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With the aim to advance the understanding of immune regulation in MCL and to identify targetable T-cell subsets, we set out to combine image analysis and spatial omic technology focused on both early and late differentiation stages of T cells. MCL patient tissue (n = 102) was explored using image analysis and GeoMx spatial omics profiling of 69 proteins and 1812 mRNAs. Tumor cells, T helper (TH) cells and cytotoxic (TC) cells of early (CD57-) and late (CD57+) differentiation stage were analyzed. An image analysis workflow was developed based on fine-tuned Cellpose models for cell segmentation and classification. TC and CD57+ subsets of T cells were enriched in tumor-rich compared to tumor-sparse regions. Tumor-sparse regions had a higher expression of several key immune suppressive proteins, tentatively controlling T-cell expansion in regions close to the tumor. We revealed that T cells in late differentiation stages (CD57+) are enriched among MCL infiltrating T cells and are predictive of an increased expression of immune suppressive markers. CD47, IDO1 and CTLA-4 were identified as potential targets for patients with T-cell-rich MCL TIME, while GITR might be a feasible target for MCL patients with sparse T-cell infiltration. In subgroups of patients with a high degree of CD57+ TC-cell infiltration, several immune checkpoint inhibitors, including TIGIT, PD-L1 and LAG3 were increased, emphasizing the immune-suppressive features of this highly differentiated T-cell subset not previously described in MCL.
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BACKGROUND: Spinocerebellar ataxia 4 (SCA4), characterized in 1996, features adult-onset ataxia, polyneuropathy, and linkage to chromosome 16q22.1; its underlying mutation has remained elusive. OBJECTIVE: To explore the radiological and neuropathological abnormalities in the entire neuroaxis in SCA4 and search for its mutation. METHODS: Three Swedish families with undiagnosed ataxia went through clinical, neurophysiological, and neuroimaging tests, including PET studies and genetic investigations. In four cases, neuropathological assessments of the neuroaxis were performed. Genetic testing included short read whole genome sequencing, short tandem repeat analysis with ExpansionHunter de novo, and long read sequencing. RESULTS: Novel features for SCA4 include dysautonomia, motor neuron affection, and abnormal eye movements. We found evidence of anticipation; neuroimaging demonstrated atrophy in the cerebellum, brainstem, and spinal cord. [18F]FDG-PET demonstrated brain hypometabolism and [11C]Flumazenil-PET reduced binding in several brain lobes, insula, thalamus, hypothalamus, and cerebellum. Moderate to severe loss of Purkinje cells in the cerebellum and of motor neurons in the anterior horns of the spinal cord along with pronounced degeneration of posterior tracts was also found. Intranuclear, mainly neuronal, inclusions positive for p62 and ubiquitin were sparse but widespread in the CNS. This finding prompted assessment for nucleotide expansions. A polyglycine stretch encoding GGC expansions in the last exon of the zink finger homeobox 3 gene was identified segregating with disease and not found in 1000 controls. CONCLUSIONS: SCA4 is a neurodegenerative disease caused by a novel GGC expansion in the coding region of ZFHX3, and its spectrum is expanded to include dysautonomia and neuromuscular manifestations.
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Proteínas de Homeodomínio , Ataxias Espinocerebelares , Humanos , Masculino , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/diagnóstico por imagem , Feminino , Adulto , Pessoa de Meia-Idade , Proteínas de Homeodomínio/genética , Linhagem , Disautonomias Primárias/genética , Tomografia por Emissão de Pósitrons , Suécia , Expansão das Repetições de Trinucleotídeos/genéticaRESUMO
Background: Biopsies of intracranial lesions are a cornerstone in the diagnosis of unresectable tumors to guide neurooncological treatment; however, the procedure is also associated with risks. The results from the cranial robot guidance system Stealth Autoguide™ were studied after introduction at a neurosurgical department. Primary aims include the presentation of clinical and radiological data, accuracy of radiological diagnosis, learning curves of the new technology, diagnostic yield, and precision. The secondary aim was to study complications. Methods: Retrospective data inclusion was performed on patientsâ ≥â 18 years undergoing biopsy with Stealth Autoguide™ due to suspected brain tumors in the first 3 years after the introduction of the technique. Data regarding clinical characteristics, intraoperative variables, pathological diagnosis, and complications were recorded. Analyses of learning curves were performed. Results: A total of 79 procedures were performed on 78 patients with a mean age of 62 years (SD 12.7, range 23-82), 30.8% were female. Tumors were often multifocal (63.3%) and supratentorial (89.9%). The diagnostic yield was 87.3%. The first-hand radiological diagnosis was correct in 62.0%. A slight decrease in operation time was observed, although not significant. The surgeon contributed to 12% of the variability. Conclusions: Robot-assisted biopsies with Stealth Autoguide™ seem to be comparable, with regards to complications, to frame-based and other frameless neurosurgical biopsies. Learning curves demonstrated no statistical differences in time of surgery and only 12% surgeon-related variation (ie, variation caused by the change of performing surgeon), suggesting a successful implementation of this technical adjunct.
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INTRODUCTION: Brain calcifications are frequent findings on imaging. In a small proportion of cases, these calcifications are associated with pathogenic gene variants, hence termed primary familial brain calcification (PFBC). The clinical penetrance is incomplete and phenotypic variability is substantial. This paper aims to characterize a Swedish PFBC cohort including 25 patients: 20 from seven families and five sporadic cases. METHODS: Longitudinal clinical assessment and CT imaging were conducted, abnormalities were assessed using the total calcification score (TCS). Genetic analyses, including a panel of six known PFBC genes, were performed in all index and sporadic cases. Additionally, three patients carrying a novel pathogenic copy number variant in SLC20A2 had their cerebrospinal fluid phosphate (CSF-Pi) levels measured. RESULTS: Among the 25 patients, the majority (76%) displayed varying symptoms during the initial assessment including motor (60%), psychiatric (40%), and/or cognitive abnormalities (24%). Clinical progression was observed in most patients (78.6%), but there was no significant difference in calcification between the first and second scans, with mean scores of 27.3 and 32.8, respectively. In three families and two sporadic cases, pathogenic genetic variants were identified, including a novel finding, in the SLC20A2 gene. In the three tested patients, the CSF-Pi levels were normal. CONCLUSIONS: This report demonstrates the variable expressivity seen in PFBC and includes a novel pathogenic variant in the SLC20A2 gene. In four families and three sporadic cases, no pathogenic variants were found, suggesting that new PFBC genes remain to be discovered.
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Calcinose , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III , Humanos , Masculino , Feminino , Calcinose/genética , Calcinose/diagnóstico por imagem , Suécia/epidemiologia , Pessoa de Meia-Idade , Estudos de Coortes , Adulto , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Idoso , Encefalopatias/genética , Encefalopatias/diagnóstico por imagem , Encefalopatias/líquido cefalorraquidiano , Tomografia Computadorizada por Raios X , Estudos Longitudinais , Encéfalo/diagnóstico por imagem , Encéfalo/patologiaRESUMO
BACKGROUND: Individual patterns of fat accumulation (visceral, subcutaneous, and/or liver fat) can determine cardiometabolic risk profile. OBJECTIVE: To investigate risk stratification using personalized fat z-scores in persons with a body mass index (BMI) of 30-40 kg/m2 from the UK Biobank imaging study. SETTING: Population-based study. METHODS: Whole-body magnetic resonance (MR) images of 40,174 participants from the UK Biobank imaging study were analyzed for visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (aSAT), and liver fat (LF) and used to calculate sex- and body size-invariant fat z-scores (VATz, aSATz, LFz). Associations between z-scores and later incident cardiovascular disease (CVD) and type 2 diabetes (T2D) were investigated using Cox proportional hazards modeling and Kaplan-Meier curves in participants with BMI 30-40 kg/m2. RESULTS: A total of 6716 participants had BMI 30-40 kg/m2 and within this group, CVD was positively associated with VATz (crude hazard ratio (cHR) [95% CI]: 1.30 [1.20-1.40], P < .001) and negatively associated with aSATz and LFz (cHR: 0.91 [0.85-0.99], P = .028, and 0.88 [0.82-0.95], P = .002). All z-scores remained significant after adjustment for sex, BMI, and age, but only VATz was significant when previous CVD was added. T2D was positively associated with VATz and LFz (cHR: 1.53 [1.40-1.67], P < .001, and 1.35 [1.23-148], P < .001) and negatively associated with aSATz (cHR: 0.90 [0.81-0.99], P = .026). All z-scores remained significant after adjustment for sex, BMI, and age. CONCLUSIONS: Personalized MR-derived fat z-scores can identify phenotypes of obesity with specific cardiometabolic risk profiles regardless of BMI. Current guidelines for bariatric surgery based on BMI exclude some of these high-risk patients.
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Diabetes Mellitus Tipo 2 , Gordura Intra-Abdominal , Imageamento por Ressonância Magnética , Gordura Subcutânea , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Massa Corporal , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/epidemiologia , Gordura Intra-Abdominal/diagnóstico por imagem , Gordura Intra-Abdominal/patologia , Fígado/diagnóstico por imagem , Fígado/patologia , Obesidade/complicações , Medição de Risco , Gordura Subcutânea/diagnóstico por imagem , Gordura Subcutânea/patologia , Reino Unido/epidemiologiaRESUMO
Introduction: The surgical procedure for severe, drug-resistant, unilateral hemispheric epilepsy is challenging. Over the last decades the surgical landscape for hemispheric disconnection procedures changed from anatomical hemispherectomy to functional hemispherotomy with a reduction of complications and stable good seizure outcome. Here, a task force of European epilepsy surgeons prepared, on behalf of the EANS Section for Functional Neurosurgery, a consensus statement on different aspects of the hemispheric disconnection procedure. Research question: To determine history, indication, timing, techniques, complications and current practice in Europe for hemispheric disconnection procedures in drug-resistant epilepsy. Material and methods: Relevant literature on the topic was collected by a literature search based on the PRISMA 2020 guidelines. Results: A comprehensive overview on the historical development of hemispheric disconnection procedures for epilepsy is presented, while discussing indications, timing, surgical techniques and complications. Current practice for this procedure in European epilepsy surgery centers is provided. At present, our knowledge of long-term seizure outcomes primarily stems from open surgical disconnection procedures. Although minimal invasive surgical techniques in epilepsy are rapidly developing and reported in case reports or small case series, long-term seizure outcome remain uncertain and needs to be reported. Discussion and conclusion: This is the first paper presenting a European consensus statement regarding history, indications, techniques and complications of hemispheric disconnection procedures for different causes of chronic, drug-resistant epilepsy. Furthermore, it serves as the pioneering document to report a comprehensive overview of the current surgical practices regarding this type of surgery employed in renowned epilepsy surgery centers across Europe.
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BACKGROUND: Data on de novo aneurysm formation after treatment for intracranial aneurysms remains scarce. We studied the incidence of de novo aneurysm formation in patients who had undergone aneurysm treatment more than 18 years prior to follow-up. As it is a disease affecting a younger patient population more specific guidelines are needed when planning a follow-up regime. METHODS: The rate of de novo aneurysm formation was assessed with Magnetic Resonance Angiography (MRA) follow-up >18 years after endovascular or microsurgical treatment for an intracranial aneurysm. Variables associated with de novo aneurysm formation were studied using logistic regression. Missing data were imputed using chained random forests. A data-driven model for the prediction of de novo aneurysm was created to calculate the relative variable importance of ten clinical features. RESULTS: De novo aneurysms were identified in 11/81 (13.6 %) patients, of whom 1 was male, over a median follow-up of 20 years. Sex was the most important variable associated with de novo aneurysm formation. Regarding the development of de novo aneurysm, men displayed an odds ratio (OR) of 0.16 (0.01-0.97), compared with women. OR for mRS score 2 or more was 0.20 (95 % CI 0.01-1.34), and OR for smokers was 3.70 (0.54-31.18). Six out of 11 patients (54.5 %) needed treatment; 1 underwent endovascular treatment (EVT) and 5 underwent microsurgical treatment (MST). The overall annual de novo aneurysm formation rate was 0.92 %. CONCLUSIONS: This study highlights the need for a longer follow-up imaging monitoring of patients that have previously undergone treatment for an intracranial aneurysm. These data are useful to take into consideration when planning a follow-up strategy.
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Aneurisma Roto , Aneurisma Intracraniano , Humanos , Masculino , Feminino , Aneurisma Intracraniano/diagnóstico por imagem , Aneurisma Intracraniano/epidemiologia , Aneurisma Intracraniano/cirurgia , Seguimentos , Fatores de Risco , Incidência , Modelos Logísticos , Aneurisma Roto/diagnóstico por imagem , Aneurisma Roto/epidemiologia , Aneurisma Roto/cirurgia , Resultado do TratamentoRESUMO
FOXC1 is a ubiquitously expressed forkhead transcription factor that plays a critical role during early development. Germline pathogenic variants in FOXC1 are associated with anterior segment dysgenesis and Axenfeld-Rieger syndrome (ARS, #602482), an autosomal dominant condition with ophthalmologic anterior segment abnormalities, high risk for glaucoma and extraocular findings including distinctive facial features, as well as dental, skeletal, audiologic, and cardiac anomalies. De Hauwere syndrome is an ultrarare condition previously associated with 6p microdeletions and characterized by anterior segment dysgenesis, joint instability, short stature, hydrocephalus, and skeletal abnormalities. Here, we report clinical findings of two unrelated adult females with FOXC1 haploinsufficiency who have ARS and skeletal abnormalities. Final molecular diagnoses of both patients were achieved using genome sequencing. Patient 1 had a complex rearrangement involving a 4.9 kB deletion including FOXC1 coding region (Hg19; chr6:1,609,721-1,614,709), as well as a 7 MB inversion (Hg19; chr6:1,614,710-8,676,899) and a second deletion of 7.1 kb (Hg19; chr6:8,676,900-8,684,071). Patient 2 had a heterozygous single nucleotide deletion, resulting in a frameshift and a premature stop codon in FOXC1 (NM_001453.3): c.467del, p.(Pro156Argfs*25). Both individuals had moderate short stature, skeletal abnormalities, anterior segment dysgenesis, glaucoma, joint laxity, pes planovalgus, dental anomalies, hydrocephalus, distinctive facial features, and normal intelligence. Skeletal surveys revealed dolichospondyly, epiphyseal hypoplasia of femoral and humeral heads, dolichocephaly with frontal bossin gand gracile long bones. We conclude that haploinsufficiency of FOXC1 causes ARS and a broad spectrum of symptoms with variable expressivity that at its most severe end also includes a phenotype overlapping with De Hauwere syndrome.
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The majority of rare diseases are genetic, and regardless of advanced high-throughput genomics-based investigations, 60% of patients remain undiagnosed. A major factor limiting our ability to identify disease-causing alterations is a poor understanding of the morbid and normal human genome. A major genomic contributor of which function and distribution remain largely unstudied are the transposable elements (TE), which constitute 50% of our genome. Here we aim to resolve this knowledge gap and increase the diagnostic yield of rare disease patients investigated with clinical genome sequencing. To this end we characterized TE insertions in 1000 Swedish individuals from the SweGen dataset and 2504 individuals from the 1000 Genomes Project (1KGP), creating seven population-specific TE insertion databases. Of note, 66% of TE insertions in SweGen were present at >1% in the 1KGP databases, proving that most insertions are common across populations. Focusing on the rare TE insertions, we show that even though ~0.7% of those insertions affect protein coding genes, they rarely affect known disease casing genes (<0.1%). Finally, we applied a TE insertion identification workflow on two clinical cases where disease causing TE insertions were suspected and could verify the presence of pathogenic TE insertions in both. Altogether we demonstrate the importance of TE insertion detection and highlight possible clinical implications in rare disease diagnostics.
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Elementos de DNA Transponíveis , Doenças Raras , Humanos , Elementos de DNA Transponíveis/genética , Mutagênese Insercional , Doenças Raras/genética , Suécia , GenômicaRESUMO
OBJECTIVE: Hypothalamic hamartomas are benign lesions associated with drug resistant epilepsy. Surgical treatment has become an increasingly utilised approach with promising results. This study aims to evaluate seizure outcome and complications after surgery in a population-based series of patients with intractable epilepsy and hypothalamic hamartoma. METHODS: All patients with hypothalamic hamartoma treated with epilepsy surgery in Sweden since 1995 with at least two years of follow-up were included. Preoperative, two-, five- and ten-year prospective longitudinal data were collected from The Swedish National Epilepsy Surgery Register. Data included seizure types and frequency, duration of epilepsy, clinical characteristics, neurological deficits, cognitive level and complications. In a subgroup from Gothenburg, we also analysed data not included in the register such as classification of hamartomas, surgical procedures and gelastic seizures. RESULTS: Eighteen patients were operated on during the period 1995-2020. The median age at epilepsy onset was 6 months and age at surgery 13 years. Four were seizure free and another four had ≥75% reduction in seizure frequency at the two-year follow-up. Two of the 13 patients with a long-term follow-up (five or ten years) were seizure-free and four had ≥75% reduction in seizure frequency. Three had an increased seizure frequency. No major complications were seen. Five had minor complications. In the Gothenburg subgroup all had open pterional disconnection or intraventricular endoscopic disconnection. Six of 12 were free from gelastic seizures at the two-year follow-up and six of eight at the long-term follow-up. CONCLUSION: This study supports surgical treatment of hypothalamic hamartomas as a safe method with a low risk of permanent complications. The seizure reduction seems to be persistent over time.
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Epilepsia Resistente a Medicamentos , Epilepsias Parciais , Epilepsia , Hamartoma , Doenças Hipotalâmicas , Humanos , Adolescente , Estudos Prospectivos , Epilepsia/cirurgia , Epilepsia/complicações , Doenças Hipotalâmicas/complicações , Doenças Hipotalâmicas/cirurgia , Hamartoma/complicações , Hamartoma/cirurgia , Epilepsias Parciais/cirurgia , Epilepsias Parciais/complicações , Convulsões/complicações , Epilepsia Resistente a Medicamentos/cirurgia , Epilepsia Resistente a Medicamentos/complicações , Resultado do Tratamento , Imageamento por Ressonância MagnéticaRESUMO
Dielectrophoresis is an electric field-based technique for moving neutral particles through a fluid. When used for particle separation, dielectrophoresis has many advantages compared to other methods, like providing label-free operation with greater control of the separation forces. In this paper, we design, build, and test a low-voltage dielectrophoretic device using a 3D printing approach. This lab-on-a-chip device fits on a microscope glass slide and incorporates microfluidic channels for particle separation. First, we use multiphysics simulations to evaluate the separation efficiency of the prospective device and guide the design process. Second, we fabricate the device in PDMS (polydimethylsiloxane) by using 3D-printed moulds that contain patterns of the channels and electrodes. The imprint of the electrodes is then filled with silver conductive paint, making a 9-pole comb electrode. Lastly, we evaluate the separation efficiency of our device by introducing a mixture of 3 µm and 10 µm polystyrene particles and tracking their progression. Our device is able to efficiently separate these particles when the electrodes are energized with ±12 V at 75 kHz. Overall, our method allows the fabrication of cheap and effective dielectrophoretic microfluidic devices using commercial off-the-shelf equipment.
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Introduction: Neuromuscular disorders (NMDs) have a heterogeneous etiology. A genetic diagnosis is key to personalized healthcare and access to targeted treatment for the affected individuals. Methods: In this study, 861 patients with NMDs were analyzed with genome sequencing and comprehensive variant calling including single nucleotide variants, small insertions/deletions (SNVs/INDELs), and structural variants (SVs) in a panel of 895 NMD genes, as well as short tandem repeat expansions (STRs) at 28 loci. In addition, for unsolved cases with an unspecific clinical presentation, the analysis of a panel with OMIM disease genes was added. Results: In the cohort, 27% (232/861) of the patients harbored pathogenic variants, of which STRs and SVs accounted for one-third of the patients (71/232). The variants were found in 107 different NMD genes. Furthermore, 18 pediatric patients harbored pathogenic variants in non-NMD genes. Discussion: Our results highlight that for children with unspecific hypotonia, a genome-wide analysis rather than a disease-based gene panel should be considered as a diagnostic approach. More importantly, our results clearly show that it is crucial to include STR- and SV-analyses in the diagnostics of patients with neuromuscular disorders.
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Bacterial spores are problematic in agriculture, the food industry, and healthcare, with the fallout costs from spore-related contamination being very high. Spores are difficult to detect since they are resistant to many of the bacterial disruption techniques used to bring out the biomarkers necessary for detection. Because of this, effective and practical spore disruption methods are desirable. In this study, we demonstrate the efficiency of a compact microfluidic lab-on-chip built around a coplanar waveguide (CPW) operating at 2.45 GHz. We show that the CPW generates an electric field hotspot of â¼10 kV/m, comparable to that of a commercial microwave oven, while using only 1.2 W of input power and thus resulting in negligible sample heating. Spores passing through the microfluidic channel are disrupted by the electric field and release calcium dipicolinic acid (CaDPA), a biomarker molecule present alongside DNA in the spore core. We show that it is possible to detect this disruption in a bulk spore suspension using fluorescence spectroscopy. We then use laser tweezers Raman spectroscopy (LTRS) to show the loss of CaDPA on an individual spore level and that the loss increases with irradiation power. Only 22% of the spores contain CaDPA after exposure to 1.2 W input power, compared to 71% of the untreated control spores. Additionally, spores exposed to microwaves appear visibly disrupted when imaged using scanning electron microscopy (SEM). Overall, this study shows the advantages of using a CPW for disrupting spores for biomarker release and detection.
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Dispositivos Lab-On-A-Chip , Técnicas Microbiológicas , Micro-Ondas , Esporos Bacterianos , Biomarcadores/análise , Estimulação Elétrica , Técnicas Microbiológicas/instrumentação , Técnicas Microbiológicas/métodos , Microscopia Eletrônica de Varredura , Pinças Ópticas , Espectrometria de Fluorescência , Análise Espectral Raman , Esporos Bacterianos/química , Esporos Bacterianos/metabolismo , Esporos Bacterianos/efeitos da radiação , Esporos Bacterianos/ultraestruturaRESUMO
Spore-forming pathogenic bacteria are adapted for adhering to surfaces, and their endospores can tolerate strong chemicals making decontamination difficult. Understanding the physico-chemical properties of bacteria and spores is therefore essential in developing antiadhesive surfaces and disinfection techniques. However, measuring physico-chemical properties in bulk does not show the heterogeneity between cells. Characterizing bacteria on a single-cell level can thereby provide mechanistic clues usually hidden in bulk measurements. This paper shows how optical tweezers can be applied to characterize single bacteria and spores, and how physico-chemical properties related to adhesion, fluid dynamics, biochemistry, and metabolic activity can be assessed.
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Pinças Ópticas , Análise Espectral Raman , Análise Espectral Raman/métodos , Esporos , Esporos Bacterianos , BactériasRESUMO
BACKGROUND: Mounting evidence suggests that wearable technologies using peripheral neuromodulation can provide novel ways of improving mobility and gait function in various patient populations including older adults. The purpose of this narrative review is to provide an overview of wearable technologies/devices to improve mobility and gait function through noninvasive peripheral neuromodulation in older adults over the age of 65 and to indicate the suggested mechanism of action behind these technologies. METHODS: We performed searches for articles and conference abstracts written in English, using the following databases: Embase Classic+Embase from 1947 to July 15, 2021; Ovid MEDLINE; Epub Ahead of Print, In-Process, In-Data-Review & Other Non-Indexed Citations, Daily and Versions from 1946 to July 15, 2021; PubMed; and Scopus. RESULTS: Forty-one technologies met the inclusion/exclusion criteria. We found that the primary implementation of the 41 technologies can be divided into 3 main categories: sensory substitution, sensory augmentation (open loop, closed loop), and motor stimulation. Using these technologies, various aspects of mobility are treated or addressed, including, gait function, fall risk, foot drop, navigating environment, and postural control. CONCLUSIONS: This narrative review summarizes wearable technologies that are currently commercially available and in stages of research and development. Overall, studies suggest that wearable peripheral neuromodulation technologies can improve aspects of mobility for older adults. Existing literature suggests that these technologies may lead to physiological changes in the brain through sensory reweighting or other neuroplastic mechanisms to enhance the performance of mobility and gait function in older adults over the age of 65.
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Marcha , Dispositivos Eletrônicos Vestíveis , Humanos , Idoso , Marcha/fisiologia , Equilíbrio Postural/fisiologiaRESUMO
As the threat of wildfire increases, it is imperative to enhance the understanding of household evacuation behavior and movements. Mobile GPS data provide a unique opportunity for studying evacuation routing behavior with high ecological validity, but there are little publicly available data. We generated a highway vehicle routing dataset derived from GPS trajectories generated by mobile devices (e.g., smartphones) in Sonoma County, California during the 2019 Kincade Fire that started on October 23, 2019. This dataset contains 21,160 highway vehicle routing records within Sonoma County from October 16, 2019 to November 13, 2019. The quality of the dataset is validated by checking trajectories and average travel speeds. The potential use of this dataset lies in analyzing and modeling evacuee route choice behavior, estimating traffic conditions during the evacuation, and validating wildfire evacuation simulation models.
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PURPOSE: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics. METHODS: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421). RESULTS: The diagnostic yield was 35% (GS-first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed. CONCLUSION: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time- and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients.
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Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Criança , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiências do Desenvolvimento/genética , Testes Genéticos/métodos , Análise em Microsséries , Transtornos do Neurodesenvolvimento/genética , Proteína do X Frágil da Deficiência Intelectual/genéticaRESUMO
DNA methylation is increasingly used for tumour classification and has expanded upon the > 100 currently known brain tumour entities. A correct diagnosis is the basis for suitable treatment for patients with brain tumours, which is the leading cause of cancer-related death in children. DNA methylation profiling is required for diagnosis of certain tumours, and used clinically for paediatric brain tumours in several countries. We therefore evaluated if the methylation-based classification is robust in different locations of the same tumour, and determined how the methylation pattern changed over time to relapse. We sampled 3-7 spatially separated biopsies per patient, and collected samples from paired primary and relapse brain tumours from children. Altogether, 121 samples from 46 paediatric patients with brain tumours were profiled with EPIC methylation arrays. The methylation-based classification was mainly homogeneous for all included tumour types that were successfully classified, which is promising for clinical diagnostics. There were indications of multiple subclasses within tumours and switches in the relapse setting, but not confirmed as the classification scores were below the threshold. Site-specific methylation alterations did occur within the tumours and varied significantly between tumour types for the temporal samples, and as a trend in spatial samples. More alterations were present in high-grade tumours compared to low-grade, and significantly more alterations with longer relapse times. The alterations in the spatial and temporal samples were significantly depleted in CpG islands, exons and transcription start sites, while enriched in OpenSea and regions not affiliated with a gene, suggesting a random location of the alterations in less conserved regions. In conclusion, more DNA methylation changes accumulated over time and more alterations occurred in high-grade tumours. The alterations mainly occurred in regions without gene affiliation, and did not affect the methylation-based classification, which largely remained homogeneous in paediatric brain tumours.