bluuebunny/crossref_metadata_2025 huggingface dataset:
RETRACTED ARTICLE: Interplay between cancer cells and M2 macrophages is necessary for miR-550a-3-5p down-regulation-mediated HPV-positive OSCC progression
Authors: Cao Ming-xin , Zhang Wei-long , Yu Xiang-hua , Wu Jia-shun , Qiao Xin-wei , Huang Mei-chang , Wang Ke , Wu Jing-biao , Tang Ya-Jie , Jiang Jian , Liang Xin-hua , Tang Ya-ling
Published: June 2020

Background

Human papillomavirus (HPV)-positive oral squamous cell carcinoma (OSCC) is increasing worldwide with typically higher grade and stage, while better prognosis. microRNAs (miRNAs) has been shown to play a critical role in cancer, however, their role in HPV-positive OSCC progression remains unclear.

Methods

miRNA microarray was performed to identify differentially expressed miRNAs. qRT-PCR and FISH were performed to determine the relative expression of miR-550a-3-5p. CCK-8, Flow cytometry, Wound healing, Cell invasion assays and xenograft experiments were conducted to analyze the biological roles of miR-550a-3-5p. Tumor-associated macrophages (TAMs) generation, co-culturing of cancer cells with TAMs, Western blot, Dual-luciferase reporter gene assay, Immunohistochemistry and animal studies were performed to explore the mechanisms underlying the functions of miR-550a-3-5p.

Results

We identified 19 miRNAs differentially expressed in HPV-positive OSCC specimens and miR-550a-3-5p was down-regulated. The low expression of miR-550a-3-5p correlated with higher tumor size and nodal metastasis of HPV-positive OSCC patients. Then, we found that miR-550a-3-5p suppressed the migration, invasion and EMT of HPV-positive OSCC cells dependent on decreasing M2 macrophages polarization. Moreover, miR-550a-3-5p, down-regulated by E6 oncoprotein, inhibited M2 macrophages polarization by YAP/CCL2 signaling, which in turn abrogating EMT program in HPV-positive OSCC cells. In addition, in both xenografts and clinical HPV-positive OSCC samples, miR-550a-3-5p levels were inversely associated with YAP, CCL2 expressions and the number of M2 macrophages.

Conclusions

E6/miR-550a-3-5p/YAP/CCL2 signaling induces M2 macrophages polarization to enhance EMT and progression, revealing a novel crosstalk between cancer cells and immune cells in HPV-positive OSCC microenvironment.
The selection of an optimal transportation strategy in urgent stroke missions: a simulation study
Authors: Pappinen Jukka , Miettinen Tuuli , Laukkanen-Nevala Päivi , Jäkälä Pekka , Kantanen Anne-Mari , Mäntyselkä Pekka , Kurola Jouni
Published: June 2020

Background

Stroke causes death, disability and increases the use of healthcare resources worldwide. The outcome of intravenous thrombolysis and mechanical endovascular thrombectomy highly depends on the delay from symptom onset to initiation of definitive treatment. The purpose of this study was to compare the various patient transportation strategies to minimize pre-hospital delays.

Methods

Emergency medical services (EMS) mission locations and ambulance response times in Finland with urgent stroke-suspected dispatch codes were collected from Emergency Response Centre (ERC) records between 1 January 2016 and 31 December 2016. Four transport scenarios were simulated for each mission, comparing ground and helicopter transportation to hospital with different treatment capabilities.

Results

In 2016, a total of 20,513 urgent stroke-suspected missions occurred in Finland. Of these, we were able to locate and calculate a route to scenario-based hospitals in 98.7% (20,240) of the missions.

For ground transport, the estimated median pre-hospital time to a thrombolysis-capable and thrombectomy-capable hospital were 54.5 min (95% confidence interval (CI), 31.7–111.4) and 94.4 min (95% CI, 33.3–195.8), respectively. Should patients be transported on the ground to thrombectomy-capable hospitals only, the pre-hospital time would increase in 11,003 (54.4%) of missions, most of which were in rural areas.

With the fastest possible transportation method, the estimated mean transport time to a thrombectomy-capable hospital was 80.84 min (median, 80.80 min; 95% CI, 33.3–143.1). Helicopter transportation was the fastest method in 68.8% (13,921) of missions, and the time saved was greater than 30 min in 27.1% (5475) of missions. In rural areas, helicopter transportation was the fastest option in nearly all missions if dispatched simultaneously with ground ambulance.

Conclusion

Helicopter transportation may significantly decrease pre-hospital delays for stroke patients, especially in rural areas, but the selection of an optimal transportation method or chain of methods should be determined case-by-case.
MAUDE: inferring expression changes in sorting-based CRISPR screens
Authors: de Boer Carl G. , Ray John P. , Hacohen Nir , Regev Aviv
Published: June 2020

Improved methods are needed to model CRISPR screen data for interrogation of genetic elements that alter reporter gene expression readout. We create MAUDE (Mean Alterations Using Discrete Expression) for quantifying the impact of guide RNAs on a target gene’s expression in a pooled, sorting-based expression screen. MAUDE quantifies guide-level effects by modeling the distribution of cells across sorting expression bins. It then combines guides to estimate the statistical significance and effect size of targeted genetic elements. We demonstrate that MAUDE outperforms previous approaches and provide experimental design guidelines to best leverage MAUDE, which is available on https://github.com/Carldeboer/MAUDE.
Metabolic regulation of ethanol-type fermentation of anaerobic acidogenesis at different pH based on transcriptome analysis of Ethanoligenens harbinense
Authors: Li Zhen , Lou Yu , Ding Jie , Liu Bing-Feng , Xie Guo-Jun , Ren Nan-Qi , Xing Defeng
Published: June 2020

Background

Ethanol-type fermentation, one of the fermentation types in mixed cultures of acidogenesis with obvious advantages such as low pH tolerance and high efficiency of H2 production, has attracted widespread attentions. pH level greatly influences the establishment of the fermentation of carbohydrate acidogenesis by shaping community assembly and the metabolic activity of keystone populations. To explore the adaptation mechanisms of ethanol-type fermentation to low pH, we report the effects of initial pH on the physiological metabolism and transcriptomes of Ethanoligenens harbinense—a representative species of ethanol-type fermentation.

Results

Different initial pH levels significantly changed the cell growth and fermentation products of E. harbinense. Using transcriptomic analysis, we identified and functionally categorized 1753 differentially expressed genes (DEGs). By mining information on metabolic pathways, we probed the transcriptional regulation of ethanol–H2 metabolism relating to pH responses. Multiple pathways of E. harbinense were co-regulated by changing gene expression patterns. Low initial pH down-regulated the expression of cell growth- and acidogenesis-related genes but did not affect the expression of H2 evolution-related hydrogenase and ferredoxin genes. High pH down-regulated the expression of H2 evolution- and acidogenesis-related genes. Multiple resistance mechanisms, including chemotaxis, the phosphotransferase system (PTS), and the antioxidant system, were regulated at the transcriptional level under pH stress.

Conclusions

Ethanoligenens adapted to low pH by regulating the gene expression networks of cell growth, basic metabolism, chemotaxis and resistance but not H2 evolution-related genes. Regulation based on pH shifts can represent an important approach to establish and enhance ethanol-type fermentation. The complete gene expression network of ethanol fermentative bacteria for pH response provides valuable insights into the acidogenic fermentation, and offers an effective regulation strategy for the sustainable energy recovery from wastewater and solid waste.
Interleukin-32 in systemic sclerosis, a potential new biomarker for pulmonary arterial hypertension
Authors: Di Benedetto Paola , Guggino Giuliana , Manzi Giovanna , Ruscitti Piero , Berardicurti Onorina , Panzera Noemi , Grazia Nicolò , Badagliacca Roberto , Riccieri Valeria , Vizza Carmine Dario , Radchenko Ganna , Liakouli Vasiliki , Ciccia Francesco , Cipriani Paola , Giacomelli Roberto
Published: June 2020

Background

Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc), associated with a progressive elevation in pulmonary vascular resistance and subsequent right heart failure and death. Due to unspecific symptoms, the diagnosis of PAH is often delayed. On this basis, it is of great value to improve current diagnostic methods and develop new strategies for evaluating patients with suspected PAH. Interleukin-32 (IL-32) is a proinflammatory cytokine expressed in damaged vascular cells, and the present study aimed to assess if this cytokine could be a new biomarker of PAH during SSc.

Methods

The IL-32 expression was evaluated in the sera and skin samples of 18 SSc-PAH patients, 21 SSc patients without PAH, 15 patients with idiopathic PAH (iPAH) and 14 healthy controls (HCs), by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC). Receiver-operating characteristic (ROC) curves were performed to evaluate the cut-off of IL-32 in identifying patients with PAH. Furthermore, in SSc patients, correlation analyses were performed between IL-32 sera levels and mean pulmonary artery pressure (mPAP) evaluated by right heart catheterization (RHC) and systolic pulmonary artery pressure (sPAP), obtained by echocardiography. Additionally, the number of skin IL-32+ cells was correlated with modified Rodnan skin score (mRSS).

Results

In SSc-PAH patients, IL-32 sera levels were significantly higher when compared with SSc patients without PAH and patients affected by iPAH. The analysis of ROC curve showed that IL-32 sera levels above 11.12 pg/ml were able to predict patients with PAH (sensitivity = 90%, specificity = 100%). Furthermore, the IL-32 sera levels of patients with SSc correlated with both mPAP and sPAP. In the skin derived from SSc-PAH patients, the number of IL-32+ cells was significantly increased when compared with the skin derived from SSc patients without PAH, correlating with the mRSS.

Conclusion

Our study suggested that sera determination of IL-32 may be a promising approach to evaluate the presence of PAH in SSc patients and together with longitudinal future studies could help to increase the understanding how these biomarkers mirror the vascular changes and the inflammatory process during SSc.
Genome-wide analysis of DNA methylation identifies S100A13 as an epigenetic biomarker in individuals with chronic (≥ 30 years) type 2 diabetes without diabetic retinopathy
Authors: Li Tao , Xu Yi , Shi Yongyong , Chen Jianhua , Lin Senlin , Zhu Jianfeng , Xu Xian , Lu Lina , Zou Haidong
Published: June 2020

Background

This study aimed to determine the epigenetic biomarkers of diabetic retinopathy (DR) in subjects with type 2 diabetes mellitus (T2DM). This retrospective study is based on the Shanghai Xinjing community prevention and treatment administrative system of chronic diseases. The subjects enrolled herein were T2DM patients who had undergone long-term follow-up evaluation in the system. Two consecutive studies were conducted. In the discovery cohort, among 19 subjects who had developed DR with a DM duration < 3 years and 21 subjects without DR > 30 years after being diagnosed with DM, an Infinium Human Methylation 850 Beadchip was used to identify differential methylation regions (DMRs) and differential methylation sites (DMSs). The function of the genes was assessed through KEGG enrichment analysis, Gene Ontology (GO) analysis, and pathway network analysis. In the replication cohort, 87 DR patients with a short DM duration and 89 patients without DR over a DM duration > 20 years were compared to assess the association between DMSs and DR upon pyrosequencing.

Results

A total of 34 DMRs were identified. Genes containing DMSs with the top 5 highest beta value differences between DR and non-DR participants were located on chromosome 1 and were present in the S100A13 gene, which was associated with 71 GO terms. Two S100A13 gene sites, i.e., cg02873163 and cg11343894, displayed a good correlation with DR on pyrosequencing.

Conclusions

DMSs in the S100A13 gene may be potential biomarkers of DR.
Decreased nuclear Pten in neural stem cells contributes to deficits in neuronal maturation
Authors: Kang Shin Chung , Jaini Ritika , Hitomi Masahiro , Lee Hyunpil , Sarn Nick , Thacker Stetson , Eng Charis
Published: June 2020

Background

PTEN, a syndromic autism spectrum disorder (ASD) risk gene, is mutated in approximately 10% of macrocephalic ASD cases. Despite the described genetic association between PTEN and ASD and ensuing studies, we continue to have a limited understanding of how PTEN disruption drives ASD pathogenesis and maintenance.

Methods

We derived neural stem cells (NSCs) from the dentate gyrus (DG) of Ptenm3m4 mice, a model that recapitulates PTEN-ASD phenotypes. We subsequently characterized the expression of stemness factors, proliferation, and differentiation of neurons and glia in Ptenm3m4 NSCs using immunofluorescent and immunoblotting approaches. We also measured Creb phosphorylation by Western blot analysis and expression of Creb-regulated genes with qRT-PCR.

Results

The m3m4 mutation decreases Pten localization to the nucleus and its global expression over time. Ptenm3m4 NSCs exhibit persistent stemness characteristics associated with increased proliferation and a resistance to neuronal maturation during differentiation. Given the increased proliferation of Ptenm3m4 NSCs, a significant increase in the population of immature neurons relative to mature neurons occurs, an approximately tenfold decrease in the ratio between the homozygous mutant and wildtype. There is an opposite pattern of differentiation in some Ptenm3m4 glia, specifically an increase in astrocytes. These aberrant differentiation patterns associate with changes in Creb activation in Ptenm3m4/m3m4 NSCs. We specifically observed loss of Creb phosphorylation at S133 in Ptenm3m4/m3m4 NSCs and a subsequent decrease in expression of Creb-regulated genes important to neuronal function (i.e., Bdnf). Interestingly, Bdnf treatment is able to partially rescue the stunted neuronal maturation phenotype in Ptenm3m4/m3m4 NSCs.

Conclusions

Constitutional disruption of Pten nuclear localization with subsequent global decrease in Pten expression generates abnormal patterns of differentiation, a stunting of neuronal maturation. The propensity of Pten disruption to restrain neurons to a more progenitor-like state may be an important feature contributing to PTEN-ASD pathogenesis.

Graphical abstract
Copy number variants (CNVs): a powerful tool for iPSC-based modelling of ASD
Authors: Drakulic Danijela , Djurovic Srdjan , Syed Yasir Ahmed , Trattaro Sebastiano , Caporale Nicolò , Falk Anna , Ofir Rivka , Heine Vivi M. , Chawner Samuel J. R. A. , Rodriguez-Moreno Antonio , van den Bree Marianne B. M. , Testa Giuseppe , Petrakis Spyros , Harwood Adrian J.
Published: June 2020

Patients diagnosed with chromosome microdeletions or duplications, known as copy number variants (CNVs), present a unique opportunity to investigate the relationship between patient genotype and cell phenotype. CNVs have high genetic penetrance and give a good correlation between gene locus and patient clinical phenotype. This is especially effective for the study of patients with neurodevelopmental disorders (NDD), including those falling within the autism spectrum disorders (ASD). A key question is whether this correlation between genetics and clinical presentation at the level of the patient can be translated to the cell phenotypes arising from the neurodevelopment of patient induced pluripotent stem cells (iPSCs).

Here, we examine how iPSCs derived from ASD patients with an associated CNV inform our understanding of the genetic and biological mechanisms underlying the aetiology of ASD. We consider selection of genetically characterised patient iPSCs; use of appropriate control lines; aspects of human neurocellular biology that can capture in vitro the patient clinical phenotype; and current limitations of patient iPSC-based studies. Finally, we consider how future research may be enhanced to maximise the utility of CNV patients for research of pathological mechanisms or therapeutic targets.
Adipose mesenchymal stem cell transplantation alleviates spinal cord injury-induced neuroinflammation partly by suppressing the Jagged1/Notch pathway
Authors: Zhou Zhilai , Tian Xiaobo , Mo Biling , Xu Huali , Zhang Li , Huang Lishan , Yao Shun , Huang Zixiang , Wang Yeyang , Xie Huan , Xu Liwei , Zhang Hui
Published: June 2020

Background

The therapeutic effects of adipose-derived mesenchymal stem cell (ADSC) transplantation have been demonstrated in several models of central nervous system (CNS) injury and are thought to involve the modulation of the inflammatory response. However, the exact underlying molecular mechanism is poorly understood. Activation of the Jagged1/Notch signaling pathway is thought to involve inflammatory and gliotic events in the CNS. Here, we elucidated the effect of ADSC transplantation on the inflammatory reaction after spinal cord injury (SCI) and the potential mechanism mediated by Jagged1/Notch signaling pathway suppression.

Methods

To evaluate the therapeutic effects of ADSC treatment and the potential inhibitory effects of ADSCs on Notch signaling, mice were subjected to contusion SCI, and GFP-labeled ADSCs were injected into the lesion site immediately after the injury. Locomotor function, spinal cord tissue morphology, and the levels of Notch-related proteins and proinflammatory transcripts were compared between groups. To validate the hypothesis that the therapeutic effects of ADSCs are partly due to Notch1 signaling inhibition, a Jagged1 small interfering RNA (siRNA) was injected into the spinal cord to knock down Jagged1/Notch signaling. Neuronal staining and analyses of microglia/macrophage activation and signaling pathways were performed.

Results

We demonstrated that ADSCs survived in the injured spinal cord for at least 28 days without differentiating into glial or neuronal elements. ADSC treatment resulted in significant downregulation of proinflammatory mediator expression and reduced ionized calcium-binding adapter molecule 1 (IBA1) and ED-1 staining in the injured spinal cord, eventually improving functional recovery. The augmentation of the Jagged1/Notch signaling pathway after SCI was suppressed by ADSC transplantation. The inhibition of the Jagged1/Notch signaling pathway by Jagged1 siRNA resulted in decreases in SCI-induced proinflammatory cytokines and the activation of microglia and an increase in the survival of neurons. Furthermore, Jagged1 knockdown suppressed the phosphorylation of JAK/STAT3 in astrocytes following SCI.

Conclusion

The results of this study demonstrated that the therapeutic effects of ADSCs in SCI mice were partly due to Jagged1/Notch signaling pathway inhibition and a subsequent reduction in JAK/STAT3 phosphorylation in astrocytes.
Reversible data hiding for binary images based on adaptive overlapping pattern
Authors: Dong Keming , Kim Hyoung Joong , Yu Xiaohan , Feng Xiaoqing
Published: June 2020

Pattern substitution (PS) method (Ho et al., Comput. Stand. Interfaces 31:787–794, 2009) is a recent reversible data hiding method for binary images. It generates one pattern pair, the patterns in which are called PM and PF, and substitutes between them to embed one bit. Two types of PS have been proposed: non-overlapping PS and overlapping PS. However, Dong et al. (ETRI J. 37:990–1000, 2015) states that the overlapping PS sometimes cannot decode correctly, which is called as miscoding problem. Moreover, to the PS-based methods (Ho et al., Comput. Stand. Interfaces 31:787–794, 2009; Dong et al., ETRI J. 37:990–1000, 2015; Dong et al., Lect. Notes Comput. Sci. 6526:3516–3522, 2011), although chosen of two patterns to form the pattern pair which relates the embedding performance much, the previous methods only use a fixed pattern pair during the whole data hiding process. In order to overcome these two shortcomings, this paper proposes an adaptive overlapping PS method. Firstly, two modes of the embedding are proposed so that the miscoding problem can be solved. Secondly, one window which contains the context of current processing pixel is generated and updated when the process proceeds to the next pixel. Thus, the optimum pair of the local context for embedding can be chosen. Thirdly, in order to get a smaller location map, a three-round embedding mechanism is also proposed. With these three improvements, our method can embed larger payloads with less distortion than the previous works.
Measurement properties of smartphone approaches to assess key lifestyle behaviours: protocol of a systematic review
Authors: Thornton Louise , Osman Bridie , Wescott Annie B. , Sunderland Matthew , Champion Katrina , Green Olivia , Kay-Lambkin Frances , Slade Tim , Newton Nickie , Chapman Cath , Teesson Maree , Mills Katherine , Birrell Louise , Lubans David , Van de Ven Pepijn , Torous John , Parmenter Belinda , Gardner Lauren ,   Health4Life team
Published: June 2020

Background

Six core behavioural risk factors (poor diet, physical activity, sedentary behaviour, alcohol misuse, smoking and unhealthy sleep patterns) have been identified as strong determinants of chronic disease, such as cardiovascular disease, diabetes and cancers. Smartphones have the potential to provide a real-time, pervasive, unobtrusive and cost-effective way to measure health behaviours and deliver instant feedback to users. Despite this, validity of using smartphones to measure these six key behaviours is largely unknown. The proposed systematic review aims to address this gap by identifying existing smartphone-based approaches to measure these health behaviours and critically appraising, comparing and summarizing the quality of their measurement properties.

Methods

A systematic search of the Ovid MEDLINE, Embase (Elsevier), Cochrane Library (Wiley), PsychINFO (EBSCOhost), CINAHL (EBSCOHost), Web of Science (Clarivate), SPORTDiscus (EBSCOhost) and IEEE Xplore Digital Library databases will be conducted from January 2007 to March 2020. Eligible studies will be those written in English that measure at least one of the six health behaviours of interest via a smartphone and report on at least one measurement property. The primary outcomes will be validity, reliability and/or responsiveness of these measurement approaches. A secondary outcome will be the feasibility (e.g. user burden, usability and cost) of identified approaches. No restrictions will be placed on the participant population or study design. Two reviewers will independently screen studies for eligibility, extract data and assess the risk of bias. The study methodological quality (or bias) will be appraised using an appropriate tool. Our results will be described in a narrative synthesis. If feasible, random effects meta-analysis will be conducted where appropriate.

Discussion

The results from this review will provide important information about the types of smartphone-based approaches currently available to measure the core behavioural risk factors for chronic disease and the quality of their measurement properties. It will allow recommendations on the most suitable and effective measures of these lifestyle behaviours using smartphones. Valid and reliable measurement of these behaviours and risk factor opens the door to targeted and real-time delivery of health behaviour interventions, providing unprecedented opportunities to offset the trajectory toward chronic disease.

Systematic review registration

PROSPERO: CRD42019122242
Some Hermite–Jensen–Mercer type inequalities for k-Caputo-fractional derivatives and related results
Authors: Zhao Shupeng , Butt Saad Ihsan , Nazeer Waqas , Nasir Jamshed , Umar Muhammad , Liu Ya
Published: June 2020

In this paper, certain Hermite–Hadamard–Mercer type inequalities are proved via k-Caputo fractional derivatives. We established some new k-Caputo fractional derivatives inequalities with Hermite–Hadamard–Mercer type inequalities for differentiable mapping $\psi^{(n)}$ψ(n) whose derivatives in the absolute values are convex.
Generation of new fractional inequalities via n polynomials s-type convexity with applications
Authors: Rashid Saima , İşcan İmdat , Baleanu Dumitru , Chu Yu-Ming
Published: June 2020

The celebrated Hermite–Hadamard and Ostrowski type inequalities have been studied extensively since they have been established. We find novel versions of the Hermite–Hadamard and Ostrowski type inequalities for the n-polynomial s-type convex functions in the frame of fractional calculus. Taking into account the new concept, we derive some generalizations that capture novel results under investigation. We present two different general techniques, for the functions whose first and second derivatives in absolute value at certain powers are n-polynomial s-type convex functions by employing $\mathcal{K}$
K
-fractional integral operators have yielded intriguing results. Applications and motivations of presented results are briefly discussed that generate novel variants related to quadrature rules that will be helpful for in-depth investigation in fractal theory, optimization and machine learning.
A scenario generation pipeline for autonomous vehicle simulators
Authors: Wen Mingyun , Park Jisun , Cho Kyungeun
Published: June 2020

To develop a realistic simulator for autonomous vehicle testing, the simulation of various scenarios that may occur near vehicles in the real world is necessary. In this paper, we propose a new scenario generation pipeline focused on generating scenarios in a specific area near an autonomous vehicle. In this method, a scenario map is generated to define the scenario simulation area. A convolutional neural network (CNN)-based scenario agent selector is introduced to evaluate whether the selected agents can generate a realistic scenario, and a collision event detector handles the collision message to trigger an accident event. The proposed event-centric action dispatcher in the pipeline enables agents near events to perform related actions when the events occur near the autonomous vehicle. The proposed scenario generation pipeline can generate scenarios containing pedestrians, animals, and vehicles, and, advantageously, no user intervention is required during the simulation. In addition, a virtual environment for autonomous driving is also implemented to test the proposed scenario generation pipeline. The results show that the CNN-based scenario agent selector chose agents that provided realistic scenarios with 92.67% accuracy, and the event-centric action dispatcher generated a visually realistic scenario by letting the agents surrounding the event generate related actions.
The Belgian health examination survey: objectives, design and methods
Authors: Nguyen Diem , Hautekiet Pauline , Berete Finaba , Braekman Elise , Charafeddine Rana , Demarest Stefaan , Drieskens Sabine , Gisle Lydia , Hermans Lize , Tafforeau Jean , Van der Heyden Johan
Published: June 2020

Background

In 2018 the first Belgian Health Examination Survey (BELHES) took place. The target group included all Belgian residents aged 18 years and older. The BELHES was organized as a second stage of the sixth Belgian Health Interview Survey (BHIS). This paper describes the study design, recruitment method and the methodological choices that were made in the BELHES.

Methods

After a pilot period during the first quarter of the BHIS fieldwork, eligible BHIS participants were invited to participate in the BELHES until a predefined number (n = 1100) was reached. To obtain the required sample size, 4918 eligible BHIS participants had to be contacted. Data were collected at the participant’s home by trained nurses. The data collection included: 1) a short set of questions through a face-to-face interview, 2) a clinical examination consisting of the measurement of height, weight, waist circumference, blood pressure and for people aged 50 years and older handgrip strength and 3) a collection of blood and urine samples. The BELHES followed as much as possible the guidelines provided in the framework of the European Health Examination Survey (EHES) initiative. Finally 1184 individuals participated in the BELHES, resulting in a participation rate of 24.1%. Results for all the core BELHES measurements were obtained for more than 90% of the participants.

Conclusion

It is feasible to organize a health examination survey as a second stage of the BHIS. The first successfully organized BELHES provides useful information to support Belgian health decision-makers and health professionals. As the BELHES followed EHES recommendations to a large extent, the results can be compared with those from similar surveys in other EU (European Union) member states.
How to deal with COVID-19 epidemic-related lockdown physical inactivity and sedentary increase in youth? Adaptation of Anses’ benchmarks
Authors: Margaritis Irène , Houdart Sabine , El Ouadrhiri Youssef , Bigard Xavier , Vuillemin Anne , Duché Pascale
Published: June 2020

Faced with the spread of the SARS-CoV-2 virus, regulatory measures aiming to prevent interpersonal contaminations have been undertaken and among these, lockdown. Due to strong restrictions out-of-home movements, we hypothesize that overall physical activity will decrease and sedentary behavior increase. This could result in highest exposure to the well-known risk related to insufficient physical activity. To mitigate physical inactivity and sedentary behaviors health-related risks related to children and adolescents lockdown and school closure, Anses (French Agency for Food, Environmental and Occupational Health & Safety) has adapted, within the first days of the public authorities’ prescription, its former benchmarks. This paper supports and comments Anses’ Opinion by raising the questions of whether, why, and how to deal with short- or medium-term lockdown-related physical inactivity and sedentary behavior increases. Short-term and unknown long term-impacts on mental health and well-being, physical fitness and eating behaviors clearly appearing for children and adolescents as being the main issues of concern are highlighted. Targeting the compensations of the physical inactivity increase, the types, frequencies and durations of physical activity, are adapted to restricted environment. Sedentary behavior limitation and frequent interruptions becomes a priority. Overall, considering children and adolescents, the emerging risk justifies proposing specific adaptations and type of activities in order to ensure maintaining health underpinned, at least partly, by physiological equilibrium and physical fitness and avoid the installation of new unhealthy habits or routines that young people could keep after lockdown.
What is the research evidence for antibiotic resistance exposure and transmission to humans from the environment? A systematic map protocol
Authors: Stanton Isobel C. , Bethel Alison , Leonard Anne F. C. , Gaze William H. , Garside Ruth
Published: June 2020

Background

Antimicrobial resistance (AMR) is a public health crisis that is predicted to cause 10 million deaths per year by 2050. The environment has been implicated as a reservoir of AMR and is suggested to play a role in the dissemination of antibiotic resistance genes (ARGs). Currently, most research has focused on measuring concentrations of antibiotics and characterising the abundance and diversity of ARGs and antibiotic resistant bacteria (ARB) in the environment. To date, there has been limited empirical research on whether humans are exposed to this, and whether exposure can lead to measureable impacts on human health. Therefore, the objective of this work is to produce two linked systematic maps to investigate previous research on exposure and transmission of AMR to humans from the environment. The first map will investigate the available research relating to exposure and transmission of ARB/ARGs from the environment to humans on a global scale and the second will investigate the prevalence of ARB/ARGs in various environments in the UK. These two maps will be useful for policy makers and research funders to identify where there are significant gluts and gaps in the current research, and where more primary and synthesis research needs to be undertaken.

Methods

Separate search strategies will be developed for the two maps. Searches will be run in 13 databases, and grey literature will be sought from key websites and engagement with experts. Hits will be managed in EndNote and screened in two stages (title/abstract then full text) against predefined inclusion criteria. A minimum of 10% will be double screened with ongoing consistency checking. All included studies will have data extracted into a bespoke form designed and piloted for each map. Data to be extracted will include bibliographic details, study design, location, exposure source, exposure route, health outcome (Map 1); and prevalence/percentage of ARB/ARG (Map 2). No validity appraisal will be undertaken. Results will be tabulated and presented narratively, together with graphics showing the types and areas of research that has been undertaken and heatmaps for key exposure-health outcomes (Map 1) and exposure-prevalence (Map 2).
The human olfactory system in two proteinopathies: Alzheimer’s and Parkinson’s diseases
Authors: Ubeda-Bañon Isabel , Saiz-Sanchez Daniel , Flores-Cuadrado Alicia , Rioja-Corroto Ernesto , Gonzalez-Rodriguez Melania , Villar-Conde Sandra , Astillero-Lopez Veronica , Cabello-de la Rosa Juan Pablo , Gallardo-Alcañiz Maria Jose , Vaamonde-Gamo Julia , Relea-Calatayud Fernanda , Gonzalez-Lopez Lucia , Mohedano-Moriano Alicia , Rabano Alberto , Martinez-Marcos Alino
Published: June 2020

Alzheimer’s and Parkinson’s diseases are the most prevalent neurodegenerative disorders. Their etiologies are idiopathic, and treatments are symptomatic and orientated towards cognitive or motor deficits. Neuropathologically, both are proteinopathies with pathological aggregates (plaques of amyloid-β peptide and neurofibrillary tangles of tau protein in Alzheimer’s disease, and Lewy bodies mostly composed of α-synuclein in Parkinson’s disease). These deposits appear in the nervous system in a predictable and accumulative sequence with six neuropathological stages. Both disorders present a long prodromal period, characterized by preclinical signs including hyposmia. Interestingly, the olfactory system, particularly the anterior olfactory nucleus, is initially and preferentially affected by the pathology. Cerebral atrophy revealed by magnetic resonance imaging must be complemented by histological analyses to ascertain whether neuronal and/or glial loss or neuropil remodeling are responsible for volumetric changes. It has been proposed that these proteinopathies could act in a prion-like manner in which a misfolded protein would be able to force native proteins into pathogenic folding (seeding), which then propagates through neurons and glia (spreading). Existing data have been examined to establish why some neuronal populations are vulnerable while others are resistant to pathology and to what extent glia prevent and/or facilitate proteinopathy spreading. Connectomic approaches reveal a number of hubs in the olfactory system (anterior olfactory nucleus, olfactory entorhinal cortex and cortical amygdala) that are key interconnectors with the main hubs (the entorhinal–hippocampal–cortical and amygdala–dorsal motor vagal nucleus) of network dysfunction in Alzheimer’s and Parkinson’s diseases.
Evaluation of disability in patients exposed to fluoroquinolones
Authors: Wilcox Marsha A. , Villasis-Keever Angelina , Sena Anthony G. , Knoll Christopher , Fife Daniel
Published: June 2020

Background

Fluoroquinolones are used for conditions including sinusitis, bronchitis, and urinary tract infections. It has been suggested that exposure to fluoroquinolones for these conditions is associated with disability resulting from adverse events in 2 or more organ systems. The objectives were to: describe: 1) fluoroquinolone, azithromycin, and sulfamethoxazole / trimethoprim utilization for these infections; 2) the rate of disability associated with exposure to each of these antibiotic classes and adverse events in 2 or more system organ classes, and 3) compare outcome rates for each of the antibiotic classes.

Methods

This study was conducted using administrative data to mitigate the limitations of spontaneous reports. The sampling frame was a U.S. population with both medical and disability insurance, including patients with the above uncomplicated infections who were prescribed the antibiotics of interest.

The primary outcome was an incident short-term disability claim associated with adverse events in 2 different organ systems within 120 days of exposure. A matched analysis was used to compare the outcome for patients receiving each of the drug classes.

Results

After propensity score matching, there were 119,653 individuals in each of the exposure groups. There were 264 fluoroquinolone associated disability events and 243 azithromycin/ sulfamethoxazole associated disability events (relative risk =1.09 (95% CI: 0.92–1.30; calibrated p = 0.84)). The results were not significantly different from the null hypothesis of no difference between groups.

Conclusion

Comparative assessments are difficult to conduct in spontaneous reports. This examination of disability associated with adverse events in different system organ classes showed no difference between fluoroquinolones and azithromycin or sulfamethoxazole in administrative data.
Chimeric antigen receptor T cells targeting PD-L1 suppress tumor growth
Authors: Qin Le , Zhao Ruocong , Chen Dongmei , Wei Xinru , Wu Qiting , Long Youguo , Jiang Zhiwu , Li Yangqiu , Wu Haipeng , Zhang Xuchao , Wu Yilong , Cui Shuzhong , Wei Wei , Yao Huihui , Liu Zixia , Cao Su , Yao Yao , Zhang Zhenfeng , Li Peng
Published: June 2020

Background

Chimeric antigen receptor T cells (CAR-T cells) therapy has been well recognized for treating B cell-derived malignancy. However, the efficacy of CAR-T cells against solid tumors remains dissatisfactory, partially due to the heterogeneity of solid tumors and T cell exhaustion in tumor microenvironment. PD-L1 is up-regulated in multiple solid tumors, resulting in T cell exhaustion upon binding to its receptor PD-1.

Methods

Here, we designed a dominant-negative form of PD-1, dPD1z, a vector containing the extracellular and transmembrane regions of human PD-1, and a CAR vector against PD-L1, CARPD-L1z, a vector employs a high-affinity single-chain variable fragment (scFv) against human PD-L1. These two vectors shared the same intracellular structure, including 4-1BB and TLR2 co-stimulatory domains, and the CD3ζ signaling domain.

Results

dPD1z T and CARPD-L1z T cells efficiently lysed PD-L1+ tumor cells and had enhanced cytokine secretion in vitro and suppressed the growth of non-small cell lung cancer (NSCLC), gastric cancer and hepatoma carcinoma in patient-derived xenograft (PDX). However, the combination of anti-mesothelin CAR-T cells (CARMSLNz T) with dPD1z T or CARPD-L1z T cells did not repress tumor growth synergistically in PDX, as CARMSLNz T cells upregulated PD-L1 expression upon activation and were subsequently attacked by dPD1z T or CARPD-L1z T cells.

Conclusions

In conclusion, we demonstrate CAR-T cells targeting PD-L1 were effective for suppressing the growth of multiple types of solid tumors in PDX models though their safety needs to be carefully examined.
Guidance for otolaryngology health care workers performing aerosol generating medical procedures during the COVID-19 pandemic
Authors: Lammers Marc J. W. , Lea Jane , Westerberg Brian D.
Published: June 2020

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for Coronavirus disease 2019 (COVID-19) has a predilection for infecting the mucosa of the upper and lower airways. Otolaryngologists and supporting health care workers (HCWs) are particularly at high risk of becoming infected while treating patients as many in-office procedures and surgeries are Aerosol Generating Medical Procedures (AGMP). Based on a review of the literature and various guidelines, recommendations are made to mitigate the risk to health care workers of becoming infected with SARS-CoV-2 while providing clinical care.

Recommendations

During the COVID-19 pandemic all elective and non-time sensitive Otolaryngology procedures should be deferred to mitigate the risk of transmission of infection to HCWs. For non-AGMPs in all patients, even COVID-19 positive patients Level 1 PPE (surgical mask, gown, gloves and face shield or goggles) is sufficient. If local prevalence is favourable and patients are asymptomatic and test negative for SARS-CoV-2, Level 1 PPE can be used during short duration AGMPs, with limited risk of infected aerosol spread. For AGMPs in patients who test positive for SARS-CoV-2 a minimum of Level 2 PPE, with adequate protection of mucosal surfaces, is recommended (N95/FFP2 respirator, gown, double gloves, goggles or face shield and head cover). For long duration AGMPs that are deemed high-risk in COVID-19 positive patients, Level 3 PPE can provide a higher level of protection and be more comfortable during long duration surgeries if surgical hoods or PAPRs are used. It is recommended that these procedures are performed in negative pressure rooms, if available. It is essential to follow strict donning and doffing protocols to minimize the risk of contamination.

Conclusions

By following strict infection prevention recommendations, the risk of HCWs becoming infected with SARS-CoV-2 while treating patients can be minimized. As the COVID-19 pandemic evolves rapidly, these recommendations should serve as guidance and need to be interpreted based on local factors and availability of healthcare resources.
Cerebrospinal fluid penetration of targeted therapeutics in pediatric brain tumor patients
Authors: Guntner Armin Sebastian , Peyrl Andreas , Mayr Lisa , Englinger Bernhard , Berger Walter , Slavc Irene , Buchberger Wolfgang , Gojo Johannes
Published: June 2020

Treatment with small-molecule inhibitors, guided by precision medicine has improved patient outcomes in multiple cancer types. However, these compounds are often not effective against central nervous system (CNS) tumors. The failure of precision medicine approaches for CNS tumors is frequently attributed to the inability of these compounds to cross the blood-brain barrier (BBB), which impedes intratumoral target engagement. This is complicated by the fact that information on CNS penetration in CNS-tumor patients is still very limited. Herein, we evaluated cerebrospinal fluid (CSF) drug penetration, a well-established surrogate for CNS-penetration, in pediatric brain tumor patients. We analyzed 7 different oral anti-cancer drugs and their metabolites by high performance liquid chromatography mass spectrometry (HPLC-MS) in 42 CSF samples obtained via Ommaya reservoirs of 9 different patients. Moreover, we related the resulting data to commonly applied predictors of BBB-penetration including ABCB1 substrate-character, physicochemical properties and in silico algorithms. First, the measured CSF drug concentrations depicted good intra- and interpatient precision. Interestingly, ribociclib, vorinostat and imatinib showed high (> 10 nM), regorafenib and dasatinib moderate (1–10 nM) penetrance. In contrast, panobinostat und nintedanib were not detected. In addition, we identified active metabolites of imatinib and ribociclib. Comparison to well-established BBB-penetrance predictors confirmed low molecular weight, high proportion of free-drug and low ABCB1-mediated efflux as central factors. However, evaluation of diverse in silico algorithms showed poor correlation within our dataset. In summary, our study proves the feasibility of measuring CSF concentration via Ommaya reservoirs thus setting the ground for utilization of this method in future clinical trials. Moreover, we demonstrate CNS presence of certain small-molecule inhibitors and even active metabolites in CSF of CNS-tumor patients and provide a potential guidance for physicochemical and biological factors favoring CNS-penetration.
Determinants of neonatal mortality at neonatal intensive care unit in Northeast Ethiopia: unmatched case-control study
Authors: Alemu Abebaw Yeshambel , Belay Getaneh Mulualem , Berhanu Mengistu , Minuye Biniam
Published: June 2020

Background

Globally, in 2016, about 38% and 3% of all neonatal death were recorded in sub-Saharan Africa and Ethiopia, respectively. In the same year, 47 neonates out of 1000 live births were not surviving in the first 28 days of age in the Amhara region, Ethiopia. Despite the highest burden of neonatal death in the region, specific or the proximate determinants of neonatal death in the neonatal intensive care unit were not well identified.

Objective

This study aimed to identify the determinants of neonatal mortality at neonatal intensive care unit in Dessie Referral Hospital, Northeast Ethiopia.

Methods

An institution-based unmatched case-control study was conducted on neonates admitted to the neonatal intensive care unit of Dessie Referral Hospital, from January 1, 2016, to December 30, 2017. A total of 390 charts (130 cases and 260 controls) were selected by simple random sampling technique. The data were abstracted from the facility-based data abstraction form. A binary logistic regression analysis was fitted to identify the determinants of neonatal mortality.

Results

Pregnancy-induced hypertension (AOR = 4.57; 95% CI 1.45–14.43), prolonged rupture of membrane (AOR = 2.04; 95% CI 1.13–3.68), very low birth weight (AOR = 7.00; 95% CI 2.10–23.35), and low birth weight (AOR = 2.12; 95% CI 1.10–4.20) were identified factors. Moreover, respiratory distress syndrome (AOR = 3.61; 95% CI 1.10–12.04), perinatal asphyxia (AOR = 2.27; 95% CI 1.18–4.39), meconium aspiration syndrome (AOR = 2.35; 95% CI 1.12–4.97), and infection (AOR = 2.26; 95% CI 1.34–3.82) were also significantly associated with neonatal death.

Conclusions

Pregnancy-induced hypertension, prolonged rupture of membrane, low birth weight, respiratory distress syndrome, perinatal asphyxia, meconium aspiration syndrome, and infections were the major determinants of neonatal mortality. Therefore, special attention will be given to small and sick babies. Moreover, early anticipation of complications and management of mothers who had pregnancy-induced hypertension and prolonged rupture of the membrane would save neonates.