bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantifying the relative impact of contact heterogeneity on MRSA transmission in ICUs - a modelling study
Authors: Lei Hao , Jones Rachael M. , Li Yuguo
Published: January 2020

Background

An efficient surface cleaning strategy would first target cleaning to surfaces that make large contributions to the risk of infections.

Methods

In this study, we used data from the literature about methicillin-resistant Staphylococcus aureus (MRSA) and developed an ordinary differential equations based mathematical model to quantify the impact of contact heterogeneity on MRSA transmission in a hypothetical 6-bed intensive care unit (ICU). The susceptible patients are divided into two types, these who are cared by the same nurse as the MRSA infected patient (Type 1) and these who are not (Type 2).

Results

The results showed that the mean MRSA concentration on three kinds of susceptible patient nearby surfaces was significantly linearly associated with the hand-touch frequency (p < 0.05). The noncompliance of daily cleaning on patient nearby high-touch surfaces (HTSs) had the most impact on MRSA transmission. If the HTSs were not cleaned, the MRSA exposure to Type 1 and 2 susceptible patients would increase 118.4% (standard deviation (SD): 33.0%) and 115.4% (SD: 30.5%) respectively. The communal surfaces (CSs) had the least impact, if CSs were not cleaned, the MRSA exposure to Type 1 susceptible patient would only increase 1.7% (SD: 1.3). The impact of clinical equipment (CE) differed largely for two types of susceptible patients. If the CE was not cleaned, the exposure to Type 1 patients would only increase 8.4% (SD: 3.0%), while for Type 2 patients, it can increase 70.4% (SD: 25.4%).

Conclusions

This study provided a framework to study the pathogen concentration dynamics on environmental surfaces and quantitatively showed the importance of cleaning patient nearby HTSs on controlling the nosocomial infection transmission via contact route.
RETRACTED ARTICLE: lncRNA TINCR sponges miR-214-5p to upregulate ROCK1 in hepatocellular carcinoma
Authors: Hu Min , Han Yaowu , Zhang Ying , Zhou Yuanfeng , Ye Lin
Published: January 2020

Background

Our preliminary bioinformatics analysis showed that lncRNA TINCR may absorb miR-214-5p by serving is sponge, while miR-214-5p targets ROCK1. This study aimed to investigate the interactions among these 3 factors in hepatocellular carcinoma (HCC).

Methods

Expression of TINCR, ROCK1 and miR-214-5p in HCC and non-tumor tissues was detected by performing qPCR. The correlations among TINCR, ROCK1 and miR-214-5p in HCC tissues were analyzed by performing linear regression. Overexpression experiments were performed to analyze gene interactions. Cell proliferation was analyzed by CCK-8 assay.

Results

We found that TINCR and ROCK1 were upregulated, while miR-214-5p was downregulated in HCC. TINCR and ROCK1 were positively correlated, while TINCR and miR-214-5p were not significantly correlated. In HCC cells, TINCR overexpression is followed by ROCK1 overexpression, while miR-214-5p overexpression induced the downregulation of ROCK1. In addition, TINCR and miR-214-5p did not affect the expression of each other. TINCR and ROCK1 overexpression led to increased rate of cancer cell proliferation, while miR-214-5p played an opposite role and reduced the effects of TINCR overexpression. Therefore, TINCR sponges miR-214-5p to upregulate ROCK1 in HCC, thereby promoting cancer cell invasion and migration.
Rapid response of stage IV colorectal cancer with APC/TP53/KRAS mutations to FOLFIRI and Bevacizumab combination chemotherapy: a case report of use of liquid biopsy
Authors: Hendricks Alexander , Rosenstiel Philip , Hinz Sebastian , Burmeister Greta , Röcken Christoph , Boersch Kathrin , Schafmayer Clemens , Becker Thomas , Franke Andre , Forster Michael
Published: January 2020

Background

Liquid biopsies of blood plasma cell free DNA can be used to monitor treatment response and potentially detect mutations that are present in resistant clones in metastatic cancer patients.

Case presentation

In our non-interventional liquid biopsy study, a male patient in his fifties diagnosed with stage IV colorectal cancer and polytope liver metastases rapidly progressed after completing chemotherapy and deceased 8 months after diagnosis. Retrospective cell free DNA testing showed that theAPC/TP53/KRASmajor clone responded quickly after 3 cycles of FOLFIRI + Bevacizumab. Retrospective exome sequencing of pre-chemotherapy and post-chemotherapy tissue samples including metastases confirmed that theAPC/TP53/KRASand other major clonal mutations (GPR50, SLC5A, ZIC3, SF3A1and others)were present in all samples. After the last chemotherapy cycle, CT imaging, CEA and CA19–9 markers validated the cfDNA findings of treatment response. However, 5 weeks later, the tumour had rapidly progressed.

Conclusion

As FOLFIRI+Bevacizumab has recently also been associated with sustained complete remission in aAPC/TP53/KRAStriple-mutated patient, these driver genes should be tested and monitored in a more in-depth manner in future patients. Patients with metastatic disease should be monitored more closely during and after chemotherapy, ideally using cfDNA.
Case report of amniotic fluid embolism coagulopathy following abortion; use of viscoelastic point-of-care analysis
Authors: Crissman Halley P. , Loder Charisse , Pancaro Carlo , Bell Jason
Published: January 2020

Background

Amniotic fluid embolism (AFE) is a rare, life threatening obstetric complication, often associated with severe coagulopathy. Induced abortions are extremely safe procedures however complications including AFE can occur.

Case presentation

A 29-year-old previously healthy woman, gravida 1 para 0, presented for a scheduled second trimester induced abortion via dilation and evacuation at 22-weeks gestation. The case was complicated by a suspected AFE with associated profound coagulopathy. Viscoelastic point-of-care coagulation analysis was used to successfully and swiftly guide management of her coagulopathy.

Conclusion

AFE can occur in the setting of induced abortion. This case report suggests viscoelastic point-of-care coagulation analyzers may aid in the management of pregnancy-related coagulopathy by providing faster coagulation assessment than laboratory testing, and facilitating timely, targeted management of coagulopathy.
Convection-enhanced delivery of temozolomide and whole cell tumor immunizations in GL261 and KR158 experimental mouse gliomas
Authors: Enríquez Pérez Julio , Kopecky Jan , Visse Edward , Darabi Anna , Siesjö Peter
Published: January 2020

Background

Glioblastomas (GBM) are therapy-resistant tumors with a profoundly immunosuppressive tumor microenvironment. Chemotherapy has shown limited efficacy against GBM. Systemic delivery of chemotherapeutic drugs is hampered by the difficulty of achieving intratumoral levels as systemic toxicity is a dose-limiting factor. Although some of its effects might be mediated by immune reactivity, systemic chemotherapy can also inhibit induced or spontaneous antitumor immune reactivity. Convection-enhanced delivery of temozolomide (CED-TMZ) can tentatively increase intratumoral drug concentration while reducing systemic side effects. The objective of this study was to evaluate the therapeutic effect of intratumorally delivered temozolomide in combination with immunotherapy and whether such therapy can generate a cellular antitumor immune response.

Methods

Single bolus intratumoral injection and 3-day mini-osmotic pumps (Alzet®) were used to deliver intratumoral TMZ in C57BL6 mice bearing orthotopic gliomas. Immunotherapy consisted of subcutaneous injections of irradiated GL261 or KR158 glioma cells. Tumor size and intratumoral immune cell populations were analyzed by immunohistochemistry.

Results

Combined CED-TMZ and immunotherapy had a synergistic antitumor effect in the GL261 model, compared to CED-TMZ or immunotherapy as monotherapies. In the KR158 model, immunization cured a small proportion of the mice whereas addition of CED-TMZ did not have a synergistic effect. However, CED-TMZ as monotherapy prolonged the median survival. Moreover, TMZ bolus injection in the GL261 model induced neurotoxicity and lower cure rate than its equivalent dose delivered by CED. In addition, we found that T-cells were the predominant cells responsible for the TMZ antitumor effect in the GL261 model. Finally, CED-TMZ combined with immunotherapy significantly reduced tumor volume and increased the intratumoral influx of T-cells in both models.

Conclusions

We show that immunotherapy synergized with CED-TMZ in the GL261 model and cured animals in the KR158 model. Single bolus administration of TMZ was effective with a narrower therapeutic window than CED-TMZ. Combined CED-TMZ and immunotherapy led to an increase in the intratumoral influx of T-cells. These results form part of the basis for the translation of the therapy to patients with GBM but the dosing and timing of delivery will have to be explored in depth both experimentally and clinically.
Radiation therapy before radical cystectomy combined with immunotherapy in locally advanced bladder cancer – study protocol of a prospective, single arm, multicenter phase II trial (RACE IT)
Authors: Schmid Sebastian C. , Koll Florestan J. , Rödel Claus , Maisch Philipp , Sauter Andreas , Beckert Franziska , Seitz Anna , Kübler Hubert , Flentje Michael , Chun Felix , Combs Stephanie E. , Schiller Kilian , Gschwend Jürgen E. , Retz Margitta
Published: January 2020

Background

Patients with locally advanced bladder cancer (cT3/4 cN0/N+ cM0) have a poor prognosis despite radical surgical therapy and perioperative chemotherapy. Preliminary data suggest that the combination of radiation and immunotherapy does not lead to excess toxicity and may have synergistic (abscopal) anti-tumor effects. We hypothesize that the combined preoperative application of the PD-1 checkpoint-inhibitor Nivolumab with concomitant radiation therapy of the bladder and pelvic region followed by radical cystectomy with standardized lymphadenectomy is safe and feasible and might improve outcome for patients with locally advanced bladder cancer.

Methods

Study design: “RACE IT” (AUO AB 65/18) is an investigator initiated, prospective, multicenter, open, single arm phase II trial sponsored by Technical University Munich. Study drug and funding are provided by the company Bristol-Myers Squibb.

Study treatment: Patients will receive Nivolumab 240 mg i.v. every 2 weeks for 4 cycles preoperatively with concomitant radiation therapy of bladder and pelvic region (max. 50.4 Gy). Radical cystectomy with standardized bilateral pelvic lymphadenectomy will be performed between week 11–15.

Primary endpoint: Rate of patients with completed treatment consisting of radio-immunotherapy and radical cystectomy at the end of week 15.

Secondary endpoints: Acute and late toxicity, therapy response and survival (1 year follow up).

Main inclusion criteria: Patients with histologically confirmed, locally advanced bladder cancer (cT3/4, cN0/N+), who are ineligible for neoadjuvant, cisplatin-based chemotherapy or who refuse neoadjuvant chemotherapy.

Main exclusion criteria: Patients with metastatic disease (lymph node metastasis outside pelvis or distant metastasis) or previous chemo-, immune- or radiation therapy.

Planned sample size: 33 patients, interim analysis after 11 patients.

Discussion

This trial aims to evaluate the safety and feasibility of the combined approach of preoperative PD-1 checkpoint-inhibitor therapy with concomitant radiation of bladder and pelvic region followed by radical cystectomy. The secondary objectives of therapy response and survival are thought to provide preliminary data for further clinical evaluation after successful completion of this trial. Recruitment has started in February 2019.

Trial registration

Protocol Code RACE IT: AB 65/18; EudraCT: 2018–001823-38; Clinicaltrials.gov: NCT03529890; Date of registration: 27 June 2018.
Fatigue in adults with Osteogenesis Imperfecta
Authors: Harsevoort Arjan G. J. , Gooijer Koert , van Dijk Fleur S. , van der Grijn Daniëlle A. F. M. , Franken Anton A. M. , Dommisse Anne Marieke V. , Janus Guus J. M.
Published: January 2020

Background

Osteogenesis Imperfecta (OI) is characterized by bone fragility, and features such as blue sclerae, dentinogenesis imperfecta, hearing loss, ligamentous laxity and short stature can be present. It has long been assumed that the functional ability and quality of life of patients with OI depends primarily on the severity of skeletal deformities. However, fatigue is often mentioned in clinic by patients with all types of OI as an important modifier of their quality of life and does not always seem to be related to their functional ability. The aim of this study is to investigate whether adults with Osteogenesis Imperfecta are significantly more fatigued than the normal population.

Methods

The Fatigue Severity Scale (FSS) was distributed by mobile phone application among 151 adult patients with different OI types. Results of the FSS in the OI group were compared with two control populations from America (n = 20) and the Netherlands (n = 113).

Results

Ninety-nine patients (OI type 1 (n = 72), OI type 3 (n = 13), OI type 4 (n = 14) completed the FSS questionnaire. The mean FSS score of this cohort was 4.4 and significantly higher than the control populations (2.3/2.9). 65% of our cohort reported at least moderate fatigue compared with 2 control populations from America and the Netherlands.

Conclusion

Fatigue in patients with OI is a frequently encountered problem in our expert clinic but research into this topic is sparse. This pilot study is the largest study to date investigating fatigue in patients with OI and results have been compared with two control groups. The mean FSS score of 4.4 in the OI group indicates that people with OI are generally significantly more fatigued than the control population. Further evaluation of fatigue and its influencers in a larger group of OI patients is important for future management.
Nursing home staff’s perspective on end-of-life care of German nursing home residents: a cross-sectional survey
Authors: Strautmann Anke , Allers Katharina , Fassmer Alexander Maximilian , Hoffmann Falk
Published: January 2020

Background

Nursing homes are becoming more important for end-of-life care. Within the industrialised world, Germany is among the countries with the most end-of-life hospitalizations in nursing home residents. To improve end-of-life care, investigation in the status quo is required. The objective was to gain a better understanding of the perspectives of nursing home staff on the current situation of end-of-life care in Germany.

Methods

A cross-sectional study was conducted as a postal survey among a random sample of 1069 German nursing homes in 2019. The survey was primarily addressed to nursing staff management. Data was analyzed using descriptive statistics. Staff was asked to rate different items regarding common practices and potential deficits of end-of-life care on a 5-point-Likert-scale. Estimations of the proportions of in-hospital deaths, residents with advance directives (AD), cases in which documented ADs were ignored, and most important measures for improvement of end-of-life care were requested.

Results

486 (45.5%) questionnaires were returned, mostly by nursing staff managers (64.7%) and nursing home directors (29.9%). 64.4% of the respondents rated end-of-life care rather good, the remainder rated it as rather bad. The prevalence of in-hospital death was estimated by the respondents at 31.5% (SD: 19.9). Approximately a third suggested that residents receive hospital treatments too frequently. Respondents estimated that 45.9% (SD: 21.6) of the residents held ADs and that 28.4% (SD: 26.8) of available ADs are not being considered. Increased staffing, better qualification, closer involvement of general practitioners and better availability of palliative care concepts were the most important measures for improvement.

Conclusions

Together with higher staffing, better availability and integration of palliative care concepts may well improve end-of-life care. Prerequisite for stronger ties between nursing home and palliative care is high-quality education of those involved in end-of-life care.
How prepared are healthcare professionals for delivering physical activity guidance to those with diabetes? A formative evaluation
Authors: Kime N. , Pringle A. , Zwolinsky S. , Vishnubala D.
Published: January 2020

Background

Physical activity is recognised as important for diabetes management and improved overall health of individuals with diabetes, yet many adults with diabetes are inactive. Healthcare professionals have been identified as key to promoting physical activity, including individuals with diabetes, but are ill-prepared to deliver this. Our paper evaluates the barriers/facilitators of healthcare professionals’ delivery of physical activity guidance to adults with diabetes and aims to inform efforts to investigate and enhance their preparedness to promote physical activity.

Methods

A sequential mixed method, two-phase design was adopted involving a purposeful sample of healthcare professionals. Phase one was an online pilot survey designed to test assumptions around healthcare professionals’ knowledge, training and preparedness to deliver physical activity guidance. Phase two comprised eighteen semi-structured interviews, thematically analysed to provide an in-depth exploration of healthcare professionals’ experiences of delivering physical activity guidance to adults with diabetes.

Results

Healthcare professionals are committed to promoting physical activity to adults with diabetes and are reasonably confident in giving basic, generic guidance. Yet, significant challenges prevent them from achieving this in their practice, including: lack of education and training around physical activity, diabetes and health; ignorance of recommended physical activity and diabetes guidelines; lack of awareness of referral options; limited time and accessibility to appropriate resources. Nevertheless, healthcare professionals believed discussions around physical activity needed to be an integral part of consultations, incorporating improved communication strategies for conveying key physical activity messages.

Conclusions

HCPs have a key role in the promotion of physical activity to people with long-term conditions such as diabetes and they are identified within both the strategic policy context and national interventions for physical activity. Yet, this study indicated that HCPs face multiple and at times complex barriers to physical activity promotion generally and with diabetes patients. Conversely HCPs also reported what works, why and how, when promoting physical activity. Rich information derived from the day-to-day, working healthcare professional is integral to shaping future practices going forward. The bottom up, iterative design adopted in this study provides an approach to tap into this information.
The transfer of knowledge on integrated care among five European regions: a qualitative multi-method study
Authors: Grooten Liset , Vrijhoef Hubertus Johannes Maria , Alhambra-Borrás Tamara , Whitehouse Diane , Devroey Dirk
Published: January 2020

Background

To examine how the knowledge transfer processes unfolded within SCIROCCO, a EU funded project (3rd Health Programme (2014–2020)) that aimed to facilitate the process of knowledge sharing across five European regions, to speed up adoption and scaling-up of integrated care initiatives.

Methods

A qualitative multi-method design was used. Data collection methods included focus groups, project documents and action plans of the regions. The data was analysed using a qualitative content-analysis procedure, which was guided by the frameworks of knowledge exchange and the why, whose, what, how framework for knowledge mobilisers.

Results

All five components (including the themes) of knowledge exchange could be identified in the approach developed on the knowledge transfer processes. The four questions and accompanying categories of the framework of knowledge mobilisation were also identified to a large degree.

Conclusions

The observed incorporation of distinct forms of knowledge from multiple sources and the observed dynamic and fluid knowledge transfer processes both suggest that SCIROCCO developed a comprehensive knowledge transfer approach aiming to enable the adoption and scaling-up of integrated care. Overall, the multi-method qualitative nature of this research has allowed some new and practical insights in the knowledge transfer activities on integrated care between several European regions. To obtain a clear understanding of the content of the knowledge transfer approaches, which could assist the operationalising of models to support the evaluation of knowledge transfer activities, it is strongly recommended that further research of this type should be conducted in other research settings.
Paediatric nurses’ general self-efficacy, perceived organizational support and perceived professional benefits from Class A tertiary hospitals in Jilin province of China: the mediating effect of nursing practice environment
Authors: Cheng Linan , Cui Yajuan , Chen Qian , Ye Yansheng , Liu Yingchun , Zhang Fengying , Zeng Weiyan , Hu Xiuying
Published: January 2020

Background

General self-efficacy is considered one of the most influential parameters affecting the quality of clinical practice and nurses’ perceived professional benefits (NPPB). Perceived organizational support (POS) is regarded as being central in understanding job-related attitudes, and it is important to enhance POS for nurses to maintain their current employment. NPPB can further reduce nurses’ job burnout and turn-over intention. Many studies have explored the relationships among general self-efficacy, POS, nursing practice environment (NPE) and NPPB. However, a moderating effect of NPE has not been fully explored in nurses, especially among paediatric nurses.

Methods

A descriptive cross-sectional study was conducted from July to October 2018 with 300 paediatric nurses from 3 Class A tertiary hospitals in Jilin Province. The respondents completed the General Self-Efficacy Scale, Perceived Organizational Support Scale, Practice Environment Scale and Nurses’ Perceived Professional Benefits Scale. The data were analyzed using path analysis and SPSS (version 23.0, IBM).

Results

General self-efficacy and POS were significantly positively associated with NPPB, which showed that the model had a good fit to the data. NPE was found to play a partial mediating role between POS and NPPB and also had a complete mediating role between general self-efficacy and NPPB.

Conclusions

The results suggest that general self-efficacy indirectly influences NPPB, and POS directly and indirectly influences NPPB by NPE. Effective measures should be taken to improve nurses’ practice environment in hospitals to raise nurses’ enthusiasm and confidence in their work.
Patients’ satisfaction with clinical Laboratory Services in Public Hospitals in Ethiopia
Authors: Hailu Hiwot Amare , Desale Adinew , Yalew Anteneh , Asrat Habtamu , Kebede Sisay , Dejene Daniel , Abebe Hiwot , Gashu Andargachew , Yenealem Dereje , Moges Birhan , Yemanebrhane Nebiyou , Melese Daniel , Gurmessa Ashebir , Mohammed Awad , Getu Zekaryas , Ayana Gonfa , Kebede Adisu , Abate Ebba
Published: January 2020

Background

Knowing customers’ level of satisfaction is relevant to improve and provide quality health care services. In the clinical laboratory, monitoring customers’ satisfaction is an important indicator of the quality management system and required by international laboratory standards. However, in Ethiopia, there has not been baseline data about the satisfaction level of patients’ with laboratory services at the national level. The aim of this national level survey was to assess patients’ satisfaction level with laboratory services at public hospitals in Ethiopia.

Methods

A national survey was conducted using an institutional based cross-sectional study design was employed from 01 to 30 November 2017. A total of 2399 patients were selected randomly from 60 public hospitals. Data was collected using structured questionnaire, entered in Epi Info and analyzed with SPSS software. Multiple logistic regression model was fitted to identify predictors of patients’ satisfaction with laboratory services. Ap-value of less than 0.05 was taken as statistically significant.

Result

Overall, 78.6% of the patients were satisfied with the clinical laboratory services. Patients were dissatisfied with cleanness of latrine (47%), long waiting time (30%), clear and understandable advisory service during specimen collection (26%), adequacy of waiting area (25%), easy accessibility of laboratory (19%) and latrine location (20%), availability of requested service (18%), unfair payment of service (17%) and missing of result (12%). The educational status (P = 0.032), and distance (P = 0.000) were significantly associated with client overall satisfaction level.

Conclusion

Most laboratory patients’ were satisfied with the service provided by public hospital laboratories in public hospitals in Ethiopia. However, patients’ were dissatisfied with the accessibility of sites, adequacy of waiting area, cleanness of latrine, long TAT, communication, missing of results, availability of requested service and cost of service. Therefore, responsible bodies in each level should act on the identified gaps and improve the need of patients in each hospital laboratory. In addition, all hospital laboratories should conduct a satisfaction survey and meet the needs of laboratory patients.
Favorable outcome of pheochromocytoma in a dog with atypical Cushing’s syndrome and diabetes mellitus following medical treatment: a case report
Authors: Lee Ga-Won , Yoo Cho-Rong , Lee Dan , Park Hee-Myung
Published: January 2020

Background

Pheochromocytoma (PCC) has poor prognosis and adrenalectomy is hard to be performed, in case of caudal vena cava invasion. The long-term administration of phenoxybenzamine in PCC has not been reported in dogs.

Case presentation

A 14-year-old castrated male Poodle dog presented with an abdominal mass. On physical examination, hypertension, increased lens opacity, calcinosis cutis, generalized alopecia, and systolic murmur were observed. Serum chemistry and urinalysis profiles revealed hyperglycemia, hypercholesterolemia, elevated liver enzymes, and glucosuria. Abdominal ultrasonography showed a right adrenal mass with invasion of the caudal vena cava, which was cytologically diagnosed as suspected PCC. An adrenal mass (width × height × length, 28 × 26 × 48 mm3) was found on computed tomography and diagnosed as PCC with increased plasma metanephrines and normetanephrines. An adrenocorticotropin hormone stimulation test showed elevated adrenal hormones (androstenedione, estradiol, progesterone, and 17-OH progesterone) with normal cortisol, compatible with atypical Cushing’s syndrome. The dog was managed with trilostane, phenoxybenzamine, and insulin therapy. Glycosylated hemoglobin and fructosamine levels gradually decreased, and hypertension resolved. In the 10-month follow-up period, the liver enzymes levels gradually decreased, and the clinical signs of the dog were well-controlled without deterioration.

Conclusions

This case report describes long-term medical management without adrenalectomy of PCC complicated with atypical Cushing’s syndrome and DM.
RETRACTED ARTICLE: Circular RNA circ_0003204 inhibits proliferation, migration and tube formation of endothelial cell in atherosclerosis via miR-370-3p/TGFβR2/phosph-SMAD3 axis
Authors: Zhang Shanchao , Song Guixiang , Yuan Jing , Qiao Shan , Xu Shan , Si Zhihua , Yang Yang , Xu Xuxu , Wang Aihua
Published: January 2020

Background

Circular RNAs (circRNAs) represent a class of non-coding RNAs (ncRNAs) which are widely expressed in mammals and tissue-specific, of which some could act as critical regulators in the atherogenesis of cerebrovascular disease. However, the underlying mechanisms by which circRNA regulates the ectopic phenotype of endothelial cells (ECs) in atherosclerosis remain largely elusive.

Methods

CCK-8, transwell, wound healing and Matrigel assays were used to assess cell viability, migration and tube formation. QRT-qPCR and Immunoblotting were used to examine targeted gene expression in different groups. The binding sites of miR-370-3p (miR-370) with TGFβR2 or hsa_circ_0003204 (circ_0003204) were predicted using a series of bioinformatic tools, and validated using dual luciferase assay and RNA immunoprecipitation (RIP) assay. The localization of circ_0003204 and miR-370 in ECs were investigated by fluorescence in situ hybridization (FISH). Gene function and pathways were enriched through Metascape and gene set enrichment analysis (GSEA). The association of circ_0003204 and miR-370 in extracellular vesicles (EVs) with clinical characteristics of patients were investigated using multiple statistical analysis.

Results

Circ_0003204, mainly located in the cytoplasm of human aorta endothelial cells (HAECs), was upregulated in the ox-LDL-induced HAECs. Functionally, the ectopic expression of circ_0003204 inhibited proliferation, migration and tube formation of HAECs exposed to ox-LDL. Mechanically, circ_0003204 could promote protein expression of TGFβR2 and its downstream phosph-SMAD3 through sponging miR-370, and miR-370 targeted the 3′ untranslated region (UTR) of TGFβR2. Furthermore, the expression of circ_0003204 in plasma EVs was upregulated in the patients with cerebral atherosclerosis, and represented a potential biomarker for diangnosis and prognosis of cerebrovascular atherogenesis.

Conclusions

Circ_0003204 could act as a novel stimulator for ectopic endothelial inactivation in atherosclerosis and a potential biomarker for cerebral atherosclerosis.
Bile and urine peptide marker profiles: access keys to molecular pathways and biological processes in cholangiocarcinoma
Authors: Voigtländer Torsten , Metzger Jochen , Husi Holger , Kirstein Martha M. , Pejchinovski Martin , Latosinska Agnieszka , Frantzi Maria , Mullen William , Book Thorsten , Mischak Harald , Manns Michael P.
Published: January 2020

Background

Detection of cholangiocarcinoma (CCA) remains a diagnostic challenge. We established diagnostic peptide biomarkers in bile and urine based on capillary electrophoresis coupled to mass spectrometry (CE-MS) to detect both local and systemic changes during CCA progression. In a prospective cohort study we recently demonstrated that combined bile and urine proteome analysis could further improve diagnostic accuracy of CCA diagnosis in patients with unknown biliary strictures. As a continuation of these investigations, the aim of the present study was to investigate the pathophysiological mechanisms behind the molecular determinants reflected by bile and urine peptide biomarkers.

Methods

Protease mapping and gene ontology cluster analysis were performed for the previously defined CE-MS based biomarkers in bile and urine. For that purpose, bile and urine peptide profiles (from samples both collected at the date of endoscopy) were investigated from a representative cohort of patients with benign (n = 76) or CCA-associated (n = 52) biliary strictures (verified during clinical follow-up). This was supplemented with a literature search for the association of the individual biomarkers included in the proteomic patterns with CCA or cancer progression.

Results

For most of the peptide markers, association to CCA has been described in literature. Protease mapping revealed ADAMTS4 activity in cleavage of both bile and urine CCA peptide biomarkers. Furthermore, increased chymase activity in bile points to mast cell activation at the tumor site. Gene ontology cluster analysis indicates cellular response to chemical stimuli and stress response as local and extracellular matrix reorganization by tissue destruction and repair as systemic events. The analysis further supports that the mapped proteases are drivers of local and systemic events.

Conclusions

The study supports connection of the CCA-associated peptide biomarkers to the molecular pathophysiology and indicates an involvement in epithelial-to-mesenchymal transition, generation of cancer-associated fibroblasts and activation of residual immune cells. Proteases, extracellular matrix components, inflammatory cytokines, proangiogenic, growth and vasoactive factors released from the tumor microenvironment are drivers of systemic early events during CCA progression.
Blood eosinophil count, a marker of inhaled corticosteroid effectiveness in preventing COPD exacerbations in post-hoc RCT and observational studies: systematic review and meta-analysis
Authors: Harries Timothy H. , Rowland Victoria , Corrigan Christopher J. , Marshall Iain J. , McDonnell Lucy , Prasad Vibhore , Schofield Peter , Armstrong David , White Patrick
Published: January 2020

Background

Blood eosinophil count has been proposed as a predictor of response to inhaled corticosteroid (ICS) in the prevention of acute exacerbations of COPD. An optimal threshold of blood eosinophil count for prescribing ICS has not been agreed. Doubt has been cast on the role by observational studies. The role of inhaled corticosteroids in this relationship, independent of long-acting bronchodilators, has not been examined.

Methods

We conducted a systematic review of post-hoc analyses of randomised controlled trials (RCTs) and observational studies examining three blood eosinophil thresholds and the independent role of ICS. Included studies were categorised by the form (relative or absolute count) and cut point of eosinophil threshold used. Thresholds assessed were relative eosinophil count of 2%, and absolute counts of 150 cells/μL and 300 cells/μL. Three meta-analyses of the effect of ICS use in post-hoc analyses of RCTs based on these counts were carried out. Initial analysis included all studies of ICS vs. any non-ICS regimen. Further analysis examined the effect of ICS, independent of the effect of long-acting bronchodilators.

Results

Sixteen studies examined the association between blood eosinophil count and response of exacerbation risk to ICS, in COPD patients. Eleven studies (25,881 patients) were post-hoc analyses of RCTs. Five studies (109,704 patients) were retrospective observational studies. The independent effect of ICS on the reduction of exacerbation risk was 20% at ≥2% blood eosinophil threshold (RR, 0.80; 95% CI, 0.74–0.85), 35% at ≥150 cells/μL blood eosinophil threshold (RR, 0.65; 0.52–0.79), and 39% at ≥300 cells/μL blood eosinophil threshold (RR, 0.61; 0.44–0.78). No association was found in four out of five observational studies.

Conclusion

This is the first systematic review to assess, in post-hoc analyses of RCTs, the independent effect of ICS in reducing the risk of COPD exacerbation across a range of blood eosinophil thresholds. Association between ICS prescription and reduced exacerbation risk at these thresholds was confirmed. The lack of association found in the observational studies questions the relevance of these observations to a “real world” COPD population. To clarify the clinical utility of this biomarker, the association should be tested in prospective effectiveness studies.
Patient-derived xenografts of different grade gliomas retain the heterogeneous histological and genetic features of human gliomas
Authors: Zeng Wenxin , Tang Zhaohua , Li Yongguo , Yin Guangnian , Liu Zili , Gao Jie , Chen Yan , Chen Feilan
Published: January 2020

Background

Gliomas account for the major part of primary brain tumors. Based on their histology and molecular alternations, adult gliomas have been classified into four grades, each with distinct biology and outcome. Previous studies have focused on cell-line-based models and patient-derived xenografts (PDXs) from patient-derived glioma cultures for grade IV glioblastoma. However, the PDX of lower grade diffuse gliomas, particularly those harboring the endogenous IDH mutation, are scarce due to the difficulty growing glioma cells in vitro and in vivo. The purpose of this study was to develop a panel of patient-derived subcutaneous xenografts of different grade gliomas that represented the heterogeneous histopathologic and genetic features of human gliomas.

Methods

Tumor pieces from surgical specimens were subcutaneously implanted into flanks of NOD-Prkdcscid ll2rgnull mice. Then, we analyzed the association between the success rate of implantation with clinical parameters using the Chi square test and resemblance to the patient’s original tumor using immunohistochemistry, immunofluorescence, short tandem repeat analysis, quantitative real-time polymerase chain reaction, and whole-exome sequencing.

Results

A total of 11 subcutaneous xenografts were successfully established from 16 surgical specimens. An increased success rate of implantation in gliomas with wild type isocitrate dehydrogenase (IDH) and high Ki67 expression was observed compared to gliomas with mutant IDH and low Ki67 expression. Recurrent and distant aggressive xenografts were present near the primary implanted tumor fragments from WHO grades II to IV. The xenografts histologically represented the corresponding patient tumor and reconstituted the heterogeneity of different grade gliomas. However, increased Ki67 expression was found in propagated xenografts. Endothelial cells from mice in patient-derived xenografts over several generations replaced the corresponding human tumor blood vessels. Short tandem repeat and whole-exome sequencing analyses indicated that the glioma PDX tumors maintained their genomic features during engraftments over several generations.

Conclusions

The panel of patient-derived glioma xenografts in this study reproduced the diverse heterogeneity of different grade gliomas, thereby allowing the study of the growth characteristics of various glioma types and the identification of tumor-specific molecular markers, which has applications in drug discovery and patient-tailored therapy.
TSPAN9 suppresses the chemosensitivity of gastric cancer to 5-fluorouracil by promoting autophagy
Authors: Qi Yaoyue , Qi Weiwei , Liu Shihai , Sun Libin , Ding Aiping , Yu Guohong , Li Hui , Wang Yixuan , Qiu Wensheng , Lv Jing
Published: January 2020

Background

The issue of drug resistance in gastric cancer has attracted global attention. TSPAN9, a 4-transmembrane protein that plays an important role in tumor progression and signal transduction, has been found to be closely related to tumor invasion, metastasis, and autophagy.

Methods

Immunoblotting was used to evaluate TSPAN9 expression in parental and drug-resistant gastric cancer cells. Functional assays, such as the CCK-8 assay, were used to detect the proliferation of gastric cancer cells and the response of TSPAN9 to 5-fluorouracil (5-FU). Western blotting was used to analyze the expression of constituents of the PI3K/AKT/mTOR-mediated autophagy pathway induced by TSPAN9. Coimmunoprecipitation was performed to assess the specific mechanism by which TSPAN9 affects the PI3K pathway.

Results

We demonstrated that TSPAN9 is overexpressed in 5-FU-resistant cells compared to parental cells. 5-FU-mediated inhibition of cell proliferation can be significantly restored by increasing TSPAN9 expression, and inhibiting this expression in drug-resistant cells can restore the sensitivity of the cells to 5-FU. In addition, TSPAN9 also significantly promoted autophagy in gastric cancer cells in vitro. Further studies indicated that TSPAN9 downregulates the expression of PI3K and proteins associated with PI3K-mediated autophagy. In addition, TSPAN9 interacts with PI3K and inhibits its catalytic activity.

Conclusion

The current study reveals the important role of TSPAN9 in drug resistance to 5-FU in gastric cancer. It also provides a new target to clinically address drug-resistant gastric cancer and will contribute to the treatment strategy of this disease.
The use of ultrasensitive quantitative-PCR to assess the impact of primaquine on asymptomatic relapse of Plasmodium vivax infections: a randomized, controlled trial in Lao PDR
Authors: Phommasone Koukeo , van Leth Frank , Imwong Mallika , Henriques Gisela , Pongvongsa Tiengkham , Adhikari Bipin , Peto Thomas J. , Promnarate Cholrawee , Dhorda Mehul , Sirithiranont Pasathorn , Mukaka Mavuto , Peerawaranun Pimnara , Day Nicholas P. J. , Cobelens Frank , Dondorp Arjen M. , Newton Paul N. , White Nicholas J. , von Seidlein Lorenz , Mayxay Mayfong
Published: January 2020

Background

Trials to assess the efficacy of the radical cure of Plasmodium vivax malaria with 8-aminoquinolines require that most post-treatment relapses are identified, but there is no consensus on the optimal duration of follow-up in either symptomatic or asymptomatic vivax malaria. The efficacy of a 14-day course of primaquine on the cumulative incidence of recurrent asymptomatic P. vivax infections detected by ultrasensitive quantitative PCR (uPCR) as a primary endpoint was assessed.

Methods

A randomized, placebo-controlled, single-blind trial was conducted in four villages of the Lao PDR during 2016–2018 nested in a larger project evaluating mass drug administrations (MDA) with dihydroartemisinin-piperaquine (DP) and a single low-dose primaquine to clear Plasmodium falciparum infections. In the nested sub-study, eligible participants with mono- or mixed P. vivax infections detected by uPCR were randomized to receive either 14 days of primaquine (0.5 mg/kg/day) or placebo during the last round of MDA (round 3) through directly observed therapy. Participants were checked monthly for 12 months for parasitaemia using uPCR. The primary outcome was cumulative incidence of participants with at least one recurrent episode of P. vivax infection.

Results

20 G6PD-normal participants were randomized in each arm. 5 (29%) of 20 participants in the placebo arm experienced asymptomatic, recurrent P. vivax infections, resulting in a cumulative incidence at month 12 of 29%. None of the 20 participants in the intervention arm had recurrent infections (p = 0.047 Fisher’s exact test). Participants with recurrent P. vivax infections were found to be parasitaemic for between one and five sequential monthly tests. The median time to recurrence of P. vivax parasitaemia was 178 days (range 62–243 days).

Conclusions

A 14-day course of primaquine in addition to a DP-MDA was safe, well-tolerated, and prevented recurrent asymptomatic P. vivax infections. Long follow-up for up to 12 months is required to capture all recurrences following the treatment of asymptomatic vivax infection. To eliminate all malarias in settings where P. vivax is endemic, a full-course of an 8-aminoquinolines should be added to MDA to eliminate all malarias.

Trial registration This study was registered with ClinicalTrials.gov under NCT02802813 on 16th June 2016. https://clinicaltrials.gov/ct2/show/NCT02802813
Relationship between disease activity status or clinical response and patient-reported outcomes in patients with non-radiographic axial spondyloarthritis: 104-week results from the randomized controlled EMBARK study
Authors: Dougados Maxime , van der Heijde Désirée , Tsai Wen-Chan , Saaibi Diego , Marshall Lisa , Jones Heather , Pedersen Ron , Vlahos Bonnie , Tarallo Miriam
Published: January 2020

Background

We assessed the external validity of composite indices Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Assessment in SpondyloArthritis international Society (ASAS) 40 response (ASAS40) by evaluating the correlations between the changes in some patient reported outcomes (PROs) for patients with non-radiographic axial spondyloarthritis (nr-axSpA) and the changes in the scores of the composite indices.

Methods

This was a post-hoc analysis of data from the EMBARK study in patients with nr-axSpA treated with etanercept. PROs were grouped according to ASDAS status (inactive [< 1.3], low [≥ 1.3 to < 2.1], high [≥ 2.1 to ≤3.5], and very high [> 3.5]), patient achievement of > 50% improvement in BASDAI (BASDAI50 responders), and > 40% improvement in ASAS (ASAS40 responders) at 104 weeks. Analyses were conducted on observed cases available at Week 104. Changes in PROs from Baseline to Week 104 were assessed using analysis of covariance with adjustment for baseline with linear contrast.

Results

Higher ASDAS disease activity at 104 weeks was associated with lower long-term improvement from baseline in PROs (e.g., total back pain [visual analog scale, cm (95% confidence interval): − 4.58 (− 4.95, − 4.21), − 3.86 (− 4.28, − 3.43), − 2.15 (− 2.68, − 1.61), and 1.30 (− 0.51, 3.12) for inactive, low, high, and very high ASDAS disease activity, respectively; Multidimensional Fatigue Inventory (MFI) general fatigue: − 4.77 (− 5.70, − 3.84), − 2.96 (− 4.04, − 1.87), − 1.00 (− 2.32, 0.31), and 2.14 (− 2.10, 6.38); all p < 0.001)]. BASDAI50 non-responders had less improvement in PROs from Baseline to Week 104 vs. responders (e.g., total back pain: − 1.61 (− 2.05, − 1.18) vs. –4.43 (− 4.69, − 4.18); MFI general fatigue: − 0.01 (− 1.12, 1.09) vs. –4.30 (− 4.98, − 3.62); all p < 0.001). ASAS40 non-responders also had less improvement in PROs from Baseline to Week 104 vs. responders (e.g., total back pain: − 1.91 (− 2.30, − 1.52) vs. –4.75 (− 5.05, − 4.46); MFI general fatigue: − 0.63 (− 1.56, 0.30) vs. –4.64 (− 5.37, − 3.91); all p < 0.001).

Conclusion

Composite indices are valid for monitoring treatment response and adequately reflect treatment-related changes experienced by patients with nr-axSpA.

Trial registration

ClinicalTrials.gov identifier: NCT01258738. Registered 9 December 2010.
Intervention Scalability Assessment Tool: A decision support tool for health policy makers and implementers
Authors: Milat Andrew , Lee Karen , Conte Kathleen , Grunseit Anne , Wolfenden Luke , van Nassau Femke , Orr Neil , Sreeram Padmaja , Bauman Adrian
Published: January 2020

Background

Promising health interventions tested in pilot studies will only achieve population-wide impact if they are implemented at scale across communities and health systems. Scaling up effective health interventions is vital as not doing so denies the community the most effective services and programmes. However, there remains a paucity of practical tools to assess the suitability of health interventions for scale-up. The Intervention Scalability Assessment Tool (ISAT) was developed to support policy-makers and practitioners to make systematic assessments of the suitability of health interventions for scale-up.

Methods

The ISAT was developed over three stages; the first stage involved a literature review to identify similar tools and frameworks that could be used to guide scalability assessments, and expert input to develop draft ISAT content. In the second stage, the draft ISAT tool was tested with end users. The third stage involved revising and re-testing the ISAT with end users to further refine the language and structure of the final ISAT.

Results

A variety of information and sources of evidence should be used to complete the ISAT. The ISAT consists of three parts. Part A: ‘setting the scene’ requires consideration of the context in which the intervention is being considered for scale-up and consists of five domains, as follows: (1) the problem; (2) the intervention; (3) strategic/political context; (4) evidence of effectiveness; and (5) intervention costs and benefits. Part B asks users to assess the potential implementation and scale-up requirements within five domains, namely (1) fidelity and adaptation; (2) reach and acceptability; (3) delivery setting and workforce; (4) implementation infrastructure; and (5) sustainability. Part C generates a graphical representation of the strengths and weaknesses of the readiness of the proposed intervention for scale-up. Users are also prompted for a recommendation as to whether the intervention (1) is recommended for scale-up, (2) is promising but needs further information before scaling up, or (3) does not yet merit scale-up.

Conclusion

The ISAT fills an important gap in applied scalability assessment and can become a critical decision support tool for policy-makers and practitioners when selecting health interventions for scale-up. Although the ISAT is designed to be a health policy and practitioner tool, it can also be used by researchers in the design of research to fill important evidence gaps.