Ketamine in DUID cases in the greater Cologne area.

INTRODUCTION: Ketamine is primarily used as an anaesthetic or for analgesics in medical treatment, but due to its dissociative and hallucinogenic effects, abuse has increased in the past years leading to several drug impaired driving cases. METHODS: Eight DUID (driving under the influence of drugs) cases involving ketamine from two institutes of legal medicine over a period from January 2021 to January 2023 were evaluated. The cases were compared with regard to psychomotor impairments, adverse effects on driving performance and co-consumption of drugs. Analyses of ketamine were carried out by high performance liquid chromatography with diode array detection (HPLC-DAD). Other drugs of abuse were either detected via liquid chromatography with tandem mass spectromety (LC-MS/MS) and/or gas chromatography with (tandem) mass spectrometry (GC-MS(/MS)). RESULTS: Ketamine plasma concentrations in a range of approx. 100-1200 ng/mL (mean: 510 ng/mL, median: 370 ng/mL) were detected. Co-consumption of at least one substance was ascertained in all cases. Besides driving impairments, recorded psychomotor impairments of the drivers comprised e.g. dilated pupils, missing or delayed pupil reactions, a slurred or decelerated speech, delayed reaction, lack of concentration, vertigo or agitation. DISCUSSION: The observed peculiarities were in-line with literature data. However, the assessment and differentiation of ketamine-induced impairments was aggravated due to co-consumption of other drugs of abuse or pharmaceuticals in the herein investigated cases. Nevertheless, in two cases impairments can be attributed mainly to ketamine consumption since the co-consumed substances were only detected in low concentrations. CONCLUSION: The presented cases provide additional data on psychomotor impairments observed in ketamine-related DUID cases. Limiting factors are co-consumption of substances, unknown habituation to drugs and the limited case number. Nevertheless, the results of this study are comparable with existing literature data. Since the abuse of ketamine has increased in the past years, these data will support forensic casework.

Implementation study of the 2021 German guideline for diagnosis and treatment of multiple sclerosis.

BACKGROUND: In May 2021, a new guideline on the diagnosis and treatment of multiple sclerosis and related disorders was released in Germany. Since the success of a guideline depends on how it integrates into everyday clinical practice, the German Society for Neurology (DGN) has launched a multimethod implementation project. Here we report on the results based on the consultation version of the guideline. METHODS: We used qualitative and quantitative data analyses to capture the nature and extent of barriers and facilitating factors to the implementation. We centered on the guideline's chapter A on diagnosis, relapse therapy, and immunotherapy of multiple sclerosis. We performed nine online focus group discussions and a web-based survey and analyzed emails and letters with comments from stakeholders and independent parties that were sent spontaneously or by invitation. RESULTS: 94 neurologists answered the survey, and ≥70% agreed with the recommendations of the guideline on each major content topic. Barriers to implementation were detected in group discussions and written input. The most controversial issues of the guideline were "early treatment", "criteria for starting or switching therapy", "stepwise escalation versus early aggressive treatment", "classification of drugs into three categories of efficacy" and the scenarios on "treatment cessation". Some appreciated the highly structured recommendations, but others felt that the guideline restricts the free choice of therapy, or they were afraid of recourse claims. Some considered the guideline as too cautious regarding treatment initiation, possibly delaying necessary therapies. Others appreciated that conflicts of interests of the guideline's authoring group were minimized and thought that the new guideline is clearer, more extensive and practical. CONCLUSION: In contrast to the survey, feedback in the focus group discussions and from individuals was diverse and sometimes more critical. Based on the overall feedback rate of about 250 people in relation to the number of 6500 board-certified neurologists in Germany, the overall appreciation of the guideline can only be considered as an indicator and not proof of acceptance. Results of this analysis were incorporated into several adjustments to the final guideline of 2021. Since the guideline is to be updated regularly under the auspices of a "living guideline", active interaction with users will continue to matter and help to improve it.

Interaction of therapeutic12C ions with bone-like targets: physical characterization and dosimetric effect at material interfaces.

Carbon therapy is a promising treatment option for cancer. The physical and biological properties of carbon ions can theoretically allow for the delivery of curative doses to the tumor, while simultaneously limiting risks of toxicity to adjacent healthy structures. The treatment effectiveness can be further improved by decreasing the uncertainties stemming from several sources, including the modeling of tissue heterogeneity. Current treatment plans employ density-based conversion methods to translate patient-specific anatomy into a water system, where dose distribution is calculated. This approach neglects differences in nuclear interactions stemming from the elemental composition of each tissue. In this work, we investigated the interaction of therapeutic carbon ions with bone-like materials. The study concentrated on nuclear interactions and included attenuation curves of 200 and 400 AMeV beams in different types of bones, as well as kinetic energy spectra of all charged fragments produced up to 29 degrees from the beam direction. The comparison between measurements and calculations of the treatment planning system TRiP98 indicated that bone tissue causes less fragmentation of carbon ions than water. Overall, hydrogen and helium particles were found to be the most abundant species, while heavier fragments were mostly detected within 5 degrees from the beam direction. We also investigated how the presence of a soft tissue-bone interface could affect the depth-dose profile. The results revealed a dose spike in the transition region, that extended from the entry channel to the target volume. The findings of this work indicated that the tissue-to-water conversion method based only on density considerations can result in dose inaccuracies. Tissue heterogeneity regions containing bones can potentially produce dose spikes, whose magnitude will depend on the patient anatomy. Dose uncertainties can be decreased by modeling nuclear interactions directly in bones, without applying the tissue-to-water conversion.

Distribution of tumor-infiltrating-T-lymphocytes and possible tumor-escape mechanisms avoiding immune cell attack in locally advanced adenocarcinomas of the esophagus

Introduction The inflammatory microenvironment has emerged as one of the focuses of cancer research. Little is known about the immune environment in esophageal adenocarcinoma (EAC) and possible tumor-escape mechanisms to avoid immune cell attack. Patients and methods We measured T cell inflammation (CD3, CD8) in the microenvironment using a standardized software-based evaluation algorithm considering different predefined tumor areas as well as expression of MHC class 1 and PD-L1 on 75 analyzable primarily resected and locally advanced (≥ pT2) EACs. We correlated these findings statistically with clinical data. Results Patients with high amounts of T cell infiltration in their tumor center showed a significant survival benefit of 41.4 months compared to 16.3 months in T cell poor tumors (p = 0.025), although CD3 fails to serve as an independent prognostic marker in multivariate analysis. For the invasion zone, a correlation between number of T-cells and overall survival was not detectable. Loss of MHC1 protein expression on tumor cells was seen in 32% and PD-L1 expression using the combined positive score (CPS) in 21.2%. Most likely due to small numbers of cases, both markers are not prognostically relevant, even though PD-L1 expression correlates with advanced tumor stages. Discussion Our analyses reveal an outstanding, though not statistically independent, prognostic relevance of T-cell-rich inflammation in our group of EACs, in particular driven by the tumor center. For the first time, we describe that the inner part of the invasion zone in EACs shows significantly fewer T-cells than other tumor segments and is prognostically irrelevant. We also demonstrate that the loss of antigen presenting ability via MHC1 downregulation by the carcinoma cells is a common escape mechanism in EACs. Future work will need to show whether tumors with MHC class 1 loss respond less well to immunotherapy (AU)

Focusing on Diversity: A Regional Internal Medicine Residency Viewpoint on Underrepresented Minority Support, Retention, and Mentoring.

BACKGROUND: While the overall percentage of residents who withdraw (2.7%) or take extended leave (1.0%) are low, subgroup analysis has found that minority physicians are approximately 30% more likely to withdraw from residency than their white counterparts and 8 times more likely to take extended leave of absence. With ongoing national efforts to support diversity in medical education through increased recruitment of underrepresented in medicine (UiM) students to residency programs, there is paucity of data identifying specific experiences challenging or contributing to their overall resiliency. Better understanding of the lived experience of UiM residents will allow residency programs to create successful curricular programing and support structures for residents to thrive. OBJECTIVE: We sought to understand UiM internal medicine residents' experiences during residency training. METHODS: We used a retrospective review of focus group transcripts of UiM internal medicine residents from 5 academic institutions in 2017 (4 in North Carolina and 1 in Georgia). RESULTS: Of 100 self-identified UiM residents from 5 institutions, 59 participated in the focus groups. Using a consensus-based review of transcripts, 25 distinct codes in 8 parent code categories were determined. Two primary themes emerged: resilience and isolation. Three secondary themes-social support, mentorship, and external expectations and/or biases-served as mediators for the primary themes. CONCLUSIONS: UiM residents who became or were already resilient commonly experienced isolation at some time in their medical career, specifically during residency. Moreover, they could be influenced and positively or negatively affected by social support, mentorship, and external expectations and biases.

Distribution of tumor-infiltrating-T-lymphocytes and possible tumor-escape mechanisms avoiding immune cell attack in locally advanced adenocarcinomas of the esophagus.

INTRODUCTION: The inflammatory microenvironment has emerged as one of the focuses of cancer research. Little is known about the immune environment in esophageal adenocarcinoma (EAC) and possible tumor-escape mechanisms to avoid immune cell attack. PATIENTS AND METHODS: We measured T cell inflammation (CD3, CD8) in the microenvironment using a standardized software-based evaluation algorithm considering different predefined tumor areas as well as expression of MHC class 1 and PD-L1 on 75 analyzable primarily resected and locally advanced (≥ pT2) EACs. We correlated these findings statistically with clinical data. RESULTS: Patients with high amounts of T cell infiltration in their tumor center showed a significant survival benefit of 41.4 months compared to 16.3 months in T cell poor tumors (p = 0.025), although CD3 fails to serve as an independent prognostic marker in multivariate analysis. For the invasion zone, a correlation between number of T-cells and overall survival was not detectable. Loss of MHC1 protein expression on tumor cells was seen in 32% and PD-L1 expression using the combined positive score (CPS) in 21.2%. Most likely due to small numbers of cases, both markers are not prognostically relevant, even though PD-L1 expression correlates with advanced tumor stages. DISCUSSION: Our analyses reveal an outstanding, though not statistically independent, prognostic relevance of T-cell-rich inflammation in our group of EACs, in particular driven by the tumor center. For the first time, we describe that the inner part of the invasion zone in EACs shows significantly fewer T-cells than other tumor segments and is prognostically irrelevant. We also demonstrate that the loss of antigen presenting ability via MHC1 downregulation by the carcinoma cells is a common escape mechanism in EACs. Future work will need to show whether tumors with MHC class 1 loss respond less well to immunotherapy.

Heritable and non-heritable uncommon causes of stroke.

Despite intensive investigations, about 30% of stroke cases remains of undetermined origin. After exclusion of common causes of stroke, there is a number of rare heritable and non-heritable conditions, which often remain misdiagnosed, that should be additionally considered in the diagnosis of cryptogenic stroke. The identification of these diseases requires a complex work up including detailed clinical evaluation for the detection of systemic symptoms and signs, an adequate neuroimaging assessment and a careful family history collection. The task becomes more complicated by phenotype heterogeneity since stroke could be the primary or unique manifestation of a syndrome or represent just a manifestation (sometimes minor) of a multisystem disorder. The aim of this review paper is to provide clinicians with an update on clinical and neuroradiological features and a set of practical suggestions for the diagnostic work up and management of these uncommon causes of stroke. The identification of these stroke causes is important to avoid inappropriate and expensive diagnostic tests, to establish appropriate management measures, including presymptomatic testing, genetic counseling, and, if available, therapy. Therefore, physicians should become familiar with these diseases to provide future risk assessment and family counseling.

Building Health Systems Science Education from the Core Domain of Interprofessional Education at Virginia Tech Carilion School of Medicine.

The Virginia Tech Carilion School of Medicine (VTCSOM) is a 4-year allopathic medical school in Roanoke, VA. The curriculum is organized into four learning domains: basic science, clinical science, research, and interprofessionalism (IPE). A recent curriculum renewal effort allowed the school to embark upon a redesign of the IPE learning domain to incorporate new core content from health systems science (HSS). We describe how our unique approach to IPE is being preserved as we innovate to produce graduates who are future thought leaders and "systems citizens," prepared to deliver patient care with an expanded knowledge of the health systems in which they will eventually practice.

Livedo racemosa in neurological diseases: an update on the differential diagnoses.

Livedo is a net-like violaceous skin pattern. It can be classified as physiological or pathological. The physiological livedo reticularis usually appears in cold conditions, whereas the pathological and irregular livedo, which persists in warm temperatures, is often labeled as 'livedo racemosa'. Some neurological pathologies are associated with livedo, most commonly those with an inflammatory component or those derived from systemic disorders. The present review summarizes the most important central and peripheral neurological diseases in pediatric and adult age groups associated with livedo, providing physicians with an overview of the clinical presentation, etiology, diagnosis and management of these conditions.

Stroke care during the COVID-19 pandemic: experience from three large European countries.

In order to cope with the exponentially increasing number of patients infected with SARS-CoV-2, European countries made enormous efforts to reorganize medical assistance and several diseases, including stroke, were particularly impacted. We report the experience of stroke neurologists from three European countries (Italy, France and Germany) that faced the pandemic at diverse time points and with different approaches, depending on their resources and healthcare system organization. Pre-hospital and in-hospital acute stroke pathways were reorganized to prioritize COVID-19 management and, in severely affected regions of Italy and France, stroke care was centralized to a limited number of centers, whereas the remaining stroke units were dedicated to patients with COVID-19. Access to acute stroke diagnostics and time-dependent therapies was limited or delayed because of reduced capacities of emergency services due to the burden of patients with COVID-19. A marked reduction in the number of patients presenting with transient ischaemic attack and stroke was noted in the emergency departments of all three countries. Although we only have preliminary data, these conditions may have affected stroke outcome. These indirect effects of the COVID-19 pandemic could negate the efforts of stroke neurologists over the last few years to improve outcome and reduce mortality of stroke patients. Although the SARS-CoV-2 infection rate is slowing down in Europe, the effects of ending lockdown in the next months are unpredictable. It is important for the European and world stroke community to share what has been learned so far to be plan strategies to ensure stroke care in the future and upcoming challenging times.

Fatal misuse of transdermal fentanyl patches.

Fentanyl is a potent synthetic opioid with a variety of possible applications. Transdermal fentanyl patches are regularly prescribed for patients with severe chronic or cancer-related pain. The potential for abuse is well-known and cases associated with illicit fentanyl intake are common. Fentanyl related fatalities due to unintentional misuse are relatively rare. This study focused on those instances and their identification in forensic examinations and adds new cases and consolidates the existing femoral blood concentrations in the event of fatal fentanyl patch misapplications. A total of 35 cases between 2010 and 2018 in which transdermal fentanyl patches were detected during forensic autopsies were identified and reviewed for the frequency of unspecific macroscopic signs of opioid intoxication. Furthermore, a detailed examination is presented for 11 cases in which toxicological results were available. The cause of death was eventually considered to be related to fentanyl patch misuse in 5 of these 11 cases. Co-administered drugs and signs of opioid intoxication, especially pulmonary edema, were frequently found. Lastly, it is advised to include norfentanyl and hair analysis in the interpretation of post-mortem fentanyl concentrations.

Backscattered electron emission after proton impact on gold nanoparticles with and without polymer shell coating.

This work aims at measuring experimentally proton induced secondary electron energy spectra after interaction with gold nano particles (GNPs) and polymer-coated GNPs. Backscattered electron energy spectra were collected over a 0 to 1000 eV energy range using a retarding field analyzer (RFA). This paper presents the spectra obtained for proton beam energies of 0.5 and 2 MeV and diameter 2.5 and 3.8 nm GNPs. The spectra were also measured for 3.8 nm GNPs after 5 and 10 MeV proton irradiations. GNPs were deposited on a 100 nm carbon film. Each experimental spectrum was compared with dedicated simulations based on existing numerical models used in the TRAX and Geant4 Monte Carlo codes. For 100 nm carbon target, good agreement between experimental, TRAX and Geant4 simulation results can be observed. For 3.8 nm GNPs, the TRAX simulations reproduce with good agreement the electron energy spectra produced after 0.5, 2, 5 and 10 MeV proton irradiations, while Geant4 spectra display a lower secondary electron yield at low energy (<600 eV) for all the studied energies. This underestimation can mostly be explained by the 790 eV threshold applied in the condensed history model used by Geant4 which impacts the secondary electron energy distribution. Results obtained for carbon and gold targets highlight the impact of the secondary electron production threshold for proton ionization process considered in condensed history models. The experimental results demonstrate that the single interaction approach used in TRAX is adapted to reproduce secondary electron emission from GNPs. On the other hand, the standard electron generation threshold implement in G4BetheBlochModel and G4BraggModel condensed-history models used in Geant4 is not adapted to reproduce low energy electron emission in gold targets. Finally, the results highlight that the GNP coating leads to a decrease of the electron yield and mostly affects low energy electrons (<500 eV) emitted from GNPs.

Utilizing general human movement models to predict the spread of emerging infectious diseases in resource poor settings.

Human mobility is an important driver of geographic spread of infectious pathogens. Detailed information about human movements during outbreaks are, however, difficult to obtain and may not be available during future epidemics. The Ebola virus disease (EVD) outbreak in West Africa between 2014-16 demonstrated how quickly pathogens can spread to large urban centers following one cross-species transmission event. Here we describe a flexible transmission model to test the utility of generalised human movement models in estimating EVD cases and spatial spread over the course of the outbreak. A transmission model that includes a general model of human mobility significantly improves prediction of EVD's incidence compared to models without this component. Human movement plays an important role not only to ignite the epidemic in locations previously disease free, but over the course of the entire epidemic. We also demonstrate important differences between countries in population mixing and the improved prediction attributable to movement metrics. Given their relative rareness, locally derived mobility data are unlikely to exist in advance of future epidemics or pandemics. Our findings show that transmission patterns derived from general human movement models can improve forecasts of spatio-temporal transmission patterns in places where local mobility data is unavailable.

Experimental measurements validate the use of the binary encounter approximation model to accurately compute proton induced dose and radiolysis enhancement from gold nanoparticles.

In protontherapy, it has been suggested that nanoparticles of high-Z material like gold (GNP) could be used as radiosensitizers. The origin of this enhancement phenomenon for proton radiation is not yet well understood and additional mechanistic insights are required. Previous works have highlighted the good capabilities of TRAX to reproduce secondary electron emission from gold material. Therefore, TRAX cross sections obtained with the binary encounter approximation (BEA) model for proton ionization were implemented within Geant4 for gold material. Based on the TRAX cross sections, improved Geant4 simulations have been developed to investigate the energy deposition and radical species production around a spherical gold nanoparticle (5 and 10 nm in diameter) placed in a water volume during proton irradiation. Simulations were performed for incident 2 MeV proton. The dose enhancement factor and the radiolysis enhancement factor were quantified. Results obtained with the BEA model were compared with results obtained with condensed-history models. Experimental irradiation of 200 nm gold films were performed to validate the secondary electron emission reproduction capabilities of physical models used in Monte Carlo (MC) simulations. TRAX simulations reproduced the experimental backscattered electron energy spectrum from gold film with better agreement than Geant4. Results on gold film obtained with the BEA model enabled to estimate the electron emission from GNPs. Results obtained in our study tend to support that the use of the BEA discrete model leads to a significant increase of the dose in the near vicinity of GNPs (<20 nm), while condensed history models used in Geant4 seem to overestimate the dose and the number of chemical species for increasing distances from the GNP. Based on discrete BEA model results, no enhancement effect due to secondary electron emitted from the GNP is expected if the GNP is not in close proximity to key cellular functional elements (DNA, mitochondria…).

Travel time to health facilities in areas of outbreak potential: maps for guiding local preparedness and response.

BACKGROUND: Repeated outbreaks of emerging pathogens underscore the need for preparedness plans to prevent, detect, and respond. As countries develop and improve National Action Plans for Health Security, addressing subnational variation in preparedness is increasingly important. One facet of preparedness and mitigating disease transmission is health facility accessibility, linking infected persons with health systems and vice versa. Where potential patients can access care, local facilities must ensure they can appropriately diagnose, treat, and contain disease spread to prevent secondary transmission; where patients cannot readily access facilities, alternate plans must be developed. Here, we use travel time to link facilities and populations at risk of viral hemorrhagic fevers (VHFs) and identify spatial variation in these respective preparedness demands. METHODS AND FINDINGS: We used geospatial resources of travel friction, pathogen environmental suitability, and health facilities to determine facility accessibility of any at-risk location within a country. We considered in-country and cross-border movements of exposed populations and highlighted vulnerable populations where current facilities are inaccessible and new infrastructure would reduce travel times. We developed profiles for 43 African countries. Resulting maps demonstrate gaps in health facility accessibility and highlight facilities closest to areas at risk for VHF spillover. For instance, in the Central African Republic, we identified travel times of over 24 h to access a health facility. Some countries had more uniformly short travel times, such as Nigeria, although regional disparities exist. For some populations, including many in Botswana, access to areas at risk for VHF nationally was low but proximity to suitable spillover areas in bordering countries was high. Additional analyses provide insights for considering future resource allocation. We provide a contemporary use case for these analyses for the ongoing Ebola outbreak. CONCLUSIONS: These maps demonstrate the use of geospatial analytics for subnational preparedness, identifying facilities close to at-risk populations for prioritizing readiness to detect, treat, and respond to cases and highlighting where gaps in health facility accessibility exist. We identified cross-border threats for VHF exposure and demonstrate an opportunity to improve preparedness activities through the use of precision public health methods and data-driven insights for resource allocation as part of a country's preparedness plans.

Reconstruction and prediction of viral disease epidemics.

A growing number of infectious pathogens are spreading among geographic regions. Some pathogens that were previously not considered to pose a general threat to human health have emerged at regional and global scales, such as Zika and Ebola Virus Disease. Other pathogens, such as yellow fever virus, were previously thought to be under control but have recently re-emerged, causing new challenges to public health organisations. A wide array of new modelling techniques, aided by increased computing capabilities, novel diagnostic tools, and the increased speed and availability of genomic sequencing allow researchers to identify new pathogens more rapidly, assess the likelihood of geographic spread, and quantify the speed of human-to-human transmission. Despite some initial successes in predicting the spread of acute viral infections, the practicalities and sustainability of such approaches will need to be evaluated in the context of public health responses.

Genomic and epidemiological monitoring of yellow fever virus transmission potential.

The yellow fever virus (YFV) epidemic in Brazil is the largest in decades. The recent discovery of YFV in Brazilian Aedes species mosquitos highlights a need to monitor the risk of reestablishment of urban YFV transmission in the Americas. We use a suite of epidemiological, spatial, and genomic approaches to characterize YFV transmission. We show that the age and sex distribution of human cases is characteristic of sylvatic transmission. Analysis of YFV cases combined with genomes generated locally reveals an early phase of sylvatic YFV transmission and spatial expansion toward previously YFV-free areas, followed by a rise in viral spillover to humans in late 2016. Our results establish a framework for monitoring YFV transmission in real time that will contribute to a global strategy to eliminate future YFV epidemics.

Visualization and Classification of Deeply Seated Collateral Networks in Moyamoya Angiopathy with 7T MRI.

BACKGROUND AND PURPOSE: Collateral networks in Moyamoya angiopathy have a complex angioarchitecture difficult to comprehend on conventional examinations. This study aimed to evaluate morphologic patterns and the delineation of deeply seated collateral networks using ultra-high-field MRA in comparison with conventional DSA. MATERIALS AND METHODS: Fifteen white patients with Moyamoya angiopathy were investigated in this prospective trial. Sequences acquired at 7T were TOF-MRA with 0.22 × 0.22 × 0.41 mm3 resolution and MPRAGE with 0.7 × 0.7 × 0.7 mm3 resolution. Four raters evaluated the presence of deeply seated collateral networks and image quality in a consensus reading of DSA, TOF-MRA, and MPRAGE using a 5-point scale in axial source images and maximum intensity projections. Delineation of deeply seated collateral networks by different imaging modalities was compared by means of the McNemar test, whereas image quality was compared using the Wilcoxon signed-rank test. RESULTS: The relevant deeply seated collateral networks were classified into 2 categories and 6 pathways. A total of 100 collateral networks were detected on DSA; 106, on TOF-MRA; and 73, on MPRAGE. Delineation of deeply seated collateral networks was comparable between TOF-MRA and DSA (P = .25); however, both were better than MPRAGE (P < .001). CONCLUSIONS: This study demonstrates excellent delineation of 6 distinct deeply seated collateral network pathways in Moyamoya angiopathy in white adults using 7T TOF-MRA, comparable to DSA.