bluuebunny/crossref_metadata_2025 huggingface dataset:
Individualized hemodynamic optimization guided by indirect measurement of the respiratory exchange ratio in major surgery: study protocol for a randomized controlled trial (the OPHIQUE study)
Authors: BAR Stéphane , Boivin Pierre , Amine Younes El , Descamps Richard , Moussa Mouhamed , Arab Osama Abou , Fischer Marc-Olivier , Dupont Hervé , Lorne Emmanuel , Guinot Pierre-Grégoire
Published: October 2020

Background: Observational studies have suggested that a high respiratory exchange ratio (RER) is associated with the occurrence of postoperative complications. The study’s primary objective is to demonstrate that the incidence of postoperative complications is lower in an interventional group (patients monitored using a hemodynamic algorithm that incorporates the RER) than in a control group (treated according to standard practice).Methods: We shall perform a prospective, multicenter, randomized, open-label, superiority trial of consecutive patients undergoing major non-cardiac surgery (i.e. abdominal, vascular and orthopedic surgery). The control group will be treated according to the current guidelines on standard hemodynamic care. The interventional group will be treated according to an algorithm based on the RER. The primary outcome will be the occurrence of at least one complication in the 7 days following surgery. The secondary outcomes will be the length of hospital stay, the total number of complications per patient, 30-day mortality, the total intraoperative volume of fluids administered, and the Sequential [sepsis-related] Organ Failure Assessment (SOFA) score and laboratory data measured on postoperative days 1, 2 and 7. A total of 350 patients will be included. Discussion: In the operating theater, the RER is potentially a continuously available, easy-to-read, indirect marker of tissue hypoperfusion and postoperative complications. If the RER does predict the occurrence of tissue hypoperfusion, it will help the physician to provide personalized hemodynamic management and limit the side effects associated with excessive hemodynamic optimization (volume overload, vasoconstriction, etc.). Trial registration: ClinicalTrials.gov identifier: NCT03852147. Registered on February 25th, 2019.
Identification of a Universal Antigen Epitope of Influenza A Virus using Peptide Microarray
Authors: Wang Qiuxia , Sun Zhihao , Li Jingzhi , Qin Tao , Ma Hongwei , Chen Sujuan , Peng Daxin , Liu Xiufan
Published: October 2020

Background
Hemagglutinin is a major surface protein in influenza A virus (IAV), and HA2 is relative conserved among different IAVs. However, identification of broad-spectrum epitopes remain less.
Results
Overlapping peptides of the HA2 protein of the H5N1 IAV A/Mallard/Huadong/S/2005 were synthesized and loaded on modified silica gel film to form a microarray, and antisera against different subtypes of IAVs were used to screen universal epitopes. The selected epitope was further confirmed by western blotting using anti-peptide immune serum and viruses rescued with amino acid substitution. The results showed that 485-FYHKCDNECME-495 of the 14th peptide in HA2 had broad-spectrum binding activity with antisera against H1, H3, H4, H5, H6, H7, H8, H9, and H10 subtype IAV. Substitution of amino acids (K or D) in rescued viruses resulted in decreased serum binding, indicating that they were critical residues for serum binding activity. In Immune Epitope Database, some epitopes containing 14 − 4 peptide were confirmed as MHC-II-restricted CD4 T cell epitope and had effects on releasing IL-2 or IFN.
Conclusion
The identified epitope should be a novel universal target for diagnostics and its ability to generate immune protection needs further exploration.
Neuropsychiatric symptoms are early indicators of an upcoming metabolic decline in Alzheimer’s disease
Authors: Ng Kok Pin , Pascoal Tharick A. , Mathotaarachchi Sulantha , Chan Yiong Huak , Jiang Lai , Therriault Joseph , Benedet Andrea L. , Shin Monica , Kandiah Nagaendran , Greenwood Celia M.T. , Rosa-Neto Pedro , Gauthier Serge
Published: October 2020

Background Neuropsychiatric symptoms (NPS) are increasingly recognized as early non-cognitive manifestations in the Alzheimer’s disease (AD) continuum. However, the role of NPS as an early marker of pathophysiological progression in AD remains unclear. Dominantly inherited AD (DIAD) mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic mutation. Hence, the study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing pathologies. In this longitudinal study, we aim to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation carriers. Methods We stratified 221 cognitively intact participants from the Dominantly Inherited Alzheimer’s Network according to their mutation carrier status. Regression mixed effect models with family-level random effects evaluated the interactions of NPS measured by the Neuropsychiatric Inventory-Questionnaire (NPI-Q), age and estimated years of onset (EYO) as a function of metabolism measured by [ 18 F]flurodeoxyglucose ([ 18 F]FDG) positron emission tomography in DIAD mutation and non-mutation carriers. An exploratory factor analysis was performed to identify the neuropsychiatric subsyndromes in DIAD mutation carriers using the NPI-Q sub-components. Regression mixed effect models then evaluated the interactions of specific neuropsychiatric subsyndromes with EYO on metabolism.Results 119 mutation and 102 non-mutation carriers were studied. The interaction of higher NPI-Q and shorter EYO was associated with more rapid global and regional [ 18 F]FDG uptake decline in the posterior cingulate and ventromedial prefrontal cortices, bilateral parietal lobes and right insula in DIAD mutation carriers. The neuropsychiatric subsyndrome of agitation, disinhibition, irritability and depression interacted with EYO to drive [ 18 F]FDG uptake decline in the DIAD mutation carriers. The interaction of NPI and EYO was not associated with [ 18 F]FDG uptake in DIAD non-mutation carriers. Conclusions NPS in cognitively intact DIAD mutation carriers may be clinical indicators of subsequent metabolic decline in brain networks vulnerable to AD, which support the emerging conceptual framework that NPS represent early manifestations of neuronal injury in AD. Further studies using different methodological approaches to identify NPS in preclinical AD are needed to validate our findings.
Impact of simulation-based teamwork training on COVID-19 distress in healthcare professionals
Authors: Beneria Anna , Arnedo Mireia , Contreras Sofia , Pérez-Carrasco Marcos , Garcia-Ruiz Itziar , Rodríguez-Carballeira Mónica , Raduà Joaquim , Bañeras Jordi
Published: October 2020

Context Non-technical skills such as leadership, communication, or situation awareness should lead to effective teamwork in a crisis. This study aimed to analyse the role of these skills in the emotional response of health professionals to the COVID-19 pandemic.Methods Before the COVID-19 outbreak, 48 doctors and 48 nurses participated in a simulation-based teamwork training program based on teaching non-technical skills through simulation. In May 2020, this group of professionals from a COVID-19 referral hospital was invited to participate in a survey exploring stress, anxiety, and depression, using the PSS-14 (Perceived Stress Scale) and the HADS (Hospital Anxiety and Depression Scale) measures. A control group that did not receive the training was included. We conducted a logistic regression to assess whether having attended a simulation-based teamwork training program modified the probability of presenting psychological distress (PSS-14>18 or HADS>12).Results A total of 141 healthcare professionals were included, 77 in the intervention group and 64 in the control group. Based on the PSS-14, 70.1% of the intervention group and 75% of the control group (p=0.342) had symptoms of stress. Having contact with COVID-19 patients [OR 4.16(1.64–10.52)]; having minors in charge [OR 2.75 (1.15–6.53)]; working as a doctor [0.39(0.16 – 0.95)], and being a woman [OR 2.94(1.09–7.91)] were related with PSS14 symptoms. Based on the HADS, 54.6% of the intervention group and 42.2% of the control group (p=0.346) had symptoms of anxiety or depression. Having contact with COVID-19 patients [OR 2.17(1.05 – 4.48)] and having minors in charge [OR 2.14(1.06 – 4.32)] were related to HADS symptoms. Healthcare professionals who attended COVID-19 patients showed higher levels of anxiety and depression [OR 2.56(1.03 – 6.36) (p=0.043)].Conclusion Healthcare professionals trained in non-technical skills through simulation tended towards higher levels of anxiety and depression and fewer levels of stress, during the COVID-19 pandemic.
Clinical profiles, Outcomes and Risk Factors among Type 2 Diabetic Inpatients with Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State: A Hospital-Based Analysis over a 6-Year Period
Authors: Wu Xiao-yan , She Dun-min , Wang Fang , Guo Gang , Li Ran , Fang Ping , Li Ling , Zhou Yun , Zhang Ke-qin , Xue Ying
Published: October 2020

Objective: Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are the two most common hyperglycemic emergencies (HEs) associated with diabetes mellitus. Individuals with HEs can present with combined features of DKA and HHS. The objective of this study is to assess the clinical characteristics, therapeutic outcomes, and associated predisposing factors of type 2 diabetic patients with isolated or combined HEs in China.Methods: We performed a retrospective analysis of 158 patients with type 2 diabetes (T2DM), complicated with DKA, HHS, or DKA combined with HHS (DKA-HHS) in Shanghai Tongji Hospital, China from 2010 to 2015. Admission clinical features, therapeutic approaches and treatment outcomes of those patients were extracted and analyzed.Results: Of the 158 patients with T2DM, 65 (41.1%) patients were DKA, 74 (46.8%) were HHS, and 19 (12.0%) were DKA-HHS. The most common precipitants were infections (111, 70.3%), newly diagnosed diabetes (28,17.7%) and non-compliance to medications (9, 5.7%). DKA patients were divided into mild, moderate and severe group, based on arterial blood gas. Spearman correlation analysis revealed that C-reaction protein (CRP) was positively correlated with severity of DKA, whereas age and fasting C peptide were inversely correlated with severity of DKA (P<0.05). The mortality was 10.8% (17/158) in total and 21.6% (16/74) in the HHS group, 5.9% (1/17) in DKA-HHS. Spearman correlation analysis indicated that death in patients with HHS was positively correlated to effective plasma osmolality (EPO), renal function indicators and hepatic enzymes, while inversely associated with the continuous subcutaneous insulin infusion (CSII) therapy. Logistic regression analysis suggested that elevated blood urea nitrogen (BUN) on admission was an independent predisposing factor of mortality in HHS, while CSII might be a protective factor for patients with HHS. Furthermore, the receiver-operating characteristic (ROC) curve analysis indicated that BUN had the largest area under the ROC curves for predicting death in patients with HHS.Conclusions: Our findings showed elevated CRP and decreased fasting C-peptide might serve as indicator for severe DKA. Elevated BUN might be an independent predictor of mortality in patients with HHS, whereas CSII might be a protective factor against death in HHS.
Total en bloc spondylectomy combined with the satellite rod technique for spinal tumors
Authors: Wei Hongyu , Dong Chunke , Wu Jun , Zhu Yuting , Ma Haoning
Published: October 2020

Background: Instrumentation failure (IF) is a common complication after total en bloc spondylectomy (TES) in spinal tumors. This study aims to evaluate the clinical outcomes of TES combined with the satellite rod technique for the treatment of primary and metastatic spinal tumors.Methods: The clinical data of 15 consecutively treated patients with spinal tumors who underwent TES combined with satellite rod technique by a single posterior approach from June 2015 to September 2018 were analyzed retrospectively. Radiographic parameters including the local kyphotic angle (LKA), anterior vertebral height (AVH), posterior vertebral height (PVH) and intervertebral titanium mesh cage height (ITMCH) were assessed preoperatively, postoperatively and at the final follow-up. The visual analog scale (VAS), Oswestry Disability Index (ODI) and American Spinal Injury Association (ASIA) scale were used to assess quality of life and neurological function. The operative duration, volume of blood loss, and complications were also recorded.Results: The mean operation time and volume of blood loss were 361.7 min and 2816.7 mL, respectively. During an average follow-up of 31.1 months, 2 patients died of tumor recurrence and multiple organ metastases, while recurrence was not found in any other patients. Solid fusion was achieved in all but one patient, and no implant-related complications occurred during the follow-up. The VAS, ODI and ASIA scores significantly improved from before to after surgery (P<0.05). The LKA, AVH and PVH significantly improved from before to immediately after surgery and to the final follow-up (P<0.05), and the postoperative and final follow-up values did not significantly differ (P>0.05).Conclusions: TES combined with the satellite rod technique can yield strong three-dimensional fixation and reduce the occurrence of rod breakage, thereby improving the long-term quality of life of patients with spinal tumors.
Exploring the mRNA expression level of RELN in peripheral blood of schizophrenia patients before and after antipsychotic treatment
Authors: Yin Jiajun , Lu Yana , Yu Shui , Dai Zhanzhan , Zhang Fuquan , Yuan Jianmin
Published: October 2020

Background: The Reelin (RELN) gene encodes the protein reelin, which is a large extracellular matrix glycoprotein that plays a key role in brain development. Additionally, this protein may be involved in memory formation, neurotransmission, and synaptic plasticity, which have been shown to be disrupted in schizophrenia (SCZ). A decreasing trend in the expression of RELN mRNA in the brain and peripheral blood of SCZ patients has been observed. There is a need to determine whether changes in RELN mRNA expression in SCZ patients are the result of long-term antipsychotic treatment rather than the etiological characteristics of schizophrenia. The expression levels of RELN mRNA in the peripheral blood of 48 healthy controls and 30 SCZ patients before and after 12-weeks of treatment were measured using quantitative real-time PCR. Results: The expression levels of RELN mRNA in the SCZ group were significantly lower than that of healthy controls; however, after 12-weeks of antipsychotic treatment, RELN mRNA levels were significantly increased in the SCZ group. Conclusion: The up-regulation of RELN mRNA expression was current in SCZ patients after antipsychotic treatment, suggesting that the changes in RELN mRNA expression were related to the effect of the antipsychotic treatment.
Gallbladder cancer-associated fibroblasts promote vasculogenic mimicry formation and tumor growth in gallbladder cancer via upregulating the expression of NOX4, a poor prognosis factor, through IL-6-JAK-STAT3 signal pathway
Authors: Pan Musu , Wang Hui , Ansari Kamar Hasan , Li Xin-Ping , Sun Wei , Fan Yue-Zu
Published: October 2020

Background: Cancer-associated fibroblasts (CAFs) and vasculogenic mimicry (VM) play important roles in the occurrence and development of tumors. However, the relationship between CAFs and VM formation, especially in gallbladder cancer (GBC) has not been clarified. In this study, we investigated whether gallbladder CAFs (GCAFs) can promote VM formation and tumor growth and explored the underlying molecular mechanism.Methods: A co-culture system of human GBC cells and fibroblasts or HUVECs was established. VM formation, proliferation, invasion, migration, tube formation assays, CD31-PAS double staining, optic/electron microscopy and tumor xenograft assay were used to detect VM formation and malignant phenotypes of 3-D co-culture matrices in vitro, as well as the VM formation and tumor growth of xenografts in vivo, respectively. Microarray analysis was used to analyze gene expression profile in GCAFs/NFs and VM (+)/VM (-) in vitro. QRT-PCR, western blotting, IHC and CIF were used to detected NOX4 expression in GCAFs/NFs, 3-D culture/co-culture matrices in vitro, the xenografts in vivo and human gallbladder tissue/stroma samples. The correlation between NOX4 expression and clinicopathological and prognostic factors of GBC patients was analyzed. And, the underlying molecular mechanism of GCAFs promoting VM formation and tumor growth in GBC was explored. Results: GCAFs promote VM formation and tumor growth in GBC; and the finding was confirmed by facts that GCAFs induced proliferation, invasion, migration and tube formation of GBC cells in vitro, and promoted VM formation and tumor growth of xenografts in vivo. NOX4 is highly expressed in GBC and its stroma, which is the key gene for VM formation, and is correlated with tumor aggression and survival of GBC patients. The GBC patients with high NOX4 expression in tumor cells and stroma have a poor prognosis. The underlying molecular mechanism may be related to the upregulation of NOX4 expression through paracrine IL-6 mediated IL-6/JAK/STAT3 signaling pathway.Conclusions: GCAFs promote VM formation and tumor growth in GBC via upregulating NOX4 expression through the activation of IL-6-JAK-STAT3 signal pathway. NOX4, as a VM-related gene in GBC, is overexpressed in GBC cells and GCAFs, which is related to aggression and unfavorable prognosis of GBC patients.
When timing matters - misdesigned dam filling impacts hydropower sustainability
Authors: Zaniolo Marta , Giuliani Matteo , Sinclair Scott , Burlando Paolo , Castelletti Andrea
Published: October 2020

Decades of sustainable dam planning efforts have focused on containing dam impacts in regime conditions, when the dam is fully filled and operational, overlooking potential disputes raised by the filling phase. Here, we argue that filling timing and operations can catalyze most of the conflicts associated to a dam’s lifetime, which can be mitigated by adaptive solutions that respond to medium-to-long term hydroclimatic fluctuations. Our retrospective analysis of the contested recent filling of Gibe III in the Omo-Turkana basin provides quantitative evidence of the benefits generated by adaptive filling strategies, attaining levels of hydropower production comparable with the historical ones while curtailing the negative impacts to downstream users. Our results can inform a more sustainable filling of the new megadam currently under construction downstream Gibe III, and are generalizable to the almost 500 planned dams worldwide in regions influenced by climate feedbacks, thus representing a significant scope to reduce the societal and environmental impacts of a large number of new hydropower reservoirs.
A novel Security Aware Sensitive Encrypted Storage approach to improve the encryption of big data
Authors: Gupta Gitanjali , Lakhwani Kamlesh
Published: October 2020

The data security and privacy have become a critical issue that restricts many cloud applications. One of the major concerns about security and privacy is the fact that cloud operators have the opportunity to access sensitive data. This concern dramatically increases user anxieties and reduces the acceptability of cloud computing in many areas, such as the financial industry and government agencies. This paper focuses on this issue and proposes an intelligent approach to cryptography, which would make it impossible for cloud service operators to reach sensitive data directly. The suggested method divides the file with precision using an intelligent classification technique. An alternative approach is designed to determine whether data packets need splitting to shorten operating time and reduce storage space. Our experimental assessments of both safety and efficiency performance and experimental results show that our approach can effectively address major cloud hazards and that it requires an acceptable computing time using an intelligent machine learning classification technique. We have proposed a novel approach entitled as a model for Security Aware Sensitive Encrypted Storage (SA-SES). In this model, we used our proposed algorithms, including Convolution Neural Network with Logistic Regression (CNN-LR), Elliptic-curve Diffie–Hellman-Shifted Adaption Homomorphism Encryption (ECDH-SAHE) and Elliptic-curve Diffie–Hellman-Shifted Adaption Homomorphism Decryption (ECDH-SAHD) .
Pro-atherogenic diet accelerates tumor growth in mice through IL-1β and myeloid cell-derived VEGF-A
Authors: Tran Thi , Esposito Bruno , Montabord Melanie , Rajau Jaouen Tran , Gruel Nadege , Lenoir Olivia , Ait-Oufella Hafid , Stockmann Christian , Mallat Ziad , Tedgui Alain , Tartour Eric , Potteaux Stephane
Published: October 2020

Aims: Myeloid inflammatory cells are recruited to the tumor microenvironment and subsequently educated in situ to acquire a pro-invasive, pro-angiogenic and immunosuppressive phenotype. Components of the metabolic syndrome are known to aggravate tumorigenesis in part through myeloid cell activation. We hypothesized that consumption of a high fat/high cholesterol pro-atherogenic diet and its associated low-grade inflammation would accelerate the initiation of solid tumors. Methods and results: Here, we show that two-week feeding of wildtype C57BL/6J mice with a pro-atherogenic diet increases the pool of circulating inflammatory Ly-6Chi monocytes available for initial melanoma development and amplifies the accumulation of myeloid cells within the tumor microenvironment, in an IL-1β-dependent manner. Under pro-atherogenic diet feeding, myeloid cells display heightened pro-angiogenic, pro-inflammatory and immunosuppressive activities. Within the first days after tumor implantation, myeloid cells become the main producer of VEGF-A in the tumor. Depletion of Ly-6Chi monocytes in mice fed with a pro-atherogenic diet limits immune cell infiltration in the tumor, and inhibits tumor growth. IL-1β deficiency or specific inhibition of VEGF-A in myeloid cells recapitulates the beneficial effect of Ly-6Chi monocyte depletion, suggesting their complementary roles in tumorigenesis in the context of mild hyperlipidemia. Conclusion: Our study shows that dyslipidemia provide high amounts of activated myeloid cells with pro-tumoral activity and shed light on cross-disease communication between cardiovascular pathologies and cancer. Translational Perspective: In this study we demonstrate that dyslipidemia accelerates the development of solid tumors through the increased infiltration of Ly6Chi monocytes that differentiate into pro-tumoral myeloid cells. These findings demonstrate that dyslipidemia can silently boost tumor development in normal-weight individuals through the action of IL-1β and VEGF-A. Our work sheds light on the potential benefit of targeting IL-1β and VEGF-A in cancer patients with moderate dyslipidemia.
Bifidobacterium adolescentis improves lifespan and healthspan by regulating catalase activity and oxidative stress-associated metabolites
Authors: Chen Shujie , Chen Luyi , Qi Yadong , Xu Jilei , Ge Qiwei , Fan Yuedan , Chen Du , Zhang Yawen , Wang Lan , Hou Tongyao , Yang Xiaohang , Xi Yongmei , Si Jianmin , Kang Lijun , Wang Liangjing
Published: October 2020

Microbiota-host interaction was involved in aging, while the specific bacterium was undetermined. To identify candidate bacterium with aging, we performed fecal microbiota sequencing. Less richness of gut microbial community, and a reduction of B.adolescentis abundance was observed in elderly individuals. B. adolescentis supplement improved osteoporosis and neurodegeneration in telomerase RNA component deletion (Terc−/−) aged mice. B.adolescentis induced prolongevity and healthspan improvement in Drosophila melanogaster and C. elegans. Transgenic deletion of ctl-2 in C. elegans abolished the effect on lifespan and healthspan by B. adolescentis. The catalase activity was decreased in skeletal muscle and brain tissues of Terc−/− mice, as well as cellular senescence in mouse embryonic fibroblasts. B. adolescentis alleviated ROS accumulation by regulation of oxidative stress-associated metabolites. These results suggest a role for B. adolescentis in improving lifespan and healthspan by regulating catalase activity and host metabolism. Supplement with commensal bacteria is a promising strategy against age related diseases.
Microscale diffusiophoresis of proteins
Authors: Peter Quentin , Jacquat Raphaël , Herling Therese , Challa Pavan , Kartanas Tadas , Knowles Tuomas
Published: October 2020

Living systems are characterised by their spatially highly inhomogeneous nature which is susceptible to modify fundamentally the behaviour of biomolecular species, including the proteins that underpin biological functionality in cells. Spatial gradients in chemical potential are known to lead to strong transport effects for colloidal particles, but their effect on molecular scale species such as proteins has remained largely unexplored. Here we demonstrate with microfluidic measurements that individual proteins can undergo strong diffusiophoretic motion in salt gradients in a manner which is sufficient to overcome diffusion and lead to dramatic changes in their spatial organisation on the scale of a cell. Moreover, we demonstrate that this phenomenon can be used to control the motion of proteins in microfluidics devices. These results open up a path towards a physical understanding of the role of gradients in living systems in the spatial organisation of macromolecules and highlight novel routes towards protein sorting applications on device.
Most cancers carry a substantial deleterious load due to Hill-Robertson interference
Authors: McFarland Christopher , Tilk Susanne , Curtis Christina , Petrov Dmitri
Published: October 2020

Cancer genomes exhibit surprisingly weak signatures of negative selection. This may be because tumors evolve under weak selective pressures (‘weak selection’) or because genome-wide linkage in cancer prevents most deleterious mutations from being removed due to Hill-Robertson interference3 (‘inefficient selection’). The weak selection model argues that most genes are only important for multicellular function and that selection acts only on a subset of essential genes. In contrast, the inefficient selection model predicts that only cancers with low mutational burdens, where linkage effects are minimal, will exhibit strong signals of negative selection against deleterious passengers and positive selection for beneficial drivers. We leverage the 10,000-fold variation in mutational burden across cancer subtypes to stratify tumors by their genome-wide mutational burden and used a normalized ratio of nonsynonymous to synonymous substitutions (dN/dS) to quantify the extent that selection varies with mutation rate. We find that appreciable negative selection (dN/dS ~ 0.4) is present in tumors with a low mutational burden, while the remaining cancers (96%) exhibit dN/dS ratios approaching 1, suggesting that the majority of tumors do not remove deleterious passengers. A parallel pattern is seen in drivers, where positive selection attenuates as the mutational burden of cancers increases. Both trends persist across tumor-types, are not exclusive to essential or housekeeping genes, are present in clonal and subclonal mutations, and persist in Copy Number Alterations. A consequence of this inability to remove deleterious passengers is that tumors with elevated mutational burdens, which are expected to harbor substantial protein folding stress, upregulate heat shock pathways. Finally, using evolutionary modeling, we find that Hill-Robertson interference alone can reproduce the patterns of attenuated selection observed in both drivers and passengers if the average fitness cost of passengers is 1.0% and the average fitness benefit of drivers is 19%. As a result, despite the weak individual fitness effects of passengers, most cancers harbor a large mutational load (median ~40% total fitness cost). Collectively, our findings suggest that the lack of observed negative selection in most tumors is not due to relaxed selective pressures, but rather the inability of selection to remove individual deleterious mutations in the presence of genome-wide linkage.
Combined Pars Plana Glaucoma Drainage Device Placement and Vitrectomy Using a Vitrectomy Sclerotomy Site for Tube Placement: A Case Series
Authors: Chang Enchi Kristina , Gupta Sanchay , Chachanidze Marika , Miller John B. , Chang Ta Chen , Valle David A. Solá-Del
Published: October 2020

Background: The purpose of this study is to report the safety and efficacy of pars plana (PP) glaucoma drainage devices (GDDs) with pars plana vitrectomy (PPV) using one of the vitrectomy sclerotomy sites for tube placement in patients with refractory glaucoma.Methods: Retrospective case series of 28 eyes of 28 patients who underwent combined PP GDD and PPV between November 2016 and September 2019 at Massachusetts Eye and Ear. Main outcome measures were intraocular pressure (IOP), glaucoma medication burden, best corrected visual acuity (BCVA), and complications. Statistical tests were performed with R and included Kaplan-Meier analyses, Wilcoxon paired signed-rank tests, and Fisher tests.Results: Mean IOP decreased from 22.8 mmHg to 11.4 mmHg at 1.5 years (p = 0.009), and mean medication burden decreased from 4.3 to 1.7 at 1.5 years (p = 0.009). Both IOP and medication burden were significantly lower at all follow-up time points. The probability of achieving 5 ≤ IOP ≤ 18 mmHg with at least 20% IOP reduction from preoperative levels was 77.7% at 1 year and 45.8% at 1.5 years. At their last visit, four eyes (14.3%) achieved complete success with IOP reduction as above without medications, and 13 eyes (46.2%) achieved qualified success with medications. Visual acuity was unchanged or improved in 23 eyes (82.1%) at their last follow-up. Two patients had a visual acuity decrease of >2 lines. Two eyes required subsequent PPV for tube obstruction, and one eye had transient hypotony.Conclusions: The results of pars plana GDD and vitrectomy using one of the vitrectomy sclerotomy sites for tube placement are promising, resulting in significant IOP and medication-burden reductions through postoperative year 1.5 without additional risk of postoperative complications. Inserting GDDs into an existing vitrectomy sclerotomy site may potentially save surgical time by obviating the need to create another sclerotomy for tube placement and suture one of the vitrectomy ports.
Combined Vaccine-Immune-Checkpoint Inhibition Constitutes a Promising Strategy for Treatment of dMMR Tumors
Authors: Salewski Inken , Kuntoff Steffen , Kuemmel Andreas , Feldtmann Rico , Felix Stephan , Henze Larissa , Junghanss Christian , Maletzki Claudia
Published: October 2020

Background: Mlh1-knock-out-driven mismatch-repair-deficient (dMMR) tumors can be targeted immunologically. By applying therapeutic tumor vaccination, tumor growth is delayed but escape mechanisms evolve, characterized by the upregulation of immune-checkpoint molecules (LAG-3, PD-L1). To counteract immune escape, we investigated the therapeutic activity of a combined tumor vaccine-immune checkpoint inhibitor therapy using α-PD-L1 monoclonal antibody clone 6E11.Design: In this trial, Mlh1-knock-out mice with established gastrointestinal tumors received single or thrice injections of α-PD-L1 monoclonal antibody clone 6E11 (2.5 mg/kg bw, q2w, i.v.) either alone or in combination with the vaccine. Longitudinal flow cytometry and PET/CT imaging studies were followed by ex vivo functional immunological and gene expression assays.Results: 6E11 monotherapy slightly increased median overall survival (mOS: 6.0 weeks vs. control 4.0 weeks). Increasing the number of injections (n=3) improved therapy outcome (mOS: 9.2 weeks) and was significantly boosted by combining 6E11 with the vaccine (mOS: 19.4 weeks vs. 10.2 weeks vaccine monotherapy). Accompanying PET/CT imaging confirmed treatment-induced tumor growth control, with the strongest inhibition in the combination group. Three mice (30%) achieved a complete remission and showed long-term survival. Decreased levels of circulating splenic and intratumoral myeloid-derived suppressor cells (MDSC) and decreased numbers of immune-checkpoint-expressing splenic T cells (LAG-3, CTLA-4) accompanied therapeutic effects. Gene expression and protein analysis of residual tumors revealed downregulation of PI3K/Akt/Wnt and TGF-signaling, leading to T cell infiltration and reduced numbers of macrophages, neutrophils, and MDSC.Conclusions: By successful uncoupling of the PD-1/PD-L1 axis, we provide further evidence for the safe and successful application of immunotherapies to combat dMMR-driven malignancies that warrants further investigation.
GRP75-upregulated HMGA1 Expression Promotes Stage I Lung Adenocarcinoma Progression by Activating the JNK/c-JUN Signaling Pathway
Authors: Qiao Guo-Bing , Wang Ren-Tao , Wang Shu-Nan , Tao Shaolin , Tan Qun-You , Jin Hua
Published: October 2020

Background: Recurrence is a major challenge in early-stage lung adenocarcinoma (LUAD) treatment. However, the recurrence mechanism is still unclear, and no biomarkers can predict recurrence in early-stage LUAD. Here, we investigated the role and mechanism of high-mobility group AT-hook 1 (HMGA1) and glucose-regulated protein 75-kDa (GRP75) in stage I LUAD and evaluated their potential as biomarkers for predicting the recurrence and prognosis of stage I LUAD.Methods: A TCGA dataset was used to investigate the clinical significance of HMGA1 and GRP75 in early-stage LUAD. Western blotting and immunohistochemistry were used to measure protein expression levels. The biological functions of HMGA1 and GRP75 in LUAD were investigated both in vitro and in vivo through overexpression and knockdown experiments. The interaction and regulation between HMGA1 and GRP75 were evaluated with coimmunoprecipitation and ubiquitination assays. The downstream signaling pathway of the GRP75/HMGA1 axis was investigated by mRNA-sequencing analysis.Results: High expression of HMGA1 and GRP75 was associated with recurrence and a poor prognosis in stage I LUAD patients. In particular, HMGA1 had potential as an independent prognostic factor. Overexpression of GRP75 or HMGA1 promoted LUAD cell growth and metastasis, while silencing GRP75 or HMGA1 inhibited LUAD cell growth and metastasis. In vitro and clinical data showed that the expression level of GRP75 positively regulated HMGA1 in LUAD and that GRP75 played an HMGA1-dependent role. In addition, GRP75 prolonged the half-life of HMGA1 by inhibiting HMGA1 ubiquitination via direct binding to HMGA1. Finally, we demonstrated that the GRP75/HMGA1 axis played a role by activating JNK/c-JUN signaling in LUAD.Conclusions: The activation of GRP75/HMGA1/JNK/c-JUN signaling is an important mechanism that promotes the progression of stage I LUAD, and a high level of HMGA1 is a novel biomarker for predicting recurrence and prognosis in patients with stage I LUAD.
Mechanical Power During Extracorporeal Membrane Oxygenation and Hospital Mortality in Patients With Acute Respiratory Distress Syndrome
Authors: Chiu Li-Chung , Lin Shih-Wei , Chuang Li-Pang , Li Hsin-Hsien , Liu Pi-Hua , Tsai Feng-Chun , Chang Chih-Hao , Hung Chen-Yiu , Lee Chung-Shu , Leu Shaw-Woei , Hu Han-Chung , Huang Chung-Chi , Wu Huang-Pin , Kao Kuo-Chin
Published: October 2020

Background: Mechanical power (MP) refers to the energy delivered by a ventilator to the respiratory system per unit of time. MP normalized to predicted body weight (PBW) or respiratory system compliance have better predictive value for mortality than MP alone in acute respiratory distress syndrome (ARDS). Our objective was to assess the potential impact of consecutive changes of normalized MP on hospital mortality among ARDS patients receiving extracorporeal membrane oxygenation (ECMO).Methods: We performed a secondary analysis of patients with severe ARDS receiving ECMO in a tertiary care referral center in Taiwan between May 2006 and October 2015. Serial changes of MP during ECMO were recorded. Results: A total of 152 patients with severe ARDS rescued with ECMO were analyzed. Overall hospital mortality was 53.3 %. There were no significant differences between survivors and nonsurvivors in terms of baseline values of MP or other ventilator settings. Cox regression models demonstrated that MP alone, MP normalized to PBW, and MP normalized to compliance during the first 3 days of ECMO were all independently associated with hospital mortality. Higher MP normalized to compliance (HR 2.289 [95% CI 1.214-4.314], p = 0.010) was associated with a higher risk of death than MP itself (HR 1.060 [95% CI 1.018-1.104], p = 0.005) or MP normalized to PBW (HR 1.004 [95% CI 1.002-1.007], p < 0.001). The 90-day hospital mortality of patients with high MP (> 14.4 J/min) during the first 3 days of ECMO was significantly higher than that of patients with low MP (≦ 14.4 J/min) (70.7 % versus 46.8 %, p = 0.004), and the 90-day hospital mortality of patients with high MP normalized to compliance (> 0.53 J/min/ml/cm H2O) during the first 3 days of ECMO was significantly higher than that of patients with low MP normalized to compliance (≦ 0.53 J/min/ml/cm H2O) (63.1 % versus 29.5 %, p < 0.001).Conclusions: MP during the first 3 days of ECMO was the only ventilator setting independently associated with 90-day hospital mortality, and MP normalized to compliance during ECMO was more predictive for mortality than was MP alone.
BiVO4/Fe3O4@polydopamine Superparticles for Tumor Multimodal Imaging and Synergistic Therapy
Authors: Wang Ze , Wang Guan , Kang Tingting , Liu Shuwei , Wang Lu , Zou Haoyang , Chong Yu , Liu Yi
Published: October 2020

Background: Despite tremendous progress has been achieved in tumor theranostic over the past decade, accurate identification and complete eradication of tumor cells remain a great challenge owing to the limitation of single imaging modality and therapeutic strategy. Results: Herein, we successfully design and construct BiVO4/Fe3O4@polydopamine (PDA) superparticles (SPs) for computed tomography (CT)/photoacoustic (PA)/magnetic resonance (MR) multimodal imaging and radiotherapy (RT)/photothermal therapy (PTT) synergistic therapy toward oral epithelial carcinoma. On the one hand, BiVO4 NPs endow BiVO4/Fe3O4@PDA SPs with impressive X-ray absorption capability due to the high X-ray attenuation coefficient of Bi, which is beneficial for their utilization as radiosensitizers for CT imaging and RT. On the other hand, Fe3O4 NPs impart BiVO4/Fe3O4@PDA SPs with the superparamagnetic property as a T2-weighted contrast agent for MR imaging. Importantly, the aggregation of Fe3O4 NPs in SPs and the presence of PDA shell greatly improve the photothermal conversion capability of SPs, making BiVO4/Fe3O4@PDA SPs as an ideal photothermal transducer for PA imaging and PTT. By integrating advantages of various imaging modalities (CT/PA/MR) and therapeutic strategies (RT/PTT), our BiVO4/Fe3O4@PDA SPs exhibit the sensitive multimodal imaging feature and superior synergistic therapeutic efficacy on tumors. Conclusion: Since there are many kinds of building blocks with unique properties appropriating for self-assembly, our work may largely enrich the library of nanomateirals for tumor diagnosis and treatment.
Protective Effects of Erythronium Japonicum and Corylopsis Coreana Uyeki Extracts Against 1,3-dichloro-2-propanol-induced Hepatotoxicity in Rats
Authors: Bae Chun-Sik , Kim Seunghyun , Boo Hee-Ock , Ahn Taeho
Published: October 2020

Erythronium japonicum (E. japonicum) and Corylopsis coreana Uyeki (C. coreana Uyeki, Korean winter hazel) have been shown to significantly decrease 1,3-dichloro-2-propanol (1,3-DCP)-induced generation of reactive oxygen species and CYP2E1 activity in HuH7, human hepatocytes. In this study, we expanded upon the previous study and investigated the effects of E. japonicum and C. coreana Uyeki extracts on 1,3-DCP-induced liver damage in rats. The pre-treatment of rats with these extracts alleviated a decrease in body weight and reduced 1,3-DCP-induced increase in catalytic activities of hepatic enzymes, such as aspartate aminotransferase and alanine aminotransferase, in the serum. Moreover, treatment with the extracts restored the 1,3-DCP-induced decreases in anti-oxidant enzyme activities, such as the activities of superoxide dismutase and catalase, in the rat liver. Histopathological studies also strongly supported the results of enzyme activities.
A Bimodal Burst Energy Distribution of a Repeating Fast Radio Burst Source
Authors: Li Di , Wang P. , Zhu Weiwei , Zhang Bing , Zhang Xinxin , Duan Ran , Zhang Yongkun , Feng Yi , Tang Ningyu , Chatterjee Shami , Cordes James , Cruces Marylin , Gajjar Vishal , Hobbs George , Jin Chengjin , Kramer Michael , Lorimer Duncan , Miao C.C. , Niu Chenhui , Niu J.R. , Pan Zhichen , Qian Lei , Dai Shi , Spitler Laura , Werthimer Dan , Xie Xiaoyao , Yue Youling , Zhang Lei , Zhi Qijun , Zhu Yan
Published: October 2020

Fast radio bursts (FRBs) are cosmic sources that emit millisecond-duration radio pulses with a wide range of luminosities and yet unknown origin(s) (Petroff et al. 2019; cordes et al. 2019). A subset of FRBs were found to repeat, the prototype of which is the first precisely-located FRB 121102 (Spitler et al. 2016), residing in a dwarf galaxy at redshift z=0.193 (Chatterjee 2017; Tendulkar et al. 2017). The source has been observed by most major telescopes and shows non-Poisson clustering of bursts over time, the hitherto highest burst rate, and a burst isotropic equivalent energy largely consistent with a power-law (Law et al. 2017; zhang et al. 2018; Gourdji et al. 2019), all of which are crucial characteristics to be compared to non-repeating sources. However, due to sensitivity limits, no true energy distribution of any FRB is known. Here we report the detection of 1652 independent bursts, more than quadruple the total of all previously published ones combined, in a total of 59.5 observing hours spanning 47 days using the Five-hundred-meter Aperture Spherical radio Telescope (FAST). The peak burst rate of 122 hr-1is by far the highest ever observed of any FRB. A characteristic peak in the isotropic equivalent energy distribution is found to be ~4.8×1037 erg at 1.25 GHz, suggesting a possible threshold for producing abundant coherent radio bursts from FRBs. The burst energy distribution is optimally described by a bimodal distribution consisting of a log-normal function plus a Cauchy function. While no periodicity was found between 1 ms and 1000 s, and the majority of the burst arrival times are consistent with being random, there exists a visible peak in the waiting time distribution at about 3.4 ms, corresponding to significant clustering. Our results start to reveal the stochastic nature of abundant weaker bursts, which could be present in other FRB sources, apparently repeating or not. FRB generation mechanisms must be efficient and economical. Expensive triggers and/or contrived conditions for burst production seem unlikely.
Breast Cancer Screening Strategies and Indicators in Iran, A Systematic Review
Authors: Omidi Zahra , Koosha Maryam , Nazeri Najmeh , Khosravi Nasim , Haghighat Shahpar
Published: October 2020

BackgroundA lot of individual health behaviors and multi-faceted approached have been introduced for breast cancer early diagnosis and prevention. This systematic review aimed to investigate the status of Breast cancer preventive behaviors and screening indicators among Iranian women.MethodsIn this study, two reviewers included English and Persian articles about breast cancer screening modalities and its indicators in Iran from January 2005 to 2020. English electronic databases of Web of Science, PubMed and Scopus and Persian databases of SID and IranMedex were used. The critical information of articles was extracted and classified to different categories according to the studied outcomes. ResultsA total of 246 articles were assessed which 129 of them were excluded and 114 studies were processed for further evaluation. Performing BSE, CBE, and Mammo in Iranian women had been reported 0- 79.4%, 4.1%-41.1%, and 1.3%-45%, respectively. All of the educational interventions had increased the knowledge, attitude and practice of participants in performing the screening behaviors. The most important screening indicators included participation rate (3.8% to 16.8%), detection rate (0.23 to 8.5 per 1000), abnormal call rate (28.77% to 33%), and recall rate (24.7%).ConclusionThis systematic review demonstrated a lot of heterogeneity in population and design of researches about breast cancer early detection in Iran. The necessity of a cost-effective screening program, presenting a proper educational method for increasing women's awareness and estimating screening indices can be the priorities of future researches. Establishing big studies at the national level in a standard framework are advised
Waterbirth: a national retrospective cohort study of factors associated with its use in 46,088 women in England
Authors: Aughey Harriet K , Jardine Jennifer , Moitt Natalie , Fearon Kriss , Hawdon Jane , Pasupathy D , Urganci Ipek , Harris Tina
Published: October 2020

Background Waterbirth is widely available in English maternity settings for women who are not at increased risk of complications during labour. Immersion in water during labour is associated with a number of maternal benefits, however for birth in water the situation is less clear, with conclusive evidence on safety lacking and little known about the characteristics of women who give birth in water. This retrospective cohort study uses electronic data routinely collected in the course of maternity care in England in 2015-16 to describe the proportion of births recorded as having occurred in water; the characteristics of women who experienced waterbirth; and the odds of key maternal and neonatal complications associated with giving birth in water.Methods Data was obtained from three population level electronic datasets linked together for the purposes of a national audit of maternity care. The study cohort included women who had no risk factors requiring them to give birth in an obstetric unit according to national guidelines. (1) Multivariate logistic regression models were used to examine maternal (postpartum haemorrhage of 1500mls or more, obstetric anal sphincter injury (OASI)) and neonatal (Apgar score less than 7, neonatal unit admission) outcomes associated with waterbirth.Results 46,088 low and intermediate risk singleton term spontaneous vaginal births in 35 NHS Trusts in England were included in the analysis cohort. Of these 6264 (13.6%) were recorded as having occurred in water. Waterbirth was more likely in older women up to the age of 40 (adjusted odds ratio (adjOR) for age group 35-39 1.27 95% confidence interval (1.15,1.41)) and less common in women under 25 (adjOR 18-24 0.76 (0.70, 0.82)), those of higher parity (parity ≥3 adjOR 0.56 (0.47,0.66)) or who were obese (BMI 30–34.9 adjOR 0.77 (0.70,0.85)) . Waterbirth was also less likely in black (adjOR 0.42 (0.36, 0.51)) and Asian (adjOR 0.26 (0.23,0.30)) women and in those from areas of increased socioeconomic deprivation (most affluent versus least affluent areas adjOR 0.47 (0.43, 0.52)).There was no association between delivery in water and low Apgar score (adjOR 0.95 (0.66,1.36)) or OASI (adjOR 1.00 (0.86,1.16). or incidence of OASI (adjOR 1.00 (0.86,1.16)). There was an association between waterbirth and reduced incidence of postpartum haemorrhage (adjOR 0.68 (0.51,0.90)) and neonatal unit admission (adjOR 0.65 (0.53,0.78)).Conclusions In this large observational cohort study, there was no association between waterbirth and specific adverse outcomes for either the mother or the baby. There was evidence that white women from higher socioeconomic backgrounds were more likely to be recorded as giving birth in water. Maternity services should focus on ensuring equitable access to waterbirth.