bluuebunny/crossref_metadata_2025 huggingface dataset:
EZH2 inhibitors reverse resistance to gefitinib in primary EGFR wild-type lung cancer cells
Authors: Gong Hao , Li Yongwen , Yuan Yin , Li Weiting , Zhang Hongbing , Zhang Zihe , Shi Ruifeng , Liu Minghui , Liu Chao , Chen Chen , Liu Hongyu , Chen Jun
Published: December 2020

Background

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. In traditional anti-cancer therapy, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) have been proven to be beneficial for patients with EGFR mutations. However, patients with EGFR wild-type NSCLC were usually not respond to EGFR-TKIs. Enhancer of zeste homolog 2 (EZH2) is a key molecular in the PRC2 complex and plays an important role in epigenetic regulation and is overexpressed in variant tumors. EZH2 inhibitors have been reported to sensitize variant tumor cells to anticancer drugs. This study aimed to investigate whether the EZH2 inhibitors, GSK343 and DZNep when combined with gefitinib can reverse EGFR-TKIs resistance in EGFR wild-type NSCLC cells.

Methods

The RNA-sequencing data of patients with NSCLC [502 patients with lung squamous cell carcinoma, including 49 paracancerous lung tissues and 513 patients with lung adenocarcinoma (LUAD), including 59 paracancerous lung tissues] from the Cancer Genome Atlas (TCGA), were analyzed for EZH2 expression. EZH2 expression was verified in 40 NSCLC tissue cancer samples and their corresponding paracancerous tissues from our institute (TJMUGH) via RT-PCR. A549 and H1299 cells treated with siRNA or EZH2 inhibitors were subjected to cell viability and apoptosis analyses as well to EGFR pathway proteins expression analyses via western blotting.

Results

EZH2 was upregulated in human NSCLC tissues and correlated with poor prognosis in patients with LUAD based on data from both TCGA and TJMUGH. Both GSK343 and DZNep sensitized EGFR wild-type LUAD cells (A549 and H1299) to gefitinib and suppressed cell viability and proliferation in vitro by downregulating the phosphorylation of EGFR and AKT and by inducing cell apoptosis. Co-administration of EZH2 inhibitors (GSK343 or DZNep) with gefitinib exerted a stronger inhibitory effect on tumor activity, cell proliferation and cell migration than single drug administration in vitro and in vivo.

Conclusions

These data suggest that the combination of EZH2 inhibitors with EGFR-TKIs may be an effective method for treating NSCLC-patients with EGFR-wild type, who do not want to undergo traditional treatment with chemotherapy.
A single-arm, phase 2 study of adjuvant chemotherapy with oral tegafur-uracil for pathologically lymphovascular invasion positive stage IA non-small cell lung cancer: LOGIK0602 study
Authors: Tsuchiya Tomoshi , Kamohara Ryotaro , Muraoka Masashi , Nagayasu Takeshi , Saeki Sho , Takenoyama Mitsuhiro , Suzuki Makoto , Inada Kazuo , Tokunaga Shoji , Hayashi Tomayoshi , Urabe Shogo , Koga Takaomi , Akamine Shinji , Sugio Kenji
Published: December 2020

Background

Lymphovascular invasion (LVI), which includes vascular or lymphatic invasions, is a representative prognostic factor even in patients with resected stage IA non-small cell lung cancer (NSCLC). Because tegafur-uracil is effective on cancers with LVI, we conducted a multi-center single-arm phase II study to estimate the efficacy of adjuvant tegafur-uracil in patients with LVI-positive stage IA NSCLC.

Methods

Patients with completely resected LVI-positive stage IA NSCLC were registered. LVI was diagnosed by consensus of two of three pathologists. Adjuvant chemotherapy consisted of 2 years of oral tegafur-uracil at 250 mg/m2/day. Fifty-five patients from 7 institutions were enrolled from June 2007 to September 2012.

Results

Among the 52 eligible patients, 36 (69.2%) completed the treatment course. There were 39 male and 13 female patients. The observation period was calculated as 562 to 3107 days using the reverse Kaplan-Meier method. The 5-year overall and relapse free survival rates were 94.2 and 88.5% respectively, which were significantly better than that of any other studies conducted on patients with LVI-positive stage IA NSCLC. Notably, the overall survival rate was 15% better than that of our prior retrospective study. The retrospective analysis of stage IA NSCLC patients who had received an operation in the same period revealed that the 5-year overall survival rate of the LVI positive group was 73.6% when adjuvant chemotherapy was not applied. Among 55 safety analysis sets, 4 cases of grade 3 hepatic function disorder (9.1%) and 5 cases of grade 2 anorexia (10.9%) were most frequently observed. No grade 4 adverse effects were encountered.

Conclusion

A 2-year course of oral tegafur-uracil administration is feasible and might have a significant benefit in the adjuvant treatment of LVI-positive stage IA NSCLC.

Trial registration

UMIN identifier: UMIN000005921; Date of enrolment of the first participant to the trial: 19 June 2007; Date of registration: 5 July 2011 (retrospectively registered).
Radotinib enhances cytarabine (Ara-C)-induced acute myeloid leukemia cell death
Authors: Heo Sook-Kyoung , Noh Eui-Kyu , Yu Ho-Min , Kim Do Kyoung , Seo Hye Jin , Lee Yoo Jin , Cheon Jaekyung , Koh Su Jin , Min Young Joo , Choi Yunsuk , Jo Jae-Cheol
Published: December 2020

Background

Acute myeloid leukemia (AML) is a heterogeneous disease that frequently relapses after standard chemotherapy. Therefore, there is a need for the development of novel chemotherapeutic agents that could treat AML effectively. Radotinib, an oral BCR-ABL tyrosine kinase inhibitor, was developed as a drug for the treatment of chronic myeloid leukemia. Previously, we reported that radotinib exerts increased cytotoxic effects towards AML cells. However, little is known about the effects of combining radotinib with Ara-C, a conventional chemotherapeutic agent for AML, with respect to cell death in AML cells. Therefore, we investigated combination effects of radotinib and Ara-C on AML in this study.

Methods

Synergistic anti-cancer effects of radotinib and Ara-C in AML cells including HL60, HEL92.1.7, THP-1 and bone marrow cells from AML patients have been examined. Diverse cell biological assays such as cell viability assay, Annexin V-positive cells, caspase-3 activity, cell cycle distribution, and related signaling pathway have been performed.

Results

The combination of radotinib and Ara-C was found to induce AML cell apoptosis, which involved the mitochondrial pathway. In brief, combined radotinib and Ara-C significantly induced Annexin V-positive cells, cytosolic cytochrome C, and the pro-apoptotic protein Bax in AML cells including HL60, HEL92.1.7, and THP-1. In addition, mitochondrial membrane potential and Bcl-xl protein were markedly decreased by radotinib and Ara-C. Moreover, this combination induced caspase-3 activity. Cleaved caspase-3, 7, and 9 levels were also increased by combined radotinib and Ara-C. Additionally, radotinib and Ara-C co-treatment induced G0/G1 arrest via the induction of CDKIs such as p21 and p27 and the inhibition of CDK2 and cyclin E. Thus, radotinib/Ara-C induces mitochondrial-dependent apoptosis and G0/G1 arrest via the regulation of the CDKI–CDK–cyclin cascade in AML cells. In addition, our results showed that combined treatment with radotinib and Ara-C inhibits AML cell growth, including tumor volumes and weights in vivo. Also, the combination of radotinib and Ara-C can sensitize cells to chemotherapeutic agents such as daunorubicin or idarubicin in AML cells.

Conclusions

Therefore, our results can be concluded that radotinib in combination with Ara-C possesses a strong anti-AML activity.
A case report of ultrasonographic findings in bilateral diffuse Uveal melanocytic proliferation
Authors: Guo Jingli , Tang Wenyi , Liu Wei , Zhou Min , Chang Qing , Jiang Chunhui , Xu Gezhi , Wang Wenji , Chen Qian
Published: December 2020

Background

To report undescribed characteristics of patients with bilateral diffuse uveal melanocytic proliferation (BDUMP) on ultrasound biomicroscopy (UBM) and high-frequency B-scan ultrasonography.

Case presentation

Two of four participants presented with worsening bilateral vision after previously diagnosed primary pulmonary or ovarian carcinoma. The other two patients were diagnosed with lung carcinoma after presentation with BDUMP. All patients had ciliary body nevi-like lesion in combination with iris or ciliary body cysts, and uveal thickening on UBM. Focally elevated choroidal nevi-like lesion and exudative retinal detachment with choroidal thickening were detected with B-scan ultrasonography.

Conclusions

Our case series demonstrates the uveal characteristics of patients with BDUMP based on high-frequency B-scan ultrasonography and UBM. Ultrasonographic findings are crucial in the diagnosis of BDUMP because it is occult in nature.
Barriers to monitoring and management of cardiovascular and metabolic health of patients prescribed antipsychotic drugs: a systematic review
Authors: Ali Ruba Azfr , Jalal Zahraa , Paudyal Vibhu
Published: December 2020

Background

The use of atypical antipsychotics which currently form the primary choice pharmacotherapy for several mental health conditions have been linked to cardiovascular and metabolic side effects. This systematic review aimed to investigate the barriers to monitoring and management of cardiovascular co-morbidities in patients prescribed antipsychotic medicines.

Methods

A protocol-led (CRD-42018106002) systematic literature review was conducted by searching Medline, Embase, and PsycINFO databases 2003 until October 2019. Cochrane, Centre for Review and Dissemination (CRD) and PRISMA guidelines were followed. Studies investigating barriers to monitoring and management of cardiovascular co-morbidities in patients prescribed antipsychotic medicines were included.

Results

A total of 23 records were included. Key barriers included a) health-care system-related factors such as lack of knowledge and expertise amongst care providers, available resources, confusion around remit and roles, fragmentation of care such as across general practitioners and psychiatrists, and time constraints and b) patient-related factors such as disability resulting from mental health conditions, knowledge and skills of the patients.

Conclusion

Barriers to monitoring and management of cardiovascular and metabolic health of patients taking antipsychotic medicines are multidimensional. Apart from educational interventions directed to both patients and health-care professionals, the results suggest a need for the improvement of wider system-related factors to improve physical health of patients prescribed antipsychotic medicines.

Clearer guidelines, clarity of remit and roles amongst service providers are necessary in addition to educational interventions directed at patients and health-care professionals in improving physical health monitoring, counselling and management of patients prescribed antipsychotic medicines.

Trial registration

A protocol was developed and registered with PROSPERO as per PRISMA-P guidelines (CRD 42018106002).
Potentially avoidable hospitalization for asthma in children and adolescents by migrant status: results from the Italian Network for Longitudinal Metropolitan Studies
Authors: Cacciani Laura , Canova Cristina , Barbieri Giulia , Dalla Zuanna Teresa , Marino Claudia , Pacelli Barbara , Caranci Nicola , Strippoli Elena , Zengarini Nicolás , Di Napoli Anteo , Agabiti Nera , Davoli Marina
Published: December 2020

Background

Global migration toward Europe is increasing. Providing health assistance to migrants is challenging because numerous barriers limit their accessibility to health services. Migrants may be at a greater risk of developing asthma and receiving lower quality healthcare assistance than non-migrants. We aim to investigate whether immigrants as children and adolescents have higher rates of potentially avoidable hospitalization (PAH) for asthma compared to Italians.

Methods

We performed a retrospective longitudinal study using six cohorts of 2–17-year-old residents in North and Central Italy from 01/01/2001 to 31/12/2014 (N = 1,256,826). We linked asthma hospital discharges to individuals using anonymized keys. We estimated cohort-specific age and calendar-year-adjusted asthma PAH rate ratios (HRRs) and 95% confidence intervals (95%CIs) among immigrants compared to Italians. We applied a two-stage random effect model to estimate asthma PAH meta-analytic rate ratios (MHRRs). We analyzed data by gender and geographical area of origin countries.

Results

Three thousand three hundred four and 471 discharges for asthma PAH occurred among Italians and immigrants, respectively. Compared to Italians, the asthma PAH cohort-specific rate was higher for immigrant males in Bologna (HRR:2.42; 95%CI:1.53–3.81) and Roma (1.22; 1.02–1.45), and for females in Torino (1.56; 1.10–2.20) and Roma (1.82; 1.50–2.20). Asthma PAH MHRRs were higher only among immigrant females (MHRRs:1.48; 95%CI:1.18–1.87). MHRRs by area of origin were 63 to 113% higher among immigrants, except for Central-Eastern Europeans (0.80; 0.65–0.98).

Conclusion

The asthma PAH meta-analytic rate was higher among female children and adolescent immigrants compared to Italians, with heterogeneity among cohorts showing higher cohort-specific PAH also among males, with some differences by origin country. Access to primary care for children and adolescent immigrants should be improved and immigrants should be considered at risk of severe asthma outcomes and consequently targeted by clinicians.
Knowledge, attitude, and practice regarding antibiotic use and resistance among medical students in Colombia: a cross-sectional descriptive study
Authors: Higuita-Gutiérrez Luis Felipe , Roncancio Villamil Gustavo Eduardo , Jiménez Quiceno Judy Natalia
Published: December 2020

Background

This study was designed to describe the knowledge, attitude, and practice regarding antibiotic use and resistance among medical students in Medellín, Colombia.

Methods

A cross-sectional study was conducted among medical students from three universities from September to December 2018. The sample size was calculated, the classrooms were visited, and those students who were willing to participate were invited to do so. The data collection instrument was constructed in three stages: i) the literature was systematically reviewed, ii) the items from the studies identified were extracted, and iii) item reduction was performed with exploratory factor analysis. Data were analyzed by calculating absolute and relative frequencies and means for quantitative variables. The indexes of knowledge, attitude, and practice were transformed to a scale from 0 (worst possible score) to 100. Comparisons were performed using the Mann-Whitney U test, Kruskall-Wallis H test, and linear regressions.

Results

Five hundred and thirty-two medical students were included with a response rate of 96%. Of the total participants, 49.1% reported having used antibiotics within the past year. Regarding knowledge, only 18.2% had heard of the term “antimicrobial stewardship” and 69.3% were aware that empiric antibiotic therapy contributes to antibiotic resistance. Regarding attitude, 11.6% considered that antibiotics should be discontinued as soon as symptoms disappear and 24.6% stated that it is better to prescribe broad-spectrum antibiotics to ensure that the patient is cured. Regarding practice, 28.5% recognized that resistance is a multifactorial problem, but they do not act on it because they consider that individual actions would have little impact. The adjusted linear regression showed that the variables associated with knowledge, attitude, and practice were socioeconomic status, training cycle, university, previous experience of research or education, the general perception of the training received, and antibiotic consumption.

Conclusion

Knowledge, attitude, and practice differ widely depending on the university, training cycle, and socioeconomic status, and a significant proportion of students consider that the standard of training received at the university on antibiotics and bacterial resistance is poor or mediocre. These findings show that there is a need to strengthen the medical students’ curriculum on antibiotics, mechanisms of antibiotic resistance, and the prudent use of antibiotics as an important strategy to combat problem-resistant public health, primarily in endemic countries.
The incorporation of HIV self-testing as an exclusive option among men who have sex with men in Spain: results of an online cross-sectional study
Authors: Hoyos J. , Guerras J. M. , Koutentakis K. , de la Fuente L. , Pulido J. , Sordo L. , Vallejo F. , Belza M. J.
Published: December 2020

Background

We assessed to what extent HIV self-testing would be incorporated by men who have sex with men (MSM) with previous testing history as their exclusive testing option and describe what actions they would take in the case of obtaining a reactive self-test.

Methods

We conducted an online survey among Spanish resident MSM recruited mainly in gay dating apps and analyze 6171 ever tested individuals. We used Poisson regression to estimate factors associated with the incorporation of self-testing as the exclusive testing option. Among those who would incorporate self-testing as their exclusive option, we described actions taken if obtaining a reactive self-test by number of tests in the past.

Results

Nearly half of the participants (48.3%) were > =35 years old, 84.6% were born in Spain, 57.9% had attained a university degree, 55.1% lived in a municipality of ≤500.000 and 86.4% self-identified as homosexual. For 37.2%, self-testing would become their exclusive testing option. The incorporation of self-testing as the exclusive option increased with age 25–34 (PR:1.1, 95%CI:1.0–1.3), 35–44 (PR:1.3, 95%CI:1.2–1.5), 45–49 (PR:1.5, 95%CI:1.3–1.7) and > 50 (PR:1.5, 95%CI:1.3–1.8) and in those who reported unprotected anal intercourse (PR:1.1, 95%CI:1.0–1.2) or having paid for sex (PR:1.2, 95%CI:1.0–1.3) in the last 12 months. It was also associated with having had < 10 HIV test in the past (2–9 tests (PR:1.3, 95%CI:1.1–1.4); 1 test (PR:1.5, 95%CI:1.3–1.7)), and having been tested ≥2 years (PR:1.4, 95%CI:1.3–1.5) or between 1 and 2 years ago (PR:1.1, 95%CI:1.0–1.2). Of participants who would use self-testing exclusively 76.6% would confirm their result in case of obtaining a reactive self-test and only 6.1% wouldn’t know how to react. Only one individual expressed that he would do nothing at all.

Conclusion

HIV self-testing could become the exclusive testing option for more than a third of our participants. It was chosen as the exclusive option especially by older, at risk and under-tested MSM. Self-testing strategies need to especially consider the linkage to care process. In this sense, only a small fraction would not know how to react and virtually nobody reported taking no action if obtaining a reactive result.
A randomized controlled TRIal of cognitive BEhavioral therapy for high Catastrophizing in patients undergoing lumbar fusion surgery: the TRIBECA study
Authors: Scarone P. , Smeets A. Y. J. M. , van Kuijk S. M. J. , van Santbrink H. , Peters M. , Koetsier E.
Published: December 2020

Background

Around 20% of patients undergoing spinal fusion surgery have persistent back or leg pain despite surgery. Pain catastrophizing is the strongest psychological predictor for chronic postsurgical pain. Psychological variables are modifiable and could be target for intervention. However, randomized controlled trials evaluating the effectiveness of psychological interventions to reduce chronic pain and disability after spinal fusion in a population of patients with high preoperative pain catastrophizing scores are missing. The aim of our study is to examine whether an intervention targeting pain catastrophizing mitigates the risk of chronic postsurgical pain and disability. Our primary hypothesis is that targeted perioperative cognitive behavioral therapy decreases the risk of chronic postsurgical pain and disability after spinal fusion surgery in high catastrophizing patients.

Methods

We will perform a two-center prospective, single-blind, randomized, controlled study comparing lumbar spinal fusion surgery outcome between 2 cohorts. Adult patients selected for lumbar spinal fusion with decompression surgery and a minimum score of 24 on the pain catastrophizing scale will be randomized with 1:1 allocation for either perioperative cognitive behavioral therapy (intervention group) or a perioperative education plus progressive exercise program (control group). Patients randomized to the intervention group will receive six individual sessions of cognitive behavioral therapy, two sessions before the operation and four after. Primary outcome is the Core Outcome Measures Index at 12 months. Secondary outcomes include pain, disability, depression and quality of life.

Discussion

This is the first trial that evaluates the effectiveness of cognitive behavioral therapy as a perioperative tool to improve pain and disability after spinal fusion surgery in comparison with an educational/exercise control intervention, in patients with high levels of pain catastrophizing. If perioperative cognitive behavioral therapy proves to be effective, this might have important clinical implications, reducing the incidence of chronic postsurgical pain and improving outcome after spinal fusion surgery.

Trial registration

Clinicaltrials (NCT03969602). Registered 31 May 2019,
No association between osteoporosis and AO classification of distal radius fractures: an observational study of 289 patients
Authors: Hjelle Anja M. , Gjertsen Jan-Erik , Apalset Ellen M. , Nilsen Roy M. , Lober Anja , Tell Grethe S. , Mielnik Pawel
Published: December 2020

Background

It is mechanically plausible that osteoporosis leads to more severe peripheral fractures, but studies investigating associations between BMD and radiographically verified complexity of distal radius fractures are scarce. This study aims to study the association between osteoporosis, as well as other risk factors for fracture, and the AO classification of distal radius fractures.

Methods

In this observational study, 289 consecutive patients aged ≥40 years with a distal radius fracture were included. Bone mineral density (BMD) of the hips and spine was measured by dual-energy x-ray absorptiometry (DXA), and comorbidities, medication, physical activity, smoking habits, body mass index (BMI), and history of previous fracture were registered. The distal radius fractures were classified according to the Müller AO system (AO) (type B and C regarded as most complex).

Results

Patients with osteoporosis (n = 130) did not have increased odds of a more complex distal radius fracture (type B + C, n = 192)) (n = vs type A (n = 92) (OR 1.1 [95% CI 0.5 to 2.3]) compared to those with osteopenia /normal BMD (n = 159). Patients with AO fracture types A or C had a higher prevalence of osteoporosis than patients with type B fracture.

Conclusions

Distal radius fracture patients with osteoporosis did not sustain more complex fractures than those with osteopenia/normal BMD according to the AO classification system. The AO classification of distal radius fracture cannot be used to decide which patients should be referred to DXA scan and considered for secondary fracture prevention.
Scleromyxedema in a 21 year old female patient with acute lymphoblastic leukemia: a case report
Authors: Rabee Hadi , Tayem Leeda , Gharbeyah Mohammad , Abugaber Dina
Published: December 2020

Background

Scleromyxedema is a rare, para-neoplastic, chronic, progressive condition of the Lichen myxedematosus (LM) family. The clinical picture consists of generalized confluent papular eruptions with possible systemic manifestations, which may be fatal as it still constitutes a therapeutic dilemma. Histologically, it is characterized by dermal mucin deposition, fibroblast proliferation with fibrosis, with monoclonal gammopathy in the absence of thyroid disease. Some atypical forms of the disease were reported in the literature, but none were reported in acute leukemia.

Case presentation

Herein, we report a case of a 21 years old female patient, known case of acute lymphoblastic leukemia (ALL), who developed numerous hyper-pigmented erythematous papules and plaques, mainly over her thighs, lower abdomen, and sub-mammary flexures. Histopathology of skin lesions confirmed the diagnosis of atypical scleromyxedema. Her symptoms significantly improved with the use of high dose intravenous immunoglobulin (IVIG).

Conclusions

Despite that scleromyxedema is associated with many hematologic disorders, it is very rarely associated with acute lymphoblastic leukemia, and a high index of suspicion is needed for diagnosis. IVIG remains a reasonable management of such a disabling disease.
Emergency and urgent dental visits among Medicaid enrollees from 2013 to 2017
Authors: Fiehn Rebekah , Okunev Ilya , Bayham Mary , Barefoot Steven , Tranby Eric P.
Published: December 2020

Background

Better understanding of the frequency of dental emergencies and the procedures performed during those emergency visits can help providers, insurers, and policymakers understand workforce and care provision needs.

Methods

Procedures performed at an emergency dental encounter and in the encounter following that encounter are assessed. Emergency dental encounters are those with a CDT code of D0140, D0160, or D0170. Data was analyzed from the IBM Watson Medicaid Marketscan data from 2013 to 2017, a nationally representative dental and medical claims database from 13 deidentified states in the United States.

Result

Consistently over time, about 10% of all dental encounters are due to a dental emergency. 28% of emergency dental encounters had no other procedure performed during those encounters. When other procedures were performed during the encounter, the majority were diagnostic in nature, primarily radiographs. Among patients who returned to the dentists following an emergency visit, 43% returned for more definitive dental treatment, most within 30 days.

Conclusions

The majority of dental emergency encounters do not result in definitive treatment, rather patients often return to the dentist at a later date for that treatment. Where possible, dental providers could utilize teledental services to triage patients to appropriate care.
An empirical application of “broken windows” and related theories in healthcare: examining disorder, patient safety, staff outcomes, and collective efficacy in hospitals
Authors: Ellis Louise A. , Churruca Kate , Tran Yvonne , Long Janet C. , Pomare Chiara , Braithwaite Jeffrey
Published: December 2020

Background

Broken windows theory (BWT) proposes that visible signs of crime, disorder and anti-social behaviour – however minor – lead to further levels of crime, disorder and anti-social behaviour. While we acknowledge divisive and controversial policy developments that were based on BWT, theories of neighbourhood disorder have recently been proposed to have utility in healthcare, emphasising the potential negative effects of disorder on staff and patients, as well as the potential role of collective efficacy in mediating its effects. The aim of this study was to empirically examine the relationship between disorder, collective efficacy and outcome measures in hospital settings. We additionally sought to develop and validate a survey instrument for assessing BWT in hospital settings.

Methods

Cross-sectional survey of clinical and non-clinical staff from four major hospitals in Australia. The survey included the Disorder and Collective Efficacy Survey (DaCEs) (developed for the present study) and outcome measures: job satisfaction, burnout, and patient safety. Construct validity was evaluated by confirmatory factor analysis (CFA) and reliability was assessed by internal consistency. Structural equation modelling (SEM) was used to test a hypothesised model between disorder and patient safety and staff outcomes.

Results

The present study found that both social and physical disorder were positively related to burnout, and negatively related to job satisfaction and patient safety. Further, we found support for the hypothesis that the relationship from social disorder to outcomes (burnout, job satisfaction, patient safety) was mediated by collective efficacy (social cohesion, willingness to intervene).

Conclusions

As one of the first studies to empirically test theories of neighbourhood disorder in healthcare, we found that a positive, orderly, productive culture is likely to lead to wellbeing for staff and the delivery of safer care for patients.
Interprofessional versus monoprofessional case-based learning in childhood cancer and the effect on healthcare professionals’ knowledge and attitudes: study protocol for a randomised trial
Authors: Topperzer Martha Krogh , Hoffmann Marianne , Larsen Hanne Bækgaard , Rosthøj Susanne , Nersting Jacob , Roug Louise Ingerslev , Pontoppidan Peter , Andrés-Jensen Liv , Lausen Birgitte , Schmiegelow Kjeld , Sørensen Jette Led
Published: December 2020

Background

Interprofessional education in childhood cancer is a multifaceted field involving multiple healthcare professionals with general and specialised knowledge and skills. Complex treatment, care and rehabilitation require continuous professional development and maintenance of healthcare professionals’ competencies in their field of expertise. However, limited knowledge exists in comparing interprofessional and monoprofessional education. Only a few randomised studies have evaluated the effectiveness and efficiency of interprofessional education.

The objective of this single-centre, investigator-initiated cluster randomised trial is to study the effect of interprofessional versus monoprofessional case-based learning on healthcare professionals’ knowledge of gastrointestinal side effects and attitudes towards team collaboration.

Methods

This study will randomise healthcare professionals to participate in either the experimental interprofessional group or the control monoprofessional group of case-based learning. The topic of the case-based intervention will be gastrointestinal side effects, one of six categories identified in a three-round Scandinavian Delphi study as relevant for interprofessional education in childhood cancer.

The primary outcome is the self-reported questionnaire Assessment of Interprofessional Team Collaboration Scale. Secondary outcomes are measured by the self-reported questionnaires Readiness for Interprofessional Learning Scale Questionnaire, Safety Attitudes Questionnaire, and knowledge will be evaluated using a multiple-choice quiz.

Participants will receive the self-reported questionnaires about 2 weeks before and 1 month after the intervention. On the day of the intervention, participants will answer a multiple-choice quiz before and after the case-based learning.

Linear mixed models will be used to compare differences between the two groups in mean scores postintervention, adjusting for preintervention scores.

Discussion

This study will provide insight into the differences between interprofessional and monoprofessional case-based learning and how it affects healthcare professionals’ knowledge of gastrointestinal side effects and attitudes towards team collaboration.

Trial registration

The intervention was registered at Clinical Trials.gov: NCT04204109 on December 102,019 and with the National Committee on Health Research Ethics: H-19087506 December 112,019 and the Danish Data Protection Agency: P-2019-637 October 152,019.
Going beyond the mean: economic benefits of myocardial infarction secondary prevention
Authors: von Wyl Viktor , Ulyte Agne , Wei Wenjia , Radovanovic Dragana , Grübner Oliver , Brüngger Beat , Bähler Caroline , Blozik Eva , Dressel Holger , Schwenkglenks Matthias
Published: December 2020

Background

Using the example of secondary prophylaxis of myocardial infarction (MI), our aim was to establish a framework for assessing cost consequences of compliance with clinical guidelines; thereby taking cost trajectories and cost distributions into account.

Methods

Swiss mandatory health insurance claims from 1840 persons with hospitalization for MI in 2014 were analysed. Included persons were predominantly male (74%), had a median age of 73 years, and 71% were pre-exposed to drugs for secondary prophylaxis, prior to index hospitalization. Guideline compliance was defined as being prescribed recommended 4-class drug prophylaxis including drugs from the following four classes: beta-blockers, statins, aspirin or P2Y12inhibitors, and angiotension-converting enzyme inhibitors or angiotensin receptor blockers. Health care expenditures (HCE) accrued over 1 year after index hospitalization were compared by compliance status using two-part regression, trajectory analysis, and counterfactual decomposition analysis.

Results

Only 32% of persons received recommended 4-class prophylaxis. Compliant persons had lower HCE (− 4865 Swiss Francs [95% confidence interval − 8027; − 1703]) and were more likely to belong to the most favorable HCE trajectory (with 6245 Swiss Francs average annual HCE and comprising 78% of all studied persons). Distributional analyses showed that compliance-associated HCE reductions were more pronounced among persons with HCE above the median.

Conclusions

Compliance with recommended prophylaxis was robustly associated with lower HCE and more favorable cost trajectories, but mainly among persons with high health care expenditures. The analysis framework is easily transferrable to other diseases and provides more comprehensive information on HCE consequences of non-compliance than mean-based regressions alone.
Layered double hydroxide nanoparticles as an adjuvant for inactivated foot-and-mouth disease vaccine in pigs
Authors: Wu Peng , Zhang Yunfeng , Yin Xinyue , He Yanhua , Zhang Qian , Chen Chuangfu
Published: December 2020

Background

Foot-and-mouth disease (FMD) is a highly transmissible disease that leads to vast economic losses in many countries. Prevention using inactivated vaccines is one effective measure used to control FMD. Unfortunately, inactivated FMD vaccines provide only short-term protection and require a cold-chain system. In recent years, many studies have shown that layered double metal hydroxides (LDHs) carrying antigens can be used to strongly induce immune responses. In this study, LDH nanoparticles (NPs) were prepared by hydrothermal synthesis. LDH particle size, electric potential, and morphology were measured and observed. The adsorption capacity of LDH NPs to FMDV was tested. The effects of LDH as an adjuvant on inactivated FMDV vaccines were further evaluated and compared with commercial FMDV Montanide ISA-206 in BALB/C female mice and Yorkshire pigs.

Results

LDH NPs were successfully prepared with a uniform particle size of ~ 87.21 nm, regular edges, a loose hexagonal shape and positive zeta charge of 32 mV. The maximum absorption concentration was 0.16–0.31 μg FMDV/μg LDH. In the mouse experiment, antibody levels in group LDH + FMDV were significantly higher compared to group saline + FMDV (P < 0.01) from days 42–98 and were significantly higher to group ISA-206 + FMDV on day 56 post-immunization (P < 0.05). After day 14 post-immunization, IFN-γ content was significantly increased (P < 0.05). In the pig experiment, antibody levels in both the ISA-206 + FMDV and LDH + FMDV were positive and were significantly higher compared with the PBS group on day 7 (P < 0.005). Antibody levels in 90% pigs were positive on day 56 in the LDH group. The neutralizing antibody levels in the LDH and ISA-206 groups were significantly higher from days 7–28 compared to the PBS control group (P < 0.05). Thus, LDH NPs were effective at inducing an immune response against FMDV.

Conclusions

LDHs with a loose hexagonal shape and a positive charge were prepared and evaluated as adjuvant for FMD vaccine. It was demonstrated that LDHs can induce immune responses in mice and pigs. In addition, the LDHs produced antibodies continuously which may indicate a slow-release effect. The study shows that LDHs may act as a potentially useful FMDV adjuvant.
Peritumoral plasmacytoid dendritic cells predict a poor prognosis for intrahepatic cholangiocarcinoma after curative resection
Authors: Hu Zhi-Qiang , Zhou Zheng-Jun , Luo Chu-Bin , Xin Hao-Yang , Li Jia , Yu Song-Yang , Zhou Shao-Lai
Published: December 2020

Background

Plasmacytoid dendritic cells (pDCs) are present in various primary and metastatic human neoplasms; however, their clinical significance in intrahepatic cholangiocarcinoma is not clear.

Methods

To evaluate pDCs’ distributions in and around tumors as well as their potential function and predictive value for prognosis in patients undergoing curative resection, we performed immunohistochemistry to examine the expression of pDC marker BDCA2, and CD3, CD4, CD8 and Foxp3 in intratumoral and peritumoral tissues from 359 patients with intrahepatic cholangiocarcinoma and compared with prognostic and clinicopathologic factors.

Results

Results showed that patients with high numbers of BDCA2+ pDCs in peritumoral tissues were more likely to have elevated levels of carbohydrate antigen 19-9 and gamma-glutamyl transferase, larger and more tumors, advanced tumor-node-metastasis staging, more vascular/bile duct invasion, and lymphatic metastasis in association with greater chance of recurrence and shorter overall survival. Peritumoral tissues with larger numbers of pDCs also showed increased Foxp3+ regulatory T cell infiltration, both of which were found to be independent factors for predicting time to recurrence and overall survival. By contrast, patient outcomes were not associated with the presence of intratumoral pDCs.

Conclusions

Peritumoral pDC infiltration may indicate an immune tolerogenic peritumor microenvironment and can be used to predict a poor prognosis for patients undergoing curative resection for intrahepatic cholangiocarcinoma.
Molecular surveillance of the Plasmodium vivax multidrug resistance 1 gene in Peru between 2006 and 2015
Authors: Villena Fredy E. , Maguiña Jorge L. , Santolalla Meddly L. , Pozo Edwar , Salas Carola J. , Ampuero Julia S. , Lescano Andres G. , Bishop Danett K. , Valdivia Hugo O.
Published: December 2020

Background

The high incidence of Plasmodium vivax infections associated with clinical severity and the emergence of chloroquine (CQ) resistance has posed a challenge to control efforts aimed at eliminating this disease. Despite conflicting evidence regarding the role of mutations of P. vivax multidrug resistance 1 gene (pvmdr1) in drug resistance, this gene can be a tool for molecular surveillance due to its variability and spatial patterns.

Methods

Blood samples were collected from studies conducted between 2006 and 2015 in the Northern and Southern Amazon Basin and the North Coast of Peru. Thick and thin blood smears were prepared for malaria diagnosis by microscopy and PCR was performed for detection of P. vivax monoinfections. The pvmdr1 gene was subsequently sequenced and the genetic data was used for haplotype and diversity analysis.

Results

A total of 550 positive P. vivax samples were sequenced; 445 from the Northern Amazon Basin, 48 from the Southern Amazon Basin and 57 from the North Coast. Eight non-synonymous mutations and three synonymous mutations were analysed in 4,395 bp of pvmdr1. Amino acid changes at positions 976F and 1076L were detected in the Northern Amazon Basin (12.8%) and the Southern Amazon Basin (4.2%) with fluctuations in the prevalence of both mutations in the Northern Amazon Basin during the course of the study that seemed to correspond with a malaria control programme implemented in the region. A total of 13 pvmdr1 haplotypes with non-synonymous mutations were estimated in Peru and an overall nucleotide diversity of π = 0.00054. The Northern Amazon Basin was the most diverse region (π = 0.00055) followed by the Southern Amazon and the North Coast (π = 0.00035 and π = 0.00014, respectively).

Conclusion

This study showed a high variability in the frequencies of the 976F and 1076L polymorphisms in the Northern Amazon Basin between 2006 and 2015. The low and heterogeneous diversity of pvmdr1 found in this study underscores the need for additional research that can elucidate the role of this gene on P. vivax drug resistance as well as in vitro and clinical data that can clarify the extend of CQ resistance in Peru.
Correction to: Long non-coding RNA HOTTIP enhances IL-6 expression to potentiate immune escape of ovarian cancer cells by upregulating the expression of PD-L1 in neutrophils
Authors: Shang Anquan , Wang Weiwei , Gu Chenzheng , Chen Chen , Zeng Bingjie , Yang Yibao , Ji Ping , Sun Junjun , Wu Junlu , Lu Wenying , Sun Zujun , Li Dong
Published: December 2020

An amendment to this paper has been published and can be accessed via the original article.
Integrin alpha-2 and beta-1 expression increases through multiple generations of the EDW01 patient-derived xenograft model of breast cancer—insight into their role in epithelial mesenchymal transition in vivo gained from an in vitro model system
Authors: Wafai Razan , Williams Elizabeth D. , de Souza Emma , Simpson Peter T. , McCart Reed Amy E. , Kutasovic Jamie R. , Waltham Mark , Snell Cameron E. , Blick Tony , Thompson Erik W. , Hugo Honor J.
Published: December 2020

Background

Breast cancers acquire aggressive capabilities via epithelial to mesenchymal transition (EMT), in which various integrins/integrin-linked kinase signalling are upregulated.

Methods

We investigated this in two patient-derived xenografts (PDXs) developed from breast-to-bone metastases, and its functional significance in a breast cancer cell line system. ED03 and EDW01 PDXs were grown subcutaneously in immunocompromised SCID mice through 11 passages and 7 passages, respectively. Tumour tissue was assessed using immunohistochemistry (IHC) for oestrogen receptor (ER)-alpha, E-cadherin, vimentin, Twist1, beta-catenin, P120-RasGAP, CD44, CD24 and Ki67, and RT-qPCR of EMT-related factors (CDH1,VIM,CD44,CD24), integrins beta 1 (ITGB1), alpha 2 (ITGA2) andILK. Integrin andILKexpression in epidermal growth factor (EGF)-induced EMT of the PMC42-ET breast cancer cell line was assessed by RT-qPCR and Western blotting, as were the effects of their transient knockdown via small interfering RNA +/− EGF. Cell migration, changes in cell morphology and adhesion of siRNA-transfected PMC42-ET cells to various extracellular matrix (ECM) substrates was assessed.

Results

The ED03 (ER+/PR−/HER2−/lobular) and EDW01 (ER+/PR−/HER2−/ductal) PDXs were both classified as molecular subtype luminal A. ED03 xenografts exhibited mutated E-cadherin with minimal expression, but remained vimentin-negative across all passages. In EDW01, the hypoxic indicator gene CAIX and Twist1 were co-ordinately upregulated at passages 4–5, corresponding with a decrease in E-cadherin. At passages 6–7,VIMwas upregulated along withITGB1andITGA2, consistent with an increasing EMT. The ED03 PDX displayed minimal change over passages in mice, for all genes examined.ILK,ITGB1andITGA2mRNAs were also increased in the EGF-induced EMT of PMC42-ET cells (in whichCDH1was downregulated) although siRNA against these targets revealed that this induction was not necessary for the observed EMT. However, their knockdown significantly reduced EMT-associated adhesion and Transwell migration.

Conclusion

Our data suggest that despite an increase inITGA2andITGB1gene expression in the EMT exhibited by EDW01 PDX over multiple generations, this pathway may not necessarily drive the EMT process.
Response to Brinkmann et al. “Re-assembly of 19th century smallpox vaccine genomes reveals the contemporaneous use of horsepox and horsepox-related viruses in the United States”
Authors: Duggan Ana T. , Holmes Edward C. , Poinar Hendrik N.
Published: December 2020

We thank Brinkmann and colleagues for their correspondence and their further investigation into these American Civil War Era vaccination strains. Here, we summarize the difficulties and caveats of work with ancient DNA.
Handwashing and disinfection precautions taken by U.S. adults to prevent coronavirus disease 2019, Spring 2020
Authors: Brown Laura G. , Hoover E. Rickamer , Barrett Catherine E. , Vanden Esschert Kayla L. , Collier Sarah A. , Garcia-Williams Amanda G.
Published: December 2020

Objectives

The objectives of this study were to assess self-reported hygiene precautions taken by U.S. adults during spring 2020 to prevent coronavirus disease 2019 (COVID-19) and to identify demographic characteristics associated with these hygiene precautions.

Results

We obtained data from Porter Novelli Public Services’s national survey, Spring ConsumerStyles, conducted March 19–April 9, 2020 among a nationally representative random sample of 6463 U.S. adults aged 18 years or older. We present data from the survey question: “What, if any, precautions are you taking to prevent coronavirus?”. Respondents replied yes or no to the following precautions: washing hands often with soap and water and disinfecting surfaces at home and work often. Most respondents reported taking hygiene-related precautions to prevent COVID-19; more respondents reported handwashing (93%) than disinfecting surfaces (74%). Men, younger respondents, those with lower income and education levels, and respondents in self-rated poor health had lower reported rates of both handwashing and disinfecting surfaces. Communications about hygiene precautions for COVID-19 prevention may need to target sub-populations with the greatest gaps in hygiene-related practices. Research identifying barriers to these practices and developing effective messaging could inform and improve these communications.
First pediatric electronic algorithm to stratify risk of penicillin allergy
Authors: Roberts Hannah , Soller Lianne , Ng Karen , Chan Edmond S. , Roberts Ashley , Kang Kristopher , Hildebrand Kyla J. , Wong Tiffany
Published: December 2020

Beta-lactam allergy is reported in 5–10% of children in North America, but up to 94–97% of patients are deemed not allergic after allergist assessment. The utility of standardized skin testing for penicillin allergy in the pediatric population has been recently questioned. Oral drug challenges when appropriate, are preferred over skin testing, and can definitively rule out immediate, IgE-mediated drug allergy. To our knowledge, this is the only pediatric study to assess the reliability of a penicillin allergy stratification tool using a paper and electronic clinical algorithm. By using an electronic algorithm, we identified 61 patients (of 95 deemed not allergic by gold standard allergist decision) as low risk for penicillin allergy, with no false negatives and without the need for allergist assessment or skin testing. In this study, we demonstrate that an electronic algorithm can be used by various pediatric clinicians when evaluating possible penicillin allergy to reliably identify low risk patients. We identified the electronic algorithm was superior to the paper version, capturing an even higher percentage of low risk patients than the paper version. By developing an electronic algorithm to accurately assess penicillin allergy risk based on appropriate history, without the need for diagnostic testing or allergist assessment, we can empower non-allergist health care professionals to safely de-label low risk pediatric patients and assist in alleviating subspecialty wait times for penicillin allergy assessment.
The pond snail Lymnaea stagnalis
Authors: Kuroda Reiko , Abe Masanori
Published: December 2020

The freshwater snail Lymnaea stagnalis has a long research history, but only relatively recently has it emerged as an attractive model organism to study molecular mechanisms in the areas of developmental biology and translational medicine such as learning/memory and neurodegenerative diseases. The species has the advantage of being a hermaphrodite and can both cross- and self-mate, which greatly facilitates genetic approaches. The establishment of body-handedness, or chiromorphogenesis, is a major topic of study, since chirality is evident in the shell coiling. Chirality is maternally inherited, and only recently a gene-editing approach identified the actin-related gene Lsdia1 as the key handedness determinant. This short article reviews the natural habitat, life cycle, major research questions and interests, and experimental approaches.