Establishment and cryptic transmission of Zika virus in Brazil and the Americas.

Transmission of Zika virus (ZIKV) in the Americas was first confirmed in May 2015 in northeast Brazil. Brazil has had the highest number of reported ZIKV cases worldwide (more than 200,000 by 24 December 2016) and the most cases associated with microcephaly and other birth defects (2,366 confirmed by 31 December 2016). Since the initial detection of ZIKV in Brazil, more than 45 countries in the Americas have reported local ZIKV transmission, with 24 of these reporting severe ZIKV-associated disease. However, the origin and epidemic history of ZIKV in Brazil and the Americas remain poorly understood, despite the value of this information for interpreting observed trends in reported microcephaly. Here we address this issue by generating 54 complete or partial ZIKV genomes, mostly from Brazil, and reporting data generated by a mobile genomics laboratory that travelled across northeast Brazil in 2016. One sequence represents the earliest confirmed ZIKV infection in Brazil. Analyses of viral genomes with ecological and epidemiological data yield an estimate that ZIKV was present in northeast Brazil by February 2014 and is likely to have disseminated from there, nationally and internationally, before the first detection of ZIKV in the Americas. Estimated dates for the international spread of ZIKV from Brazil indicate the duration of pre-detection cryptic transmission in recipient regions. The role of northeast Brazil in the establishment of ZIKV in the Americas is further supported by geographic analysis of ZIKV transmission potential and by estimates of the basic reproduction number of the virus.

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.

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.

Cerebrospinal fluid findings in reversible cerebral vasoconstriction syndrome: a way to differentiate from cerebral vasculitis?

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by an acute onset of severe headache and multi-focal segmental vasoconstriction of cerebral arteries resolving within 12 weeks. Diagnostic criteria include normal or near-normal findings in cerebrospinal fluid (CSF) analysis, especially leucocyte levels < 10/mm³. Distinguishing RCVS from primary angiitis of the central nervous system (PACNS) is essential to avoid unnecessary and sometimes unfavourable immunosuppressive treatment. We reviewed retrospectively the clinical and diagnostic data of 10 RCVS patients who presented in our neurological department from 1 January 2013 to February 2017. The main purpose was to verify whether CSF leucocyte counts < 10/mm³ serve to discriminate RCVS from PACNS. Five of six patients who underwent lumbar puncture presented with CSF leucocyte levels ≥ 10/mm³. Two patients had a history of misinterpretation of CSF pleocytosis as cerebral vasculitis and of immunosuppressive treatment. A complete restitution of cerebral vasoconstriction was evident in all. No patient had further cerebral strokes or bleedings without immunosuppressive treatment over more than 12 weeks. Despite the established diagnostic criteria, RCVS can manifest with CSF leucocyte levels > 10/mm³. Careful anamnesis and the response of 'vasculitis-like angiography' to nimodipine given as a test during angiography and as oral medication are key to differentiate RCVS from cerebral vasculitis.

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.

Perception of emotional prosody in adults with attention deficit hyperactivity disorder.

OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is associated with social conflicts. The purpose of this study was to explore domains of social cognition in adult patients with ADHD. METHODS: The assessment of social cognition was based on established neuropsychological tests: the Tübinger Affect Battery (TAB) for prosody and the Cambridge Behaviour Scale (CBS) for empathy. The performance of adults with ADHD (N = 28) was compared with the performance of a control group (N = 29) matched according to basic demographic variables. RESULTS: Treatment-naïve adults with ADHD showed deficits in emotional prosody (P = 0.02) and in the ability to empathize (P < 0.02) independent of executive functioning. In particular, their ability to perceive angry feelings was found to be compromised (P = 0.04). When emotional prosody was considered in relation to facial expressions, patients and controls showed no impairments (P > 0.2). No gender differences concerning social cognitive skills were detected. CONCLUSIONS: ADHD is associated with social cognition impairments involving both emotional prosody and empathy.

Global distribution and environmental suitability for chikungunya virus, 1952 to 2015.

Chikungunya fever is an acute febrile illness caused by the chikungunya virus (CHIKV), which is transmitted to humans by Aedes mosquitoes. Although chikungunya fever is rarely fatal, patients can experience debilitating symptoms that last from months to years. Here we comprehensively assess the global distribution of chikungunya and produce high-resolution maps, using an established modelling framework that combines a comprehensive occurrence database with bespoke environmental correlates, including up-to-date Aedes distribution maps. This enables estimation of the current total population-at-risk of CHIKV transmission and identification of areas where the virus may spread to in the future. We identified 94 countries with good evidence for current CHIKV presence and a set of countries in the New and Old World with potential for future CHIKV establishment, demonstrated by high environmental suitability for transmission and in some cases previous sporadic reports. Aedes aegypti presence was identified as one of the major contributing factors to CHIKV transmission but significant geographical heterogeneity exists. We estimated 1.3 billion people are living in areas at-risk of CHIKV transmission. These maps provide a baseline for identifying areas where prevention and control efforts should be prioritised and can be used to guide estimation of the global burden of CHIKV.

Cerebral vasculitis in adults: what are the steps in order to establish the diagnosis? Red flags and pitfalls.

Cerebral vasculitis is a rare cause of juvenile stroke. It may occur as primary angiitis of the central nervous system (PACNS) or as CNS manifestation in the setting of systemic vasculitis. Clinical hints for vasculitis are headache, stroke, seizures, encephalopathy and signs of a systemic inflammatory disorder. Diagnostic work-up includes anamnesis, whole body examination, laboratory and cerebral spinal fluid (CSF) studies, magnetic resonance imaging (MRI), angiography and brain biopsy. Due to the rarity of the disease, exclusion of more frequent differential diagnoses is a key element of diagnostic work -up. This review summarizes the steps that lead to the diagnosis of cerebral vasculitis and describes the red flags and pitfalls. Despite considering the dilemma of angiography-negative vasculitis and false-negative brain biopsy in some cases, it is important to protect patients from 'blind' immunosuppressive therapy in unrecognized non-inflammatory differential diagnosis.

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.

What is the expert's option on antiplatelet therapy in moyamoya disease? Results of a worldwide Survey.

BACKGROUND AND PURPOSE: Moyamoya disease (MMD) is a rare idiopathic vasculopathy characterized by an extensive network of fine collaterals in the setting of bilateral progressive stenosis and finally occlusion of the intracranial portion of the internal carotid artery and proximal anterior and medial arteries of Circle of Willis. Owing to the rarity of the disease and ethical concerns, double-blinded, randomized controlled trials about treatment options are completely lacking. The appropriate conservative treatment instead, before or after revascularization surgery, is nearly completely neglected in scientific literature, even in Asia. METHODS: We developed a questionnaire with response options offered in the multiple choice method. The survey was sent with the request to reply within September 2010 to January 2011 by email to experts in the treatment of MMD. As an international expert, authors were selected who had written more than one scientific article or book chapter on the subject. We took special care not to select only Asian scientists, but also considered experts on the disease in Caucasian patients. RESULTS: Among the 77 physicians surveyed, 32 (41.55%) responded. Twenty-one (65.6%) Asian experts and 11 (34.4%) non-Asian experts participated in this survey. The majority of experts thought that long-term antiplatelet therapy is not essential in the treatment of MMD. Ten of 32 (31%) participants agreed to long-term antiplatelet treatment with acetylsalicylic acid 100 mg/day. There was a significant difference in answers between Asian and non-Asian experts (P = 0.0128). CONCLUSION: It is interesting that the majority of Non-Asian respondents recommend antiplatelet drugs, while this is an unusual approach in MMD of the Asian experts. Perhaps, this significant difference is well founded by the different experiences of the experts related to the difference in disease presentation between Asians and Caucasians. The role of conservative and surgical treatment in MMD needs further evaluation with larger cohorts and a focus on long-term clinical outcome.

Inheritance of moyamoya disease in a Caucasian family.

BACKGROUND AND PURPOSE: Moyamoya disease is a very rare occlusive cerebrovascular disorder characterized by progressive stenosis or occlusion of the intracranial portion of the internal carotid artery and proximal cerebral arteries with an extensive network of fine collaterals. The aetiology and genetic susceptibility of moyamoya disease, especially in Caucasians, still remains unclear. METHODS AND RESULTS: We describe the cases of affected German father, daughter and son with juvenile stroke because of idiopathic moyamoya disease. The rare existing literature is reviewed and discussed. CONCLUSIONS: This is the first report on a father-to-child inheritance pattern in Caucasian patients with idiopathic Moyamoya disease (MMD). Our cases indicate possible genetic risk factors for the genesis of Caucasian Moyamoya disease.

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.

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.

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.

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.

Prospective analysis between the therapy of immunosuppressive medication and allogeneic microchimerism after liver transplantation.

After liver transplantation, migration of donor-derived hematopoietic cells to recipient can be detected in peripheral blood. This state is termed microchimerism. The aim of this study was to investigate prospectively the presence of allogeneic microchimerism, the occurrence of acute cellular rejection and the level of immunosuppression in transplanted patients. Microchimerism occurrence between 10 days and 12 months after liver transplantation was analyzed in 47 patients aged between 15 and 65 by a two-stage nested PCR/SSP technique to detect donor MHC HLA-DR gene specifically. A pre-transplant blood sample was collected from each patient to serve as individual negative control. Microchimerism was demonstrated in 32 (68%) of the 47 patients; of these, only 10 patients (31.2%) presented rejection. Early microchimerism was observed in 25 patients (78.12%) and late microchimerism in 7 patients (21.8%). Among the patients with microchimerism, 14 were given CyA and 18 were given FK506. In the group without microchimerism, 12 patients were given CyA and 03 were given FK506. There was a significant association between the presence of microchimerism and the absence of rejection (p=0.02) and also between microchimerism and the type of immunosuppression used. Our data indicate that microchimerism and probably differentiation of donor-derived leukocytes can have relevant immunologic effects both in terms of sensitization of recipient and in terms of immunomodulation toward tolerance induction.