Grading of dysplasia in Barrett's oesophagus: substantial interobserver variation between general and gastrointestinal pathologists

AIMS: To determine interobserver variation in grading of dysplasia in Barrett's oesophagus (BO) between non-expert general pathologists and expert gastrointestinal pathologists on the one hand and between expert pathologists on the other hand. METHODS AND RESULTS: In this prospective multicentre study, non-expert and expert pathologists graded biopsy specimens of 920 patients with endoscopic BO, which were blindly reviewed by one member of a panel of expert pathologists (panel experts) and by a second panel expert in case of disagreement on dysplasia grade. Agreement between two of three pathologists was established as the final diagnosis. Analysis was performed by kappa statistics. Due to absence of intestinal metaplasia, 127/920 (14%) patients were excluded. The interobserver agreement for dysplasia [no dysplasia (ND) versus indefinite for dysplasia/low-grade dysplasia (IND/LGD) versus high-grade dysplasia (HGD)/adenocarcinoma (AC)] between non-experts and first panel experts and between initial experts and first panel experts was fair (kappa = 0.24 and kappa = 0.27, respectively), and substantial for differentiation of HGD/AC from ND/IND/LGD (kappa = 0.62 and kappa = 0.58, respectively). CONCLUSIONS: There was considerable interobserver variability in the interpretation of ND or IND/LGD in BO between non-experts and experts, but also between expert pathologists. This suggests that less subjective markers are needed to determine the risk of developing AC in BO.     

Antibody GD3G7 selected against embryonic glycosaminoglycans defines chondroitin sulfate-E domains highly up-regulated in ovarian cancer and involved in vascular endothelial growth factor binding

Chondroitin sulfate (CS) is abundantly present in the tumor stroma, and tumor-specific CS modifications might be potential targets to influence tumor development. We applied the phage display technology to select antibodies that identify these tumor-specific CS modifications. Antibody GD3G7 was selected against embryonic glycosaminoglycans, and it reacted strongly with CS-E (rich in GlcA-GalNAc4S6S units). In ovarian adenocarcinomas, strong expression of this CS-E epitope was found in the extracellular matrix, and occasionally on tumor cells. No expression was found in normal ovary and cystadenomas. Differential expression was found in ovarian carcinoma cell lines, which correlated with the gene expression of the GalNAc4S-6st enzyme, involved in biosynthesis of CS-E. Vascular endothelial growth factor (VEGF)-sensitive fenestrated (in normal tissues) and tumor blood vessels were both identified by antibody GD3G7, which might implicate a role for CS-E in VEGF biology. VEGF bound to CS-E and antibody GD3G7 could compete for binding of VEGF to CS-E. In conclusion, antibody GD3G7 identified rare CS-E-like structures that were strongly expressed in ovarian adenocarcinomas. This antibody might therefore be instrumental for identifying tumor-related CS alterations.     

What Are the Interobserver and Intraobserver Variability of Gap and Stepoff Measurements in Acetabular Fractures?

BackgroundGap and stepoff values in the treatment of acetabular fractures are correlated with clinical outcomes. However, the interobserver and intraobserver variability of gap and stepoff measurements for all imaging modalities in the preoperative, intraoperative, and postoperative phase of treatment is unknown. Recently, a standardized CT-based measurement method was introduced, which provided the opportunity to assess the level of variability.Questions/purposes(1) In patients with acetabular fractures, what is the interobserver variability in the measurement of the fracture gaps and articular stepoffs determined by each observer to be the maximum one in the weightbearing dome, as measured on pre- and postoperative pelvic radiographs, intraoperative fluoroscopy, and pre- and postoperative CT scans? (2) What is the intraobserver variability in these measurements?MethodsSixty patients with a complete subset of pre-, intra- and postoperative high-quality images (CT slices of < 2 mm), representing a variety of fracture types with small and large gaps and/or stepoffs, were included. A total of 196 patients with nonoperative treatment (n = 117), inadequate available imaging (n = 60), skeletal immaturity (n = 16), bilateral fractures (n = 2) or a primary THA (n = 1) were excluded. The maximum gap and stepoff values in the weightbearing dome were digitally measured on pelvic radiographs and CT images by five independent observers. Observers were free to decide which gap and/or stepoff they considered the maximum and then measure these before and after surgery. The observers were two trauma surgeons with more than 5 years of experience in pelvic surgery, two trauma surgeons with less than 5 years of experience in pelvic surgery, and one surgical resident. Additionally, the final intraoperative fluoroscopy images were assessed for the presence of a gap or stepoff in the weightbearing dome. All observers used the same standardized measurement technique and each observer measured the first five patients together with the responsible researcher. For 10 randomly selected patients, all measurements were repeated by all observers, at least 2 weeks after the initial measurements. The intraclass correlation coefficient (ICC) for pelvic radiographs and CT images and the kappa value for intraoperative fluoroscopy measurements were calculated to determine the inter- and intraobserver variability. Interobserver variability was defined as the difference in the measurements between observers. Intraobserver variability was defined as the difference in repeated measurements by the same observer.ResultsPreoperatively, the interobserver ICC was 0.4 (gap and stepoff) on radiographs and 0.4 (gap) and 0.3 (stepoff) on CT images. The observers agreed on the indication for surgery in 40% (gap) and 30% (stepoff) on pelvic radiographs. For CT scans the observers agreed in 95% (gap) and 70% (stepoff) of images. Postoperatively, the interobserver ICC was 0.4 (gap) and 0.2 (stepoff) on radiographs. The observers agreed on whether the reduction was acceptable or not in 60% (gap) and 40% (stepoff). On CT images the ICC was 0.3 (gap) and 0.4 (stepoff). The observers agreed on whether the reduction was acceptable in 35% (gap) and 38% (stepoff). The preoperative intraobserver ICC was 0.6 (gap and stepoff) on pelvic radiographs and 0.4 (gap) and 0.6 (stepoff) for CT scans. Postoperatively, the intraobserver ICC was 0.7 (gap) and 0.1 (stepoff) on pelvic radiographs. On CT the intraobserver ICC was 0.5 (gap) and 0.3 (stepoff). There was no agreement between the observers on the presence of a gap or stepoff on intraoperative fluoroscopy images (kappa -0.1 to 0.2).ConclusionsWe found an insufficient interobserver and intraobserver agreement on measuring gaps and stepoffs for supporting clinical decisions in acetabular fracture surgery. If observers cannot agree on the size of the gap and stepoff, it will be challenging to decide when to perform surgery and study the results of acetabular fracture surgery.Level of EvidenceLevel III, diagnostic study.     

Quilting Prevents Seroma Formation Following Breast Cancer Surgery: Closing the Dead Space by Quilting Prevents Seroma Following Axillary Lymph Node Dissection and Mastectomy

Background

Seroma is a frequent problem after mastectomy (ME) and axillary lymph node dissection (ALND). Seroma is associated with pain, discomfort, impaired mobilisation and repeated aspirations, often resulting in a surgical site infection (SSI). It has already been demonstrated that minimizing dead space through fixation of the skin flaps to the underlying muscles (quilting) lowers the incidence of seroma. The aim of this study was to evaluate the effect of quilting on the incidence of seroma, and SSI.

Methods

Two consecutive groups with a total of 176 patients following ME and/or ALND were retrospectively compared. Endpoints were the incidence of seroma, and number and volume of aspirations and SSIs. Analysed risk factors were age, ME, lymph node dissection, neoadjuvant therapy, body mass index (BMI) and hypertension.

Results

The quilted group (n = 89) scored significantly better on all endpoints compared with the conventional group (n = 87). The incidence of seroma decreased from 80.5 % to 22.5 % (p < 0.01), the mean number of aspirations from 4.86 to 2.40 (p = 0.015), the volume of aspirations from 1660 ml to 611 ml (p = 0.05) and the SSIs from 31.0 % to 11.2 % (p < 0.01). Increasing age and lymph node dissection were found to be risk factors for seroma; quilting was a protective factor.

Conclusion

Quilting is an effective method for preventing seroma and its complications.     

Implementation of a dynamic intestinal gut-on-a-chip barrier model for transport studies of lipophilic dioxin congeners

Novel microfluidic technologies allow the manufacture of in vitro organ-on-a-chip systems that hold great promise to adequately recapitulate the biophysical and functional complexity of organs found in vivo. In this study, a gut-on-a-chip model was developed aiming to study the potential cellular association and transport of food contaminants. Intestinal epithelial cells (Caco-2) were cultured on a porous polyester membrane that was tightly clamped between two glass slides to form two separate flow chambers. Glass syringes, polytetrafluoroethylene tubing and glass microfluidic chips were selected to minimize surface adsorption of the studied compounds (i.e. highly lipophilic dioxins), during the transport studies. Confocal microscopy studies revealed that, upon culturing under constant flow for 7 days, Caco-2 cells formed complete and polarized monolayers as observed after culturing for 21 days under static conditions in Transwells. We exposed Caco-2 monolayers in the chip and Transwell to a mixture of 17 dioxin congeners (7 polychlorinated dibenzo-p-dioxins and 10 polychlorinated dibenzofurans) for 24 h. Gas chromatography-high resolution mass spectrometry was used to assess the cellular association and transport of individual dioxin congeners across the Caco-2 cell monolayers. After 24 h, the amount of transported dioxin mixture was similar in both the dynamic gut-on-a-chip model and the static Transwell model. The transport of individual congeners corresponded with their number of chlorine atoms and substitution patterns as revealed by quantitative structure–property relationship modelling. These results show that the gut-on-a-chip model can be used, as well as the traditional static Transwell system, to study the cellular association and transport of lipophilic compounds like dioxins.

Novel microfluidic technologies allow the manufacture of in vitro organ-on-a-chip systems that hold great promise to adequately recapitulate the biophysical and functional complexity of organs found in vivo.     

What Do Medical Students Do and Want When Caring for “Difficult Patients”?

Phenomenon: Medical students, like physicians, experience negative emotions such as frustration when interacting with some patients, and many of these interactions occur for the first time during clinical clerkships. Students receive preclinical training in the social and behavioral sciences, often including learning about “difficult patient” interactions, yet little is known about their desire for training during clinical education. We explored students’ strategies in these difficult clinical interactions, whether they felt prepared by the curriculum, and what support they would have liked. These data inform proposed strategies for supporting clinical learning. Approach: We interviewed 4th-year students about interactions with patients toward whom they felt negative emotions and sought to identify strategies and supports needed in these interactions. Interviews ended when theoretical sufficiency was achieved. We used qualitative content analysis to organize strategies into themes about areas benefiting from curricular supports. We mapped students’ desired curricular support examples to cognitive apprenticeship teaching methods—modeling, coaching, reflection, scaffolding, exploration, and articulation—and aligned them with traditional pedagogical techniques. Findings: We interviewed 26 medical students (44 volunteered/180 invited). Their strategies formed five themes: finding empathy (with a subtheme of focusing on social determinants of health), using learned communication approaches, anticipating challenging interactions, seeking support, and considering it an opportunity for more responsibility. Students described ideal clinical teaching, including postinteraction debriefs with an emphasis on validating their emotional reactions and challenges. Students mentioned all cognitive apprenticeship teaching methods, most prominently modeling (observing supervisors in such interactions) and supported oral reflection. They also identified a need for faculty and resident development to enact these teaching methods. Insights: Although students use some learned strategies in interactions in which they feel negative emotions toward patients, they desire more preparation and support during their clinical rotations. Their desires map to traditional pedagogical techniques and to methods of cognitive apprenticeship. Our findings point to the need to use these techniques to enhance clinical learning for students who experience emotionally challenging patient interactions.     

Drying-induced hydrophobic polymer collapse

We have used computer simulation to study the collapse of a hydrophobic chain in water. We find that the mechanism of collapse is much like that of a first-order phase transition. The evaporation of water in the vicinity of the polymer provides the driving force for collapse, and the rate limiting step is the nucleation of a sufficiently large vapor bubble. The study is made possible through the application of transition path sampling and a coarse-grained treatment of liquid water. Relevance of our findings to understanding the folding and assembly of proteins is discussed.     

Prognostic value of predischarge 12 lead electrocardiogram after myocardial infarction compared with other routine clinical variables.

The prognostic value of QRS score (Selvester), ST depression, ST elevation, extrasystoles, P terminal force in V1, and QTc derived from the predischarge 12 lead electrocardiogram was assessed after myocardial infarction in 474 patients without intraventricular conduction defects, ventricular hypertrophy, or atrial fibrillation. The usefulness of these results in risk assessment was compared with that of other clinical data. During follow up 45 patients died. Logistic regression analysis showed that QRS score, ST depression, and QTc were independently predictive of cardiac mortality. When multivariate analysis was applied to clinical and electrocardiographic data together, however, the 12 lead electrocardiogram did not provide independent information additional to that provided by other routine clinical findings and laboratory tests such as a history of previous myocardial infarction, clinical signs of persistent heart failure, indication for digitalis or antiarrhythmic drugs at discharge, and enlarged heart on chest x ray. In conclusion, the electrocardiogram has important prognostic value; however, it is not powerful enough to further improve the risk assessment of post-infarction patients.     

Heart conduction disturbance: an HLA-B27 associated disease.

In recent studies from Sweden an increased prevalence of HLA-B27 associated diseases and of HLA-B27 was found in an unselected group of men with permanently implanted pacemakers and with a heart block. Furthermore, a significantly increased prevalence of HLA-B27 was found in men with a pacemaker who had no clinical or radiological signs of HLA-B27 associated disease. To obtain more insight into the association between HLA-B27 and heart block, and the possible role of HLA-B27 in causing this block, a study was made of 35 patients with a pacemaker and heart block of unknown cause, selected from a total group of 350 men with pacemakers who were still alive at the time of the study. One of these 35 men had ankylosing spondylitis and two patients had an asymptomatic sacroiliitis, but all three were HLA-B27 negative. HLA-B27 was present in five (14%) patients, which is a significantly higher prevalence than in healthy controls (17/292, 6%). This percentage is equal to the percentage of HLA-B27 positivity found in the Swedish study on unselected men with an implanted pacemaker, in whom the presence of an HLA-B27 associated disease had been excluded. It suggests that factors other than HLA-B27 are important in the pathogenesis of heart block in most patients.