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Abstract Impedance-matched Marx generators (IMGs) are considered next generation pulsed-power drivers because of their long lifetime (> 10,000 shots), repetition rate (> 0.1-Hz), fast rise time (~ 100-ns), and high-energy-delivery efficiency (~ 90%). “TITAN” is a 14-stage IMG designed to deliver 1-TW to a 2-Ω matched load. In this paper, design, simulation, and experimental results for six stages of TITAN including its triggering system, air delivery system, and pulse shaping are presented. To achieve efficiency over 85% and maximize the capability of an IMG, synchronized triggering, reduced pre-fire rate, and pulse shaping ability are crucial. In this paper, novel engineering solutions are introduced, tested, and proven to overcome those challenges. 6-stage TITAN, powered by 102 identical bricks and 102 field-distortion-triggered gas switches, could generate ~ 600-kA and ~ 700-kV across a ~ 0.9-Ω matched load when fully charged to ± 100-kV. In these experiments, 6-stage TITAN is tested up to ± 70-kV charge voltage which delivers a peak power of 330-GW to a 1.2-Ω resistive load.

Abstract Escalating wildfire activity in the western United States has accelerated adverse societal impacts. Observed increases in wildfire severity and impacts to communities have diverse anthropogenic causes—including the legacy of fire suppression policies, increased development in high-risk zones, and aridification by a warming climate. However, the intentional use of fire as a vegetation management tool, known as “prescribed fire,” can reduce the risk of destructive fires and restore ecosystem resilience. Prescribed fire implementation is subject to multiple constraints, including the number of days characterized by weather and vegetation conditions conducive to achieving desired outcomes. Here, we quantify observed and projected trends in the frequency and seasonality of western United States prescribed fire days. We find that while ~2 C of global warming by 2060 will reduce such days overall (−17%), particularly during spring (−25%) and summer (−31%), winter (+4%) may increasingly emerge as a comparatively favorable window for prescribed fire especially in northern states.

Background. The course of the COVID-19 epidemic process depends on population immunity which prevents pathogen spread. Aim: to study an evolution of SARS-CoV-2 humoral immunity in the Belarusian population rela- tive to COVID-19 pandemic dynamics. Materials and methods. The work was carried out according to a methodology for assessing herd immunity developed by Rospotrebnadzor (Russia) and the Belarusian Ministry of Health involving the St. Petersburg Pasteur Institute (SPPI) by taking into account the WHO recommendations. The study was approved by the Bioethics Committee of Belarus and the SPPI Bioethics Committee. Participant selection was carried out by ques- tionnaire using a cloud (internet server) service. To monitor herd immunity, a cohort of 4661 subjects (involved at all stages of seromonitoring) was formed from the total volunteer group. Study subjects were randomized into groups based on age (117, 1829, 3039, 4049, 5059, 6069, 70+ years), geographic region, and occupation. For the detection of antibodies (Abs) against SARS-CoV-2 nucleocapsid (Nc) and S glycoprotein receptor-binding domain (RBD), rel- evant assay systems were used according to the manufacturers instructions. A four-stage study was conducted according to a unified scheme. Results. At stage 1 (pandemic month 15), herd immunity was mainly accounted for by Nc+RBD+ Ab status alone. By stage 2 (4 months later), its specific proportion decreased by 1.2-fold, whereas percentage of subjects solely bearing RBD-specific Abs increased by 1.7-fold. At stages 3 and 4 (9 and 19 months after the onset) vs. stage 2, percent- age of subjects with RBD+Nc decreased by 3.5%; the proportion of persons with Nc+RBD Abs increased by 1.5-fold. The most important contributor in herd immunity turned out to be due to population vaccination, with coverage reaching 70% by stage 4. Among vaccines, compared with whole-virion, inactivated BIBP-CorV vaccine the Sputnik V and Sputnik Light vector were used most often. Conclusion. The evolution of herd SARS-CoV-2 humoral immunity included a series of changes in circulating Ab levels (Nc, RBD). The hybrid immunity formed helped to reduce the incidence of COVID-19 to sporadic level.

Diffuse large B-cell lymphoma (DLBCL) is the most common malignancy that develops in patients with ataxia-telangiectasia, a cancer-predisposing inherited syndrome characterized by inactivating germline ATM mutations. ATM is also frequently mutated in sporadic DLBCL. To investigate lymphomagenic mechanisms and lymphoma-specific dependencies underlying defective ATM, we applied ribonucleic acid (RNA)-seq and genome-scale loss-offunction clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens to systematically interrogate B-cell lymphomas arising in a novel murine model (Atm-/-nu-/-) with constitutional Atm loss, thymic aplasia but residual T-cell populations. Atm-/-nu-/-lymphomas, which phenotypically resemble either activated B-cell-like or germinal center Bcell-like DLBCL, harbor a complex karyotype, and are characterized by MYC pathway activation. In Atm-/-nu-/-lymphomas, we discovered nucleotide biosynthesis as a MYCdependent cellular vulnerability that can be targeted through the synergistic nucleotidedepleting actions of mycophenolate mofetil (MMF) and the WEE1 inhibitor, adavosertib (AZD1775). The latter is mediated through a synthetically lethal interaction between RRM2 suppression and MYC dysregulation that results in replication stress overload in Atm-/-nu-/-lymphoma cells. Validation in cell line models of human DLBCL confirmed the broad applicability of nucleotide depletion as a therapeutic strategy for MYC-driven DLBCL independent of ATM mutation status. Our findings extend current understanding of lymphomagenic mechanisms underpinning ATM loss and highlight nucleotide metabolism as a targetable therapeutic vulnerability in MYC-driven DLBCL.

# Background/Purpose No studies have observed the effects of a collegiate lacrosse season on movement pattern quality, dynamic postural control, or the accuracy of athletes’ perceived movement pattern quality. The purpose was to examine the effects of a nontraditional fall season on movement pattern quality, perceived movement pattern quality, and dynamic postural control in collegiate lacrosse athletes. # Design Cross-sectional laboratory study. # Methods Fifty men’s (age=19.38±1.24 years, height=182.63±6.16 cm, mass=82.37±8.46 kg) and 22 women’s (age=19.68±1.17 years, height=165.10±6.88 cm, mass=64.09±8.72 kg) lacrosse players were recruited. Outcome measures included individual Functional Movement Screen™ (FMS™) scores, self-reported perceived movement pattern quality scores, lower and upper extremity Y-Balance Test (YBT) measurements, and active dorsiflexion range of motion (ROM) before the start and again at the end of the fall lacrosse season. Pre- and post-season measurements were assessed using paired t-tests and chi-squared analyses. # Results FMS™ composite scores did not significantly change from preseason to postseason for males (p=0.74) or females (p=0.07). Male perceived movement pattern quality was significantly higher than measured for 10 of 12 movements (p

The escalating climate and wildfire crises have generated worldwide interest in using proactive forest management (e.g. forest thinning, prescribed fire, cultural burning) to mitigate the risk of wildfire-caused carbon loss in forests. To estimate the risk of wildfire-caused carbon loss in western United States (US) conifer forests, we used a generalizable framework to evaluate interactions among wildfire hazard and carbon exposure and vulnerability. By evaluating where high social adaptive capacity for proactive forest management overlaps with carbon most vulnerable to wildfire-caused carbon loss, we identified opportunity hot spots for reducing the risk of wildfire-caused carbon loss. We found that relative to their total forest area, California, New Mexico, and Arizona contained the greatest proportion of carbon highly vulnerable to wildfire-caused loss. We also observed widespread opportunities in the western US for using proactive forest management to reduce the risk of wildfire-caused carbon loss, with many areas containing opportunities for simultaneously mitigating the greatest risk from wildfire to carbon and human communities. Finally, we highlighted collaborative and equitable processes that provide pathways to achieving timely climate- and wildfire-mitigation goals at opportunity hot spots.

Purpose: To report a case of a sterile iris abscess associated with herpes zoster ophthalmicus (HZO). Observations: A 69-year-old African American female presented to SUNY Downstate Medical Center complaining of left-sided eye pain for two weeks. The patient had a best-corrected visual acuity of 20/30 OD and 20/200 OS. On external exam, vesicles were noted on the left upper lid and tip of the nose. Anterior segment exam was notable for decreased sensation without epithelial defects. The patient had 2+ stromal edema with 3+ cell and flare. The iris was flat with 1+ nuclear sclerosis OU. The intraocular pressure (IOP) was 14 mmHg OD and 40 mmHg OS. The patient was diagnosed with HZO with secondary uveitic glaucoma.At ten weeks, anterior segment inflammation resolved and IOP stabilized. However, an iris nodule was noted superior nasal which continued to enlarge by 16 weeks follow up. Iris ultrasound revealed a 3 × 3 mm elevated lesion with internal homogeneity suggestive of an abscess.At five months, a dense, mature cataract developed. The patient underwent cataract extraction with sector iridectomy. Gram staining and cultures were negative for organisms but positive for polymorphic neutrophils. Histopathology revealed fibrosis, surface necrosis, and stromal infiltration with chronic inflammatory cells consistent with chronic iritis and a sterile abscess secondary to HZO. Conclusions and Importance: HZO is associated with a range of ocular sequelae with acquired iris nodule only mentioned once in the literature. As the second documented case, our findings will add to the general fund of knowledge regarding iris lesions and HZO.

Mucopolysaccharidosis (MPS) type I is a rare lysosomal storage disorder caused by an accumulation of glycosaminoglycans (GAGs) resulting in multisystem disease. Neurological morbidity includes hydrocephalus, spinal cord compression, and cognitive decline. While many neurological symptoms have been described, stroke is not a widely-recognized manifestation of MPS I. Accordingly, patients with MPS I are not routinely evaluated for stroke, and there are no guidelines for managing stroke in patients with this disease. We report the case of a child diagnosed with MPS I who presented with overt stroke and repeated neurological symptoms with imaging findings for severe ventriculomegaly, infarction, and bilateral terminal carotid artery stenosis. Direct intracranial pressure evaluation proved negative for hydrocephalus. The patient was subsequently treated with cerebral revascularization and at a 3-year follow-up, the patient reported no further neurological events or new ischemia on cerebral imaging. Cerebral arteriopathy in patients with MPS I may be associated with GAG accumulation within the cerebrovascular system and may predispose patients to recurrent strokes. However, further studies are required to elucidate the etiology of cerebrovascular arteriopathy in the setting of MPS I. Although the natural history of steno-occlusive arteriopathy in patients with MPS I remains unclear, our findings suggest that cerebral revascularization is a safe treatment option that may mitigate the risk of future strokes and should be strongly considered within the overall management guidelines for patients with MPS I.

We examine the changes in the commercial model adopted by the mobile ICT industry, due to the advent of 5G technology. This includes consideration of the challenges involved in rolling out a new infrastructure, which new markets this is likely to open up and how this affects partnering decisions. We show that as technology horizons expand, their degree of overlap increases and previously complimentary technologies may compete with each other, impacting the size of the addressable market. It is expected that 5G, whilst supporting its existing markets, will offer additional machine to machine, low latency and highly reliable services. We consider the synergies and the drivers for adoption for the wider 5G propositions and consider the impetus for more bandwidth and services and how the new technology impacts selling approaches. We identify the risks and uncertainties for the network providers and the likely requirements for a sustainable 5G business model and will describe our view of the steps necessary for a 5G successful outcome

Background A significant number of people with autism require in-patient psychiatric care. Although the requirement to adequately meet the needs of people with autism in these settings is enshrined in UK law and supported by national guidelines, little information is available on current practice. Aims To describe characteristics of UK in-patient psychiatric settings admitting people with autism. Also to examine psychiatric units for their suitability, and the resultant impact on admission length and restrictive interventions. Method Multiple-choice questions about in-patient settings and their ability to meet the needs of people with autism and the impact on their outcomes were developed as a cross-sectional study co-designed with a national autism charity. The survey was distributed nationally, using an exponential and non-discriminatory snowballing technique, to in-patient unit clinicians to provide a current practice snapshot. Results Eighty responses were analysed after excluding duplications, from across the UK. Significant variation between units across all enquired parameters exist. Lack of autism-related training and skills across staff groups was identified, this becoming disproportionate when comparing intellectual disability units with general mental health units particularly regarding psychiatrists working in these units (psychiatrists: 94% specialist skills in intellectual disability units versus 6% specialist skills in general mental health units). In total, 28% of survey respondents felt people with autism are more likely to be subject to seclusion and 40% believed in-patients with autism are likely to end in segregation. Conclusions There is no systematic approach to supporting people with autism who are admitted to in-patient psychiatric units. Significant concerns are highlighted of lack of professional training and skill sets resulting in variable clinical practice and care delivery underpinned by policy deficiency. This could account for the reported in-patient outcomes of longer stay and segregation experienced by people with autism.

The development of cooperative control strategies for microgrids has become an area of increasing research interest in recent years, often a result of advances in other areas of control theory such as multi-agent systems and enabled by rapid advances in wireless communications technology and power electronics. Though the basic concept of cooperative action in microgrids is intuitively well-understood, a comprehensive survey of this approach with respect to its limitations and wide range of potential applications has not yet been provided. The objective of this paper is to provide a broad overview of cooperative control theory as applied to microgrids, introduce other possible applications not previously described, and discuss recent advances and open problems in this area of microgrid research.

Purpose: To report a case of solar retinopathy due to inadvertent exposure to the sun while piloting a drone without protective eyewear. Methods: A 29-year-old male underwent a complete eye exam including optical coherence tomography (OCT) of the macula. Results: Bilateral juxtafoveal outer retinal microcystic cavities present on OCT consistent with solar retinopathy. Conclusion: With the increasing popularity of unmanned aircrafts, eye protection awareness during drone use is essential. Keywords: Drone, Solar retinopathy

BackgroundIntracranial arteriovenous malformation (AVM) is a common cause of primary intracerebral hemorrhage in young adults. Lesions typically are sporadic and contain somatic mutations in KRAS or BRAF. The purpose of this study was to identify somatic mutations in a cohort of participants with brain AVM and to determine if any genotype-phenotype associations exist.MethodsHuman brain AVM specimens (n = 16) were collected during a clinically-indicated procedure and subjected to multiplex targeted sequencing using molecular inversion probe (MIP-seq) for mutations in KRAS, BRAF, HRAS, NRAS, and MAP2K1. Endothelial cells (ECs) were separated from non-ECs by immune-affinity purification. Droplet digital PCR (ddPCR) was used to confirm mutations and to screen for mutations that may have been missed by MIP-seq. Patient and AVM characteristics were recorded.ResultsWe detected somatic mutations in 10 of 16 specimens (63%). Eight had KRAS mutations [G12D (n = 5), G12V (n = 3)] and two had BRAF mutations [V600E (n = 1), Q636X (n = 1)]. We found no difference in age, sex, presenting symptom, AVM location, or AVM size between patients with a confirmed mutation and those without. Nor did we observe differences in these features between patients with KRAS or BRAF mutations. However, two patients with BRAF mutations presented at an older age than other study participants.ConclusionsSomatic mutations in KRAS and, less commonly in BRAF, are found in many but not all intracranial AVM samples. Currently, there are no obvious genotype-phenotype correlations that can be used to predict whether a somatic mutation will be detected and, if so, which gene will be mutated.

ObjectivesDuchenne muscular dystrophy (DMD) is a rare neuromuscular disorder that causes progressive weakness and early death. Gene therapy is an area of new therapeutic development. This qualitative study explored factors influencing parents' and adult patients' preferences about gene therapy.MethodsWe report qualitative data from 17 parents of children with DMD and 6 adult patients. Participants responded to a hypothetical gene therapy vignette with features including non-curative stabilizing benefits to muscle, cardiac and pulmonary function; a treatment-related risk of death; and one-time dosing with time-limited benefit of 8-10 years. We used NVivo 11 to code responses and conduct thematic analyses.ResultsAll participants placed high value on benefits to skeletal muscle, cardiac, and pulmonary functioning, with the relative importance of cardiac and pulmonary function increasing with disease progression. More than half tolerated a hypothetical 1% risk of death when balanced against Duchenne progression and limited treatment options. Risk tolerance increased at later stages. Participants perceived a 'right time' to initiate gene therapy. Most preferred to wait until a highly-valued function was about to be lost.ConclusionParticipants demonstrated a complex weighing of potential benefits against harms and the inevitable decline of untreated Duchenne. Disease progression increased risk tolerance as participants perceived fewer treatment options and placed greater value on maintaining remaining function. In the context of a one-time treatment like gene therapy, our finding that preferences about timing of initiation are influenced by disease state suggest the importance of assessing 'lifetime' preferences across the full spectrum of disease progression.

Molecular profiling of tumor tissue to detect alterations, such as oncogenic mutations, plays a vital role in determining treatment options in oncology. Hence, there is an increasing need for a robust and high-throughput technology to detect oncogenic hotspot mutations. Although commercial assays are available to detect genetic alterations in single genes, only a limited amount of tissue is often available from patients, requiring multiplexing to allow for simultaneous detection of mutations in many genes using low DNA input. Even though next-generation sequencing (NGS) platforms provide powerful tools for this purpose, they face challenges such as high cost, large DNA input requirement, complex data analysis, and long turnaround times, limiting their use in clinical settings. We report the development of the next generation mutation multi-analyte panel (MUT-MAP), a high-throughput microfluidic, panel for detecting 120 somatic mutations across eleven genes of therapeutic interest (AKT1, BRAF, EGFR, FGFR3, FLT3, HRAS, KIT, KRAS, MET, NRAS, and PIK3CA) using allele-specific PCR (AS-PCR) and Taqman technology. This mutation panel requires as little as 2 ng of high quality DNA from fresh frozen or 100 ng of DNA from formalin-fixed paraffin-embedded (FFPE) tissues. Mutation calls, including an automated data analysis process, have been implemented to run 88 samples per day. Validation of this platform using plasmids showed robust signal and low cross-reactivity in all of the newly added assays and mutation calls in cell line samples were found to be consistent with the Catalogue of Somatic Mutations in Cancer (COSMIC) database allowing for direct comparison of our platform to Sanger sequencing. High correlation with NGS when compared to the SuraSeq500 panel run on the Ion Torrent platform in a FFPE dilution experiment showed assay sensitivity down to 0.45%. This multiplexed mutation panel is a valuable tool for high-throughput biomarker discovery in personalized medicine and cancer drug development.

Modelling is a technique that can be used in the development and sizing of networks. It involves building a mathematical representation of a physical system and is often computer based, allowing system behaviour to be investigated based on the variation of key parameters. This paper will describe some applicable tools for network modelling and consider a range of applications. Whilst modelling and simulation tools are used extensively to design and size ICT solutions, each tool tends to be targeted at a specific range of applications and a specific user community. It is shown that different tools expect different levels of expertise from their user communities. The benefits of using such tools are described, as are some of their limitations. Modelling and simulation provide a cheaper and faster approach to trying new ideas than building prototypes or test networks. They provide a valuable guide to designing networks and can predict operational outcomes.

Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene. The R6/2 mouse model of HD expresses a mutant version of exon 1 HTT and develops motor and cognitive impairments, a widespread huntingtin (HTT) aggregate pathology and brain atrophy. Despite the vast number of studies that have been performed on this model, the association between the molecular and cellular neuropathology with brain atrophy, and with the development of behavioral phenotypes remains poorly understood. In an attempt to link these factors, we have performed longitudinal assessments of behavior (rotarod, open field, passive avoidance) and of regional brain abnormalities determined through magnetic resonance imaging (MRI) (whole brain, striatum, cortex, hippocampus, corpus callosum), as well as an end-stage histological assessment. Detailed correlative analyses of these three measures were then performed. We found a gender-dependent emergence of motor impairments that was associated with an age-related loss of regional brain volumes. MRI measurements further indicated that there was no striatal atrophy, but rather a lack of striatal growth beyond 8 weeks of age. T2 relaxivity further indicated tissue-level changes within brain regions. Despite these dramatic motor and neuroanatomical abnormalities, R6/2 mice did not exhibit neuronal loss in the striatum or motor cortex, although there was a significant increase in neuronal density due to tissue atrophy. The deposition of the mutant HTT (mHTT) protein, the hallmark of HD molecular pathology, was widely distributed throughout the brain. End-stage histopathological assessments were not found to be as robustly correlated with the longitudinal measures of brain atrophy or motor impairments. In conclusion, modeling pre-manifest and early progression of the disease in more slowly progressing animal models will be key to establishing which changes are causally related.

Targeted anticancer therapies rely on the identification of patient subgroups most likely to respond to treatment. Predictive biomarkers play a key role in patient selection, while diagnostic and prognostic biomarkers expand our understanding of tumor biology, suggest treatment combinations, and facilitate discovery of novel drug targets. We have developed a high-throughput microfluidics method for mutation detection (MUT-MAP, mutation multi-analyte panel) based on TaqMan or allele-specific PCR (AS-PCR) assays. We analyzed a set of 71 mutations across six genes of therapeutic interest. The six-gene mutation panel was designed to detect the most common mutations in the EGFR, KRAS, PIK3CA, NRAS, BRAF, and AKT1 oncogenes. The DNA was preamplified using custom-designed primer sets before the TaqMan/AS-PCR assays were carried out using the Biomark microfluidics system (Fluidigm; South San Francisco, CA). A cross-reactivity analysis enabled the generation of a robust automated mutation-calling algorithm which was then validated in a series of 51 cell lines and 33 FFPE clinical samples. All detected mutations were confirmed by other means. Sample input titrations confirmed the assay sensitivity with as little as 2 ng gDNA, and demonstrated excellent inter- and intra-chip reproducibility. Parallel analysis of 92 clinical trial samples was carried out using 2-100 ng genomic DNA (gDNA), allowing the simultaneous detection of multiple mutations. DNA prepared from both fresh frozen and formalin-fixed, paraffin-embedded (FFPE) samples were used, and the analysis was routinely completed in 2-3 days: traditional assays require 0.5-1 µg high-quality DNA, and take significantly longer to analyze. This assay can detect a wide range of mutations in therapeutically relevant genes from very small amounts of sample DNA. As such, the mutation assay developed is a valuable tool for high-throughput biomarker discovery and validation in personalized medicine and cancer drug development.