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Graphical abstract, The presence of antiphospholipid antibodies was shown to be associated with thrombosis in coronavirus disease 2019 (COVID-19) patients. Recently, according to reports from several studies, the vaccine-induced immune thrombotic thrombocytopenia is mediated by anti-platelet factor 4 (PF4)-polyanion complex in adenovirus-vectored COVID-19 vaccine recipients. It is impendent to explore whether inactivated COVID-19 vaccine widely used in China influences prothrombotic autoantibody production and induces thrombosis. In this prospective study, we recruited 406 healthcare workers who received two doses, 21 days apart, of inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine (BBIBP-CorV, Sinopharm). Paired blood samples taken before vaccination and four weeks after the second vaccination were used in detecting prothrombotic autoantibodies, including anticardiolipin (aCL), anti-β2 glycoprotein I (aβ2GP1), anti-phosphatidylserine/prothrombin (aPS/PT), and anti-PF4-heparin. The seroconversion rate of SARS-CoV-2 specific antibodies was 95.81% (389/406) four weeks after vaccination. None of the subjects had spontaneous thrombosis or thrombocytopenia over a minimum follow-up period of eight weeks. There was no significant difference in the presence of all ten autoantibodies between samples collected before and after vaccination: for aCL, IgG (7 vs. 8, P = 0.76), IgM (41 vs. 44, P = 0.73), IgA (4 vs. 4, P = 1.00); anti-β2GP1, IgG (7 vs. 6, P = 0.78), IgM (6 vs. 5, P = 0.76), IgA (3 vs. 5, P = 0.72); aPS/PT IgG (0 vs. 0, P = 1.00), IgM (6 vs. 5, P = 0.76); aPF4-heparin (2 vs. 7, P = 0.18), and antinuclear antibody (ANA) (18 vs. 21, P = 0.62). Notably, seven cases presented with anti-PF4-heparin antibodies (range: 1.18–1.79 U/mL) after vaccination, and none of them exhibited any sign of thrombotic disorder. In conclusion, inactivated SARS-CoV-2 vaccine does not influence the profile of antiphospholipid antibody and anti-PF4-heparin antibody nor increase the risk of thrombosis.

OBJECTIVE The antenatal screening strategy remains inadequate for eliminating congenital syphilis. To further eliminate maternal fetal transmission, preconception syphilis screening is considered an option. In this study, we investigated syphilis seropositivity and intra-couple discordance among married couples planning a pregnancy in China to provide essential baseline evidence for preconception syphilis screening. DESIGN Population-based survey. SETTING National preconception registered data. POPULATION Married Chinese couples planning conception within 6 months between 2013 and 2018. METHODS Syphilis was screened using rapid plasma reagin (RPR); infection self-reporting and sociodemographic characteristics were collected through questionnaires and medical records, respectively. r 3.2.2 and arcgis 10.2 were used for statistical analyses and geographic mapping. MAIN OUTCOME MEASURES RPR seropositivity. RESULTS Among 31 955 041 couples, 29 737 172 (93.06%) had complete RPR results for both spouses; of those, 0.62% (186 100) were seropositive, with dramatic intra-couple discordance, with 0.33% positivity in wives, 0.24% positivity in husbands and 0.05% positivity in both spouses. Across time, both seropositivity and intra-couple discordance remained stable. Seropositivity in different regions varied significantly, with provincial rates ranging geographically from Tibet (0.8%) to Hebei (0.2%) (P

Tongtong Zhou,1,2,&ast; Li Tan,1,&ast; Yang Gui,1 Jing Zhang,1 Xueqi Chen,1 Menghua Dai,3 Mengsu Xiao,1 Qing Zhang,1 Xiaoyan Chang,4 Qun Xu,5 Chunmei Bai,6 Yuejuan Cheng,6 Qiang Xu,3 Xue Wang,7 Hua Meng,1 Wanying Jia,1 Ke Lv,1 Yuxin Jiang1 1Department of Ultrasound, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 2Department of Ultrasound, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 3Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 4Department of Pathology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 5Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, People’s Republic of China; 6Department of Medical Oncology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 7Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ke Lv; Yuxin JiangDepartment of Ultrasound, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of ChinaTel/Fax +86 10-69155493; +86 10-69155491Email lvke@163.com; yuxinjiangxh@163.comObjective: Investigate the CEUS enhancement patterns of PDAC and analyse correlations between the CEUS enhancement pattern and both the degree of tumour tissue differentiation and overall survival (OS).Methods: The study included 56 patients with locally advanced PDAC, performed conventional ultrasound and CEUS, and analysed characteristics of the CEUS enhancement patterns. In addition, clinical data, such as serum level of CA19-9, TNM stage were collected, and patients’ survival times were followed up. TICs of dynamic CEUS images were acquired using image processing software to obtain the peak, TP, sharpness, and AUC. Correlations of the CEUS enhancement patterns of PDAC with the degree of differentiation of tumour tissue and OS were quantitatively analysed, as were the correlations of the TIC parameters and CEUS enhancement patterns with OS.Results: Enhancement in the arterial phase included iso-enhancement (30.3%) and hypo-enhancement (69.6%), and was not significantly correlated with sex, age at disease onset, or lesion size. Also was not significantly correlated with tumour tissue differentiation. Clear survival times were obtained for 50 patients during follow-up, and the median survival time was significantly longer for the patients with iso-enhancement than hypo-enhancement. Among the TIC parameters, peaktumour, sharpnesstumour, AEsharpness, and REsharpness differed significantly between the group with iso-enhancement and hypo-enhancement (p < 0.05).Conclusion: The CEUS enhancement patterns of PDAC in the arterial phase include iso-enhancement and hypo-enhancement. Enhancement pattern was not significantly correlated with the degree of differentiation of tumour tissue, but patient survival time differed significantly between the two enhancement patterns, with longer survival for patients with iso-enhancement.Keywords: contrast-enhanced ultrasound, pancreatic ductal adenocarcinoma, survival time, enhancement pattern, time-intensity curve

The associations between high-density lipoprotein cholesterol (HDL-C) and blood pressure (BP) or hypertension are inconsistent in previous studies. This study aimed to assess these associations in a large cohort of Chinese adults and across different age groups. This cross-sectional association study included 22,081 Chinese adults. Associations of HDL-C with BP and hypertension were analyzed using linear or logistic regression, with or without adjustment for confounding factors. HDL-C was inversely associated with BP and hypertension. These associations were still apparent after adjustment for age, sex, fasting plasma glucose, and low-density lipoprotein cholesterol. Sub-analyses revealed: (1) in the whole cohort and females alone, HDL-C was inversely associated with BP and hypertension in young and middle-aged but not older participants; (2) in males alone, HDL-C was not associated with systolic BP or hypertension. However, HDL-C was either inversely, or not, or positively associated with BP in young, middle-aged, and older males, respectively. After further adjustment for body mass index (BMI), the negative associations of HDL-C with BP and hypertension in the whole cohort became positive ones, and the positive associations only presented in males. These findings suggest that further adjustment for BMI changes inverse associations of HDL-cholesterol with BP and hypertension to positive associations in a cohort of Chinese adults.

The aim of this review was to evaluate the efficacy and safety of tetracyclines for treatment of pemphigoid. We searched PubMed, EMBASE, Ovid, Web of Science, and the Cochrane Library for studies involving pemphigoid patients treated with tetracyclines published in English before 29 February 2020. References of included studies were also screened to widen the scope of the literature search. Data regarding predefined clinical outcomes of 341 patients from 77 studies were extracted and analyzed. A meta-analysis was conducted on the basis of 4 studies including 2 randomized controlled trials and 2 comparative studies. The patients had a mean age of 74.60 ± 13.18 years, 45.4% were males, and 54.6% were females. There were 185 patients with mild-to-moderate and 143 patients with severe disease. The average initial doses were 1.62 ± 0.39 g/day for tetracycline, 0.20 ± 0.01 g/day for doxycycline, and 0.11 ± 0.05 g/day for minocycline. The average time on tetracyclines was 3.74 ± 5.99 months, and 261 (81.3%) patients reported partial or complete remission. Relapses occurred in 72 (28.3%) cases. Adverse effects were experienced by 130 (41.9%) patients. The pooled ORs for short-term effectiveness, relapse, adverse effects, and 1-year survival in patients treated with oral tetracyclines vs. systemic corticosteroids were 0.40 (95% CI, 0.22–0.76), 0.69 (95% CI, 0.44–1.10), 0.47 (95% CI, 0.27–0.82) and 2.02 (95% CI, 1.16–3.50), respectively. Compared to doxycycline and minocycline, tetracycline was significantly associated with better treatment outcomes and fewer adverse effects (p

This study was aimed to investigate the prevalence and factors associated with anxiety and depressive symptoms among hospitalized patients with COVID-19 during the epidemic outbreak in Wuhan, China. A total of 99 COVID-19 patients were recruited and completed the Hospital Anxiety and Depression Scale (HADS) and the modified Medical Research Council (mMRC) Scale. Results showed there was no significant difference in anxiety or depressive symptoms between male and female. Patients aged 46–60 years old had a higher ratio of both anxiety and depressive symptoms. Besides, patients whose hospital stays was longer than 14 days had a higher risk of depressive symptoms than those stays was less than 7 days. There was no significant difference in the correlation between level of dyspnea and the levels of anxiety or depressive symptoms. In conclusion, COVID-19 patients might have anxiety and depressive symptoms during hospitalization. Clinicians should pay attention to the middle age group and patients with longer hospital stays.

Cerebral small vessel disease (CSVD) is a common disease among elderly individuals and recognized as a major cause of vascular cognitive impairment. Recent studies demonstrated that CSVD is a disconnection syndrome. However, due to the covert neurological symptoms and subtle changes in clinical performance, the connection alterations during the stage of preclinical cognitive impairment (PCI) and mild cognitive impairment (MCI) are usually neglected and still largely unknown. Using diffusion tensor imaging (DTI), we investigated the early structural network changes in PCI and MCI patients. The PCI group demonstrated well preserved rich-club organization, less nodal strength loss, and disruption of connections centered in the feeder and local connections. Nevertheless, the MCI group manifested a disruption in the rich-club organization, a worse nodal strength loss especially in hub nodes, and an overall disturbance in rich-club, feeder and local connections. Moreover, in all CSVD patients, the strength of the rich-club, feeder and local connections was significantly correlated with multiple cognitive scores, especially in attention, executive, and memory domains; while in MCI patients, only the strength of the rich-club connections was significantly correlated with cognition. Furthermore, based on the network-based statistic analysis, we also identified distinct network component disruption pattern between the PCI group and the MCI group, validating the results described above. These results suggest a disruption pattern from peripheral to central connections with the change of cognitive status, shedding light on the early identification and the underlying disruption of CSVD.

Purpose Evidence about bone microarchitecture in Asian type 1 diabetes (T1D) patients is lacking. We assessed the bone microarchitecture in T1D patients versus controls and compare the differences between juvenile-onset and adult-onset T1D patients. Methods This cross-sectional study recruited 32 Asian males with T1D and 32 age-, sex-, and body mass index (BMI)-matched controls. Dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT) for ultradistal nondominant radius and tibia were performed. The data were analyzed using Student’s t test and analysis of covariance. Results Among the patients, 15 had juvenile-onset T1D, with a median disease duration of 11 years, and 17 had adult-onset T1D, with a median disease duration of 7 years. At the radius, adult-onset and juvenile-onset T1D patients had lower total volumetric bone mineral density (vBMD), trabecular vBMD, trabecular bone volume fraction (BV/TV), and trabecular thickness (Tb.Th) (p p p Conclusions T1D patients were associated with compromised bone microarchitecture, adult-onset and juvenile-onset T1D patients demonstrated some differences in cortical and trabecular microarchitecture.

To explore the function of curcumin chitosan on the proliferation of human colorectal cancer HT29 cells and to explore its effect on apoptosis. We applied MTT assay to test the inhibitory effect of curcumin chitosan on the proliferation of HT29 cells. The alterations of colorectal cancer cell morphology were observed by optical microscope and electron microscope. The change of early apoptosis rate was determined by flow cytometry using Annexin-V/PI double staining. By Comparison with the control group, curcumin chitosan significantly suppressed the cell proliferation and promoted cell apoptosis of HT29 cells in not only dose- but also time-dependent manner; through light microscopy and electron microscopy, the cell volume was reduced, the cell membrane was shrunk, chromatin was significantly concentrated. Typical apoptotic features such as aggregation; flow cytometry confirmed a significant increase in apoptotic rates (p < 0 05).

Objectives: Human papillomavirus (HPV) ranks the first cause of cervical cancer. Cervical cancer has high prevalence rates in women around the world. The HPV-E7 oncoprotein is expressed in cervical cancer and is a target of developing immunotherapies against HPV-associated tumors. However, the antigenicity of this protein is low. Due to this reason, potent adjuvants are required to enhance its therapeutic efficacy. This preliminary study aims to evaluate whether lymphotoxin (LT) could act as an effective immune adjuvant for HPV infection in mice models. Material and methods: Intranasal immunization was used to explore the effect of HPV-E7 and/or LT immune response. After the third intranasal immunization, the titer for the HPV-E7 antibody was detected in serum and vaginal washing fluid. Also, we assessed the expression of chemokine ligand 13 (CXCL13) and Peripheral Node Addressin (PNAd) in the lymph nodes after intranasal immunization with immunohistochemical analysis. Results: compared to HPV-E7 immunization, intranasal immunization with HPV-E7 plus LT significantly increased HPV-E7-specific serum IgG and vaginal IgA titers. Furthermore, the combined use of HPV-E7 and LT strongly induced E7-specific CTL responses. Conclusions: LT can be effective for intranasal immunized HPV-E7 to improve E7-specific immune responses to HPV infection. It is new approach to eradicate chronic HPV infection capable of inducing an effective anti-infection method.

Objectives The high prevalence of sleep disorders has greatly increased the demands for diagnosis and treatment; while the imbalance in geographical distribution of necessary medical resources coupled with lacking of specialist care expertise in China raise the challenges further. This study aims to explore the effectiveness of our proposed innovative PSGCloud system in providing or enhancing primary care institutions with sleep medicine service capabilities. We will introduce the entire study through a series of three research papers: this first one focuses on sleep structure and arousal analysis, and the other two ensuing papers will cover respiratory as well as limb movement issue, respectively. Methods Firstly, the three Sleep Medical Centers involved in the study uploaded their respectively recorded polysomnography (PSG) data to the PSGCloud system. Secondly, the designated PSG technicians ran the cloud-integrated PSG scoring client of the PSGCloud to download and score PSG recordings, while the same technicians also used the standalone PSG systems built-in scoring software to score the data of the corresponding patient to generate two PSG monitoring reports, respectively. Finally, the two corresponding reports for each patient were compared and analyzed in respect of 20 parameters related to sleep structure and arousal analysis as per their differences, correlations, and agreements. Results The dataset in this study included PSG recordings of 30 patients’ (17 male, 13 female, aged 40.8 ± 12.63 years, Body Mass Index 26.37 ± 4.34 kg/m2). For the parameters related to sleep structure, there was no significant difference between the two systems with regard to total sleep time, sleep efficiency, wake time after sleep onset, sleep latency, and so on. For the parameters concerning arousal, there was no statistically significant difference either. Significant correlations (all ICC > 0.8, and most ICC > 0.9, ICC stands for intra-class correlation) were found in parameters of the two systems. The Bland-Altman analysis showed positive agreements between the two systems. Conclusions This study demonstrated clearly that the sleep scoring agent of our proposed PSGCloud system exhibited high agreement with that of the clinically recognized gold standard of the standalone PSG systems’ in terms of sleep structure and arousal analysis parameters within a limited sampling scope. And it would motivate the implementation of a large-scale validation study for the PSGCloud’s sleep care service delivery model.

Aryloxypropanolamine is an essential structural scaffold for a variety of β-adrenergic receptor antagonists such as metoprolol. Molecules with such a structural motif tend to degrade into α, β–hydroxypropanolamine impurities via a radical–initiated oxidation pathway. These impurities are typically polar and nonchromophoric, and are thus often overlooked using traditional reversed phase chromatography and UV detection. In this work, stress testing of metoprolol confirmed the generation of 3-isopropylamino-1,2-propanediol as a degradation product, which is a specified impurity of metoprolol in the European Pharmacopoeia (impurity N). To ensure the safety and quality of metoprolol drug products, hydrophilic interaction chromatography (HILIC) methods using Halo Penta HILIC column (150 mm × 4.6 mm, 5 μm) coupled with charged aerosol detection (CAD) were developed and optimized for the separation and quantitation of metoprolol impurity N in metoprolol drug products including metoprolol tartrate injection, metoprolol tartrate tablets, and metoprolol succinate extended-release tablets. These HILIC-CAD methods were validated per USP validation guidelines with respect to specificity, linearity, accuracy, and precision, and have been successfully applied to determine impurity N in metoprolol drug products., Graphical abstract Image 1, Highlights • The combination of HILIC and CAD technologies for the detection and quantitation of a polar and nonchromaphoric impurity in metoprolol drug products. • Technical barriers were solved and hands-on “tricks” were delineated for the practical application of CAD to drug products analysis. • A general solution for the analysis of atypical impurities in drug products.

Most randomized trials for acute promyelocytic leukemia (APL) have investigated highly selected patients under idealized conditions, and the findings need to be validated in the real world. We conducted a population-based study of all APL patients in Zhejiang Province, China, with a total population of 82 million people, to assess the generalization of all-trans retinoic acid (ATRA) and arsenic as front-line treatment. The outcomes of APL patients were also analyzed. Between January 2015 and December 2019, 1,233 eligible patients were included in the final analysis. The rate of ATRA and arsenic as front-line treatment increased steadily from 66.2% in 2015 to 83.3% in 2019, with no difference among the size of the center (≥5 or p = 0.12) or age (≥60 or p = 0.35). The early death (ED) rate, defined as death within 30 days after diagnosis, was 8.2%, and the 3-year overall survival (OS) was 87.9% in the whole patient population. Age (≥60 years) and white blood cell count (>10 × 109/L) were independent risk factors for ED and OS in the multivariate analysis. This population-based study showed that ATRA and arsenic as front-line treatment are widely used under real-world conditions and yield a low ED rate and a high survival rate, which mimic the results from clinical trials, thereby supporting the wider application of APL guidelines in the future.

Diffusion weighted imaging (DWI) is a widely recognized neuroimaging technique to evaluate the microstructure of brain white matter. The objective of this study is to establish an improved automated DWI marker for estimating white matter integrity and investigating ageing related cognitive decline. The concept of Wasserstein distance was introduced to help establish a new measure: difference in distribution functions (DDF), which captures the difference of reshaping one's mean diffusivity (MD) distribution to a reference MD distribution. This new DWI measure was developed using a population-based cohort (n=19,369) from the UK Biobank. Validation was conducted using the data drawn from two independent cohorts: the Sydney Memory and Ageing Study, a community-dwelling sample (n=402), and the Renji Cerebral Small Vessel Disease Cohort Study (RCCS), which consisted of cerebral small vessel disease (CSVD) patients (n=171) and cognitively normal controls (NC) (n=43). DDF was associated with age across all three samples and better explained the variance of changes than other established DWI measures, such as fractional anisotropy, mean diffusivity and peak width of skeletonized mean diffusivity (PSMD). Significant correlations between DDF and cognition were found in the UK Biobank cohort and the MAS cohort. Binary logistic analysis and receiver operator characteristic curve analysis of RCCS demonstrated that DDF had higher sensitivity in distinguishing CSVD patients from NC than the other DWI measures. To demonstrate the flexibility of DDF, we calculated regional DDF which also showed significant correlation with age and cognition. DDF can be used as a marker for monitoring the white matter microstructural changes and ageing related cognitive decline in the elderly.

In anti-tumour therapy, the toll-like receptor 2/4 (TLR2/4) signalling pathway has been a double-edged sword. TLR2/4 agonists are commonly considered adjuvants for immune stimulation, whereas TLR2/4 antagonists demonstrate more feasibility for anti-tumour therapy under specific chronic inflammatory situations. In individuals with cancer retaliatory proliferation and metastasis after surgery, blocking the TLR2/4 signalling pathway may produce favourable prognosis for patients. Therefore, here, we developed a small-molecule co-inhibitor that targets the TLR2/4 signalling pathway. After high-throughput screening of a compound library containing 14 400 small molecules, followed by hit-to-lead structural optimisation, we finally obtained the compound TX-33, which has effective inhibitory properties against the TLR2/4 signalling pathways. This compound was found to significantly inhibit multiple pro-inflammatory cytokines released by RAW264.7 cells. This was followed by TX-33 demonstrating promising efficacy in subsequent anti-tumour experiments. The current results provide a novel understanding of the role of TLR2/4 in cancer and a novel strategy for anti-tumour therapy.

Widespread impairments in white matter and cerebrovascular integrity have been consistently implicated in the pathophysiology of patients with small vessel disease (SVD). However, the neural circuit mechanisms that underlie the developing progress of clinical cognitive symptoms remain largely elusive. Here, we conducted cross-modal MRI scanning including diffusion tensor imaging and arterial spin labeling in a cohort of 113 patients with SVD, which included 74 patients with vascular mild cognitive impairment (vMCI) and 39 patients without vMCI symptoms, and hence developed multimode imaging-based machine learning models to identify markers that discriminated SVD subtypes. Diffusion and perfusion features, respectively, extracted from individual white matter and gray matter regions were used to train three sets of classifiers in a nested 10-fold fashion: diffusion-based, perfusion-based, and combined diffusion-perfusion-based classifiers. We found that the diffusion-perfusion combined classifier achieved the highest accuracy of 72.57% with leave-one-out cross-validation, with the diffusion features largely spanning the capsular lateral pathway of the cholinergic tracts, and the perfusion features mainly distributed in the frontal-subcortical-limbic areas. Furthermore, diffusion-based features within vMCI group were associated with performance on executive function tests. We demonstrated the superior accuracy of using diffusion-perfusion combined multimode imaging features for classifying vMCI subtype out of a cohort of patients with SVD. Disruption of white matter integrity might play a critical role in the progression of cognitive impairment in patients with SVD, while malregulation of coritcal perfusion needs further study.

Background Pulmonary embolism (PE) is a life-threatening condition. Few studies have evaluated the relationship between air pollution and PE, and these results have been inconsistent. Therefore, our study aimed to investigate the association between air pollutant exposure and the risk of hospitalization due to PE. Materials and methods Daily PE admissions, meteorological data, and ambient pollution data from January 1, 2015, to December 31, 2018, were collected in Beijing. A quasi-Poisson regression model combined with time-stratified case-crossover design and a distributed lag nonlinear model was used to determine the effect of air pollutant exposure on PE admission. To examine the stability of air pollutants' effects, multi-pollutant analyses were performed. Stratified analyses by age and sex were further conducted. Results There were 5060 PE admissions during the study period, with an estimated incidence of 6.5 per 100,000. PM2.5, PM10, SO2, O3 and CO exposures were significantly associated with elevated risk of PE hospitalization. The highest cumulative risks were observed at a lag of 0–28 days for PM2.5 (relative risk [RR] = 1.056, 95% confidence intervals [CI]: 1.015–1.098), PM10 (RR = 1.042, 95%CI: 1.010–1.075), and CO (RR = 1.466, 95%CI: 1.127–1.906), at a lag of 0–27 days for SO2 (RR = 1.674, 95%CI: 1.200–2.335), and at a lag of 0–4 days for O3 (RR = 1.019, 95%CI: 1.001–1.038). All associations mentioned above except O3 remained significant in multi-pollutant models. Stratified analyses showed that women and those aged ≥65 years people were more sensitive to PM10 and CO exposure than men and those aged Conclusions Exposure to PM2.5, PM10, SO2, and CO showed a positive association with PE hospitalization. High-risk PE groups should take special precautions on days with poor air quality.

Objectives: We aim to investigate whether multi-dimensional diffusion tensor imaging (DTI) measures can sensitively identify different cognitive status of cerebral small vessel disease (CSVD) and to explore the underlying pattern of white matter disruption in CSVD.Methods: Two hundred and two participants were recruited, composed of 99 CSVD patients with mild cognitive impairment (VaMCI) and 60 with no cognitive impairment (NCI) and 43 healthy subjects as normal controls (NC). Full domain neuropsychological tests and diffusion-weighted imaging were performed on each subject. DTI metrics such as fractional anisotropy (FA), mean diffusivity (MD), the skeletonized mean diffusivity (PSMD), and structural brain network measures including network strength, global efficiency (EGlobal), and local efficiency (ELocal) were calculated. Region of interest (ROI) analysis of 42 white matter tracts was performed to examine the regional anatomical white matter disruption for each group.Results: Significant differences of multiple cognitive test scores across all cognitive domains especially processing and executive function existed among the three groups. DTI measures (FA, MD, and PSMD) showed significant group difference with the cognitive status changing. FA and EGlobal showed significant correlation with processing speed, executive function, and memory. ROI analysis found that white matter integrity impairment occurred from the preclinical stage of vascular cognitive impairment (VCI) due to CSVD. These lesions in the NCI group mainly involved some longitudinal fibers such as right superior longitudinal fasciculus (SLF-R), right superior fronto-occipital fasciculus (SFO-R), and right uncinate fasciculus (UNC-R), which might be more vulnerable to the cerebrovascular aging and disease process.Conclusions: DTI measures are sensitive neuroimaging markers in detecting the early cognitive impairment and able to differentiate the different cognitive status due to CSVD. Subtle changes of some vulnerable white matter tracts may be observed from the preclinical stage of VCI and have a local to general spreading pattern during the disease progression.

Diabetes mellitus (DM) is a common chronic disease worldwide. Ambient air pollution has long been proven to be associated with type 2 diabetes mellitus (T2DM) progression, but the underlying mechanism is not clear yet. In addition, previous studies mainly focused on the prevention of healthy people against the incidence of T2DM. We designed a panel study including two follow-ups and enrolled 39 patients with T2DM living in Beijing. Linear mixed model was fitted to assess the association between two pairs of variables (ambient air pollution exposure and C3 levels, ambient air pollution exposures and T2DM index). Mediation analysis of C3 between ambient air pollution exposure and indicators of T2DM progression was conducted. We found that PM2.5 exposures is are negatively associated with serum complement C3. Given that C3 might act as a protector of pancreas β cell, PM2.5 exposures could accelerate disease in T2DM populations. No mediation effects were found. This study reveals that exposures to PM2.5 can cause progression of diseases among T2DM populations.

Introduction TET2, a member of the Ten-Eleven translocation gene family, catalyzes the conversion of 5-methylcytosine to 5-hydroxymethylcytosine in DNA. Low expression of TET2 has been reported as a prognostic factor for several types of malignancies in adult patients. However, there have been few data on the effect of TET2 mRNA level on the prognosis of children with ALL so far. Methods In this study, TET2 expression of samples cryopreserved in the liquid nitrogen from January 1, 2007 through December 31, 2011 was retrospectively analyzed in 136 newly diagnosed ALL patients by real-time polymerase chain reaction (PCR) assay. The patients' samples were divided into two groups by the median value of patients group and divided into TET2 low and TET2 high groups. Results A total of 136 childhood ALL patients demonstrated lower TET2 expression than control group (P = .038). TET2 mRNA expression levels were correlated with the disease status. In addition, patients with low TET2 expression had lower platelet counts and lower CR rates. Survival analysis showed that low TET2 expression in children with ALL was associated with lower 5-year overall survival (OS) (63% vs 88%, P = .011) and event-free survival (EFS) (60% vs 85%, P = .003). Multivariate analysis revealed that low TET2 expression was an independent poor prognostic factor of OS and EFS. Conclusion Low expression of TET2 in children with ALL is associated with poor prognosis and can be used as a molecular prognostic marker for risk group stratification.

This article has been retracted, and the online PDF has been watermarked “RETRACTION”. The retraction notice is available at http://doi.org/10.3233/MGC-220954.

Immune thrombocytopenia (ITP) is a common immune-mediated bleeding disorder in children, and intravenous immunoglobulin (IVIG) is widely used as the initial therapy of ITP. Effective predictive factors of response to IVIG in ITP are important for guiding the treatment decisions. A retrospective study was performed on 197 Chinese ITP patients, and the data of their serum interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) levels, age at onset, duration of disease, white blood cell count (WBC), platelet count, and gender ratio were collected. Our results showed that ITP patients had higher IL-2, IL-6, IL-10, and IFN-γ levels than healthy children. Moreover, lower IL-4 level ( 6.37*109/L), and higher platelet count (>12 * 109/L) at diagnosis were favorable predictive factors for IVIG response in the newly diagnosed ITP. In addition, ITP patients with lower IL-10 level ( 2.84 years) were more resistant to therapy and developed to chronic ITP more easily. These findings may help guide the treatment decisions making for ITP patients.

The aim of this study is to systematically compare the performance of C-reactive protein (CRP), procalcitonin (PCT) and serum cytokines in identifying pediatric cancer patients with high-risk infection. A prospective observational study was performed from January 2014 through December 2016. Consecutive pediatric cancer patients who experienced febrile illness during hospitalization were enrolled. The CRP, PCT, interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were determined within 6 h of fever onset. A total of 3118 episodes of febrile illness were included, with 13.1% episodes documented as bloodstream infection (BSI) and 3.5% diagnosed as septic shock. Patients with BSI presented much higher levels of PCT, IL-6, IL-10 and TNF-α than patients with other types of fever and have much higher incidence of septic shock (11.2% vs. 2.3%, P 0.001). IL-6 and IL-10 showed better performance in identifying patients with gram-negative bacteremia (GNB) and septic shock than CRP and PCT, respectively. The area under the curve (AUCs) of receiver operating characteristic (ROC) curve for septic shock prediction were 0.65, 0.78, 0.89 and 0.87 for CRP, PCT, IL-6 and IL-10, respectively. Furthermore, elevation of IL-6 and IL-10 were strongly associated with the development of GNB and septic shock. Our results indicate that BSI, especially GNB, is a high-risk form of infection which results in high incidence of septic shock. IL-6 and IL-10 performance better than CRP and PCT in identifying patients with high-risk febrile illness.

Exposure to airborne particulate matter with an aerodynamic diameter less than or equivalent to 2.5 microns (PM2.5) easily induces acute myocardial infarction in populations with high-risk cardiovascular diseases such as hyperlipidemia, but its mechanism remains unclear. In this study, hyperlipidemic rats were used to examine the effects of PM2.5 exposure on the cardiovascular system and the mechanism for its induction of cardiovascular events. We found that PM2.5 exposure resulted in bigger changes in the myocardial enzyme profile (cTnI, LDH, CK, CK-MB) in hyperlipidemic rats than that of control rats, as well as a significant increase in the C-reactive protein (CRP) level and a decrease in the superoxide dismutase (SOD) activity. It promoted a hypercoagulable state, significantly increased blood pressure and heart rate, while decreased the variability of heart rate in hyperlipidemic rats. In addition, pathological test showed that PM2.5 exposure more easily deteriorated myocardial injury in hyperlipidemic rats. It upregulated the phosphorylation levels of myocardial c-Jun NH2-terminal kinase (JNK) and P53, resulting in the elevated expression of downstream effector protein Bax and the decreased expression of Bcl-2, and then increased caspase3 level leading to cardiomyocyte apoptosis, while little change of caspase2 was observed. Taken together, PM2.5 exposure induced more serious inflammation and oxidative stress in the circulation system of hyperlipidemic rats, promoted a hypercoagulable state and triggered cardiomyocyte apoptosis, in which JNK/P53 pathway played a key role.

Due to the occurrence of bacterial resistance, there is a significant need to develop alternative antimicrobials to conventional antibiotics. Antibacterial photodynamic therapy (PDT) has been recognized as a promising antibacterial strategy with a low likelihood of generating bacterial resistance. In this work, a maltoheptaose-decorated boron-dipyrromethene (BODIPY) photosensitizer (BODIPY-Mal-I) was synthesized via a copper(I)-catalyzed azide alkyne cycloaddition (CuAAC) reaction, followed by diiodo substitution at the 2,6-positions of the BODIPY core. The as-obtained BODIPY-Mal-I, consisting of a hydrophobic 2,6-diiodo-tetramethyl BODIPY unit and a hydrophilic maltoheptaose segment, can self-assemble and form microaggregates in aqueous medium. Under light illumination, BODIPY-Mal-I in water could generate singlet oxygen rapidly. The generated singlet oxygen could kill the planktonic cells of Gram-positive bacteria efficiently. BODIPY-Mal-I could also eradicate early-stage biofilms of Gram-positive bacteria in the presence of light illumination. In addition, BODIPY-Mal-I exhibits low cytotoxicity to zebrafish embryo without light illumination.

Emerging literature have illustrated the vital regulatory roles of long noncoding RNAs (lncRNAs) on the breast cancer tumorigenesis. Although series of researches have been proceeded on the pathogenesis, there are still much of unsolved mysteries worth investigating. This study uncovered that CASC15 expression level was aberrantly high-expressed in breast cancer tissue specimens and cells. Functionally, the loss-of-functional experiments showed that knockdown of CASC15 suppressed the malignant behaviors of breast cancer cells, such as proliferation, invasion and tumor growth in vitro and vivo. Mechanically, we confirmed that CASC15 functioned as a competing endogenous RNA (ceRNA) of miR-153–3p, besides, miR-153–3p targeted the 3‘-UTR of KLF5 mRNA utilizing the bioinformatics online tools, luciferase reporter assay and RNA immunoprecipitation. Interestingly, we confirmed that the transcription factor KLF5 binds with the promoter region of CASC15 and activates the transcription. In conclusion, we validated the positive feedback loop of KLF5/CASC15/miR-153–3p/KLF5 in the acceleration of breast cancer malignant behaviors and tumorigenesis, suggesting the important biologic roles of CASC15 on the breast cancer tumorigenesis.

Background Managing noncommunicable diseases through primary healthcare has been identified as the key strategy to achieve universal health coverage but is challenging in most low- and middle-income countries. Stroke is the leading cause of death and disability in rural China. This study aims to determine whether a primary care-based integrated mobile health intervention (SINEMA intervention) could improve stroke management in rural China. Methods and findings Based on extensive barrier analyses, contextual research, and feasibility studies, we conducted a community-based, two-arm cluster-randomized controlled trial with blinded outcome assessment in Hebei Province, rural Northern China including 1,299 stroke patients (mean age: 65.7 [SD:8.2], 42.6% females, 71.2% received education below primary school) recruited from 50 villages between June 23 and July 21, 2017. Villages were randomly assigned (1:1) to either the intervention or control arm (usual care). In the intervention arm, village doctors who were government-sponsored primary healthcare providers received training, conducted monthly follow-up visits supported by an Android-based mobile application, and received performance-based payments. Participants received monthly doctor visits and automatically dispatched daily voice messages. The primary outcome was the 12-month change in systolic blood pressure (BP). Secondary outcomes were predefined, including diastolic BP, health-related quality of life, physical activity level, self-reported medication adherence (antiplatelet, statin, and antihypertensive), and performance in “timed up and go” test. Analyses were conducted in the intention-to-treat framework at the individual level with clusters and stratified design accounted for by following the prepublished statistical analysis plan. All villages completed the 12-month follow-up, and 611 (intervention) and 615 (control) patients were successfully followed (3.4% lost to follow-up among survivors). The program was implemented with high fidelity, and the annual program delivery cost per capita was US$24.3. There was a significant reduction in systolic BP in the intervention as compared with the control group with an adjusted mean difference: −2.8 mm Hg (95% CI −4.8, −0.9; p = 0.005). The intervention was significantly associated with improvements in 6 out of 7 secondary outcomes in diastolic BP reduction (p < 0.001), health-related quality of life (p = 0.008), physical activity level (p < 0.001), adherence in statin (p = 0.003) and antihypertensive medicines (p = 0.039), and performance in “timed up and go” test (p = 0.022). We observed reductions in all exploratory outcomes, including stroke recurrence (4.4% versus 9.3%; risk ratio [RR] = 0.46, 95% CI 0.32, 0.66; risk difference [RD] = 4.9 percentage points [pp]), hospitalization (4.4% versus 9.3%; RR = 0.45, 95% CI 0.32, 0.62; RD = 4.9 pp), disability (20.9% versus 30.2%; RR = 0.65, 95% CI 0.53, 0.79; RD = 9.3 pp), and death (1.8% versus 3.1%; RR = 0.52, 95% CI 0.28, 0.96; RD = 1.3 pp). Limitations include the relatively short study duration of only 1 year and the generalizability of our findings beyond the study setting. Conclusions In this study, a primary care-based mobile health intervention integrating provider-centered and patient-facing technology was effective in reducing BP and improving stroke secondary prevention in a resource-limited rural setting in China. Trial registration ClinicalTrials.gov NCT03185858., Lijing Yan and colleagues evaluate a mobile health intervention for secondary stroke prevention in China., Author summary Why was this study done? In low- and middle-income countries, there is an urgent need to develop effective and cost-effective approaches to strengthen primary healthcare system in noncommunicable disease management. Rural China suffers from an increasing burden due to stroke, with no existing effective strategy to manage community-dwelling stroke patients. Results from mobile health studies, usually not integrating health solutions for both primary healthcare providers and patients, were mixed with some demonstrating effectiveness while others had neutral findings. What did the researchers do and find? We conducted a cluster-randomized controlled trial in rural China to investigate whether a primary care-based integrated mobile health intervention could improve blood pressure (BP) control and secondary prevention of stroke. We identified individuals with stroke from 50 villages. Villages allocated in the intervention arm received both provider and patient-facing interventions over 12 months. There was a significant net reduction in systolic BP between the intervention and control groups, and the intervention also led to significant improvement in other health outcomes and reduction in hospitalization and mortality among stroke patients in rural China. The program was well implemented with relatively high fidelity and low cost (US$24.3 per participant per year). What do these findings mean? A primary care-based integrated mobile health intervention that aims to overcome both health system and individual barriers could lead to an improvement in BP control and secondary prevention of stroke in rural China. This model, with low program delivery cost, has the potential, when adapted to local contexts appropriately, to be relevant to other chronic conditions and in other resource-limited settings.

Background New therapies are urgently needed for Alzheimer’s disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China. Methods We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored. Results A total of 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time point, measurable at the week 4 visit and continuing throughout the trial. The difference between the groups in change from baseline was − 2.15 points (95% confidence interval, − 3.07 to − 1.23; p Conclusions GV-971 demonstrated significant efficacy in improving cognition with sustained improvement across all observation periods of a 36-week trial. GV-971 was safe and well-tolerated. Trial registration ClinicalTrials.gov, NCT02293915. Registered on November 19, 2014

Epidemiological studies have demonstrated that various kinds of urinary element concentrations were different between healthy, prediabetes, and diabetes patients. Meanwhile, many studies have explored the relationship between element concentration and fasting blood glucose (FBG), but the association between joint exposure to co-existing elements and FBG level has not been well understood. The study explored the associations of joint exposure to co-existing urinary elements with FBG level in a cross-sectional design. 275 retired elderly people were recruited from Beijing, China. The questionnaire survey was conducted, and biological samples were collected. The generalized linear model (GLM) and two-phase Bayesian kernel machine regression (BKMR) model were used to perform in-depth association analysis between urinary elements and FBG. The GLM analysis showed that Zn, Sr, and Cd were significantly correlated with the FBG level, under control potential confounding factors. The BKMR analysis demonstrated 8 elements (Zn, Se, Fe, Cr, Ni, Cd, Mn, and Al) had a higher influence on FBG (Posterior inclusion probabilities >0.1). Further intensive analyses result of the BKMR model indicated that the overall estimated exposure of 8 elements was positively correlated with the FBG level and was statistically significant when all element concentrations were at their 65th percentile. Meanwhile, the BKMR analysis showed that Cd and Zn had a statistically significant association with FBG levels when other co-existing elements were controlled at different levels (25th, 50th or 75th percentile), respectively. The results of the GLM and BKMR model were inconsistent. The BKMR model could flexibly calculate the joint exposure to co-existing elements, evaluate the possible interaction effects and nonlinear correlations. The meaningful conclusions were found that it was difficult to get by traditional methods. This study will provide methodological reference and experimental evidence for the association between joint exposure to co-existing elements and FBG in elderly people.

Loss of white matter (WM) integrity contributes to subcortical vascular mild cognitive impairment (svMCI). Diffusion tensor imaging (DTI) has revealed damage beyond the area of WM hyperintensity (WMH) including in normal-appearing WM (NAWM); however, the functional significance of this observation is unclear. To answer this question, in this study we investigated the relationship between microstructural changes in the WMH penumbra (WMH-P) and cognitive function in patients with svMCI by regional tract-based analysis. A total of 111 patients with svMCI and 72 patients with subcortical ischemic vascular disease (SIVD) without cognitive impairment (controls) underwent DTI and neuropsychological assessment. WMH burden was determined before computing mean values of fractional anisotropy (FA) and mean diffusivity (MD) within WMHs and WMH-Ps. Pearson’s partial correlations were used to assess the relationship between measurements showing significant intergroup differences and composite Z-scores representing global cognitive function. Multiple linear regression analysis was carried out to determine the best model for predicting composite Z-scores. We found that WMH burden in the genu, body, and splenium of the corpus callosum (GCC, BCC, and SCC respectively); bilateral anterior, superior, and posterior corona radiata; left sagittal stratum was significantly higher in the svMCI group than in the control group (p < 0.05). The WMH burden of the GCC, BCC, SCC, and bilateral anterior corona radiata was negatively correlated with composite Z-scores. Among diffusion parameters showing significant differences across the 10 WM regions, mean FA values of WMH and WMH-P of the BCC were correlated with composite Z-scores in svMCI patients. The results of the multiple linear regression analysis showed that the FA of WMH-P of the BCC and WMH burden of the SCC and GCC were independent predictors of composite Z-score, with the FA of WMH-P of the BCC making the largest contribution. These findings indicate that disruption of the CC microstructure—especially the WMH-P of the BCC—may contribute to the cognitive deficits associated with SIVD.

The findings that nitrosamine impurities, mutagenic carcinogens, have been detected in several classes of medicines, including valsartan, have raised safety concerns; regulatory authorities responded by strengthening surveillance, creating specific guidance and risk assessment strategies. At the core of these responses are a number of highly sensitive analytical methodologies to detect and quantitate trace amounts of nitrosamines in pharmaceutical products. However, many of the issued methods rely on high resolution or other advanced mass spectrometers which may not be readily available or ideally suited for routine analysis of large sample sets for risk assessment. Here we describe our efforts to develop an alternative approach based on a LC method coupled with a single quadrupole mass spectrometer. Six nitrosamines, N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisopropylamine (NEIPA), N-nitrosodibutylamine (NDBA), and N-nitrosomethylaminobutyric acid (NMBA) were investigated and a LC/MS method was developed for the detection and quantitation of the six nitrosamine impurities in valsartan. Two commonly used techniques, large-volume injection (LVI) and matrix precipitation for sample preparation, were incorporated to enhance sensitivity. The developed single quadrupole LC/MS method has the capacity for detection and quantitation of the six nitrosamines listed with a LOQ of 0.05 ppm relative to valsartan. Furthermore, the method was validated within a wide dynamic range (0.05 – 3.6 ppm) and applied to commercial valsartan samples.