Lysine catabolism reprograms tumour immunity through histone crotonylation.

Cancer cells rewire metabolism to favour the generation of specialized metabolites that support tumour growth and reshape the tumour microenvironment1,2. Lysine functions as a biosynthetic molecule, energy source and antioxidant3-5, but little is known about its pathological role in cancer. Here we show that glioblastoma stem cells (GSCs) reprogram lysine catabolism through the upregulation of lysine transporter SLC7A2 and crotonyl-coenzyme A (crotonyl-CoA)-producing enzyme glutaryl-CoA dehydrogenase (GCDH) with downregulation of the crotonyl-CoA hydratase enoyl-CoA hydratase short chain 1 (ECHS1), leading to accumulation of intracellular crotonyl-CoA and histone H4 lysine crotonylation. A reduction in histone lysine crotonylation by either genetic manipulation or lysine restriction impaired tumour growth. In the nucleus, GCDH interacts with the crotonyltransferase CBP to promote histone lysine crotonylation. Loss of histone lysine crotonylation promotes immunogenic cytosolic double-stranded RNA (dsRNA) and dsDNA generation through enhanced H3K27ac, which stimulates the RNA sensor MDA5 and DNA sensor cyclic GMP-AMP synthase (cGAS) to boost type I interferon signalling, leading to compromised GSC tumorigenic potential and elevated CD8+ T cell infiltration. A lysine-restricted diet synergized with MYC inhibition or anti-PD-1 therapy to slow tumour growth. Collectively, GSCs co-opt lysine uptake and degradation to shunt the production of crotonyl-CoA, remodelling the chromatin landscape to evade interferon-induced intrinsic effects on GSC maintenance and extrinsic effects on immune response.

Frequency of bystander exposure to antibiotics for enteropathogenic bacteria among young children in low-resource settings.

Children in low-resource settings carry enteric pathogens asymptomatically and are frequently treated with antibiotics, resulting in opportunities for pathogens to be exposed to antibiotics when not the target of treatment (i.e., bystander exposure). We quantified the frequency of bystander antibiotic exposures for enteric pathogens and estimated associations with resistance among children in eight low-resource settings. We analyzed 15,697 antibiotic courses from 1,715 children aged 0 to 2 y from the MAL-ED birth cohort. We calculated the incidence of bystander exposures and attributed exposures to respiratory and diarrheal illnesses. We associated bystander exposure with phenotypic susceptibility of E. coli isolates in the 30 d following exposure and at the level of the study site. There were 744.1 subclinical pathogen exposures to antibiotics per 100 child-years. Enteroaggregative Escherichia coli was the most frequently exposed pathogen, with 229.6 exposures per 100 child-years. Almost all antibiotic exposures for Campylobacter (98.8%), enterotoxigenic E. coli (95.6%), and typical enteropathogenic E. coli (99.4%), and the majority for Shigella (77.6%), occurred when the pathogens were not the target of treatment. Respiratory infections accounted for half (49.9%) and diarrheal illnesses accounted for one-fourth (24.6%) of subclinical enteric bacteria exposures to antibiotics. Bystander exposure of E. coli to class-specific antibiotics was associated with the prevalence of phenotypic resistance at the community level. Antimicrobial stewardship and illness-prevention interventions among children in low-resource settings would have a large ancillary benefit of reducing bystander selection that may contribute to antimicrobial resistance.

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.

An inverse latitudinal gradient in speciation rate for marine fishes.

Far more species of organisms are found in the tropics than in temperate and polar regions, but the evolutionary and ecological causes of this pattern remain controversial1,2. Tropical marine fish communities are much more diverse than cold-water fish communities found at higher latitudes3,4, and several explanations for this latitudinal diversity gradient propose that warm reef environments serve as evolutionary 'hotspots' for species formation5-8. Here we test the relationship between latitude, species richness and speciation rate across marine fishes. We assembled a time-calibrated phylogeny of all ray-finned fishes (31,526 tips, of which 11,638 had genetic data) and used this framework to describe the spatial dynamics of speciation in the marine realm. We show that the fastest rates of speciation occur in species-poor regions outside the tropics, and that high-latitude fish lineages form new species at much faster rates than their tropical counterparts. High rates of speciation occur in geographical regions that are characterized by low surface temperatures and high endemism. Our results reject a broad class of mechanisms under which the tropics serve as an evolutionary cradle for marine fish diversity and raise new questions about why the coldest oceans on Earth are present-day hotspots of species formation.

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.

Reflect to interact - fostering medical students' communication through reflection-focused e-learning.

BACKGROUND: Previous research indicates that reflection can foster medical communication competence. However, best practices for embedding reflection in online medical education are missing. This study examined how reflection processes can be promoted and embedded in an e-learning course on physician-patient communication to foster learning. METHODS: We investigated three differently designed e-learning conditions featuring different proportions of reflection triggers and compared their effects on students' reflections. We had 114 medical students in their first clinical year complete one of the variants: video modelling (VM, n = 39), video reflection (VR, n = 39), or a variant merging both approaches (VMR, n = 36). Each student wrote a total of nine reflections based on the same guiding questions at three time points embedded in the course. The students' levels of reflection were measured using an adapted version of the REFLECT rubric (scale 0-18). RESULTS: Students of all course variants achieved good levels of reflection beyond the descriptive level at all three time points, with no significant differences between the variants. The mean reflection scores at the end of the course were M = 14.22 for VM (SD = 2.23), M = 13.56 for VR (SD = 2.48), and M = 13.24 for VMR (SD = 2.21). Students who completed VM showed significantly improved levels of reflection over the course, whereas we found no statistically significant development for those in VR or VMR. The reflection scores correlated significantly positively with each other, as did the text lengths of the written reflections. Reflection scores also correlated significantly positively with text length. CONCLUSIONS: Our study offers a teaching strategy that can foster good levels of reflection, as demonstrated in the three e-learning variants. The developed reflection prompts can be easily embedded in various e-learning environments and enable reflections of good quality, even in settings with limited available teaching time.

Student mistakes and teacher reactions in bedside teaching.

We analyse interactions between teachers and students during video-recorded bedside teaching sessions in internal medicine, orthopaedics and neurology. Multiple raters used a high-inference categorical scheme on 36 sessions. Our research questions concern the types of student mistakes, clinical teachers' reactions to them and if they use different strategies to address different types of mistakes. We used a Poisson model and generalized mixed models to analyse these research questions. Most frequently, students made reproduction mistakes. Relatively high rates of rejection and a similar prevalence of low and high levels of elaboration and correction time for students were observed. Reproduction mistakes were associated with the highest level of rejection and the lowest level of elaboration. High levels of elaboration were observed when students were applying skills in new situations. Students were most often allowed time to correct when mistakes in the areas of analysis or application of skills and knowledge had occurred. There is a decrease in the rate of making mistakes for neurology and orthopaedics compared to internal medicine. Reproduction mistakes influence significantly the outcome feedback compared to application mistakes. Analytic and reproduction mistakes influence elaboration significantly compared to application mistakes. We found a significant effect whether the lecturer allows time for correction of reproduction mistakes compared to application mistakes. These results contribute to the understanding of interactive, patient-centred clinical teaching as well as student mistakes and how teachers are reacting to them. Our descriptive findings provide an empirical basis for clinical teachers to react to student mistakes in didactically fruitful ways.

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.

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.

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.

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.

Comparative metabolomics in the Pahenu2 classical PKU mouse identifies cerebral energy pathway disruption and oxidative stress.

Classical phenylketonuria (PKU, OMIM 261600) owes to hepatic deficiency of phenylalanine hydroxylase (PAH) that enzymatically converts phenylalanine (Phe) to tyrosine (Tyr). PKU neurologic phenotypes include impaired brain development, decreased myelination, early onset mental retardation, seizures, and late-onset features (neuropsychiatric, Parkinsonism). Phe over-representation is systemic; however, tissue response to hyperphenylalaninemia is not consistent. To characterize hyperphenylalaninemia tissue response, metabolomics was applied to Pahenu2 classical PKU mouse blood, liver, and brain. In blood and liver over-represented analytes were principally Phe, Phe catabolites, and Phe-related analytes (Phe-conjugates, Phe-containing dipeptides). In addition to Phe and Phe-related analytes, the metabolomic profile of Pahenu2 brain tissue evidenced oxidative stress responses and energy dysregulation. Glutathione and homocarnosine anti-oxidative responses are apparent Pahenu2 brain. Oxidative stress in Pahenu2 brain was further evidenced by increased reactive oxygen species. Pahenu2 brain presents an increased NADH/NAD ratio suggesting respiratory chain complex 1 dysfunction. Respirometry in Pahenu2 brain mitochondria functionally confirmed reduced respiratory chain activity with an attenuated response to pyruvate substrate. Glycolysis pathway analytes are over-represented in Pahenu2 brain tissue. PKU pathologies owe to liver metabolic deficiency; yet, Pahenu2 liver tissue shows neither energy disruption nor anti-oxidative response. Unique aspects of metabolomic homeostasis in PKU brain tissue along with increased reactive oxygen species and respiratory chain deficit provide insight to neurologic disease mechanisms. While some elements of assumed, long standing PKU neuropathology are enforced by metabolomic data (e.g. reduced tryptophan and serotonin representation), energy dysregulation and tissue oxidative stress expand mechanisms underlying neuropathology.

Programs to encourage working as a general practitioner in rural areas: why do medical students not want to participate? A cross-sectional study.

BACKGROUND: In many countries, not enough students are interested to work as general practitioners in rural areas. To solve this problem, several, sometimes partly extracurricular, programs have been developed. Most of these programs are based on continuity, which means that students stay in a rural region for an extended period of time, by completing clerkships. Although the effects of these programs are positive, it is often difficult to motivate students to participate. The purpose of the present study is to get insight into the reasons why students choose not to participate in these programs. METHODS: We carried out a questionnaire study among medical students in the clinical phase of the Technical University of Munich in Germany. First, we asked the students whether they actively informed themselves about the program which aims to reduce the shortage of general practitioners in rural areas in Bavaria. Furthermore, the questionnaire focused on the reasons for not participating in this program. RESULTS: Based on the answers of 442 students from study years 3-6, the most frequently chosen reason for not participating in the program is "identification with another discipline" with 61.0%, directly followed by "not willing to commit long-term" (56.1%). In third place is "personal connections to another region" with 30.5%. In the open comments, we find the same reasons: many students do not want to commit to a certain direction too early. In addition, students indicate that the number of regions where this program is offered is too limited for them. CONCLUSIONS: Offering programs to prepare and motivate students for work as general practitioners in rural areas can contribute to increasing the pool of future general practitioners. To encourage students to participate in such a program, it is important to consider the motives of students. Many students who might be interested in general practice do not choose to take part in such a program because they do not want to commit to a particular specialty or region at an early stage. It is important to take these insights into account when designing and implementing these programs.

How is modern bedside teaching structured? A video analysis of learning content, social and spatial structures.

BACKGROUND: Bedside teaching (BST) is an essential and traditional clinical teaching format. It has been subject to various impediments and has transformed over time. Besides a decrease in bedside time, there has also been a didactic diversification. In order to use time at the bedside effectively and understand the current design of BST, we here offer an evidence-based insight into how BST is practiced. This may serve as a basis for a refinement of its didactic design. METHODS: In the current study, we investigate the interrelationships between learning content and the social as well as spatial structures of BST. To this end, we have empirically analysed almost 80 hours of video material from a total of 36 BST sessions with good interrater reliability. RESULTS: BST lasted on average 125 min, most of which was spent in plenary and less than a third of the time at the patient's bedside. History taking was primarily practiced at the bedside while case presentations, clinical reasoning and theoretical knowledge were largely taught away from the patient. Clinical examination took place to a similar extent in the patient's room and in the theory room. CONCLUSIONS: Even though the filmed BSTs are not purely "bedside", the teaching format investigated here is a typical example of undergraduate medical education. In order to maximize the teaching time available, a suitable learning space should be provided in addition to the bedside. Moreover, the clinical examination should be revised in its general sequence prior to the BST, and conscious decisions should be made regarding the social structure so as to optimize the potential of small groups and plenary sessions.

Changes in medical students´ and anesthesia technician trainees´ attitudes towards interprofessionality - experience from an interprofessional simulation-based course.

BACKGROUND: Interprofessional simulation based education (IPSBE) programs positively impact participants' attitudes towards interprofessional collaboration and learning. However, the extent to which students in different health professions benefit and the underlying reasons for this are subject of ongoing debate. METHODS: We developed a 14-h IPSBE course with scenarios of critical incidents or emergency cases. Participants were final year medical students (FYMS) and final year anesthesia technician trainees (FYATT). To assess attitudes towards interprofessionalism, the University of the West of England Interprofessional Questionnaire was administrated before and after the course. Using focus group illustration maps, qualitative data were obtained from a subcohort of the participants (n = 15). RESULTS: After the course, self-assessment of communication and teamwork skills, attitudes towards interprofessional interactions and relationships showed comparative improvement in both professions. Attitudes towards interprofessional learning improved only in FYMS. Qualitative data revealed teamwork, communication, hierarchy and the perception of one's own and other health profession as main topics that might underlie the changes in participants' attitudes. An important factor was that participants got to know each other during the course and understood each other's tasks. CONCLUSIONS: Since adequate communication and teamwork skills and positive attitudes towards interprofessionality account to effective interprofessional collaboration, our data support intensifying IPSBE in undergraduate health care education.

Disentangling thermal effects using life cycle simulation modelling on the biology and demographic parameters of Dolichogenidea gelechiidivoris, a parasitoid of Tuta absoluta.

Dolichogenidea gelechiidivoris (Marsh) (Syn. Apanteles gelechiidivoris) (Hymenoptera: Braconidae), a konoibiont larval endoparasitoid of the South American tomato pinworm Tuta absoluta (Meyrick), was imported into Kenya in 2017 for the first classical biological control of T. absoluta in Africa. We determined the thermal thresholds of D. gelechiidivoris, with T. absoluta as host, using life cycle simulation modelling. Life-table data of D. gelechiidivoris were generated at six constant temperatures (10, 15, 20, 25, 30, and 35 °C, 65 ± 5% RH, and 12L: 12D photoperiod). Multiple non-linear functions were fitted to model some aspects of the biology of the parasitoid, including its longevity, mortality, reproduction, and senescence using Insect Life Cycle Modelling (ILCYM) software. The phenology models established were used to estimate life table parameters. Except at 35 °C, D. gelechiidivoris completed its development (i.e., egg-larval-pupa-adult) at all tested temperatures. The minimum temperature threshold from egg to cocoon was 7.0 °C and 5.9 °C from cocoon to adult wasp, while the maximum temperature thresholds were 34 °C and 36 °C, respectively. The optimal temperature for immature survival was 20-25 °C, while fecundity was optimum at 22.5 °C, with 69.5 eggs per female. Simulations of the population growth parameters indicated that the intrinsic rate of increase (rm) was maximum at 20 °C with 15 daughters per female per generation. Based on our findings the release of D. gelechiidivoris for inoculative augmentation in countries with temperatures ranging between 15 and 30 °C could be considered to control the pest.

Duration of Postdiarrheal Enteric Pathogen Carriage in Young Children in Low-resource Settings.

BACKGROUND: Prolonged enteropathogen shedding after diarrhea complicates the identification of etiology in subsequent episodes and is an important driver of pathogen transmission. A standardized approach has not been applied to estimate the duration of shedding for a wide range of pathogens. METHODS: We used a multisite birth cohort of children 0-24 months of age from whom diarrheal and monthly nondiarrheal stools were previously tested by quantitative polymerase chain reaction for 29 enteropathogens. We modeled the probability of detection of the etiologic pathogen before and after diarrhea using a log-normal accelerated failure time survival model and estimated the median duration of pathogen carriage as well as differences in subclinical pathogen carriage 60 days after diarrhea onset in comparison to a prediarrhea baseline. RESULTS: We analyzed 3247 etiologic episodes of diarrhea for the 9 pathogens with the highest attributable burdens of diarrhea. The median duration of postdiarrheal carriage varied widely by pathogen, from about 1 week for rotavirus (median, 8.1 days [95% confidence interval {CI}, 6.2-9.6]) to >1 month for Cryptosporidium (39.5 days [95% CI, 30.6-49.0]). The largest increases in subclinical pathogen carriage before and after diarrhea were seen for Cryptosporidium (prevalence difference between 30 days prior and 60 days after diarrhea onset, 0.30 [95% CI, .23-.39]) and Shigella (prevalence difference, 0.21 [95% CI, .16-.27]). CONCLUSIONS: Postdiarrheal shedding was widely variable between pathogens, with strikingly prolonged shedding seen for Cryptosporidium and Shigella. Targeted antimicrobial therapy and vaccination for these pathogens may have a relatively large impact on transmission.

Phenylalanine hydroxylase deficient phenylketonuria comparative metabolomics identifies energy pathway disruption and oxidative stress.

Classical phenylketonuria (PKU, OMIM 261600) owes to hepatic deficiency of phenylalanine hydroxylase (PAH) that enzymatically converts phenylalanine (Phe) to tyrosine (Tyr). PKU neurologic phenotypes include impaired brain development, decreased myelination, early onset mental retardation, seizures, and late-onset features (neuropsychiatric, Parkinsonism). PAH deficiency leads to systemic hyperphenylalaninemia; however, the impact of Phe varies between tissues. To characterize tissue response to hyperphenylalaninemia, metabolomics was applied to tissue from therapy noncompliant classical PKU patients (blood, liver), the Pahenu2 classical PKU mouse (blood, liver, brain) and the PAH deficient pig (blood, liver, brain, cerebrospinal fluid). In blood, liver, and CSF from both patients and animal models over-represented analytes were principally Phe, Phe catabolites, and Phe-related analytes (conjugates, Phe-containing dipeptides). In addition to Phe and Phe-related analytes, the metabolomic profile of PKU brain tissue (mouse, pig) evidenced oxidative stress responses and energy dysregulation. In Pahenu2 and PKU pig brain tissues, anti-oxidative response by glutathione and homocarnosine is apparent. Oxidative stress in Pahenu2 brain was further demonstrated by increased reactive oxygen species. In Pahenu2 and PKU pig brain, an increased NADH/NAD ratio suggests a respiratory chain dysfunction. Respirometry in PKU brain mitochondria (mouse, pig) functionally confirmed reduced respiratory chain activity. Glycolysis pathway analytes are over-represented in PKU brain tissue (mouse, pig). PKU pathologies owe to liver metabolic deficiency; yet, PKU liver tissue (mouse, pig, human) shows neither energy disruption nor anti-oxidative response. Unique aspects of metabolomic homeostasis in PKU brain tissue along with increased reactive oxygen species and respiratory chain deficit provide insight to neurologic disease mechanisms. While some elements of assumed, long standing PKU neuropathology are enforced by metabolomic data (e.g. reduced tryptophan and serotonin representation), energy dysregulation and tissue oxidative stress expand mechanisms underlying neuropathology.

Radiation oncology as part of medical education-current status and possible digital future prospects.

PURPOSE: Education as part of medical education is currently changing rapidly. Not least because of the corona crisis, more and more digital teaching formats and innovative teaching concepts such as the flipped classroom model are finding their way into teaching. We analyzed the acceptance and effectiveness of traditional teaching methods as well as the interest in innovative e­learning methods among medical students in the field of radiation oncology at the medical school of the Technical University of Munich. METHODS: We carried out an online-based survey as well as a knowledge test on all students from two terms who had completed the seminar series of radiation oncology. The survey comprised seven questions on the frequency of participation, acceptance, and judgment of the effectiveness in terms of learning and on a potential use of e­learning methods using a six-point Likert scale. The test consisted of 10 multiple-choice questions. RESULTS: Traditional teaching methods are largely accepted by students and most students consider the current learning format to be effective in terms of the teaching effect in the field of radiation oncology. However, only about 50% of all knowledge questions were answered correctly. The possible use of e­learning methods was judged critically or desired in roughly equal parts among the students. CONCLUSION: Traditional seminars enjoy a high level of acceptance among students. Effectiveness with regard to the internalization of content taught, however, should be increased. After all, the future seems to lie in the integration of e­learning in the form of educational videos and practical seminars.

A contemporary update on glioblastoma: molecular biology, current management, and a vision towards bio-adaptable personalized care.

INTRODUCTION: Glioblastoma (GBM) is the most fatal brain tumor in adults. Current survival rates of GBM remain below 2 years due to GBM's aggressive cellular migration and genetically driven treatment escape pathways. Despite our rapidly increasing understanding of GBM biology, earlier diagnoses, and refined surgical techniques, only moderate survival benefits have been achieved. Nonetheless, the pressing need for better survival rates has brought forward a multitude of newer therapeutic approaches and opened the door for potential personalization of these modalities in the near future. METHODS: We reviewed the published literature discussing the current state of knowledge regarding GBM biology and therapy and summarized the information that may point toward future personalized therapeutic strategies. RESULTS: Several novel modalities such as oncolytic viruses, targeted immune, and molecular therapies, and tumor treating fields have been introduced. To date, there is no single treatment modality for GBM, but rather a wide spectrum of combined modalities that address intratumoral cellular and genetic variabilities. While the current state of GBM research and clinical trial landscape may hold promise, current literature lacks any fruitful progress towards personalized GBM therapy. CONCLUSION: In this review, we are discussing our recent knowledge of the GBM genetic biologic landscape and the current advances in therapy, as well as providing a blueprint for an envisioned GBM management paradigm that should be personalized and adaptable to accommodate each patient's diverse genetic variations and therapy response/escape patterns.