasites/µL, and a pool size of ≤36 did not significantly affect assay performance. When coupled with a matrix pooling strategy, the assay drastically increased throughput to thousands of samples per run while reducing the assay cost to cents per sample. In the active screening, CLIP-PCR identified 14 infections, including 4 asymptomatic ones, with <500 tests, costing

Quantitative survey of multiple CpGs from 5 genes identifies CpG methylation panel discriminating between high- and low-grade cervical intraepithelial neoplasia.

BACKGROUND: Studies of methylation biomarkers for cervical cancer often involved only few randomly selected CpGs per candidate gene analyzed by methylation-specific PCR-based methods, with often inconsistent results from different laboratories. We evaluated the role of different CpGs from multiple genes as methylation biomarkers for high-grade cervical intraepithelial neoplasia (CIN). RESULTS: We applied a mass spectrometry-based platform to survey the quantitative methylation levels of 34 CpG units from SOX1, PAX1, NKX6-1, LMX1A, and ONECUT1 genes in 100 cervical formalin-fixed paraffin-embedded (FFPE) tissues. We then used nonparametric statistics and Random Forest algorithm to rank significant CpG methylations and support vector machine with 10-fold cross validation and 200 times bootstrap resampling to build a predictive model separating CIN II/III from CIN I/normal subjects. We found only select CpG units showed significant differences in methylation between CIN II/III and CIN I/normal groups, while mean methylation levels per gene were similar between the two groups for each gene except PAX1. An optimal classification model involving five CpG units from SOX1, PAX1, NKX6-1, and LMX1A achieved 81.2% specificity, 80.4% sensitivity, and 80.8% accuracy. CONCLUSIONS: Our study suggested that during CIN development, the methylation of CpGs within CpG islands is not uniform, with varying degrees of significance as biomarkers. Our study emphasizes the importance of not only methylated marker genes but also specific CpGs for identifying high-grade CINs. The 5-CpG classification model provides a promising biomarker panel for the early detection of cervical cancer.