All-trans retinoic acid induces durable tumor immunity in IDH-mutant gliomas by rescuing transcriptional repression of the CRBP1-retinoic acid axis.

Diffuse gliomas are epigenetically dysregulated, immunologically cold, and fatal tumors characterized by mutations in isocitrate dehydrogenase (IDH). Although IDH mutations yield a uniquely immunosuppressive tumor microenvironment, the regulatory mechanisms that drive the immune landscape of IDH mutant (IDHm) gliomas remain unknown. Here, we reveal that transcriptional repression of retinoic acid (RA) pathway signaling impairs both innate and adaptive immune surveillance in IDHm glioma through epigenetic silencing of retinol binding protein 1 (RBP1) and induces a profound anti-inflammatory landscape marked by loss of inflammatory cell states and infiltration of suppressive myeloid phenotypes. Restorative retinoic acid therapy in murine glioma models promotes clonal CD4 + T cell expansion and induces tumor regression in IDHm, but not IDH wildtype (IDHwt), gliomas. Our findings provide a mechanistic rationale for RA immunotherapy in IDHm glioma and is the basis for an ongoing investigator-initiated, single-center clinical trial investigating all-trans retinoic acid (ATRA) in recurrent IDHm human subjects.

Seeing with Different Eyes. The Module Life & Science of the Elite-Master Program Biomedical Neuroscience.

From its beginnings in 2018, the international elite-master program Biomedical Neuroscience of TUM School of Medicine and Health at Technical University of Munich was guided by two convictions: First, excellent research depends not only on the mediation of scientific knowledge and skills, but also on a multifaceted understanding of science itself. Second, teaching must recognize and support not only student's growing expertise but also their personal and professional development. To this end, the module Life & Science was designed. It gives students the opportunity to explore neuroscience from different angles to deepen the epistemological, sociological, and cultural understanding of their chosen profession.

The role of spine stereotactic radiosurgery for patients with breast cancer metastases.

PURPOSE: Breast cancer that metastasizes to the spine is associated with low quality of life and poor survival. Radiosurgery has an increasing role in this patient population. This single-institution (2003-2023) study analyzes clinical outcomes and prognostic factors for patients who underwent spinal stereotactic radiosurgery (SSRS) for metastatic breast cancer. METHODS: Ninety patients (155 unique breast cancer spinal metastases) were treated with SSRS. The median age was 57 years (range: 35-88), and the median KPS was 80 (range: 40-100). Forty-two (27%) lesions were managed surgically prior to radiosurgery. At SSRS, 75 (48%) lesions impinged or compressed the spinal cord per the epidural spinal cord scale (ESCC). Seventy-nine (51%) lesions were categorized as potentially unstable or unstable by the Spinal Instability Neoplastic Score (SINS). RESULTS: The median follow-up was 15 months (range: 1-183). The median single-session tumor volume was 25.4 cc (range: 2-197), and the median single-fraction prescription dose was 17 Gy (range: 12-25). Seven (5%) lesions locally progressed. The 1-, 2-, and 5-year local control rates were 98%, 97%, and 92%, respectively. The median overall survival (OS) for the cohort was 32 months (range: 2-183). The 1-, 2-, and 5-year OS rates were 72%, 53%, and 30%, respectively. On univariate analysis, KPS ≥ 80 (p = 0.009, HR: 0.51, 95% CI: 0.31-0.84) was associated with improved OS. Patient-reported pain improved (68%), remained stable (29%), or worsened (3%) following radiosurgery. Fifteen (10%) radiation-induced toxicities were reported. CONCLUSIONS: Spinal radiosurgery is a safe and highly effective long-term treatment modality for metastases to the spine that originate from breast cancer.

The macroevolutionary singularity of snakes.

Snakes and lizards (Squamata) represent a third of terrestrial vertebrates and exhibit spectacular innovations in locomotion, feeding, and sensory processing. However, the evolutionary drivers of this radiation remain poorly known. We infer potential causes and ultimate consequences of squamate macroevolution by combining individual-based natural history observations (>60,000 animals) with a comprehensive time-calibrated phylogeny that we anchored with genomic data (5400 loci) from 1018 species. Due to shifts in the dynamics of speciation and phenotypic evolution, snakes have transformed the trophic structure of animal communities through the recurrent origin and diversification of specialized predatory strategies. Squamate biodiversity reflects a legacy of singular events that occurred during the early history of snakes and reveals the impact of historical contingency on vertebrate biodiversity.

Erratum: Prevalence and distribution of selected cervical human papillomavirus types in HIV infected and HIV uninfected women in South Africa, 1989-2021: A narrative review.

[This corrects the article DOI: 10.4102/sajid.v37i1.363.].

Associating T1-Weighted and T2-Weighted Magnetic Resonance Imaging Radiomic Signatures With Preoperative Symptom Severity in Patients With Cervical Spondylotic Myelopathy.

BACKGROUND: Preoperative symptom severity in cervical spondylotic myelopathy (CSM) can be variable. Radiomic signatures could provide an imaging biomarker for symptom severity in CSM. This study utilizes radiomic signatures of T1-weighted and T2-weighted magnetic resonance imaging images to correlate with preoperative symptom severity based on modified Japanese Orthopaedic Association (mJOA) scores for patients with CSM. METHODS: Sixty-two patients with CSM were identified. Preoperative T1-weighted and T2-weighted magnetic resonance imaging images for each patient were segmented from C2-C7. A total of 205 texture features were extracted from each volume of interest. After feature normalization, each second-order feature was further subdivided to yield a total of 400 features from each volume of interest for analysis. Supervised machine learning was used to build radiomic models. RESULTS: The patient cohort had a median mJOA preoperative score of 13; of which, 30 patients had a score of >13 (low severity) and 32 patients had a score of ≤13 (high severity). Radiomic analysis of T2-weighted imaging resulted in 4 radiomic signatures that correlated with preoperative mJOA with a sensitivity, specificity, and accuracy of 78%, 89%, and 83%, respectively (P < 0.004). The area under the curve value for the ROC curves were 0.69, 0.70, and 0.77 for models generated by independent T1 texture features, T1 and T2 texture features in combination, and independent T2 texture features, respectively. CONCLUSIONS: Radiomic models correlate with preoperative mJOA scores using T2 texture features in patients with CSM. This may serve as a surrogate, objective imaging biomarker to measure the preoperative functional status of patients.

Training in medical communication competence through video-based e-learning: How effective are video modeling and video reflection?

OBJECTIVE: The present study investigated the efficacy of the didactic approaches of video modeling (VM, best-practice examples), video reflection (VR, problem-based approach), and the combination of both (VMR) in fostering medical communication competence in a video-based digital learning environment. METHODS: N = 126 third-year medical students who participated in the pre-post study were assigned to either the intervention groups (VM, VR, and VMR) or the wait-list control group. The efficacy of the three approaches was assessed by means of a situational judgment test (SJT) of medical communication competence. To investigate the differences between the wait-list control and the intervention groups (H1), between the single-mode and combined conditions (H2), and between VM and VR (H3), we applied planned contrast analyses. RESULTS: The planned contrasts showed that the VR condition significantly improved learning outcomes in comparison to the VM condition (H3). The decreased mean scores of the VM condition offset the increased mean scores of VR, and thus no significant differences could be found in H1 and H2. CONCLUSIONS: Our study provides promising evidence that VR fosters medical communication competence more effectively than VM. PRACTICAL IMPLICATIONS: Medical students' learning in video-based digital environments can be facilitated by the use of interactive VR.

A western trauma association multicenter comparison of mesh versus non-mesh repair of blunt traumatic abdominal wall hernias.

BACKGROUND: Blunt traumatic abdominal wall hernias (TAWH) occur in <1 % of trauma patients. Optimal repair techniques, such as mesh reinforcement, have not been studied in detail. We hypothesize that mesh use will be associated with increased surgical site infections (SSI) and not improve hernia recurrence. MATERIALS AND METHODS: A secondary analysis of the Western Trauma Association blunt TAWH multicenter study was performed. Patients who underwent TAWH repair during initial hospitalization (1/2012-12/2018) were included. Mesh repair patients were compared to primary repair patients (non-mesh). A logistic regression was conducted to assess risk factors for SSI. RESULTS: 157 patients underwent TAWH repair during index hospitalization with 51 (32.5 %) having mesh repair: 24 (45.3 %) synthetic and 29 (54.7 %) biologic. Mesh patients were more commonly smokers (43.1 % vs. 22.9 %, p = 0.016) and had a larger defect size (10 vs. 6 cm, p = 0.003). Mesh patients had a higher rate of SSI (25.5 % vs. 9.5 %, p = 0.016) compared to non-mesh patients, but a similar rate of recurrence (13.7 % vs. 10.5%, p = 0.742), hospital length of stay (LOS), and mortality. Mesh use (OR 3.66) and higher ISS (OR 1.06) were significant risk factors for SSI in a multivariable model. CONCLUSION: Mesh was used more frequently in flank TAWH and those with a larger defect size. Mesh use was associated with a higher incidence and risk of SSI but did not reduce the risk of hernia recurrence. When repairing TAWH mesh should be employed judiciously, and prospective randomized studies are needed to identify clear indications for mesh use in TAWH.

An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma.

Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.

Fluorescence-guided resection of intradural spinal tumors: a systematic review and meta-analysis.

Intradural spinal tumors present significant challenges due to involvement of critical motor and sensory tracts. Achieving maximal resection while preserving functional tissue is therefore crucial. Fluorescence-guided surgery aims to improve resection accuracy and is well studied for brain tumors, but its efficacy has not been fully assessed for spinal tumors. This meta-analysis aims to delineate the efficacy of fluorescence guidance in intradural spinal tumor resection. The authors performed a systematic review in four databases. We included studies that have utilized fluorescence agents, 5-aminolevulinic acid (5-ALA) or sodium fluorescein, for the resection of intradural spinal tumors. A meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A total of 12 studies involving 552 patients undergoing fluorescence-guided intradural spinal tumor resection were included. Meningiomas demonstrated a 98% fluorescence rate and were associated with a homogenous florescence pattern; however, astrocytomas had variable fluorescence rate with pooled proportion of 70%. There was no significant difference in gross total resection (GTR) rates between fluorescein and 5-ALA (94% vs 84%, p = .22). Pre-operative contrast enhancement was significantly associated with intraoperative fluorescence with fluorescein. Intramedullary tumors with positive intraoperative fluorescence were significantly associated with higher GTR rates (96% vs 73%, p = .03). Utilizing fluorescence guidance during intradural spinal tumor resection holds promise of improving intraoperative visualization for specific intradural spinal tumors. Meningiomas and ependymomas have the highest fluorescence rates especially with sodium fluorescein; on the other hand, astrocytomas have variable fluorescence rates with no superiority of either agent. Positive fluorescence of intramedullary tumors is associated with a higher degree of resection.

Structure and quality of bedside teaching: A videographic analysis.

Bedside teaching (BST) is a core element of medical education. In light of a reported decrease in BST, evidence on how to use BST time most efficiently should be developed. Given that little research into the tangible quality characteristics of good BST has been reported, we investigated the influence of various teacher and structural characteristics on the perceived quality of BST. We filmed and coded 36 BSTs involving 24 lecturers and 259 students. Structural characteristics of interest were: number of students and patients, overall duration, and the proportion of clinical examination. Lecturer questionnaires provided insight into teaching experience and intrinsic motivation, and student evaluations assessed the quality of BSTs in three dimensions. Correlations are reported using the Pearson r and a linear mixed model (LMM). The intrinsic motivation of lecturers was significantly positively correlated with perceived quality, but their experience was only weakly so correlated. In the LMM, a significant association was observed for the quality dimension of clinical teaching with the number of patients and the proportion of time spent on clinical examination. Based on our findings, we recommend including multiple patients in BSTs, and providing substantial opportunities for clinical examination. Regarding lecturers, motivation matters more than experience.

TP53-PTEN-NF1 depletion in human brain organoids produces a glioma phenotype in vitro.

Glioblastoma (GBM) is fatal and the study of therapeutic resistance, disease progression, and drug discovery in GBM or glioma stem cells is often hindered by limited resources. This limitation slows down progress in both drug discovery and patient survival. Here we present a genetically engineered human cerebral organoid model with a cancer-like phenotype that could provide a basis for GBM-like models. Specifically, we engineered a doxycycline-inducible vector encoding shRNAs enabling depletion of the TP53, PTEN, and NF1 tumor suppressors in human cerebral organoids. Designated as inducible short hairpin-TP53-PTEN-NF1 (ish-TPN), doxycycline treatment resulted in human cancer-like cerebral organoids that effaced the entire organoid cytoarchitecture, while uninduced ish-TPN cerebral organoids recapitulated the normal cytoarchitecture of the brain. Transcriptomic analysis revealed a proneural GBM subtype. This proof-of-concept study offers a valuable resource for directly investigating the emergence and progression of gliomas within the context of specific genetic alterations in normal cerebral organoids.

Experiences of medical students and nursing trainees from unexpected death through simulation training.

BACKGROUND: Dying in simulation training is controversially discussed. On the one hand, the danger of an emotional overload of the learners is pointed out. On the other hand, dying in simulation settings is addressed as an opportunity to prepare future health professionals to deal with patient death. The present study investigates how medical students and nursing trainees experience the sudden death of a simulated patient and how and under which conditions it can be valuable to simulate the patient's death. METHODS: At the TUM School of Medicine in Munich, Germany, we developed an interprofessional, simulation-based course in which participants were unexpectedly confronted with a cardiac arrest scenario within which resuscitation had to be discontinued due to an advanced directive. After the course, focus groups were conducted with nine medical students and six nursing trainees. Data were analysed using Grounded Theory techniques. RESULTS: The participants reported low to high emotional involvement. The active renunciation of life-sustaining measures was felt to be particularly formative and caused a strange feeling and helplessness. Questions of what could have been done differently determined interviewees' thoughts. The participants appreciated the opportunity to experience what it feels like to lose a patient. The course experience encouraged interviewees to reflect on dying and the interviewees explained that they feel better prepared to face death after the course. The unexpected character of the confrontation, presence of the advanced directive and debriefing positively affected the impact of the simulation. CONCLUSIONS: The study recognises simulation training as a promising approach for preparing future health care professionals to encounter a patient's death.

Measuring informal workplace learning outcomes in residency training: a validation study.

BACKGROUND: Informal workplace learning (WPL) has no concrete learning objective and takes place without a responsible supervisor, which makes it difficult to assess its learning outcomes. Formal learning situations, as they are known from universities or schools, do not exist in this context and make a conventional assessment of learning goals and achievements impossible. Informal learning in the workplace is of central importance, and the assessment of informal learning outcomes in medical education is an under-researched area. The aim of our study was to adapt and validate an informal WPL questionnaire (originally developed for social workers) to assess learning outcomes due to informal WPL in residency training. METHODS: A total of 528 residents (n = 339 female; age: M = 29.79; SD = 3.37 years) completed an adapted questionnaire on informal WPL outcomes and the Freiburg Questionnaire to Assess Competencies in Medicine (i.e. medical knowledge, communication, and scholarship). Exploratory factor analysis was used to determine the underlying factor structure. The reliability of the factors was tested using McDonald's omega, and the correlation between the factors and the three subscales of the Freiburg questionnaire was tested using Spearman's rho correlation coefficient. To investigate construct validity, a structural equation model was calculated to examine the relationships between medical competencies and informal learning outcomes. RESULTS: The exploratory factor analysis yielded a four-factor solution that best fit the data. The scores of all four factors (GLO-CD: generic learning outcomes-competence development, GLO-R: generic learning outcomes-reflection, JSLO: job-specific learning outcomes, and OLLO: organisational learning outcomes) showed good internal consistency (Ω ≥ .69). The structural equation model showed that "medical expertise" had an impact on all four factors of informal learning at work. "Scholarship" seemed to predict GLO-CD and GLO-R. CONCLUSIONS: Our four-factor model reveals meaningful determinants of informal WPL in relation to residency training. The instrument is therefore the first promising attempt to assess informal WPL in the broader context of medical education during residency, thus supporting its construct validity.

Structured interviews on self-regulated learning strategies of medical students in the final year of medical school.

BACKGROUND: In the final year of medical school, the educational focus is on experiences in the clinical environment. This is where students acquire most of their practical knowledge for their future career and need to optimise their Self-Regulated Learning (SRL) strategies. Hence, the current study aims to explore which SRL strategies medical students use during their clerkships in different learning settings. METHODS: Structured interviews were conducted between May 2019 and December 2020 with 43 medical students during their final year in Munich, Germany. The students were surveyed about their SRL strategies. The transcribed data were thematically analysed using the measurements Strategy Use (SU) and Strategy Frequency (SF). RESULTS: Interview data were organized into 11 SRL strategy categories. The most used SRL strategy in general was "seeking information in the internet in form of a text" (SU: 1; SF: 2.605), with an e-learning tool; followed by "seeking social assistance from doctors" (SU: 0.977; SF: 1.884), and "seeking information in books" (SU: 0.884; SF: 1.419). There were differences in the usage of SRL in different learning contexts between female and male students. For example, 95.3% of students are "seeking social assistance from doctors" when having difficulties on the ward, but only 55.8% when they need help with written tasks (e.g. medical letter). The results show a difference in SRL usage when preparing for oral-practical (79.1% books) and written (97.7% e-learning tool) exam. However, it also appears that some students do not have SRL strategies for certain situations, mostly due to a lack of time. CONCLUSION: Medical students in the clinical phase are adapting their SRL strategy to the learning situation. To better support students´ SRL, it is necessary to ensure availability for their preferred resources: e-learning tool and experienced physicians as supervisors. Future research should focus on strategies to handle the limited time during clerkships.

Early-Life Enteric Pathogen Exposure, Socioeconomic Status, and School-Age Cognitive Outcomes.

Early-life experiences of enteric infections and diarrheal illness are common in low-resource settings and are hypothesized to affect child development. However, longer-term associations of enteric infections with school-age cognitive outcomes are difficult to estimate due to lack of long-term studies. The objective of this study was to examine the relationship between enteropathogen exposure in the first 2 years of life with school-age cognitive skills in a cohort of children followed from birth until 6 to 8 years in low-resource settings in Brazil, Tanzania, and South Africa. The study included participants from three sites from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health Study who were enrolled just after birth and followed for enteric infections, diarrheal illness, and cognitive development until 2 years of age. When the children were school-age, further data were collected on reasoning skills and semantic/phonemic fluency. We estimated associations between the burden of specific enteric pathogens and etiology-specific diarrhea from 0 to 2 years with cognitive test scores at 6 to 8 years using linear regression and adjusting for confounding variables. In this study, children who carried more enteric pathogens in the first 2 years of life showed overall decreases in school-age cognitive abilities, particularly children who carried protozoa, although this was not statistically significant in this sample. Socioeconomic factors such as maternal education and income were more closely associated with school-age cognitive abilities. Early-life enteric pathogens may have a small, lasting influence on school-age cognitive outcomes, although other socioeconomic factors likely contribute more significantly.

Characterization of neural mechanotransduction response in human traumatic brain injury organoid model.

The ability to model physiological systems through 3D neural in-vitro systems may enable new treatments for various diseases while lowering the need for challenging animal and human testing. Creating such an environment, and even more impactful, one that mimics human brain tissue under mechanical stimulation, would be extremely useful to study a range of human-specific biological processes and conditions related to brain trauma. One approach is to use human cerebral organoids (hCOs) in-vitro models. hCOs recreate key cytoarchitectural features of the human brain, distinguishing themselves from more traditional 2D cultures and organ-on-a-chip models, as well as in-vivo animal models. Here, we propose a novel approach to emulate mild and moderate traumatic brain injury (TBI) using hCOs that undergo strain rates indicative of TBI. We subjected the hCOs to mild (2 s[Formula: see text]) and moderate (14 s[Formula: see text]) loading conditions, examined the mechanotransduction response, and investigated downstream genomic effects and regulatory pathways. The revealed pathways of note were cell death and metabolic and biosynthetic pathways implicating genes such as CARD9, ENO1, and FOXP3, respectively. Additionally, we show a steeper ascent in calcium signaling as we imposed higher loading conditions on the organoids. The elucidation of neural response to mechanical stimulation in reliable human cerebral organoid models gives insights into a better understanding of TBI in humans.

The Effect of Area Social Deprivation on Health Behavior and Health Care Utilization in an Adult Trauma Population.

Social determinants of health may mediate health disparities, but these variables are not routinely measured in clinical practice. This is a retrospective, single-institution study that evaluates the effect of area deprivation on outcomes after trauma admission. Adult trauma patients 18 years and older were eligible. Patients were stratified into high-area (HSD) or low-area (LSD) social deprivation cohorts using zip code of residence. Regression modeling was used to explain the association between HSD, sociodemographic characteristics, and clinical outcomes. Patients who resided in HSD areas made up 29.5% of the study population, were more likely to be younger, male, and identify as a non-White race. Patients in the HSD cohort were also less likely to be admitted to the ICU (OR 0.84, CI 0.71-0.98) and discharged with additional services (OR 0.73, CI 0.57-0.94). We found that independently, area social deprivation affects trauma outcomes and the resources a patient is provided after discharge.