Ultrasound-assisted thrombolysis for acute intermediate-high-risk pulmonary embolism.

INTRODUCTION: Eustachian tube dysfunction (ETD) may result in hearing loss, chronic otitis and cholesteatoma. With advances in treatment options, the identification of patients with obstructive ETD is becoming increasingly important. The objective of this study was to validate a Danish translation of the 7-item Eustachian Tube Dysfunction Questionnaire (ETDQ-7). METHODS: All participants underwent tympanometry, otomicroscopy and completed the ETDQ-7. We included 34 ears from patients with obstructive ETD who had abnormal tympanometry curves but no history of cholesteatoma or adhesive otitis. As a control group, 48 otherwise healthy ears with a normal tympanometry curve were included from patients with known sensorineural hearing loss or normal hearing. RESULTS: A Cronbach's alpha of 0.77 indicated a good internal consistency reliability of the questionnaire. The mean ETDQ-7 score in the obstructive ETD group was 31 versus 13.5 in the control group (p = 0.00). A receiver operating characteristics analysis produced an area under the curve of 94%, showing excellent discriminatory abilities between the groups. CONCLUSIONS: The ETDQ-7 has previously been validated in English, German, Dutch and Portuguese, demonstrating good clinical relevance. The Danish translation of the ETDQ-7 has produced similar results and may be valuable in diagnosing obstructive ETD and in monitoring the effect of balloon dilation of the Eustachian tube. FUNDING: none. The study was approved by the Danish Data Protection Agency (VD-2018-33, I-Suite 6229).

A phase II study of Epirubicin in oxaliplatin-resistant patients with metastatic colorectal cancer and TOP2A gene amplification.

UNLABELLED: The overall purpose of this study is to provide proof of concept for introducing the anthracycline epirubicin as an effective, biomarker-guided treatment for metastatic colorectal cancer (mCRC) patients who are refractory to treatment with oxaliplatin-based chemotherapy and have TOP2A gene amplification in their tumor cells. BACKGROUND: Epirubicin is an anthracycline that targets DNA topoisomerase 2-α enzyme encoded by the TOP2A gene. It is used for treatment of several malignancies, but currently not in CRC. TOP2A gene amplifications predict improved efficacy of epirubicin in patients with breast cancer and thus could be an alternative option for patients with CRC and amplified TOP2A gene. We have previously analysed the frequency of TOP2A gene aberrations in CRC and found that 46.6% of these tumors had TOP2A copy gain and 2.0% had loss of TOP2A when compared to adjacent normal tissue. The TOP2A gene is located on chromosome 17 and when the TOP2A/CEN-17 ratio was applied to identify tumors with gene loss or amplifications, 10.5% had a ratio ≥ 1.5 consistent with gene amplification and 2.6% had a ratio ≤ 0.8 suggesting gene deletions. Based on these observations and the knowledge gained from treatment of breast cancer patients, we have initiated a prospective clinical, phase II protocol using epirubicin (90 mg/m2 iv q 3 weeks) in mCRC patients, who are refractory to treatment with oxaliplatin. METHODS/DESIGN: The study is an open label, single arm, phase II study, investigating the efficacy of epirubicin in patients with oxaliplatin refractory mCRC and with a cancer cell TOP2A/CEN-17 ratio ≥ 1.5. TOP2A gene amplification measured by fluorescence in situ hybridization. A total of 25 evaluable patients (15 + 10 in two steps) will be included (Simon's two-stage minimax design). Every nine weeks, response is measured by computed tomography imaging and evaluated according to RECIST 1.1. The primary end-point of the study is progression-free survival. TRIAL REGISTRATION: Eudract no. 2013-001648-79.

Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance.

Current standard treatments for metastatic colorectal cancer (CRC) are based on combination regimens with one of the two chemotherapeutic drugs, irinotecan or oxaliplatin. However, drug resistance frequently limits the clinical efficacy of these therapies. In order to gain new insights into mechanisms associated with chemoresistance, and departing from three distinct CRC cell models, we generated a panel of human colorectal cancer cell lines with acquired resistance to either oxaliplatin or irinotecan. We characterized the resistant cell line variants with regards to their drug resistance profile and transcriptome, and matched our results with datasets generated from relevant clinical material to derive putative resistance biomarkers. We found that the chemoresistant cell line variants had distinctive irinotecan- or oxaliplatin-specific resistance profiles, with non-reciprocal cross-resistance. Furthermore, we could identify several new, as well as some previously described, drug resistance-associated genes for each resistant cell line variant. Each chemoresistant cell line variant acquired a unique set of changes that may represent distinct functional subtypes of chemotherapy resistance. In addition, and given the potential implications for selection of subsequent treatment, we also performed an exploratory analysis, in relevant patient cohorts, of the predictive value of each of the specific genes identified in our cellular models.

Association between endovascular performance in a simulated setting and in the catheterization laboratory.

INTRODUCTION: Simulation-based assessment studies have related simulator performance to clinical experience instead of actual clinical performance. This study validates a novel rating scale for coronary angiography (CA) performance and at the same time explores the association between CA performance in a simulated setting and in the catheterization laboratory. METHODS: Ten cardiologists and cardiology residents with varying degrees of CA experience performed 2 CAs in the catheterization laboratory and 2 CAs in a simulated setting. The residents had prior simulator experience opposite cardiologists. Two raters assessed the operators' video-recorded performances using the novel CA rating scale (CARS). RESULTS: The correlation between CARS scores in the catheterization laboratory and the simulated setting was R = 0.20 (P = 0.195). Residents' scores were higher in the simulated setting than in the catheterization laboratory. The correlation between operators' previous clinical experience in CA and CARS scores was R = 0.65 (P = 0.005) in the catheterization laboratory and R = 0.11 (P = 0.353) in the simulated setting. CONCLUSIONS: The association between CA performance in a simulated setting and actual performance in the catheterization laboratory is not linear. The novel rating scale for CA (CARS) seems to be a valid proficiency assessment instrument in the catheterization laboratory. Familiarity with the simulator may overestimate proficiency, which means that simulator performance as a predictor of clinical performance should be interpreted with caution.

A study of the effect of dyad practice versus that of individual practice on simulation-based complex skills learning and of students' perceptions of how and why dyad practice contributes to learning.

PURPOSE: The aims of this study were (1) to explore the effectiveness of dyad practice compared with individual practice on a simulator for learning a complex clinical skill and (2) to explore medical students' perceptions of how and why dyad practice on a simulator contributes to learning a complex skill. METHOD: In 2011, the authors randomly assigned 84 medical students to either the dyad or the individual practice group to learn coronary angiography skills using instruction videos and a simulator. Two weeks later, participants each performed two video-recorded coronary angiographies on the simulator. Two raters used a rating scale to assess the participants' video-recorded performance. The authors then interviewed the participants in the dyad practice group. RESULTS: Seventy-two (86%) participants completed the study. The authors found no significant difference between the performance scores of the two groups (mean±standard deviation, 68%±13% for individual versus 63%±16% for dyad practice; P=.18). Dyad practice participants noted that several key factors contributed to their learning: being equal-level novices, the quality of the cooperation between partners, observational learning and overt communication, social aspects and motivation, and meta-cognition. CONCLUSIONS: Dyad practice is more efficient and thus more cost-effective than individual practice and can be used for costly virtual reality simulator training. However, dyad practice may not apply to clinical training involving real patients because learning from errors and overt communication, both keys to dyad practice, do not transfer to clinical practice.

An Electronic Patch for wearable health monitoring by reflectance pulse oximetry.

We report the development of an Electronic Patch for wearable health monitoring. The Electronic Patch is a new health monitoring system incorporating biomedical sensors, microelectronics, radio frequency (RF) communication, and a battery embedded in a 3-dimensional hydrocolloid polymer. In this paper the Electronic Patch is demonstrated with a new optical biomedical sensor for reflectance pulse oximetry so that the Electronic Patch in this case can measure the pulse and the oxygen saturation. The reflectance pulse oximetry solution is based on a recently developed annular backside silicon photodiode to enable low power consumption by the light emitting components. The Electronic Patch has a disposable part of soft adhesive hydrocolloid polymer and a reusable part of hard polylaurinlactam. The disposable part contains the battery. The reusable part contains the reflectance pulse oximetry sensor and microelectronics. The reusable part is 'clicked' into the disposable part when the patch is prepared for use. The patch has a size of 88 mm by 60 mm and a thickness of 5 mm.

MicroRNA alterations and associated aberrant DNA methylation patterns across multiple sample types in oral squamous cell carcinoma.

BACKGROUND: MicroRNA (miRNA) expression is broadly altered in cancer, but few studies have investigated miRNA deregulation in oral squamous cell carcinoma (OSCC). Epigenetic mechanisms are involved in the regulation of >30 miRNA genes in a range of tissues, and we aimed to investigate this further in OSCC. METHODS: TaqMan® qRT-PCR arrays and individual assays were used to profile miRNA expression in a panel of 25 tumors with matched adjacent tissues from patients with OSCC, and 8 control paired oral stroma and epithelium from healthy volunteers. Associated DNA methylation changes of candidate epigenetically deregulated miRNA genes were measured in the same samples using the MassArray® mass spectrometry platform. MiRNA expression and DNA methylation changes were also investigated in FACS sorted CD44(high) oral cancer stem cells from primary tumor samples (CSCs), and in oral rinse and saliva from 15 OSCC patients and 7 healthy volunteers. RESULTS: MiRNA expression patterns were consistent in healthy oral epithelium and stroma, but broadly altered in both tumor and adjacent tissue from OSCC patients. MiR-375 is repressed and miR-127 activated in OSCC, and we confirm previous reports of miR-137 hypermethylation in oral cancer. The miR-200 s/miR-205 were epigenetically activated in tumors vs normal tissues, but repressed in the absence of DNA hypermethylation specifically in CD44(high) oral CSCs. Aberrant miR-375 and miR-200a expression and miR-200c-141 methylation could be detected in and distinguish OSCC patient oral rinse and saliva from healthy volunteers, suggesting a potential clinical application for OSCC specific miRNA signatures in oral fluids. CONCLUSIONS: MiRNA expression and DNA methylation changes are a common event in OSCC, and we suggest miR-375, miR-127, miR-137, the miR-200 family and miR-205 as promising candidates for future investigations. Although overall activated in OSCC, miR-200/miR-205 suppression in oral CSCs indicate that cell specific silencing of these miRNAs may drive tumor expansion and progression.

miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA.

MicroRNAs (miRNAs) are ∼22 nt non-coding RNAs that typically bind to the 3' UTR of target mRNAs in the cytoplasm, resulting in mRNA destabilization and translational repression. Here, we report that miRNAs can also regulate gene expression by targeting non-coding antisense transcripts in human cells. Specifically, we show that miR-671 directs cleavage of a circular antisense transcript of the Cerebellar Degeneration-Related protein 1 (CDR1) locus in an Ago2-slicer-dependent manner. The resulting downregulation of circular antisense has a concomitant decrease in CDR1 mRNA levels, independently of heterochromatin formation. This study provides the first evidence for non-coding antisense transcripts as functional miRNA targets, and a novel regulatory mechanism involving a positive correlation between mRNA and antisense circular RNA levels.

Use of performance curves in estimating number of procedures required to achieve proficiency in coronary angiography.

BACKGROUND: Current guidelines in cardiology training programs recommend 100-300 coronary angiography procedures for certification. We aimed to assess the number of procedures needed to reach sufficient proficiency. METHODS: Procedure time, fluoroscopy time, dose area product (DAP), and contrast media volume were used as indicators of quality of performance. We analyzed data from 4,200 coronary angiographies. Performance curves of seven trainees were compared with recommended reference levels and to those of seven interventional cardiologists. RESULTS: On average, the number of procedures needed for trainees to reach recommended reference levels was estimated as 226 and 353, for DAP and use of contrast media, respectively. After 300 procedures, trainees' procedure time, fluoroscopy time, DAP, and contrast media volume were significantly higher compared with experts' performance, P < 0.001 for all parameters. To approach the experts' level of DAP and contrast media use, trainees need 394 and 588 procedures, respectively. Performance curves showed large individual differences in the development of competence. CONCLUSION: On average, trainees needed 300 procedures to reach sufficient level of proficiency, and this is in accordance with current guidelines. However, because of large individual differences, performance curves might be useful in monitoring individual trainees' progress and ensure documentation of sufficient competence when dealing with patients at risk.

Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer.

MicroRNAs (miRNA) are small noncoding RNAs commonly deregulated in cancer. The miR-200 family (miR-200a, -200b, -200c, -141 and -429) and miR-205 are frequently silenced in advanced cancer and have been implicated in epithelial to mesenchymal transition (EMT) and tumor invasion by targeting the transcriptional repressors of E-cadherin, ZEB1 and ZEB2. ZEB1 is also known to repress miR-200c-141 transcription in a negative feedback loop, but otherwise little is known about the transcriptional regulation of the miR-200 family and miR-205. Recently, miR-200 silencing was also reported in cancer stem cells, implying that miR-200 deregulation is a key event in multiple levels of tumor biology. However, what prevents miR-200 expression remains largely unanswered. Here we report concerted transcriptional regulation of the miR-200 and miR-205 loci in bladder tumors and bladder cell lines. Using a combination of miRNA expression arrays, qPCR assays and mass spectrometry DNA methylation analyses, we show that the miR-200 and miR-205 loci are specifically silenced and gain promoter hypermethylation and repressive chromatin marks in muscle invasive bladder tumors and undifferentiated bladder cell lines. Moreover, we report that miR-200c expression is significantly correlated with early stage T1 bladder tumor progression, and propose miR-200 and miR-205 silencing and DNA hypermethylation as possible prognostic markers in bladder cancer. In addition, we observe that the mesoderm transcription factor TWIST1 and miR-200 expression are inversely correlated in bladder tumor samples and cell lines. TWIST1 associates directly with the miR-200 and miR-205 promoters, and may act as a repressor of miR-200 and miR-205 expression.

Making post-mortem implantable cardioverter defibrillator explantation safe.

AIMS: The aim of this study is to investigate whether protection with rubber or plastic gloves during post-mortem explantation of an implantable cardioverter defibrillator (ICD) offers enough protection for the explanting operator during a worst-case scenario (i.e. ICD shock). METHODS AND RESULTS: We investigated the insulating properties of rubber and plastic gloves (double layer) within the first 60 min exposure (mimicking the maximum time of an explantation procedure) to saline (simulating the effects of body fluids on the gloves). For latex gloves, we measured an increase in voltage up to 68.1 V (P < 0.0001), for neoprene a maximum voltage of 5.3 V (P = 0.245), and for plastic a voltage of 2.3 V within the first hour. If the exposure time to fluid did not exceed 50 min, a double pair of intact gloves made of latex, neoprene, or plastic constituted such a large resistance that the resting voltage over the operating person would not exceed 50 V. CONCLUSION: The use of intact medical gloves made of latex, neoprene, or plastic eliminates the potential electrical risk during explantation of an ICD. Two gloves on each hand offer sufficient protection. We will recommend the use of neoprene gloves.