Mutational profiles of metastatic colorectal cancer treated with FOLFIRI plus cetuximab or bevacizumab before and after secondary resection (AIO KRK 0306; FIRE-3)

Secondary resection of metastases is recommended in metastatic colorectal cancer (mCRC). Data describing changes in mutational profiles of corresponding primary tumor and metastatic tissue after conversion treatment are limited. Next generation sequencing was performed in formalin-fixed mCRC samples from patients of the FIRE-3 trial (FOLFIRI plus cetuximab or bevacizumab) before treatment start (baseline) and after secondary resection of metastases (post baseline). Changes of mutational profiles and tumor mutational burden (TMB) were assessed within a post-hoc analysis. Median overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were compared between treatment arms. Paired tumor samples were obtained from 25 patients (19 RAS wild-type, 6 RAS mutant by pyrosequencing). ORR (92.0% vs 58.0%) and OS (60.8 vs 35.4 months, hazard ratio = 0.39 [95% CI 0.14-1.12], P = .08) were higher for patients receiving cetuximab. After conversion therapy, 56 alterations (42 in the cetuximab and 14 in the bevacizumab arm) were newly observed in 18 patients (9 each treated with cetuximab or bevacizumab). Gains (n = 21) and losses (n = 21) of alterations occurred during cetuximab-based treatment, while mainly gains of alterations occurred during bevacizumab (n = 10). Three of nine patients treated with cetuximab that presented a change of mutational profiles, developed resistance to cetuximab. Mutational profiles were largely comparable before and after treatment with anti-VEGF or anti-EGFR directed monoclonal antibodies after secondary resection. Mutations associated with resistance to anti-EGFR antibodies were observed in only one-third of patients

Dental injuries resulting from tracheal intubation - a retrospective study

Even though it is known that dental injuries may occur in connection with tracheal intubation, the topic has hardly been evaluated in literature so far. Thus, this retrospective study was conducted including the data of 115-151 patients. All patients involved had been exposed to general anesthesia between 1995 and 2005. The resulting tooth injuries were assessed according to the following parameters: age, kind of hospital conducting treatment, intubation difficulties, pre-existing tooth damage, type and localization of tooth, type of tooth damage, and the number of teeth injured. At least 170 teeth were injured in 130 patients, while patients 50 years of age and older were especially affected. In contrast to older patients where in the majority of cases the periodontium (lateral dislocation) was injured, in younger patients dental hard tissue (crown fracture) was more likely to be affected. It was calculated that patients from the cardiothoracic surgery clinic were showing the highest risk of tooth damage. In more than three-fourth of all cases the anterior teeth of the maxilla, especially the maxillary central incisors, were affected. Pre-existing dental pathology like caries, marginal periodontitis and tooth restorations were often distinguishable prior to operation. Mouthguards in connection with tracheal intubation are not generally recommended as preventive device, due to the already limited amount of space available. Instead, pre-existing risk factors should be thoroughly explored before the induction of intubation narcosis

Strategies for residual stress adjustment in bulk metal forming

The family of bulk forming technologies comprises processes characterised by a complex threedimensional stress and strain state. Besides shape and material properties also residual stresses are modified during a bulk metal forming process. The state of residual stresses affects important properties, like fatigue behaviour and corrosion resistance. An adjustment of the residual stresses is possible through subsequent process steps such as heat treatments or mechanical surface modification technologies, like shot peening and deep rolling. However, these additional manufacturing steps involve supplementary costs, longer manufacturing times and harmful effects on the product quality. Therefore, an optimized strategy consists in a targeted introduction of residual stresses during the forming processes. To enable this approach, a fundamental understanding of the underlying mechanisms of residual stress generation in dependence of the forming parameters is necessary. The current state of the art is reviewed in this paper. Strategies for the manipulation of the2 residual stresses in different bulk forming processes are classified according to the underlying principles of process modification

Structural and mechanistic insights into mechanoactivation of focal adhesion kinase

9 p.-7 fig.-1 tab.Focal adhesion kinase (FAK) is a key signaling molecule regulating cell adhesion, migration, and survival. FAK localizes into focal adhesion complexes formed at the cytoplasmic side of cell attachment to the ECM and is activated after force generation via actomyosin fibers attached to this complex. The mechanism of translating mechanical force into a biochemical signal is not understood, and it is not clear whether FAK is activated directly by force or downstream to the force signal. We use experimental and computational single-molecule force spectroscopy to probe the mechanical properties of FAK and examine whether force can trigger activation by inducing conformational changes in FAK. By comparison with an open and active mutant of FAK, we are able to assign mechanoactivation to an initial rupture event in the low-force range. This activation event occurs before FAK unfolding at forces within the native range in focal adhesions. We are also able to assign all subsequent peaks in the force landscape to partial unfolding of FAK modules. We show that binding of ATP stabilizes the kinase domain, thereby altering the unfolding hierarchy. Using all-atom molecular dynamics simulations, we identify intermediates along the unfolding pathway, which provide buffering to allow extension of FAK in focal adhesions without compromising functionality. Our findings strongly support that forces in focal adhesions applied to FAK via known interactions can induce conformational changes, which in turn, trigger focal adhesion signaling.C.D. and F.G. are grateful for support from the state of Baden-Wu¨ rttemberg through high performance computing in Baden-Wu¨ rttemberg (bwHPC) and Deutsche Forschungsgemeinschaft (DFG) Grant INST 35/1134-1 FUGG. H.E.G. acknowledges funding from DFG Grant Sonderforschungsbereich 1032. F.G. acknowledges funding from the DFG through the research group SHENC (Shear Flow Regulation of Hemostasis—Bridging the Gap Between Nanomechanics and Clinical Presentation) and from the Klaus Tschira Foundation. D.L. acknowledges support from Spanish Ministry of Economy, Industry and Competitiveness Retos Grant BFU2016-77665-R cofunded by the European Regional Development Fund and Volkswagen Foundation Grant Az: 86 416-1. D.L. is the recipient of Worldwide Cancer Research Award 15-1177.Peer reviewe

Effectiveness of IV Cannulation Skills Laboratory Training and Its Transfer into Clinical Practice: A Randomized, Controlled Trial

<div><h3>Background</h3><p>The effectiveness of skills laboratory training is widely recognized. Yet, the transfer of procedural skills acquired in skills laboratories into clinical practice has rarely been investigated. We conducted a prospective, randomised, double-blind, controlled trial to evaluate, if students having trained intravenous (IV) cannulation in a skills laboratory are rated as more professional regarding technical and communication skills compared to students who underwent bedside teaching when assessed objectively by independent video assessors and subjectively by patients.</p> <h3>Methodology and Principal Findings</h3><p>84 volunteer first-year medical students were randomly assigned to one of two groups. Three drop-outs occurred. The intervention group (IG; <em>n</em> = 41) trained IV cannulation in a skills laboratory receiving instruction after Peyton's ‘Four-Step Approach’. The control group (CG; <em>n</em> = 40) received a bedside teaching session with volunteer students acting as patients. Afterwards, performance of IV cannulation of both groups in a clinical setting with students acting as patients was video-recorded. Two independent, blinded video assessors scored students' performance using binary checklists (BC) and the Integrated Procedural Protocol Instrument (IPPI). Patients assessed students' performance with the Communication Assessment Tool (CAT) and a modified IPPI. IG required significantly shorter time needed for the performance on a patient (IG: 595.4 SD(188.1)s; CG: 692.7 SD(247.8)s; 95%CI 23.5 s to 45.1 s; p = 0.049) and completed significantly more single steps of the procedure correctly (IG: 64% SD(14) for BC items; CG: 53% SD(18); 95%CI 10.25% to 11.75%; p = 0.004). IG also scored significantly better on IPPI ratings (median: IG: 3.1; CG: 3.6; p = 0.015;). Rated by patients, students' performance and patient-physician communication did not significantly differ between groups.</p> <h3>Conclusions</h3><p>Transfer of IV cannulation-related skills acquired in a skills laboratory is superior to bedside teaching when rated by independent video raters by means of IPPI and BC. It enables students to perform IV cannulation more professionally on volunteer students acting as patients.</p> </div

Study design.

<p>* Kolb = Kolb Learning Style Inventory; JSPE = Jefferson Scale of Physician Empathy; GSE = General Self-Efficacy; SE = IV cannulation related Self-Efficacy. Post-interventional Evaluation = Evaluation of teaching model acceptance. IPPI = Integrated Procedural Protocol Instrument; CAT = Communication Assessment Tool; BC = Binary Checklist. Figure modified from the CONSORT 2010 flow diagram templates <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032831#pone.0032831-Moher1" target="_blank">[50]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032831#pone.0032831-Moher2" target="_blank">[51]</a>.</p

Baseline data.

<p>LSI = Kolb Learning Style Inventory; JSPE = Jefferson Scale of Physician Empathy; GSE = General Self-Efficacy. Data are means (SD) or numbers (%) or medians. P-values were calculated using students t-test for age, chi-quadrat test for gender, preceeding health care related or medical profession other than paramedic or nurse (i.e. physiotherapy, dental assistant, etc.), civil service and nursing electives. Mann-Whitney U-Tests for LSI, JSPE, GSE and Pre-Interventional IV cannulation-related Self-Efficacy.</p

Results of the patient-ratings of students' IV cannulation skills.

<p>CAT = Communication Assessment Tool (12 items, Likert-scale rating ranging from 1 = “very good” to 6 = “unsatisfactory”); IPPI = Integrated Procedural Performance Instrument (11 items, Likert-scale rating ranging from 1 = “very good” to 6 = “unsatisfactory”); median; P-values were calculated using Mann-Whitney U-Test results.</p

Results of the video ratings of students' IV cannulation skills.

<p>BC = binary checklist (percent of correctly demonstrated procedural single steps); IPPI = Integrated Procedural Performance Instrument (11 items, Likert-scale rating ranging from 1 = very good to 6 = unsatisfactory); SD = standard deviation; SEM_D = standard error of the mean difference; P-values are calculated with students T-test results for BC and Mann-Whitney U-Test results for IPPI.</p