Nuclear PGK1 Alleviates ADP-Dependent Inhibition of CDC7 to Promote DNA Replication.

DNA replication is initiated by assembly of the kinase cell division cycle 7 (CDC7) with its regulatory activation subunit, activator of S-phase kinase (ASK), to activate DNA helicase. However, the mechanism underlying regulation of CDC7-ASK complex is unclear. Here, we show that ADP generated from CDC7-mediated MCM phosphorylation binds to an allosteric region of CDC7, disrupts CDC7-ASK interaction, and inhibits CDC7-ASK activity in a feedback way. EGFR- and ERK-activated casein kinase 2α (CK2α) phosphorylates nuclear phosphoglycerate kinase (PGK) 1 at S256, resulting in interaction of PGK1 with CDC7. CDC7-bound PGK1 converts ADP to ATP, thereby abrogating the inhibitory effect of ADP on CDC7-ASK activity, promoting the recruitment of DNA helicase to replication origins, DNA replication, cell proliferation, and brain tumorigenesis. These findings reveal an instrumental self-regulatory mechanism of CDC7-ASK activity by its kinase reaction product ADP and a nonglycolytic role for PGK1 in abrogating this negative feedback in promoting tumor development.

Informing Urban Flood Risk Adaptation by Integrating Human Mobility Big Data During Heavy Precipitation.

Understanding the impact of heavy precipitation on human mobility is critical for finer-scale urban flood risk assessment and achieving sustainable development goals #11 to build resilient and safe cities. Using ∼2.6 million mobile phone signal data collected during the summer of 2018 in Jiangsu, China, this study proposes a novel framework to assess human mobility changes during rainfall events at a high spatial granularity (500 m grid cell). The fine-scale mobility map identifies spatial hotspots with abnormal clustering or reduced human activities. When aggregating to the prefecture-city level, results show that human mobility changes range between -3.6 and 8.9%, revealing varied intracity movement across cities. Piecewise structural equation modeling analysis further suggests that city size, transport system, and crowding level directly affect mobility responses, whereas economic conditions influence mobility through multiple indirect pathways. When overlaying a historical urban flood map, we find such human mobility changes help 23 cities reduce 2.6% flood risks covering 0.45 million people but increase a mean of 1.64% flood risks in 12 cities covering 0.21 million people. The findings help deepen our understanding of the mobility pattern of urban dwellers after heavy precipitation events and foster urban adaptation by supporting more efficient small-scale hazard management.

Water Scarcity Assessment of Hydropower Plants in China under Climate Change, Sectoral Competition, and Energy Expansion.

Hydropower plays a pivotal role in low-carbon electricity generation, yet many projects are situated in regions facing heightened water scarcity risks. This research devised a plant-level Hydropower Water Scarcity Index (HWSI), derived from the ratio of water demand for electricity generation to basin-scale available runoff water. We assessed the water scarcity of 1736 hydropower plants in China for the baseline year 2018 and projected into the future from 2025 to 2060. The results indicate a notable increase in hydropower generation facing moderate to severe water scarcity (HWSI >0.05), rising from 10% in 2018 to 24-34% of the national total (430-630 TWh), with a projected peak in the 2030s-2040s under the most pessimistic scenarios. Hotspots of risk are situated in the southwest and northern regions, primarily driven by decreased river basin runoff and intensified sectoral water use, rather than by hydropower demand expansion. Comparative analysis of four adaptation strategies revealed that sectoral water savings and enhancing power generation efficiency are the most effective, potentially mitigating a high of 16% of hydropower risks in China. This study provides insights for formulating region-specific adaptation strategies and assessing energy-water security in the face of evolving environmental and societal challenges.

Care Needs of Older Adults With Urinary Incontinence: A Cross-Sectional Study.

PURPOSE: To explore care requirements of older adults with urinary incontinence (UI) and contributing factors. METHOD: This cross-sectional study used the Older Adults Urinary Incontinence Care Needs Inventory to survey participants with UI in three large-scale tertiary hospitals located in Guangzhou City, China, from January 2023 to November 2023. Statistical analyses, including analysis of variance, t tests, correlation analyses, and linear regression models, were conducted to assess factors influencing participants' care needs. RESULTS: A total of 530 older adults with UI participated in the survey and mean standardized score for overall care needs was 78.65 (SD = 5.01), with mean scores for each dimension ranging from 70.88 (SD = 10.55) for social participation needs to 82.45 (SD = 7.11) for health education needs. Factors that were found to influence incontinence care needs in older adults included age, literacy level, number of leaks, and type of disease (F = 37.07, adjusted R2 = 0.290, p < 0.001). CONCLUSION: Comprehensive care for older adults with UI, encompassing physiological, psychological, and social aspects, is crucial. It is essential to tailor care to individual needs and characteristics, taking into account factors, such as age and education, to ensure effective care. [Journal of Gerontological Nursing, 50(5), 43-49.].

SARS-CoV-2 BA.2 (Omicron) variant infection in pediatric liver transplanted recipients and cohabitants during 2022 Shanghai outbreak: a prospective cohort.

BACKGROUND: The Omicron variant BA.2 was the dominant variant in the COVID-19 outbreak in Shanghai since March 2022. We aim to investigate the characteristics of SARS-CoV-2 Omicron variant infection in pediatric liver-transplanted recipients. METHODS: We conducted a single-center, prospective, observational, single-arm study. We enrolled pediatric liver-transplanted patients infected with the Omicron variant BA.2 from March 19th to October 1st, 2022 and analyzed their demographic, clinical, laboratory, and outcome data. The management of COVID-19 was conducted according to the 9th trial edition of the Chinese guideline. The immunosuppressive therapy was tailored considering the patients' infection developments and liver functions. RESULTS: Five children were included. The primary diseases included Niemann-Pick disease, propionic acidemia, decompensated cirrhosis, biliary atresia, and Crigler-Najjar syndrome type I. All of the patients were onset with fever before or when getting RNA-positive results at the age of 3 (Range: 1-13) years. The infection duration was 29 (Range: 18-40) days. Three and two children were diagnosed with mild and moderate COVID-19 respectively. Two patients were tested RNA-positive within 14 days after having been tested negative. The immunosuppressants were paused or extenuated in four patients. Eight of all nine cohabitants were injected with at least two doses of inactivated SARS-CoV-2 vaccine. The disease courses were significantly longer than the patients (P < 0.05). CONCLUSIONS: Post-transplant immunosuppression slows down the virus clearance and increases the risk of relapse but does not affect symptom duration or infection severity in pediatric patients. Patients can usually gain a favorable outcome and prognosis by extenuating immunosuppressants.

Sliding Window-Based Machine Learning for Environmental Inspection Resource Allocation.

Environmental regulation is pivotal in mitigating environmental risks and promoting sustainable development, yet regulators frequently encounter resource constraints when inspecting enterprises. To address this limitation, we employed four sliding window-based machine learning techniques to enhance effective environmental inspections. Utilizing feature-engineered time-series data of characteristic and compliance records from 16,777 chemical enterprises in Jiangsu between 2010 and 2021, the four models were used to establish the predictive models that link enterprise characteristics to the likelihood of inspection failure. The results indicated that the models were comparable with the widely utilized deep learning sequence model, the Long Short-Term Memory model, achieving areas under the ROC (receiver operating characteristic) curves exceeding 0.83. Past violation significantly influences future violations, with a more recent violation history exerting stronger impacts. Besides, using predicted failure rates, we proposed seven resource allocation scenarios, considering different regulation intensities to target high-risk enterprises. Notably, the provincial-level risk-based method yielded a significant inspection failure rate increase (detecting violation), surpassing 8-fold the baseline. Overall, our study offers regulators an optimized inspection resource allocation method, thereby enhancing the regulatory effectiveness. Moreover, this study demonstrates the potential of window-based machine learning techniques in environmental regulation and highlights the importance of data-driven decision-making for promoting sustainable development.

Economic Growth Facilitates Household Fuel Use Transition to Reduce PM2.5-Related Deaths in China.

Exposure to ambient and indoor particle matter (PM2.5) leads to millions of premature deaths in China. In recent years, indoor air pollution and premature deaths associated with polluting fuel cooking demonstrate an abrupt decline. However, the driving forces behind the mortality change are still unclear due to the uncertainty in household fuel use prediction. Here, we propose an integrated approach to estimate the fuel use fractions and PM2.5-related deaths from outdoor and indoor sources during 2000-2020 across China. Our model estimated 1.67 and 1.21 million premature deaths attributable to PM2.5 exposure in 2000 and 2020, respectively. We find that the residential energy transition is associated with a substantial reduction in premature deaths from indoor sources, with 100,000 (95% CI: 76,000-122,000) for urban and 265,000 (228,000-300,000) for rural populations during 2000-2020. Economic growth is the dominant driver of fuel use transition and avoids 21% related deaths (357,000, 315,000-402,000) from polluting fuel cooking since 2000, which offsets the adverse impact of ambient emissions contributed by economic growth. Our findings give an insight into the coupled impact of socioeconomic factors in reshaping health burden in exposure pathways.

Integrating Augmented In Situ Measurements and a Spatiotemporal Machine Learning Model To Back Extrapolate Historical Particulate Matter Pollution over the United Kingdom: 1980-2019.

Historical PM2.5 data are essential for assessing the health effects of air pollution exposure across the life course or early life. However, a lack of high-quality data sources, such as satellite-based aerosol optical depth before 2000, has resulted in a gap in spatiotemporally resolved PM2.5 data for historical periods. Taking the United Kingdom as an example, we leveraged the light gradient boosting model to capture the spatiotemporal association between PM2.5 concentrations and multi-source geospatial predictors. Augmented PM2.5 from PM10 measurements expanded the spatiotemporal representativeness of the ground measurements. Observations before and after 2009 were used to train and test the models, respectively. Our model showed fair prediction accuracy from 2010 to 2019 [the ranges of coefficients of determination (R2) for the grid-based cross-validation are 0.71-0.85] and commendable back extrapolation performance from 1998 to 2009 (the ranges of R2 for the independent external testing are 0.32-0.65) at the daily level. The pollution episodes in the 1980s and pollution levels in the 1990s were also reproduced by our model. The 4-decade PM2.5 estimates demonstrated that most regions in England witnessed significant downward trends in PM2.5 pollution. The methods developed in this study are generalizable to other data-rich regions for historical air pollution exposure assessment.

Source Contributions to PM2.5-Related Mortality and Costs: Evidence for Emission Allocation and Compensation Strategies in China.

The emissions from various pollution sources were not proportional to their contributions to ambient PM2.5 concentrations and associated health burdens. That means even with the same total abatement targets, different abatement allocation strategies across emission sources can have distinct health benefits. Insufficient knowledge of various sources' contributions to health burdens in China, the country suffering substantial PM2.5-related deaths, hindered the government from seeking optimized abatement allocation strategies. In this context, we separated the contributions of 155 emission sources (31 provinces × 5 sectors) to PM2.5-related mortality across China in 2017 by coupling the Comprehensive Air Quality Model with Extensions (CAMx), Weather Research and Forecasting model (WRF), and health impact assessment model. We further identified the priority-control emission sources and quantified interprovincial ecological compensation volumes to alleviate inequality induced by emission allocation strategies. Results showed that PM2.5 pollution caused 899,443 excess deaths and around 127 billion USD costs in 2017. Approximately half of the deaths and costs were attributable to emissions from sources outside the boundary of the regions where the deaths occurred. Twenty-five out of 155 emission sources that contributed to the top 60% mortality burdens and had high marginal abatement efficiencies in China shall be the priority-control emission sources. A 1 µg/m3 decrease of PM2.5 concentration in regions where these key emission sources occur shall be compensated by 76-153 million USD in their receptor regions. Our study sheds light on the sources' contributions to mortality burdens and costs and provides scientific evidence for optimizing the emission allocation and compensation strategies in China. It also has wide implications for other countries suffering similar problems.

Large Virtual Transboundary Hazardous Waste Flows: The Case of China.

The Basel Convention and prior studies mainly focused on the physical transboundary movements of hazardous waste (transporting waste from one region to another for cheaper disposal). Here, we take China, the world's largest waste producer, as an example and reveal the virtual hazardous waste flows in trade (outsourcing waste by importing waste-intensive products) by developing a multiregional input-output model. Our model characterizes the impact of international trade between China and 140 economies and China's interprovincial trade on hazardous waste generated by 161,599 Chinese enterprises. We find that, in 2015, virtual hazardous waste flows in China's trade reached 26.6 million tons (67% of the national total), of which 31% were generated during the production of goods that were ultimately consumed abroad. Trade-related production is much dirtier than locally consumed production, generating 26% more hazardous waste per unit of GDP. Under the impact of virtual flows, 40% of the waste-intensive production and relevant disposal duty is unequally concentrated in three Chinese provinces (including two least-developed ones, Qinghai and Xinjiang). Our findings imply the importance of expanding the scope of transboundary waste regulations and provide a quantitative basis for introducing consumer responsibilities. This may help relieve waste management burdens in less-developed "waste havens".

Ulinastatin inhibits the metastasis of nasopharyngeal carcinoma by involving uPA/uPAR signaling.

Distant metastasis is the primary reason for treatment failure in patients with nasopharyngeal carcinoma (NPC). In this study, we investigated the effect of ulinastatin (UTI) on NPC metastasis and its underlying mechanism. Highly-metastatic NPC cell lines S18 and 58F were treated with UTI and the effect on cell proliferation, migration, and invasion were determined by MTS and Transwell assays. S18 cells with luciferase-expressing (S18-1C3) were injected into the left hind footpad of nude mice to establish a model of spontaneous metastasis from the footpad to popliteal lymph node (LN). The luciferase messenger RNA (mRNA) was measured by quantitative polymerase chain reaction (qPCR), and the metastasis inhibition rate was calculated. Key molecular members of the UTI-related uPA, uPAR, and JAT/STAT3 signaling pathways were detected by qPCR and immunoblotting. UTI suppressed the migration and infiltration of S18 and 5-8F cells and suppressed the metastasis of S18 cells in vivo without affecting cell proliferation. uPAR expression decreased from 24 to 48 h after UTI treatment. The antimetastatic effect of UTI is partly due to the suppression of uPA and uPAR. UTI partially suppresses NPC metastasis by downregulating the expression of uPA and uPAR.

A Hybrid Genetic Algorithm Based on Imitation Learning for the Airport Gate Assignment Problem.

Airport gates are the main places for aircraft to receive ground services. With the increased number of flights, limited gate resources near to the terminal make the gate assignment work more complex. Traditional solution methods based on mathematical programming models and iterative algorithms are usually used to solve these static situations, lacking learning and real-time decision-making abilities. In this paper, a two-stage hybrid algorithm based on imitation learning and genetic algorithm (IL-GA) is proposed to solve the gate assignment problem. First of all, the problem is defined from a mathematical model to a Markov decision process (MDP), with the goal of maximizing the number of flights assigned to contact gates and the total gate preferences. In the first stage of the algorithm, a deep policy network is created to obtain the gate selection probability of each flight. This policy network is trained by imitating and learning the assignment trajectory data of human experts, and this process is offline. In the second stage of the algorithm, the policy network is used to generate a good initial population for the genetic algorithm to calculate the optimal solution for an online instance. The experimental results show that the genetic algorithm combined with imitation learning can greatly shorten the iterations and improve the population convergence speed. The flight rate allocated to the contact gates is 14.9% higher than the manual allocation result and 4% higher than the traditional genetic algorithm. Learning the expert assignment data also makes the allocation scheme more consistent with the preference of the airport, which is helpful for the practical application of the algorithm.

[Impact of assisted reproductive technology on birth weight discordance in twins]. / è¾ åŠ©ç”Ÿæ®–æŠ€æœ¯å¯¹åŒèƒŽå‡ºç”Ÿä½“é‡ä¸ä¸€è‡´çš„å½±å“.

OBJECTIVES: To explore the association between assisted reproductive technology (ART) and birth weight discordance in twins (BWDT). METHODS: A retrospective analysis was conducted on twin infants born between January 2011 and December 2020 at the Third Affiliated Hospital of Guangzhou Medical University, with complete basic birth data. The impact of ART on the occurrence of BWDT was identified by the multivariate logistic regression analysis. RESULTS: A total of 3 974 pairs of twins were included, with 1 431 conceived naturally and 2 543 through ART. Neonates in the ART group had higher birth weights than those in the naturally conceived group (P<0.001). The incidence of BWDT was lower in the ART group compared to the naturally conceived group (16.17% vs 21.09%, P<0.001). The multivariate logistic regression analysis, adjusting for confounding factors such as maternal age, parity, pre-pregnancy body mass index, gestational diabetes, hypothyroidism, gestational age, and chorionic properties, showed no significant difference in the risk of BWDT between the ART and naturally conceived groups (P>0.05). CONCLUSIONS: ART is not associated with the risk of BWDT.

GPS2 promotes erythroid differentiation by control of the stability of EKLF protein.

Erythropoiesis is a complex multistage process that involves differentiation of early erythroid progenitors to enucleated mature red blood cells, in which lineage-specific transcription factors play essential roles. Erythroid Krüppel-like factor (EKLF/KLF1) is a pleiotropic erythroid transcription factor that is required for the proper maturation of the erythroid cells, whose expression and activation are tightly controlled in a temporal and differentiation stage-specific manner. Here, we uncover a novel role of G-protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor/silencing mediator of retinoic acid and thyroid hormone receptor corepressor complex, in erythrocyte differentiation. Our study demonstrates that knockdown of GPS2 significantly suppresses erythroid differentiation of human CD34+ cells cultured in vitro and xenotransplanted in nonobese diabetic/severe combined immunodeficiency/interleukin-2 receptor γ-chain null mice. Moreover, global deletion of GPS2 in mice causes impaired erythropoiesis in the fetal liver and leads to severe anemia. Flow cytometric analysis and Wright-Giemsa staining show a defective differentiation at late stages of erythropoiesis in Gps2-/- embryos. Mechanistically, GPS2 interacts with EKLF and prevents proteasome-mediated degradation of EKLF, thereby increasing EKLF stability and transcriptional activity. Moreover, we identify the amino acids 191-230 region in EKLF protein, responsible for GPS2 binding, that is highly conserved in mammals and essential for EKLF protein stability. Collectively, our study uncovers a previously unknown role of GPS2 as a posttranslational regulator that enhances the stability of EKLF protein and thereby promotes erythroid differentiation.

The MRI enhancement ratio and plaque steepness may be more accurate for predicting recurrent ischemic cerebrovascular events in patients with intracranial atherosclerosis.

OBJECTIVES: To assess the complementary value of high-resolution multi-contrast MRI (hrMRI) in identifying symptomatic patients with intracranial atherosclerosis (ICAS) who are likely to experience recurrent ischemic cerebrovascular events. METHODS: In this retrospective cohort study, eighty patients with acute ischemic events attributed to ICAS who underwent hrMRI examination between January 2015 and January 2019 were included. Median follow-up for all patients was 30 months (range: 1 to 52 months) and recurrent ischemic cerebrovascular events were recorded. Cox regression analysis and time-dependent ROC were performed to quantify the association between the plaque characteristics and recurrent events. RESULTS: During the follow-up, 14 patients experienced recurrent ischemic cerebrovascular events. Young males and those with diabetes and poor medication persistence were more likely to experience recurrent events. ICAS in patients with recurrence had significantly higher enhancement ratio and steepness which is defined as the ratio between the plaque height and length than those without (p < 0.001 and p = 0.015, respectively). After adjustment of clinical factors, enhancement ratio (HR, 13.13 [95% CI, 3.58-48.20], p < 0.001) and plaque steepness (HR, 110.27 [95% CI, 4.75-2560.91], p = 0.003) were independent imaging biomarkers associated with recurrent events. Time-dependent ROC indicated that integrated high enhancement ratio and steepness into clinical risk factors improved discrimination power with the ROC increased from 0.79 to 0.94 (p = 0.008). CONCLUSIONS: The enhancement ratio and plaque steepness improved the accuracy over traditional clinical risk factors in predicting recurrent ischemic cerebrovascular events for patients with ICAS. KEY POINTS: • High-resolution magnetic resonance imaging helps clinicians to evaluate high-risk Intracranial plaque. • The higher enhancement ratio and plaque steepness (= height/length) were the primary biomarkers associated with future ischemic cerebrovascular events. • High-resolution magnetic resonance imaging combined with clinical characteristics showed a higher accuracy for the prediction of recurrent events in patients with intracranial atherosclerosis.

[Sex differences in clinical outcomes of extremely preterm infants/extremely low birth weight infants: a propensity score matching study]. / è¶ æ—©äº§å„¿/è¶ ä½Žå‡ºç”Ÿä½“é‡å„¿ä¸´åºŠç»“å±€çš„æ€§åˆ«å·®å¼‚ï¼šä¸€é¡¹å€¾å‘æ€§è¯„åˆ†åŒ¹é ç ”ç©¶.

OBJECTIVES: To study the effect of sex on the clinical outcome of extremely preterm infants (EPIs)/extremely low birth weight infants (ELBWIs) by propensity score matching. METHODS: A retrospective analysis was performed for the medical data of 731 EPIs or ELBWIs who were admitted from January 1, 2011 to December 31, 2020. These infants were divided into two groups: male and female. A propensity score matching analysis was performed at a ratio of 1:1. The matching variables included gestational age, birth weight, percentage of withdrawal from active treatment, percentage of small-for-gestational-age infant, percentage of use of pulmonary surfactant, percentage of 1-minute Apgar score ≤3, percentage of mechanical ventilation, duration of mechanical ventilation, percentage of antenatal use of inadequate glucocorticoids, and percentage of hypertensive disorders in pregnancy. The two groups were compared in the incidence rate of main complications during hospitalization and the rate of survival at discharge. RESULTS: Before matching, compared with the female group, the male group had significantly higher incidence rates of neonatal respiratory distress syndrome, bronchopulmonary dysplasia (BPD), severe intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, and patent ductus arteriosus (P<0.05), while after matching, the male group only had a significantly higher incidence rate of BPD than the female group (P<0.05). There was no significant difference in the rate of survival at discharge between the two groups before and after matching (P>0.05). CONCLUSIONS: Male EPIs/ELBWIs have a higher risk of BPD than female EPIs/ELBWIs, but male and female EPIs/ELBWIs tend to have similar outcomes.

Clinical treatment outcomes and their changes in extremely preterm twins: a multicenter retrospective study in Guangdong Province, China. / è¶ æœªæˆç†ŸåŒèƒŽå„¿ä¸´åºŠæ•‘æ²»ç»“å±€åŠå˜åŒ–åˆ†æžï¼šä¸€é¡¹å¹¿ä¸œçœå¤šä¸­å¿ƒå›žé¡¾æ€§ç ”ç©¶.

OBJECTIVES: To investigate the clinical treatment outcomes and the changes of the outcomes over time in extremely preterm twins in Guangdong Province, China. METHODS: A retrospective analysis was performed for 269 pairs of extremely preterm twins with a gestational age of <28 weeks who were admitted to the department of neonatology in 26 grade A tertiary hospitals in Guangdong Province from January 2008 to December 2017. According to the admission time, they were divided into two groups: 2008-2012 and 2013-2017. Besides, each pair of twins was divided into the heavier infant and the lighter infant subgroups according to birth weight. The perinatal data of mothers and hospitalization data of neonates were collected. The survival rate of twins and the incidence rate of complications were compared between the 2008-2012 and 2013-2017 groups. RESULTS: Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of severe asphyxia and smaller head circumference at birth (P<0.05). The mortality rates of both of the twins, the heavier infant of the twins, and the lighter infant of the twins were lower in the 2013-2017 group compared with the 2008-2012 group (P<0.05). Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of pulmonary hemorrhage, patent ductus arteriosus (PDA), periventricular-intraventricular hemorrhage (P-IVH), and neonatal respiratory distress syndrome (NRDS) and a higher incidence rate of bronchopulmonary dysplasia (P<0.05). CONCLUSIONS: There is a significant increase in the survival rate over time in extremely preterm twins with a gestational age of <28 weeks in the 26 grade A tertiary hospitals in Guangdong Province. The incidences of severe asphyxia, pulmonary hemorrhage, PDA, P-IVH, and NRDS decrease in both the heavier and lighter infants of the twins, but the incidence of bronchopulmonary dysplasia increases. With the improvement of diagnosis and treatment, the multidisciplinary collaboration between different fields of fetal medicine including prenatal diagnosis, obstetrics, and neonatology is needed in the future to jointly develop management strategies for twin pregnancy.

Spectrum of Germline RET variants identified by targeted sequencing and associated Multiple Endocrine Neoplasia type 2 susceptibility in China.

BACKGROUND: Germline RET mutations and variants are involved in development of multiple endocrine neoplasia type 2 (MEN2). The present study investigated a spectrum of RET variants, analyzed genotype-phenotype relationships, and evaluated their effect on the MEN2 phenotype in Han Chinese patients. METHODS: Targeted sequencing detected germline RET variants in 697 individuals, including 245 MEN2, 120 sporadic medullary thyroid cancer (MTC), and 15 pheochromocytoma (PHEO) patients and their 493 relatives. In silico analyses and classifications following ACMG-2015 were performed. Demographic, clinical variant types, and endocrine neoplasia molecular diagnosis records were also analyzed. RESULTS: Nineteen different RET mutations (18 point and 1 del/ins mutations) in 214 patients with MEN2A (97.7%) or MEN2B (2.3%) were found, of which exon 11/10 mutations accounted for 79% (169/214). Nineteen compound mutations were found in 31 patients with MEN2A. Twenty-three variants (18 single and 5 double base substitution/compound variants) non-classification were also found. Of these, 17 (3 of pathogenic, 10 of uncertain significance, 2 of likely benign and 2 as benign) were found in 31 patients with MTC/PHEO. The remaining 6 variants (4 of uncertain significance and 2 of likely benign) found in 8 carriers had no evidence of MEN2. The entire cohort showed MEN2A-related PHEO, all occurring in exons 11/10, particularly at C634. Kaplan-Meier curves showed age-dependent penetration rates of MTC and PHEO, and occurrence rates of PHEO in patients with exon 11 mutations were all higher than those within exon 10; these bilateral PHEO were always associated with exon 11 mutations (all P < 0.05). While patient offspring had PHEO, parents with MEN2A had none, the frequency was approximately 10%. Interestingly, at least 6.8% of families were adoptive. Also, 3 non-hotspot RET variants (R114H, T278N, and D489N) appeared with high frequency. Conversely, polymorphism S836S was absent. CONCLUSIONS: These data are largely consistent with current evidence-based recommendations in the clinical practice guidelines. Diversity of RET variants or carriers may involve a different natural disease course. Further large-scale targeted sequencing studies will serve as an accurate and cost-effective approach to investigating MEN2 genotype-phenotype correlations for discovery of rare or unknown variants of RET.

Decrease in the chronic health effects from PM2.5 during the 13th Five-Year Plan in China: Impacts of air pollution control policies.

The Chinese government implemented a series of policies to improve air quality during the Thirteenth Five-Year Plan (13th FYP). However, the long-term health effects of the 13th FYP air pollution control policies have not been evaluated, and the outbreak of coronavirus disease 2019 (COVID-19) has brought great uncertainty regarding the evaluation of the effects. In this study, we selected 329 cities in mainland China to study the chronic health effects due to the decrease in fine particulate matter (PM2.5) during the 13th FYP. The relative risk (RR) of PM2.5 exposure was obtained from a previous study, and the total premature deaths were calculated. We also applied the grey prediction model to predict the PM2.5 concentration in each city in 2020 to evaluate the impacts of COVID-19. The results showed that the annual PM2.5 concentration was reduced from 49.7 µg/m3 in 2015 to 33.2 µg/m3 in 2020, and premature deaths were reduced from 1,186,201 (95% CI: 910,339-1,451,102) and 446,415 (in key regions, 95% CI: 343,426-544,813) in 2015 to 997,955 (95% CI: 762,167-1,226,652) and 368,786 (in key regions, 95% CI: 282,114-452,567) in 2020, respectively. A total of 188,246 (95% CI: 148,172-224,450) people avoided premature deaths due to the reduction in PM2.5 concentrations from 2015 to 2020. Although the impacts of COVID-19 in 2020 brought a significant reduction of 35.3% in February (14.2 µg/m3, p < 0.0001) and in March by 17.6% (5.8 µg/m3, p = 0.001), we found that COVID-19 showed few obvious influences on China's long-term air pollution control plans. The observed data and predicted data are very close in annual mean values and showed no statistical significance both in all cities (p = 0.98) and in key regions (p = 0.56) in 2020.

Driving Risk Assessment Using Near-Miss Events Based on Panel Poisson Regression and Panel Negative Binomial Regression.

This study proposes a method for identifying and evaluating driving risk as a first step towards calculating premiums in the newly emerging context of usage-based insurance. Telematics data gathered by the Internet of Vehicles (IoV) contain a large number of near-miss events which can be regarded as an alternative for modeling claims or accidents for estimating a driving risk score for a particular vehicle and its driver. Poisson regression and negative binomial regression are applied to a summary data set of 182 vehicles with one record per vehicle and to a panel data set of daily vehicle data containing four near-miss events, i.e., counts of excess speed, high speed brake, harsh acceleration or deceleration and additional driving behavior parameters that do not result in accidents. Negative binomial regression (AICoverspeed = 997.0, BICoverspeed = 1022.7) is seen to perform better than Poisson regression (AICoverspeed = 7051.8, BICoverspeed = 7074.3). Vehicles are separately classified to five driving risk levels with a driving risk score computed from individual effects of the corresponding panel model. This study provides a research basis for actuarial insurance premium calculations, even if no accident information is available, and enables a precise supervision of dangerous driving behaviors based on driving risk scores.