Glucose Concentration in Regulating Induced Pluripotent Stem Cells Differentiation Toward Insulin-Producing Cells.

The generation of insulin-producing cells from human-induced pluripotent stem cells holds great potential for diabetes modeling and treatment. However, existing protocols typically involve incubating cells with un-physiologically high concentrations of glucose, which often fail to generate fully functional IPCs. Here, we investigated the influence of high (20 mM) versus low (5.5 mM) glucose concentrations on IPCs differentiation in three hiPSC lines. In two hiPSC lines that were unable to differentiate to IPCs sufficiently, we found that high glucose during differentiation leads to a shortage of NKX6.1+ cells that have co-expression with PDX1 due to insufficient NKX6.1 gene activation, thus further reducing differentiation efficiency. Furthermore, high glucose during differentiation weakened mitochondrial respiration ability. In the third iPSC line, which is IPC differentiation amenable, glucose concentrations did not affect the PDX1/NKX6.1 expression and differentiation efficiency. In addition, glucose-stimulated insulin secretion was only seen in the differentiation under a high glucose condition. These IPCs have higher KATP channel activity and were linked to sufficient ABCC8 gene expression under a high glucose condition. These data suggest high glucose concentration during IPC differentiation is necessary to generate functional IPCs. However, in cell lines that were IPC differentiation unamenable, high glucose could worsen the situation.

Simultaneous LC-MS determination of glucose regulatory peptides secreted by stem cell-derived islet organoids.

For studying stem cell-derived islet organoids (SC-islets) in an organ-on-chip (OoC) platform, we have developed a reversed-phase liquid chromatography-tandem mass spectrometry (RPLC-MS/MS) method allowing for simultaneous determination of insulin, somatostatin-14, and glucagon, with improved matrix robustness compared to earlier methodology. Combining phenyl/hexyl-C18 separations using 2.1 mm inner diameter LC columns and triple quadrupole mass spectrometry, identification and quantification were secured with negligible variance in retention time and quantifier/qualifier ratios, negligible levels of carryover (<2%), and sufficient precision (±10% RSD) and accuracy (±15% relative error) with and without use of an internal standard. The obtained lower limits of quantification were 0.2 µg/L for human insulin, 0.1 µg/L for somatostatin-14, and 0.05 µg/L for glucagon. The here-developed RPLC-MS/MS method showed that the SC-islets have an insulin response dependent on glucose concentration, and the SC-islets produce and release somatostatin-14 and glucagon. The RPLC-MS/MS method for these peptide hormones was compatible with an unfiltered offline sample collection from SC-islets cultivated on a pumpless, recirculating OoC (rOoC) platform. The SC-islets background secretion of insulin was not significantly different on the rOoC device compared to a standard cell culture well-plate. Taken together, RPLC-MS/MS method is well suited for multi-hormone measurements of SC-islets on an OoC platform.

Control of transverse mode in a He-Ne laser using an astigmatic resonator.

The realization of output of the controllable transverse mode in a laser resonator has always been the key problem in applications of lasers. At present, the theory of optical resonators for passive resonators is relatively mature, but the non-uniformity of gain media greatly affects the output of the laser transverse mode for astigmatic resonators in operation; especially for gas lasers, controllable high-order modes have not been studied. To realize the theory of an astigmatic passive resonator of a gas laser as a good approximation of an active resonator, this paper develops the theory of selecting the laser eigenmode through an astigmatic resonator, and verifies that the two-dimensional tilt of the cavity mirror can break the axial symmetry. Controllable output of the laser mode is realized in real time and conveniently for the first time, to the best of our knowledge. This scheme is not only common to all kinds of lasers, but also has important research significance for the high-order modes required for real-time and rapid regulation of gas lasers under operating conditions.

The Burden of Chronic Hepatitis C in China From 2004 to 2050: An Individual-Based Modeling Study.

The launch of new direct-acting antivirals (DAAs) is expected to substantially reduce the burden of hepatitis C virus (HCV) in China. However, the effect of these changes has not yet been modeled in China. Therefore, we aim to predict the burden of HCV-related diseases in China by simulating different scenarios that incorporate recent therapeutic advances of HCV and China's current screening strategy. We developed an individual-based microsimulation Markov model that simulated disease progression of HCV-infected patients in China from 2004 to 2050. We simulated four scenarios with different assumptions about treatment, including a natural history scenario, a pre-DAAs scenario, a DAA treatment for all patients with a METAVIR fibrosis score ≥F3 (DAAs [≥F3]) scenario, and a DAAs (≥F0) scenario. The introduction of DAAs is predicted to have great impacts on the burden of HCV in China, particularly under the DAAs (≥F0) scenario in which we rapidly expand DAAs to all HCV-infected patients (≥F0) in 2021. Under this scenario, prevalence of chronic HCV is expected to peak at 10.75 million (95% confidence interval [CI], 8.30-12.85) around 2020 and then decrease to 7.92 million (95% CI, 5.41-10.08) in 2050. Conclusion: If the future increasing burden of HCV-related diseases is to be averted, China needs to start launching the new DAA treatment and rapidly increase the number of patients treated. However, to maximize the benefits of new DAAs, expanded screening is necessary to identify more cases that require treatment in the short term. Without these changes, the HCV burden in China will remain high in the future.

Changing trends in viral hepatitis mortality in East and Southeast Asia between 1987 and 2015 and its prediction until 2030.

BACKGROUND & AIMS: Trends in long-term mortality rates for viral hepatitis in East and Southeast Asia have been rarely reported. The aim of our study was to explore the long-term trends in viral hepatitis mortality rates in East and Southeast Asian countries between 1987 and 2015 and provide predictions of mortality to 2030. METHODS: We obtained viral hepatitis mortality data from the WHO Mortality Database for six East and Southeast Asian countries between 1987 and 2015. We produced choropleth maps of viral hepatitis mortality rates in 1987 and 2015 in East and Southeast Asia to illustrate geographic variations. We made predictions of mortality rates for each included country until the year 2030 using a series of joinpoint models. RESULTS: Viral hepatitis mortality rates declined in China (the average annual percent change (AAPC) = -5.1%, 95% CI: -7.5, -2.6), Singapore (AAPC = -5.4%, 95% CI: -7.5, -3.2), and the Philippines (AAPC = -3.4%, 95% CI: -4.9, -1.8). In contrast, Japan, the Republic of Korea, and Malaysia have experienced increasing trends in mortality rates, followed by decreasing trends. Our predictions indicate that all countries will experience slight to moderate downward trends until 2030. CONCLUSION: Favourable decreasing trends have been noted in East and Southeast Asian countries, which may not only inform the control and management of viral hepatitis in this region but also guide the prevention of viral hepatitis deaths in another region with a similar viral hepatitis epidemic.

Patterns and Trends of Liver Cancer Incidence Rates in Eastern and Southeastern Asian Countries (1983-2007) and Predictions to 2030.

BACKGROUND & AIMS: We examined temporal trends in liver cancer incidence rates overall and by histological type from 1983 through 2007. We predict trends in liver cancer incidence rates through 2030 for selected Eastern and Southeastern Asian countries. METHODS: Data on yearly liver cancer incident cases by age group and sex were drawn from 6 major selected Eastern and Southeastern Asian countries or regions with cancer registries available in the CI5plus database, including China, Japan, Hong Kong Special Administrative Region (SAR), the Philippines, Singapore, and Thailand. We also analyzed data for the United States and Australia for comparative purposes. Age-standardized incidence rates were calculated and plotted from 1983 through 2007. Numbers of new cases and incidence rates were predicted through 2030 by fitting and extrapolating age-period-cohort models. RESULTS: The incidence rates of liver cancer have been decreasing, and decreases will continue in all selected Eastern and Southeastern Asian countries, except for Thailand, whose liver cancer incidence rate will increase due to the increasing incidence rate of intrahepatic cholangiocarcinomas. Even though the incidence rates of liver cancer are predicted to decrease in most Eastern and Southeastern Asian countries, the burden, in terms of new cases, will continue to increase because of population growth and aging. CONCLUSIONS: Based on an analysis of data from cancer registries from Asian countries, incidence rates of liver cancer are expected to decrease through 2030 in most Eastern and Southeastern Asian countries. However, in Thailand, the incidence rate of intrahepatic cholangiocarcinomas is predicted to increase, so health education programs are necessary.

Establishment and development of national community-based collaborative innovation demonstration areas to achieve the control target of hepatitis B in China.

BACKGROUND: The major infectious diseases of hepatitis B has constituted an acute public health challenge in China. An effective and affordable HBV control model is urgently needed. A national project of Community-based Collaborative Innovation HBV (CCI-HBV) demonstration areas has optimized the existing community healthcare resources and obtained initial results in HBV control. METHODS: Based on the existing community healthcare network, CCI-HBV project combined the community health management and health contract signing service for long-staying residents in hepatitis B screening. Moreover, HBV field research strategy was popularized in CCI-HBV areas. After screening, patients with seropositive results were enrolled in corresponding cohorts and received treatment at an early stage. And the uninfected people received medical supports including health education through new media, behavior intervention and HBV vaccinations. In this process, a cloud-based National Information Platform (NIP) was established to collect and store residents' epidemiological data. In addition, a special quality control team was set up for CCI project. RESULTS: After two rounds of screening, HBsAg positive rate dropped from 5.05% (with 5,173,003 people screened) to 4.57% (with 3,819,675 people screened), while the rate of new HBV infections was 0.28 per 100 person-years in the fixed cohorts of 2,584,322 people. The quality control team completed PPS sampling simultaneously and established the serum sample database with 2,800,000 serum samples for unified testing. CONCLUSIONS: CCI-HBV project has established a large-scale field research to conduct whole-population screening and intervention. We analyzed the HBsAg prevalence and new infection rate of HBV in the fixed population for the epidemic trend and intervention effect. The purpose of CCI-HBV project is to establish and evaluate a practical model of grid management and field strategy, to realize the new goal to control hepatitis B in China. To provide policymakers with a feasible model, our results are directly applicable. TRIAL REGISTRATION: The project was funded by the Major Projects of Science Research for the 11th and 12th five-year plans of China, entitled "The prevention and control of AIDS, viral hepatitis and other major infectious diseases", Grant Nos. 2009ZX10004901, 2011ZX10004901, 2013ZX10004904, 2014ZX10004007 and 2014ZX10004008.

Biomedical semantic indexing by deep neural network with multi-task learning.

BACKGROUND: Biomedical semantic indexing is important for information retrieval and many other research fields in bioinformatics. It annotates biomedical citations with Medical Subject Headings. In face of unbalanced category distribution in the training data, sampling methods are difficult to apply for semantic indexing task. RESULTS: In this paper, we present a novel deep serial multi-task learning model. The primary task treats the biomedical semantic indexing as a multi-label text classification issue that considers the relations of the labels. The auxiliary task is a regression task that predicts the MeSH number of the citation and provides hints for the network to make it converge faster. The experimental results on the BioASQ-Task5A open dataset show that our model outperforms the state-of-the-art solution "MTI", proposed by the US National Library of Medicine. Further, it not only achieves the highest precision among all the solutions in BioASQ-Task5A but also has faster convergence speed compared with some naive deep learning methods. CONCLUSIONS: Rather than parallel in an ordinary multi-task structure, the tasks in our model are serial and tightly coupled. It can achieve satisfied performance without any handcrafted feature.

Pneumonia Mortality in Children Aged <5 Years in 56 Countries: A Retrospective Analysis of Trends from 1960 to 2012.

BACKGROUND: Pneumonia is now the second leading cause of death for children aged <5 years worldwide. However, analyses of the long-term evolution of under-5 mortality from pneumonia are still scarce in the literature. We aimed to explore long-term trends of under-5 mortality from pneumonia in 56 countries from 1960 to 2012. METHODS: Data on under-5 mortality from pneumonia were extracted from the World Health Organization mortality database. Long-term trends were assessed for 56 countries and for 4 national income transition groups. We also used joinpoint regression analysis to detect distinct period segments of long-term trends and estimate the annual percent of changes of each period segment. RESULTS: The average mortality rate from pneumonia for children aged 0-4 years in 56 countries declined from 163.0 per 100000 children (95% confidence interval [CI], 119.4 to 212.8) in 1960 to 9.9 per 100000 children (95% CI, 6.4 to 13.4) in 2012, with an average annual percent of change of -5.6% (95% CI, -7.2% to -3.9%). The temporal trends of childhood mortality were different between national income transition groups. CONCLUSIONS: Our findings suggest a striking overall downward trend in under-5 mortality from pneumonia between 1960 and 2012. However, the rate and absolute terms of decline differ by national income transition group. These variable patterns between national income transition groups may inform further intervention setting and priority setting.

Worse than imagined: Unidentified virtual water flows in China.

The impact of virtual water flows on regional water scarcity in China had been deeply discussed in previous research. However, these studies only focused on water quantity, the impact of virtual water flows on water quality has been largely neglected. In this study, we incorporate the blue water footprint related with water quantity and grey water footprint related with water quality into virtual water flow analysis based on the multiregional input-output model of 2007. The results find that the interprovincial virtual flows accounts for 23.4% of China's water footprint. The virtual grey water flows are 8.65 times greater than the virtual blue water flows; the virtual blue water and grey water flows are 91.8 and 794.6 Gm3/y, respectively. The use of the indicators related with water quantity to represent virtual water flows in previous studies will underestimate their impact on water resources. In addition, the virtual water flows are mainly derived from agriculture, chemical industry and petroleum processing and the coking industry, which account for 66.8%, 7.1% and 6.2% of the total virtual water flows, respectively. Virtual water flows have intensified both quantity- and quality-induced water scarcity of export regions, where low-value-added but water-intensive and high-pollution goods are produced. Our study on virtual water flows can inform effective water use policy for both water resources and water pollution in China. Our methodology about virtual water flows also can be used in global scale or other countries if data available.

Generation of Human Embryonic Stem Cell Line Expressing zsGreen in Cholinergic Neurons Using CRISPR/Cas9 System.

Lineage specific human embryonic stem cell (hESC) reporter cell line is a versatile tool for biological studies on real time monitoring of differentiation, physiological and biochemical features of special cell types and pathological mechanism of disease. Here we report the generation of ChAT-zsGreen reporter hESC line that express zsGreen under the control of the choline acetyltransferase (ChAT) promoter using CRISPR (Clustered Regularly Interspersed Short Palindromic Repeats)/Cas9 system. We show that the ChAT-zsGreen hESC reporter cell lines retain the features of undifferentiated hESC. After cholinergic neuronal differentiation, cholinergic neurons were clearly labeled with green fluorescence protein (zsGreen). The ChAT-zsGreen reporter hESC lines are invaluable not only for the monitoring cholinergic neuronal differentiation but also for study physiological and biochemical hallmarks of cholinergic neurons.

Preparative agarose gel electrophoresis for reducing matrix interferences of organoid cell medium prior to LC-MS analysis of insulin.

Organoids are 3D cell cultures with microanatomies mimicking aspects of real organs, useful for e.g. animal-free studies of development, disease, and drug discovery. The cell medium of organoid models of Langerhans islets, regulating blood glucose levels by insulin secretion, can be analyzed by liquid chromatography-mass spectrometry (LC-MS). However, organoid medium complexity is a major challenge, as matrix interferences can reduce sensitivity and selectivity, even with optimized LC-MS conditions. By applying preparative agarose gel electrophoresis-electrodialysis (PGE-ED), we were able to decrease the cell medium background signal, allowing for reduced interferences affecting LC-MS analysis of human insulin.

Pump-Less, Recirculating Organ-on-Chip (rOoC) Platform to Model the Metabolic Crosstalk between Islets and Liver.

Type 2 diabetes mellitus (T2DM), obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD) are epidemiologically correlated disorders with a worldwide growing prevalence. While the mechanisms leading to the onset and development of these conditions are not fully understood, predictive tissue representations for studying the coordinated interactions between central organs that regulate energy metabolism, particularly the liver and pancreatic islets, are needed. Here, a dual pump-less recirculating organ-on-chip platform that combines human pluripotent stem cell (sc)-derived sc-liver and sc-islet organoids is presented. The platform reproduces key aspects of the metabolic cross-talk between both organs, including glucose levels and selected hormones, and supports the viability and functionality of both sc-islet and sc-liver organoids while preserving a reduced release of pro-inflammatory cytokines. In a model of metabolic disruption in response to treatment with high lipids and fructose, sc-liver organoids exhibit hallmarks of steatosis and insulin resistance, while sc-islets produce pro-inflammatory cytokines on-chip. Finally, the platform reproduces known effects of anti-diabetic drugs on-chip. Taken together, the platform provides a basis for functional studies of obesity, T2DM, and MASLD on-chip, as well as for testing potential therapeutic interventions.

Cell identity dynamics and insight into insulin secretagogues when employing stem cell-derived islets for disease modeling.

Stem cell-derived islets (SC-islets) are not only an unlimited source for cell-based therapy of type 1 diabetes but have also emerged as an attractive material for modeling diabetes and conducting screening for treatment options. Prior to SC-islets becoming the established standard for disease modeling and drug development, it is essential to understand their response to various nutrient sources in vitro. This study demonstrates an enhanced efficiency of pancreatic endocrine cell differentiation through the incorporation of WNT signaling inhibition following the definitive endoderm stage. We have identified a tri-hormonal cell population within SC-islets, which undergoes reduction concurrent with the emergence of elevated numbers of glucagon-positive cells during extended in vitro culture. Over a 6-week period of in vitro culture, the SC-islets consistently demonstrated robust insulin secretion in response to glucose stimulation. Moreover, they manifested diverse reactivity patterns when exposed to distinct nutrient sources and exhibited deviant glycolytic metabolic characteristics in comparison to human primary islets. Although the SC-islets demonstrated an aberrant glucose metabolism trafficking, the evaluation of a potential antidiabetic drug, pyruvate kinase agonist known as TEPP46, significantly improved in vitro insulin secretion of SC-islets. Overall, this study provided cell identity dynamics investigation of SC-islets during prolonged culturing in vitro, and insights into insulin secretagogues. Associated advantages and limitations were discussed when employing SC-islets for disease modeling.

Association between transforming growth factor-α polymorphism and ankylosing spondylitis: a meta-analysis update.

OBJECTIVES: The reported results of the relationship between genetic polymorphisms of tumor necrosis factor (TNF)-α -238, -308 locus and ankylosing spondylitis (AS) susceptibility are not always consistent. This article aims to perform a meta-analysis to collect all the relevant studies to date to further clarify the relationship between those genetic polymorphisms and AS. METHODS: A computer search was carried out up to September 2011 for literature pertaining to AS and TNF-α polymorphisms. RESULTS: Twenty-two articles were included, with 2,506 cases of AS and 3,023 normal controls. We searched for genotypes A allele vs. G allele, AA vs. GG + GA, and GA + AA vs. GG in a fixed/random-effects model. The effect summary odds ratios (ORs) and 95 % confidence intervals (CIs) were obtained, which shows there was no association between genetic polymorphisms and AS. As the heterogeneity was observed, in a subgroup analysis by ethnicity, the degree of risk of two genes with AS susceptibility was similar in populations of European and Asian origin. For the human leukocyte antigen (HLA)-B27+ population, results were not statistically significant. CONCLUSION: ORs of various comparisons indicate that there is no association between TNF-α -238, -308 polymorphisms and AS susceptibility in the overall population and in the subgroup of Asian and non-Asian descent.

Characterization of human stem cell-derived hepatic stellate cells and liver sinusoidal endothelial cells during extended in vitro culture.

Background: There is a significant need for predictive and stable in vitro human liver representations for disease modeling and drug testing. Hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs) are important non-parenchymal cell components of the liver and are hence of relevance in a variety of disease models, including hepatic fibrosis. Pluripotent stem cell- (PSC-) derived HSCs (scHSCs) and LSECs (scLSECs) offer an attractive alternative to primary human material; yet, the suitability of scHSCs and scLSECs for extended in vitro modeling has not been characterized. Methods: In this study, we describe the phenotypic and functional development of scHSCs and scLSECs during 14 days of 2D in vitro culture. Cell-specific phenotypes were evaluated by cell morphology, immunofluorescence, and gene- and protein expression. Functionality was assessed in scHSCs by their capacity for intracellular storage of vitamin A and response to pro-fibrotic stimuli induced by TGF-ß. scLSECs were evaluated by nitric oxide- and factor VIII secretion as well as endocytic uptake of bioparticles and acetylated low-density lipoprotein. Notch pathway inhibition and co-culturing scHSCs and scLSECs were separately tested as options for enhancing long-term stability and maturation of the cells. Results and Conclusion: Both scHSCs and scLSECs exhibited a post-differentiation cell type-specific phenotype and functionality but deteriorated during extended culture with PSC line-dependent variability. Therefore, the choice of PSC line and experimental timeframe is crucial when designing in vitro platforms involving scHSCs and scLSECs. Notch inhibition modestly improved long-term monoculture in a cell line-dependent manner, while co-culturing scHSCs and scLSECs provides a strategy to enhance phenotypic and functional stability.

Case report of atypical undernutrition of hypoproteinemia type.

Albumin and prealbumin serve as vital markers reflecting hepatic synthesis activity and overall body nutrient status. Hypoproteinemia can result from various etiological factors, with reduced blood inflow into the liver due to portal vein thrombosis being one such cause. However, literature addressing this specific association remains limited. This report presents an atypical case of malnutrition involving a patient who experienced prolonged hypoproteinemia attributable to a gradual decline in hepatic blood perfusion caused by progressive portal thrombosis and cavernous transformation of the portal vein (CTPV). The case encompasses an in-depth analysis of the factors contributing to undernutrition, the etiology and diagnosis of hypoproteinemia, and its clinical implications. Vigilance for the presence of hypoproteinemia is essential in the management of patients afflicted by progressive portal vein thrombosis complicated by CTPV. Timely and effective interventions aimed at rectifying hypoproteinemia can significantly enhance clinical outcomes. Moreover, reduced hepatic blood flow should be considered a plausible underlying cause in cases of unexplained hypoproteinemia, warranting thorough evaluation. This case underscores the importance of recognizing the intricate interplay between hepatic vascular pathology and protein homeostasis in clinical practice.

Determination of insulin secretion from stem cell-derived islet organoids with liquid chromatography-tandem mass spectrometry.

Organoids are laboratory-grown 3D organ models, mimicking human organs for e.g. drug development and personalized therapy. Islet organoids (typically 100-200 µm), which can be grown from the patient́s own cells, are emerging as prototypes for transplantation-based therapy of diabetes. Selective methods for quantifying insulin production from islet organoids are needed, but sensitivity and carry-over have been major bottlenecks in previous efforts. We have developed a reverse phase liquid chromatography-tandem mass spectrometry (RPLC-MS/MS) method for studying the insulin secretion of islet organoids. In contrast to our previous attempts using nano-scale LC columns, conventional 2.1 mm inner diameter LC column (combined with triple quadrupole mass spectrometry) was well suited for sensitive and selective measurements of insulin secreted from islet organoids with low microliter-scale samples. Insulin is highly prone to carry-over, so standard tubings and injector parts were replaced with shielded fused silica connectors. As samples were expected to be very limited, an extended Box-Behnken experimental design for the MS settings was conducted to maximize performance. The finale method has excellent sensitivity, accuracy and precision (limit of detection: ≤0.2 pg/µL, relative error: ≤±10%, relative standard deviation: <10%), and was well suited for measuring 20 µL amounts of Krebs buffer containing insulin secreted from islet organoids.

Association between MTHFR C677T polymorphism and osteonecrosis of the femoral head: a meta-analysis.

The results of studies on association between the C677T polymorphism of the 5,10-methylene-tetrahydrofolate reductase (MTHFR) gene and osteonecrosis of the femoral head (ONFH) are controversial. To derive a more precise estimation of the relationship between the MTHFR C677T polymorphism and ONFH, a meta-analysis was performed. Eight studies on MTHFR C677T association with ONFH were searched up to April 2011, and the genotype frequencies in control group were consistent with Hardy-Weinberg equilibrium. The effect summary odds ratio (OR) and 95% confidence intervals were obtained. Publication bias was tested by funnel plot, Egger's regression test, and heterogeneity was assessed. Eight studies containing 778 cases and 1,162 controls were included. Heterogeneity was observed (χ(2) = 18.58, P = 0.01). Under the random effects model, the common OR was 1.38 (95% CI: 0.92-2.08; P = 0.12). In the subgroup meta-analysis, there was an association between MTHFR C677T polymorphism and ONFH in non-Asian population for CT + TT vs. CC (OR = 1.72; 95% CI: 1.21-2.43; P = 0.002; I(2) = 37.9%, P = 0.17), but not for Asian population (OR = 0.88; 95% CI: 0.66-1.66; P = 0.35; I(2) = 45.4%, P = 0.16). There was heterogeneity between studies and no clear evidence of an association on a worldwide population. When stratifying for the race, this meta-analysis did not provide an evidence of confirming association between MTHFR C677T polymorphism and ONFH. The large sample and well-designed study based on different ethnic groups should be considered in future associated studies to clarify the association of MTHFR C677T polymorphism with ONFH susceptibility.

Is the linear modeling technique good enough for optimal form design? A comparison of quantitative analysis models.

How to design highly reputable and hot-selling products is an essential issue in product design. Whether consumers choose a product depends largely on their perception of the product image. A consumer-oriented design approach presented in this paper helps product designers incorporate consumers' perceptions of product forms in the design process. The consumer-oriented design approach uses quantification theory type I, grey prediction (the linear modeling technique), and neural networks (the nonlinear modeling technique) to determine the optimal form combination of product design for matching a given product image. An experimental study based on the concept of Kansei Engineering is conducted to collect numerical data for examining the relationship between consumers' perception of product image and product form elements of personal digital assistants (PDAs). The result of performance comparison shows that the QTTI model is good enough to help product designers determine the optimal form combination of product design. Although the PDA form design is used as a case study, the approach is applicable to other consumer products with various design elements and product images. The approach provides an effective mechanism for facilitating the consumer-oriented product design process.