Observational Study About the Impact of Simulation Training of Non-Technical Skills on Teamwork: Towards a Paradigm Shift in Undergraduate Medical Training.

INTRODUCTION: Recently, simulation as an educational method has gained increasing importance in Medicine. However, medical education has favored the acquisition of individual knowledge and skills, while overlooking the development of teamwork skills. Since most errors in clinical practice are due to human factors, i.e., non-technical skills, the aim of this study was to assess the impact that training in a simulation environment has on teamwork in an undergraduate setting. MATERIAL AND METHODS: This study took place in a simulation center, with a study population of 23 participants, fifth year undergraduate students, randomly divided into teams of four elements. Twenty simulated scenarios of teamwork in the initial assessment and resuscitation of critically ill trauma patients were recorded. Video recordings were made at three distinct learning moments (before training, end of the semester, and six months after the last training), and a blinded evaluation was performed by two independent observers, who applied the Trauma Team Performance Observation Tool (TPOT). Additionally, the Team STEPPS Teamwork Attitudes Questionnaire (T-TAQ) was applied to the study population before and after the training to assess any change in individual attitudes towards non-technical skills. A 5% (or 0.05) significance level was considered for statistical analysis. RESULTS: With a moderate level of inter-observer agreement (Kappa = 0.52, p = 0.002), there was a statistically significant improvement in the team's overall approach, evidenced by the TPOT scores (median of 4.23, 4.35 and 4.50, in the three time-points assessed, respectively, p = 0.003). In the T-TAQ, there was an improvement in non-technical skills, that was statistically significant for "Mutual Support" (median from 2.50 to 3.00, p = 0.010). CONCLUSION: In this study, incorporating non-technical skills education and training in undergraduate medical education was associated with sustained improvement in team performance in the approach to the simulated trauma patient. Consideration should be given to introducing non-technical skills training and teamwork in the emergency setting during undergraduate training.

Serum interleukin-6, procalcitonin, and C-reactive protein at hospital admission can identify patients at low risk for severe COVID-19 progression.

Background: COVID-19 can show a variable course, from asymptomatic infections to acute respiratory failure and death. For efficient allocation of resources, patients should be stratified according to their risk for a severe course as early as possible. Methods: 135 hospitalized patients with COVID-19 pneumonia at four German hospitals were prospectively included in this observational study. A standardized clinical laboratory profile was taken at hospital admission and a panel of serum markers with possible roles in the COVID-associated cytokine storm were also determined. 112 patients could be evaluated. The primary endpoint of ventilator requirement or death within 30 days of symptom onset was met by 13 patients. Results: Serum elevations of interleukin-6 (IL-6), procalcitonin (PCT), and C-reactive protein (CRP) at hospital admission were each highly significantly (p < 0.001) associated with ventilator requirement/death within 30 days of symptom onset. With a sensitivity of 92% and a specificity of 65-67%, IL-6 ≥ 52.8 pg/ml, PCT ≥ 0.11 ng/ml, and CRP ≥ 71.1 mg/L were predictive of a severe course of COVID-19. Positive likelihood ratios were between 2.6-2.8 and negative likelihood ratios were between 0.11-0.13 for these three markers. Conclusion: Negative likelihood ratios indicate that IL-6, PCT, and CRP at hospital admission can be used for identifying patients at low risk for severe COVID-19 progression.

Exploring the Potential of PEG-Heparin Hydrogels to Support Long-Term Ex Vivo Culture of Patient-Derived Breast Explant Tissues.

Breast cancer is a complex, highly heterogenous, and dynamic disease and the leading cause of cancer-related death in women worldwide. Evaluation of the heterogeneity of breast cancer and its various subtypes is crucial to identify novel treatment strategies that can overcome the limitations of currently available options. Explant cultures of human mammary tissue have been known to provide important insights for the study of breast cancer structure and phenotype as they include the context of the surrounding microenvironment, allowing for the comprehensive exploration of patient heterogeneity. However, the major limitation of currently available techniques remains the short-term viability of the tissue owing to loss of structural integrity. Here, an ex vivo culture model using star-shaped poly(ethylene glycol) and maleimide-functionalized heparin (PEG-HM) hydrogels to provide structural support to the explant cultures is presented. The mechanical support allows the culture of the human mammary tissue for up to 3 weeks and prevent disintegration of the cellular structures including the epithelium and surrounding stromal tissue. Further, maintenance of epithelial phenotype and hormonal receptors is observed for up to 2 weeks of culture which makes them relevant for testing therapeutic interventions. Through this study, the importance of donor-to-donor variability and intra-patient tissue heterogeneity is reiterated.

Label-free isolation and cultivation of patient-matched human mammary epithelial and stromal cells from normal breast tissue.

Breast cancer is primarily derived from mammary epithelial cells, the main cell type in human mammary glands. The majority of knowledge gained thus far around breast cancer has come from research using immortalized epithelial cell lines. The use of primary cells derived from breast tissue can be used in research to provide more biological relevance representative of the heterogeneous nature of breast cancer development and metastasis in its natural microenvironment. However, the successful isolation and propagation of human primary mammary gland cells can be costly and difficult due to their complex in vivo microenvironment and sensitivity when isolated. Here, we present a gentle isolation method for viable human mammary epithelial cells (hMECs) and donor-matched human mammary fibroblasts (hMFbs) from human mammary gland tissue. We isolated, expanded and passaged the hMECs and hMFbs in vitro and characterized cultures using cell-specific markers. A total of four primary cell lines were isolated and established from normal breast tissue and characterized through various markers, including pan cytokeratin (panCK), CK14, CD44, CD31, fibronectin and vimentin by immunofluorescence. To determine functional potential for subsequent studies, epithelial cells were examined via Matrigel® assays to assess spheroid development. Both cell type cultures expressed lineage specific markers with hMECs but not hMFbs forming spheroid structures in 3D Matrigel® assays. Our analyses confirm the successful isolation of two different cell phenotypes from normal breast tissues. This robust technique provides an inexpensive and accessible approach for mammary cell isolation.

Three-Dimensional Models as a New Frontier for Studying the Role of Proteoglycans in the Normal and Malignant Breast Microenvironment.

The extracellular matrix (ECM) provides cues to direct mammogenesis, tumourigenesis and metastatic processes. Over the past several decades, two-dimensional (2D) culture models have been invaluable in furthering our understanding of the tumor microenvironment (TME), however, they still do not accurately emulate the associated biological complexities. In contrast, three-dimensional (3D) culture models provide a more physiologically relevant platform to study relevant physicochemical signals, stromal-epithelial cell interactions, vascular and immune components, and cell-ECM interactions in the human breast microenvironment. A common thread that may weave these multiple interactions are the proteoglycans (PGs), a prominent family of molecules in breast tissue. This review will discuss how these PGs contribute to the breast cancer TME and provide a summary of the traditional and emerging technologies that have been utilized to better understand the role of PGs during malignant transformation. Furthermore, this review will emphasize the differences that PGs exhibit between normal tissues and tumor ECM, providing a rationale for the investigation of underexplored roles of PGs in breast cancer progression using state-of-the-art 3D culture models.

Stromal fibroblasts regulate microvascular-like network architecture in a bioengineered breast tumour angiogenesis model.

The plasticity of the tumour microenvironment is a key contributor to cancer development and progression. Here, we present a bioengineered breast tumour angiogenesis model comprised of mammary derived epithelial, endothelial and fibroblast cells, to dissect the mechanisms of cancer-associated fibroblasts (CAFs) on microvascular-like network formation and epithelial spheroid morphology. Primary patient-derived mammary endothelial cells, normal breast fibroblasts (NBF, patient matched) and CAFs were cultured within three-dimensional (3D) semi-synthetic hydrogels where CAFs promoted an increase in the density and morphology of the microvascular-like network. The mammary microenvironment also increased the number of MCF-10a epithelial spheroids when compared with a non-mammary microenvironment, and a malignant mammary microenvironment resulted in further morphological differences in the epithelial spheroids. The morphological changes observed following interactions between breast CAFs and endothelial cells, highlight the plasticity of the malignant stroma in tumour vascularisation. Our in vitro bioengineered breast cancer microenvironment provides a robust model to study cell-cell and cell-matrix interactions. Statement of Significance In recent years there has been an increase in the sophistication of 3D culture models, however less attention has been paid to the cell source utilised. In this study, we describe the influence of a normal and malignant stromal microenvironment on vessel-like behaviour in a 3D model. Using a semi-synthetic hydrogel, we studied the effects of mammary-derived cancer-associated fibroblasts and normal fibroblasts on human umbilical vein endothelial cells or human mammary microvascular endothelial cells. An increase in vessel-like network and epithelial cell density was seen in a mammary versus non-mammary microenvironment. This study highlights the importance of using tissue-specific endothelial cells in cancer research and demonstrates the microenvironmental impact of fibroblasts on endothelial and epithelial growth and morphology.

Ruptured Hemorrhagic Hepatic Cyst: An Unusual Case Report.

BACKGROUND: Hemorrhagic rupture of a hepatic cyst is rare. To date, very few cases have been reported in the literature. CASE REPORT: A patient with a history of a suspected liver hydatid cyst presented to the emergency department with abdominal pain and fever. She was admitted with the presumptive diagnosis of acute cholecystitis. During hospitalization, the patient presented with hemodynamic instability and abrupt worsening of the abdominal pain. The abdominal angio-chemotherapy scan showed an abundant free peritoneal effusion and an apparent effacement of the anterior wall of a hepatic cyst of 16 cm. The patient underwent an exploratory laparotomy, deroofing of the cyst, and peritoneal lavage. The anatomopathological results showed a simple hepatic cyst. DISCUSSION: Hemorrhagic rupture of simple hepatic cysts is a life-threatening complication and, although rare, should be included in the differential diagnosis of sudden abdominal pain in patients with a history of simple hepatic cysts.

INTRODUÇÃO: A ruptura hemorrágica de um quisto hepático é rara. Até à data, foram descritos poucos casos na literatura. RELATO DE CASO: Uma doente com antecedentes de um provável quisto hidático hepático recorreu ao serviço de urgência por dor abdominal e febre. Foi internada com o diagnóstico presumível de colecistite aguda. Durante o internamento, a doente iniciou um quadro de instabilidade hemodinâmica e agravamento súbito da dor abdominal. A angio-TC abdominal revelou um volumoso derrame peritoneal livre e uma aparente efração da parede anterior de um quisto hepático com 16 cm. A doente foi submetida a uma laparotomia exploradora, excisão da cúpula saliente do quisto e lavagem peritoneal. O exame anatomopatológico foi concordante com um quisto hepático simples. DISCUSSÃO: A ruptura hemorrágica de quistos hepáticos simples é uma complicação com risco de mortalidade, e, embora rara, deve ser incluída no diagnóstico diferencial de abdómen agudo em doentes com história de quistos hepáticos simples.

Predicting Blood Donations in a Tertiary Care Center Using Time Series Forecasting.

The current algorithm to support platelets stock management assumes that there are always sufficient whole blood donations (WBD) to produce the required amount of pooled platelets. Unfortunately, blood donation rate is uncertain so there is the need to backup pooled platelets productions with single-donor (apheresis) collections to compensate periods of low WBD. The aim of this work was to predict the daily number of WBD to a tertiary care center to preemptively account for a decrease of platelets production. We have collected 62,248 blood donations during 3 years, the daily count of which was used to feed (standalone and ensemble versions of) six prediction models, which were evaluated using the Mean Absolute Error (MAE). Forecast models have shown better performances with a MAE of about 8.6 donations, 34% better than using means or medians alone. Trend lines of donations are better modeled by autoregressive integrated moving average (ARIMA) using a frequency of 365 days, the trade-off being the need for at least two years of data.

An In Vitro Model of Angiogenesis during Wound Healing Provides Insights into the Complex Role of Cells and Factors in the Inflammatory and Proliferation Phase.

Successful vascularization is essential in wound healing, the histo-integration of biomaterials, and other aspects of regenerative medicine. We developed a functional in vitro assay to dissect the complex processes directing angiogenesis during wound healing, whereby vascular cell spheroids were induced to sprout in the presence of classically (M1) or alternatively (M2) activated macrophages. This simulated a microenvironment, in which sprouting cells were exposed to the inflammatory or proliferation phases of wound healing, respectively. We showed that M1 macrophages induced single-cell migration of endothelial cells and pericytes. In contrast, M2 macrophages augmented endothelial sprouting, suggesting that vascular cells infiltrate the wound bed during the inflammatory phase and extensive angiogenesis is initiated upon a switch to a predominance of M2. Interestingly, M1 and M2 shared a pro-angiogenic secretome, whereas pro-inflammatory cytokines were solely secreted by M1. These results suggested that acute inflammatory factors act as key inducers of vascular cell infiltration and as key negative regulators of angiogenesis, whereas pro-angiogenic factors are present throughout early wound healing. This points to inflammatory factors as key targets to modulate angiogenesis. The here-established wound healing assay represents a useful tool to investigate the effect of biomaterials and factors on angiogenesis during wound healing.

Label-free multiphoton microscopy reveals relevant tissue changes induced by alginate hydrogel implantation in rat spinal cord injury.

The development of therapies promoting recovery after spinal cord injury is a challenge. Alginate hydrogels offer the possibility to develop biocompatible implants with mechanical properties tailored to the nervous tissue, which could provide a permissive environment for tissue repair. Here, the effects of non-functionalized soft calcium alginate hydrogel were investigated in a rat model of thoracic spinal cord hemisection and compared to lesioned untreated controls. Open field locomotion tests were employed to evaluate functional recovery. Tissue analysis was performed with label-free multiphoton microscopy using a multimodal approach that combines coherent anti-Stokes Raman scattering to visualize axonal structures, two-photon fluorescence to visualize inflammation, second harmonic generation to visualize collagenous scarring. Treated animals recovered hindlimb function significantly better than controls. Multiphoton microscopy revealed that the implant influenced the injury-induced tissue response, leading to decreased inflammation, reduced scarring with different morphology and increased presence of axons. Demyelination of contralateral white matter near the lesion was prevented. Reduced chronic inflammation and increased amount of axons in the lesion correlated with improved hindlimb functions, being thus relevant for locomotion recovery. In conclusion, non-functionalized hydrogel improved functional outcome after spinal cord injury in rats. Furthermore, label-free multiphoton microscopy qualified as suitable technique for regeneration studies.

[High-Quality Endoscopic Mucosal Resection - The Process Explained]. / Endoskopische Mukosaresektion (EMR) ­ Schritt für Schritt.

Colonoscopy with polypectomy has been shown to reduce the risk of colon cancer development. It is considered a fundamental skill for all endoscopists who perform colonoscopy. A variety of polypectomy techniques and devices are available, and their use can vary greatly based on local availability and preferences. Polyps that are difficult to remove due to location or size require advanced resection techniques, such as endoscopic mucosal resection (EMR) and the use of special devices for safe and effective removal. However, colonic EMR is not routinely part of the standard endoscopic curriculum that is normally offered to gastroenterologists. It requires dedicated training in advanced endoscopic resection techniques, clinical and interpretive skills, and the knowledge and ability to manage complications.The two most common post-polypectomy complications are bleeding and perforation. Their frequency can be limited with the use of meticulous polypectomy techniques and the application of some prophylactic manoeuvres.This paper gives a review of the step by step technique of polypectomy and its complications from the perspective of the practicing gastroenterologist.

Inflammation-related alterations of lipids after spinal cord injury revealed by Raman spectroscopy.

Spinal cord injury (SCI) triggers several lipid alterations in nervous tissue. It is characterized by extensive demyelination and the inflammatory response leads to accumulation of activated microglia/macrophages, which often transform into foam cells by accumulation of lipid droplets after engulfment of the damaged myelin sheaths. Using an experimental rat model, Raman microspectroscopy was applied to retrieve the modifications of the lipid distribution following SCI. Coherent anti-Stokes Raman scattering (CARS) and endogenous two-photon fluorescence (TPEF) microscopies were used for the detection of lipid-laden inflammatory cells. The Raman mapping of CH2 deformation mode intensity at 1440 cm(−1) retrieved the lipid-depleted injury core. Preserved white matter and inflammatory regions with myelin fragmentation and foam cells were localized by specifically addressing the distribution of esterified lipids, i.e., by mapping the intensity of the carbonyl Raman band at 1743 cm(−1), and were in agreement with CARS/TPEF microscopy. Principal component analysis revealed that the inflammatory regions are notably rich in saturated fatty acids. Therefore, Raman spectroscopy enabled to specifically detect inflammation after SCI and myelin degradation products.

Sourcing of an alternative pericyte-like cell type from peripheral blood in clinically relevant numbers for therapeutic angiogenic applications.

Autologous cells hold great potential for personalized cell therapy, reducing immunological and risk of infections. However, low cell counts at harvest with subsequently long expansion times with associated cell function loss currently impede the advancement of autologous cell therapy approaches. Here, we aimed to source clinically relevant numbers of proangiogenic cells from an easy accessible cell source, namely peripheral blood. Using macromolecular crowding (MMC) as a biotechnological platform, we derived a novel cell type from peripheral blood that is generated within 5 days in large numbers (10-40 million cells per 100 ml of blood). This blood-derived angiogenic cell (BDAC) type is of monocytic origin, but exhibits pericyte markers PDGFR-ß and NG2 and demonstrates strong angiogenic activity, hitherto ascribed only to MSC-like pericytes. Our findings suggest that BDACs represent an alternative pericyte-like cell population of hematopoietic origin that is involved in promoting early stages of microvasculature formation. As a proof of principle of BDAC efficacy in an ischemic disease model, BDAC injection rescued affected tissues in a murine hind limb ischemia model by accelerating and enhancing revascularization. Derived from a renewable tissue that is easy to collect, BDACs overcome current short-comings of autologous cell therapy, in particular for tissue repair strategies.

Not all MSCs can act as pericytes: functional in vitro assays to distinguish pericytes from other mesenchymal stem cells in angiogenesis.

Pericytes play a crucial role in angiogenesis and vascular maintenance. They can be readily identified in vivo and isolated as CD146(+)CD34(-) cells from various tissues. Whether these and other markers reliably identify pericytes in vitro is unclear. CD146(+)CD34(-) selected cells exhibit multilineage potential. Thus, their perivascular location might represent a stem cell niche. This has spurred assumptions that not only all pericytes are mesenchymal stromal cells (MSCs), but also that all MSCs can act as pericytes. Considering this hypothesis, we developed functional assays by confronting test cells with endothelial cultures based on matrigel assay, spheroid sprouting, and cord formation. We calibrated these assays first with commercial cell lines [CD146(+)CD34(-) placenta-derived pericytes (Pl-Prc), bone marrow (bm)MSCs and fibroblasts]. We then functionally compared the angiogenic abilities of CD146(+)CD34(-)selected bmMSCs with CD146(-) selected bmMSCs from fresh human bm aspirates. We show here that only CD146(+)CD34(-) selected Pl-Prc and CD146(+)CD34(-) selected bmMSCs maintain endothelial tubular networks on matrigel and improve endothelial sprout morphology. CD146(-) selected bmMSCs neither showed these abilities, nor did they attain pericyte function despite progressive CD146 expression once passaged. Thus, cell culture conditions appear to influence expression of this and other reported pericyte markers significantly without correlation to function. The newly developed assays, therefore, promise to close a gap in the in vitro identification of pericytes via function. Indeed, our functional data suggest that pericytes represent a subpopulation of MSCs in bm with a specialized role in vascular biology. However, these functions are not inherent to all MSCs.

The health benefits of selective taxation as an economic instrument in relation to IHD and nutrition-related cancers.

OBJECTIVE: The present study aimed to estimate the health benefits of selective taxation of healthy and unhealthy food commodities in relation to CVD and nutrition-related cancers. DESIGN: The potential health effects of a selective taxation scenario were estimated as changes in the burden of disease, measured by disability-adjusted life years, from health outcomes affected by the changes in food intake. The change in burden of a disease was calculated as the change in incidence of the disease due to a modified exposure level, using the potential impact fraction. Estimates of relative risk for the associations between various foods and relevant diseases were found through a literature search and used in the calculation of potential impact fractions. SETTING: The study was based in Denmark, estimating the health effects of a Danish selective taxation scenario. SUBJECTS: The potential health effects of selective taxation were modelled for the adult Danish population. RESULTS: Halving the rate of value-added tax on fruit and vegetables and increasing the tax on fats would result in moderate reductions in the burden of disease from IHD, ischaemic stroke, and colorectal, lung and breast cancer (0·4­2·4 % change). The largest effect could be obtained through increased intake of fruit and vegetables (0·9­2·4 %). CONCLUSIONS: Applying selective taxation to healthy and unhealthy foods can moderately reduce the burden of disease in the Danish population.

Hepatocolangitis por drogas simulando un hepatocarcinoma / Drug-induced hepatocholangitis with characteristics of hepatocarcinoma

La hepatotoxicidad por drogas es una entidad frecuente, con un amplio espectro de manifestaciones y muchas veces subestimada por los médicos. Existen escasos reportes acerca de los hallazgos anatomopatológicos en pacientes con toxicidad hepática aguda causada por drogas...El hallazgo de atipias celulares que simulan neoplasias en tejidos agredidos por drogas es una situación en la cual la experiencia del patólogo y una historia clínica completa son decisivos para orientar el diagnóstico.

Prokinetic drug utility in the treatment of gastroesophageal reflux esophagitis: a systematic review of randomized controlled trials.

BACKGROUND: Esophagitis caused by gastroesophageal reflux disease (GERD) results in appreciable morbidity and economic burden. No systematic review has addressed the effectiveness of prokinetic drugs in the treatment of GERD esophagitis in adults. OBJECTIVE: To determine the utility of prokinetic drugs in improving symptoms and endoscopic lesions in patients with GERD esophagitis. METHODS: We included randomized controlled trials that compared prokinetic drugs with placebo. A systematic search included the Cochrane Controlled Trial Register, MEDLINE, CINAHL, LILACS, EMBASE, a manual search of books and article references, and contact with pharmaceutical companies. Reviewers assessed methodological quality and extracted data that were combined using a random effects model. RESULTS: Eighteen articles met the eligibility criteria; of these, 13 used prokinetic drugs alone, 4 tested prokinetic drugs as additional therapy in patients receiving histamine-2 receptor blockers, and 1 tested them in patients receiving proton pump inhibitors. Seven studies evaluated clinical improvement only, 5 addressed endoscopic improvement only, and 6 reported both outcomes. Four studies failed to provide adequate data for pooling; 3 of the 4 reported results that suggested symptomatic benefit with prokinetic agents. Nine studies (379 patients) that provided the required data suggested a higher incidence of clinical improvement with prokinetic drugs versus placebo (relative risk [RR] 1.70, 95% confidence interval [CI] 1.37-2.12, heterogeneity p = 0.47, I(2) = 0%). Clinical improvement occurred in 53 out of 175 patients (30%) of the control group; applying the relative risk of 1.70 and associated confidence interval suggests that absolute increases in patients improved might vary from 18% to 41% (number needed to treat approximately 3 to 6). Improvement was similar in 4 studies in which the prokinetic agent was added to an antisecretory drug. The funnel plot, however, suggests the possibility of publication bias. Eleven studies (887 patients) suggested a higher likelihood of endoscopic improvement or healing esophagitis with prokinetic drugs (RR 1.26, 95% CI 1.03-1.53) but with significant heterogeneity (heterogeneity p = .05, I(2) = 46.2%) that we couldn't explain with an a priori hypothesis. When we evaluated endoscopic healing as the main outcome we observed a trend toward better results in the treatment group, also with inexplicable heterogeneity (RR 1.36, CI 95% 0.97-1.89, I(2) = 61%). CONCLUSIONS: Randomized controlled trials provide moderate-quality evidence that prokinetic drugs improve symptoms in patients with reflux esophagitis and low-quality evidence that they have an impact on endoscopic healing.