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The investigation of two-dimensional (2D) materials has advanced into practical device applications, such as cascaded logic stages. However, incompatible electrical properties and inappropriate logic levels remain enormous challenges. In this work, a doping-free strategy is investigated by top gated (TG) MoS2 field-effect transistors (FETs) using various metal gates (Au, Cu, Ag, and Al). These metals with different work functions provide a convenient tuning knob for controlling threshold voltage (Vth) for MoS2 FETs. For instance, the Al electrode can create an extra electron doping (n-doping) behavior in the MoS2 TG-FETs due to a dipole effect at the gate-dielectric interface. In this work, by achieving matched electrical properties for the load transistor and the driver transistor in an inverter circuit, we successfully demonstrate wafer-scale MoS2 inverter arrays with an optimized inverter switching threshold voltage (VM) of 1.5 V and a DC voltage gain of 27 at a supply voltage (VDD) of 3 V. This work offers a novel scheme for the fabrication of fully integrated multistage logic circuits based on wafer-scale MoS2 film.

Evidence-based decision making often relies on meta-analyzing multiple studies, which enables more precise estimation and investigation of generalizability. Integrative analysis of multiple heterogeneous studies is, however, highly challenging in the ultra high dimensional setting. The challenge is even more pronounced when the individual level data cannot be shared across studies, known as DataSHIELD constraint (Wolfson et al., 2010). Under sparse regression models that are assumed to be similar yet not identical across studies, we propose in this paper a novel integrative estimation procedure for data-Shielding High-dimensional Integrative Regression (SHIR). SHIR protects individual data through summary-statistics-based integrating procedure, accommodates between study heterogeneity in both the covariate distribution and model parameters, and attains consistent variable selection. Theoretically, SHIR is statistically more efficient than the existing distributed approaches that integrate debiased LASSO estimators from the local sites. Furthermore, the estimation error incurred by aggregating derived data is negligible compared to the statistical minimax rate and SHIR is shown to be asymptotically equivalent in estimation to the ideal estimator obtained by sharing all data. The finite-sample performance of our method is studied and compared with existing approaches via extensive simulation settings. We further illustrate the utility of SHIR to derive phenotyping algorithms for coronary artery disease using electronic health records data from multiple chronic disease cohorts.

To evaluate the correlation between “hot cross bun” sign (HCBs) and disease severity in multiple system atrophy (MSA). We recruited patients with probable and possible MSA with parkinsonism (MSA-P) or the cerebellar ataxia (MSA-C) subtypes. Clinical and imaging characteristics were collected and comparison was performed between MSA-C and MSA-P cases. Spearman test was used to evaluate the correlation between HCBs and other variables. Curve estimate and general linear regression was performed to evaluate the relationship between HCBs and the Scale for Assessment and Rating of Ataxia (SARA). Unified Multiple System Atrophy Rating Scale (UMSARS) IV was used to assess the severity of disease. Multinomial ordered logistic regression was used to confirm the increased likelihood of disability for the disease. Eighty-one MSA with HCBs comprising of 50 MSA-C and 31 MSA-P were recruited. We demonstrated that the severity of HCBs showed a positive linear correlation with SARA scores in MSA-C. Multinomial ordered logistic regression test revealed that the increase in the HCBs grade may be associated with an increased likelihood of disability for the disease severity in MSA, especially in those with cerebellar ataxia subtype. We demonstrated that HCBs is a potential imaging marker for the severity of cerebellar ataxia. The increase in the HCBs grade may be associated with an increased likelihood of disability in MSA-C, but not MSA-P cases, suggesting that it may be a useful imaging indicator for disease progression in Chinese patients with MSA-C.

Background Human migration facilitate the spread of tuberculosis (TB). Migrants face an increased risk of TB infection. In this study, we aim to explore the spatial inequity of sputum smear-positive pulmonary TB (SS + PTB) in China; and the spatial heterogeneity between SS + PTB and internal migration. Methods Notified SS + PTB cases in 31 provinces in mainland China were obtained from the national web-based PTB surveillance system database. Internal migrant data were extracted from the report on China’s migrant population development. Spatial autocorrelations were explored using the global Moran’s statistic and local indicators of spatial association. The spatial variation in temporal trends was performed using Kulldorff’s scan statistic. Fixed effect and spatial autoregressive models were used to explore the spatial inequity between SS + PTB and internal migration. Results A total of 2 380 233 SS + PTB cases were reported in China between 2011 and 2017, of which, 1 716 382 (72.11%) were male and 663 851 (27.89%) were female. Over 70% of internal migrants were from rural households and had lower income and less education. The spatial variation in temporal trend results showed that there was an 9.9% average annual decrease in the notification rate of SS + PTB from 2011 to 2017; and spatial clustering of SS + PTB cases was mainly located in western and southern China. The spatial autocorrelation results revealed spatial clustering of internal migration each year (2011–2017), and the clusters were stable within most provinces. Internal emigration, urban-to-rural migration and GDP per capita were significantly associated with SS + PTB, further, internal emigration could explain more variation in SS + PTB in the eastern region in mainland. However, internal immigration and rural-to-urban migration were not significantly associated with SS + PTB across China. Conclusions Our study found the spatial inequity between SS + PTB and internal migration. Internal emigration, urban-to-rural migration and GDP per capita were statistically associated with SS + PTB; the negative association was identified between internal emigration, urban-to-rural migration and SS + PTB. Further, we found those migrants with lower income and less education, and most of them were from rural households. These findings can help stakeholders to implement effective PTB control strategies for areas at high risk of PTB and those with high rates of internal migration.

There are limited data on vascular, inflammatory, metabolic risk factors of dementia in Parkinson's disease (PD) with type 2 diabetes mellitus (DM) (PD-DM). In a study of 928 subjects comprising of 215 PD with DM (including 31 PD-DM with dementia, PD-DMD), 341 PD without DM (including 31 PD with dementia, PDD) and 372 DM without PD (including 35 DM with dementia, DMD) patients, we investigated if vascular, inflammatory, metabolic, and magnetic resonance imaging (MRI) markers were associated with dementia in PD-DM. Lower fasting blood glucose (FBG15μmol/L, OR=3.131; 95%CI: 1.243-7.888; p=0.015) and hyperlipidemia (OR=3.075; 95%CI: 1.142-8.277; p=0.026), increased age (OR=1.043; 95%CI: 1.003-1.084; p=0.034) were the most significant risk factors in PDD patients. Lower low-density lipoprotein cholesterol (LDL-C4g/L, OR=4.066; 95%CI: 1.467-11.274; p=0.007) were the most significant risk factors in PD-DMD patients. The area under the curve (AUC) for fibrinogen and LDL-C was 0.717 (P=0.001), with a sensitivity of 80.0% for the prediction of PD-DMD.In summary, we identified several factors including LDL-C and fibrinogen as significant risk factors for PD-DMD and these may have prognostic and treatment implications.

Acute lung injury (ALI) is a common critical illness in clinical anesthesia and the intensive care unit that can cause acute hypoxic respiratory insufficiency. Despite various therapeutic regimes having been investigated, there is currently no effective pharmacotherapy available to treat ALI. Previous studies have reported that the NOD‑like receptor protein 3 (NLRP3) signaling pathway plays an important role in the inflammatory response and is involved in the pathogenesis of ALI. Moreover, dexmedetomidine (Dex), an α2‑adrenergic receptor activating agent, has been routinely used as an adjuvant therapy in treating inflammatory diseases, including ALI. However, the precise pathological mechanisms of Dex in ALI remain to be elucidated. Thus, the present study aimed to investigate the effects of the p38/heme oxygenase 1 (HO‑1) signaling pathways in the pathological mechanisms of Dex in ALI. Newborn male Sprague‑Dawley rats (n=48) were randomly divided into four groups (n=12 each), and an intravenous injection of lipopolysaccharide (LPS) was used to successfully induce the ALI model, with increased pulmonary damage, cell apoptosis, interleukin‑1β (IL‑1β) secretion and edema fluid in lungs. Moreover, the mRNA and protein expression levels of NLRP3 were significantly upregulated, while that of HO‑1 were downregulated by LPS treatment. Furthermore, the levels of phosphorylated p38 were also upregulated in ALI rats. It was demonstrated that Dex administration significantly alleviated LPS‑induced ALI, downregulated the secretion of IL‑1β, decreased the expression of NLRP3, inhibited the phospho‑activation of p38 and increased HO‑1 expression. In addition, pharmacological inhibition of p38 using the inhibitor SB20380 further enhanced the effect of Dex. Collectively, these preliminarily results identified the effects of Dex intervention on the pathogenesis of ALI via the regulation of p38/HO‑1 signaling pathways, which impacted the inflammatory effects, thus providing a theoretical basis and novel evidence for the development of new targets for clinical treatment of ALI.

Multiple lines of evidence indicate that immune system dysfunction has a role in Parkinson disease (PD); this evidence includes clinical and genetic associations between autoimmune disease and PD, impaired cellular and humoral immune responses in PD, imaging evidence of inflammatory cell activation and evidence of immune dysregulation in experimental models of PD. However, the mechanisms that link the immune system with PD remain unclear, and the temporal relationships of innate and adaptive immune responses with neurodegeneration are unknown. Despite these challenges, our current knowledge provides opportunities to develop immune-targeted therapeutic strategies for testing in PD, and clinical studies of some approaches are under way. In this Review, we provide an overview of the clinical observations, preclinical experiments and clinical studies that provide evidence for involvement of the immune system in PD and that help to define the nature of this association. We consider autoimmune mechanisms, central and peripheral inflammatory mechanisms and immunogenetic factors. We also discuss the use of this knowledge to develop immune-based therapeutic approaches, including immunotherapy that targets α-synuclein and the targeting of immune mediators such as inflammasomes. We also consider future research and clinical trials necessary to maximize the potential of targeting the immune system. In this Review, Tan et al. provide an overview of the clinical and preclinical evidence that immune system dysfunction is involved in Parkinson disease, and discuss how increasing knowledge of the underlying mechanisms is driving development of immune-based therapeutic approaches.

Layered molybdenum disulfide (MoS 2 ) is one of the representative two-dimensional (2D) semiconductors, offering a tantalizing prospect in the application of nanoelectronic devices and circuits. Here abnormal electrical and optoelectrical characteristics in transferred multilayer MoS 2 transistors are observed and discussed. Such phenomena can be explained by the MoS 2 intrinsic defects and the trapped charge impurities at the MoS 2 -dielectric and MoS 2 -MoS 2 interfaces, as well as its charge screening effect. Our findings highlight the significance of controlling the dielectric interface and the material quality of 2D semiconductors, which are critical for the reliability of future 2D nanoelectronic devices.

This study examine how Artificial Intelligence (AI) tools can help restaurants improve service quality and create a better customer experience. Robots, chatbots, facial recognition, voice-activated technology, sentiment analysis, and perceived usefulness have all been investigated. Questionnaires were used as the survey tool in this investigation. A total of 250 questionnaire sets were collected successfully. The findings demonstrate that all AI technologies have a favourable link with service quality, with Voice-Activated Technology having the strongest correlation.

The prevalence of dementia has been widely reported, and its potential risk and protective factors are well-characterized. However, there is a scarcity of related information regarding mild cognitive impairment (MCI). Thus this population-based study aimed to determine the prevalences of MCI and its subtypes, as well as to identify the risk and protective factors for MCI in the Chinese elderly population of Singapore. Results showed that the overall prevalence of MCI was 12.5%, while the gender-adjusted prevalence of MCI was 12.3%. Gender was found to be significantly associated with the subtypes of MCI, with males more likely to have amnestic MCI and females more likely to have non-amnestic MCI. Older age, lower educational levels, lower social activity levels, depression, hypertension, hyperlipidemia, diabetes and stroke were found to be risk factors for MCI in univariate analysis. However, multivariable analysis showed that only hypertension and stroke were the significant risk factors for MCI. Higher educational levels and active social engagements were significant protective factors for MCI in multivariable analysis. Age and depression had boundary significant associations with the prevalence of MCI. After adjusting for gender, the influence of hypertension, stroke, social engagement, age and depression on MCI remained unchanged, except that education became a boundary significant lower risk factor of MCI development. In conclusion, this study presented the prevalence, risk and protective factors for MCI among Singaporean Chinese older adults, which facilitates the screening of vulnerable groups for MCI.

Chimeric antigen receptor T (CAR-T) cell therapy is a novel cellular immunotherapy that is widely used to treat hematological malignancies, including acute leukemia, lymphoma, and multiple myeloma. Despite its remarkable clinical effects, this therapy has side effects that cannot be underestimated. Cytokine release syndrome (CRS) is one of the most clinically important and potentially life-threatening toxicities. This syndrome is a systemic immune storm that involves the mass cytokines releasing by activated immune cells. This phenomenon causes multisystem damages and sometimes even death. In this study, we reported the management of a patient with recurrent and refractory multiple myeloma and three patients with acute lymphocytic leukemia who suffered CRS during CAR-T treatment. The early application of tocilizumab, an anti-IL-6 receptor antibody, according to toxicity grading and clinical manifestation is recommended especially for patients who suffer continuous hyperpyrexia, hypotensive shock, acute respiratory failure, and whose CRS toxicities deteriorated rapidly. Moreover, low doses of dexamethasone (5-10 mg/day) were used for refractory CRS not responding to tocilizumab. The effective management of the toxicities associated with CRS will bring additional survival opportunities and improve the quality of life for patients with cancer.

ObjectivesTo investigate the expression levels of aromatase cytochrome P450 enzyme (P450AROM) and related molecules—estrogen receptor-beta (ER-β), Ki-67, and p53—in prolactinoma tumor tissue from pre- and post-menopausal women, and to determine the associations of tumor invasiveness with expression levels of these genes.MethodsThis study recruited 90 patients with prolactinoma who underwent adenoidectomy between 2012 and 2017. Information was collected regarding clinical characteristics, hormones, laboratory tests, and magnetic resonance imaging-assessed tumor invasiveness. Expression levels of P450AROM, ER-β, Ki-67, and p53 were examined by immunohistochemistry in prolactinoma tissues.ResultsIncreased P450AROM expression was found in invasive prolactinoma tissues in post-menopausal women, compared with its expression in non-invasive prolactinoma tissues. ER-β level was significantly higher in patients resistant to treatment with bromocriptine, a dopamine agonist. However, there were no differences in rate of resistance to treatment (8.2% vs. 3.4%) or expression levels of P450AROM, Ki-67, p53, and ER-β between pre- and post-menopausal patients.ConclusionsOur results demonstrated that increased P450AROM expression in prolactinoma of post-menopausal women was positively associated with invasiveness. Moreover, ER-β level was higher in both pre- and post-menopausal patients who were resistant to dopamine agonist treatment.

Background Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM). Methods This ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80 years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300 mg/m2. LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 × 106 cells/kg [range, 0.07 to 2.1 × 106]) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group. Results At data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were reported in 37/57 patients (65%); most common were leukopenia (17/57; 30%), thrombocytopenia (13/57; 23%), and aspartate aminotransferase increased (12/57; 21%). Cytokine release syndrome occurred in 51/57 patients (90%); 4/57 (7%) had grade ≥ 3 cases. One patient reported neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity. The overall response rate was 88% (95% confidence interval [CI], 76 to 95); 39/57 patients (68%) achieved a complete response, 3/57 (5%) achieved a very good partial response, and 8/57 (14%) achieved a partial response. Minimal residual disease was negative for 36/57 (63%) patients. The median time to response was 1 month (range, 0.4 to 3.5). At a median follow-up of 8 months, median progression-free survival was 15 months (95% CI, 11 to not estimable). Median overall survival for all patients was not reached. Conclusions LCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM. Trial registration ClinicalTrials.gov, NCT03090659; Registered on March 27, 2017, retrospectively registered Electronic supplementary material The online version of this article (10.1186/s13045-018-0681-6) contains supplementary material, which is available to authorized users.

Introduction and objective To improve the complete remission (CR) rate of newly diagnosed acute myeloid leukemia (AML) patients and alleviate the severe side effects of double induction chemotherapy, we combined a standard regimen with granulocyte colony-stimulating factor (G-CSF) priming chemotherapy to compose a new double induction regimen for AML patients who failed to achieve CR after the first course. Patients and methods Ninety-seven patients with AML who did not achieve CR after the first course of standard chemotherapy were enrolled. Among them, 45 patients received G-CSF priming combined with low-dose chemotherapy during days 20–22 of the first course of chemotherapy, serving as priming group, 52 patients were administered standard chemotherapy again, serving as control group. Results Between the two groups there were no differences in the French–American–British (FAB) classification, risk status, the first course of chemotherapy, blood cell count or blasts percentage of bone marrow before the second course. But the CR rate was significantly higher and the adverse effect was much lower in the priming group than the control group. Cox multivariate regression analysis showed that WBC level before the second course and the selection of the second chemotherapy regimen were two independent factors for long survival of patients. Discussion These results elucidate that standard chemotherapy followed by G-CSF priming new double induction chemotherapy is an effective method for AML patients to improve CR rate and reduce adverse effects.

Tea is a popular daily beverage worldwide, especially in China. Tea white scab disease affects tea quality is poorly understood. In the current study, we aimed determine whether tea quality will variation. we collected green tea samples from five samples (with varying morbidity from CK to Ⅳ on Baiyun Mountain in Hunan Province. Results showed that tea quality are obviously decreased as infected by tea white scab disease . Results showed that an increase in incidence rate decreased total tea polyphenols (TP) , water extract and caffeine but increased amino acids (AA) , Nonetheless, the constituents of polyphenolic compounds were differentially altered. Additionally, the percentage of (−)-epicatechin (EC) and (−)-epicatechin-3-gallate (ECG) increased with increasing morbidity. (−)-epigallocatechin (EGC) and (−)-epigallocatechin-3-gallate(EGCG) just the opposite. The constituents of AA, especially Alanine, γ-aminobutyric acid, serine and phenylalanine increased with increasing elevational gradients. Proline, and theanine were reduce along with morbidity level. As a whole. This observation demands development of effective measures for sustaining green tea quality in the face of tea white scab disease.

The immune system has been increasingly recognized as a major contributor in the pathogenesis of Parkinson’s disease (PD). The double-edged nature of the immune system poses a problem in harnessing immunomodulatory therapies to prevent and slow the progression of this debilitating disease. To tackle this conundrum, understanding the mechanisms underlying immune-mediated neuronal death will aid in the identification of neuroprotective strategies to preserve dopaminergic neurons. Specific innate and adaptive immune mediators may directly or indirectly induce dopaminergic neuronal death. Genetic factors, the gut-brain axis and the recent identification of PD-specific T cells may provide novel mechanistic insights on PD pathogenesis. Future studies to address the gaps in the identification of autoantibodies, variability in immunophenotyping studies and the contribution of gut dysbiosis to PD may eventually provide new therapeutic targets for PD.

Increasing evidence suggests an association between gastrointestinal (GI) disorders and susceptibility and progress of Parkinson's disease (PD). Gut–brain axis has been proposed to play important roles in the pathogenesis of PD, though the exact pathophysiologic mechanism has yet to be elucidated. Here, we discuss the common factors involved in both PD and GI disorders, including genes, altered gut microbiota, diet, environmental toxins, and altered mucosal immunity. Large-scale prospective clinical studies are needed to define the exact relationship between dietary factors, microbiome, and genetic factors in PD. Identification of early diagnostic markers and demonstration of the efficacy of diet modulation and regulation of gut microbiome through specific therapeutics can potentially change the treatment paradigm for PD.

Objective We aimed to identify key susceptibility gene targets in multiple datasets generated from postmortem brains and blood of Parkinson’s disease (PD) patients and healthy controls (HC). Methods We performed a multitiered analysis to integrate the gene expression data using multiple-gene chips from 244 human postmortem tissues. We identified hub node genes in the highly PD-related consensus module by constructing protein–protein interaction (PPI) networks. Next, we validated the top four interacting genes in 238 subjects (90 sporadic PD, 125 HC and 23 Parkinson’s Plus Syndrome (PPS)). Utilizing multinomial logistic regression analysis (MLRA) and receiver operating characteristic (ROC), we analyzed the risk factors and diagnostic power for discriminating PD from HC and PPS. Results We identified 1333 genes that were significantly different between PD and HCs based on seven microarray datasets. The identified MEturquoise module is related to synaptic vesicle trafficking (SVT) dysfunction in PD (P Conclusions This study highlights that SVT genes, especially SYNJ1, may be promising markers in discriminating PD from HCs and PPS.

Graphene with excellent electrical properties has a wide range of applications in electronic devices. Graphene-based planar resistance random access memory (RRAM) has received much attention due to its simple preparation methods and unique working mechanisms. However, the thermal reliability of graphene-based planar RRAM has rarely been reported. Here, we explore the reliability of the graphene-based RRAM at different temperatures, especially at high temperatures. The result shows that graphene-based planar RRAM could work in the temperature range from 100 K to 570 K.

In order to put forward theoretical foundation for the airlines to strengthen the airline overbooking decision-making systems and do the best to protect the interests of both airlines and passengers. Apply mathematical statistics and probability theory. Analyzed the methods in accordance with the time line, and explains the problems of overbooking, and takes Nanjing Lukou International Airport as an example to carry out the collection and collation of single flight basic data. Based on the model hypothesis is defined. Through the MATLAB software, which verifies the correctness and effectiveness of the model. Research conclusions, according to laws operational and risk aversion mechanism, the making decision of operation method of airline passenger overbooking behavior is scientificity and feasibility.

BACKGROUND Mild parkinsonian signs (MPS) are common in the older adult and associated with a wide range of adverse health outcomes. There is limited data on the prevalence of MPS and its significance. OBJECTIVE To determine the prevalence of MPS in the community ambulant population and to evaluate the relationship of MPS with prodromal features of Parkinson's disease (PD) and cognition. METHODS This cross-sectional community-based study involved participants aged ≥50 years. Parkinsonian signs were assessed using the modified Unified Parkinson's Disease Rating Scale (mUPDRS) and cognition using the Montreal Cognitive Assessment (MoCA). Premotor symptoms of PD were screened using a self-reported questionnaire. Linear regression was used to assess the association of MPS with premotor symptoms of PD and cognitive impairment. RESULTS Of 392 eligible participants, MPS was present in 105 (26.8%). Mean age of participants with MPS was 68.8±6.9 years and without MPS was 66.1±5.9 years (p

How diet is related with cognition and health has not been systematically examined in Asians whose eating habits are very different from their counterparts in the West and the biological mechanisms underlying such links are not well known yet. The diet and healthy aging (DaHA) study is a community-based longitudinal study conducted to examine the role of diet and nutrition in promoting cognitive, emotional, and physical health among community-living elderly Singaporeans. The first wave of DaHA, conducted from 2011 to 2017, provided detailed information on diet and baseline cognitive function and health from 1010 community-living elderly in Singapore. Biomarkers of oxidative stress, systemic inflammation, and genetic information were collected. The ongoing second wave of DaHA is conducted from 2017 to 2020, which provides follow- up assessments using established cognitive tests and clinical tools. This well-characterized cohort, with its archived biological samples and high-quality data on diet and lifestyle factors will allow researchers to explore the relationships among diet, nutrition, genes, cognition, mental and physical health in an extremely cost-effective manner. Translations of the research findings into clinical and public health practices will potentially help to promote cognitive health at the population level and reduce healthcare costs related to cognitive impairment. National Medical Research Council (NMRC) Published version This work is supported by the following grants awarded to Dr Lei Feng: the National University of Singapore Virtual Institute for the Study of Ageing [grant number VG-8]; the Alice Lim Memorial Fund, Singapore [grant number ALMFA/2010]; the National Medical Research Council of Singapore [grant number NMRC/TA/ 0053/2016].

Multimodal integrative analysis fuses different types of data collected on the same set of experimental subjects. It is becoming a norm in many branches of scientific research, such as multi-omics and multimodal neuroimaging analysis. In this article, we address the problem of simultaneous covariance inference of associations between multiple modalities, which is of a vital interest in multimodal integrative analysis. Recognizing that there are few readily available solutions in the literature for this type of problem, we develop a new simultaneous testing procedure. It provides an explicit quantification of statistical significance, a much improved detection power, as well as a rigid false discovery control. Our proposal makes novel and useful contributions from both the scientific perspective and the statistical methodological perspective. We demonstrate the efficacy of the new method through both simulations and a multimodal positron emission tomography study of associations between two hallmark pathological proteins of Alzheimer’s disease.

Objective: We aimed to identify key susceptibility gene targets in multiple datasets generated from post-mortem brains of Parkinson’s disease (PD) patients and healthy controls (HC). Methods: We performed a multi-tiered analysis to integrate the gene expression data using multiple-gene chips from 244 human post mortem tissues. We identified hub node genes in the highly PD-related consensus module by constructing protein-protein interaction (PPI) networks. Next we validated the top four interacting genes in 238 subjects (90 sporadic PD, 125 HC and 23 Parkinson’s Plus Syndrome (PPS)). Utilizing multinomial logistic regression analysis(MLRA) and Receiver Operating Characteristic(ROC), we analyzed the risk factors and diagnostic power for discriminating PD from HC and PPS. Results: We identified 1333 genes that were significantly different between PD and HCs based on seven microarray datasets. The identified MEturquoise module is related to synaptic vesicle trafficking (SVT) dysfunction in PD (P

This letter presents a 0.43 GHz/0.9 GHz/1.575 GHz/ 2.45 GHz quadruplexer with ripple bandwidth of 40 MHz/ 70 MHz/60 MHz/100 MHz using a common lumped-element quadruple-mode resonator (LE-QMR). One resonant mode from LE-QMR and two resonant modes from two $LC$ resonators constitute every channel of the proposed quadruplexer. The dual-plane structure configuration is employed in this design to relieve the limited physical space. A step-to-step design procedure is given to validate our design approach. The measured result shows that the fabricated quadruplexer exhibits low insertion loss, up to 40-dB port-to-port isolation and compact size of $0.071\lambda _{g}\times 0.097\lambda _{g}\times 0.002\lambda _{g}$ .

In this Letter, a miniaturised tri-band lowpass-bandpass (LP-BP) filter is proposed by using lumped-element structure. The lowpass passband (LP) and the first bandpass passband (1-BP) are produced by using the transmission zeros to divide a lowpass filtering response into a dual-band LP-BP filtering response. The second bandpass passband (2-BP) is produced by further loading a lumped-element circuit. As an example, an LP with 3 dB cut-off frequency of 1 GHz, and two BPs centred at 2.45/5.2 GHz for the WLAN applications are designed. The fabricated tri-band LP-BP filter has low passband insertion losses of 0.08/0.69/1.38 dB, and occupies a compact circuit area of 0.055 λ gc × 0.063 λ gc .

Background: Oral contraceptive use is associated with a significantly reduced risk of ovarian cancer among BRCA1 and BRCA2 mutation carriers. To date, there have been no prospective analyses of this relationship, and the impact of other types of contraception (e.g. intrauterine device (IUD), implant, patch, injection) on BRCA-associated ovarian cancer risk is unknown. The goal of this study is to prospectively evaluate the relationship between types of contraception and ovarian cancer incidence in women with a BRCA1 or BRCA2 mutation. Methods: The longitudinal study included 3,298 eligible BRCA1/2 mutation carriers. Self-reported information regarding contraceptive use, including medication name, start year, end year, duration of use and method of administration were collected by biennial questionnaire. Women were classified according to history of contraceptive use (ever/never), duration of use, contraceptive method, calendar year of initiation and time since last use. Time-dependent Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of ovarian cancer associated with each contraceptive method. Results: There were 84 incident ovarian cancer cases diagnosed over a mean follow-up period of 5.1 years. There was no significant association between ever use of an IUD (HR: 0.78; 95% CI: 0.28-2.14) and risk of ovarian cancer compared to IUD never users. Ongoing analyses will focus on the relationships between other contraceptive methods, formulations and duration of use on ovarian cancer risk, further stratified by histology and site of origin. Conclusions: Preliminary findings from this prospective analysis suggest that IUD use may not be protective among BRCA1/2 mutation carriers. Ongoing results will elucidate the impact of contraceptive formulation and method on ovarian cancer risk to inform clinical recommendations surrounding the use of contraceptive agents for chemoprevention in high risk women. Citation Format: Yue Yin Xia, Jan Lubinski, Barry Rosen, Pal Moller, Andrea Eisen, Peter Ainsworth, Leigha Senter, Louise Bordeleau, Susan L. Neuhausen, Christian F. Singer, Jennifer Brooks, Ping Sun, Steven A. Narod, Joanne Kotsopoulos. Contraceptive use and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers: A prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 878.

To analyze retrospectively the indications and the results obtained with the transotic approach in a series of patients with vestibular schwannoma. The study included 36 patients from 2007 to 2013 with a vestibular schwannoma that was removed with a transotic approach. All patients underwent preoperative pure tone audiometry, evaluation of facial function and CT and MR imaging. All patients having (1) a hearing loss of more than 50 dB, (2) an average tumor size of 2.7 cm (range 0.5-5.0 cm) and (3) signs of a contracted mastoid (high jugular bulb, anteriorly located sigmoid sinus, low middle cranial fossa, or reduced pneumatization) were selected. The tumor was totally removed in 34 and near-totally removed in 2 patients. The facial nerve was preserved in all patients. The postoperative facial function after 6 weeks was House-Brackmann grade I in 7, grade II in 27, and grade III in 2 patients. All patients presented postoperatively with unilateral total deafness. Seven patients experienced transitory postoperative imbalance. There were two patients who required revision surgery, one with intracranial hemorrhage and another with a CSF leak. There were no deaths and no severe complications such as hemiplegia or intracranial infections. The transotic approach has proven to be of value for the removal of vestibular schwannomas up to 5.0 cm in the presence of temporal bone contraction. Hearing was not preserved; however, other clinical outcomes were very favorable, including high rates of total tumor removal and facial nerve preservation, and low rates of complications.

While tuberculosis (TB) in pregnant women is reported globally, clinical data is unavailable in China. To describe clinical features and identify difficulties in the diagnosis of pregnancy-related TB, we performed a retrospective study of 28 TB inpatients at Beijing Chest Hospital. The results were presented in terms of interquartile range (IQR) for age, and medians and percentages with respect to the categorical variables. One patient (3.6%) was immediately diagnosed; for 27 patients (96.4%), the median interval from the initial onset of symptoms to diagnosis was five weeks. Eight cases (28.6%) were microbiologically confirmed. 22 (78.6%) were pulmonary TB (PTB), while six (21.4%) were extrapulmonary TB (EPTB). In addition, eight (28.6%) were miliary TB and six (21.4%) were cerebral TB. 27 (96.4%) were cured and one (3.6%) died. 15 neonates were identified, nine of which were healthy. Two were small for the gestational age (SGA) and one was a stillbirth. Three had neonatal TB, one of which died. Nine were legal abortions and four were spontaneous abortions. Indeed, there was a substantial delay in the diagnosis of TB in the pregnant women and a high incidence of both miliary and cerebral TB was evident. With timely treatment, prognosis is positive.

Inferring brain connectivity network and quantifying the significance of interactions between brain regions are of paramount importance in neuroscience. Although there have recently emerged some tests for graph inference based on independent samples, there is no readily available solution to test the change of brain network for paired and correlated samples. In this article, we develop a paired test of matrix graphs to infer brain connectivity network when the groups of samples are correlated. The proposed test statistic is both bias corrected and variance corrected, and achieves a small estimation error rate. The subsequent multiple testing procedure built on this test statistic is guaranteed to asymptotically control the false discovery rate at the pre-specified level. Both the methodology and theory of the new test are considerably different from the two independent samples framework, owing to the strong correlations of measurements on the same subjects before and after the stimulus activity. We illustrate the efficacy of our proposal through simulations and an analysis of an Alzheimer's Disease Neuroimaing Initiative dataset., 30 pages, 1 figure, 5 tables

BACKGROUND: Gentamicin is a potent aminoglycoside antibiotic that targets gram-negative bacteria, but nephrotoxicity limits its clinical application. The cause of gentamicin-induced AKI has been attributed mainly to apoptosis of the proximal tubule cells. However, blocking apoptosis only partially attenuates gentamicin-induced AKI in animals. METHODS: Mice treated with gentamicin for 7 days developed AKI, and programmed cell death pathways were examined using pharmacologic inhibitors and in RIPK3-deficient mice. Effects in porcine and murine kidney cell lines were also examined. RESULTS: Gentamicin caused a low level of apoptosis in the proximal tubules and significant ultrastructural alterations consistent with necroptosis, occurring predominantly in the collecting ducts (CDs), including cell and organelle swelling and rupture of the cell membrane. Upregulation of the key necroptotic signaling molecules, mixed lineage kinase domain-like pseudokinase (MLKL) and receptor-interacting serine/threonine-protein kinase 3 (RIPK3), was detected in gentamicin-treated mice and in cultured renal tubule cells. In addition, gentamicin induced apical accumulation of total and phosphorylated MLKL (pMLKL) in CDs in mouse kidney. Inhibiting a necroptotic protein, RIPK1, with necrostatin-1 (Nec-1), attenuated gentamicin-induced necrosis and upregulation of MLKL and RIPK3 in mice and cultured cells. Nec-1 also alleviated kidney inflammation and fibrosis, and significantly improved gentamicin-induced renal dysfunction in mice. Furthermore, deletion of RIPK3 in the Ripk3(−/−) mice significantly attenuated gentamicin-induced AKI. CONCLUSIONS: A previously unrecognized role of programmed necrosis in collecting ducts in gentamicin-induced kidney injury presents a potential new therapeutic strategy to alleviate gentamicin-induced AKI through inhibiting necroptosis.

Basilepta melanopus is a serious insect pest of tea plantations in southern China. This tea pest poses a great threat to the tea industry in China. No effective and environmentally friendly methods have been established to control this pest at present. Olfactory genes play key roles in insect behaviour, and can potentially be used as targets for developing environmentally-friendly approaches for pest control. In this study, we produced a transcriptome derived from dissected antennae from B. melanopus using high-throughput sequencing. We identified gene families that are potentially involved in odorant reception and detection, including unigenes encoding 63 odorant receptors (ORs), 16 gustatory receptors (GRs), 18 ionotropic receptors (IRs), four sensory neuron membrane proteins (SNMPs), 46 odorant binding proteins (OBPs), and 19 chemosensory proteins (CSPs). Analyses of tissue expression profiles revealed that all 63 OR transcripts, 14 antennal IRs, one SNMP and six OBPs were predominately expressed in antennae. Real-time quantitative PCR assays were also adapted to examine sex-biased expression of selected antenna-predominant genes. Our results provide valuable information for further functional studies of olfactory genes in B. melanopus and potential novel targets for developing new pest control measures.

With the fierce competition in society, the acquisition of knowledge is no longer just through school education, but through continuing education. In the 21st century, the whole world is advocating lifelong learning. China is also making efforts. Beijing, as the capital of China, its citizens’ lifelong learning status are directly related to the construction and development of Beijing’s lifelong education system. This study used a questionnaire survey method, and used stratified sampling to extract 1,597 people from all districts in Beijing. The purpose of the study was to investigate the current situation, needs and difficulties of adult lifelong learning in Beijing, to explore the general situation, differences and analyze the affect factors based on the survey results. We hope the conclusions and suggestions of this study can provide relevant policy references and guidance for the Beijing government , Adult Education Society and other units.

BACKGROUND Klotho G-395-A gene polymorphism is associated with several diseases; however, its association with calcium-phosphate metabolism disorders in end-stage renal disease (ESRD) is unknown. METHODS A total of 137 patients with ESRD and 80 healthy adults (control) were enrolled in the study. Patients with ESRD were divided into three subgroups: haemodialysis (A1, n = 52), peritoneal dialysis (A2, n = 30), and non-dialysis (A3, n = 55). The klotho G-395-A genotype was detected by TaqMan PCR assay, and ELISA was used to detect the soluble klotho protein (sKL) and fibroblast growth factor (FGF23). Intact parathyroid hormone (iPTH) and other related clinical biochemical parameters were also analyzed for all subjects. RESULTS (i) Three genotypes (GG, GA and AA) of KL G-395A were detected, and a significant difference between the ESRD and control groups was observed, (ii) sKL was inversely associated with FGF23 in each subgroup and phosphate and positively associated with calcium in A1 and A3. FGF23 was positively associated with phosphate and inversely associated with calcium in each subgroup, (iii) a statistical difference in levels of sKL and FGF23 was observed between GG and AA, as well as between GA and AA. The expression of sKL was lowest and the level of FGF23 was highest in AA and (iv). GA + AA genotypes and FGF23 were risk factors and sKL might be protective factor of calcium-phosphate metabolism disorders. CONCLUSION Soluble klotho protein and FGF23 were associated with the regulation of calcium and phosphate metabolism, and the A allele of the G-395A klotho gene polymorphism could be a risk factor on calcium-phosphate metabolism disorders in patients with ESRD.

Non-volatile memory (NVM) devices with non-volatility and low power consumption properties are important in the data storage field. The switching mechanism and packaging reliability issues in NVMs are of great research interest. The switching process in NVM devices accompanied by the evolution of microstructure and composition is fast and subtle. Transmission electron microscopy (TEM) with high spatial resolution and versatile external fields is widely used in analyzing the evolution of morphology, structures and chemical compositions at atomic scale. The various external stimuli, such as thermal, electrical, mechanical, optical and magnetic fields, provide a platform to probe and engineer NVM devices inside TEM in real-time. Such advanced technologies make it possible for an in situ and interactive manipulation of NVM devices without sacrificing the resolution. This technology facilitates the exploration of the intrinsic structure-switching mechanism of NVMs and the reliability issues in the memory package. In this review, the evolution of the functional layers in NVM devices characterized by the advanced in situ TEM technology is introduced, with intermetallic compounds forming and degradation process investigated. The principles and challenges of TEM technology on NVM device study are also discussed.

Background: Extramedullary disease (EMD) is characterized as the presence of myeloma cells invasion outside the bone marrow in a patient with multiple myeloma (MM), it may be found 6%~8% in de novo patients, and 10% to 30% in relapsed or refractory (R/R) MM patients across the overall disease course (Joan Blade et al. 2011, Matthew Weinstock et al. 2013 and 2015, Cyrille Touzeau et al. 2015). EMD was considered as high-risk group of myeloma and is associated with adverse prognosis and the management is particularly challenging. Here we discuss and improve the understanding of the clinical characters and prognoses of the R/R MM with EMD in the treatment of CAR T therapy, illustrate our experience in a single institution. Methods: LCAR-B38M is a Chimeric antigen receptor (CAR) T cell therapy with 4-1BB as the co-stimulator, a dual epitope-binding CAR T cell therapy directed against 2 distinct B cell maturation antigen (BCMA) epitopes. In total of 57 patients were treated in China from The Second Affiliated Hospital of Xi'an Jiaotong University (LEGEND-2, NCT03090659), 17 patients with R/R MM with EMD were included and received the CAR T treatment. The study was initiated on March 30, 2016, and the analysis reported here is from a data cutoff date of July 31, 2019, the detailed treatment schema was presented in the former paper (Zhao et al, 2018). Results: Overall, 17 (29.8%) of 57 treated patients with EMD were included in our CAR T treatment. The median age of R/R MM patients with EMD (EMD group) and without EMD (non-EMD group) were 55 (range, 27-72) and 53.3 (range, 42-73) years old respectively, and the median number of prior therapy lines were 3 (range, 1-6 and 1-9) in both groups. There were no statistical difference in the proportion of male and female patients, median time from initial diagnosis and ISS stage in EMD group and non-EMD group. The Eastern Cooperative Oncology Group (ECOG) scores of patients receiving CAR T treatment were 0-2 points, the proportion of ECOG 1-2 points in EMD group were higher than non-EMD group (P < 0.05, R=0.1474, 95% CI, 0.03 to 0.73). IgG and IgA subtype were the main types in the non-EMD patients while the light chain type was more frequently seen in EMD group (P = 0.014, OR=0.1886, 95% CI, 0.05 to 0.66). The overall response rates (ORR) in the EMD group and non-EMM group were 82.4% and 90% respectively (Fig 1 A), and there were no significant difference in the median time to the first response and the best response between the EMD group and non-EMD group(P > 0.05). At cutoff, the median follow-up was 25 months, the median progression-free survival (PFS) in EMD group and non-EMD group were 8.1 months and 25 months (P < 0.001, R=0.32, 95% CI, -0.19 to 0.84), and the median overall survival (OS) were 13.9 months and not reached (P = 0.0019, R=4.833, 95% CI, 1.91 to 12.22), survival curves were shown in Fig 1 B, C . Conclusions: LCAR-B38M is a highly effective therapy in R/R MM patients with EMD and without EMD, and both groups had similar response time and reached a high ORR rate. R/R MM patients with EMD demonstrated a poor prognosis and they may lost their best response in a relatively shorter time compared with the patients without EMD. With a median follow-up of 25 months, LCARB38M manifested a relatively durable therapeutic effect in this high-risk R/R MM patients with EMD. Disclosures No relevant conflicts of interest to declare.

// Ying Shi 1, * , Xiao-Xiao Huang 1, * , Guo-Bin Chen 1, 6, * , Ying Wang 1 , Qiang Zhi 1 , Yuan-Sheng Liu 1 , Xiao-Ling Wu 1 , Li-Fen Wang 1 , Bing Yang 1 , Chuan-Xing Xiao 1 , Hui-Qin Xing 5 , Jian-Lin Ren 1 , Yin Xia 3, 4 , Bayasi Guleng 1, 2 1 Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, China 2 State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China 3 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China 4 School of Biomedical Sciences Core Laboratory, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, China 5 Department of Basic Medical Sciences, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, China 6 Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China * These authors contributed equally to this work Correspondence to: Bayasi Guleng, email: bayasi@xmu.edu.cn Yin Xia, email: Xia.Yin@cuhk.edu.hk Ying Shi, email: shiying@stu.xmu.edu.cn Keywords: Dragon, oxaliplatin resistance, colon cancer, JNK, p38 MAPK Received: December 21, 2015 Accepted: June 12, 2016 Published: June 30, 2016 ABSTRACT Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality. Chemotherapy resistance remains a major challenge for treating advanced CRC. Therefore, the identification of targets that induce drug resistance is a priority for the development of novel agents to overcome resistance. Dragon (also known as RGMb) is a member of the repulsive guidance molecule (RGM) family. We previously showed that Dragon expression increases with CRC progression in human patients. In the present study, we found that Dragon inhibited apoptosis and increased viability of CMT93 and HCT116 cells in the presence of oxaliplatin. Dragon induced resistance of xenograft tumor to oxaliplatinin treatment in mice. Mechanistically, Dragon inhibited oxaliplatin-induced JNK and p38 MAPK activation, and caspase-3 and PARP cleavages. Our results indicate that Dragon may be a novel target that induces drug resistance in CRC.

Background Patients 8 courses of chemotherapy (high-dose CHOP, CHOP-E, EPOCH, MAED, MMED, and HyperCVAD). The control group included 91 patients (46.0%) who received 6–8 courses of CHOP-based treatment. Response rate (RR), survival, relapse, and adverse effects were compared. Results Baseline characteristics of the patients were similar between the 2 groups. Median follow-up was 64.5 months. RR in the high-intensity and control groups was 88.8% and 84.6% (P=0.387), respectively; 5-year overall survival was 66.4% and 36.3% (P

Image-based tracking for motion compensation is an important topic in image-guided interventions, as it enables physicians to operate in a less complex space. In this paper, we propose an automatic motion compensation scheme to boost image guidence power in transcatheter aortic valve implantation (TAVI). The proposed tracking algorithm automatically discovers reliable regions that correlate strongly with the target. These discovered regions can assist to estimate target motion under severe occlusion, even if target tracker fails. We evaluate the proposed method for pigtail tracking during TAVI. We obtain significant improvement (12 %) over the baseline in a clinical dataset. Calcification regions are automatically discovered during tracking, which would aid TAVI processes. In this work, we open a new paradigm to provide dynamic real-time guidance for TAVI without user interventions, specially in case of severe occlusion where conventional tracking methods are challenged.

Background Extranodal NK/T-cell lymphoma (ENKTL) of the nasal type is highly invasive and relatively resistant to chemotherapy. This study aimed to assess the efficacy and safety of an extended chemotherapy regimen with increased dose intensity. Material/Methods This was a retrospective cohort study of 69 patients 8 courses of high-intensity chemotherapy (n=37) vs. 6–8 courses (n=18) and 8 courses group. Results The mean follow-up was 52 months (8 to 82 months). Remission rate did not differ significantly when compared among the 3 groups after 3 courses of chemotherapy (83.8%, 77.8%, and 78.6%, respectively, overall P=0.834), but the 5-year overall survival (OS) differed significantly (63.5%, 45.1%, and 22.9%, respectively, overall P=0.030), as did progression-free survival (PFS) (59.1%, 36.0%, and 15.1%, respectively, overall P=0.020), disease-free survival (DFS) (54.1%, 35.5%, and 12.9%, respectively, overall P=0.022), and total relapse rate throughout follow-up (37.04%, 50.0%, and 88.89%, respectively, overall P=0.027). There were no differences in adverse effects among the 3 groups. Conclusions These results suggest improved OS, PFS, DFS, and relapse rate in young patients with ENKTL receiving >8 courses of high-intensity chemotherapy.

Broadband infrared photodetectors based on two-dimensional (2D) materials which are the research focus in the infrared field, have wide applications in remote sensing, thermal imaging, and astronomy observation. In this article, the photodetector based on 2D ferromagnetic material CoSe is studied at room temperature, demonstrating the air-stable, broadband, and up to long wavelength properties. The CoSe material is applied to infrared photodetectors for the first time. The 2D material CoSe is synthesized by using the chemical vapor deposition method. The size of the as-grown CoSe is up to 71.8 μm. The photoresponse of the CoSe photodetector ranges from 450 nm to 10.6 μm. The photoresponsivity of this photodetector is up to 2.58 A W-1 under the 10.6 μm illumination at room temperature. This work provides a new material for broadband photodetector at room temperature and builds a bridge for the magnetoelectronic and broadband photoelectric fields.