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Background There existed evidence that type 2 diabetes mellitus (T2DM) prevalence and control rate have seasonal variation. Our study aimed to examine the ambient temperature and fasting plasma glucose (FPG) association and estimate temperature-adjusted T2DM prevalence and control rate. Methods Four cross-sectional health surveys with 26,350 respondents were conducted in Guangdong Province from 2007 to 2015. Multistage cluster sampling was used to recruit study participants. The data of demographic characteristics, lifestyle factors, diet and use of hypoglycemic medicine, height, weight, FPG and meteorological information were collected. And an inverse distance-weighted method was employed to estimate daily temperature exposures at the individual’ s residential district/county. Base on World Health Organization 2006 criteria, participants were divided into normal fasting glucose (NFG) participants (n = 23,877), known T2DM patients (n = 916) and newly detected T2DM patients (n = 1557). Generalized additive mixed model was employed to evaluate the nonlinear associations between temperature and FPG among different T2DM subgroups. The T2DM prevalence and control rate were estimated based on temperature-FPG association. Results The curves of temperature and FPG were downward parabola for total, NFG and known T2DM groups, while it was “U”-shaped for newly detected T2DM patients. When temperature decreased from 30 °C to 4 °C, the FPG significantly increased 0.24 (95%CI: 0.15, 0.33) mmol/L, 0.10 (95%CI: 0.06, 0.14) mmol/L and 1.34 (95%CI: 0.56, 2.12) mmol/L in total, NFG and known T2DM groups, respectively. Compared to 19 °C, newly detected T2DM patients’ FPGs were increased 0.73 (95%CI: 0.13, 1.30) mmol/L at 4 °C and 0.53 (0.00, 1.07) mmol/L at 30 °C. The model-estimated temperature-adjusted T2DM prevalence had a down and up trend, with 9.7% at 5 °C, 8.9% at 20 °C and 9.4% at 30 °C, respectively. At 5, 10, 15, 20, 25 and 30 °C, the model-estimated temperature-adjusted T2DM control rates were 33.2, 35.4, 38.2, 43.6, 49.1 and 55.2%. Conclusion Temperature was negatively associated with FPG for NFG and known T2DM subgroups, while their association was U-shape for newly detected T2DM patients. Hence, the temperature-adjusted T2DM prevalence show a dip/peak pattern and T2DM control rate display a rising trend when temperature increase. Our findings suggest temperature should be considered in T2DM clinic management and epidemiological survey.

Objectives To analyse the patterns of transition of health burden for 110 causes of death by stratification of age, sex and geographic regions in Guangdong between 2005 and 2015. Methods We analysed the age-specific, sex-specific, region-specific mortality in Guangdong based on assembled databases. County-level surveillance data were calculated to inform city-level changes. Results The age-standardised mortality of all causes, non-communicable diseases (NCDs), communicable diseases, maternal diseases, neonatal diseases, malnutrition and injury declined progressively. Despite declining mortality of NCDs, the overall burden of disease was dominated by NCDs (ie, cerebrovascular disease, chronic obstructive pulmonary disease) that still accounted for 86.93% and 88.12% of death in 2005 and 2015, respectively. Considerable variations across geographic regions were observed (lowest in Pearl River Delta and highest in west Guangdong). There was a modest shift to transport injuries at younger ages and unintentional injuries in the elderly. Conclusions We have documented a dramatic change in the overall mortality and age-specific, sex-specific and cause-specific mortality in Guangdong province between 2005 and 2015. The significant burden of NCDs remains a major healthcare issue despite the notable progress in reducing mortality in Guangdong, China. Our findings highlight important unmet needs to refine healthcare services by taking into account the inequity of age, sex and geographic regions. Identification of the ‘treatable’ risk factors and improved disease surveillance should be continuously improved to minimised the overall and cause-specific mortality.

Objective: Patient-derived xenograft (PDX) models have shown great promise in preclinical and translational applications, but their consistency with primary tumors in phenotypic, genetic, and pharmacodynamic heterogeneity has not been well-studied. This study aimed to establish a PDX repository for non-small cell lung cancer (NSCLC) and to further elucidate whether it could preserve the heterogeneity within and between tumors in patients. Methods: A total of 75 surgically resected NSCLC specimens were implanted into immunodeficient NOD/SCID mice. Based on the successful establishment of the NSCLC PDX model, we compared the expressions of vimentin, Ki67, EGFR, and PD-L1 proteins between cancer tissues and PDX models using hematoxylin and eosin staining and immunohistochemical staining. In addition, we detected whole gene expression profiling between primary tumors and PDX generations. We also performed whole exome sequencing (WES) analysis in 17 first generation xenografts to further assess whether PDXs retained the patient heterogeneities. Finally, paclitaxel, cisplatin, doxorubicin, atezolizumab, afatininb, and AZD4547 were used to evaluate the responses of PDX models to the standard-of-care agents. Results: A large collection of serially transplantable PDX models for NSCLC were successfully developed. The histology and pathological immunohistochemistry of PDX xenografts were consistent with the patients’ tumor samples. WES and RNA-seq further confirmed that PDX accurately replicated the molecular heterogeneities of primary tumors. Similar to clinical patients, PDX models responded differentially to the standard-of-care treatment, including chemo-, targeted- and immuno-therapeutics. Conclusions: Our established PDX models of NSCLC faithfully reproduced the molecular, histopathological, and therapeutic characteristics, as well as the corresponding tumor heterogeneities, which provides a clinically relevant platform for drug screening, biomarker discovery, and translational research.

Background: Because the halo around the tumor in shear wave elastography (SWE) is defined as the “stiff rim” sign, the diagnosis of breast lesions with the stiff rim sign is popular. However, only a few studies have described the stiff rim sign quantitatively. Objective: This study aimed to investigate the usefulness of the stiff rim sign in the diagnosis and tumor, node, metastasis stage of breast cancer. Methods: Two hundred and ten breast lesions were analyzed retrospectively. The maximum, mean, minimum Young's modulus (YM), and the YM standard deviation in the lesion, the peritumoral stiffness (shell), and the region containing lesion and shell were obtained. The suspicious SWE feature with the best diagnostic performance was chosen to downgrade or upgrade the Breast Imaging Reporting and Data System (BI-RADS) classification. The coincidence rates of SWE and B-mode ultrasound in T staging and their positive predictive value (PPV) for T staging were compared. Results: The presence of “stiff rim” sign was selected to upgrade or downgrade the BI-RADS classification because of its best performance. In pathological benign lesions, 18.9% (25 of 132) of lesions should undergo biopsy if BI-RADS combined with the stiff rim sign were referred while it was 57.6% (76 of 132) if BI-RADS alone was referred. The coincidence rate of T2 staging evaluated by SWE was significantly higher than B-mode ultrasound (about 30% increase, P < 0.001). The PPVs of SWE for T1 and T2 staging were higher than B-mode ultrasound (P < 0.05). Conclusions: BI-RADS combined with “stiff rim” sign is expected to improve the diagnostic performance of breast lesions to avoid unnecessary biopsy. The maximum diameter of the lesion measured in SWE is more accurate than B-mode ultrasound in the estimation of T staging, which is beneficial to the treatment and prognosis of breast cancer.

Background Short-term exposure to fine particulate matter (PM2.5) increases the excess risk (ER) of deaths. The metals are important constituents that are responsible for health risks of PM2.5. However, the short-term mortality risks that are associated with individual PM2.5-bound metals are not comprehensively understood. Objective Estimate the short-term mortality risks and corresponding thresholds of PM2.5-bound metals, with the purpose of advancing our understanding of the health risks of PM2.5 exposure, meanwhile, guiding the policy making of PM2.5 pollution prevention and early warning. Methods Daily PM2.5 samples, which were collected in the urban region of Guangzhou from 2015 to 2016, were analyzed for metals. Air pollutants, meteorological and mortality data were collected during the same period. A distributed lag non-linear model was used to associate the ER of mortality with individual PM2.5-bound metals. A cluster analysis was processed to classify the cumulative ER of different metals into groups. Results 11 PM2.5-bound metals were statistically significantly associated with non-accidental death; the highest cumulative ER of mortality was 2.22%, 1.85%, 1.42%, 2.04%, 1.41%, 1.26%, 0.65%, 2.24%, 1.23%, 2.86%, and 1.84% for an interquartile range (IQR) increase in concentrations of lead (Pb), cadmium (Cd), arsenic (As), selenium (Se), antimony (Sb), manganese (Mn), nickel (Ni), thallium (Tl), barium (Ba), aluminum (Al), and iron (Fe), respectively. The metals were classified into high (Pb, Cd, Se, Tl, and Al), middle (As, Sb, Mn, Ba, and Fe), and low (Ni, copper, and zinc) ER groups according to their highest cumulative ER values. No threshold was found for concentration-response relationships between all the metals and mortality. Conclusion Pb, Cd, Se, Tl, and Al had more contributions to PM2.5-related mortality risk than the other metals. Specific emission source-control measures were needed to reduce the mortality risk of PM2.5 exposure. The mortality risks, which were associated with low-level exposure of PM2.5-bound metals, deserve attention in the design of early warning and self-prevention. Comprehensive exposure assessment of PM2.5-bound metals is required to understand and reduce the PM2.5-related health risks.

Although studies have investigated the associations between PM2.5 and mortality risk, evidence from rural areas is scarce. We aimed to compare the PM2.5-mortality associations between urban cities and rural areas in China. Daily mortality and air pollution data were collected from 215 locations during 2014–2017 in China. A two-stage approach was employed to estimate the location-specific and combined cumulative associations between short-term exposure to PM2.5 (lag 0–3 days) and mortality risks. The excess risks (ER) of all-cause, respiratory disease (RESP), cardiovascular disease (CVD), and cerebrovascular disease (CED) mortality for each 10 μg/m3 increment in PM2.5 across all locations were 0.54% (95% confidence interval [CI]: 0.38%, 0.70%), 0.51% (0.10%, 0.93%), 0.74% (0.50%, 0.97%), and 0.52% (0.20%, 0.83%), respectively. Slightly stronger associations for CVD (0.80% versus 0.60%) and CED (0.61% versus 0.26%) mortality were observed in urban cities than in rural areas, and slightly greater associations for RESP mortality (0.51% versus 0.43%) were found in rural areas than in urban cities. A mean of 2.11% (attributable fraction [AF], 95% CI: 1.48%, 2.76%) of all-cause mortality was attributable to PM2.5 exposure in China, with a larger AF in urban cities (2.89% [2.12%, 3.67%]) than in rural areas (0.61% [−0.60%, 1.84%]). Disparities in PM2.5-mortality associations between urban cities and rural areas were also found in some subgroups classified by sex and age. This study provided robust evidence on the associations of PM2.5 with mortality risks in China and demonstrated urban-rural disparities of PM2.5-mortality associations for various causes of death.

We hypothesized that exposure to polluting fuels for cooking was associated with abnormality of glucose metabolism and diabetes mellitus (DM) in south urban China. 3414 residents were surveyed in 14 urban areas of Guangdong Province in 2018. We recorded polluting fuels for cooking exposure, different DM status (DM, prediabetes), fasting blood glucose (FBG), oral glucose tolerance test (OGTT), glycated hemoglobin (HbA1c ), and other covariates by using a structured questionnaire. We conducted logistic regression model and multivariate linear regression model based on propensity-score method (inverse probability of weighting) to examine the effect of polluting fuels for cooking exposure on DM and glucose metabolism. Exposure to polluting fuels for cooking was associated with DM (odds ratio: 2.57, 95% confidence interval: 1.71 to 3.86) and prediabetes (odds ratio: 1.98, 95% confidence interval: 1.52 to 2.58) in both the adjusted and unadjusted models (all p

Background Hyperthyroidism-induced hypercalcemia has been reported previously, but hypercalcemia accompanied by severe osteoporosis and significant thymic enlargement in patients with hyperthyroidism is quite rare. We report the coexistence of hypercalcemia, osteoporosis and thymic enlargement in a patient with Graves’ disease. Case presentation A 22-year-old female was diagnosed as Graves’ disease with obviously elevated serum calcium and reduced parathyroid hormone levels. Dual-energy x-ray absorptiometry and chest enhanced computer tomography (CT) revealed severe osteoporosis and a significant enlargement of thymus. After the successful control of hyperthyroidism with methimazole, hypercalcemia was corrected, bone mineral density was improved and thymus also shrank obviously. Conclusion This is a very rare case of hypercalcemia accompanied by severe osteoporosis and significant thymic enlargement induced by Graves’ disease. In clinical practice, examination of thymus and bone density should be considered when a patient with Graves’ disease was present with hypercalcemia.

BackgroundSmall-cell lung cancer (SCLC) remains an aggressive cancer with short-term survival due to limited therapeutic options. Apatinib is a small-molecule tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor-2. This study aimed to investigate the efficacy and safety of apatinib in patients with extensive-stage (EC) SCLC who had progressed after two or three previous therapies.MethodsEligible patients were histologically confirmed ES-SCLC after two or three previous treatments, including a platinum-based regimen. Patients received apatinib at an initial dose of 500 mg once daily. The primary endpoint was the objective response rate.ResultsForty patients were enrolled. At the data cut-off time (November 15, 2018), the median follow-up was 7.4 months; no patients remained on treatment, and five were still in follow-up. An objective response was achieved in 7 of 40 patients (17.5%) in the intention-to-treat population, and 7 of 38 patients (18.4%) in the per-protocol population. The median progression-free survival and overall survival were 3.0 months and 5·8 months, respectively. The most commonly observed grade 3 or greater treatment-related adverse events were hypertension, hand–foot syndrome, increased L-gamma-glutamyltransferase.ConclusionsApatinib exhibited efficacy and an acceptable safety profile in previously heavily-treated ES-SCLC patients. Further exploration of apatinib in phase III trials is warranted.Trial registrationNCT02945852.

This multicenter phase-II trial aimed to investigate the efficacy, safety, and predictive biomarkers of toripalimab plus chemotherapy as second-line treatment in patients with EGFR-mutant-advanced NSCLC. Patients who failed from first-line EGFR-TKIs and did not harbor T790M mutation were enrolled. Toripalimab plus carboplatin and pemetrexed were administrated every three weeks for up to six cycles, followed by the maintenance of toripalimab and pemetrexed. The primary endpoint was objective-response rate (ORR). Integrated biomarker analysis of PD-L1 expression, tumor mutational burden (TMB), CD8 + tumor-infiltrating lymphocyte (TIL) density, whole-exome, and transcriptome sequencing on tumor biopsies were also conducted. Forty patients were enrolled with an overall ORR of 50.0% and disease-control rate (DCR) of 87.5%. The median progression free survival (PFS) and overall survival were 7.0 and 23.5 months, respectively. The most common treatment-related adverse effects were leukopenia, neutropenia, anemia, ALT/AST elevation, and nausea. Biomarker analysis showed that none of PD-L1 expression, TMB level, and CD8 + TIL density could serve as a predictive biomarker. Integrated analysis of whole-exome and transcriptome sequencing data revealed that patients with DSPP mutation had a decreased M2 macrophage infiltration and associated with longer PFS than those of wild type. Toripalimab plus chemotherapy showed a promising anti-tumor activity with acceptable safety profiles as the second-line setting in patients with EGFR-mutant NSCLC. DSPP mutation might serve as a potential biomarker for this combination. A phase-III trial to compare toripalimab versus placebo in combination with chemotherapy in this setting is ongoing (NCT03924050).

Background: Transurethral resection of the prostate (TURP) is regarded as the “gold standard” for the treatment of benign prostatic hyperplasia (BPH) in elderly men. However, ~15% of patients who had undergone TURP had intraoperative and postoperative complications, such as bleeding, urinary incontinence and urethral stricture. Transperineal percutaneous laser ablation (TPLA) is a method that places the optical fibre directly into the prostate with the guidance of ultrasound imaging, and the percutaneous transperineal approach is performed distal to the urethra and rectum to protect these structures and reduce urethral or postoperative infection. Several studies on TPLA for BPH treatment have been reported recently; however, high-quality randomised controlled trial (RCT) to evaluate its efficacy, safety, and long-term follow up remain absent.Methods: This study is a multicentre, open-label RCT to assess the efficacy and safety of TPLA vs. TURP to treat BPH. We hypothesise that the TPLA has non-inferior efficacy to TURP in the International Prostate Symptom Score (IPSS) at 3 months changing from the baseline and lower incidence of post-surgery complications. One hundred and fourteen patients with BPH will be recruited at 19 sites and randomly assigned at 1:1 to TPLA or TURP groups. The patients will be followed up at 1, 3, 6, 12, and 24 months after the procedure.Discussion: The study will be the first multicentre clinical trial including 16 participating centres in China, Italy, Switzerland, and Poland with relatively large sample size 114. By comprehensively compare the safety and efficacy of TPLA with TURP in patients with BPH, especially concerning the improvement of lower urinary tract symptoms (LUTS) and complication incidence, the study will help to illustrate the clinical value of TPLA and provide a beneficial alternative treatment for BPH patients.Clinical Trial Registration: The study has been registered on Chinese Clinical Trial Registry (http://www.chictr.org.cn), identifier [ChiCTR1900022739].

ObjectivesTo examine the long-term survival outcome of dabrafenib in combination with trametinib in Chinese patients with unresectable or metastatic acral/cutaneous melanoma with BRAF-V600 mutation and to explore potential predictors of effectiveness.MethodsThis was a long-term follow-up of Chinese patients with unresectable or metastatic BRAF V600-mutant acral/cutaneous melanoma administered dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily) in an open-label, multicenter, single-arm, phase IIa study (NCT02083354). Efficacy endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). The impacts of baseline characteristics on PFS and OS were analyzed.ResultsA total of sixty patients were included. The median age was 48 years, and 24 patients (40.0%) were male. Totally 12 individuals (20.0%) had acral melanoma, and 45 (75.0%) had failed previous systemic therapy. Up to July 2020, the median duration of follow-up was 37.0 (95% confidence interval [CI] 29.1-44.9) months. The updated ORR was 71.7% (95%CI 60.3%-83.1%). The 3-year OS rate was 28.8% (95%CI 19.1-43.6%) in the overall population, and 35.7% (95%CI 15.5–82.4%) in acral melanoma patients. The median DOR was 7.5 months (95%CI 4.5 to 10.5). Baseline normal lactic dehydrogenase (LDH), metastatic organ sitesConclusionDabrafenib combined with trametinib confer long-term survival in Chinese patients with BRAF V600-mutant, unresectable or metastatic acral/cutaneous melanoma.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT02083354, identifier NCT02083354.

OBJECTIVE Many authors, including us, elucidated that vitamin D deficiency was a risk factor for benign paroxysmal position vertigo. We speculated vitamin D deficiency was likely to intervene otoconia formation by globular substance (GS). METHODS Kunming mice were randomly divided into three groups: vitamin D sufficient group (12-wk standard control diet), vitamin D deficiency group (16-wk vitamin D deficiency diet), and vitamin D supplement group (16-wk vitamin D deficiency diet and followed 8-wk standard control diet). At 12, 16, and 24 weeks, blood was collected for measuring vitamin D and macula utriculi were obtained for research under scanning electron microscope (SEM). We randomly selected 10 SEM photographs of macula utriculi in each mouse, counted cilium and GS, and measured diameters of counted GS. The ratio of the number of GS to cilium in each SEM photograph was defined as density of GS. RESULTS The diameter and density of GS were larger and higher in vitamin D deficiency group than sufficient group (p

Background: Osteonecrosis of the femoral head (ONFH) remains a major cause of disability in patients with systemic lupus erythematosus (SLE) and seriously impairs quality of life. This study aimed to investigate associations between glucocorticoids (GCs), antiphospholipid antibodies (aPLs), and ONFH in patients with SLE. Methods: We conducted a multicentre cohort study on patients with SLE and used a directed acyclic graph-based analysis strategy. Details of GC therapy, aPLs status, other drug administration and other SLE-related characteristics were collected. ONFH occurrence during follow-up was determined by magnetic resonance imaging. Multivariable logistic regression and generalized estimating equation models were performed to assess their effects on ONFH, and a simplified scoring system comprising these factors for short- and medium-term SLE-ONFH prediction was developed by receiver operating characteristic curve analysis. Results: Of 449 SLE patients with a median follow-up duration of 5.3 years, 41 (9.1%) developed ONFH. Independently risk factors of SLE-ONFH including: average daily GC dose with an adjusted odds ratio (aOR) of 1.1 and 95% confidence interval (CI) of 1.0–1.1; GC therapy duration (3–5 years: aOR 3.3, 95% CI 1.4–7.8; >5 years: aOR 8.0, 95% CI 3.3–19.4); initial intravenous GC (aOR 4.4, 95% CI 1.9–10.1); positive aPLs (aOR 2.8, 95% CI 1.4–5.8); and Arterial hypertension secondary to GC usage (aOR 5.2, 95% CI 1.4–19.1). And we successfully developed the simplified scoring system (SCORE model) with an area under the curve of 0.88 (95% CI 0.82–0.94). Conclusion: Based on the risk factors involved in the development of SLE-ONFH, a novel SCORE model was developed, which might be helpful for risk stratification of SLE-ONFH in clinical practice.

Background Drowning is a leading cause of accidental death in children under 14 years of age in Guangdong, China. We developed a statistical model to classify the risk of drowning among children based on the risk factors. Methods A multiple-stage cluster random sampling was employed to select the students in Grades 3 to 9 in two townships in Qingyuan, Guangdong. Questionnaire was a self-reported measure consisting of general information, knowledge, attitudes and activities. A univariate logistic regression model was used to preliminarily select the independent variables at a P value of 0.1 for multivariable model. Three-quarters of the participants were randomly selected as a training sample to establish the model, and the remaining were treated as a testing sample to validate the model. Results A total of 8390 children were included in this study, about 12.18% (1013) experienced drowning during the past one year. In the univariate logistic regression model, introvert personality, unclear distributions of water areas on the way to school, and bad relationships with their classmates and families were positively associated with drowning. However, females, older age and lower swimming skills were negatively associated with drowning. After employing the prediction model with these factors to estimate drowning risk of the students in the testing samples, the results of Hosmer-Lemeshow tests showed non-significant differences between the predictive results and actual risk (χ2 = 5.97, P = 0.65). Conclusions Male, younger children, higher swimming skills, bad relationship with their classmates and families, introvert personality and unclear distributions of water areas on the way to school were important risk factors of non-fatal drowning among children. The prediction model based on these variables has an acceptable predictive ability.

The Lung-molGPA index is based on the original diagnosis-specific graded prognostic assessment (DS-GPA) and incorporates recently reported gene alteration data, predicting the outcomes of non-small cell lung cancer (NSCLC) patients with brain metastases (BM). However, the prognostic values of both DS-GPA and Lung-molGPA remain undetermined, especially for patients with different molecular types.A total of 1184 NSCLC patients with BM were analyzed for clinical factors and outcomes at Zhejiang Cancer Hospital, China. All prognostic factors were weighted for significance by hazard ratios. The applicability of DS-GPA and Lung-molGPA were reappraised in NSCLC patients with BM and various genetic profiles. Additionally, a modified Lung-molGPA was newly developed for NSCLC patients with gene variations.NSCLC patients in the present study had a median survival time of 14.0 months from BM diagnosis. Both the DS-GPA and Lung-molGPA models could effectively predict the outcomes of NSCLC patients with BM (P 0.001), and the Lung-molGPA model appeared to deliver more accurate predictions. Furthermore, Lung-molGPA scores demonstrated discriminatory capability in patients with gene variations (P 0.001), and no significant difference was reached in wild-type patients (P = 0.133). Regarding oncogene-positive NSCLC patients with BM, a modified Lung-molGPA index was established based on the prognostic factors with a C-index of 0.73 (95% CI: 0.68-0.80) to accurately calculate survival probability (P 0.001).In the era of precision medicine, Lung-molGPA accurately predicted the prognosis of NSCLC patients with mutant genotypes and BM, although it did not perform well in wild-type patients. Thus, it is worthwhile to explore the prognostic model for patients with positive driving genes.

While increasing evidence suggested that PM2.5 is the most harmful fraction of the particle pollutants, the health effects of coarse particles (PM10–2.5) have been inconclusive, especially on cerebrovascular diseases, we thus evaluated the effects of PM10, PM2.5, and PM10–2.5 on stroke mortality in six Chinese subtropical cities using generalized additive models. We also conducted random-effects meta-analyses to estimate the overall effects across the six cities. We found that PM10, PM2.5, and PM10-2.5 were significantly associated with stroke mortality. Each 10 μg/m3 increase of PM10, PM2.5 and PM10-2.5 (lag03) was associated with an increase of 1.88% (95% CI: 1.37%, 2.39%), 3.07% (95% CI: 2.35%, 3.79%), and 5.72% (95% CI: 3.82%, 7.65%) in overall stroke mortality. Using the World Health Organization's guideline as reference concentration, we estimated that 3.21% (95% CI: 1.65%, 3.01%) of stroke mortality (corresponding to 1743 stroke mortalities, 95% CI: 896, 1633) were attributed to PM10, 5.57% (95% CI: 0.50%, 1.23%) stroke mortality (3019, 95% CI: 2286, 3777) were attributed to PM2.5, and 2.02% (95% CI: 1.85%, 3.08%) of stroke mortality (1097, 95% CI: 1005, 1673) could be attributed to PM10-2.5. Our analysis indicates that both PM2.5 and PM10-2.5 are important risk factors of stroke mortality and should be considered in the prevention and control of stroke in the study area.

IntroductionImmune checkpoint inhibitors (ICIs) have changed the management of non-small cell lung cancer (NSCLC). However, resistance is inevitable. The disease progression patterns, sequential treatment, and prognosis beyond ICI resistance are not completely understood.MethodsWe retrospectively analyzed stage IV NSCLC patients who underwent ICI treatment at Zhejiang Cancer Hospital between January 2016 and January 2020 and who suffered disease progression after at least stable disease on immunotherapy for more than 3 months (at least two cycles). Oligoprogression and systematic progression were defined as previous reports. The main outcome measures were progression-free survival (PFS), second PFS (PFS2), and overall survival (OS). Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazards model was used for multivariate analysis.ResultsTotally 1,014 NSCLC patients were administered immunotherapy. Of them, 208 NSCLC patients were included in this retrospective study. The estimated PFS, PFS2 and OS were 6.3 months (95% CI 5.6–7.0 months), 10.7 months (95% CI 10.1–12.7 months), and 21.4 months (95% CI 20.6–26.4 months), respectively. After resistance, 55.3% (N = 115) patients developed oligoprogression, and 44.7% (N = 93) systemic progression. For patients with systemic progression, chemotherapy (N = 35, 37.6%), best supportive care (N = 30, 32.3%), and antiangiogenic therapy alone (N = 11, 11.8%) were the major strategies. A combination of local radiotherapy (N = 38, 33.0%) with continued ICIs was the most common treatment used in oligoprogression group, followed by continued immunotherapy with antiangiogenic therapy (N = 19, 16.5%) and local radiotherapy only (N = 17, 14.9%). For patients with oligoprogression, continued immunotherapy plus local radiotherapy can lead to a significantly longer PFS2 (12.9 vs. 10.0 months; p = 0.006) and OS (26.3 vs. 18.5 months, p = 0.001). The PFS2 and OS of patients with oligoprogression were superior to those of patients with systemic progression (PFS2: 13.1 vs. 10.0 months, p = 0.001; OS: 25.8 vs. 19.1 months, p = 0.003).ConclusionsThe major progression pattern after acquired resistance from immunotherapy is oligoprogression. Local radiotherapy with continued immunotherapy beyond oligoprogression in responders was feasible and led to prolonged PFS2 and OS in advanced NSCLC patients.

Background Previous studies have shown negative relationships between ambient temperature and blood pressure (BP). However, few studies estimated temperature-adjusted hypertension prevalence and control rate in different population. Objective To estimate the effects of temperature on BP, and further calculate temperature-adjusted hypertension prevalence and control rate. Methods Meteorological and BP data in Guangdong Province from 2004 to 2015 were collected. There were 31 351 participants aged 18 years and over. Based on 2018 European society Arterial Hypertension Guidelines, participants were divided into normotensive patients (n = 23 046), known hypertensive patients (n = 2807), and newly detected hypertensive patients (n = 5498). We first used generalized additive model to establish the nonlinear relationship between daily mean temperature and BP, and then calculated the linear effects of temperature on BP among populations with different hypertension status. Finally, we calculated the temperature-adjusted hypertension prevalence and control rate. Results Generally, there is an inverse relationship between temperature and BP. For a 1 °C increase in temperature, the decreased SBPs for normotensive patients, newly detected hypertensive patients, and known hypertensive patients were 0.37 [95% confidence interval (CI): -0.40, -0.33] mmHg, 0.21 (95% CI: -0.32, -0.10) mmHg and 0.81 (95% CI: -1.02, -0.59) mmHg, while reduced DBPs were 0.19 (95% CI: -0.21, -0.16) mmHg, 0.01 (95% CI: -0.06,0.08) mmHg, and 0.44 (95% CI: -0.56, -0.32) mmHg, respectively. At 5, 10, 15, 20, and 25 °C, the hypertension prevalence rates were 32.5, 29.7, 27.7, 26.0, and 25.0%, respectively, and the control rates were 12.0, 17.5, 23.5, 30.1, and 37.1%, respectively. Conclusion Low temperature increased BP for all populations, especially for known hypertensive patients, which makes hypertension prevalence increase and control rate decrease if temperature reduce. Our findings suggest that temperature should be considered in hypertension clinic management and epidemiological survey.

Background Several studies have investigated the associations between ambient temperature and years of life lost (YLLs), but few focused on the difference of life loss attributable to temperature among different socioeconomic development levels. Objectives We investigated the disparity in temperature-YLL rate relationships and life loss per death attributable to nonoptimal temperature in regions with various development levels. Methods Three hundred sixty-four Chinese counties or districts were classified into 92 high-development regions (HDRs) and 272 low-development regions (LDRs) according to socioeconomic factors of each location using K-means clustering approach. We used distributed lag non-linear models (DLNM) and multivariate meta-analysis to estimate the temperature-YLL rate relationships. We calculated attributable fraction (AF) of YLL and temperature-related average life loss per death to compare mortality burden of temperature between HDRs and LDRs. Stratified analyses were conducted by region, age, sex and cause of death. Results We found that non-optimal temperatures increased YLL rates in both HDRs and LDRs, but all subgroups in LDRs were more vulnerable. The disparity of cold effects between HDRs and LDRs was significant, while the difference in heat effect was insignificant. The overall AF of non-optimal temperature in LDRs [AF = 12.2, 95% empirical confidence interval (eCI):11.0–13.5%] was higher than that in HDRs (AF = 8.9, 95% eCI: 8.3–9.5%). Subgroups analyses found that most groups in LDRs had greater AFs than that in HDRs. The average life loss per death due to non-optimal temperature in LDRs (1.91 years, 95% eCI: 1.72–2.10) was also higher than that in HDRs (1.32 years, 95% eCI: 1.23–1.41). Most of AFs and life loss per death were caused by moderate cold in both HDRs and LDRs. Conclusions Mortality burden caused by temperature was more significant in LDRs than that in HDRs, which means that more attention should be paid to vulnerable populations in LDRs in planning adaptive strategies.

Treatment options in the second-line extensive-stage SCLC (ED-SCLC) setting are limited. The PASSION study (ClinicalTrials.gov identifier: NCT03417895) was a phase 2 study of camrelizumab plus apatinib in ED-SCLC after platinum-based chemotherapy.In stage I of the study, patients were randomized (1:1:1) to receive camrelizumab 200 mg every 2 weeks plus apatinib 375 mg once daily (QD), 5 days on and 2 days off, or 7 days on and 7 days off (six patients each cohort). On the basis of tolerability during the first 28-day cycle and efficacy data at stage I, one cohort was chosen to expand to 45 patients at stage II. The primary end point was objective response rate (ORR).From April 20, 2018 to March 12, 2019, a total of 59 patients were enrolled, with 47 patients in the QD cohort. In the QD cohort, confirmed ORR reached 34.0% (95% confidence interval: 20.9‒49.3), the median progression-free survival was 3.6 months, and the median overall survival was 8.4 months. Chemotherapy-sensitive and chemotherapy-resistant patients (defined as patients with disease relapse at ≥90 and90 d after platinum-based chemotherapy, respectively) had comparable confirmed ORR (37.5% versus 32.3%), median progression-free survival (3.6 versus 2.7 mo), and median overall survival (9.6 versus 8.0 mo). Treatment-related adverse events of grade 3 or higher were reported in 43 of 59 patients (72.9%). Five patients (8.5%) discontinued because of treatment-related adverse events.Camrelizumab plus apatinib exhibited potential antitumor activity in patients with both chemotherapy-sensitive and chemotherapy-resistant ED-SCLC who had failed platinum-based chemotherapy with an acceptable toxicity profile. This phase 2 data warrant further clinical studies of camrelizumab plus apatinib in SCLC.

The short-term effects of ambient temperature on mortality have been widely investigated. However, the epidemiological evidence on the long-term effects of temperature on mortality is rare. In present study, we conducted a nationwide quasi-experimental design, which based on a variant of difference-in-differences (DID) approach, to examine the association between long-term exposure to ambient temperature and mortality risk in China, and to analyze the effect modification of population characteristics and socioeconomic status. Data on mortality were collected from 364 communities across China during 2006–2017, and environmental data were obtained for the same period. We estimated a 2.93 % (95 % CI: 2.68 %, 3.18 %) increase in mortality risk per 1 °C decreases in annual temperature, the greater effects were observed on respiratory diseases (5.16 %, 95 % CI: 4.53 %, 5.79 %) than cardiovascular diseases (3.43 %, 95 % CI: 3.06 %, 3.80 %), and on younger people (4.21 %, 95 % CI: 3.73 %, 4.68 %) than the elderly (2.36 %, 95 % CI: 2.06 %, 2.65 %). In seasonal analysis, per 1 °C decreases in average temperature was associated with 1.55 % (95 % CI: 1.23 %, 1.87 %), −0.53 % (95 % CI: −0.89 %, −0.16 %), 2.88 % (95 % CI: 2.45 %, 3.31 %) and 4.21 % (95 % CI: 3.98 %, 4.43 %) mortality change in spring, summer, autumn and winter, respectively. The effects of long-term temperature on total mortality were more pronounced among the communities with low urbanization, low education attainment, and low GDP per capita. In total, the decrease of average temperature in summer decreased mortality risk, while increased mortality risk in other seasons, and the associations were modified by demographic characteristics and socioeconomic status. Our findings suggest that populations with disadvantaged characteristics and socioeconomic status are vulnerable to long-term exposure of temperature, and targeted policies should be formulated to strengthen the response to the health threats of temperature exposure.

Background Although the effect of ambient temperature on cardiovascular disease (CVDs) has been well explored, studies using years of life lost (YLLs) as the outcome especially evaluating the average life loss per death attributable to temperatures were rare. We examine the associations between ambient temperature and YLLs of CVDs, and further quantify temperature-related life loss per death. Methods Daily YLL rates were calculated using death data from 364 locations across China during 2006–2017, and meteorological data were collected for the same period. A distributed-lag nonlinear model and meta-regression were applied to examine the relationships between temperature and YLL rates of CVDs. Subgroup analyses by age, gender, region, and cause-specific CVDs were investigated. The total YLLs and average YLLs per death attributable to temperature were further quantified to assess life loss caused by non-optimal temperature. Results Both high and low temperatures significantly increased YLL rates of CVDs, with greater effects for cold than heat. Cerebrovascular diseases (CEDs) account for the largest proportion (47.17%) of total YLLs of CVDs attributable to non-optimal temperature. On average, life loss per CVD death attributable to non-optimal temperatures was 1.51 (95% eCI: 1.33, 1.69) years, with 1.07 (95% eCI: 1.00, 1.15) years from moderate cold. Average life losses per death were observed higher for males (1.71, 95% eCI: 1.43, 1.99), younger population (3.82, 95% eCI: 2.86, 4.75), central China (1.62; 95% eCI: 1.41, 1.83) and hemorrhagic stroke (2.86, 95% eCI: 2.63, 3.10) than their correspondents. Conclusions We found that non-optimal temperature significantly aggravated premature death of CVD, with CEDs being the most affected, and most of temperature-related life loss of CVD was attributed to moderate cold. Our findings imply that peoples with CEDs in moderate cold days are vulnerable populations, which may contribute to a better understanding the adverse effects and pathogenesis of temperature on CVDs.

Background Guangdong province is dominated by three cultural regions: Canton, Hakka and Hoklo. However, little is known about the disease burden within these regions, particularly because different population,environmental and socioeconomic risk factors might cause different patterns of mortality, disability-adjusted life-years (DALY), life expectancy and healthy life expectancy (HALE). We aimed to compare the patterns of disease burden in Canton, Hakka and Hoklo regions between 2005 and 2015. Method We calculated the mortality, YLL, YLD for 116 diseases for different cultural regions between 2005 and 2015. We calculated the DALYs for 116 causes as the sum of YLLs and YLDs. We estimated the life expectancy and HALE by using sex-specific mortality rates and YLDs for the three cultural regions. Results With a respective reduction of 22.3, 15.8 and 17.8% in 2015 compared with 2005, the age-standardized DALY rates in 2015 was 19,988.0, 14,396.5 and 20,436.6 in Hakka, Canton and Hoklo region. Canton region had a significantly lower mortality and DALYs in most diseases, followed by Hoklo and Hakka regions. The life expectancy and HALE at birth were highest in Canton region in both 2005 and 2015, than in Hoklo and Hakka region. Conclusions Our findings call for improved public health care via the refinement of policy and effective measures for disease prevention. Understanding the environmental and culture-related risk factors of diseases in Hoklo and Hakka regions may help inform public health sectors to reduce the disease burden and the between-region inequality.

Objective: The correlation between benign paroxysmal positional vertigo (BPPV) and vitamin D levels was controversial. We explored age- and sex-related effects on 25-hydroxyvitamin D (25(OH)D) and correlation between 25(OH)D levels and BPPV.Subjects and Methods: We recruited 380 patients with BPPV and collected 25(OH)D records of 3,125 control subjects who were further divided into age- and sex-based subgroups. We respectively investigated the effects of sex and age on 25(OH)D by comparing sex- or age-based subgroups. Then, we separately compared levels of 25(OH)D in sex-and age-based subgroups between the BPPV and control group.Results: 25(OH)D levels in male subgroups were significant higher than those in female subgroup both in the BPPV and control group. With increasing age, 25(OH)D levels gradually increased, and there were significant between-subgroup differences for age in the control group. In males, the significant between-subgroup difference was observed only in the 70 years, and male patients with BPPV aged >40 years, the correlation between vitamin D and BPPV is non-existent.

Background: Depression is a common emotional disorder, which can be life-threatening and seriously affects the quality of life especially in cancer patients No

The efficacy of immunotherapy in epidermal growth factor receptor (EGFR)-activating non-small cell lung cancer (NSCLC) is limited. However, a series of patients with uncommon EGFR alterations was reported to derive clinical benefit from PD-1 blockade. To characterize the tumor immune microenvironment, we retrospectively evaluated tumor PD-L1 expression and T cells infiltration among NSCLC patients with uncommon EGFR mutations.Immunohistochemistry was used to analyze the expression of PD-L1 and the abundance of CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs). Chi-square test and Cox proportional hazards regression were conducted to investigate the correlations between the immune microenvironment features and clinicopathological variables and survival, as well as to explore the potential of immunotherapy in this patient population.Among 600 NSCLC patients with EGFR alterations, we identified 49 (8.2 %) bearing uncommon mutations, including G719X, L861Q, S768I, and Ex20 ins. In total, 49.0 % (24/49) of these patients showed positive PD-L1 expression in tumor cells, markedly higher than the proportion in patients with classic sensitive mutations (19del and L858R, 12.2 % [67/551], P0.05). Furthermore, PD-L1 expression was associated with relatively short overall survival (OS; 15.2 vs 29.3 months, P = 0.006) and was identified as an independent predictor of OS (hazard ratio=2.57, 95 % confidence interval: 1.03-7.12, P = 0.045). Additionally, PD-L1 positivity was predominantly observed among tumors with CD8+ TILs infiltration (P = 0.001). Uncommon EGFR-mutant tumors had a high frequency (36.7 %) of concurrent PD-L1 expression and abundant CD8 + TILs infiltration. Moreover, this dual-positive group exhibited the most unfavorable prognosis (P = 0.023). Notably, patients with PD-L1 and CD8 dual positivity showed a favorable response to PD-1 inhibitors.High rates of concomitant PD-L1 expression and CD8 + TILs within the tumor microenvironment were observed in NSCLC patients with uncommon EGFR mutations. Further investigations are needed to confirm the therapeutic sensitivity to PD-1 blockade in this subgroup.

Aim: To evaluate the diagnostic accuracy of real-time elastography as a method for detecting prostate cancer.Material and methods: Relevant studies applying real-time elastography as the diagnostic modality and biopsy as the reference standard, published by March 1, 2018 were retrieved from PubMed, EMBASE, Web of Science and Cochrane Library databases. Two independent reviewers inspected all these articles to confirm the matching of the inclusion criteria. One reviewer with methodological expertise extracted the data from the included studies. Sensitivity, specificity and diagnostic odds ratio (DOR) were used to obtain overall estimates. Randomized effect method, meta-regression and subgroup analysis were performed.Results: Twenty-four studies out of 1156 identified articles met the inclusion criteria. Three groups were set: analysisby patient (Group 1), by core (Group 2), and by image (Group 3) and subgroups set in Group 1. The pooled estimate ofreal-time elastography sensitivity/ specificity/ DOR calculated with the identical P-value 0.00. Within subgroups “Asia” and“PSA>=10 ng/ml”, the pooled sensitivity, specificity and DOR were 0.83, 0.65 (p=0.01, I2=73.40%; p=0.02, I2=69.5%), 0.80, 0.82 (p=0.66, I2=0.00%; p=0.58, I2=0.00%) and 20.2, 8.67 (p=0.09, I2=54.2%; p=0.20, I2=35.5%), respectively. In these three groups, the areas under the SROC curve were 0.7417, 0.9246, and 0.6213 independently.Conclusions: Real-time elastography is a promising, reliable modality for the non-invasive diagnosis of patients with prostate cancer. The diagnostic accuracy of real-time elastography correlates tightly to the presence of higher PSA level and may help avoid unnecessary biopsy. It seems to be a useful tool in systemic biopsy.

The peak shear strength of discontinuities between two different rock types is essential to evaluate the stability of a rock slope with interlayered rocks. However, current research has paid little attention to shear strength parameters of discontinuities with different joint wall compressive strength (DDJCS). In this paper, a neural network methodology was used to predict the peak shear strength of DDJCS considering the effect of joint wall strength combination, normal stress and joint roughness. The database was developed by laboratory direct shear tests on artificial joint specimens with seven different joint wall strength combinations, four designed joint surface topographies and six types of normal stresses. A part of the experimental data was used to train a back-propagation neural network model with a single-hidden layer. The remaining experimental data was used to validate the trained neural network model. The best geometry of the neural network model was determined by the trial-and-error method. For the same data, multivariate regression analysis was also conducted to predict the peak shear strength of DDJCS. Prediction precision of the neural network model and multivariate regression model was evaluated by comparing the predicted peak shear strength of DDJCS with experimental data. The results showed that the capability of the developed neural network model was strong and better than the multivariate regression model. Finally, the established neural network model was applied in the stability evaluation of a typical rock slope with DDJCS as the critical surface in the Badong formation of China.

Background: Daily mean concentration cannot fully address the hourly variations of air pollution within one day. As such, we proposed a new indicator, daily exceedance concentration hours (DECH), to explore the acute cardiovascular effects of ambient PM2.5 (particles with aerodynamic diameters less than 2.5μm). The DECH in PM2.5 was defined as daily total concentration-hours >25μg/m3. Methods: A generalized additive model with a quasi-Poisson link was applied to estimate the associations between day-to-day variation in PM2.5 DECH and day-to-day variation in cardiovascular mortality in six subtropical cities in Guangdong Province, China. Results: The analysis revealed significant associations between PM2.5 DECHs and cardiovascular mortality. A 500μg/m3∗h increase in PM2.5 DECHs at lag03 was associated with an increase of 4.55% (95% confidence interval (CI): 3.59%, 5.52%) in cardiovascular mortality, 4.45% (95% CI: 2.81%, 6.12%) in ischemic cardiovascular mortality, 5.02% (95% CI: 3.41%, 6.65%) in cerebrovascular mortality, and 3.00% (95% CI: 1.13%, 4.90%) in acute myocardial infarction mortality. We further observed a greater mortality burden using PM2.5 DECHs than daily mean PM2.5 (6478 (95% CI: 5071, 7917) VS 5136 (95% CI: 3990, 6305)). Conclusion: This study reveals that PM2.5 DECH is one important exposure indicator of ambient PM2.5 to measure its cardiovascular mortality effects in Pearl River Delta region; and that using daily mean concentration could under-estimate the mortality burden compared with this new indicator. Keywords: Air pollution, PM2.5, Cardiovascular mortality, China

Purpose: Leptomeningeal metastasis (LM) is a detrimental complication of non–small cell lung cancer (NSCLC) and associated with poor prognosis. However, the underlying mechanisms of the metastasis process are still poorly understood. Experimental Design: We performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF), and matched normal controls from epidermal growth factor receptor (EGFR) mutation-positive NSCLC patients with LM. Results: The status of EGFR-activating mutations was highly concordant between primary tumor and CSF. PIK3CA aberrations were high in these patients, implicating an association with LM risk. Intriguingly, low overlapping of somatic protein-changing variants was observed between paired CSF and primary lesions, exhibiting tumor heterogeneity and genetic divergence. Moreover, genes with CSF-recurrent genomic alterations were predominantly involved in cell-cycle regulation and DNA-damage response (DDR), suggesting a role of the pathway in LM development. Conclusions: Our study has shed light on the genomic variations of NSCLC-LM, demonstrated genetic heterogeneity and divergence, uncovered involvement of cell-cycle and DDR pathway, and paved the way for potential therapeutic approaches to this unmet medical need. Clin Cancer Res; 24(1); 209–16. ©2017 AACR.

Magnetic-hyperthermia-ablation is considered as an effective and minimally invasive technology for tumor therapy. However, inappropriate temperature control could induce an excessively high temperature which brings potential safety problems and limits clinical transformation of this technique. Herein, aiming to control the temperature during magnetic hyperthermia ablation, we develop an intermittent time-set technique for temperature control in magnetic hyperthermia ablation of tumors using a polylactic-co-glycolic acid (PLGA)-Fe3O4 implant. In vitro, the intermittent time is set as follows: tubes are continuously heated for 110 seconds. Then the heating process is paused for 20 seconds, and then the tubes are reheated for 10 seconds, followed by repeating the last two processes. The temperature elevation profile upon magnetic hyperthermia interestingly also demonstrates good controllability despite some differences in time-setting between in vitro and in vivo. The in vivo results show the temperature fluctuates within the range of 6.45 ± 1.34 °C after reaching the target temperature. Furthermore, we observe the deformation of an implant employing three-dimensional (3D) ultrasound to better understand the temperature change. The results show no significant deformation of the implant after being heated. The microscopic images prove that this simple technique can successfully cause tumor regression. This temperature control technique provides great benefits for hyperthermia ablation against tumors, advancing the magnetic hyperthermal ablation technology in clinical translation.

We sought to investigate the association between household exposure to biomass fuel and metabolic syndrome (MetS) and its components including blood pressure, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG) and waist circumference among females in southern rural China.We surveyed 1664 residents in the Chronic Disease and Risk Factors Surveillance, conducted in 14 districts of Guangdong province. We recorded the use of biomass fuel, MetS and its components, and other covariates by using a structured questionnaire. Logistic regression model and multivariate linear regression model were adopted for analysis.Exposure to biomass fuel was significantly associated with an increase of systolic blood pressure (SBP) (β: 2.15, 95% confidence interval: 0.13 to 4.17) and FBG (β: 0.19, 95% confidence interval: 0.01 to 0.37) in the adjusted and unadjusted models (all P 0.05). Among participants with exposure to biomass fuel, being overweight or obese was associated with an increased risk of having hypertension (odds ratio: 3.19, 95% confidence interval: 2.13 to 4.76) and higher FBG levels (odds ratio: 2.10, 95% confidence interval: 1.46 to 3.02). Exposure to biomass fuel was significantly associated with a decrease of the prevalence of central obesity (P 0.05). However, exposure to biomass fuel was not associated with MetS, diastolic blood pressure and TG (all P 0.05).Exposure to biomass fuel is associated with an increase in blood pressure and FBG levels, but not MetS per se. Efforts should be made to protect females in southern rural China from the adverse effects associated with biomass fuel pollution.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. However, the efficacy of EGFR-TKIs in patients with uncommon EGFR mutations (other than exon 19 deletions or exon 21 L858R mutation) remains undetermined. Seven hundred and fifty-five non-small cell lung cancer (NSCLC) patients with EGFR mutation analyses for TKI therapy were identified between October 2010 and December 2015 in East of China. And 66 patients bearing uncommon EGFR mutations were included to collect data from TKI response and prognosis. We categorised EGFR uncommon mutations as: sensitizing rare mutations (group 1: G719X, L861Q, S768I); Ex20 ins (group 2), or complex mutations (G719X + L861Q, G719X + S768I, 19 del + T790M, 19 del + L858R, L858R + S768I, and L858R + T790M; group 3). Of 66 patients given EGFR-TKI treatment, rare sensitive mutations, Ex20 ins, and complex mutations were identified in 37 (56.1%), 9 (13.6%), and 20 (33.3%) cases, respectively. TKI efficacy in patients harboring uncommon EGFR mutations exhibited a tumor response rate of 28.8% and a median progression-free survival (PFS) of 4.8 months. Additionally, patients with complex EGFR mutations had significantly longer PFS when compared with the remaining sensitizing rare mutations or Ex20 ins cases (8.6 vs. 4.1 vs. 3.1 months; p = 0.041). Importantly, complex EGFR mutations were independent predictors of increased overall survival (Hazard Ratios = 0.31; 95% confidence intervals: 0.11–0.90; p = 0.031). Among them, patients harboring Del-19 combined with L858R mutations showed a tendency to have higher response rate (RR) and improved PFS than those with other complex mutation patterns (RR: 66.7 vs. 14.3%, p = 0.021; PFS: 10.1 vs. 8.6 months, p = 0.232). Personalized treatment should be evolving in different types of uncommon EGFR mutations. Clinical benefit from EGFR-TKIs was higher in NSCLC patients with complex EGFR mutations than those with other uncommon EGFR mutation types.

Although non-small-cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations are responsive to EGFR-tyrosine kinase inhibitors, drug resistances are always inevitable. The secondary somatic EGFR threonine–methionine substitution at position 790 (T790M) mutation accounts for ∼50% of acquired resistance mechanisms. Small cell lung cancer (SCLC) transformation is a relatively rare mechanism, but has recently attracted considerable attention. The coexistence of both the mechanisms in one patient is much more scarce in clinic. In this case report, we described a 37-year-old woman who underwent refractory after second-line gefitinib therapy and was confirmed to have SCLC transformation without the T790M mutation in the left lobar nodule, but concomitant with the plasma-genotyped EGFR T790M mutation. Our case report uncovered the underling relationship between SCLC transformation and the T790M mutation, and the fluid biopsy approach may help overcome the problem of heterogeneity in acquired resistance to EGFR-tyrosine kinase inhibitors.

Background Global warming may increase the frequency of compound hot extremes (CHEs). This study aimed to assess the current mortality burden and future mortality risk attributable to CHEs in China. Methods Daily meteorological, air pollution and mortality data were collected in 364 locations from 2006 to 2017 across China. Hot day/night was identified as a day where daily Tmax/Tmin was higher than its 90th percentile in summer. CHE was defined as a hot night with a following hot day. Mortality risk attributed to CHEs in each location was first evaluated using a distributed lag non-linear model. Location-specific association was pooled using a multivariate meta-analysis model, and attributable fraction in the current time and mortality risk from CHEs under different climate change scenarios (RCP 2.6, RCP 4.5, RCP 8.5) in the future were assessed. Results CHEs (RR: 1.23, 95%CI: 1.19–1.28) were associated with greater mortality risk, and 0.96% mortality was attributable to CHEs. We found that female, the elderly, and people living in north China were more vulnerable to CHEs. In addition, more intensive (RR: 1.07, 95%CI: 1.06–1.08) and consecutive CHEs (RR: 1.09, 95%CI: 1.02–1.17) could increase mortality risk. We further observed a seven to nineteen fold deaths attributable to CHEs in 2090s under middle and high climate change scenarios. Conclusion Our study found that CHEs significantly increased mortality risk and would cause considerable mortality burden in future. These findings suggest that it is necessary to develop clinical and public health policy to alleviate the mortality burden associated with CHEs.

Many studies have linked temperature with respiratory deaths, but epidemiological evidence of temperature-attributable years of life lost (YLL) from respiratory diseases is limited. Daily respiratory YLL rates were calculated using mortality data from 364 locations of China during 2006–2017, and meteorological data were collected for the same period. First, the distributed lag non-linear model (DLNM) was applied to estimate specific temperature-respiratory YLL rate associations in each location. Then multivariable meta-analysis was conducted to pool the location-specific estimates. Finally, we calculated the average life loss per death (LLD) to quantify the respiratory mortality burden of non-optimal temperature. Subgroup analyses were conducted by gender, age, region and cause of death. Inversely J-shaped association was observed between non-optimal temperature and respiratory YLL rate in China. The minimum YLL-rate temperature was 26.9 °C nationwide. An average of 1.37 years (95% CI: 1.06–1.65) LLD was attributable to non-optimal temperatures with 2.06 years (95% CI: 1.57–2.60) for pneumonia, 2.03 years (95% CI: 1.76–2.31) for chronic lower respiratory infections (LRTI), 0.88 years (95% CI: 0.65–1.09) for chronic obstructive pulmonary disease (COPD), most of which was attributed to moderate cold (0.73 years, 95% CI: 0.65–0.80). LLD caused by non-optimal temperature was higher in males, the young, and north China. Exposure to non-optimal temperature increases respiratory YLL rate in China, most of which were attributed to moderate cold. People with respiratory diseases including pneumonia, chronic LRTI and COPD are vulnerable to non-optimal temperature exposure. The result of this study provides useful information to reduce temperature-related respiratory disease burden.

// Lulu Miao 1, * , Yunyun Lu 1, * , Yanjun Xu 1 , Gu Zhang 2 , Zhiyu Huang 1 , Lei Gong 1 and Yun Fan 1 1 Department of Thoracic Medical Oncology, Hangzhou, 310022, Zhejiang, People’s Republic of China 2 Department of Pathology, Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Yun Fan, email: fanyun@csco.org.cn Keywords: small cell lung cancer, PD-L1, c-MET, expression, prognosis Received: October 31, 2015 Accepted: April 29, 2016 Published: June 1, 2016 ABSTRACT Background : Blocking the binding between the PD-1 and PD-L1 has been reported to produce antitumor responses. The MET/HGF axis appears to be another signaling pathway frequently altered in small cell lung cancer (SCLC). Our study was aimed to investigate the expression and prognostic roles of PD-L1 and c-MET in SCLC. Methods : The expression levels of PD-L1 and c-MET were evaluated by immunohistochemical analysis in 83 SCLC specimens. Survival analysis was performed using the Kaplan-Meier method. Results: Of the SCLC specimens, 51.8% and 25.3% exhibited positivity for PD-L1 and c-MET, respectively. Higher PD-L1 expression in tumor specimens was significantly correlated with a limited disease (LD) stage, normal levels of serum lactate dehydrogenase (LDH) and neuron-specific enolase (NSE). No association was found between the levels of c-MET and PD-L1 expression or between c-MET expression and other clinical characteristics. SCLC patients with PD-L1-positive tumors showed significantly longer overall survival (OS) than patients with PD-L1-negative tumors (17.0 vs 9.0, p=0.018). Conversely, those with positive c-MET expression exhibited a shorter OS trend (12.0 vs 15.0, p=0.186). However, sub-analysis of LD-stage patients revealed longer OS among the c-MET-negative group (25.0 vs 14.0; p=0.011). The OS of patients with positivity for both PD-L1 and c-MET showed no significant difference compared with other patients (p=0.17). According to multivariate analyses, neither PD-L1 nor c-MET immunoreactivity was a prognostic factor. Conclusion: Expression of PD-L1 was correlated with LD stage and might serve as a prognostic for better OS in SCLC patients. In LD-stage patients, high c-MET expression might be predictive of a poor outcome.

Hourly peak concentration may capture health effects of ambient fine particulate matter pollution (PM2.5) better than daily averages. We examined the associations of hourly peak concentration of PM2.5 with cardiovascular mortality in Guangzhou, China. We obtained daily data on cardiovascular mortality and hourly PM2.5 concentrations in Guangzhou from 19 January 2013 through 30 June 2015. Generalized additive models were applied to evaluate the associations with adjustment for potential confounding factors. Significant associations were found between hourly peak concentrations of PM2.5 and cardiovascular mortality, particularly from ischemic heart diseases (IHD) and cerebrovascular diseases (CBD). Every 10 μg/m3 increment of hourly peak PM2.5 at lag 03 day was associated with a 1.15% (95% CI: 0.67%, 1.63%); 1.02% (95% CI: 0.30%, 1.74%) and 1.09% (95% CI: 0.27%, 1.91%) increase in mortalities from total cardiovascular diseases, IHD and CBD, respectively. The effects remained after adjustment for daily mean PM2.5 and gaseous air pollutants, though there was a high correlation between PM2.5 peak and PM2.5 mean (correlation coefficient=0.95). No significant association was observed for acute myocardial infarction (AMI). In addition to daily mean concentration of PM2.5, hourly peak concentration of PM2.5 might be one important risk factor of cardiovascular mortality and should be considered as an important air pollution indicator when assessing the possible cardiovascular effects of PM2.5.

To estimate the mortality risk from haze and the modifying effects by three characteristics of haze (intensity, duration and timing), data on haze and mortality in the Pearl River Delta region from 2013 to 2016 were collected. We first estimated mortality risk during haze days compared with non-haze days. Then we classified haze into several categories by considering one or any two of the three haze characteristics together, and further calculated the mortality risks separately. The mortality risk increased 5.0% (95% confidence intervals (CI): 3.1%–6.9%) during hazy days compared with non-haze days, with larger effect for the elderly ≥ 85 years old (Excess risk (ER): 8.7%, 95% CI: 3.9%–13.6%) than other age groups. Mortality risk increased in longer haze (ER: 4.4%, 95% CI: 2.9%–6.0%) compared with shorter haze (ER: 1.9%, 95% CI: 0.7%–3.2%). The greatest effect of any two of haze characteristics was observed when haze was intense and long (ER: 4.8%, 95% CI: 3.0%–6.6%). Our study indicates that haze significantly increased mortality risk in the Pearl River Delta. The health effects of haze may be under-estimated when using a single air pollutant concentration during haze periods to assess health risk of haze events. The haze intensity, duration, and time of occurrence should be accounted for in appropriate risk assessment of haze.

This prospective trial was performed to verify whether microwave ablation (MWA) in combination with chemotherapy could provide superior survival benefit compared with chemotherapy alone. From March 1, 2015, to June 20, 2017, treatment-naive patients with pathologically verified advanced or recurrent non-small cell lung cancer (NSCLC) were randomly assigned to MWA plus chemotherapy group or chemotherapy group. The primary endpoint was progression-free survival (PFS), while the secondary endpoints included overall survival (OS), time to local progression (TTLP), and objective response rate (ORR). The complications and adverse events were also reported. A total of 293 patients were randomly assigned into the two groups. One hundred forty-eight patients with 117 stage IV tumors were included in the MWA plus chemotherapy group. One hundred forty-five patients with 113 stage IV tumors were included in the chemotherapy group. The median follow-up period was 13.1 months and 12.4 months, respectively. Median PFS was 10.3 months (95% CI 8.0–13.0) in the MWA plus chemotherapy group and 4.9 months (95% CI 4.2–5.7) in the chemotherapy group (HR = 0.44, 95% CI 0.28–0.53; p

Owing to the promotion and development of big data, artificial intelligence and new engineering, the demand for massive open online workbench is becoming more and more urgent, and as the software evolves towards the form of Cloudware, it provides an opportunity for the construction of the massive open online workbench. This paper explores the online training needs under the guidance of cognitive science, and pioneers the concept of Massive Open Online Workbench (MOOBench), and a complete set of the methods and critical technologies of building the large-scale cloud software training platform is systematically given. This paper verifies the effectiveness of the proposed approach in large-scale user experience and cloud resource utilization by constructing the Data science and big data training platform and the practical application in the actual curriculum in the past two years. It also provides support of learning theory and information technology for building an excellent education-oriented training environment.

Objective In this study, we aimed to estimate the updated incidence and mortality of primary bone cancers based on population-based cancer registration data in 2014, collected by the National Central Cancer Registry of China (NCCRC). Methods In 2017, 339 registries’ data were qualified based on data quality criteria set down by the NCCRC. Cases of primary bone cancers were retrieved from the national database. We estimated numbers of primary bone cancer cases and deaths in China using age-specific rates and corresponding national population stratified by area, sex, age-group (0, 1−4, 5−9, 10−14, …, 85+). Chinese standard population in 2000 and Segi’s World population were applied for the calculation of age-standardized incidence and mortality rates. Results In 2014, 24,000 primary bone cancer cases and 17,200 deaths attributable to primary bone cancers were estimated to have occurred in China. The crude incidence rate of primary bone cancers was 1.76/100,000, with age-standardized incidence rate by Chinese standard population (ASIRC) and by World standard population (ASIRW) being 1.35/100,000 and 1.32/100,000, respectively. The crude mortality rate of primary bone cancers was 1.26/100,000, with age-standardized mortality rate by Chinese standard population (ASMRC) and by World standard population (ASMRW) being 0.88/100,000 and 0.86/100,000, respectively. Age-specific incidence curve was bimodally distributed with age, with the first peak occurring in the second decade of the life and the second peak in the elderly. Males had higher crude and age-standardized rates for both incidence and mortality compared with females. Both crude and age-standardized incidence rates were higher in rural areas than in urban areas, so were the crude and age-standardized mortality rates. Conclusions This population-based study presents the most recently available estimates on primary bone cancers in China, revealing that the males are 1.34 times as much as females suffering from primary bone cancers and the adolescents in puberty and the elderly are predominantly affected groups by these cancers. High-quality cancer registration data are a prerequisite for undertaking further study for gaining insight into the causes and risk factors for primary bone cancers in China.

Background As the fourth leading cause of death, injury is an important public health concern in Guangdong Province, China. The epidemiological characteristics of injury mortality is changing along with the social development. This study described the epidemiological characteristics of injury mortality in Guangdong Province by analyzing the death surveillance data in a few areas in Guangdong Province in 2015. Methods Using the mortality data from the Disease Surveillance Points (DSP) system, injury deaths were classified according to the International Classification of Disease-10th Revision (ICD-10). The data were stratified by areas (urban/rural), gender, age groups, injury types, and then overall and type-specific injury mortality rates were estimated for the whole Guangdong Province, China. Results We estimated that about 38,200 individuals died from injury in Guangdong Province in 2015, producing a mortality rate of 43.11/100,000. The overall age-standardized injury mortality in men was higher in rural areas compared with urban areas (41.29/100,000 versus 24.89/100,000). In terms of injury intent, unintentional injuries were the commonnest injury type, which accounted for 83.93% of the overall injury deaths, however, the deaths caused by suicide should not be ignored, which occupied 12.67% of the total injury deaths. In terms of injury cause type, falls, road-traffic accidents, suicide, drowning, and accidental poisoning were the top five leading types of injury deaths. Conclusions In Guangdong Province, injury is an important cause of death. Road-traffic accidents, falls, suicide, drowning, and accidental poisoning should be the priorities of intervention. Moreover, in rural areas, the men were the most targeted subpopulation of the prevention activities.

Background: Small-cell lung cancer (SCLC) remains an aggressive cancer with dismal long-term survival due to the limited therapeutic options available after failure of chemotherapy. Apatinib is a novel oral, small-molecule tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor 2. This study aimed to investigate the efficacy and safety of apatinib in patients with extensive-stage (EC) SCLC who had progressed after two or three previous therapies. Methods: This phase II, single-arm, prospective study was conducted at three medical centers in China. Eligible patients were aged 18 years or older and had histologically-confirmed ES-SCLC after two or three previous treatments, including a platinum-based regimen. Patients were assigned to receive oral apatinib at an initial dose of 500 mg once daily. The primary endpoint was the objective response rate (ORR) in both the intention-to-treat (ITT) and per-protocol populations. The safety analysis included all patients who received at least one dose of study medication. Findings: Forty patients were enrolled, all of whom received at least one dose of apatinib. At the data cut off time (Nov 15, 2018), the median follow-up was 7.4 months (IQR 1·0-22·2); no patients remained on treatment, and 5 were still in follow-up. An objective response was achieved in 7 of 40 patients (17.5%) in the ITT population, and 7 of 38 patients (18.4%) in the per-protocol population. The median progression-free survival and overall survival were 3·0 months (95% CI 2·2-3·7) and 5·8 months (95% CI 3·7-7·9), respectively. The median response duration was 2·6 months (95% CI 1·8-3·3). During treatment, apatinib was generally well tolerated, the most commonly observed grade 3 or greater treatment-related adverse events were hypertension (25%; 10/40), hand-foot syndrome (10%; 4/40), increased L gamma-glutamyltransferase (10%; 4/40), increased aspartate transaminase (7·5%; 3/40), and thrombocytopenia (7·5%, 3/40). Interpretation: Apatinib exhibited promising efficacy and an acceptable safety profile in previously heavily-treated patients with ES-SCLC. Further exploration of apatinib in phase III trials is warranted. Clinical Trial Registatration: NCT02945852. Funding Statement: Jiangsu Hengrui Pharmaceuticals Company, China. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The study protocol was approved by the relevant institutional review board or ethics committee at each medical center, and it was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, as defined by the International Conference on Harmonisation. All enrolled patients provided written informed consent before any study-specific procedures were performed.

We present a novel method for vehicle detection and classification in aerial imagery. First, change detection analyzes a pair of mutually aligned images captured at the same location but at different time instants to generate vehicle proposals. Next, a trained Convolutional Neural Network (CNN) classifier is applied to (1) determine if a proposal truly contains a vehicle, and (2) classify any vehicle present into major categories. Experimental results using infrared (IR) data demonstrate the efficacy of our method: vehicle detection rate is over 99%; light-duty vehicles (e.g. sedan) are classified with 89% accuracy, medium-duty vehicles (e.g., van and pickup) with 79% and heavy-duty vehicles (e.g., trucks and buses) with 73% accuracies. The classification performance difference among different vehicle types is attributed to the size of training samples available in each category. Our system can process data at video rate making it feasible for real-time traffic monitoring.

Background Immune checkpoint inhibitors (ICIs) prolong overall survival (OS) in patients with advanced lung squamous cell carcinoma (LUSC). However, predictive and prognostic factors related to ICIs in LUSC remain elusive. This study aimed to identify predictors that are related to better clinical benefit and outcomes in LUSC patients treated with immunotherapy. Methods Capture-based targeted sequencing was performed in 64 patients with advanced LUSC who underwent immunotherapy. Tumor mutational burden (TMB) was defined as the sum of nonsynonymous single nucleotide and indel variants. Programmed cell death ligand-1 (PD-L1) expression was evaluated by immunohistochemical analysis. Clinicopathological characteristics including age, sex, performance status, smoking history, body mass index (BMI), blood fat, brain metastases, liver metastases, previous thoracic radiotherapy, and treatment lines were analyzed. Results The most commonly mutated genes included TP53, CDKN2A, KEAP1, CREBBP, KRAS, BIM, AMER1, and APC. Copy number variations most frequently occurred in AR, SOX2, PIK3CA, EGFR, RICTOR, FGFR1, and ZNF703. The median and mean TMB was 9.35 and 10.62 mutations per megabase, respectively. Positive PD-L1 expression was detected in 29.7% patients. Patients with a history of heavy smoking (≥ 40 pack-years) were more likely to have positive PD-L1 expression (35% vs. 16.7%, P=0.04) and higher TMB (11.1 vs. 9.8 mut/Mb, P=0.04). Gene alterations had no impact on PD-L1 expression or TMB level. The median progression-free survival (PFS) was 6.7 months and median OS was 13.7 months. Higher TMB was independently associated with longer PFS (P=0.01) and OS (P=0.02), and this correlation was more pronounced in patients treated with ICIs as a single agent (P=0.0001). Higher TMB was also associated with better disease control rate (DCR) (P=0.02). Compared with wild-type, patients with KRAS mutation and EGFR amplification had higher objective response rates (ORR, P=0.01). Conclusions The predictive value of TMB is more significant in LUSC patients receiving ICI as a single agent than as a combination therapy. The combination of Eastern Cooperative Oncology Group performance status (ECOG-PS), smoking status, TMB, PD-L1, and genomic variation might be helpful for personalized immunotherapy decisions in clinical practice for advanced LUSC.