[177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high­dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study.

BACKGROUND: There are currently no standard first-line treatment options for patients with higher grade 2-3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) treatment. METHODS: NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting. FINDINGS: Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the 177Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7-13·8) in the control group and 22·8 months (19·4-not estimated) in the 177Lu-Dotatate group (stratified hazard ratio 0·276 [0·182-0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the 177Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period. INTERPRETATION: First-line 177Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177Lu-Dotatate should be considered a new standard of care in first-line therapy in this population. FUNDING: Advanced Accelerator Applications, a Novartis Company.

Model Simulations and Predictions of Hydroxymethanesulfonate (HMS) in the Beijing-Tianjin-Hebei Region, China: Roles of Aqueous Aerosols and Atmospheric Acidity.

Hydroxymethanesulfonate (HMS) has been found to be an abundant organosulfur aerosol compound in the Beijing-Tianjin-Hebei (BTH) region with a measured maximum daily mean concentration of up to 10 µg per cubic meter in winter. However, the production medium of HMS in aerosols is controversial, and it is unknown whether chemical transport models are able to capture the variations of HMS during individual haze events. In this work, we modify the parametrization of HMS chemistry in the nested-grid GEOS-Chem chemical transport model, whose simulations provide a good account of the field measurements during winter haze episodes. We find the contribution of the aqueous aerosol pathway to total HMS is about 36% in winter in Beijing, due primarily to the enhancement effect of the ionic strength on the rate constants of the reaction between dissolved formaldehyde and sulfite. Our simulations suggest that the HMS-to-inorganic sulfate ratio will increase from the baseline of 7% to 13% in the near future, given the ambitious clean air and climate mitigation policies for the BTH region. The more rapid reductions in emissions of SO2 and NOx compared to NH3 alter the atmospheric acidity, which is a critical factor leading to the rising importance of HMS in particulate sulfur species.

Characterizing the emission trends and pollution evolution patterns during the transition period following COVID-19 at an industrial megacity of central China.

After the resumption of work and production following the COVID-19 pandemic, many cities entered a "transition phase", characterized by the gradual recovery of emission levels from various sources. Although the overall PM2.5 emission trends have recovered, the specific changes in different sources of PM2.5 remain unclear. Here, we investigated the changes in source contributions and the evolution pattern of pollution episodes (PE) in Wuhan during the "transition period" and compared them with the same period during the COVID-19 lockdown. We found that vehicle emissions, industrial processes, and road dust exhibited significant recoveries during the transition period, increasing by 5.4%, 4.8%, and 3.9%, respectively, during the PE. As primary emissions increased, secondary formation slightly declined, but it still played a predominant role (accounting for 39.1∼ 43.0% of secondary nitrate). The reduction in industrial activities was partially offset by residential burning. The evolution characteristics of PE exhibited significant differences between the two periods, with PM2.5 concentration persisting at a high level during the transition period. The differences in the evolution patterns of the two periods were also reflected in their change rates at each stage, which mostly depend on the pre-PE concentration level. The transition period shows a significantly higher value (8.4 µg m-3 h-1) compared with the lockdown period, almost double the amount. In addition to local emissions, regional transport should be a key consideration in pollution mitigation strategies, especially in areas adjacent to Wuhan. Our study quantifies the variations in sources between the two periods, providing valuable insights for optimizing environmental planning to achieve established goals.

Integrating Nurse-Led Interventions in Ophthalmology Care: A Systematic Review.

BACKGROUND: Nurse-led interventions in ophthalmology care can enhance the overall patient experience while optimizing health care system efficiency. PURPOSE: The purpose of this study was to investigate the impact of nurse-led interventions in ophthalmology care. METHODS: A comprehensive search was conducted across multiple databases for articles published from 2000 to 2023. Randomized controlled trials, quasi-experimental, and observational studies were included. Quality assessments were performed using the Cochrane Risk of Bias tool or Newcastle-Ottawa Scale, based on study design. RESULTS: Nineteen studies were included. Nurse-led interventions positively impacted patient outcomes, improved efficiency and resource utilization, enhanced patient satisfaction and adherence, maintained safety and efficacy, and demonstrated notable diagnostic accuracy. Included studies originated from different countries and employed diverse methodologies, offering a global perspective on nurse-led interventions in ophthalmology care. CONCLUSION: The findings advocate for the integration of nurse-led strategies in routine practice to realize equitable, efficient, and patient-centered eye care.

Sensitivity analyses for the principal ignorability assumption using multiple imputation.

In the context of clinical trials, there is interest in the treatment effect for subpopulations of patients defined by intercurrent events, namely disease-related events occurring after treatment initiation that affect either the interpretation or the existence of endpoints. With the principal stratum strategy, the ICH E9(R1) guideline introduces a formal framework in drug development for defining treatment effects in such subpopulations. Statistical estimation of the treatment effect can be performed based on the principal ignorability assumption using multiple imputation approaches. Principal ignorability is a conditional independence assumption that cannot be directly verified; therefore, it is crucial to evaluate the robustness of results to deviations from this assumption. As a sensitivity analysis, we propose a joint model that multiply imputes the principal stratum membership and the outcome variable while allowing different levels of violation of the principal ignorability assumption. We illustrate with a simulation study that the joint imputation model-based approaches are superior to naive subpopulation analyses. Motivated by an oncology clinical trial, we implement the sensitivity analysis on a time-to-event outcome to assess the treatment effect in the subpopulation of patients who discontinued due to adverse events using a synthetic dataset. Finally, we explore the potential usage and provide interpretation of such analyses in clinical settings, as well as possible extension of such models in more general cases.

Impacts of meteorology and precursor emission change on O3 variation in Tianjin, China from 2015 to 2021.

Deterioration of surface ozone (O3) pollution in Northern China over the past few years received much attention. For many cities, it is still under debate whether the trend of surface O3 variation is driven by meteorology or the change in precursors emissions. In this work, a time series decomposition method (Seasonal-Trend decomposition procedure based on Loess (STL)) and random forest (RF) algorithm were utilized to quantify the meteorological impacts on the recorded O3 trend and identify the key meteorological factors affecting O3 pollution in Tianjin, the biggest coastal port city in Northern China. After "removing" the meteorological fluctuations from the observed O3 time series, we found that variation of O3 in Tianjin was largely driven by the changes in precursors emissions. The meteorology was unfavorable for O3 pollution in period of 2015-2016, and turned out to be favorable during 2017-2021. Specifically, meteorology contributed 9.3 µg/m3 O3 (13%) in 2019, together with the increase in precursors emissions, making 2019 to be the worst year of O3 pollution since 2015. Since then, the favorable effects of meteorology on O3 pollution tended to be weaker. Temperature was the most important factor affecting O3 level, followed by air humidity in O3 pollution season. In the midday of summer days, O3 pollution frequently exceeded the standard level (>160 µg/m3) at a combined condition with relative humidity in 40%-50% and temperature > 31°C. Both the temperature and the dryness of the atmosphere need to be subtly considered for summer O3 forecasting.

Preliminary evaluation of the Chinese version of the patient-reported outcomes measurement information system 29-item profile in patients with aortic dissection.

BACKGROUND: The Patient-Reported Outcomes Measurement Information System 29-item Profile (PROMIS-29) has been widely used to measure health outcomes from the patient's perspective. It has not been validated in adults with aortic disease. The aim of this study was to explore the reliability and validity of the Chinese PROMIS-29 among patients undergoing surgery for aortic dissection (AD). METHODS: A cross-sectional design was applied. Eligible patients completed a questionnaire that contained the PROMIS-29 and legacy measures, including the Short Form-12 Health Survey (SF-12), 8-item Somatic Symptom Scale (SSS-8), Generalized Anxiety Disorder-2 (GAD-2), and Patient Health Questionnaire-2 (PHQ-2). The structural validity of the PROMIS-29 was evaluated using confirmatory factor analysis (CFA). Reliability was evaluated with Cronbach's α. Construct validity was assessed by calculating Spearman's rank correlations and comparing known-group differences. RESULTS: In total, a sample of 327 AD patients was included in the final analysis. Most of them were male (89%) with a mean age of 52.7 (± 10.3). CFA revealed good model fit of the seven-factor structure within PROMIS-29, as well as most domains in single-factor analysis. Reliability was confirmed with Cronbach's α > 0.90. Correlations between comparable domains of the PROMIS-29 and those of legacy questionnaires and most know-group comparisons were observed as hypothesized. CONCLUSIONS: This study found evidence for acceptable structural validity, construct validity and internal consistency of the PROMIS-29 in a sample of AD patients. It can be applied to AD survivors by researchers or clinicians, measuring outcomes after surgery and identifying those with worse health status.

Anticentromere antibody induced by immunization with centromere protein and Freund's complete adjuvant may interfere with mouse early-stage embryo.

BACKGROUND: Anticentromere antibody (ACA) is a member of the antinuclear antibody spectrum (ANAs) which has been speculated to be associated with subfertility. Thus, the present study aimed to investigate the induction of ACA production and its potential interference with early-stage embryos. METHODS: Recombinant centromere protein-A (CENP-A) or centromere protein-B (CENP-B) and complete Freund's adjuvant (CFA) were used to immunize mice. Serum ACA level was then evaluated by using an indirect immunofluorescence test. Immunofluorescence assay was performed to detect IgG in follicles in ovarian tissues and early-stage embryos. RESULTS: Following treatment, serum positive ACA was observed in mice treated with CENP and CFA. Furthermore, IgG were detected in follicular fluid and early-stage embryos from mice treated with CENP and CFA. CONCLUSIONS: This study preliminarily indicated that ACA induced by CENP and CFA may penetrate into the living embryos of early-stage in mice.

Spring Festival and COVID-19 Lockdown: Disentangling PM Sources in Major Chinese Cities.

Responding to the 2020 COVID-19 outbreak, China imposed an unprecedented lockdown producing reductions in air pollutant emissions. However, the lockdown driven air pollution changes have not been fully quantified. We applied machine learning to quantify the effects of meteorology on surface air quality data in 31 major Chinese cities. The meteorologically normalized NO2, O3, and PM2.5 concentrations changed by -29.5%, +31.2%, and -7.0%, respectively, after the lockdown began. However, part of this effect was also associated with emission changes due to the Chinese Spring Festival, which led to ∼14.1% decrease in NO2, ∼6.6% increase in O3 and a mixed effect on PM2.5 in the studied cities that largely resulted from festival associated fireworks. After decoupling the weather and Spring Festival effects, changes in air quality attributable to the lockdown were much smaller: -15.4%, +24.6%, and -9.7% for NO2, O3, and PM2.5, respectively.

Long intergenic noncoding RNA 00473 promoting migration and invasion of trophoblastic cell line HTR-8/SVneo via regulating miR-424-5p-mediated wnt3a/ß-catenin signaling pathway.

BACKGROUND: Preeclampsia (PE) is a serious obstetric complication. Recent studies point out that the functions of long intergenic noncoding RNA 00473 (linc00473), miR-424-5p, and Wnt/ß-catenin signaling pathway were involved in the invasion and migration of extravillous trophoblast. Here, we investigated the role and mechanism of linc00473 in HTR-8/SVneo trophoblastic cell line and its role in PE. METHOD: The expression levels of linc00473 and miR-424-5p in placental tissues and the transfection efficiency of miR-424-5p were detected by quantitative real-time polymerase chain reaction (qRT-PCR). HTR-8/SVneo cell invasion and proliferation were determined by transwell and Cell Counting Kit-8 (CCK-8) assays. The protein expressions of wnt3a, p-GSK3ß, GSK3ß, active ß-catenin, and total ß-catenin were detected by Western blot. The apoptosis and migration of HTR-8/SVneo cells were detected by flow cytometry and wound healing assays. The targeting relationships between linc00473, miR-424-5p, and wnt3a were predicted by ENCORI database and TargetScan V7.2 and were determined using dual-luciferase reporter assay. RESULTS: The expression level of linc00473 was low and miR-424-5p was high in placenta of PE patients. Linc00473 can target miR-424-5p, while miR-424-5p target wnt3a. High expression of linc00473 and wnt3a promoted cell proliferation, migration, invasion, and inhibited cell apoptosis. However, miR-424-5p mimic inhibited HTR-8/SVneo cells proliferation, migration, invasion, while promoted cell apoptosis, partially reversed the effect of linc00473, while wnt3a overexpression partially counteracted the effect of miR-424-5p mimic. CONCLUSION: Linc00473 mediates the regulation of Wnt/ß-catenin signaling pathway by miR-424-5p to affect the invasion and migration ability of trophoblastic cell line HTR-8/SVneo. It indicated that linc00473 is involved in PE and could be a therapeutic target.

Impact of meteorological condition changes on air quality and particulate chemical composition during the COVID-19 lockdown.

Stringent quarantine measures during the Coronavirus Disease 2019 (COVID-19) lockdown period (January 23, 2020 to March 15, 2020) have resulted in a distinct decrease in anthropogenic source emissions in North China Plain compared to the paralleled period of 2019. Particularly, 22.7% decrease in NO2 and 3.0% increase of O3 was observed in Tianjin, nonlinear relationship between O3 generation and NO2 implied that synergetic control of NOx and VOCs is needed. Deteriorating meteorological condition during the COVID-19 lockdown obscured the actual PM2.5 reduction. Fireworks transport in 2020 Spring Festival (SF) triggered regional haze pollution. PM2.5 during the COVID-19 lockdown only reduced by 5.6% in Tianjin. Here we used the dispersion coefficient to normalize the measured PM2.5 (DN-PM2.5), aiming to eliminate the adverse meteorological impact and roughly estimate the actual PM2.5 reduction, which reduced by 17.7% during the COVID-19 lockdown. In terms of PM2.5 chemical composition, significant NO3- increase was observed during the COVID-19 lockdown. However, as a tracer of atmospheric oxidation capacity, odd oxygen (Ox = NO2 + O3) was observed to reduce during the COVID-19 lockdown, whereas relative humidity (RH), specific humidity and aerosol liquid water content (ALWC) were observed with noticeable enhancement. Nitrogen oxidation rate (NOR) was observed to increase at higher specific humidity and ALWC, especially in the haze episode occurred during 2020SF, high air humidity and obvious nitrate generation was observed. Anomalously enhanced air humidity may response for the nitrate increase during the COVID-19 lockdown period.

Size distribution and chemical characteristics of particles from crop residue open burning in North China.

Crop residue open burning is an important emission source of ambient particles in China. This study analyzed the particle emission characteristics of crop residue open burning through combustion experiments with a novel open combustion simulation device using three typical crop straws in north China (corn, wheat, and rice). Particle samples size ranging from 0.006-9.890 µm were collected by an Electrical Low Pressure Impactor plus, a high size-resolution instrument capable of dividing particles into 14 size stages. The size distributions of organic carbon (OC), elemental carbon (EC), water-soluble ions, and elements were analyzed, and source chemical profiles were constructed for PM0.1, PM1, PM2.5, and PM10. The number concentration of particles was concentrated in the Aiken nuclei mode (0.006-0.054 µm), accounting for 75% of the total number, whereas the mass concentration was concentrated in the accumulation mode (0.054-0.949 µm), accounting for 85.43% of the mass loading. OC, EC, Cl-, and K(include total K and water-soluble K) were the major chemical components of the particles, whose mass percentage distributions differed from those of other components. These five main components exhibited a bell-shaped size distribution in the 0.006-9.890 µm range, whereas the other components exhibited a U-shaped distribution. Among the chemical profiles for PM0.1-PM10, OC was the most important component at 10-30%, followed by EC at 2%-8%. The proportions of K+, Cl-, and K varied substantially in different experimental groups, ranging from 0-15%, and K+ and Cl- were significantly correlated (r = 0.878, α = 0.000).

Dispersion Normalized PMF Provides Insights into the Significant Changes in Source Contributions to PM2.5 after the COVID-19 Outbreak.

Factor analysis utilizes the covariance of compositional variables to separate sources of ambient pollutants like particulate matter (PM). However, meteorology causes concentration variations in addition to emission rate changes. Conventional positive matrix factorization (PMF) loses information from the data because of these dilution variations. By incorporating the ventilation coefficient, dispersion normalized PMF (DN-PMF) reduces the dilution effects. DN-PMF was applied to hourly speciated particulate composition data from a field campaign that included the start of the COVID-19 outbreak. DN-PMF sharpened the morning coal combustion and rush hour traffic peaks and lowered the daytime soil, aged sea salt, and waste incinerator contributions that better reflect the actual emissions. These results identified significant changes in source contributions after the COVID-19 outbreak in China. During this pandemic, secondary inorganic aerosol became the predominant PM2.5 source representing 50.5% of the mean mass. Fireworks and residential burning (32.0%), primary coal combustion emissions (13.3%), primary traffic emissions (2.1%), soil and aged sea salt (1.2%), and incinerator (0.9%) represent the other contributors. Traffic decreased dramatically (70%) compared to other sources. Soil and aged sea salt also decreased by 68%, likely from decreased traffic.

Money matters: a multicenter cross-sectional study of depressive symptoms among the caregivers of children on peritoneal dialysis in Mainland China.

BACKGROUND: The caregivers of children on peritoneal dialysis face heavy care burdens and may have a high risk of depression. This study aimed to describe the prevalence and severity of depression and identify its related demographic and socioeconomic factors in the caregivers of children on peritoneal dialysis in China. METHODS: A multicenter cross-sectional study was conducted in four pediatric dialysis centers in four tertiary children's hospitals in mainland China. Primary caregivers of children with end-stage kidney disease and currently on peritoneal dialysis were screened and recruited from December 2018 to July 2019. A self-developed questionnaire and the Self-Rating Depression Scale (SDS) were administered to the participants by a trained nurse in each center. The chi-square test or Fisher's exact test, one-way ANOVA, and the Mann-Whitney U test were used to compare the prevalence of depressive symptoms by demographic features. A multivariate logistic regression analysis was used to identify factors related to depressive symptoms in caregivers of children on peritoneal dialysis. RESULTS: One hundred twenty-one caregivers were included in the data analysis. The mean age of the caregivers was 40.1 ± 8.1 years. More than 75% of the participants were female, married, and unemployed. The overall prevalence of depressive symptoms was 59%. In total, 46 (38%), 20 (17%) and 5 (4%) caregivers reported mild, moderate, and severe depressive symptoms, respectively. In the univariate analysis, caregivers with an average household income per month under 4000 RMB and caregivers of children undergoing laparoscopic surgery had a higher prevalence of depressive symptoms. Characteristics such as treatment center, duration on PD, PD modalities, and history of peritonitis episodes showed no difference in terms of the prevalence of depressive symptoms. The multivariate logistic regression analysis demonstrated that an average household income per month under 4000 RMB was the associated factor for caregivers' depressive symptoms. CONCLUSIONS: The caregivers of children on peritoneal dialysis in mainland China were socially vulnerable and experienced depression. Those who had a higher average household income were less vulnerable to depression.

Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial.

BACKGROUND: Patients with relapsed or refractory FLT3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia have a poor prognosis, including high frequency of relapse, poorer response to salvage therapy, and shorter overall survival than those with FLT3 wild-type disease. We aimed to assess whether single-agent quizartinib, an oral, highly potent and selective type II FLT3 inhibitor, improves overall survival versus salvage chemotherapy. METHODS: QuANTUM-R is a randomised, controlled, phase 3 trial done at 152 hospitals and cancer centres in 19 countries. Eligible patients aged 18 years or older with ECOG performance status 0-2 with relapsed or refractory (duration of first composite complete remission ≤6 months) FLT3-ITD acute myeloid leukaemia after standard therapy with or without allogeneic haemopoietic stem-cell transplantation were randomly assigned (2:1; permuted block size of 6; stratified by response to previous therapy and choice of chemotherapy via a phone-based and web-based interactive response system) to quizartinib (60 mg [30 mg lead-in] orally once daily) or investigator's choice of preselected chemotherapy: subcutaneous low-dose cytarabine (subcutaneous injection of cytarabine 20 mg twice daily on days 1-10 of 28-day cycles); intravenous infusions of mitoxantrone (8 mg/m2 per day), etoposide (100 mg/m2 per day), and cytarabine (1000 mg/m2 per day on days 1-5 of up to two 28-day cycles); or intravenous granulocyte colony-stimulating factor (300 µg/m2 per day or 5 µg/kg per day subcutaneously on days 1-5), fludarabine (intravenous infusion 30 mg/m2 per day on days 2-6), cytarabine (intravenous infusion 2000 mg/m2 per day on days 2-6), and idarubicin (intravenous infusion 10 mg/m2 per day on days 2-4 in up to two 28-day cycles). Patients proceeding to haemopoietic stem-cell transplantation after quizartinib could resume quizartinib after haemopoietic stem-cell transplantation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02039726, and follow-up is ongoing. FINDINGS: Between May 7, 2014, and Sept 13, 2017, 367 patients were enrolled, of whom 245 were randomly allocated to quizartinib and 122 to chemotherapy. Four patients in the quizartinib group and 28 in the chemotherapy group were not treated. Median follow-up was 23·5 months (IQR 15·4-32·3). Overall survival was longer for quizartinib than for chemotherapy (hazard ratio 0·76 [95% CI 0·58-0·98; p=0·02]). Median overall survival was 6·2 months (5·3-7·2) in the quizartinib group and 4·7 months (4·0-5·5) in the chemotherapy group. The most common non-haematological grade 3-5 treatment-emergent adverse events (within ≤30 days of last dose or >30 days if suspected to be a treatment-related event) for quizartinib (241 patients) and chemotherapy (94 patients) were sepsis or septic shock (46 patients [19%] for quizartinib vs 18 [19%] for chemotherapy), pneumonia (29 [12%] vs eight [9%]), and hypokalaemia (28 [12%] vs eight [9%]). The most frequent treatment-related serious adverse events were febrile neutropenia (18 patients [7%]), sepsis or septic shock (11 [5%]), QT prolongation (five [2%]), and nausea (five [2%]) in the quizartinib group, and febrile neutropenia (five [5%]), sepsis or septic shock (four [4%]), pneumonia (two [2%]), and pyrexia (two [2%]) in the chemotherapy group. Grade 3 QT prolongation in the quizartinib group was uncommon (eight [3%] by central reading, ten [4%] by investigator report); no grade 4 events occurred. There were 80 (33%) treatment-emergent deaths in the quizartinib group (31 [13%] of which were due to adverse events) and 16 (17%) in the chemotherapy group (nine [10%] of which were due to adverse events). INTERPRETATION: Treatment with quizartinib had a survival benefit versus salvage chemotherapy and had a manageable safety profile in patients with rapidly proliferative disease and very poor prognosis. Quizartinib could be considered a new standard of care. Given that there are only a few available treatment options, this study highlights the value of targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor. FUNDING: Daiichi Sankyo.

Insight into the critical factors determining the particle number concentrations during summer at a megacity in China.

To identify the critical factors impacting the number concentration of particles with the aerodynamic diameters less than 2.5µm (PNC2.5), the continuous measurement of PNC2.5, chemical components in PM2.5, gaseous pollutants and meteorological conditions were conducted at an urban site in Tianjin in June 2015. Results indicated that the average PNC2.5 was 2839±2430 dN/dlogDp 1/cm3 during the campaign. Compared to other meteorological parameters, the relative humidity (RH) had the strongest relationship with PNC2.5, with a Pearson's correlation coefficient of 0.53, and RH larger than 30% influenced strongly PNC2.5. The important influence of secondary reactions on PNC2.5 was inferred due to higher correlation coefficients between PNC2.5 and SO42-, NO3-, NH4+ (r=0.78-0.89; p<0.01) and between PNC2.5 and ratios that represent the conversion of nitrogen and sulfur oxides to particulate matter (r=0.42-0.49; p<0.01). Under specific RH conditions, there were even stronger correlations between PNC2.5 and NO3-, SO42-, NH4+, while those between PNC2.5 and EC, OC were relatively weak, especially when RH exceeded 50%. Principal component analysis (PCA) and Pearson's correlation analysis indicated that secondary sources, vehicle emission and coal combustion might be major contributors to PNC2.5. Backward trajectory and potential source contribution function (PSCF) analysis suggested that the transport of air masses originated from these regions around Tianjin (Liaoning, Hebei, Shandong and Jiangsu) influenced critically PNC2.5. The north of Jiangsu, the west of Shandong, and the east of Hebei were distinguished as major potential source-areas of PNC2.5 by PSCF model.

A Promising Generation: Future Academic Leadership of China.

With the world's largest population at 1.3 billion and a rising number of foreigners, China requires physicians and a healthcare system that meets the needs of a large and diverse population. Along with rapid economic and technological advancements, the Medical Administration Division of the National Health and Family Planning Commission remarked that medical services through online appointments and payments have improved its efficacy over the past 2 years. According to the official report from the National Health and Family Planning Commission of the People's Republic of China website, China has so far established a total of 25,000 hospitals and 981,000 community health centers, that includes 17,100 dermatologists and 190,000 residents in training.

Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Disease progression in patients with HER2-positive breast cancer receiving trastuzumab might be associated with activation of the PI3K/Akt/mTOR intracellular signalling pathway. We aimed to assess whether the addition of the mTOR inhibitor everolimus to trastuzumab might restore sensitivity to trastuzumab. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited women with HER2-positive, trastuzumab-resistant, advanced breast carcinoma who had previously received taxane therapy. Eligible patients were randomly assigned (1:1) using a central patient screening and randomisation system to daily everolimus (5 mg/day) plus weekly trastuzumab (2 mg/kg) and vinorelbine (25 mg/m(2)) or to placebo plus trastuzumab plus vinorelbine, in 3-week cycles, stratified by previous lapatinib use. The primary endpoint was progression-free survival (PFS) by local assessment in the intention-to-treat population. We report the final analysis for PFS; overall survival follow-up is still in progress. This trial is registered with ClinicalTrials.gov, number NCT01007942. FINDINGS: Between Oct 26, 2009, and May 23, 2012, 569 patients were randomly assigned to everolimus (n=284) or placebo (n=285). Median follow-up at the time of analysis was 20.2 months (IQR 15.0-27.1). Median PFS was 7.00 months (95% CI 6.74-8.18) with everolimus and 5.78 months (5.49-6.90) with placebo (hazard ratio 0.78 [95% CI 0.65-0.95]; p=0.0067). The most common grade 3-4 adverse events were neutropenia (204 [73%] of 280 patients in the everolimus group vs 175 [62%] of 282 patients in the placebo group), leucopenia (106 [38%] vs 82 [29%]), anaemia (53 [19%] vs 17 [6%]), febrile neutropenia (44 [16%] vs ten [4%]), stomatitis (37 [13%] vs four [1%]), and fatigue (34 [12%] vs 11 [4%]). Serious adverse events were reported in 117 (42%) patients in the everolimus group and 55 (20%) in the placebo group; two on-treatment deaths due to adverse events occurred in each group. INTERPRETATION: The addition of everolimus to trastuzumab plus vinorelbine significantly prolongs PFS in patients with trastuzumab-resistant and taxane-pretreated, HER2-positive, advanced breast cancer. The clinical benefit should be considered in the context of the adverse event profile in this population.

Assessing emission-driven changes in health risk of source-specific PM2.5-bound heavy metals by adjusting meteorological covariates.

Heavy metals (HMs) in PM2.5 gain much attention for their toxicity and carcinogenic risk. This study evaluates the health risks of PM2.5-bound HMs, focusing on how meteorological conditions affect these risks against the backdrop of PM2.5 reduction trends in China. By applying a receptor model with a meteorological normalization technique, followed by health risk assessment, this work reveals emission-driven changes in health risk of source-specific HMs in the outskirt of Tianjin during the implementation of China' second Clean Air Action (2018-2020). Sources of PM2.5-bound HMs were identified, with significant contributions from vehicular emissions (on average, 33.4 %), coal combustion (26.3 %), biomass burning (14.1 %), dust (11.7 %), industrial boilers (9.7 %), and shipping emission and sea salt (4.7 %). The source-specific emission-driven health risk can be enlarged or dwarfed by the changing meteorological conditions over time, demonstrating that the actual risks from these source emissions for a given time period may be higher or smaller than those estimated by traditional assessments. Meteorology contributed on average 56.1 % to the interannual changes in source-specific carcinogenic risk of HMs from 2018 to 2019, and 5.6 % from 2019 to 2020. For the source-specific noncarcinogenic risk changes, the contributions were 38.3 % and 46.4 % for the respective periods. Meteorology exerts a more profound impact on daily risk (short-term trends) than on annual risk (long-term trends). Such meteorological impacts differ among emission sources in both sign and magnitude. Reduced health risks of HMs were largely from targeted regulatory measures on sources. Therefore, the meteorological covariates should be considered to better evaluate the health benefits attributable to pollution control measures in health risk assessment frameworks.

Aerosol in global oceanic regions: Four-decade trends, spatial patterns, and policy implications.

High aerosol loadings are observed not only in megacities on continents but also in oceanic regions like the Bohai Sea. This work provides a comprehensive analysis of the spatial and temporal variations in Aerosol Optical Depth (AOD) across different ocean regions worldwide over the past four decades, using remote sensing reanalysis data. The mean AOD value across all oceanic grids is approximately 0.112, with higher levels recorded in the Central Atlantic (~0.206), followed by the North Indian Ocean (~0.201), and the Western North Pacific (~0.197). A latitudinal analysis reveals that high AOD values are predominantly found in the Northern Hemisphere's oceanic regions, especially between latitudes 0° and 70° N. Except for the Gulf of California and Hudson Bay, AOD values in the other fourteen surveyed inland seas surpass the mean levels found at similar latitudes in oceanic regions. Among which, the Bohai Sea stands out as the most polluted oceanic region with AOD value of 0.35. Over the last four decades, AOD trends have revealed a significant decrease across about 89.5 % of global oceanic grids, while an increase in AOD is observed in low-latitude oceanic areas (30° S-30° N). Investigation into inland seas shows that nearly two-thirds have experienced a declining AOD trend, while sharply upward trends in AOD are primarily found in Asia. The Bohai Sea shows the largest increase in AOD, with an annual growth rate of 1.4 %. The turning-points of the AOD in each inland sea confirm the success of regional emission control policies initiated on the adjacent continents. To improve air quality in inland seas like the Bohai Sea, adjusting industrial layouts, such as relocating heavy industries from the surrounding coastal cities' proximities to areas near open seas, could significantly benefit public health.