Development, validation, and evaluation of a risk assessment tool for personalized screening of gastric cancer in Chinese populations.

BACKGROUND: Effective risk prediction models are lacking for personalized endoscopic screening of gastric cancer (GC). We aimed to develop, validate, and evaluate a questionnaire-based GC risk assessment tool for risk prediction and stratification in the Chinese population. METHODS: In this three-stage multicenter study, we first selected eligible variables by Cox regression models and constructed a GC risk score (GCRS) based on regression coefficients in 416,343 subjects (aged 40-75 years) from the China Kadoorie Biobank (CKB, development cohort). In the same age range, we validated the GCRS effectiveness in 13,982 subjects from another independent Changzhou cohort (validation cohort) as well as in 5348 subjects from an endoscopy screening program in Yangzhou. Finally, we categorized participants into low (bottom 20%), intermediate (20-80%), and high risk (top 20%) groups by the GCRS distribution in the development cohort. RESULTS: The GCRS using 11 questionnaire-based variables demonstrated a Harrell's C-index of 0.754 (95% CI, 0.745-0.762) and 0.736 (95% CI, 0.710-0.761) in the two cohorts, respectively. In the validation cohort, the 10-year risk was 0.34%, 1.05%, and 4.32% for individuals with a low (≤ 13.6), intermediate (13.7~30.6), and high (≥ 30.7) GCRS, respectively. In the endoscopic screening program, the detection rate of GC varied from 0.00% in low-GCRS individuals, 0.27% with intermediate GCRS, to 2.59% with high GCRS. A proportion of 81.6% of all GC cases was identified from the high-GCRS group, which represented 28.9% of all the screened participants. CONCLUSIONS: The GCRS can be an effective risk assessment tool for tailored endoscopic screening of GC in China. Risk Evaluation for Stomach Cancer by Yourself (RESCUE), an online tool was developed to aid the use of GCRS.

Model-based risk assessment of dengue fever transmission in Xiamen City, China.

Background: Quantitative assessment of the risk of local transmission from imported dengue cases makes a great challenge to the development of public health in China. The purpose of this study is to observe the risk of mosquito-borne transmission in Xiamen City through ecological and insecticide resistance monitoring. Quantitative evaluation of mosquito insecticide resistance, community population and the number of imported cases affecting the transmission of dengue fever (DF) in Xiamen was carried out based on transmission dynamics model, so as to reveal the correlation between key risk factors and DF transmission. Methods: Based on the dynamics model and combined with the epidemiological characteristics of DF in Xiamen City, a transmission dynamics model was built to simulate the secondary cases caused by imported cases to evaluate the transmission risk of DF, and to explore the influence of mosquito insecticide resistance, community population and imported cases on the epidemic situation of DF in Xiamen City. Results: For the transmission model of DF, when the community population is between 10,000 and 25,000, changing the number of imported DF cases and the mortality rate of mosquitoes will have an impact on the spread of indigenous DF cases, however, changing the birth rate of mosquitoes did not gain more effect on the spread of local DF transmission. Conclusions: Through the quantitative evaluation of the model, this study determined that the mosquito resistance index has an important influence on the local transmission of dengue fever caused by imported cases in Xiamen, and the Brayton index can also affect the local transmission of the disease.

Erratum: Improved accuracy of cerebral blood flow quantification in the presence of systemic physiology cross-talk using multi-layer Monte Carlo modeling.

[This corrects the article DOI: 10.1117/1.NPh.8.1.015001.].

Liquid biopsy posttreatment surveillance in endemic nasopharyngeal carcinoma: a cost-effective strategy to integrate circulating cell-free Epstein-Barr virus DNA.

BACKGROUND: The optimal posttreatment surveillance strategy for nasopharyngeal carcinoma (NPC) remains unclear. Circulating cell-free Epstein-Barr virus (cfEBV) DNA has been recognized as a promising biomarker to facilitate early detection of NPC recurrence. Therefore, we aim to determine whether integrating circulating cfEBV DNA into NPC follow-up is cost-effective. METHODS: For each stage of asymptomatic nonmetastatic NPC patients after complete remission to primary NPC treatment, we developed a Markov model to compare the cost-effectiveness of the following surveillance strategies: routine follow-up strategy, i.e., (1) routine clinical physical examination; routine imaging strategies, including (2) routine magnetic resonance imaging plus computed tomography plus bone scintigraphy (MRI + CT + BS); and (3) routine 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT); cfEBV DNA-guided imaging strategies, including (4) cfEBV DNA-guided MRI + CT + BS and (5) cfEBV DNA-guided PET/CT. Clinical probabilities, utilities, and costs were derived from published studies or databases. Sensitivity analyses were performed. RESULTS: For all disease stages, cfEBV DNA-guided imaging strategies demonstrated similar survival benefits but were considerably more economical than routine imaging strategies. They only required approximately one quarter of the number of imaging studies compared with routine imaging strategies to detect one recurrence. Specifically, cfEBV DNA-guided MRI + CT + BS was most cost-effective for stage II (incremental cost-effectiveness ratio [ICER] $57,308/quality-adjusted life-year [QALY]) and stage III ($46,860/QALY) patients, while cfEBV DNA-guided PET/CT was most cost-effective for stage IV patients ($62,269/QALY). However, routine follow-up was adequate for stage I patients due to their low recurrence risk. CONCLUSIONS: The cfEBV DNA-guided imaging strategies are effective and cost-effective follow-up methods in NPC. These liquid biopsy-based strategies offer evidence-based, stage-specific surveillance modalities for clinicians and reduce disease burden for patients.

Improved accuracy of cerebral blood flow quantification in the presence of systemic physiology cross-talk using multi-layer Monte Carlo modeling.

Significance: Contamination of diffuse correlation spectroscopy (DCS) measurements of cerebral blood flow (CBF) due to systemic physiology remains a significant challenge in the clinical translation of DCS for neuromonitoring. Tunable, multi-layer Monte Carlo-based (MC) light transport models have the potential to remove extracerebral flow cross-talk in cerebral blood flow index ( CBF i ) estimates. Aim: We explore the effectiveness of MC DCS models in recovering accurate CBF i changes in the presence of strong systemic physiology variations during a hypercapnia maneuver. Approach: Multi-layer slab and head-like realistic (curved) geometries were used to run MC simulations of photon propagation through the head. The simulation data were post-processed into models with variable extracerebral thicknesses and used to fit DCS multi-distance intensity autocorrelation measurements to estimate CBF i timecourses. The results of the MC CBF i values from a set of human subject hypercapnia sessions were compared with CBF i values estimated using a semi-infinite analytical model, as commonly used in the field. Results: Group averages indicate a gradual systemic increase in blood flow following a different temporal profile versus the expected rapid CBF response. Optimized MC models, guided by several intrinsic criteria and a pressure modulation maneuver, were able to more effectively separate CBF i changes from scalp blood flow influence than the analytical fitting, which assumed a homogeneous medium. Three-layer models performed better than two-layer ones; slab and curved models achieved largely similar results, though curved geometries were closer to physiological layer thicknesses. Conclusion: Three-layer, adjustable MC models can be useful in separating distinct changes in scalp and brain blood flow. Pressure modulation, along with reasonable estimates of physiological parameters, can help direct the choice of appropriate layer thicknesses in MC models.

An optimal posttreatment surveillance strategy for cancer survivors based on an individualized risk-based approach.

The optimal post-treatment surveillance strategy that can detect early recurrence of a cancer within limited visits remains unexplored. Here we adopt nasopharyngeal carcinoma as the study model to establish an approach to surveillance that balances the effectiveness of disease detection versus costs. A total of 7,043 newly-diagnosed patients are grouped according to a clinic-molecular risk grouping system. We use a random survival forest model to simulate the monthly probability of disease recurrence, and thereby establish risk-based surveillance arrangements that can maximize the efficacy of recurrence detection per visit. Markov decision-analytic models further validate that the risk-based surveillance outperforms the control strategies and is the most cost-effective. These results are confirmed in an external validation cohort. Finally, we recommend the risk-based surveillance arrangement which requires 10, 11, 13 and 14 visits for group I to IV. Our surveillance strategies might pave the way for individualized and economic surveillance for cancer survivors.

Myocardial hypertrophy is improved with berberine treatment via long non-coding RNA MIAT-mediated autophagy.

OBJECTIVES: This study aimed to evaluate berberine (BBR) effects on myocardial hypertrophy (MH) and associated mechanisms. METHODS: BBR effects on MH were evaluated in rats with constriction of abdominal aorta (CAA). qRT-PCR assay was used to measure MH-related genes, long non-coding RNAs (lncRNAs) and autophagy-related genes expressions. Western blot was performed to detect autophagy markers expression. Filamentous actin and phalloidin expressions were detected using immunofluorescence assay. KEY FINDINGS: BBR significantly attenuated CAA-induced MH and cardiomyocyte enlargement. CAA upregulated ß myosin heavy chain and atrial natriuretic peptide expressions in heart tissues, which was attenuated by BBR. BBR suppressed myocardial infarction associated transcript (MIAT) expression in rats with CAA. p62 mRNA expression was upregulated and beclin1 and autophagy related 5 were downregulated in CAA versus control groups. The effects were abolished by BBR. In vitro studies showed that BBR ameliorated angiotensin II-induced MH and attenuated Ang II-induced MIAT expression in H9C2 cells. Expressions of phosphorylated mTOR, phosphorylated AMPK and LC3 were upregulated in H9C2 cells after Ang II stimulation, and the effects were abolished by BBR. CONCLUSIONS: BBR exerted beneficial effects on MH induced by CCA, and the mechanisms were associated with decreased MIAT expression and enhanced autophagy.

Exploring glycogen biosynthesis through Monte Carlo simulation.

Glycogen, a complex branched polymer of glucose (average chain length ~10 monomer units), is the blood-sugar reservoir in humans and other animals. Certain aspects of its molecular structure relevant to its biological functions are currently unamenable to experimental exploration. Knowledge of these is needed to develop future models for quantitative data-fitting to obtain mechanistic understanding of the biosynthetic processes that give rise to glycogen structure. Monte Carlo simulations of the biosynthesis of this structure with realistic macromolecular parameters reveal how chain growth and stoppage (the latter assumed to be through both the action of glycogen branching enzyme and other degradative enzymes, and by hindrance) control structural features. The simulated chain-length, pair-distance and radial density distributions agree semi-quantitatively with the limited available data. The simulations indicate that a steady state in molecular structure and size is rapidly obtained, that molecular density reaches a maximum near the center of the particle (not at the periphery, as is the case with dendrimers), and that particle size is controlled by both enzyme activity and hindrance. This knowledge will aid in the understanding of diabetes (loss of blood-sugar control), which has been found to involve subtle differences in glycogen molecular structure.

Differentiation of pancreatic carcinoma and mass-forming focal pancreatitis: qualitative and quantitative assessment by dynamic contrast-enhanced MRI combined with diffusion-weighted imaging.

Differentiation between pancreatic carcinoma (PC) and mass-forming focal pancreatitis (FP) is invariably difficult. For the differential diagnosis, we qualitatively and quantitatively assessed the value of dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted imaging (DWI) in PC and FP in the present study. This study included 32 PC and 18 FP patients with histological confirmation who underwent DCE-MRI and DWI. The time-signal intensity curve (TIC) of PC and FP were classified into 5 types according to the time of reaching the peak, namely, type I, II, III, IV, and V, respectively, and two subtypes, namely, subtype-a (washout type) and subtype-b (plateau type) according to the part of the TIC profile after the peak. Moreover, the mean and relative apparent diffusion coefficient (ADC) value between PC and FP on DWI were compared. The type V TIC was only recognized in PC group (P < 0.01). Type IV b were more frequently observed in PC (P = 0.036), while type- IIa (P < 0.01), type- Ia (P = 0.037) in FP. We also found a significant difference in the mean and relative ADC value between PC and FP. The combined image set of DCE-MRI and DWI yielded an excellent sensitivity, specificity, and diagnostic accuracy (96.9%, 94.4%, and 96.0%). The TIC of DCE-MRI and ADC value of DWI for pancreatic mass were found to provide reliable information in differentiating PC from FP, and the combination of DCE-MRI and DWI can achieve a higher sensitivity, specificity, and diagnostic accuracy.

Three-dimensional Contrast-enhanced Ultrasound in Response Assessment for Breast Cancer: A Comparison with Dynamic Contrast-enhanced Magnetic Resonance Imaging and Pathology.

To compare the capabilities of three-dimensional contrast enhanced ultrasound (3D-CEUS) and dynamic contrast-enhanced magnetic resonance (DCE-MRI) in predicting the response to neoadjuvant chemotherapy (NAC) among breast cancer patients, 48 patients with unilateral breast cancer were recruited for 3D-CEUS and DCE-MRI examinations both before and after NAC; pathology was used to validate the results. This study was approved by the institutional review board, and written informed consent was obtained from each patient. Imaging feature changes and pathological vascularity response, including microvessel density (MVD) and vascular endothelial growth factor (VEGF), were calculated. Pathological complete response (pCR) and major histological response (MHR) were used as references. The 3D-CEUS score, DCE-MRI score, MVD and VEGF significantly decreased (P < 0.0001) after NAC. The correlations between Δ3D-CEUS and ΔDCE-MRI with pCR (r = 0.649, P < 0.0001; r = 0.639, P < 0.0001) and MHR (r = 0.863, P < 0.0001; r = 0.836, P < 0.0001) were significant. All scores showed significant differences between the pCR and non-pCR groups with folder changes of 0.1, 0.1, 2.4, and 2.3, respectively (P = 0.0001, <0.0001, <0.0001 and <0.0001). In conclusion, 3D-CEUS is effective in assessing the response of breast cancer patients undergoing NAC.

Cost-efficient FPGA implementation of basal ganglia and their Parkinsonian analysis.

The basal ganglia (BG) comprise multiple subcortical nuclei, which are responsible for cognition and other functions. Developing a brain-machine interface (BMI) demands a suitable solution for the real-time implementation of a portable BG. In this study, we used a digital hardware implementation of a BG network containing 256 modified Izhikevich neurons and 2048 synapses to reliably reproduce the biological characteristics of BG on a single field programmable gate array (FPGA) core. We also highlighted the role of Parkinsonian analysis by considering neural dynamics in the design of the hardware-based architecture. Thus, we developed a multi-precision architecture based on a precise analysis using the FPGA-based platform with fixed-point arithmetic. The proposed embedding BG network can be applied to intelligent agents and neurorobotics, as well as in BMI projects with clinical applications. Although we only characterized the BG network with Izhikevich models, the proposed approach can also be extended to more complex neuron models and other types of functional networks.

Laminar flow mediated continuous single-cell analysis on a novel poly(dimethylsiloxane) microfluidic chip.

A novel microfluidic chip with simple design, easy fabrication and low cost, coupled with high-sensitive laser induced fluorescence detection, was developed to provide continuous single-cell analysis based on dynamic cell manipulation in flowing streams. Making use of laminar flows, which formed in microchannels, single cells were aligned and continuously introduced into the sample channel and then detection channel in the chip. In order to rapidly lyse the moving cells and completely transport cellular contents into the detection channel, the angle of the side-flow channels, the asymmetric design of the channels, and the number, shape and layout of micro-obstacles were optimized for effectively redistributing and mixing the laminar flows of single cells suspension, cell lysing reagent and detection buffer. The optimized microfluidic chip was an asymmetric structure of three microchannels, with three microcylinders at the proper positions in the intersections of channels. The microchip was evaluated by detection of anticancer drug doxorubicin (DOX) uptake and membrane surface P-glycoprotein (P-gp) expression in single leukemia K562 cells. An average throughput of 6-8 cells min(-1) was achieved. The detection results showed the cellular heterogeneity in DOX uptake and surface P-gp expression within K562 cells. Our researches demonstrated the feasibility and simplicity of the newly developed microfluidic chip for chemical single-cell analysis.

Comparative assessment of detergent-based protocols for mouse lung de-cellularization and re-cellularization.

Several different detergent-based methods are currently being explored for de-cellularizing whole lungs for subsequent use as three-dimensional scaffolds for ex vivo lung tissue generation. However, it is not yet clear which of these methods may provide a scaffold that best supports re-cellularization and generation of functional lung tissue. Notably, the detergents used for de-cellularization activate matrix metalloproteinases that can potentially degrade extracellular matrix (ECM) proteins important for subsequent binding and growth of cells inoculated into the de-cellularized scaffolds. We assessed gelatinase activation and the histologic appearance, protein composition, and lung mechanics of the end product scaffolds produced with three different detergent-based de-cellularization methods utilizing either Triton-X 100/sodium deoxycholate (Triton/SDC), sodium dodecyl sulfate (SDS), or 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). There were significant differences both in gelatinase activation and in the retention of ECM and other intracellular proteins, assessed by immunohistochemistry, mass spectrometry, and western blotting as well as in airways resistance and elastance of lungs de-cellularized with the different methods. However, despite these differences, binding and initial growth following intratracheal inoculation with either bone marrow-derived mesenchymal stromal cells or with C10 mouse lung epithelial cells was similar between lungs de-cellularized with each method. Therefore despite differences in the structural composition of the de-cellularized lungs, initial re-cellularization does not appear significantly different between the three de-cellularization approaches studied.

Influence of osseointegration degree and pattern on resonance frequency in the assessment of dental implant stability using finite element analysis.

PURPOSE: Resonance frequency analysis (RFA) has been widely used to predict dental implant stability by assessing conditions surrounding the implant. The aim of this study was to investigate the influence of osseointegration degree and pattern on the resonance frequency of implant-bone structure by means of finite element analysis (FEA). MATERIALS AND METHODS: A basic FEA model was created to represent a titanium implant in a portion of the maxillary bone at the left first premolar region. This model was then used to compute the vibration behaviors for 5 osseointegration degrees and 8 osseointegration pattern models using modal and harmonic analysis. RESULTS: In the arbitrarily set osseointegration pattern models, a significant influence of osseointegration degree on the resonance frequency (P < .001) could be expressed as the linear function R2 = 0.99. No significant influence from the osseointegration pattern could be observed (P = .89). While the coronal-osseointegration model had a slightly higher resonance frequency than others and the apical-osseointegration model had the lowest, the difference between the highest and lowest value was within 5% (P = .51). In the randomly set osseointegration models, the osseointegration degree had a statistically significant influence on the resonance frequency (P < .001); the pattern of random osseointegration for a certain osseointegration degree had little influence. CONCLUSION: It seems that RFA can detect implant-stability changes related to the increase in osseointegration degree. However, careful consideration should be given to its use in predicting the stability in vivo of loss of osseointegration at the marginal bone.

Rapid quantitative determination and assessment of insulin in oil formulation by micellar electrokinetic capillary chromatography.

A rapid, simple and precise micellar electrokinetic capillary chromatrography (MEKC) with diode array detector had been developed to the determination of insulin in oil formulation. As the micelle-forming ampholytic surfactant, Labrasol was chosen for the separation and analysis of the hydrophobic insulin in oil formulation in this experiment. A buffer containing 10 mmol/ml Tris-HCl plus 10% acetonitrile (ACN) at pH 8.2 was used for running buffer. Samples and tested samples were successfully separated during 8 min with a good linear range(r>0.99) and a concentration detection limit of 0.01 mg/ml. Furthermore, quantitative determinations of insulin in oil formulation had been described and assessed after handled with different pre-treatment conditions to reveal the effect of pH, temperature and tryptic digestion.