Tumour expression of leptin is associated with chemotherapy resistance and therapy-independent prognosis in gastro-oesophageal adenocarcinomas.

BACKGROUND: Cytotoxic chemotherapy remains the main systemic therapy for gastro-oesophageal adenocarcinoma, but resistance to chemotherapy is common, resulting in ineffective and often toxic treatment for patients. Predictive biomarkers for chemotherapy response would increase the probability of successful therapy, but none are currently recommended for clinical use. We used global gene expression profiling of tumour biopsies to identify novel predictive biomarkers for cytotoxic chemotherapy. METHODS: Tumour biopsies from patients (n=14) with TNM stage IB-IV gastro-oesophageal adenocarcinomas receiving platinum-based combination chemotherapy were used as a discovery cohort and profiled with Affymetrix ST1.0 Exon Genechips. An independent cohort of patients (n=154) treated with surgery with or without neoadjuvant platinum combination chemotherapy and gastric adenocarcinoma cell lines (n=22) were used for qualification of gene expression profiling results by immunohistochemistry. A cisplatin-resistant gastric cancer cell line, AGS Cis5, and the oesophageal adenocarcinoma cell line, OE33, were used for in vitro validation investigations. RESULTS: We identified 520 genes with differential expression (Mann-Whitney U, P<0.020) between radiological responding and nonresponding patients. Gene enrichment analysis (DAVID v6.7) was used on this list of 520 genes to identify pathways associated with response and identified the adipocytokine signalling pathway, with higher leptin mRNA associated with lack of radiological response (P=0.011). Similarly, in the independent cohort (n=154), higher leptin protein expression by immunohistochemistry in the tumour cells was associated with lack of histopathological response (P=0.007). Higher leptin protein expression by immunohistochemistry was also associated with improved survival in the absence of neoadjuvant chemotherapy, and patients with low leptin protein-expressing tumours had improved survival when treated by neoadjuvant chemotherapy (P for interaction=0.038). In the gastric adenocarcinoma cell lines, higher leptin protein expression was associated with resistance to cisplatin (P=0.008), but not to oxaliplatin (P=0.988) or 5fluorouracil (P=0.636). The leptin receptor antagonist SHLA increased the sensitivity of AGS Cis5 and OE33 cell lines to cisplatin. CONCLUSIONS: In gastro-oesophageal adenocarcinomas, tumour leptin expression is associated with chemoresistance but a better therapy-independent prognosis. Tumour leptin expression determined by immunohistochemistry has potential utility as a predictive marker of resistance to cytotoxic chemotherapy, and a prognostic marker independent of therapy in gastro-oesophageal adenocarcinoma. Leptin antagonists have been developed for clinical use and leptin and its associated pathways may also provide much needed novel therapeutic targets for gastro-oesophageal adenocarcinoma.

Transmission of methicillin-resistant Staphylococcus aureus infection through solid organ transplantation: confirmation via whole genome sequencing.

We describe two cases of donor-derived methicillin-resistant Staphylococcus aureus (MRSA) bacteremia that developed after transplantation of organs from a common donor who died from acute MRSA endocarditis. Both recipients developed recurrent MRSA infection despite appropriate antibiotic therapy, and required prolonged hospitalization and hospital readmission. Comparison of S. aureus whole genome sequence of DNA extracted from fixed donor tissue and recipients' isolates confirmed donor-derived transmission. Current guidelines emphasize the risk posed by donors with bacteremia from multidrug-resistant organisms. This investigation suggests that, particularly in the setting of donor endocarditis, even a standard course of prophylactic antibiotics may not be sufficient to prevent donor-derived infection.

Bartonella henselae-mediated disease in solid organ transplant recipients: two pediatric cases and a literature review.

Bartonella henselae, the etiologic agent of cat-scratch disease, causes a well-defined, self-limited syndrome of fever and regional lymphadenopathy in immunocompetent hosts. In immunocompromised hosts, however, B. henselae can cause severe disseminated disease and pathologic vasoproliferation known as bacillary angiomatosis (BA) or bacillary peliosis. BA was first recognized in patients infected with human immunodeficiency virus. It has become more frequently recognized in solid organ transplant (SOT) recipients, but reports of pediatric cases remain rare. Our review of the literature revealed only one previously reported case of BA in a pediatric SOT recipient. We herein present 2 pediatric cases, one of which is the first reported case of BA in a pediatric cardiac transplant recipient, to our knowledge. In addition, we review and summarize the literature pertaining to all cases of B. henselae-mediated disease in SOT recipients.

Paper versus electronic feedback in high stakes assessment.

Tablet computers have emerged as increasingly useful tools in medical education, particularly for assessment. However, it is not fully established whether tablet computers influence the quality and/or quantity of feedback provided in high stakes assessments. It is also unclear how electronically-recorded feedback relates to student performance. Our primary aim was to determine whether differences existed in feedback depending on the tool used to record it. METHODS: We compared quantitative and qualitative feedback between paper-scoring sheets versus iPads™ across two consecutive years of a final year MBChB (UK medical degree) Objective Structured Clinical Examination. Quality of comments (using a validated five-point rating scale), number of examiner comments and number of words were compared across both methods of recording assessment performance using chi-squared analysis and independent t-test. We also explored relationships between student performance (checklist and global scoring) and feedback. RESULTS: Data from 190 students (2850 paper scored interactions) in 2015 and 193 (2895 iPad™ scored interactions) in 2016 were analysed. Overall, a greater number of comments were given with iPad™ compared to written (42% versus 20%; p < 0.001) but the quality of feedback did not differ significantly. For both written and electronic feedback, students with low global scores were more likely to receive comments (p < 0.001). CONCLUSION: The use of iPads™ in high stakes assessment increases the quantity of feedback compared to traditional paper scoring sheets. The quantity and quality of feedback for poorer performing candidates (by global score) were also better with iPad™ feedback.

Tablet computers in assessing performance in a high stakes exam: opinion matters.

Background Tablet computers have emerged as a tool to capture, process and store data in examinations, yet evidence relating to their acceptability and usefulness in assessment is limited. Methods We performed an observational study to explore opinions and attitudes relating to tablet computer use in recording performance in a final year objective structured clinical examination at a single UK medical school. Examiners completed a short questionnaire encompassing background, forced-choice and open questions. Forced choice questions were analysed using descriptive statistics and open questions by framework analysis. Results Ninety-two (97% response rate) examiners completed the questionnaire of whom 85% had previous use of tablet computers. Ninety per cent felt checklist mark allocation was 'very/quite easy', while approximately half considered recording 'free-type' comments was 'easy/very easy'. Greater overall efficiency of marking and resource savings were considered the main advantages of tablet computers, while concerns relating to technological failure and ability to record free type comments were raised. Discussion In a context where examiners were familiar with tablet computers, they were preferred to paper checklists, although concerns were raised. This study adds to the limited literature underpinning the use of electronic devices as acceptable tools in objective structured clinical examinations.

Enrollment in English-as-a-second-language class as a predictor of tuberculosis infection in schoolchildren.

OBJECTIVE: To assess the rate of tuberculosis infection among Hispanic students enrolled in English-as-a-Second-Language classes compared with Hispanic and non-Hispanic students not enrolled in such classes. METHODS: Using Mantoux tuberculin skin tests, the authors screened 720 students--out of 844 eligible--in two schools with predominantly Hispanic populations. Ethnicity and enrollment in the English-as-a-Second Language classes were recorded for each student. The rate of skin test positivity was compared for students enrolled and not enrolled in these classes. RESULTS: The incidence of positive tests among Hispanic students enrolled in an English-as-a-Second-Language class was 10.6%, compared with 1.3% for Hispanic students not enrolled (relative risk 8.3, 95% confidence interval 2.92, 23.8). There was no statistically significant difference in incidence rates for non-Hispanic students (0.5%) and Hispanic students (1.3%) who were not enrolled in English-as-a-Second-Language class (relative risk 2.4, 95% confidence interval 0.27, 20.9). CONCLUSION: School-based tuberculin screening programs targeted at students enrolled in English-as-a-Second-Language classes can be effective and are not racially discriminatory.

Endobronchial ultrasound-transbronchial needle aspiration and its practical application.

Endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) has emerged over the past decade as one of the most exciting and innovative developments in the field of respiratory medicine. This procedure allows sampling of mediastinal lymph nodes and masses in both malignant and benign disease and overcomes some of the disadvantages associated with mediastinoscopy and blind transbronchial needle aspiration. We describe the clinical use, indications for and limitations of EBUS-TBNA along with several illustrated clinical examples.

The evolution of targeted populations in a school-based tuberculin testing program.

A review of tuberculosis surveillance data from a program of school-based tuberculin testing demonstrates the natural evolution of targeted populations. In the 7 years encompassed by this study, the prevalence of tuberculin reactivity ranged from 4.3% to 6.1% in the Amarillo public school populations which were tested. The initial screening was a sampling of all students in the school district. In subsequent years' screening, the targeted populations were increasingly refined to eliminate lower-risk populations. Children enrolled in "English as a Second Language" (ESL) classes were found to have an 8.5% tuberculosis infection rate. The purpose of this study was to alert nurses that culturally sensitive approaches are needed for successful future testing.

Research misconduct.

Good research practice is important to the scientific community. An awareness of what constitutes poor practice is important. Various types of research misconduct are defined in this article. The extent of research misconduct in the field of radiology has been assessed by contacting five English language radiology journals. Redundant or duplicate publication has been reported infrequently, Radiology (1), American Journal of Roentgenology (3), Clinical Radiology (3), British Journal of Radiology (2) and European Radiology (1). The issue of how the radiology community might tackle research misconduct is discussed with reference to guidance from the Medical Research Council, the Wellcome Trust and the Committee of Publication Ethics.

Baroreflex unimpaired by operant avoidance or classical aversive conditioning in dogs.

Previous studies showed that baroreflex control of heart rate is impaired during operant shock avoidance conditioning and classical aversive conditioning. However, the effects of such "emotionally stressful" paradigms on the ability of the baroreflex to control arterial pressure have not been directly assessed. We prepared the carotid sinus regions of dogs for reversible isolation from the systemic circulation, and we derived complete stimulus-response relations for the effects of carotid sinus pressure on both heart rate and arterial pressure. For any given carotid sinus pressure, arterial pressure and heart rate were higher during operant shock-avoidance conditioning and during classical aversive conditioning than in a neutral environment, which indicates an upward resetting of the baroreflex. However, threshold and saturation carotid sinus pressures were unaffected by operant conditioning or classical conditioning, which indicates that the baroreceptors themselves were not reset. The ranges over which the carotid baroreflex could vary arterial pressure and heart rate were significantly increased during both operant conditioning and classical conditioning. Baroreflex gain was unchanged during operant conditioning and was significantly increased during classical conditioning. We conclude that the baroreflex is not impaired during operant shock-avoidance conditioning or classical aversive conditioning in dogs. However, the baroreflex is reset and regulates blood pressure at an elevated level.

Intracoronary veratrine attenuates carotid baroreceptor reflex regulation of blood pressure in conscious dogs.

1. The effect of activation of left ventricular cardiac receptors on carotid baroreflex control of blood pressure, heart rate, cardiac output, and total peripheral resistance was determined in conscious dogs. Previous studies in conscious subjects assessed only the effect on baroreflex control of heart rate. 2. Dogs with denervated aortic baroreceptors were equipped with aortic flow probes, cardiac pacing electrodes, and catheters in the aorta, vena cava, and left circumflex coronary artery. Both carotid sinus regions were prepared for reversible vascular isolation. 3. Left ventricular receptors were stimulated by an infusion of veratrine (0.1-1.0 micrograms kg-1 min-1) into the left circumflex coronary artery. 4. Veratrine infusion decreased control blood pressure only 10 +/- 2 mmHg, but it decreased the range of baroreflex control of blood pressure by 50% and decreased maximum baroreflex gain by 42%. Both the cardiac output and total peripheral resistance components of the baroreflex were attenuated. 5. Baroreflex control of blood pressure was unaffected by intravenous veratrine or by intracoronary infusion of vehicle. 6. Intracoronary veratrine had no effect after autonomic ganglionic blockade. 7. When cardiac output was kept nearly constant (by beta-adrenergic and cholinergic receptor blockade or by beta-blockade and cardiac pacing), intracoronary veratrine still attenuated baroreflex control of blood pressure and total peripheral resistance. Veratrine impaired the ability of the baroreflex to utilize alpha-adrenergic mechanisms to control total peripheral resistance. 8. We conclude that activation of ventricular receptors attenuates baroreflex regulation of blood pressure in conscious dogs through an attenuation of baroreflex control of both cardiac output and total peripheral resistance.