Birth characteristics and risk of Ewing sarcoma.

PURPOSE: The incidence of Ewing sarcoma varies according to race and ethnicity, and genetic susceptibility is known to affect disease risk. Apart from these factors, the etiology of Ewing sarcoma is largely unknown. METHODS: We compared the birth characteristics of a population-based series of 556 Ewing sarcoma cases born in California in 1978-2015 and diagnosed in 1988-2015 with those of 27,800 controls selected from statewide birth records and frequency-matched to cases on the year of birth, using multivariable logistic regression models. We also assessed whether Ewing sarcoma clustered within families. RESULTS: Compared to non-Hispanic White subjects, Black (odds ratio [OR] = 0.07, 95% confidence interval [CI] 0.03-0.18), Asian (OR = 0.57, 95% CI 0.41-0.80), and Hispanic (OR = 0.73, 95% CI 0.62-0.88) individuals had a significantly lower risk of Ewing sarcoma. Race and ethnicity differences were more profound for metastatic Ewing sarcoma. Birthweight was also identified as a significant risk factor (OR = 1.09, 95% CI 1.00-1.18 for each 500 g increase in birthweight). A separate family-based cancer clustering analysis did not suggest any strong role for familial predisposition alleles. CONCLUSIONS: This population-based study with minimal selection bias provides support for a role of accelerated fetal growth in the etiology of Ewing sarcoma in addition to more precise estimates of racial and ethnic variations in disease risk. This comparatively large analysis of birth characteristics and Ewing sarcoma in a multiethnic population should stimulate further investigations into genetic and environmental causes.

Using cultural historical activity theory to reflect on the sociocultural complexities in OSCE examiners' judgements.

Examiners' judgements play a critical role in competency-based assessments such as objective structured clinical examinations (OSCEs). The standardised nature of OSCEs and their alignment with regulatory accountability assure their wide use as high-stakes assessment in medical education. Research into examiner behaviours has predominantly explored the desirable psychometric characteristics of OSCEs, or investigated examiners' judgements from a cognitive rather than a sociocultural perspective. This study applies cultural historical activity theory (CHAT) to address this gap in exploring examiners' judgements in a high-stakes OSCE. Based on the idea that OSCE examiners' judgements are socially constructed and mediated by their clinical roles, the objective was to explore the sociocultural factors that influenced examiners' judgements of student competence and use the findings to inform examiner training to enhance assessment practice. Seventeen semi-structured interviews were conducted with examiners who assessed medical student competence in progressing to the next stage of training in a large-scale OSCE at one Australian university. The initial thematic analysis provided a basis for applying CHAT iteratively to explore the sociocultural factors and, specifically, the contradictions created by interactions between different elements such as examiners and rules, thus highlighting the factors influencing examiners' judgements. The findings indicated four key factors that influenced examiners' judgements: examiners' contrasting beliefs about the purpose of the OSCE; their varying perceptions of the marking criteria; divergent expectations of student competence; and idiosyncratic judgement practices. These factors were interrelated with the activity systems of the medical school's assessment practices and the examiners' clinical work contexts. Contradictions were identified through the guiding principles of multi-voicedness and historicity. The exploration of the sociocultural factors that may influence the consistency of examiners' judgements was facilitated by applying CHAT as an analytical framework. Reflecting upon these factors at organisational and system levels generated insights for creating fit-for-purpose examiner training to enhance assessment practice.

Towards a global partnership model in interprofessional education for cross-sector problem-solving.

OBJECTIVES: A partnership model in interprofessional education (IPE) is important in promoting a sense of global citizenship while preparing students for cross-sector problem-solving. However, the literature remains scant in providing useful guidance for the development of an IPE programme co-implemented by external partners. In this pioneering study, we describe the processes of forging global partnerships in co-implementing IPE and evaluate the programme in light of the preliminary data available. METHODS: This study is generally quantitative. We collected data from a total of 747 health and social care students from four higher education institutions. We utilized a descriptive narrative format and a quantitative design to present our experiences of running IPE with external partners and performed independent t-tests and analysis of variance to examine pretest and posttest mean differences in students' data. RESULTS: We identified factors in establishing a cross-institutional IPE programme. These factors include complementarity of expertise, mutual benefits, internet connectivity, interactivity of design, and time difference. We found significant pretest-posttest differences in students' readiness for interprofessional learning (teamwork and collaboration, positive professional identity, roles, and responsibilities). We also found a significant decrease in students' social interaction anxiety after the IPE simulation. CONCLUSIONS: The narrative of our experiences described in this manuscript could be considered by higher education institutions seeking to forge meaningful external partnerships in their effort to establish interprofessional global health education.

Evaluation of a co-designed Parkinson's awareness audio podcast for undergraduate nursing students in Northern Ireland.

BACKGROUND: Parkinson's Disease (PD) is a common neurological condition that often causes stiffness, tremor and slow movement. People living with PD are likely to encounter nursing students throughout their journey from pre-diagnosis to death. Despite this, there is a paucity of evidence about current practice in PD education amongst nursing students. The present study provides an evaluation of a co-designed Parkinson's Awareness audio podcast amongst nursing students in Northern Ireland. METHODS: Following co-design of an audio podcast about PD, a mixed methods evaluation was carried out. 332 student nurses completed pre-/post-test questionnaires about their knowledge and perceptions of PD before and after listening to the audio podcast. Further to this, 35 student nurses participated in focus-group interviews six months following listening to explore how the podcast influenced practice. RESULTS: Student nurses posted a mean score of 52% before listening to the audio podcast. This mean increased to 80% post-test. These findings were statistically significant (p < 0.001), demonstrating significant increases in PD awareness after listening. Findings from the focus groups suggested that the audio podcast improved empathy and practice towards people with PD. The findings also suggested that students perceived audio podcasts to be a good way to learn about PD. CONCLUSION: Provision of a co-designed audio podcast about PD has the potential to improve student nurse knowledge and practice related to PD as evidenced in this study.

Engaging clinical examiners with structured feedback to enhance assessment practices.

INTRODUCTION: Examiners' professional judgements of student performance are pivotal to making high-stakes decisions to ensure graduating medical students are competent to practise. Clinicians play a key role in assessment in medical education. They are qualified in their clinical area but may require support to further develop their understanding of assessment practices. However, there are limited studies on providing examiners with structured feedback on their assessment practices for professional development purposes. METHODS: This study adopts an interpretive paradigm to develop an understanding of clinical examiners' interpretations of receiving structured feedback and its impacts on enhancing their assessment literacy and practice. Data were collected from 29 interviews with clinical examiners who assessed the final-year medical objective structured clinical examinations (OSCEs) at one university. RESULTS: Inductive thematic analysis of these data revealed that the examiners considered the feedback to be useful with practical functions in facilitating communication, comparisons and self-reflection. However, the examiners' level of confidence in the appropriateness of their assessment practices and difficulties in interpreting feedback could be barriers to adopting better practices. CONCLUSION: Feedback for examiners needs to be practical, targeted, and relevant to support them making accountable and defensible judgements of student performance.

APC conditional knock-out mouse is a model of infantile spasms with elevated neuronal ß-catenin levels, neonatal spasms, and chronic seizures.

Infantile spasms (IS) are a catastrophic childhood epilepsy syndrome characterized by flexion-extension spasms during infancy that progress to chronic seizures and cognitive deficits in later life. The molecular causes of IS are poorly defined. Genetic screens of individuals with IS have identified multiple risk genes, several of which are predicted to alter ß-catenin pathways. However, evidence linking malfunction of ß-catenin pathways and IS is lacking. Here, we show that conditional deletion in mice of the adenomatous polyposis coli gene (APC cKO), the major negative regulator of ß-catenin, leads to excessive ß-catenin levels and multiple salient features of human IS. Compared with wild-type littermates, neonatal APC cKO mice exhibit flexion-extension motor spasms and abnormal high-amplitude electroencephalographic discharges. Additionally, the frequency of excitatory postsynaptic currents is increased in layer V pyramidal cells, the major output neurons of the cerebral cortex. At adult ages, APC cKOs display spontaneous electroclinical seizures. These data provide the first evidence that malfunctions of APC/ß-catenin pathways cause pathophysiological changes consistent with IS. Our findings demonstrate that the APC cKO is a new genetic model of IS, provide novel insights into molecular and functional alterations that can lead to IS, and suggest novel targets for therapeutic intervention.

Development of a Droplet Digital™ PCR DNA methylation detection and quantification assay of prenatal tobacco exposure.

DNA methylation is a labile modification associated with gene expression control and environmental adaptations. High throughput, scalable and quantitative assessments of specific DNA methylation modifications in complex genomic regions for use in large population studies are needed. The performance of Droplet Digital™ PCR (ddPCR™) was investigated for DNA methylation detection against next-generation bisulfite sequencing (NGS) to demonstrate the ability of ddPCR to detect and validate DNA methylation levels and complex patterns among neighboring CpGs in regions associated with prenatal tobacco exposure. While both techniques are reproducible, ddPCR demonstrates a unique advantage for high-throughput DNA methylation analysis in large-scale population studies and provides the specificity to accurately measure DNA methylation of target CpGs in complex regions.

Clinical implementation of kVCT-guided tomotherapy with ClearRT.

A helical fan-beam kilovoltage computed tomography (kVCT) was recently introduced into Tomotherapy units. This study aims to share the initial experience of kVCT in clinical workflow, compare its performance with that of the existing megavoltage computed tomography (MVCT), and explore its potential in adaptive planning. We retrospectively enrolled 23 patients who underwent both MVCT and kVCT scans. The clinical performance data regarding image acquisition time, nominal dose length product (DLP), registration time and registration corrections were extracted and compared. Image quality was scored by six experienced radiation therapists and quantified based on phantom measurements. CT number stability and the implementation of adaptive radiotherapy were dosimetrically evaluated by performing the dose recalculation on kVCT. Compared to MVCT, kVCT significantly reduced DLP (except the highest kVp protocol), image acquisition and registration time. KVCT obtained higher scores than MVCT on all criteria except artifacts. Phantom measurements also revealed a better image performance characterization of kVCT except for image uniformity. The CT number variation could lead to a dose difference of 0.5% for D95% of target and Dmean of organ-at-risk. For the treatment planning with kVCT, a systematic dose difference (> 1%) in PTV dose metrics was observed at regions with large longitudinal density discontinuities compared to the reference plans. The new kVCT imaging provides enhanced soft-tissue visualization. The improved efficiency with kVCT-guided treatment will allow more patients to be treated each day. In most cases, the dose calculation accuracy of kVCT images is acceptable except for regions with severe artifacts.

Increased burden of familial-associated early-onset cancer risk among minority Americans compared to non-Latino Whites.

Background: The role of race/ethnicity in genetic predisposition of early-onset cancers can be estimated by comparing family-based cancer concordance rates among ethnic groups. Methods: We used linked California health registries to evaluate the relative cancer risks for first-degree relatives of patients diagnosed between ages 0 and 26, and the relative risks of developing distinct second primary malignancies (SPMs). From 1989 to 2015, we identified 29,631 cancer patients and 62,863 healthy family members. We calculated the standardized incident ratios (SIRs) of early-onset primary cancers diagnosed in proband siblings and mothers, as well as SPMs detected among early-onset patients. Analyses were stratified by self-identified race/ethnicity. Results: Given probands with cancer, there were increased relative risks of any cancer for siblings and mothers (SIR = 3.32; 95% confidence interval [CI]: 2.85-3.85) and of SPMs (SIR = 7.27; 95% CI: 6.56-8.03). Given a proband with solid cancer, both Latinos (SIR = 4.98; 95% CI: 3.82-6.39) and non-Latino Blacks (SIR = 7.35; 95% CI: 3.36-13.95) exhibited significantly higher relative risk of any cancer in siblings and mothers when compared to non-Latino White subjects (SIR = 3.02; 95% CI: 2.12-4.16). For hematologic cancers, higher familial risk was evident for Asian/Pacific Islanders (SIR = 7.56; 95% CI: 3.26-14.90) compared to non-Latino whites (SIR = 2.69; 95% CI: 1.62-4.20). Conclusions: The data support a need for increased attention to the genetics of early-onset cancer predisposition and environmental factors in race/ethnic minority families in the United States. Funding: This work was supported by the V Foundation for funding this work (Grant FP067172).

A Warburg-like metabolic program coordinates Wnt, AMPK, and mTOR signaling pathways in epileptogenesis.

Epilepsy is a complex neurological condition characterized by repeated spontaneous seizures and can be induced by initiating seizures known as status epilepticus (SE). Elaborating the critical molecular mechanisms following SE are central to understanding the establishment of chronic seizures. Here, we identify a transient program of molecular and metabolic signaling in the early epileptogenic period, centered on day five following SE in the pre-clinical kainate or pilocarpine models of temporal lobe epilepsy. Our work now elaborates a new molecular mechanism centered around Wnt signaling and a growing network comprised of metabolic reprogramming and mTOR activation. Biochemical, metabolomic, confocal microscopy and mouse genetics experiments all demonstrate coordinated activation of Wnt signaling, predominantly in neurons, and the ensuing induction of an overall aerobic glycolysis (Warburg-like phenomenon) and an altered TCA cycle in early epileptogenesis. A centerpiece of the mechanism is the regulation of pyruvate dehydrogenase (PDH) through its kinase and Wnt target genes PDK4. Intriguingly, PDH is a central gene in certain genetic epilepsies, underscoring the relevance of our elaborated mechanisms. While sharing some features with cancers, the Warburg-like metabolism in early epileptogenesis is uniquely split between neurons and astrocytes to achieve an overall novel metabolic reprogramming. This split Warburg metabolic reprogramming triggers an inhibition of AMPK and subsequent activation of mTOR, which is a signature event of epileptogenesis. Interrogation of the mechanism with the metabolic inhibitor 2-deoxyglucose surprisingly demonstrated that Wnt signaling and the resulting metabolic reprogramming lies upstream of mTOR activation in epileptogenesis. To augment the pre-clinical pilocarpine and kainate models, aspects of the proposed mechanisms were also investigated and correlated in a genetic model of constitutive Wnt signaling (deletion of the transcriptional repressor and Wnt pathway inhibitor HBP1). The results from the HBP1-/- mice provide a genetic evidence that Wnt signaling may set the threshold of acquired seizure susceptibility with a similar molecular framework. Using biochemistry and genetics, this paper outlines a new molecular framework of early epileptogenesis and advances a potential molecular platform for refining therapeutic strategies in attenuating recurrent seizures.

Health care students experience of using digital technology in patient care: A scoping review of the literature.

OBJECTIVES: To explore how undergraduate health care students use digital technology to deliver patient care during their clinical placements. DESIGN: A scoping review of primary research was conducted using the extended PRISMA guidelines. DATA SOURCES: A subject specialist librarian assisted in searching for the academic literature in four electronic databases: CINAHL, PubMed, Scopus and ERIC. REVIEW METHODS: Four reviewers, working in pairs, independently reviewed a total of 332 potentially relevant articles according to set inclusion and exclusion criteria. Then, all included papers underwent an independent quality review by two reviewers. RESULTS: Seven studies involving medical or nursing/midwifery students were included in the review. Three studies evaluated the use of mobile learning devices in patient care with four studies evaluating the use of digital systems in practice. Due to the heterogeneity of studies, which used differing digital systems and instruments, the researchers decided the most suitable method of analysis was a narrative review. The results are explained using four key themes: student learning needs when using technology in practice; access to technology in placements; perceptions of using technology in placements; and impact of technology on patient care. CONCLUSION: The use of digital systems in clinical settings creates challenges and benefits to student learning in delivering patient care. When students are prepared and facilitated to use digital systems, a sense of confidence and belonging to the team is fostered. Lack of availability and access to these systems, however, may impede students' ability to be involved in all aspects of patient care. Limitations of the current review included the relatively low quality of the educational research being conducted in this field of research. Further quality research is needed to explore how students in the health care professions are supported in digital environments and how higher education institutions are adapting their curricula to meet the digital learning needs of health care students.

Birth Characteristics and Risk of Early-Onset Synovial Sarcoma.

BACKGROUND: Synovial sarcoma is a rare cancer with peak incidence in the young adult period. Despite poor outcomes of this aggressive cancer, there is little epidemiologic research addressing its etiology. METHODS: We collected birth characteristic data on synovial sarcoma cases born during 1978-2015 and diagnosed during 1988-2015 in California (n = 244), and 12,200 controls frequency-matched on year of birth. We also constructed a dataset of cancer cases in siblings of sarcoma subjects to assess familial risk. RESULTS: In multivariable logistic regression analyses, synovial sarcoma was more frequent in Hispanics compared with non-Hispanic whites [OR, 1.48; 95% confidence interval (CI), 1.06-2.08]. Higher birth weight was a risk factor in Hispanics; each 500 g increase in birth weight was associated with a 22% increase in disease risk (OR, 1.22; 95% CI, 1.00-1.48). Also, a strong role for birth order was suggested, with highest risk for the first born (second child compared with first: OR, 0.61; 95% CI, 0.44-0.84; third or later compared with first: OR, 0.53; 95% CI, 0.36-0.77). Siblings of patients with synovial sarcoma did not display elevated cancer incidence, suggesting the low likelihood that strong familial predisposition alleles play a significant role in this disease. CONCLUSIONS: The associations with birth weight and birth order suggest that nutritional, developmental, and environmental factors may play a role in the etiology of synovial sarcoma. IMPACT: Further epidemiologic research on synovial sarcoma should evaluate epigenetic and developmental mechanisms and the formation of the archetypical t(X;18) translocation that defines this disease.

The HBP1 transcriptional repressor participates in RAS-induced premature senescence.

Oncogene-mediated premature senescence has emerged as a potential tumor-suppressive mechanism in early cancer transitions. Previous work shows that RAS and p38 MAPK participate in premature senescence, but transcriptional effectors have not been identified. Here, we demonstrate that the HBP1 transcriptional repressor participates in RAS- and p38 MAPK-induced premature senescence. In cell lines, we had previously isolated HBP1 as a retinoblastoma (RB) target but have determined that it functions as a proliferation regulator by inhibiting oncogenic pathways as a transcriptional repressor. In primary cells, the results indicate that HBP1 is a necessary component of premature senescence by RAS and p38 MAPK. Similarly, a knockdown of WIP1 (a p38 MAPK phosphatase) induced premature senescence that also required HBP1. Furthermore, HBP1 requires regulation by RB, in which few transcriptional regulators for premature senescence have been shown. Together, the data suggest a model in which RAS and p38 MAPK signaling engage HBP1 and RB to trigger premature senescence. As an initial step toward clinical relevance, a bioinformatics approach shows that the relative expression levels of HBP1 and WIP1 correlated with decreased relapse-free survival in breast cancer patients. Together, these studies highlight p38 MAPK, HBP1, and RB as important components for a premature-senescence pathway with possible clinical relevance to breast cancer.

Alterations of the HBP1 transcriptional repressor are associated with invasive breast cancer.

Invasive breast cancer has a high risk of recurrence to incurable disease and needs improved prognostic and therapeutic tools. Our work combines clinical and molecular analyses to show that the transcriptional repressor HBP1 may be a new target for invasive breast cancer. Previous work indicated that HBP1 regulated proliferation and senescence and inhibited Wnt signaling. Two of these functions have been associated with invasive breast cancer. In 76 breast tumors, we identified 10 HBP1 mutations/variants that were associated with fully invasive breast cancer. In a separate analysis, we found that a subset of invasive breast cancer specimens also had reduced HBP1 mRNA levels. These clinical correlations suggested that mutation or reduction of HBP1 occurs in invasive breast cancer and that HBP1 might regulate the proliferation and invasiveness of this breast cancer type. Analysis of the HBP1 mutants showed they were functionally defective for suppressing Wnt signaling. To test the consequences of reduced HBP1 levels, we used RNA interference to knock down HBP1 and observed increased Wnt signaling, tumorigenic proliferation, and invasiveness in cell and animal breast cancer models. Lastly, statistical analysis of a breast cancer patient database linked reduced HBP1 expression to breast cancer recurrence. In considering two-gene criteria for relapse potential, reduced expression of HBP1 and SFRP1, which is another Wnt inhibitor that was recently linked to invasive breast cancer, strikingly correlated with recurrence. Together, these data indicate that HBP1 may be a molecularly and clinically relevant regulator of breast cancer transitions that eventually lead to poor prognosis.

MRI-guided adaptive brachytherapy for locally advanced cervix cancer: Treatment outcomes from a single institution in Hong Kong.

BACKGROUND: Paradigm has shifted from 2D to image-guided adaptive brachytherapy (IGABT) for locally advanced cervix cancer (LACC). Increasing reports from pioneering institutions and large retrospective multicenter series have demonstrated improvements in outcome and reduction in toxicity with IGABT. However, there is scarcity of data on magnetic resonance (MR)-IGABT in Chinese patients. PURPOSE: To evaluate the clinical outcome of MR-IGABT for LACC in a single institution in Hong Kong. MATERIAL AND METHODS: Patients with FIGO stage IB-IVA LACC treated with definitive external beam radiotherapy +/- concurrent cisplatin followed by MR-IGABT from January 2015 to January 2018 were included. Brachytherapy planning and dose reporting followed the GEC-ESTRO recommendations. Dosimetric and clinical outcomes including local control (LC), pelvic control (PC), cancer-specific survival, overall survival (OS), and toxicity were analyzed. RESULTS: Forty-two consecutive patients were included. 71% were FIGO stage IIB or above; 52% had pelvic node involvement. Median high-risk clinical target volume (HRCTV) was 34.7 cm3 (12.3-155.1 cm3). Median dose to HRCTV D90 was 88.5 Gy (63.4-113.4 Gy) (EQD210). Median doses to the D2cc of bladder, rectum, sigmoid, and small bowel were 83.1 Gy, 67.5 Gy, 69.0 Gy, and 68.9 Gy (EQD23), respectively. Median followup was 20.3 months (4.0-35.1 months). 24-month actuarial LC, PC, cancer-specific survival, and OS were 90%, 84%, 90%, and 90%, respectively. Stratification by clinical variables showed that FIGO stage had significant impact on LC and dose to HRCTV on both LC and PC. Treatment was well tolerated without any severe late toxicity. CONCLUSIONS: Intermediate-term results from systematic MR-IGABT for LACC demonstrate very promising outcomes with minimal toxicity. This fills the gap in evidence for MR-IGABT in Chinese patients.