bluuebunny/crossref_metadata_2025 huggingface dataset:
Workforce experience of the implementation of an advanced clinical practice framework in England: a mixed methods evaluation
Authors: Lawler Jessica , Maclaine Katrina , Leary Alison
Published: October 2020

Background This study aims to understand how the implementation of the Advanced Clinical Practice framework in England (2017) was experienced by the workforce to check assumptions for a national workforce modelling project. The Advanced Clinical Practice framework was introduced in England in 2017 by Health Education England to clarify the role of advanced practice in the National Health Service.Methods: As part of a large-scale workforce modelling project, a self-completed questionnaire was distributed via the Association of Advanced Practice Educators UK aimed at those studying to be an Advanced Clinical Practitioner or who are practicing at this level in order to check assumptions. Semi-structured phone interviews were carried out with this same group. Questionnaires were summarised using descriptive statistics in Excel for categorical responses and interviews and survey free-text were analysed using thematic analysis in NVivo 10.Results: The questionnaire received over 500 respondents (ten times that expected) and 15 interviews were carried out. Advanced Clinical Practice was considered by many respondents the only viable clinical career progression. Respondents felt that employers were not clear about what practicing at this level involved or its future direction. 54% (287) thought that ‘ACP’ was the right job title for them. 19% (98) of respondents wanted their origin registered profession to be included in their title. Balancing Advanced Clinical Practice education concurrently with a full-time role was challenging, participants underestimated the workload and expectations of employer’s training. There is an apparent dichotomy that has developed from the implementation of the 2017 framework: that of Advanced Clinical Practice as an advanced level of practice within a profession, and that of Advanced Clinical Practitioner as a new generic role in the medical model.Conclusions: Efforts to establish further clarity and structure around advanced clinicalpractice are needed for both the individuals practising at this level and their employers. A robust evaluation of the introduction of this role should take place.
Short-term Outcomes and Safety of Radiotherapy for Immediate Breast Reconstruction with Autologous Flap Transfer Following Breast-conserving Surgery
Authors: Zhang Shu-Ling , Song Jun , Wang Yan-Ru , Guo Yi-Jia , Zhao Jian-Zhu , Sun Li , Huang Le-Tian , Ma Jie-Tao , Han Cheng-Bo
Published: October 2020

Background: The outcomes of immediate autologous breast reconstruction (IABR) after partial mastectomy followed by postoperative radiotherapy (RT) in terms of aesthetics, treatment-related complications, and local control are unclear. In this study, we evaluated the efficacy of IABR after partial mastectomy with or without breast RT, and thus the impact of radiation on autologous flap transfer.Method: A retrospective cohort study involving consecutive breast cancer patients who underwent IABR after partial mastectomy between July 2011 and December 2017 at Shengjing Hospital was performed. Patients were divided into two groups based on whether or not they received RT after IABR. We compared aesthetic outcomes and changes in the flap size over the three-dimensional coordinates at various timepoints (pre-RT, 1, 6, and 12 months post-RT), as well as postoperative complications, survival, and recurrence rates between the two groups. Results: No significant difference was found in the rate of regional recurrence between the two groups (3.13% vs. 3.85%, P=1.00), and no local recurrences occurred in either group. At the timepoints pre-RT, 1, and 6 months post-RT (approximately 4, 7, and 12 months after IABR, respectively), 77 (91.7%), 70 (83.3%), and 83 (98.8%) patients, respectively, had achieved very good or good cosmetic outcomes, and only changes in breast skin color at 1 month after RT (7 months after IABR) significantly differed between the RT and non-RT groups, with very good or good cosmetic result rates of 62.5% vs. 96.2%, respectively (P<0.001). No significant difference in the reduction of flap size was observed at any timepoint between the RT and non-RT groups. The flap size was significantly reduced at 4 months after IABR compared with the initial size during surgery, and then tended to be stable in both groups. There were no significant differences between the two groups in the rates of postoperative complications including necrosis of the flap, infection, hematoma, or seroma (all P>0.05). Finally, no grade 3 or greater RT-associated adverse events occurred during or after RT.Conclusion: RT following IABR provides aesthetically satisfactory results without intolerable adverse complications and may safely be performed in patients who underwent IABR after partial mastectomy.
Impact of Superparamagnetic Iron Oxide Nanoparticles on In Vitro and In Vivo Radiosensitisation of Cancer Cells
Authors: Russell Emily , Dunne Victoria , Russell Ben , Mohamud Hibaaq , Ghita Mihaela , McMahon Stephen , Butterworth Karl , Schettino Giuseppe , McGarry Conor , Prise Kevin
Published: October 2020

PurposeThe recent implementation of MR-Linacs has highlighted theranostic opportunities of contrast agents in both imaging and radiotherapy. There is a lack of data exploring the potential of superparamagnetic iron oxide nanoparticles (SPIONs) as radiosensitisers. This study aimed to characterise the uptake and radiobiological effects of SPIONs in tumour cell models in vitro and to provide proof-of-principle application in a xenograft tumour model. MethodsSPION uptake was measured using ICP-MS in 6 cancer cell lines; H460, MiaPaCa2, DU145, MCF7, U87 and HEPG2. The impact of SPIONs on radiobiological response was determined by measuring DNA damage using 53BP1 immunofluorescence and cell survival. Measured dose enhancement factors (DEFs) were with the predicted DEFs based on physical absorption estimations. In vivo efficacy was demonstrated using a subcutaneous H460 xenograft tumour model in SCID mice by following intra-tumoural injection of SPIONs. ResultsSPIONs significantly increased DNA damage in all cell lines with the exception of U87 cells at a dose of 1 Gy, 1 hr post-irradiation. Levels of DNA damage correlated with the cell survival, in which all cell lines except U87 cells showed an increased sensitivity (P < 0.05) in the linear quadratic curve fit for 1 hr exposure to 0.1 mM SPIONs. There was also a 30.1 % increase in the number of DNA damage foci found for HEPG2 cells at 2 Gy. No strong correlation was found between SPION uptake and DNA damage at any dose, yet the biological consequences of SPIONs on radiosensitisation were found to be much greater, with DEFs up to 1.28 ± 0.03, compared with predicted physical dose enhancement levels of 1.0001. In vivo, intra-tumoural injection of SPIONs combined with radiation showed significant tumour growth delay compared to animals treated with radiation or SPIONs alone (p < 0.05). ConclusionsSPIONs showed radiosensitising effects in 5 out of 6 cancer cell lines. No correlation was found between the cell-specific uptake of SPIONs into the cells and DNA damage levels. The in vivo study found a significant decrease in the tumour growth rate.
Development and evaluation of duplex TaqMan real-time PCR assay for detection and differentiation of wide-type and MGF505-2R gene-deleted African swine fever viruses
Authors: Guo zhenhua , Li Kunpeng , Qiao Songlin , Chen Xinxin , Deng Ruiguang , Zhang Gaiping
Published: October 2020

Background: African swine fever (ASF) is the most important disease to the pigs and cause serious economic losses to the countries with large-scale swine production. Vaccines are recognized as the most useful tool to prevent and control ASF virus (ASFV) infection. Currently, the MGF505 and MGF360 gene-deleted ASFVs or combined with CD2v deletion were confirmed to be the most promising vaccine candidates. Thus, it is essential to develop a diagnosis method to discriminate wide-type strain from the vaccines used.Results: In this study, we established a duplex TaqMan real-time PCR based on the B646L gene and MGF505-2R gene. The sequence alignment showed that the targeted regions of primers and probes are highly conserved in the genotype II ASFVs. The duplex real-time assay can specifically detect B646L and MGF505-2R gene single or simultaneously without cross-reaction with other porcine viruses tested. The limit of detection was 5.8 copies and 3.0 copies for the standard plasmids containing B646L and MGF505-2R genes, respectively. Clinical samples were tested in parallel by duplex real-time PCR and a commercial ASFV detection kit. The detection results of these two assays against B646L gene were well consistent.Conclusion: We successfully developed and evaluated a duplex TaqMan real-time PCR method which can effectively distinguish the wide type and MGF505 gene-deleted ASFVs. It would be a useful tool for the clinical diagnosis and control of ASF.
Are activated B cells involved in the process of myocardial fibrosis after acute myocardial infarction? An in vivo experiment
Authors: Mo Fanrui , Luo Ying , Yan Yuluan , Li Juan , Lai Shayi , Wu Weifeng
Published: October 2020

Background Inflammatory cells infiltrate into the ischemic and hypoxic myocardial tissue after myocardial infarction. B cells gather at the site of myocardial injury and secrete cytokines to regulate immune inflammation and fiber repair processes. Methods The animal experiment used ligation of the left anterior descending (LAD) artery of C57BL/6 mice to establish a mouse acute myocardial infarction (AMI) model to observe changes in activated B cells and cytokines at different time points. Twelve-week-old C57BL/6 male mice were randomly divided into the Sham group (24 mice) (thread under the LAD artery without ligation) and the AMI group (64 mice). In addition, C57BL/6 B-cell knockout (BKO) mice and C57BL/6 wild-type (WT) mice were used to establish AMI models to observe the expression levels of cardiomyocyte cytokines, such as TNF-α IL-1β, IL-6, TGF-β1, COL1-A1, COL3-AIII, TIMP, and MMP9. Moreover, pathological and collagen changes in the myocardium were analysed. One-way ANOVA and LSD method was used for comparisons of multiple and pairwise groups respectively. P<0.05 indicated significant differences. Results An AMI model of C57BL/6 mice was established successfully. The ratio of activated B cells and the expression of TNF-α, IL-1β, IL-6, TGF-β1, and B cell activating factor (BAFF) in the 5-day subgroup were the highest in the myocardium, spleen and peripheral blood with the most obvious myocardial inflammatory cell infiltration. The cytokines mRNA expression levels in the 5-day subgroup of the BKO group were decreased compared with those in the WT group (P<0.05). Among the 2-week subgroups of the Sham, WT and BKO groups, the the LVEDd and LVESd of the BKO group were lower than those of the WT group (P<0.05), and the left ventricular ejection fraction (LVEF) was higher than that of the WT group (P<0.05). Conclusion Activated B cells participate in the sustained state of myocardial inflammation and immune system activation after AMI, and may affect the metabolism of myocardial collagen after AMI by secreting cytokines. Moreover, B cells promote the expression of myocardial collagen Type I and Type III and damage the left ventricular ejection function.
Network pharmacology based research into the effect and mechanism of Yinchenhao Decoction against Cholangiocarcinoma
Authors: Chen Zhiqiang , Lin Tong , Liao Xiaozhong , Li Zeyun , Lin Ruiting , Qi Xiangjun , Chen Guoming , Sun Lingling , Lin Lizhu
Published: October 2020

Background

This study aimed to screen out the effective active components of Yinchenhao decoction (YCHD) using network pharmacology, estimate their potential targets, screen out the pathways, as well as delve into the potential mechanisms on treating cholangiocarcinoma.

Methods

By the traditional Chinese medicine system pharmacology database and analysis platform (TCMSP) as well as literature review, the major active components and their corresponding targets were estimated and screened out. Using the software Cytoscape 3.6.0, a visual network was established using the active components of YCHD and the targets of cholangiocarcinoma. Based on STRING online database, the protein interaction network of vital targets was built and analyzed. With the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server, the gene ontology (GO) biological processes and the Kyoto encyclopedia of genes and genomes (KEGG) signaling pathways of the targets enrichment were performed. The AutoDock Vina was used to perform molecular docking and calculate the binding affinity. The PyMOL software was utilized to visualize the docking results of active compounds and protein targets. In vivo experiment, the IC 50 values and apoptosis rate in PI-A cells were detected using CCK-8 kit and Cell Cycle Detection Kit. The predicted targets were verified by the real-time PCR and western blot methods.

Results

32 effective active components with anti-tumor effects of YCHD were sifted in total, covering 209 targets, 96 of which were associated with cancer. Quercetin, kaempferol, beta-sitosterol, isorhamnetin, and stigmasterol were identified as the vital active compounds, and AKT1, IL6, MAPK1, TP53 as well as VEGFA were considered as the major targets. The molecular docking revealed that these active compounds and targets showed good binding interactions. These 96 putative targets exerted therapeutic effects on cancer by regulating signaling pathways (e.g., hepatitis B, the MAPK signaling pathway, the PI3K-Akt signaling pathway, and MicroRNAs in cancer). Our in vivo experimental results confirmed that YCHD showed therapeutic effects on cholangiocarcinoma by decreasing IC 50 values, down-regulating apoptosis rate of cholangiocarcinoma cells, and lowering protein expressions.

Conclusion

As predicted by network pharmacology strategy and validated by the experimental results, YCHD exerts anti-tumor effects through multiple components, targets, and pathways, thereby providing novel ideas and clues for the development of preparations and the treatment of cholangiocarcinoma.
Paracrine stimulation of perinatal lung functional and structural maturation by mesenchymal stem cells.
Authors: Obendorf Janine , Fabian Claire , Thome Ulrich H. , Laube Mandy
Published: October 2020

Background: Mesenchymal stem cells (MSCs) were shown to harbor therapeutic potential in models of respiratory diseases, such as Bronchopulmonary Dysplasia (BPD), the most common sequel of preterm birth. In these studies cells or animals were challenged with hyperoxia or other injury-inducing agents. However, little is known about the effect of MSCs on immature fetal lungs and whether MSCs are able to improve lung maturity, which may alleviate lung developmental arrest in BPD. Methods: We aimed to determine if conditioned medium (CM) of MSCs stimulates functional and structural lung maturation. As a measure of functional maturation, Na + transport in primary fetal distal lung epithelial cells (FDLE) was studied in Ussing chambers. Na + transporter and surfactant protein mRNA expression was determined by qRT-PCR. Structural maturation was assessed by microscopy in fetal rat lung explants. Results: MSC-CM strongly increased the activity of the epithelial Na + channel (ENaC) and the Na,K-ATPase as well as their mRNA expression. Branching and growth of fetal lung explants, and surfactant protein mRNA expression were enhanced by MSC-CM. Epithelial integrity and metabolic activity of FDLE cells were not influenced by MSC-CM. Since MSC’ actions are mainly attributed to paracrine signaling, prominent lung growth factors were blocked. None of the tested growth factors (VEGF, BMP, PDGF, EGF, TGF-β, FGF, HGF) contributed to the MSC-induced increase of Na + transport. In contrast, inhibition of PI3-K/AKT and Rac1 signaling reduced MSC-CM efficacy, suggesting an involvement of these pathways in the MSC-CM-induced Na + transport. Conclusion: The results demonstrate that MSC-CM strongly stimulated functional and structural maturation of fetal lungs. These effects were at least partially mediated by the PI3-K/AKT and Rac1 signaling pathway. Thus MSCs not only repair a deleterious tissue environment, but also target lung cellular immaturity itself.
The prospects for sustaining evidence-based responses to the US opioid epidemic: State leadership perspectives
Authors: Caton Lauren , Yuan Mina , Louie Dexter , Gallo Carlos , Abram Karen , Palinkas Lawrence , Brown C Hendricks , McGovern Mark
Published: October 2020

Background: The US 21st Century Cures Act provided $7.5 billion in grant funding to states and territories for evidence-based responses to the opioid epidemic. Currently, little is known about optimal strategies for sustaining these programs beyond this start-up funding. Methods: Using an inductive, conventional content analysis, we conducted key informant interviews with former and current state leaders (n=16) about barriers/facilitators to sustainment and strategies for sustaining time-limited grants. Results: Financing and reimbursement, service integration, and workforce capacity were the most cited barriers to sustainment. Status in state government structure, public support, and spending flexibility were noted as key facilitators. Effective levers to increase chances for sustainment included strong partnerships with other state agencies, workforce and credentialing changes, and marshalling advocacy through public awareness campaigns.Conclusions: Understanding the strategies that leaders have successfully used to sustain programs in the past can inform how to continue future time-limited, grant-funded initiatives.
Diversities of antimicrobial resistance patterns across Staphylococcus aureus and Coagulase-Negative Staphylococci isolated from dairy herbs in Jiangsu province, China
Authors: Jin Weijie , Lin Weidong , Feng Qing , Zhang Dashuai , Yang Juan , Qin Aijian
Published: October 2020

Background

As mastitis major causing agents, Coagulase-Negative Staphylococci (CNS) and Staphylococcus aureus (SA), are important and their connections are special and worth comparing. The overall aim of this study is to investigate antimicrobial resistance patterns of CNS and SA. Understanding the special characters of staphylococci is essential for finding the precise strategies or directions against them.
Results

Staphylococci (47.63%) were the commonest pathogens in subclinical mastitis in Jiangsu province. 73.34% and 45.78% of CNS respectively were extensively drug-resistant (XDR) strains and multiple drug-resistant (MDR) strains, mainly resisting penicillin (77.78%) and ceftazidime (55.95%); for SA, 62.52% of them were MDR strains and resistant to penicillin (94.05%) and norfloxacin (58.33%). Notably, 4 CNS were pandrug-resistant (PDR) strains. According to the chi-square test results, we summary and find that SA was more resistant to quinolones (ciprofloxacin, levofloxacin, and norfloxacin) and co-trimoxazole antibiotics than CNS, significantly; on the other hand, CNS were significantly more resistant to lincomycins (clindamycin), macrolides (including erythromycin and clarithromycin), tetracycline, and nitrofurantoin antibiotics than SA,, in total. Resistance genes were detected more frequently in CNS than SA; nearly a third of CNS resit penicillin by β-lactamase coded by blaZ and CNS resist tetracycline mainly by protein pump mechanism. For SA, blaZ was detected out 27.2%, and the other five resistance genes were rare to be found.
Conclusion

Responding to antibiotics interfering with metabolisms of nucleotide, SA might be more resistant than CNS; while CNS strains are more likely to become mutations to survive under the stress of antibiotics interfering with protein synthesis. These might provide the advantages for CNS to represent like a reservoir of resistance genes for other staphylococci as the previous researches’ assumption.
In vivo evidence of microstructural hypo-connectivity of brain white matter in 22q11.2 deletion syndrome
Authors: Raven Erika , Veraart Jelle , Kievit Rogier , Genc Sila , Ward Isobel , Cunningham Adam , Doherty Joanne , Bree Marianne van den , Jones Derek
Published: October 2020

22q11.2 Deletion Syndrome, or 22q11.2DS, is a genetic syndrome associated with high rates of schizophrenia, autism, and attention deficit hyperactivity disorder, in addition to widespread structural and functional abnormalities throughout the brain. Experimental animal models have identified neuronal connectivity deficits, e.g., decreased axonal length and complexity of axonal branching, as a primary mechanism underlying atypical brain development in 22q11.2DS. However, it is still unclear whether deficits in axonal morphology can also be observed in people with 22q11.2DS. Here, we provide an unparalleled in vivo characterisation of white matter microstructure in both typically-developing children and children with 22q11.2DS using a dedicated magnetic resonance imaging scanner which is sensitive to axonal morphology. By extracting a rich array of diffusion metrics, we present microstructural profiles of typical and atypical white matter development, and provide new evidence of connectivity differences between typically-developing and 22q11.2DS children. A recent, large-scale consortium study identified higher diffusion anisotropy and reduced overall mobility of water as hallmark microstructural alterations of white matter in 22q11.2DS, in particular for commissural fibers. We observed similar findings across all white matter tracts in this study, in addition to identifying deficits in axonal morphology. This, in combination with reduced tract volume measurements, supports the hypothesis that microstructural connectivity in 22q11.2DS is mediated by densely packed axons with disproportionately small diameters. Our findings provide insight into the in vivo mechanistic features of 22q11.2DS, and promote further investigation of shared features in neurodevelopmental and psychiatric disorders.
A rapid and efficient screening system for neutralizing antibodies and its application for SARS-CoV-2
Authors: Han Xiaojian , Wang Yingming , Li Shenglong , Hu Chao , Li Tingting , Gu Chenjian , Wang Kai , Shen Meiying , Wang Jianwei , Hu Jie , Wu Ruixin , Mu Song , Gong Fang , Chen Qian , Gao Fengxia , Huang Jingjing , Long Yingyi , Luo Feiyang , Song Shuyi , Long Shunhua , Hao Yanan , Li Luo , Wu Yang , Xu Wei , Cai Xia , Gao Qingzhu , Zhang Guiji , He Changlong , Deng Kun , Du Li , Nai Yaru , Wang Wang , Xie Youhua , Qu Di , Huang Ailong , Tang Ni , Jin Aishun
Published: October 2020

After the epidemic of COVID-19, neutralizing antibodies (NAbs) against SARS-CoV-2 has been developed for the preventative and therapeutic purposes. However, few methodologies are reported in detail on how to rapidly and efficiently generate NAbs of interest. Here, we present a strategically optimized screening method for NAbs, which has enabled us to obtain SARS-CoV-2 receptor-binding domain (RBD) specific monoclonal Abs within 4 days, followed by additional 2 days to evaluate their neutralizing activities. Using this method, we obtained 198 specific Abs against SARS-CoV-2 RBD from the blood samples of COVID-19 convalescent patients, and 96 of them showed neutralizing activity. At least 20% of these NAbs exhibited high neutralizing potency. The top 2 NAbs showed the half-maximal inhibitory concentration (IC50) to block authentic SARS-CoV-2 at 9.88 and 11.13 ng/ml, respectively. Altogether, our study provides a fundamental methodology for discovering NAbs with potential preventative and therapeutic value for emerging infectious diseases.
Upconverted excitation energy lock-in for deep-ultraviolet enhancement
Authors: Su Qianqian , Wei Han-Lin , Wang Shuai , Chen Chaohao , Ming Guan , Su Yan , Wang Haifang , Chen Zhigang , Jin Dayong
Published: October 2020

Photon upconversion of near-infrared (NIR) irradiation into deep-ultraviolet (UV) emission offers many exciting opportunities for drug release in deep tissues, photodynamic therapy, solid-state lasing, energy storage, and photocatalysis. However, NIR-to-deep-UV upconversion remains a daunting challenge due to low quantum efficiency. Here, we report an unusual six-photon upconversion process in Gd3+/Tm3+-codoped nanoparticles comprising a heterogeneous, core-multishell nanostructure. This multishell design efficiently suppresses energy consumption induced by interior energy traps, maximizes cascade sensitizations of the NIR excitation, and promotes upconverted deep-UV emission from high-lying excited states. We released the intense six-photon-upconverted UV emissions at 253 nm under 808-nm excitation. This work provides new insight into mechanistic understanding of the upconversion process within the heterogeneous architecture, while offering exciting opportunities for developing nanoscale deep-UV emitters that can be remotely controlled in deep tissues upon NIR illumination.
Long-term persistence of neutralizing memory B cells in SARS-CoV-2
Authors: Bull Rowena , Abayasingam Arunasingam , Balachandran Harikrishnan , Agapiou David , Rodrigo Chaturaka , Keoshkerian Elizabeth , Li Hui , Brasher Nicholas , Christ Daniel , Rouet Romain , Burnett Deborah , Grubor-Bauk Branka , Rawlinson William , Turville Stuart , Aggarwal Anupriya , Brilot Fabienne , Mina Michael , Post Jeffrey , Hudson Bernard , Gilroy Nicky , Dwyer Dominic , Sasson Sarah , Tea Fiona , Pilli Deepti , Tedla Nicodemus , Lloyd Andrew , Martinello Marianne
Published: October 2020

Considerable concerns relating to the duration of protective immunity against SARS-CoV-2 have been raised, with evidence of antibody titres declining rapidly after infection and reports of reinfection. Here we monitored antibody responses against SARS-CoV-2 receptor binding domain (RBD) for up to six months after infection. While antibody titres were maintained, half of the cohort’s neutralising responses had returned to background. However, encouragingly in a selected subset of 13 participants, 12 had detectable RBD-specific memory B cells and these generally increased out to 6 months. Furthermore, we were able to generate monoclonal antibodies with SARS-CoV-2 neutralising capacity from these memory B cells. Overall our study suggests that the loss of neutralising antibodies in plasma may be countered by the maintenance of neutralising capacity in the memory B cell repertoire.
Impact of a Pandemic on Surgical Neuro-Oncology - Maintaining Functionality in Crisis
Authors: Hameed N.U.Farrukh , Ma Yixin , Zhen Zili , Wu Shuai , Feng Rui , Li Weiping , Huang Guodong , Wu Jinsong , Chen Zhongping
Published: October 2020

Background: The Coronavirus disease 2019 (COVID-19) pandemic has extraordinarily impacted global healthcare. Neuro-oncological surgery units have peculiar features that make them highly relevant in the strategic reaction to the pandemic. In this Chinese Society of Neuro-Oncology (CSNO) initiated survey, we appraise the changes implemented in neurosurgery hospitals across different Asian countries and provide expert recommendations for responses at different stages of the pandemic.Methods: A 42-question survey was distributed to neurosurgery hospitals across different Asian countries by the CSNO on April 1, 2020, with responses closed on April 18, 2020.Results: 144 hospitals completed the questionnaire. Most were in WHO post-peak phase of the pandemic and reported a median reduction in neurosurgery volume of 25-50%. Most(67.4%) resumed elective surgery in only COVID-19 negative patients;11.1% performed only emergency cases irrespective of COVID-19 status;2.1% suspended all surgical activity. Ninety-one(63.2%) relocated personnel from neurosurgery to other departments. Fifty-two(36.1%) hospitals suspended post-operative adjuvant therapy and 94(65.2%) instituted different measures to administer post-operative adjuvant therapy. Majority(59.0%) of the hospitals suspended research activity. Most(70%) respondents anticipate that current neurosurgery restrictions will continue to remain for >1 month.Conclusions: Majority of the respondents to our survey reported reduced neurosurgery activity, policy modification, personnel reallocation, and curtailment of educational/research activities in response to the COVID-19 pandemic. The persistent widespread interruption of surgical neuro-oncology in even post-peak phases of the pandemic raises serious concerns about the long-term impact of the pandemic on neuro-oncological patients and highlights the essence of timely measures for pandemic preparedness, patient triage, and workforce protection.
Novel Adapter CAR-T cell Technology for precisely controllable Multiplex Cancer Targeting
Authors: Seitz Christian , Mittelstaet Joerg , Hau Jana , Reiter Selina , Illi Clara , Kieble Verena , Engert Fabian , Drees Britta , Bender Giulia , Atar Daniel , Krahl Ann-Christin , Knopf Philipp , Schroeder Sarah , Paulsen Nikolas , Rokhvarguer Alexander , Scheuermann Sophia , Rapp Elena , Mast Anna-Sophia , Rabsteyn Armin , Schleicher Sabine , Grote Stefan , Schilbach Karin , Kneilling Manfred , Pichler Bernd , Lock Dominik , Kotter Bettina , Dapa Sandra , Miltenyi Stefan , Kaiser Andrew , Lang Peter , Handgretinger Rupert , Schlegel Patrick
Published: October 2020

Chimeric antigen receptor (CAR)-T therapy holds great promise to sustainably improve cancer treatment. However, currently, a broad applicability of CAR-T cell therapies is hampered by limited CAR-T cell versatility and tractability and the lack of exclusive target antigens to discriminate cancerous from healthy tissues. To achieve temporal and qualitative control on CAR-T function, we engineered the Adapter CAR (AdCAR) system. AdCAR-T are redirected to surface antigens via biotin-labeled adapter molecules in the context of a specific linker structure, referred to as Linker-Label-Epitope. AdCAR-T execute highly specific and controllable effector function against a multiplicity of target antigens. In mice, AdCAR-T durably eliminate aggressive lymphoma. Importantly, AdCAR-T might prevent antigen evasion by combinatorial simultaneous or sequential targeting of multiple antigens and are capable to identify and differentially lyse cancer cells by integration of adapter molecule mediated signals based on multiplex antigen expression profiles.
Concepturealize™: A New Contribution to Generate Real-needs-focussed, User-centred, Lean Business Models
Authors: Allen Graeme
Published: October 2020

It is widely accepted that somewhere in the region of 90% to 95% of startups fail. It is often suggested that the majority of unsuccessful startups either failed to identify a viable idea, or they failed to execute the idea effectively enough to get to market before running out of cash. Two approaches stand out as being particularly well-suited to addressing these problems: Design Thinking and Lean Startup, respectively. This paper presents the Concepturealize™ methodology that crossapplies Design Thinking and Lean Startup as a single iterative process and that enables the entrepreneur to generate real-needs-focussed, user-centred, lean business models.
Deep Post-GWAS Analysis Identifies Potential Risk Genes and Causal Variants for Alzheimer’s Disease, Providing New Insights Into Its Disease Mechanisms
Authors: WANG ZHEN , Zhang Quanwei , Lin Jhih-Rong , Jabalamel M.Reza , Mitra Joydeep , Nguyen Nha , Zhang Zhengdong
Published: October 2020

Background: Alzheimer’s disease (AD) is a genetically complex, multifactorial neurodegenerative disease. It affects more than 45 million people worldwide and currently remains untreatable. Although genome-wide association studies (GWAS) have identified many AD-associated common variants, only about 25 genes are currently known to affect the risk of developing AD, despite its highly polygenic nature. Moreover, the causal variants underlying GWAS AD-association signals remain unknown.Methods: We developed a computational pipeline that integrates 936 AD-associated SNPs, linkage disequilibrium and genomic data from multiple sources – e.g., disease genes databases, functional annotation of genetic variants, GTEx, and the 1000 Genomes Project – to predict both AD risk genes and their causal variants.Results: We identified 342 putative AD risk genes in 203 risk regions spanning 502 AD-associated common variants. 246 AD risk genes have not been identified as AD risk genes by previous GWAS, and 115 of them are outside the risk regions, likely under the regulation of transcriptional regulatory elements contained therein. Even more significantly, for 109 AD risk genes, we predicted 150 causal variants, of both coding and regulatory (in promoters or enhancers) types, and 85 (57%) of them are supported by functional annotation. In-depth functional analyses showed that AD risk genes were overrepresented in AD-related pathways or GO terms – e.g., the complement and coagulation cascade and phosphorylation and activation of immune response – and their expression was relatively enriched in microglia, endothelia, and pericytes of the human brain. We found nine AD risk genes – e.g., IL1RAP, PMAIP1, LAMTOR4 – as predictors for the prognosis of AD survival and genes such as ARL6IP5 with altered network connectivity between AD patients and normal individuals involved in AD progression.Conclusions: Our findings provide novel biological insights into the genetic architecture, expression profiles, functional pathways involved in the AD etiology, and open new strategies for developing therapeutics targeting AD risk genes or causal variants to influence AD pathogenesis.
Unusual Urticaria Pigmentosa in an Asian Man With Indolent Systemic Mastocytosis: A Case Report
Authors: Wongsa Chamard , Sompornrattanaphan Mongkhon , Thongngarm Torpong , Owattanapanich Weerapat , Sitthinamsuwan Panitta , Sukpanichnant Sanya , Sukakul Thanisorn
Published: October 2020

Background: The diagnosis of mastocytosis remains challenging. Given that the disease has a low prevalence and its clinical presentations range from asymptomatic to severe life-threatening conditions, physicians’ lack of awareness of mastocytosis is the main barrier to its diagnosis. Skin involvement is common. In adults, skin lesions are highly suggestive of systemic mastocytosis; however, clinical demonstration of lesions is difficult if they are minimal in number. In Asian, who had dark brown skin color, urticaria pigmentosa was not easy to identify. Here we present the case of indolent systemic mastocytosis with an unusual urticaria pigmentosa. Case presentation: A 48-year-old man had had recurrent severe honeybee anaphylaxis since he was 23. He had small, subtle, brownish skin lesions on his chest and abdomen, which he and previous physicians had not recognized. The skin lesions were compatible with urticaria pigmentosa, also known as maculopapular cutaneous mastocytosis. His clinical findings and an elevated baseline tryptase level triggered a thorough systemic mastocytosis investigation. The skin and bone marrow were infiltrated by abnormal, spindle-shaped mast cells, and KIT and TET2 mutations were in the patient’s serum. The honeybee anaphylaxis mechanism in this patient was IgE mediated, supported by a positive result of specific IgE to honeybee. The final diagnosis was indolent systemic mastocytosis with IgE-mediated honeybee anaphylaxis. As venom immunotherapy is unavailable in Thailand, we prescribed treatment with a regular, oral, nonsedating H1-antihistamine and an epinephrine self-injector. At the 2-year follow-up, the patient had not progressed to advanced systemic mastocytosis nor experienced any anaphylactic episodes.Conclusion: Urticaria pigmentosa is a small, round, brown, or red maculopapular lesion. In the Asian population with dark brown skin color, physician should be exclusively careful examination, particularly in a hidden area and in anaphylaxis cases. Early recognition of urticaria pigmentosa in the adult patient might reduce the delay in diagnosis of indolent systemic mastocytosis.
Predictive Model of Multiple Emergency Department Visits Among Adults: Analysis of the Data from the National Survey of Drug Use and Health (NSDUH)
Authors: Bobashev Georgiy , Warren Lauren , Wu Li-Tzy
Published: October 2020

Objective. In this methodological paper, we use a novel, predictive approach to examine how demographics, substance use, mental and other health indicators predict multiple visits (≥3) to emergency departments (ED) within a year. Methods. State-of-the-art predictive methods were used to evaluate predictive ability and factors predicting multiple visits to ED within a year and to identify factors that influenced the strength of the prediction. The analysis used public-use datasets from the 2015-2018 National Surveys on Drug Use and Health (NSDUH), which used the same questionnaire on the variables of interest. Analysis focused on adults aged ≥18 years. Several predictive models (regressions, trees, and random forests) were validated and compared on independent datasets. Results. Predictive ability on a test set for multiple ED visits (≥3 times within a year) measured as the area under the receiver operating characteristic (ROC) was 0.79, which is good for a national survey. Models revealed consistency in predictive factors across the 4 survey years. The most influential variables for predicting ≥3 ED visits per year were fair/poor self-rated health, having a lower income, asthma, heart condition/disease, having chronic obstructive pulmonary disease (COPD), African-American race, female sex, having diabetes, being restless/fidgety, and being of younger age (18-25). Conclusions. The findings reveal the need to address behavioral and mental health contributors to ED visits and reinforce the importance of developing integrated care models in primary care settings to improve mental health for medically vulnerable patients. Presented modeling approach can be broadly applied to national and other large surveys.
Mesenchymal Stem Cell-conditioned Medium Alleviates High Fat-induced Hyperglucagonemia via miR-181a-5p and its Target PTEN/AKT Signaling
Authors: Song Jia , He Qin , Guo Xinghong , Wang Lingshu , Wang Jinbang , Cui Chen , Hu Huiqing , Yang Mengmeng , Cui Yixin , Yan Fei , Qin Jun , Sun Zheng , Hou Xinguo , Li Wenjuan , Chen Li
Published: October 2020

Background: Pancreatic α-cells are critical to glucose homeostasis because they release glucagon and stimulate the liver to produce glucose. Dysregulation of α-cells gives rise to fasting and postprandial hyperglycemia in type 2 diabetes mellitus(T2DM). Mesenchymal stem cells (MSCs) or their conditioned medium can improve islet function and enhance insulin sensitivity in target tissues. However, studies showing the direct effect of MSCs on islet α-cell dysfunction are limited. Methods: In this study, we used high-fat diet (HFD)-induced mice and α-cell line exposure to palmitate (PA) to determine the effects of bone marrow-derived MSC-conditioned medium (bmMSC-CM) involved in glucagon secretion. To investigate the potential signaling pathways, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) , AKT and phosphorylated AKT(p-AKT) were assessed by Western blotting.Results: In vivo, bmMSC-CM infusion protected against HFD-induced hyperglycemia and hyperglucagonemia. Consistently, bmMSC-CM decreased PA-induced glucagon secretion in α-cells and isolated islets. Additionally, bmMSC-CM reduced intracellular PTEN expression and rescued AKT signaling. Previous studies and the TargetScan database indicate that miR-181a and its target PTEN play vital roles in ameliorating α-cell dysfunction. We observed that miR-181a-5p is highly expressed in BM-MSCs but prominently lower in αTC1-6 cells. Overexpression or downregulation of miR-181a-5p respectively alleviates or aggravates glucagon secretion in αTC1-6 cells via the PTEN/AKT signaling pathway. Conclusions: Our observations suggest that MSC-secreted miR-181a-5p mitigates glucagon secretion of α-cells by regulating PTEN/AKT signaling. These findings might provide a novel understanding of MSC-based treatment.
A Machine Learning Model to Predict Death Outcome in Severe COVID-19 Patients
Authors: Yang Qiao , Li Jixi , Zhang Zhijia , Wu Xiaocheng , Liao Tongquan , Yu Shiyong , You Zaichun , Hou Xianhua , Ye Jun , Liu Gang , Ma Siyuan , Xie Ganfeng , Zhou Yi , Li Mengxia , Wu Meihui , Feng Yimei , Wang Weili , Li Lufeng , Xie Dongjing , Hu Yunhui , Liu Xi , Wang Bin , Zhao Songtao , Li Li , Luo Chunmei , Tang Tang , Wu Hongmei , Hu Tianyu , Yang Guangrong , Luo Bangyu , Li Lingchen , Yang Xiu , Li Qi , Xu Zhi , Wu Hao , Sun Jianguo
Published: October 2020

BackgroundThe novel coronavirus disease 2019 (COVID-19) spreads rapidly among people and causes a global pandemic. It is of great clinical significance to identify COVID-19 patients with high risk of death.MethodsA total of 2,169 adult COVID-19 patients were enrolled from Wuhan, China between February 10th and April 15th, 2020. Difference analyses of medical records were performed between severe and non-severe groups as well as between survivors and non-survivors. In addition, we developed a decision tree classifier to identify risk factors for death outcome.ResultsOf the 2,169 COVID-19 patients, the median age was 61 years and male patients accounted for 48%. A total of 646 patients were diagnosed with severe illness, and 75 patients died. The most common system symptoms were respiratory, systemic and digestive symptoms. Obvious differences in demographics, clinical characteristics and laboratory examinations were found between severe and non-severe groups, as well as between survivors and non-survivors. A machine learning model was developed to predict death outcome in severe patients. The decision tree classifier included three biomarkers, neutrophil-to-lymphocyte ratio, C-reactive protein and lactic dehydrogenase. The area under the curve of the receiver operating characteristic of this model was 0.96. This model performed well both in train dataset and test dataset. The accuracy of this model was 0.98 and 0.98, respectively.ConclusionThe machine learning model was robust and effective in predicting the death outcome in severe COVID-19 patients.
WITHDRAWN: Prevalence and Correlates of Secondhand Smoking Exposure Among Pregnant and Postnatal Chinese Women
Authors: YANG YUAN , Zhang Meng , Bo Haixin , Zhang Dongying , Ma Liangkun , Wang PeiHong , Liu XiaoHua , Ge LiNa , Lin WenJuan , Xu Yang , Zhang YaLan , Li FengJuan , Xu XuJuan , Wu HongHe , Jackson Todd , Ungvari Gabor , Chueng Teris , Meng LiRong , Xiang YuTao
Published: October 2020

BackgroundInhalation of secondhand smoke during pregnancy and postnatal period is detrimental to developing infants and increases risk for health problems throughout the lifespan. This study examined the prevalence of exposure to secondhand smoke, its correlates, and its association with QOL among pregnant and postnatal Chinese women.MethodsThis multicenter, cross-sectional study was conducted between February and October 2019 in China. Participants were pregnant and postnatal women. We assessed associations of frequency and location of secondhand smoking with sample characteristics as well as depression and quality of life based on EPDS and WHOQOL-BREF, respectively.ResultsA total of 992 women participated in the study, of whom, 211 (21.3%, 95%CI=18.7-23.8%) had been exposed to secondhand smoking. Secondhand smoking was most common in public areas (56.4%), and residential homes (20.5%), while workplaces had the lowest rate of secondhand smoking (13.7%). Women with physical comorbidities were more likely to report secondhand smoking exposure, while younger women, women living in urban areas, and those with college or higher education level were less likely to report exposure to secondhand smoking.ConclusionThe prevalence of exposure to secondhand smoking is becoming lower among pregnant and postnatal women in China compared to findings reported in previous studies. Due to the detrimental impact of secondhand smoking on physical health, legal legislation should be promptly enforced to establish smoke-free environments in both public and private urban/rural areas for protection of pregnant and postnatal women, especially those who are physically vulnerable and less educated.
Chromosome Y as A Marker for Sex Discrepancies in Patients With Organ Transplants: A Case Report
Authors: Balaguer Nuria , Mateu-Brull Emilia , Naja Roy Pascal , Nagi Jara Ben , Milán Miguel
Published: October 2020

Background: Organ transplantations cause discrepancy in results from cell-free DNA (cfDNA) testing, but scientific literature is scarce.Case: A 33-year old gravida underwent cfDNA testing, which showed high levels of Y chromosome (ChrY) in the maternal bloodstream. The ChrY pattern was comparable to an adult male reference. As a result, cfDNA testing was only informative for autosomes. Routine 20-week ultrasound scan showed no structural alterations and the presence of female external genitalia. Post-clinical research revealed that the patient received a bone marrow transplant from a male donor several years before. Fluorescence in situ hybridization showed that 100% of nuclei analysed from the patient’s lymphocytes presented a ChrY.Conclusion: This case demonstrates ChrY can be used as a marker to avoid sex discrepancies in certain patients with organ transplants.
Emergency Medicine Matters: Epidemiology of Medical Pathology and Changes in Patient Outcomes after Implementation of a Post-graduate Training Program at a Tertiary Teaching Hospital in Kigali, Rwanda
Authors: Moretti Katelyn , Uwamahoro Doris Lorette , Naganathan Sonya , Uwamahoro Chantal , Karim Naz , Nkeshimana Menelas , Aluisio Adam R.
Published: October 2020

Background: Emergency care is a new but growing specialty across Africa where medical conditions have been estimated to account for 92% of all disability-adjusted life years. This study describes the epidemiology of medical emergencies and the impact of formalized emergency care training on patient outcomes for medical conditions in Rwanda.Methods: A retrospective cohort study was performed using a database of randomly sampled patients presenting to the emergency center (EC) at the University Teaching Hospital of Kigali. All patients, > 15 years of age treated for medical emergencies pre- and post-implementation of an Emergency Medicine (EM) residency training program were eligible for inclusion. Patient characteristics and final diagnosis were described by time period (January 2013 - September 2013 versus September 2015 - June 2016). Univariate chi-squared analysis was performed for diagnoses, EC interventions, and all cause EC and inpatient mortality stratified by time period. Results: A random sample of 1,704 met inclusion with 929 patients in the pre-residency time period and 775 patients in the post-implementation period. Demographics, triage vital signs, and shock index were not different between time periods. Most frequent diagnoses included: gastrointestinal, infectious disease and neurologic pathology. Differences by time period in EC management included: antibiotic use (37.2% vs. 42.2%, p=0.04), vasopressor use (1.9% vs. 0.5%, p=0.01), IV crystalloid fluid (IVF) use (55.5% vs. 47.6%, p=0.001) and mean IVF administration (2,057 ml vs. 2,526 ml, p<0.001). EC specific mortality fell from 10.0% to 1.4% (p<0.0001) across time periods.Conclusions: Mortality rates fell across top medical diagnoses after implementation of an EM residency program. Changes in resuscitation care may explain, in part, this mortality decrease. This study demonstrates that committing to emergency care can potentially have large effects on reducing mortality.