National Health and Family Planning Commission

BACKGROUND: Human infections with zoonotic coronaviruses (CoVs), including severe acute respiratory syndrome (SARS)-CoV and Middle East respiratory syndrome (MERS)-CoV, have raised great public health concern globally. Here, we report a novel bat-origin CoV causing severe and fatal pneumonia in humans. METHODS: We collected clinical data and bronchoalveolar lavage (BAL) specimens from five patients with severe pneumonia from Wuhan Jinyintan Hospital, Hubei province, China. Nucleic acids of the BAL were extracted and subjected to next-generation sequencing. Virus isolation was carried out, and maximum-likelihood phylogenetic trees were constructed. RESULTS: Five patients hospitalized from December 18 to December 29, 2019 presented with fever, cough, and dyspnea accompanied by complications of acute respiratory distress syndrome. Chest radiography revealed diffuse opacities and consolidation. One of these patients died. Sequence results revealed the presence of a previously unknown β-CoV strain in all five patients, with 99.8% to 99.9% nucleotide identities among the isolates. These isolates showed 79.0% nucleotide identity with the sequence of SARS-CoV (GenBank NC_004718) and 51.8% identity with the sequence of MERS-CoV (GenBank NC_019843). The virus is phylogenetically closest to a bat SARS-like CoV (SL-ZC45, GenBank MG772933) with 87.6% to 87.7% nucleotide identity, but is in a separate clade. Moreover, these viruses have a single intact open reading frame gene 8, as a further indicator of bat-origin CoVs. However, the amino acid sequence of the tentative receptor-binding domain resembles that of SARS-CoV, indicating that these viruses might use the same receptor. CONCLUSION: A novel bat-borne CoV was identified that is associated with severe and fatal respiratory disease in humans.

BACKGROUND: Faced with the coronavirus disease 2019 (COVID-19) pandemic, the development of COVID-19 vaccines has been progressing at an unprecedented rate. This study aimed to evaluate the acceptance of COVID-19 vaccination in China and give suggestions for vaccination strategies and immunization programs accordingly. METHODS: In March 2020, an anonymous cross-sectional survey was conducted online among Chinese adults. The questionnaire collected socio-demographic characteristics, risk perception, the impact of COVID-19, attitudes, acceptance and attribute preferences of vaccines against COVID-19 during the pandemic. Multivariate logistic regression was performed to identify the influencing factors of vaccination acceptance. RESULTS: Of the 2058 participants surveyed, 1879 (91.3%) stated that they would accept COVID-19 vaccination after the vaccine becomes available, among whom 980 (52.2%) wanted to get vaccinated as soon as possible, while others (47.8%) would delay the vaccination until the vaccine's safety was confirmed. Participants preferred a routine immunization schedule (49.4%) to emergency vaccination (9.0%) or either of them (41.6%). Logistic regression showed that being male, being married, perceiving a high risk of infection, being vaccinated against influenza in the past season, believing in the efficacy of COVID-19 vaccination or valuing doctor's recommendations could increase the probability of accepting COVID-19 vaccination as soon as possible, while having confirmed or suspected cases in local areas, valuing vaccination convenience or vaccine price in decision-making could hinder participants from immediate vaccination. CONCLUSION: During the pandemic period, a strong demand for and high acceptance of COVID-19 vaccination has been shown among the Chinese population, while concerns about vaccine safety may hinder the promotion of vaccine uptake. To expand vaccination coverage, immunization programs should be designed to remove barriers in terms of vaccine price and vaccination convenience, and health education and communication from authoritative sources are important ways to alleviate public concerns about vaccine safety.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has become a public health emergency. The widely used reverse transcription-polymerase chain reaction (RT-PCR) method has limitations for clinical diagnosis and treatment. METHODS: A total of 323 samples from 76 COVID-19-confirmed patients were analyzed by droplet digital PCR (ddPCR) and RT-PCR based 2 target genes (ORF1ab and N). Nasal swabs, throat swabs, sputum, blood, and urine were collected. Clinical and imaging data were obtained for clinical staging. RESULTS: In 95 samples that tested positive by both methods, the cycle threshold (Ct) of RT-PCR was highly correlated with the copy number of ddPCR (ORF1ab gene, R2 = 0.83; N gene, R2 = 0.87). Four (4/161) negative and 41 (41/67) single-gene positive samples tested by RT-PCR were positive according to ddPCR with viral loads ranging from 11.1 to 123.2 copies/test. The viral load of respiratory samples was then compared and the average viral load in sputum (17 429 ± 6920 copies/test) was found to be significantly higher than in throat swabs (2552 ± 1965 copies/test, P < .001) and nasal swabs (651 ± 501 copies/test, P < .001). Furthermore, the viral loads in the early and progressive stages were significantly higher than that in the recovery stage (46 800 ± 17 272 vs 1252 ± 1027, P < .001) analyzed by sputum samples. CONCLUSIONS: Quantitative monitoring of viral load in lower respiratory tract samples helps to evaluate disease progression, especially in cases of low viral load.

OBJECTIVES: To examine the association between temperature and cause specific mortality, and to quantify the corresponding disease burden attributable to non-optimum ambient temperatures. DESIGN: Time series analysis. SETTING: 272 main cities in China. POPULATION: Non-accidental deaths in 272 cities covered by the Disease Surveillance Point System of China, from January 2013 to December 2015. MAIN OUTCOMES AND MEASURES: Daily numbers of deaths from all non-accidental causes and main cardiorespiratory diseases. Potential effect modifiers included demographic, climatic, geographical, and socioeconomic characteristics. The analysis used distributed lag non-linear models to estimate city specific associations, and multivariate meta-regression analysis to obtain the effect estimates at national and regional levels. RESULTS: 1 826 186 non-accidental deaths from total causes were recorded in the study period. Temperature and mortality consistently showed inversely J shaped associations. At the national average level, relative to the minimum mortality temperature (22.8°C, 79.1st centile), the mortality risk of extreme cold temperature (at -1.4°C, the 2.5th centile) lasted for more than 14 days, whereas the risk of extreme hot temperature (at 29.0°C, the 97.5th centile) appeared immediately and lasted for two to three days. 14.33% of non-accidental total mortality was attributable to non-optimum temperatures, of which moderate cold (ranging from -1.4 to 22.8°C), moderate heat (22.8 to 29.0°C), extreme cold (-6.4 to -1.4°C), and extreme heat (29.0 to 31.6°C) temperatures corresponded to attributable fractions of 10.49%, 2.08%, 1.14%, and 0.63%, respectively. The attributable fractions were 17.48% for overall cardiovascular disease, 18.76% for coronary heart disease, 16.11% for overall stroke, 14.09% for ischaemic stroke, 18.10% for haemorrhagic stroke, 10.57% for overall respiratory disease, and 12.57% for chronic obstructive pulmonary diseases. The mortality risk and burden were more prominent in the temperate monsoon and subtropical monsoon climatic zones, in specific subgroups (female sex, age ≥75 years, and ≤9 years spent in education), and in cities characterised by higher urbanisations rates and shorter durations of central heating. CONCLUSIONS: This nationwide study provides a comprehensive picture of the non-linear associations between ambient temperature and mortality from all natural causes and main cardiorespiratory diseases, as well as the corresponding disease burden that is mainly attributable to moderate cold temperatures in China. The findings on vulnerability characteristics can help improve clinical and public health practices to reduce disease burden associated with current and future abnormal weather.

The Coronavirus Disease 2019 (COVID-19) pandemic has become a global crisis and is more devastating than any other previous infectious disease. It has affected a significant proportion of the global population both physically and mentally, and destroyed businesses and societies. Current evidence suggested that immunopathology may be responsible for COVID-19 pathogenesis, including lymphopenia, neutrophilia, dysregulation of monocytes and macrophages, reduced or delayed type I interferon (IFN-I) response, antibody-dependent enhancement, and especially, cytokine storm (CS). The CS is characterized by hyperproduction of an array of pro-inflammatory cytokines and is closely associated with poor prognosis. These excessively secreted pro-inflammatory cytokines initiate different inflammatory signaling pathways via their receptors on immune and tissue cells, resulting in complicated medical symptoms including fever, capillary leak syndrome, disseminated intravascular coagulation, acute respiratory distress syndrome, and multiorgan failure, ultimately leading to death in the most severe cases. Therefore, it is clinically important to understand the initiation and signaling pathways of CS to develop more effective treatment strategies for COVID-19. Herein, we discuss the latest developments in the immunopathological characteristics of COVID-19 and focus on CS including the current research status of the different cytokines involved. We also discuss the induction, function, downstream signaling, and existing and potential interventions for targeting these cytokines or related signal pathways. We believe that a comprehensive understanding of CS in COVID-19 will help to develop better strategies to effectively control immunopathology in this disease and other infectious and inflammatory diseases.

Importance: Stroke is the leading cause of death in China. However, recent data about the up-to-date stroke burden in China are limited. Objective: To investigate the urban-rural disparity of stroke burden in the Chinese adult population, including prevalence, incidence, and mortality rate, and disparities between urban and rural populations. Design, Setting, and Participants: This cross-sectional study was based on a nationally representative survey that included 676 394 participants aged 40 years and older. It was conducted from July 2020 to December 2020 in 31 provinces in mainland China. Main Outcomes and Measures: Primary outcome was self-reported stroke verified by trained neurologists during a face-to-face interviews using a standardized protocol. Stroke incidence were assessed by defining first-ever strokes that occurred during 1 year preceding the survey. Strokes causing death that occurred during the 1 year preceding the survey were considered as death cases. Results: The study included 676 394 Chinese adults (395 122 [58.4%] females; mean [SD] age, 59.7 [11.0] years). In 2020, the weighted prevalence, incidence, and mortality rates of stroke in China were 2.6% (95% CI, 2.6%-2.6%), 505.2 (95% CI, 488.5-522.0) per 100 000 person-years, and 343.4 (95% CI, 329.6-357.2) per 100 000 person-years, respectively. It was estimated that among the Chinese population aged 40 years and older in 2020, there were 3.4 (95% CI, 3.3-3.6) million incident cases of stroke, 17.8 (95% CI, 17.5-18.0) million prevalent cases of stroke, and 2.3 (95% CI, 2.2-2.4) million deaths from stroke. Ischemic stroke constituted 15.5 (95% CI, 15.2-15.6) million (86.8%) of all incident strokes in 2020, while intracerebral hemorrhage constituted 2.1 (95% CI, 2.1-2.1) million (11.9%) and subarachnoid hemorrhage constituted 0.2 (95% CI, 0.2-0.2) million (1.3%). The prevalence of stroke was higher in urban than in rural areas (2.7% [95% CI, 2.6%-2.7%] vs 2.5% [95% CI, 2.5%-2.6%]; P = .02), but the incidence rate (485.5 [95% CI, 462.8-508.3] vs 520.8 [95% CI, 496.3-545.2] per 100 000 person-years; P < .001) and mortality rate (309.9 [95% CI, 291.7-328.1] vs 369.7 [95% CI, 349.1-390.3] per 100 000 person-years; P < .001) were lower in urban areas than in rural areas. In 2020, the leading risk factor for stroke was hypertension (OR, 3.20 [95% CI, 3.09-3.32]). Conclusions and Relevance: In a large, nationally representative sample of adults aged 40 years or older, the estimated prevalence, incidence, and mortality rate of stroke in China in 2020 were 2.6%, 505.2 per 100 000 person-years, and 343.4 per 100 000 person-years, respectively, indicating the need for an improved stroke prevention strategy in the general Chinese population.

Abstract To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance ( P &lt; 2.5 × 10 −6 ), including five new risk genes ( NAV3 , ITSN1 , MARK2 , SCAF1 and HNRNPUL2 ). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes ( NAV3 , ITSN1 , SCAF1 and HNRNPUL2 ; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes ( CHD8, SCN2A, ADNP, FOXP1 and SHANK3 ) (59% vs 88%, P = 1.9 × 10 −6 ). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.

OBJECTIVE: To describe the temporal and spatial trends of mortality and disability adjusted life years (DALYs) due to chronic respiratory diseases, by age and sex, across the world during 1990-2017 using data from the Global Burden of Disease Study 2017. DESIGN: Systematic analysis. DATA SOURCE: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017. METHODS: Mortality and DALYs from chronic respiratory diseases were estimated from the Global Burden of Disease Study 2017 using DisMod-MR 2.1, a Bayesian meta-regression tool. The estimated annual percentage change of the age standardised mortality rate was calculated using a generalised linear model with a Gaussian distribution. Mortality and DALYs were stratified according to the Socio-demographic index. The strength and direction of the association between the Socio-demographic index and mortality rate were measured using the Spearman rank order correlation. Risk factors for chronic respiratory diseases were analysed from exposure data. RESULTS: Between 1990 and 2017, the total number of deaths due to chronic respiratorydiseases increased by 18.0%, from 3.32 (95% uncertainty interval 3.01 to 3.43) million in 1990 to 3.91 (3.79 to 4.04) million in 2017. The age standardised mortality rate of chronic respiratory diseases decreased by an average of 2.41% (2.28% to 2.55%) annually. During the 27 years, the annual decline in mortality rates of chronic obstructive pulmonary disease (COPD; 2.36%, uncertainty interval 2.21% to 2.50%) and pneumoconiosis (2.56%, 2.44% to 2.68%) has been slow, whereas the mortality rate for interstitial lung disease and pulmonary sarcoidosis (0.97%, 0.92% to 1.03%) has increased. Reductions in DALYs for asthma and pneumoconiosis have been seen, but DALYs due to COPD, and interstitial lung disease and pulmonary sarcoidosis have increased. Mortality and the annual change in mortality rate due to chronic respiratory diseases varied considerably across 195 countries. Assessment of the factors responsible for regional variations in mortality and DALYs and the unequal distribution of improvements during the 27 years showed negative correlations between the Socio-demographic index and the mortality rates of COPD, pneumoconiosis, and asthma. Regions with a low Socio-demographic index had the highest mortality and DALYs. Smoking remained the major risk factor for mortality due to COPD and asthma. Pollution from particulate matter was the major contributor to deaths from COPD in regions with a low Socio-demographic index. Since 2013, a high body mass index has become the principal risk factor for asthma. CONCLUSIONS: Regions with a low Socio-demographic index had the greatest burden of disease. The estimated contribution of risk factors (such as smoking, environmental pollution, and a high body mass index) to mortality and DALYs supports the need for urgent efforts to reduce exposure to them.

Cadmium, a toxic heavy metal, is widely present in food. It has been reported that chronic cadmium exposure is associated with kidney disease, osteoporosis, cardiovascular disease and cancer. The aim of this study was to assess the dietary cadmium exposure and potential health risk in different age-sex groups of the Chinese population (children aged 4-11 years, young people aged 12-17 years and adults aged over 18 years), and in the southern and northern population using a semi-probabilistic method. Cadmium was detected in 228,687 food samples from 32 food categrories by graphite furnace atomic absorption spectrometry. The dietary cadmium exposures were estimated by combining the cadmium concentration data with food consumption data derived from the China National Nutrient and Health Survey 2002, and evaluated against the Provisional Tolerable Monthly Intake (PTMI) of 25 μg/kg BW/month established by the Joint FAO/WHO expert committee on food additives (JECFA). The mean dietary cadmium exposure of the general Chinese population (15.3 μg/kg BW/month) was below the PTMI. The high consumer exposures (95th percentile, P95) for the general population and different sub-groups were higher than the PTMI. The dietary cadmium exposure of the southern population was apparently higher than that of the northern population. Rice was the most important contributor to cadmium exposure for Chinese people, especially those living in the southern areas of China. These findings indicated that the health risk from dietary cadmium exposure of the general Chinese people was low, but the health risk of cadmium exposure of certain sub-groups should be of concern.

BACKGROUND: The complexity of influenza seasonal patterns in the inter-tropical zone impedes the establishment of effective routine immunization programs. China is a climatologically and economically diverse country, which has yet to establish a national influenza vaccination program. Here we characterize the diversity of influenza seasonality in China and make recommendations to guide future vaccination programs. METHODS AND FINDINGS: We compiled weekly reports of laboratory-confirmed influenza A and B infections from sentinel hospitals in cities representing 30 Chinese provinces, 2005-2011, and data on population demographics, mobility patterns, socio-economic, and climate factors. We applied linear regression models with harmonic terms to estimate influenza seasonal characteristics, including the amplitude of annual and semi-annual periodicities, their ratio, and peak timing. Hierarchical Bayesian modeling and hierarchical clustering were used to identify predictors of influenza seasonal characteristics and define epidemiologically-relevant regions. The annual periodicity of influenza A epidemics increased with latitude (mean amplitude of annual cycle standardized by mean incidence, 140% [95% CI 128%-151%] in the north versus 37% [95% CI 27%-47%] in the south, p<0.0001). Epidemics peaked in January-February in Northern China (latitude ≥33°N) and April-June in southernmost regions (latitude <27°N). Provinces at intermediate latitudes experienced dominant semi-annual influenza A periodicity with peaks in January-February and June-August (periodicity ratio >0.6 in provinces located within 27.4°N-31.3°N, slope of latitudinal gradient with latitude -0.016 [95% CI -0.025 to -0.008], p<0.001). In contrast, influenza B activity predominated in colder months throughout most of China. Climate factors were the strongest predictors of influenza seasonality, including minimum temperature, hours of sunshine, and maximum rainfall. Our main study limitations include a short surveillance period and sparse influenza sampling in some of the southern provinces. CONCLUSIONS: Regional-specific influenza vaccination strategies would be optimal in China; in particular, annual campaigns should be initiated 4-6 months apart in Northern and Southern China. Influenza surveillance should be strengthened in mid-latitude provinces, given the complexity of seasonal patterns in this region. More broadly, our findings are consistent with the role of climatic factors on influenza transmission dynamics. Please see later in the article for the Editors' Summary.

BACKGROUND: Ovarian cancer (OV) is the most lethal gynecological cancer in women. We aim to develop a generalized, individualized immune prognostic signature that can stratify and predict overall survival for ovarian cancer. METHODS: The gene expression profiles of ovarian cancer tumor tissue samples were collected from 17 public cohorts, including 2777 cases totally. Single sample gene set enrichment (ssGSEA) analysis was used for the immune genes from ImmPort database to develop an immune-based prognostic score for OV (IPSOV). The signature was trained and validated in six independent datasets (n = 519, 409, 606, 634, 415, 194). FINDINGS: ]). Further, we compared IPSOV with nine reported ovarian cancer prognostic signatures as well as the clinical characteristics including stage, grade and debulking status. The IPSOV achieved the highest mean C-index (0.625) compared with the other signatures (0.516 to 0.602) and clinical characteristics (0.555 to 0.583). Further, we integrated IPSOV with stage, grade and debulking, which showed improved prognostic accuracy than clinical characteristics only. INTERPRETATION: The proposed clinical-immune signature is a promising biomarker for estimating overall survival in ovarian cancer. Prospective studies are needed to further validate its analytical accuracy and test the clinical utility. FUND: This work was supported by National Key Research and Development Program of China, National Natural Science Foundation of China and Natural Science Foundation of the Jiangsu Higher Education Institutions of China.

BACKGROUND: Repair deficiency after endometrial injury is an important reason for intra-uterine adhesions, amenorrhea, and infertility in females. Bone marrow-derived mesenchymal stem cell (BMSC) transplantation is effective in repairing the damaged endometrium. However, the possibility of using umbilical cord-derived MSCs (UC-MSCs) to treat endometrial injury is rarely reported. METHODS: Ethanol (95%) was injected into rat uterus to establish a model of endometrial injury. UC-MSCs were injected through the tail vein, either as a single, twice, or thrice administration. Functional restoration of the uterus was assessed by testing embryo implantation rates. Endometrial morphological alteration was observed by hematoxylin and eosin staining. Endometrial fibrosis, markers of epithelial and stromal cells of endometrium, cell proliferation and angiogenesis, and inflammatory factors were detected using immunohistochemistry, Western blotting, and quantitative reverse-transcription polymerase chain reaction. RESULTS: Endometrial morphology and embryo implantation rates were significantly improved on day 8 of transplantation among single-, twice-, or thrice-administered rats. Moreover, UC-MSCs could alleviate fibrosis in general, and reduced the expression of fibrosis markers, α-smooth muscle actin (α-SMA) and transforming growth factor (TGF)-β. The cell proliferation marker Ki-67 had a positive expression in the injured endometrium after UC-MSC transplantation. The endometrial stromal marker vimentin and epithelial marker cytokeratin-19 (CK-19) expressions were visibly increased. The expression of vascular markers CD31, vascular endothelial growth factor (VEGF)A, and matrix metalloprotein (MMP)9 was generally upregulated. Proinflammatory factors interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-2 were significantly downregulated in the rats administered UC-MSCs twice and thrice. CONCLUSIONS: UC-MSC transplantation contributed to the repair of endometrial injury and restoration of fertility, likely through the suppression of excessive fibrosis and inflammation, and enhancement of endometrial cell proliferation and vascular remodeling.

BACKGROUND: Mobile health interventions (mHealth) based on smartphone applications (apps) are promising tools to help improve diabetes care and self-management; however, more evidence on the efficacy of mHealth in diabetes care is needed. The objective of this study was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the effect of mHealth apps on changes in hemoglobin A1c (HbA1c), blood glucose, blood pressure, serum lipids, and body weight in type 2 diabetes mellitus (T2DM) patients. METHODS: Two independent reviewers searched three online databases (PubMed, the Cochrane Library, and EMBASE) to identify relevant studies published between January 2005 and June 2016. Of the 2,596 articles retrieved, 13 RCTs were included. We used random effects model to estimate the pooled results. RESULTS: Thirteen studies were selected for the systematic review, six of which with data available containing 1,022 patients were included for the meta-analysis. There was a moderate effect on glycemic control after the mHealth app-based interventions. The overall effect on HbA1c shown as mean difference (MD) was -0.40% (-4.37 mmol/mol) (95% confidence interval [CI] -0.69 to -0.11% [-7.54 to -1.20 mmol/mol]; p = 0.007) and standardized mean differences (SMD) was -0.40% (-4.37 mmol/mol) (95% confidence interval [CI] -0.69 to -0.10% [-7.54 to -1.09 mmol/mol]; p = 0.008). A subgroup analysis showed a similar effect with -0.33% (-3.61 mmol/mol) (95% CI -0.59 to -0.06% [-6.45 to -0.66 mmol/mol]; p = 0.02) in MD and -0.38% (-4.15 mmol/mol) (95% CI -0.71 to -0.05% [-7.76 to -0.55 mmol/mol]; p = 0.02) in SMD in studies where patients' baseline HbA1c levels were less than 8.0%. No effects of mHealth app interventions were found on blood pressure, serum lipids, or weight. Assessment of overall study quality and publication bias demonstrated a low risk of bias among the six studies. CONCLUSIONS: Smartphone apps offered moderate benefits for T2DM self-management. However, more research with valid study designs and longer follow-up is needed to evaluate the impact of mHealth apps for diabetes care and self-management.

The emergence of the H7N9 influenza virus in humans in Eastern China has raised concerns that a new influenza pandemic could occur. Here, we used a ferret model to evaluate the infectivity and transmissibility of A/Shanghai/2/2013 (SH2), a human H7N9 virus isolate. This virus replicated in the upper and lower respiratory tracts of the ferrets and was shed at high titers for 6 to 7 days, with ferrets showing relatively mild clinical signs. SH2 was efficiently transmitted between ferrets via direct contact, but less efficiently by airborne exposure. Pigs were productively infected by SH2 and shed virus for 6 days but were unable to transmit the virus to naïve pigs or ferrets. Under appropriate conditions, human-to-human transmission of the H7N9 virus may be possible.

PURPOSE ADJUVANT-CTONG1104 (ClinicalTrials.gov identifier: NCT01405079 ), a randomized phase III trial, showed that adjuvant gefitinib treatment significantly improved disease-free survival (DFS) versus vinorelbine plus cisplatin (VP) in patients with epidermal growth factor receptor ( EGFR) mutation-positive resected stage II-IIIA (N1-N2) non–small-cell lung cancer (NSCLC). Here, we report the final overall survival (OS) results. METHODS From September 2011 to April 2014, 222 patients from 27 sites were randomly assigned 1:1 to adjuvant gefitinib (n = 111) or VP (n = 111). Patients with resected stage II-IIIA (N1-N2) NSCLC and EGFR-activating mutation were enrolled, receiving gefitinib for 24 months or VP every 3 weeks for four cycles. The primary end point was DFS (intention-to-treat [ITT] population). Secondary end points included OS, 3-, 5-year (y) DFS rates, and 5-year OS rate. Post hoc analysis was conducted for subsequent therapy data. RESULTS Median follow-up was 80.0 months. Median OS (ITT) was 75.5 and 62.8 months with gefitinib and VP, respectively (hazard ratio [HR], 0.92; 95% CI, 0.62 to 1.36; P = .674); respective 5-year OS rates were 53.2% and 51.2% ( P = .784). Subsequent therapy was administered upon progression in 68.4% and 73.6% of patients receiving gefitinib and VP, respectively. Subsequent targeted therapy contributed most to OS (HR, 0.23; 95% CI, 0.14 to 0.38) compared with no subsequent therapy. Updated 3y DFS rates were 39.6% and 32. 5% with gefitinib and VP ( P = .316) and 5y DFS rates were 22. 6% and 23.2% ( P = .928), respectively. CONCLUSION Adjuvant therapy with gefitinib in patients with early-stage NSCLC and EGFR mutation demonstrated improved DFS over standard of care chemotherapy. Although this DFS advantage did not translate to a significant OS difference, OS with adjuvant gefitinib was one of the longest observed in this patient group compared with historic data.

BACKGROUND: Congenital heart disease (CHD) is the leading cause of morbidity and mortality from birth defects worldwide. We report an overview of trends in CHD mortality in 204 countries and territories over the past 30 years and associations with age, period, and birth cohort. METHODS: Cause-specific CHD mortality estimates were derived from the Global Burden of Disease 2019 study. We utilised an age-period-cohort model to estimate overall annual percentage changes in mortality (net drifts), annual percentage changes from 0 to 4 to 65-69 years (local drifts), period and cohort relative risks (period/cohort effects) between 1990 and 2019. This approach allows for the examination and differentiation of age, period, and cohort effects in the mortality trends, with the potential to identify disparities and treatment gaps in cardiac care. FINDINGS: CHD is the leading cause of deaths from non-communicable diseases (NCDs) in those under 20 years. Global CHD deaths in 2019 were 217,000 (95% uncertainty interval 177,000-262,000). There were 129 countries with at least 50 deaths. India, China, Pakistan, and Nigeria had the highest mortality, accounting for 39.7% of deaths globally. Between 1990 and 2019, the net drift of CHD mortality ranged from -2.41% per year (95% confidence interval [CI] -2.55, -2.67) in high Socio-demographic Index (SDI) countries to -0.62% per year (95% CI: -0.82, -0.42) in low-SDI countries. Globally, there was an emerging transition in the age distribution of deaths from paediatric to adult populations, except for an increasing trend of mortality in those aged 10-34 years in Mexico and Pakistan. During the past 30 years, favourable mortality reductions were generally found in most high-SDI countries like South Korea (net drift = -4.0% [95% CI -4.8 to -3.1] per year) and the United States (-2.3% [-2.5 to -2.0]), and also in many middle-SDI countries like Brazil (-2.7% [-3.1 to 2.4]) and South Africa (-2.5% [-3.2 to -1.8]). However, 52 of 129 countries had either increasing trends (net drifts ≥0.0%) or stagnated reductions (≥-0.5%) in mortality. The relative risk of mortality generally showed improving trends over time and in successively younger birth cohorts amongst high- and high-middle-SDI countries, with the exceptions of Saudi Arabia and Kazakhstan. 14 middle-SDI countries such as Ecuador and Mexico, and 16 low-middle-SDI countries including India and 20 low-SDI countries including Pakistan, had unfavourable or worsening risks for recent periods and birth cohorts. INTERPRETATION: CHD mortality is a useful and accessible indicator of trends in the provision of congenital cardiac care both in early childhood and across later life. Improvements in the treatment of CHD should reduce the risk for successively younger cohorts and shift the risk for all age groups over time. Although there were gains in CHD mortality globally over the past three decades, unfavourable period and cohort effects were found in many countries, raising questions about adequacy of their health care for CHD patients across all age groups. These failings carry significant implications for the likelihood of achieving the Sustainable Development Goal targets for under-5 years and NCD mortality. FUNDING: Supported by the National Natural Science Foundation of China (81525002, 31971048, 82073573 to ZZ and HZ), Shanghai Outstanding Medical Academic Leader program (2019LJ22 to HZ), and Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01 to HZ), the Bill & Melinda Gates Foundation for the Global Burden of Disease Project (to NJK) and NHMRC fellowship administered through the University of Melbourne (to GCP).

The incidence of allergic diseases continues to rise. Cross-sectional and longitudinal studies have indicated that allergic diseases occur in a time-based order: from atopic dermatitis and food allergy in infancy to gradual development into allergic asthma and allergic rhinitis in childhood. This phenomenon is defined as the "atopic march". Some scholars have suggested that the atopic march does not progress completely in a temporal pattern with genetic and environmental factors. Also, the mechanisms underlying the atopic march are incompletely understood. Nevertheless, the concept of the atopic march provides a new perspective for the mechanistic research, prediction, prevention, and treatment of atopic diseases. Here, we review the epidemiology, related diseases, mechanistic studies, and treatment strategies for the atopic march.

The crosstalk between vascular pericytes and endothelial cells (ECs) is critical for microvascular stabilization and remodeling; however, the crosstalk is often disrupted by diabetes, leading to severe and even lethal vascular damage. Circular RNAs are a class of endogenous RNAs that regulate several important physiological and pathological processes. Here we show that diabetes-related stress up-regulates cPWWP2A expression in pericytes but not in ECs. In vitro studies show that cPWWP2A directly regulates pericyte biology but indirectly regulates EC biology via exosomes carrying cPWWP2A. cPWWP2A acts as an endogenous miR-579 sponge to sequester and inhibit miR-579 activity, leading to increased expression of angiopoietin 1, occludin, and SIRT1. In vivo studies show that cPWWP2A overexpression or miR-579 inhibition alleviates diabetes mellitus-induced retinal vascular dysfunction. By contrast, inhibition of cPWWP2A-mediated signaling by silencing cPWWP2A or overexpressing miR-579 aggravates retinal vascular dysfunction. Collectively, this study unveils a mechanism by which pericytes and ECs communicate. Intervention of cPWWP2A or miR-579 expression may offer opportunities for treating diabetic microvascular complications.

Aminoglycosides are toxic to sensory hair cells (HCs). Macroautophagy/autophagy is an essential and highly conserved self-digestion pathway that plays important roles in the maintenance of cellular function and viability under stress. However, the role of autophagy in aminoglycoside-induced HC injury is unknown. Here, we first found that autophagy activity was significantly increased, including enhanced autophagosome-lysosome fusion, in both cochlear HCs and HEI-OC-1 cells after neomycin or gentamicin injury, suggesting that autophagy might be correlated with aminoglycoside-induced cell death. We then used rapamycin, an autophagy activator, to increase the autophagy activity and found that the ROS levels, apoptosis, and cell death were significantly decreased after neomycin or gentamicin injury. In contrast, treatment with the autophagy inhibitor 3-methyladenine (3-MA) or knockdown of autophagy-related (ATG) proteins resulted in reduced autophagy activity and significantly increased ROS levels, apoptosis, and cell death after neomycin or gentamicin injury. Finally, after neomycin injury, the antioxidant N-acetylcysteine could successfully prevent the increased apoptosis and HC loss induced by 3-MA treatment or ATG knockdown, suggesting that autophagy protects against neomycin-induced HC damage by inhibiting oxidative stress. We also found that the dysfunctional mitochondria were not eliminated by selective autophagy (mitophagy) in HEI-OC-1 cells after neomycin treatment, suggesting that autophagy might not directly target the damaged mitochondria for degradation. This study demonstrates that moderate ROS levels can promote autophagy to recycle damaged cellular constituents and maintain cellular homeostasis, while the induction of autophagy can inhibit apoptosis and protect the HCs by suppressing ROS accumulation after aminoglycoside injury.

The sarcomeric interaction of α-myosin heavy chain (α-MHC) with Titin is vital for cardiac structure and contraction. However, the mechanism regulating this interaction in normal and failing hearts remains unknown. Lactate is a crucial energy substrate of the heart. Here, we identify that α-MHC undergoes lactylation on lysine 1897 to regulate the interaction of α-MHC with Titin. We observed a reduction of α-MHC K1897 lactylation in mice and patients with heart failure. Loss of K1897 lactylation in α-MHC K1897R knock-in mice reduces α-MHC-Titin interaction and leads to impaired cardiac structure and function. Furthermore, we identified that p300 and Sirtuin 1 act as the acyltransferase and delactylase of α-MHC, respectively. Decreasing lactate production by chemical or genetic manipulation reduces α-MHC lactylation, impairs α-MHC-Titin interaction and worsens heart failure. By contrast, upregulation of the lactate concentration by administering sodium lactate or inhibiting the pivotal lactate transporter in cardiomyocytes can promote α-MHC K1897 lactylation and α-MHC-Titin interaction, thereby alleviating heart failure. In conclusion, α-MHC lactylation is dynamically regulated and an important determinant of overall cardiac structure and function. Excessive lactate efflux and consumption by cardiomyocytes may decrease the intracellular lactate level, which is the main cause of reduced α-MHC K1897 lactylation during myocardial injury. Our study reveals that cardiac metabolism directly modulates the sarcomeric structure and function through lactate-dependent modification of α-MHC.