Knowledge Transfer and Networking Upon Implementation of a Transdisciplinary Digital Health Curriculum in a Unique Digital Health Training Culture: Prospective Analysis.

Background: Digital health has been taught at medical faculties for a few years. However, in general, the teaching of digital competencies in medical education and training is still underrepresented. Objective: This study aims to analyze the objective acquisition of digital competencies through the implementation of a transdisciplinary digital health curriculum as a compulsory elective subject at a German university. The main subject areas of digital leadership and management, digital learning and didactics, digital communication, robotics, and generative artificial intelligence were developed and taught in a transdisciplinary manner over a period of 1 semester. Methods: The participants evaluated the relevant content of the curriculum regarding the competencies already taught in advance during the study, using a Likert scale. The participants' increase in digital competencies were examined with a pre-post test consisting of 12 questions. Statistical analysis was performed using an unpaired 2-tailed Student t test. A P value of <.05 was considered statistically significant. Furthermore, an analysis of the acceptance of the transdisciplinary approach as well as the application of an alternative examination method (term paper instead of a test with closed and open questions) was carried out. Results: In the first year after the introduction of the compulsory elective subject, students of human medicine (n=15), dentistry (n=3), and medical biotechnology (n=2) participated in the curriculum. In total, 13 participants were women (7 men), and 61.1% (n=11) of the participants in human medicine and dentistry were in the preclinical study stage (clinical: n=7, 38.9%). All the aforementioned learning objectives were largely absent in all study sections (preclinical: mean 4.2; clinical: mean 4.4; P=.02). The pre-post test comparison revealed a significant increase of 106% in knowledge (P<.001) among the participants. Conclusions: The transdisciplinary teaching of a digital health curriculum, including digital teaching methods, considers perspectives and skills from different disciplines. Our new curriculum facilitates an objective increase in knowledge regarding the complex challenges of the digital transformation of our health care system. Of the 16 student term papers arising from the course, robotics and artificial intelligence attracted the most interest, accounting for 9 of the submissions.

Publication activities relating to digital teaching and learning in the GMS Journal for Medical Education - a descriptive analysis (1984-2020).

Aims and objectives: Digital teaching, learning and assessment have been part of medical education and continuing education for decades. The objective of this review paper is to highlight developments and perspectives in these areas in the GMS Journal for Medical Education (GMS JME). Methodology: In the spring of 2020, we conducted a systematic literature search of the Journal for Medical Education (JME) and analysed the articles with regard to different categories such as article type, digital tools used or mode of data collection. Results: Of the 132 articles analysed, 78 were digital interventions (53 of which were exploratory-descriptive), 28 were project descriptions, 16 were surveys of needs or equipment and 10 were concept papers. About one-third of the studies and project reports each dealt with virtual patients or case-based learning, whereas no articles were published on trends such as serious games or virtual reality. Overall, our analysis shows that in many respects, the studies on digital teaching were more broadly based, especially between 2006 and 2010, after which this trend tended to decline again. Conclusions: Our analysis shows that publications in the JME consider some key aspects of digital teaching in medical education and continuing education, such as educational videos or virtual patients. The variability of information and methods of presentation advocate the use of guidelines to optimise the quality of scientific papers. Furthermore, clues for future research topics and experimental study designs are identified.

Endoplasmic reticulum stress and the unfolded protein response in skeletal muscle of subjects suffering from peritoneal sepsis.

We provide a descriptive characterization of the unfolded protein response (UPR) in skeletal muscle of human patients with peritoneal sepsis and a sepsis model of C57BL/6J mice. Patients undergoing open surgery were included in a cross-sectional study and blood and skeletal muscle samples were taken. Key markers of the UPR and cluster of differentiation 68 (CD68) as surrogate of inflammatory injury were evaluated by real-time PCR and histochemical staining. CD68 mRNA increased with sepsis in skeletal muscle of patients and animals (p < 0.05). Mainly the inositol-requiring enzyme 1α branch of the UPR was upregulated as shown by elevated X-box binding-protein 1 (XBP1u) and its spliced isoform (XBP1s) mRNA (p < 0.05, respectively). Increased expression of Gadd34 indicated activation of PRKR-Like Endoplasmic Reticulum Kinase (PERK) branch of the UPR, and was only observed in mice (p < 0.001) but not human study subjects. Selected cell death signals were upregulated in human and murine muscle, demonstrated by increased bcl-2 associated X protein mRNA and TUNEL staining (p < 0.05). In conclusion we provide a first characterization of the UPR in skeletal muscle in human sepsis.

The online inverted classroom model (oICM). A blueprint to adapt the inverted classroom to an online learning setting in medical and health education.

This article was migrated. The article was marked as recommended. The idea of this paper is to offer a blueprint, with that facilitators have a guide to set up a complete digital teaching scenario according to the latest insights of didactical research. The corona pandemic forced higher education institutions all around the world to radically shift their curricula from a mix of face-to-face and remote teaching methods to a fully remote curriculum. Though challenging, this time provides opportunities to implement new educational methods and improve the quality of digital teaching. The classical concept of the inverted classroom was modified to meet the special needs of online settings. The proposed online Inverted Classroom Model (oICM) includes the following phases: (1) pre-phase, (2) self-learning-phase, (3) Synchronous online face-to-face phase, (4) transfer-phase, (5) evaluation. Recommendations and potential tools are provided for each phase. The oICM is an innovative and easy to use approach to shape digital teaching and learning processes during and after the CoVid19 pandemic. This blueprint is developed by the committee "Digitalization" of the German Association for Medical Education (GMA) for facilitators without any prior experience with the ICM, but also for those who already teach in a traditional ICM.

A family with limb girdle muscular dystrophy type 1B and multiple exostoses.

INTRODUCTION: Next-generation sequencing in cases of hereditary neuromuscular disorders often yields multiple candidate gene variants. Here, we describe a case with mutations in two genes, lamin A/C (LMNA) and exostosin glycosyltransferase 2 (EXT2), which led to hereditary myopathy combined with multiple exostoses. CASE HISTORY: A 51-year-old German woman with a history of removal of multiple exostoses during childhood presented with proximal limb-girdle muscular dystrophy and a newly diagnosed cardiomyopathy with atrioventricular conduction block. Because her younger son had exostoses and her younger brother had died at age 44 after heart transplantation due to dilated cardiomyopathy, an autosomal dominant inheritance was suspected. RESULTS: Muscle biopsy revealed features of chronic myopathy associated with focal myofibrillar disintegration. Electron microscopy showed myonuclear, myofibrillar, and Z-disc alterations, accumulations of granulofilamentous material, and a large sporadic osmiophilic inclusion body reminiscent of a nemaline body. Mendeliome and Sanger sequencing detected both a c.1129>T LMNA mutation of known pathogenicity and a c.1101_1102delAG (E368Kfs*18) truncating EXT2 mutation in the patient and her affected son. DISCUSSION: The clinical, genetic, and muscle biopsy findings suggest that both mutations are pathogenic. The EXT2 mutation was most likely responsible for the multiple exostoses phenotype in mother and son, whereas the myopathy was probably caused by a combined effect of the LMNA and EXT2 mutations.

Buzz groups facilitate collaborative learning and improve histopathological competencies of students.

INTRODUCTION: Traditional teacher-centered histopathology training is based on theoretical lectures and practical tutorials. We hypothesize that learning outcomes improve if students are activated by demonstrating cardinal features of slides to each other and discussing their pathogenesis. Buzz groups (BGs) could facilitate this. The aim of this study was to investigate the effectiveness of student-centered BGs, i.e., peer-teaching, versus traditional teacher-centered histopathology teaching. Furthermore, we compared digital with analog microscopy. MATERIALS AND METHODS: In addition to traditional guided instruction and explanation of slides, neighboring students demonstrated to each other histopathological features and discussed associated pathogenesis. RESULTS: After only 4 course lessons, the BG students did much better than the control group (ANCOVA p = 0.002; F = 9.7). Then the control group also applied the BG technique. After another 4 lessons, the control group was able to catch up almost completely (ANCOVA p = 0.36; F = 0.9). Overall, there was no difference in time on task. DISCUSSION: Collaborative BGs improve the learning of histopathological competencies. They motivate and activate students to learn. The course also increased the appreciation of students for histopathology. For BGs, digital microscopy was better suited than traditional analog microscopy. The application of BGs in the context of analyzing microscopic images should be disseminated and studied on larger cohorts.

Microcephaly, short stature, and limb abnormality disorder due to novel autosomal biallelic DONSON mutations in two German siblings.

Recently, variants in DONSON have been reported to cause different disorders of the microcephalic primordial dwarfism spectrum. Using whole-exome sequencing, we identified two novel, compound heterozygous DONSON variants in a pair of siblings, one of whom was previously diagnosed with Fanconi anemia. This occurred because the present cases exhibited clinical findings in addition to those of the microcephalic primordial dwarfism disorder, including severe limb malformations. These findings suggest that the DONSON and Fanconi anemia proteins could have supplementary roles in developmental processes as they have in the maintenance of genomic integrity, resulting in related disease phenotypes.

Value of the eazyplex® CSF direct assay in rapid diagnosis of invasive meningococcal disease - Case report.

There is a need for easy-to-use molecular assays for diagnosis of invasive meningococcal disease. Here, we report the rapid identification of Neisseria meningitidis in a cerebrospinal fluid sample from a patient with purulent meningitis using a commercially available loop-mediated isothermal amplification assay, resulting in a prompt de-escalation of the initial empiric antibiotic therapy.

Detection and characterization of early plaque formations by Raman probe spectroscopy and optical coherence tomography: an in vivo study on a rabbit model.

Intravascular imaging techniques provide detailed specification about plaque appearance and morphology, but cannot deliver information about the biochemical composition of atherosclerotic plaques. As the biochemical composition is related to the plaque type, important aspects such as the risk of a plaque rupture and treatment are still difficult to assess. Currently, various spectroscopic techniques are tested for potential applications for the chemical analysis of plaque depositions. Here, we employ Raman spectroscopy in combination with optical coherence tomography (OCT) for the characterization of plaques on rabbits in vivo. Experiments were carried out on New Zealand white rabbits treated with a fat- and cholesterol-enriched diet, using a Raman probe setup with a 785-nm multimode laser as an excitation source. Subsequently, OCT images were acquired with a swept source at 1305±55 nm at 22.6 mW. Raman spectra were recorded from normal regions and regions with early plaque formations. The probe positioning was monitored by x-ray angiography. The spectral information identified plaque depositions consisting of lipids, with triglycerides as the major component. Afterward, OCT images of the spectroscopically investigated areas were obtained. The spectral information correlates well with the observed intravascular morphology and is in good agreement with histology. Raman spectroscopy can provide detailed biochemical specification of atherosclerotic plaques.

Deciphering caveolar functions by syndapin III KO-mediated impairment of caveolar invagination.

Several human diseases are associated with a lack of caveolae. Yet, the functions of caveolae and the molecular mechanisms critical for shaping them still are debated. We show that muscle cells of syndapin III KO mice show severe reductions of caveolae reminiscent of human caveolinopathies. Yet, different from other mouse models, the levels of the plasma membrane-associated caveolar coat proteins caveolin3 and cavin1 were both not reduced upon syndapin III KO. This allowed for dissecting bona fide caveolar functions from those supported by mere caveolin presence and also demonstrated that neither caveolin3 nor caveolin3 and cavin1 are sufficient to form caveolae. The membrane-shaping protein syndapin III is crucial for caveolar invagination and KO rendered the cells sensitive to membrane tensions. Consistent with this physiological role of caveolae in counterpoising membrane tensions, syndapin III KO skeletal muscles showed pathological parameters upon physical exercise that are also found in CAVEOLIN3 mutation-associated muscle diseases.

Chemerin in peritoneal sepsis and its associations with glucose metabolism and prognosis: a translational cross-sectional study.

BACKGROUND: Stress hyperglycaemia (SHG) is a common complication in sepsis associated with poor outcome. Chemerin is an adipocytokine associated with inflammation and impaired glucose homeostasis in metabolic diseases such as type 2 diabetes (T2D). We aimed to investigate how alterations of circulating chemerin levels and corresponding visceral adipose tissue (VAT) expression are linked to glucose metabolism and prognosis in sepsis. METHODS: Clinical data and tissue samples were taken from a cross-sectional study including control, T2D and sepsis patients, all undergoing laparotomy. A second independent patient cohort of patients with sepsis was included to evaluate associations with prognosis. This was complemented by a murine model of peritoneal infection and a high-fat diet. We analysed circulating chemerin by enzyme-linked immunosorbent assay and VAT messenger RNA (mRNA) expression by real-time polymerase chain reaction. RESULTS: Circulating chemerin was increased in sepsis 1.69-fold compared with controls (p = 0.012) and 1.47-fold compared with T2D (p = 0.03). Otherwise, chemerin VAT mRNA expression was decreased in patients with sepsis (p = 0.006) and in septic diabetic animals (p = 0.009). Circulating chemerin correlated significantly with intra-operative glucose (r = 0.662; p = 0.01) and in trend with fasting glucose (r = 0.528; p = 0.052). After adjusting for body mass index or haemoglobin A1c, chemerin correlated in trend with insulin resistance evaluated using the logarithmised homeostasis model assessment of insulin resistance (r = 0.539, p = 0.071; r = 0.553, p = 0.062). Chemerin was positively associated with Acute Physiology and Chronic Health Evaluation II score in patients with sepsis (p = 0.036) and with clinical severity in septic mice (p = 0.031). In an independent study population, we confirmed association of chemerin with glucose levels in multivariate linear regression analysis (ß = 0.556, p = 0.013). In patients with sepsis with SHG, non-survivors had significantly lower chemerin levels than survivors (0.38-fold, p = 0.006), while in patients without SHG, non-survivors had higher chemerin levels, not reaching significance (1.64-fold, p = 0.089). No difference was apparent in patients with pre-existing T2D (p = 0.44). CONCLUSIONS: We show, for the first time to our knowledge, that chemerin is increased in sepsis and that it associates with impaired glucose metabolism and survival in these patients. It could be further evaluated as a biomarker to stratify mortality risk of patients with SHG.

Development and characterization of an ex vivo arterial long-term proliferation model for restenosis research.

One of the main limitations of percutaneous coronary interventions is the restenosis, occurring in small-diameter arteries, and efforts are high to find improved intracoronary devices to prevent in-stent-restenosis. Aim of this study was to produce a new in vitro test platform for restenosis research, suitable for long-term cell proliferation and migration studies in stented vessels. Fresh segments of porcine coronary arteries were obtained for decellularization and were then reseeded with human coronary artery endothelial (HCAEC) and human coronary artery smooth muscle cells (HCASMC). Subsequently, bare metal stents (BMS) and drug eluting stents (DES), respectively, were implanted and the segments were reseeded with HCAEC and HCASMC for up to three months. The stented segments were examined at time zero and after 2, 4, 6, 8 and 12 weeks by histochemical and immunohistochemical characterization and the reseeded areas before and after stent implantation were measured. We have found that cells formed multiple layers after three months, and the detection with both CD31 and a-smooth muscle actin specific antibodies showed that HCAEC and HCASMC are adherent and growing in several layers. Furthermore, we could show a significantly smaller proliferation area in DES (70% ± 3.5%), compared to BMS (17% ± 2.3%). These data are similar to animal and human studies. Therefore, this vessel model might appear as an initial benchmark for testing new anti-proliferative endovascular therapies and consequently helps to reduce animal experiments in this research area.

Coherent anti-Stokes Raman scattering and two photon excited fluorescence for neurosurgery.

OBJECTIVE: There is no established method for in vivo imaging during biopsy and surgery of the brain, which is capable to generate competitive images in terms of resolution and contrast comparable with histopathological staining. METHODS: Coherent anti-Stokes Raman scattering (CARS) and two photon excited fluorescence (TPEF) microscopy are non-invasive all optical imaging techniques that are capable of high resolution, label-free, real-time, nondestructive examination of living cells and tissues. They provide image contrast based on the molecular composition of the specimen which allows the study of large tissue areas of frozen tissue sections ex vivo. RESULTS: Here, preliminary data on 55 lesions of the central nervous system are presented. The generated images very nicely demonstrate cytological and architectural features required for pathological tumor typing and grading. Furthermore, information on the molecular content of a probe is provided. The tool will be implemented into a biopsy needle or endoscope in the near future for in vivo studies. CONCLUSION: With this promising multimodal imaging approach the neurosurgeon might directly see blood vessels to minimize the risk for biopsy associated hemorrhages. The attending neuropathologist might directly identify the tumor and guide the selection of representative specimens for further studies. Thus, collection of non-representative material could be avoided and the risk to injure eloquent brain tissue minimized.

BRAF-mutated pleomorphic xanthoastrocytoma is associated with temporal location, reticulin fiber deposition and CD34 expression.

BRAF V600E mutation and homozygous deletion of CDKN2A (p16) are frequent molecular alterations in pleomorphic xanthoastrocytomas (PXAs). We investigated 49 PXAs for clinical, histological and immunohistochemical characteristics related to BRAF mutation status. BRAF mutation was detected by immunohistochemical assay and DNA sequencing in 38/49 (78%) tumors. All but one PXA located in the temporal lobe harbored a BRAF V600E mutation (23/24; 96%) compared with 10/19 nontemporal PXAs (53%; P = 0.0009). Histological and immunohistochemical analysis demonstrated increased reticulin deposition (76% vs. 27%; P = 0.003) and a more frequent expression of CD34 in BRAF-mutant PXAs (76% vs. 27%; P = 0.003). We further investigated the utility of combined BRAF V600E (VE1) and p16 analysis by immunohistochemistry to distinguish PXAs from relevant histological mimics like giant-cell glioblastoma. Among PXAs, 38/49 (78%) were VE1-positive, and 30/49 (61%) had a loss of p16 expression. The combined features (VE1 positivity/p16 loss) were observed in 25/49 PXAs (51%) but were not observed in giant-cell glioblastoma (VE1 0/28, p16 loss 14/28). We demonstrate that temporal location, reticulin deposition and CD34 expression are associated with BRAF mutation in PXA. Combined VE1 positivity and p16 loss represents a frequent immunoprofile of PXA and may therefore constitute an additional diagnostic tool for its differential diagnosis.

Treatment of elastase-induced intracranial aneurysms in New Zealand white rabbits by use of a novel neurovascular embolization stent device.

INTRODUCTION: This study aims to test a novel balloon expandable stent covered with a polytetrafluoroethylene membrane (neurovascular embolization cover (NEC), NFocus Neuromedical, Palo Alto, California) regarding angiographic and histologic aneurysm occlusion. Radiopacity, stent placement, navigation, flexibility, and intimal proliferation were also evaluated. METHODS: Eight aneurysms were induced in New Zealand white rabbits. Digital subtraction angiography (DSA) was performed directly after stent placement and after 5 and 10 min. Four and 8 weeks after stent placement, an intra-arterial DSA control was performed. The animals were then sacrificed and the aneurysms histologically evaluated. RESULTS: The radiopaque markers were clearly visible. Although all the stents were easily navigated into the subclavian artery, the limited flexibility of the stent resulted in straightening of the vessel in four cases. As a result, exact stent placement was achieved and acutely confirmed in only two cases. However, at sacrifice, angiographic and histologic occlusion was noted at follow-up in five aneurysms. CONCLUSION: In tortuous anatomy, the relative stiffness of the stent makes exact stent placement challenging. This may have been exacerbated by the movement of the vessels due to proximity to the heart in this model. Future studies should evaluate whether existing residual flow into an aneurysm lumen might lead to embolization without any additional treatment. Anticoagulation remains a very important part of aneurysm treatment with stents. The trend toward aneurysm occlusion by excluding it from the blood circulation seems a promising method in future endovascular therapy. The NEC device shows good potential.

Expanding multimodal microscopy by high spectral resolution coherent anti-Stokes Raman scattering imaging for clinical disease diagnostics.

Over the past years fast label-free nonlinear imaging modalities providing molecular contrast of endogenous disease markers with subcellular spatial resolution have been emerged. However, applications of these imaging modalities in clinical settings are still at the very beginning. This is because single nonlinear imaging modalities such as second-harmonic generation (SHG) and two-photon excited fluorescence (TPEF) have only limited value for diagnosing diseases due to the small number of endogenous markers. Coherent anti-Stokes Raman scattering (CARS) microscopy on the other hand can potentially be added to SHG and TPEF to visualize a much broader range of marker molecules. However, CARS requires a second synchronized laser source and the detection of a certain wavenumber range of the vibrational spectrum to differentiate multiple molecules, which results in increased experimental complexity and often inefficient excitation of SHG and TPEF signals. Here we report the application of a novel near-infrared (NIR) fiber laser of 1 MHz repetition rate, 65 ps pulse duration, and 1 cm(-1) spectral resolution to realize an efficient but experimentally simple SGH/TPEF/multiplex CARS multimodal imaging approach for a label-free characterization of composition of complex tissue samples. This is demonstrated for arterial tissue specimens demonstrating differentiation of elastic fibers, triglycerides, collagen, myelin, cellular cytoplasm, and lipid droplets by analyzing the CARS spectra within the C-H stretching region only. A novel image analysis approach for multispectral CARS data based on colocalization allows correlating spectrally distinct pixels to morphologic structures. Transfer of this highly precise but compact and simple to use imaging approach into clinical settings is expected in the near future.

A compact microscope setup for multimodal nonlinear imaging in clinics and its application to disease diagnostics.

The past years have seen increasing interest in nonlinear optical microscopic imaging approaches for the investigation of diseases due to the method's unique capabilities of deep tissue penetration, 3D sectioning and molecular contrast. Its application in clinical routine diagnostics, however, is hampered by large and costly equipment requiring trained staff and regular maintenance, hence it has not yet matured to a reliable tool for application in clinics. In this contribution implementing a novel compact fiber laser system into a tailored designed laser scanning microscope results in a small footprint easy to use multimodal imaging platform enabling simultaneously highly efficient generation and acquisition of second harmonic generation (SHG), two-photon excited fluorescence (TPEF) as well as coherent anti-Stokes Raman scattering (CARS) signals with optimized CARS contrast for lipid imaging for label-free investigation of tissue samples. The instrument combining a laser source and a microscope features a unique combination of the highest NIR transmission and a fourfold enlarged field of view suited for investigating large tissue specimens. Despite its small size and turnkey operation rendering daily alignment dispensable the system provides the highest flexibility, an imaging speed of 1 megapixel per second and diffraction limited spatial resolution. This is illustrated by imaging samples of squamous cell carcinoma of the head and neck (HNSCC) and an animal model of atherosclerosis allowing for a complete characterization of the tissue composition and morphology, i.e. the tissue's morphochemistry. Highly valuable information for clinical diagnostics, e.g. monitoring the disease progression at the cellular level with molecular specificity, can be retrieved. Future combination with microscopic probes for in vivo imaging or even implementation in endoscopes will allow for in vivo grading of HNSCC and characterization of plaque deposits towards the detection of high risk plaques.