Use of a disposable vascular pressure device to guide balloon inflation of resuscitative endovascular balloon occlusion of the aorta: a bench study.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) for rapid hemorrhage control is increasingly being used in trauma management. Its beneficial hemodynamic effects on unstable patients beyond temporal hemostasis has led to growing interest in its use in other patient populations, such as during cardiac arrest from nontraumatic causes. The ability to insert the catheters without fluoroscopic guidance makes the technique available in the prehospital setting. However, in addition to correct positioning, challenges include reliably achieving aortic occlusion while minimizing the risk of balloon rupture. Without fluoroscopic control, inflation of the balloon relies on estimated aortic diameters and on the disappearing pulse in the contralateral femoral artery. In the case of cardiac arrest or absent palpable pulses, balloon inflation is associated with excess risk of overinflation and adverse events (vessel damage, balloon rupture). In this bench study, we examined how the pressure in the balloon is related to the surrounding blood pressure and the balloon's contact with the vessel wall in two sets of experiments, including a pulsatile circulation model. With this data, we developed a rule of thumb to guide balloon inflation of the ER-REBOA catheter with a simple disposable pressure-reading device (COMPASS). We recommend slowly filling the balloon with saline until the measured balloon pressure is 160 mmHg, or 16 mL of saline have been used. If after 16 mL the balloon pressure is still below 160 mmHg, saline should be added in 1-mL increments, which increases the pressure target about 10 mmHg at each step, until the maximum balloon pressure is reached at 240 mmHg (= 24 mL inflation volume). A balloon pressure greater than 250 mmHg indicates overinflation. With this rule and a disposable pressure-reading device (COMPASS), ER-REBOA balloons can be safely filled in austere environments where fluoroscopy is unavailable. Pressure monitoring of the balloon allows for recognition of unintended deflation or rupture of the balloon.

A dangerously underrated entity? Non-specific complaints at emergency department presentation are associated with utilisation of less diagnostic resources.

BACKGROUND: Patients presenting with non-specific complaints (NSC), such as generalised weakness, or feeling unwell, constitute about 20% of emergency care consultations. In contrast to patients presenting with specific symptoms, these patients experience more hospitalisations, longer stays in hospital and even higher mortality. However, little is known about the actual resources spent on patients with NSC in the emergency department (ED). METHODS: We have conducted a retrospective analysis from January 1st, 2013 until December 31st, 2017 in a Swiss tertiary care ED to assess the impact of NSC on the utilisation of diagnostic resources in adult patients with highlyurgent or urgent medical complaints. RESULTS: We randomly selected 1500 medical consultations from our electronic health record database: The majority of patients (n = 1310, 87.3%) presented with a specific complaint; n = 190 (12.7%) with a NSC. Univariate analysis showed no significant difference in the utilisation of total diagnostic resources in the ED [specific complaints: 844 (577-1313) vs. NSC: 778 (551-1183) tax points, p = 0.092, median (interquartile range)]. A backward selection logistic regression model was adjusted for the identified covariates (age, diabetes, cerebrovascular and liver disease, malignancy, past myocardial infarction, antihypertensive, antithrombotic or antidiabetic medication, night or weekend admission and triage category). This identified a significant association of NSC with lower utilisation of ED diagnostic resources [geometric mean ratio (GMR) 0.91, 95% CI: 0.84-0.99, p = 0.042]. CONCLUSIONS: Non-specific complaints (NSC) are a frequent reason for emergency medicine consultations and are associated with lower utilisation of diagnostic resources during ED diagnostic testing than with specific complaints.

Man or machine? Impact of tutor-guided versus simulator-guided short-time bronchoscopy training on students learning outcomes.

BACKGROUND: Simulation based medical education is efficient for the acquisition of flexible bronchoscopy navigational skills and the knowledge of the tracheobronchial anatomy. However, bronchoscopy simulator training is not routinely integrated into pneumologic fellowship programs or undergraduate medical education for time and/or cost reasons. Our study compares the effect of self-guided bronchoscopy simulator training versus tutor guided training on the acquisition of navigational skills and knowledge of the bronchial anatomy. METHODS: Third-year undergraduate medical students were randomized to either a tutor- or simulator guided bronchoscopy simulator training focusing on the acquisition of navigational skills and the knowledge of the tracheobronchial anatomy. Every student performed a baseline bronchoscopy followed by a structured bronchoscopy simulator training and finally an assessment bronchoscopy at the end of the training program. Groups were compared by means of a repeated measurement ANOVA and effect sizes calculated as Cohens' d. RESULTS: Fifty-four eligible students participated in the study. Knowledge of the tracheobronchial anatomy significantly increased from pre- to post training (all p < 0.001; all d > 2), navigational skills significantly decreased (all p < 0.005; all d < 1). There were no significant differences between groups. Instruction by the simulator as well as by the tutor was rated as helpful by the students. Twenty-two (84.6%) of the participants of the simulator guided group would have appreciated an additional instruction by a tutor. CONCLUSION: Short-time simulator guided bronchoscopy training improves knowledge of the tracheobronchial anatomy in novice bronchoscopists as much as tutor guided training, but navigational skills seem to worsen in both groups. Further studies assessing transfer to clinical practice are needed to find the optimal teaching method for basic flexible bronchoscopy.

Online forward triage during the COVID-19 outbreak.

Health systems face major challenges during the COVID-19 pandemic with new information and challenges emerging daily and frequently changing guidelines. Online forward triage tools (OFTTs) provide useful information, direct patients and free physician resources.We implemented an OFTT targeted at the current pandemic, adapted the content and goals and assessed its effects. The OFTT was implemented on 2 March 2020 and modified regularly based on the revised testing criteria issued by the Swiss Federal Office of Public Health. After testing criteria liberalised, a chatbot tool was set up on 9 April 2020 to assess urgency of testing, referral to available testing sites and need for emergency care.In the first 40 days of the OFTT, there were more than 17 300 visitors and 69.8% indicated they would have contacted the healthcare system if the online test had not been available. During the initial week of operation, using the conservative testing strategy, 9.1% of visitors received recommendations to be tested, which increased to 36.0% of visitors after a change in testing criteria on 9 March 2020. Overall, since the implementation of the tool, 26.27% of all users of the site have been directed to obtain testing. The Chatbot tool has had approximately 50 consults/day.Setting up an OFTT should be considered as part of local strategies to cope with the COVID-19 pandemic. It may ease the burden on the healthcare system, reassure patients and inform authorities. To account for the dynamic development of the pandemic, frequent adaptation of the tool is of great importance. Further research on clinical outcomes of OFTT is urgently needed.

High prevalence of recreational and illicit drug use in German people living with HIV with a potential for drug-drug interactions with antiretroviral therapy.

Recreational drug use is higher in people living with HIV (PLHIV) than in the general population in Europe. This use increases the risk for drug-drug interactions (DDIs) and adverse events. We assessed the prevalence and clinical consequences of substance abuse among PLHIV. BESIDE was a cross-sectional, multi-center study in 2016/18, evaluating comorbidities, polypharmacy and recreational/illicit drug use in PLHIV on antiretroviral therapy (ART) in Germany. Legal and illicit drug use was recorded using two anonymous patient questionnaires one year apart (Q1 and Q2). The BESIDE study population consisted of 453 PLHIV (22% female, median age 46 years). Recreational drug use was reported by the majority (Q1: ever used 73%, within previous 6 months 56%): nitrite inhalants ("poppers"), cannabis and PDE-5 inhibitors were common across all age groups; ecstasy, (meth-)amphetamine and gamma-hydroxybutyrate/gamma-butyrolactone were predominantly reported by younger PLHIV. Based on Q2, two-thirds of PLHIV (67%) had been informed about potential risks of drug abuse by their doctors, whereas one-third (33%) had talked to their doctors on their own initiative with only 7% considering drug use in combination with ART a problem. Strikingly, 44% and 42% had undergone medical treatment or had been hospitalized due to drug use. These data emphasize the high clinical relevance of recreational drug use in PLHIV and the need for treating physicians to pro-actively communicate the potential risks.

High prevalence of comorbidities and use of concomitant medication in treated people living with HIV in Germany - results of the BESIDE study.

Due to demographic changes in people living with HIV (PLHIV), physicians are challenged with age-related comorbidities and their management. In the absence of comprehensive data collection, the burden of comorbidities and co-medication in addition to antiretroviral therapy (ART) remains unclear for the German real-world setting. BESIDE was an observational, cross-sectional study evaluating the prevalence of comorbidities and use of co-medication in treated PLHIV. Regional distribution of study centers (n = 20), consecutive patient recruitment, and age-stratified sampling in alignment with national epidemiologic data aimed to ensure a representative sample (n = 453). The overall prevalence of comorbidities was 91.2%; 31.6% of patients had ≥4 comorbidities. The most common diagnoses were vitamin D deficiency (29.1%), depressive episode (27.8%), arterial hypertension (16.3%), and hypercholesterolemia (10.8%). 83.7% of patients were on co-medication; 21.2% taking ≥4 medications. The most common medications or supplements were vitamins (31.6%), anti-inflammatory agents (16.1%), renin-angiotensin system agents (12.1%), acid suppressants (11.7%), lipid modifying agents (10.8%); 1.3% of patients were on co-medication that should not be co-administered with ART, 41.5% on co-medication with potential for drug-drug interactions. The prevalence of comorbidities and use of co-medication among treated PLHIV in Germany is consistently high and increases across age groups, illustrating the complexity of HIV care involving appropriate ART selection.

Anemia and iron metabolism in COVID-19: a systematic review and meta-analysis.

Iron metabolism and anemia may play an important role in multiple organ dysfunction syndrome in Coronavirus disease 2019 (COVID-19). We conducted a systematic review and meta-analysis to evaluate biomarkers of anemia and iron metabolism (hemoglobin, ferritin, transferrin, soluble transferrin receptor, hepcidin, haptoglobin, unsaturated iron-binding capacity, erythropoietin, free erythrocyte protoporphyrine, and erythrocyte indices) in patients diagnosed with COVID-19, and explored their prognostic value. Six bibliographic databases were searched up to August 3rd 2020. We included 189 unique studies, with data from 57,563 COVID-19 patients. Pooled mean hemoglobin and ferritin levels in COVID-19 patients across all ages were 129.7 g/L (95% Confidence Interval (CI), 128.51; 130.88) and 777.33 ng/mL (95% CI, 701.33; 852.77), respectively. Hemoglobin levels were lower with older age, higher percentage of subjects with diabetes, hypertension and overall comorbidities, and admitted to intensive care. Ferritin level increased with older age, increasing proportion of hypertensive study participants, and increasing proportion of mortality. Compared to moderate cases, severe COVID-19 cases had lower hemoglobin [weighted mean difference (WMD), - 4.08 g/L (95% CI - 5.12; - 3.05)] and red blood cell count [WMD, - 0.16 × 1012 /L (95% CI - 0.31; - 0.014)], and higher ferritin [WMD, - 473.25 ng/mL (95% CI 382.52; 563.98)] and red cell distribution width [WMD, 1.82% (95% CI 0.10; 3.55)]. A significant difference in mean ferritin levels of 606.37 ng/mL (95% CI 461.86; 750.88) was found between survivors and non-survivors, but not in hemoglobin levels. Future studies should explore the impact of iron metabolism and anemia in the pathophysiology, prognosis, and treatment of COVID-19.

Somatic gene editing ameliorates skeletal and cardiac muscle failure in pig and human models of Duchenne muscular dystrophy.

Frameshift mutations in the DMD gene, encoding dystrophin, cause Duchenne muscular dystrophy (DMD), leading to terminal muscle and heart failure in patients. Somatic gene editing by sequence-specific nucleases offers new options for restoring the DMD reading frame, resulting in expression of a shortened but largely functional dystrophin protein. Here, we validated this approach in a pig model of DMD lacking exon 52 of DMD (DMDΔ52), as well as in a corresponding patient-derived induced pluripotent stem cell model. In DMDΔ52 pigs1, intramuscular injection of adeno-associated viral vectors of serotype 9 carrying an intein-split Cas9 (ref. 2) and a pair of guide RNAs targeting sequences flanking exon 51 (AAV9-Cas9-gE51) induced expression of a shortened dystrophin (DMDΔ51-52) and improved skeletal muscle function. Moreover, systemic application of AAV9-Cas9-gE51 led to widespread dystrophin expression in muscle, including diaphragm and heart, prolonging survival and reducing arrhythmogenic vulnerability. Similarly, in induced pluripotent stem cell-derived myoblasts and cardiomyocytes of a patient lacking DMDΔ52, AAV6-Cas9-g51-mediated excision of exon 51 restored dystrophin expression and amelioreate skeletal myotube formation as well as abnormal cardiomyocyte Ca2+ handling and arrhythmogenic susceptibility. The ability of Cas9-mediated exon excision to improve DMD pathology in these translational models paves the way for new treatment approaches in patients with this devastating disease.

Linkage between growth retardation and pituitary cell morphology in a dystrophin-deficient pig model of Duchenne muscular dystrophy.

OBJECTIVE: Human patients with Duchenne muscular dystrophy (DMD) commonly exhibit a short stature, but the pathogenesis of this growth retardation is not completely understood. Due to the suspected involvement of the growth hormone/insulin-like growth factor 1 (GH/IGF1) system, controversial therapeutic approaches have been developed, including both GH- administration, as well as GH-inhibition. In the present study, we examined relevant histomorphological and ultrastructural features of adenohypophyseal GH-producing somatotroph cells in a porcine DMD model. METHODS: The numbers and volumes of immunohistochemically labelled somatotroph cells were determined in consecutive semi-thin sections of plastic resin embedded adenohypophyseal tissue samples using unbiased state-of-the-art quantitative stereological analysis methods. RESULTS: DMD pigs displayed a significant growth retardation, accounting for a 55% reduction of body weight, accompanied by a significant 50% reduction of the number of somatotroph cells, as compared to controls. However, the mean volumes of somatotroph cells and the volume of GH-granules per cell were not altered. Western blot analyses of the adenohypophyseal protein samples showed no differences in the relative adenohypophyseal GH-abundance between DMD pigs and controls. CONCLUSION: The findings of this study do not provide evidence for involvement of somatotroph cells in the pathogenesis of growth retardation of DMD pigs. These results are in contrast with previous findings in other dystrophin-deficient animal models, such as the golden retriever model of Duchenne muscular dystrophy, where increased mean somatotroph cell volumes and elevated volumes of intracellular GH-granules were reported and associated with DMD-related growth retardation. Possible reasons for the differences of somatotroph morphology observed in different DMD models are discussed.

Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells.

The transcriptional regulator BRD4 has been shown to be important for the expression of several oncogenes including MYC. Inhibiting of BRD4 has broad antiproliferative activity in different cancer cell types. The small molecule JQ1 blocks the interaction of BRD4 with acetylated histones leading to transcriptional modulation. Depleting BRD4 via engineered bifunctional small molecules named PROTACs (proteolysis targeting chimeras) represents the next-generation approach to JQ1-mediated BRD4 inhibition. PROTACs trigger BRD4 for proteasomale degradation by recruiting E3 ligases. The aim of this study was therefore to validate the importance of BRD4 as a relevant target in colorectal cancer (CRC) cells and to compare the efficacy of BRD4 inhibition with BRD4 degradation on downregulating MYC expression. JQ1 induced a downregulation of both MYC mRNA and MYC protein associated with an antiproliferative phenotype in CRC cells. dBET1 and MZ1 induced degradation of BRD4 followed by a reduction in MYC expression and CRC cell proliferation. In SW480 cells, where dBET1 failed, we found significantly lower levels of the E3 ligase cereblon, which is essential for dBET1-induced BRD4 degradation. To gain mechanistic insight into the unresponsiveness to dBET1, we generated dBET1-resistant LS174t cells and found a strong downregulation of cereblon protein. These findings suggest that inhibition of BRD4 by JQ1 and degradation of BRD4 by dBET1 and MZ1 are powerful tools for reducing MYC expression and CRC cell proliferation. In addition, downregulation of cereblon may be an important mechanism for developing dBET1 resistance, which can be evaded by incubating dBET1-resistant cells with JQ1 or MZ1.

Carditis: a relevant marker of gastroesophageal reflux disease. Data from a prospective central European multicenter study on histological and endoscopic diagnosis of esophagitis (histoGERD trial).

The columnar-lined mucosa at the gastroesophageal junction may contain an inflammatory infiltrate, commonly referred to as carditis (or cardia gastritis). The etiology of carditis is not entirely clear since published data are conflicting. Some authors believe it to be secondary to gastroesophageal reflux disease (GERD) and others to Helicobacter pylori gastritis. This prospective study aims at clarifying the relationship between carditis and the histological, clinical, and endoscopic findings of GERD, in a large cohort of individuals negative for H. pylori infection. Eight hundred and seventy-three individuals (477 females and 396 males, median age 53 years) participated in this study. Biopsy material was systematically sampled from above and below the gastroesophageal junction. Reflux-associated changes of the esophageal squamous epithelium were assessed according to the Esohisto consensus guidelines. Grading of carditis was performed according to the Updated Sydney System, known from the histological evaluation of gastritis. In total, 590 individuals (67.5%) had chronic carditis. Of these, 468 (53.6%) had mild chronic inflammation, with 321 individuals (68.6%) showing no or minimal changes on endoscopic examination (Los Angeles Categories N and M). The presence of chronic carditis was associated with several GERD-related parameters of the esophageal squamous epithelium (P < 0.0001), and data retained statistical significance even when analysis was restricted to individuals with mild chronic carditis and/or endoscopically normal mucosa. Chronic carditis was also associated with the presence of intestinal metaplasia (P < 0.0001). In addition, chronic carditis had a statistically significant association with patients' symptoms of GERD (P = 0.0107). This observation remained valid for mild chronic carditis in all patients (P = 0.0038) and in those with mild chronic carditis and normal endoscopic mucosa (P = 0.0217). In conclusion, chronic carditis appears to be the immediate consequence of GERD, correlating with patients' symptoms and endoscopic diagnosis. These results are valid in individuals with nonerosive reflux disease, which indicates a higher sensitivity of histological diagnosis. Our findings may impact the routine assessment of reflux patients.

Impact of the communication and patient hand-off tool SBAR on patient safety: a systematic review.

OBJECTIVES: Communication breakdown is one of the main causes of adverse events in clinical routine, particularly in handover situations. The communication tool SBAR (situation, background, assessment and recommendation) was developed to increase handover quality and is widely assumed to increase patient safety. The objective of this review is to summarise the impact of the implementation of SBAR on patient safety. DESIGN: A systematic review of articles published on SBAR was performed in PUBMED, EMBASE, CINAHL, Cochrane Library and PsycINFO in January 2017. All original research articles on SBAR fulfilling the following eligibility criteria were included: (1) SBAR was implemented into clinical routine, (2) the investigation of SBAR was the primary objective and (3) at least one patient outcome was reported. SETTING: A wide range of settings within primary and secondary care and nursing homes. PARTICIPANTS: A variety of heath professionals including nurses and physicians. PRIMARY AND SECONDARY OUTCOME MEASURES: Aspects of patient safety (patient outcomes) defined as the occurrence or incidence of adverse events. RESULTS: Eight studies with a before-after design and three controlled clinical trials performed in different clinical settings met the inclusion criteria. The objectives of the studies were to improve team communication, patient hand-offs and communication in telephone calls from nurses to physicians. The studies were heterogeneous with regard to study characteristics, especially patient outcomes. In total, 26 different patient outcomes were measured, of which eight were reported to be significantly improved. Eleven were described as improved but no further statistical tests were reported, and six outcomes did not change significantly. Only one study reported a descriptive reduction in patient outcomes. CONCLUSIONS: This review found moderate evidence for improved patient safety through SBAR implementation, especially when used to structure communication over the phone. However, there is a lack of high-quality research on this widely used communication tool. TRIAL REGISTRATION: none.

A paternal methyl donor-rich diet altered cognitive and neural functions in offspring mice.

Dietary intake of methyl donors, such as folic acid and methionine, shows considerable intra-individual variation in human populations. While it is recognized that maternal departures from the optimum of dietary methyl donor intake can increase the risk for mental health issues and neurological disorders in offspring, it has not been explored whether paternal dietary methyl donor intake influences behavioral and cognitive functions in the next generation. Here, we report that elevated paternal dietary methyl donor intake in a mouse model, transiently applied prior to mating, resulted in offspring animals (methyl donor-rich diet (MD) F1 mice) with deficits in hippocampus-dependent learning and memory, impaired hippocampal synaptic plasticity and reduced hippocampal theta oscillations. Gene expression analyses revealed altered expression of the methionine adenosyltransferase Mat2a and BK channel subunit Kcnmb2, which was associated with changes in Kcnmb2 promoter methylation in MD F1 mice. Hippocampal overexpression of Kcnmb2 in MD F1 mice ameliorated altered spatial learning and memory, supporting a role of this BK channel subunit in the MD F1 behavioral phenotype. Behavioral and gene expression changes did not extend into the F2 offspring generation. Together, our data indicate that paternal dietary factors influence cognitive and neural functions in the offspring generation.

Improving patient safety through better teamwork: how effective are different methods of simulation debriefing? Protocol for a pragmatic, prospective and randomised study.

INTRODUCTION: Medical errors have an incidence of 9% and may lead to worse patient outcome. Teamwork training has the capacity to significantly reduce medical errors and therefore improve patient outcome. One common framework for teamwork training is crisis resource management, adapted from aviation and usually trained in simulation settings. Debriefing after simulation is thought to be crucial to learning teamwork-related concepts and behaviours but it remains unclear how best to debrief these aspects. Furthermore, teamwork-training sessions and studies examining education effects on undergraduates are rare. The study aims to evaluate the effects of two teamwork-focused debriefings on team performance after an extensive medical student teamwork training. METHODS AND ANALYSES: A prospective experimental study has been designed to compare a well-established three-phase debriefing method (gather-analyse-summarise; the GAS method) to a newly developed and more structured debriefing approach that extends the GAS method with TeamTAG (teamwork techniques analysis grid). TeamTAG is a cognitive aid listing preselected teamwork principles and descriptions of behavioural anchors that serve as observable patterns of teamwork and is supposed to help structure teamwork-focused debriefing. Both debriefing methods will be tested during an emergency room teamwork-training simulation comprising six emergency medicine cases faced by 35 final-year medical students in teams of five. Teams will be randomised into the two debriefing conditions. Team performance during simulation and the number of principles discussed during debriefing will be evaluated. Learning opportunities, helpfulness and feasibility will be rated by participants and instructors. Analyses will include descriptive, inferential and explorative statistics. ETHICS AND DISSEMINATION: The study protocol was approved by the institutional office for data protection and the ethics committee of Charité Medical School Berlin and registered under EA2/172/16. All students will participate voluntarily and will sign an informed consent after receiving written and oral information about the study. Results will be published.

Shame in Medical Education: A Randomized Study of the Acquisition of Intimate Examination Skills and Its Effect on Subsequent Performance.

THEORY: Although medical students are exposed to a variety of emotions, the impact of emotions on learning has received little attention so far. Shame-provoking intimate examinations are among the most memorable events for students. Their emotions, however, are rarely addressed during training, potentially leading to withdrawal and avoidance and, consequently, performance deficits. However, emotions of negative valance such as shame may be particularly valuable for learning, as they might prompt mental rehearsal. We investigated the effect of shame on learning from the perspective of cognitive load theory. HYPOTHESES: We hypothesized that (a) training modality determines state shame, (b) state shame directly affects the quality of a clinical breast examination as one example of a shame-provoking exam, and (c) students who experience shame during training outperform those who just discuss the emotion during subsequent performance assessments. METHOD: Forty-nine advanced medical students participated in a randomized controlled, single-blinded study. After a basic, low-fidelity breast examination training, students were randomized to further practice either on a high-fidelity mannequin including a discussion of their emotions or by examining a standardized patient's real breasts. Last, all students conducted a breast examination in a simulated doctor's office. Dependent variables were measures of outcome and process quality and of situational shame. RESULTS: Students training with a standardized patient experienced more shame during training (p < .001, d = 2.19), spent more time with the patient (p = .005, d = 0.89), and documented more breast lumps (p = .026, d = 0.65) than those training on a mannequin. Shame interacted with training modality, F(1, 45) = 21.484, p < .001, η2 = 0.323, and differences in performance positively correlated to decline in state shame (r = .335, p = .022). CONCLUSIONS: Students experiencing state shame during training do reenact their training and process germane load-in other words, learn. Furthermore, altering simulation modality offers a possibility for educators to adjust the affective component of training to their objectives.

OmoMYC blunts promoter invasion by oncogenic MYC to inhibit gene expression characteristic of MYC-dependent tumors.

MYC genes have both essential roles during normal development and exert oncogenic functions during tumorigenesis. Expression of a dominant-negative allele of MYC, termed OmoMYC, can induce rapid tumor regression in mouse models with little toxicity for normal tissues. How OmoMYC discriminates between physiological and oncogenic functions of MYC is unclear. We have solved the crystal structure of OmoMYC and show that it forms a stable homodimer and as such recognizes DNA in the same manner as the MYC/MAX heterodimer. OmoMYC attenuates both MYC-dependent activation and repression by competing with MYC/MAX for binding to chromatin, effectively lowering MYC/MAX occupancy at its cognate binding sites. OmoMYC causes the largest decreases in promoter occupancy and changes in expression on genes that are invaded by oncogenic MYC levels. A signature of OmoMYC-regulated genes defines subgroups with high MYC levels in multiple tumor entities and identifies novel targets for the eradication of MYC-driven tumors.

The target cell of transformation is distinct from the leukemia stem cell in murine CALM/AF10 leukemia models.

The CALM/AF10 fusion gene is found in various hematological malignancies including acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia and malignant lymphoma. We have previously identified the leukemia stem cell (LSC) in a CALM/AF10-driven murine bone marrow transplant AML model as B220+ lymphoid cells with B-cell characteristics. To identify the target cell for leukemic transformation or 'cell of origin of leukemia' (COL) in non-disturbed steady-state hematopoiesis, we inserted the CALM/AF10 fusion gene preceded by a loxP-flanked transcriptional stop cassette into the Rosa26 locus. Vav-Cre-induced panhematopoietic expression of the CALM/AF10 fusion gene led to acute leukemia with a median latency of 12 months. Mice expressing CALM/AF10 in the B-lymphoid compartment using Mb1-Cre or CD19-Cre inducer lines did not develop leukemia. Leukemias had a predominantly myeloid phenotype but showed coexpression of the B-cell marker B220, and had clonal B-cell receptor rearrangements. Using whole-exome sequencing, we identified an average of two to three additional mutations per leukemia, including activating mutations in known oncogenes such as FLT3 and PTPN11. Our results show that the COL for CALM/AF10 leukemia is a stem or early progenitor cell and not a cell of B-cell lineage with a phenotype similar to that of the LSC in CALM/AF10+ leukemia.

Use of botulinum toxin type A in symptomatic accessory soleus muscle: first five cases.

Symptomatic accessory soleus muscle (ASM) can cause exercise-induced leg pain due to local nerve/vascular compression, muscle spasm, or local compartment syndrome. As intramuscular injections of botulinum toxin type A (BTX-A) can reduce muscle tone and mass, we investigated whether local BTX-A injections relieve the pain associated with symptomatic ASM. We describe five patients presenting peri/retromalleolar exertional pain and a contractile muscle mass in the painful region. Com-pression neuropathy was ruled out by electromyo-graphic analysis of the lower limb muscles. Doppler ultrasonography was normal, excluding a local vascular compression. ASM was confirmed by magnetic resonance imaging. After a treadmill stress test, abnormal intramuscular pressure values in the ASM, confirmed the diagnosis of compartment syndrome only in one patient. All five patients received BTX-A injections in two points of the ASM. The treatment efficacy was evaluated based on the disappearance of exercise-induced pain and the resumption of normal physical and sports activities. After BTX-A injection, exertional pain disappeared and all five patients resumed their normal level of physical and sports performances. Neither side effects nor motor deficits were observed. BTX-A is well tolerated in patients with ASM and could be used as a new conservative therapeutic strategy for the treatment of symptomatic ASM before surgery.

Laparoscopic cholecystectomy in acute cholecystitis: support for an early interval surgery.

BACKGROUND AND STUDY AIMS: Although laparoscopic cholecystectomy is advocated for acute cholecystitis, debate still exists about its optimal timing. This retrospective study compares the outcome of laparoscopic cholecystectomy within versus later than 5 days of onset of symptoms in patients with acute cholecystitis. PATIENTS AND METHODS: One hundred thirty six patients with acute cholecystitis grade I or II were included in the study and divided in two groups. Group 1 received surgery within 5 days of symptoms and group 2 received conservative therapy and delayed surgery after 6 weeks. RESULTS: Group 1 and 2 consisted of 100 and 36 patients respec- tively. Because of failure of conservative therapy 5 patients of group 2 had surgery before 6 weeks. The remaining 31 patients underwent surgery after 6 weeks. Preoperative ERCP was indicated in 2 and 11 patients in groups 1 and 2 respectively (p < 0.001). The median total hospital stay was 3.0 days for group 1 and 11.0 days for group 2 (p < 0.001). In terms of operation time, conversion rates, intraoperative cholangiography, postoperative ERCP, morbidity or mortality both groups were comparable (p > 0.05). CONCLUSION: Laparoscopic cholecystectomy can be performed safely within 5 days after the onset of symptoms in patients with acute cholecystitis. Because of shortened total hospital stay and risk of failure of conservative therapy, early laparoscopic cholecystectomy should be favored.