Assessment of a novel variation in DHODH gene causing Miller syndrome: The first report in Chinese population.

BACKGROUND: Miller syndrome is a rare type of postaxial acrofacial dysostosis caused by biallelic mutations in the DHODH gene, which is characterized mainly by craniofacial malformations of micrognathia, orofacial clefts, cup-shaped ears, and malar hypoplasia, combined with postaxial limb deformities like the absence of fifth digits. METHODS: In this study, a prenatal case with multiple orofacial-limb abnormities was enrolled, and a thorough clinical and imaging examination was performed. Subsequently, genetic detection with karyotyping, chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) was carried out. In vitro splicing analysis was also conducted to clarify the impact of one novel variant. RESULTS: The affected fetus displayed typical manifestations of Miller syndrome, and WES identified a diagnostic compound heterozygous variation in DHODH, consisting of two variants: exon(1-3)del and c.819 + 5G > A. We conducted a further in vitro validation with minigene system, and the result indicated that the c.819 + 5G > A variant would lead to an exon skipping in mRNA splicing. CONCLUSIONS: These findings provided with the first exonic deletion and first splice site variant in DHODH, which expanded the mutation spectrum of Miller syndrome and offered reliable evidence for genetic counseling to the affected family.

Lifetime Risks, Life Expectancy, and Health Care Expenditures for Rheumatoid Arthritis: A Nationwide Cohort Followed Up From 2003 to 2016.

OBJECTIVE: This study was undertaken to estimate the cumulative incidence rate of rheumatoid arthritis (RA) in the Taiwanese population ages 16-84 years, and life expectancy, loss of life expectancy, and lifetime health care expenditures for incident RA in Taiwan after 2003, when biologics began to be prescribed. METHODS: We obtained all claims data for the period 1999 to 2016 from the National Health Insurance program of Taiwan, and validated the data against the Catastrophic Illness Registry to establish the study cohort. We estimated the survival function for RA and extrapolated to lifetime using a rolling-over algorithm. For every RA case, we simulated sex-, age-, and calendar year-matched referents from vital statistics and estimated their life expectancy. The difference between the life expectancy of the referent and the life expectancy of the RA patient was the loss of life expectancy for the RA patient. Average monthly health care expenditures were multiplied by the corresponding survival rates and summed up throughout the lifetime to calculate the lifetime health care expenditures. RESULTS: A total of 29,352 new RA cases were identified during 2003-2016. There was a decreasing trend in cumulative incidence rate in those ages 16-84 for both sexes. Mean life expectancy after diagnosis of RA was 26.3 years, and mean lifetime cost was $72,953. RA patients had a mean loss of life expectancy of 4.97 years. Women with RA survived 1-2 years longer than men with RA of the same age, which resulted in higher lifetime expenditures for the former. Since the life expectancy for women in Taiwan was 6-7 years higher than that for men, the loss of life expectancy for women with RA was higher than that for men with RA. Annual health care expenditures were similar for both sexes. CONCLUSION: Our findings indicate that since biologics became available, RA patients have lived longer and had higher lifetime expenditures, which should be monitored and evaluated for cost-effectiveness.

Real-world cost-effectiveness associated with infliximab maintenance therapy for moderate to severe Crohn's disease in China.

BACKGROUND: Infliximab was the first approved biologic treatment for moderate to severe Crohn's disease (MS-CD) in China. However, the cost-effectiveness of infliximab maintenance therapy (IMT) for MS-CD relative to conventional maintenance therapy remained unclarified. AIM: To assess the cost-effectiveness of IMT for MS-CD in Chinese patients from the perspective of Chinese public insurance payer. METHODS: A cohort of MS-CD patients managed in a Chinese tertiary care hospital was created to compare IMT with conventional maintenance therapy (CMT) for clinical outcomes and direct medical costs over a 1-year observation time using conventional regression analyses. A decision-analytic model with the generated evidence was constructed to assess the cost-effectiveness of IMT relative to CMT using reimbursed medical costs. RESULTS: Based on the included 389 patients, IMT was associated with significantly higher disease remission chance [odds ratio: 4.060, P = 0.003], lower risk of developing new complications (odds ratio: 0.527, P = 0.010), higher utility value for quality of life (coefficient 0.822, P = 0.008), and lower total hospital costs related to disease management (coefficient -0.378, P = 0.008) than CMT. Base-case cost-effectiveness analysis estimated that IMT could cost Chinese health insurance payers ¥55260 to gain one quality-adjusted life year (QALY). The cost-effectiveness of IMT was mainly driven by the estimate of quality of life, treatment efficacy of maintenance therapy, mortality risk associated with active disease, and unit price of infliximab. The probability that IMT was cost-effective at a willingness-to-pay threshold of three times gross domestic product [2018 Chinese gross domestic product per capita (GDPPC)] was 86.4%. CONCLUSION: IMT significantly improved real-world health outcomes and cost the Chinese public health insurance payers less than one GDPPC to gain one QALY in Chinese MS-CD patients.

Synthesis of recurrent neural dynamics for monotone inclusion with application to Bayesian inference.

We propose a top-down approach to construct recurrent neural circuit dynamics for the mathematical problem of monotone inclusion (MoI). MoI in a general optimization framework that encompasses a wide range of contemporary problems, including Bayesian inference and Markov decision making. We show that in a recurrent neural circuit/network with Poisson neurons, each neuron's firing curve can be understood as a proximal operator of a local objective function, while the overall circuit dynamics constitutes an operator-splitting system of ordinary differential equations whose equilibrium point corresponds to the solution of the MoI problem. Our analysis thus establishes that neural circuits are a substrate for solving a broad class of computational tasks. In this regard, we provide an explicit synthesis procedure for building neural circuits for specific MoI problems and demonstrate it for the specific case of Bayesian inference and sparse neural coding.

Assessment of groundwater quality and 222Rn distribution in the Xuzhou region, China.

Evaluation of groundwater quality represents significant input for the development and utilization of water resources. Increasing exploitation of groundwater and man-made pollution has seriously affected the groundwater quality of the North China Plain, such as in the Xuzhou region which is the target of this investigation. The assessment of the groundwater quality and sources in the region was based on analyses of water chemistry and 222Rn activity in samples collected from wells penetrating unconfined and confined aquifers. The results indicate that most of the untreated groundwater in the region is not suitable for the long-term drinking based on permissible limits of the Chinese Environmental Agency and the World Health Organization. However, the groundwater can be used as healthy source of drinking water when they can pass the biological test and softening water treatment. Most of the groundwater is suitable for irrigation. Excessive amounts of SO42- and NO3- are attributed to mainly influence of wastewater, irrigation, and dissolution of sulfate minerals in local coal strata. The major source of the groundwater is meteoric recharge with addition from irrigation and wastewater discharges. Variability of the water quality seems to be also reflecting the type of aquifers where the highest concentration of HCO3- occurs in water of the carbonate fractured aquifer, while the highest Cl- concentration in the unconfined aquifer. Source of 222Rn activity is mainly related to the rock-water interaction with possible addition from the agricultural fertilizers. Protection of groundwater is vital to maintain sustainable drinking quality through reducing infiltration of irrigation water and wastewater.

SO2 emission cap planning for Chengdu-Chongqing economic zone.

The SO2 emission sources of the Chengdu-Chongqing economic zone were divided into 556 emissions units according to four different categories, which are city, industry, point sources, and area sources. The CALPUFF model was used to calculate the contribution of each unit, and consequently obtain an influence-transferring matrix. To ensure that the SO2 concentrations of 46 cities and counties in the Chengdu-Chongqing economic zone meet air quality standards, an emission optimization model was developed to calculate optimal emissions of each emission unit under different development scenarios. The result showed the optimal emissions of SO2 by different provinces and industries. To achieve the target of restricting and optimizing development, corresponding planning programs were developed for every district.

Molecular origins of homogeneous crystal nucleation.

We review the molecular principles underlying the homogeneous nucleation of a crystal phase from the melt phase, as elucidated by molecular simulation methods. Classical nucleation theory serves as the starting point for describing the nature of nucleation processes, but it does not derive from molecular principles itself. Density functional theory and molecular simulations offer tools for delving into the molecular origins of nucleation. Here, we emphasize the rapid development of molecular simulation methodologies for studying crystal nucleation from the melt. These methodologies are broadly categorized as free energy sampling methods, dynamical or mean first-passage time methods, and composite approaches that take advantage of both. The crucial selection of order parameters to distinguish the crystal phase from the liquid phase and important features of the reaction coordinate are emphasized. The system size dependence of the nucleation free energy barrier is also examined.

[Assessment of correction effect in relation to fulcrum bending flexibility in adult idiopathic scoliosis patients].

OBJECTIVE: To study the relationship between the fulcrum bending flexibility (FBF) and correction rate (CR) of adult idiopathic scoliosis, and to explore the ability of FBF to assess the correction effect in relation to fulcrum bending flexibility. METHODS: 69 patients with adult idiopathic scoliosis with structural curves at thoracic or lumbarthoracic segments, 16 males and 53 females, aged 26.5 (19 - 53) were treated by pedicle screws instrumentation. Pre-operative standing and fulcrum bending films and postoperative standing X-ray film were taken. Cobb angle was measured. The data underwent regression analysis with the software SPSS 10.0. RESULTS: A regression formula was established: CR = 0.213 + 0.768 x FBF with P < 0.01. CONCLUSION: A definite linear relation exists between the FBF and CR of adult idiopathic scoliosis. By using the formula in proper samples, the effects of new instrumentation or correction technique can be objectively assessed.

[Assessment of flexibility in adolescent idiopathic scoliosis by curved planar reformation using multi-slice spiral CT scanning].

OBJECTIVE: To investigate the role of curved planar reformation (CPR) using multi-slice spiral CT scanning to evaluate the coronal and sagittal plane in scoliosis so as to affirm the features of supine coronal and sagittal plane in idiopathic scoliosis. METHODS: Thoracic and lumbar spine multi-slice spiral CT scanning was undertaken on 45 patients with adolescent idiopathic scoliosis (AIS), all female, age 10 - 18. CPR was used to reconstruct the spine coronal and sagittal planes respectively. The values of main curve and compensate curve Cobb angles were obtained and compared with those obtained by X-ray films. RESULTS: The average CPR coronal main curve Cobb angle was smaller by 10.17 degrees than that obtained by standing position film. The average CPR coronal compensate curve Cobb angle was smaller by 6.97 degrees than that obtained by standing position film. For scoliosis coronal flexibility assessment, fulcrum-bending method offered better surgical correction result than other methods. Only the post-operational Cobb angle was different between the 10 - 14 year-old group and 15 - 18 year-old group. Bending film showed differences in correction rate and flexibility rate between the main thoracic group and main lumbar/thoracolumbar group. The correction rate and flexibility rate of main curve and compensate curve of the 10 - 14 year-old group were significantly higher than those of the 15 - 18 year-old group. In the sagittal plane, the CPR thoracic kyphotic angle (T5-T12) and upper thoracic curve kyphosis of the main thoracic group were both smaller than those of the main lumbar/thoracolumbar group. The CPR thoracic kyphotic angle (T5-T12) of the 10 - 14 year-old group was significantly smaller than that of the 15 - 18 year-old group. Correlation analysis showed that the CPR main curve flexibility and bending film flexibility were positively corrected with the surgical correction rate. CONCLUSION: CPR using multi-slice spiral CT scanning is able to obtain multiple three-dimensional assessment by one scanning and is helpful in scoliosis curve type diagnosis and scoliosis 3D analysis.

[Assessment of curve flexibility in adolescent idiopathic scoliosis before operation].

OBJECTIVE: To compare the effects in assessing the curve flexibility of the adolescent idiopathic scoliosis (AIS) and predicting the outcomes of operation among different radiological techniques: supine lateral bending (SB), traction (Tr), and fulcrum bending radiographs. METHODS: 68 consecutive AIS patients, all with the single-curve types Ia/Ib/Ic according to the PUMC classification, divided into 4 groups according to the magnitude of Cobb's angle: moderate thoracic curve (n = 19, 40 degrees < Cobb's angle < or = 60 degrees ), severe thoracic curve (n = 13, Cobb's angle > 60 degrees ), moderate lumbar curve (n = 28, 35 degrees < Cobb's angle < or = 60 degrees ), and severe lumbar curve(n = 8, Cobb's angle > 60 degrees ) who were treated surgically underwent preoperative radiological evaluation including standing anteroposterior and lateral Tr, SB, and fulcrum bending radiographs. COBB angle was measured and the flexibility ratio was determined on each radiograph. The amounts of correction obtained by all radiographic methods were compared with the amount of surgical correction. RESULTS: The post-operative Cobb's angle of the moderate thoracic curve group was 9 degrees , not significantly different from that by fulcrum bending radiograph (P = 0.076), but significantly different from those by the other methods (both P < 0.01). The post-operative COBB angle of the severe thoracic curve group was 40 degrees , significantly different from all the radiographs before operation (all P < 0.01). The post-operative Cobb's angle of the moderate lumbar curve group was 4 degrees , significantly different from those by fulcrum bending and Tr radiographs (both P < 0.01) and that by SB (P = 0.013). The post-operative Cobb's angle of the severe lumbar curve group was 24 degrees , significantly different from those of anteroposterior and Tr radiograph (both P < 0.01) and those of fulcrum-bending and SB radiographs (P = 0.021 and P = 0.011). In the moderate thoracic curve group the operation correction rate was not significantly different from the flexibility rate by fulcrum-bending radiograph (P = 0.111), and was significantly different from the flexibility rates by SB and Tr radiographs (P = 0.011 and P = 0.000). In the severe thoracic curve group the operation correction rate was significantly different from the flexibility rates by different kinds of radiograph (all P = 0.111). In the moderate lumbar curve group the operation correction rate was significantly different from the flexibility rates by different kinds of radiograph (P < 0.111 or P = 0.019). In the severe lumbar curve group the operation correction rate was significantly different from the flexibility rates by different kinds of radiograph (P < 0.01 or P = 0.017). CONCLUSION: Fulcrum-bending radiography can better assess the flexibility and correction rate of thoracic curves in AIS, however, it can only predict those in moderate thoracic curves. Fulcrum-bending radiograph and SB radiograph are similar in predicting the flexibility in lumbar curves.