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Wetland environments are well documented to contain unique hydrogeomorphic subsystems that benefit from nutrient and temperature regimes provided by upwelling groundwater sources. Matrix seepage and preferential flow can both serve as groundwater inputs that control carbon-cycling within these environments. Recent work in a northern boreal peatland of Maine illuminates parallel dynamics to other wetland environments, with matrix seepage and preferential flow pathways (PFPs) identified and quantified proximal to peatland pools. PFPs around the peatland pools have been interpreted as peat pipes, known to transport nutrients within the peat matrix. Thermal signatures surrounding the peatland pool sources were mapped using point temperature measurements, handheld thermal imagery, and airborne thermal infrared mapping. Electrical geophysical methods were deployed to image the structure and stratigraphy of the underlying mineral sediments to delineate the source of focused upwelling around the peatland pools. Ground-penetrating radar (GPR) surveys show discontinuities in the impermeable glacio-marine clay controlling the hydrogeomorphic development of the peatlands studied. These mineral soil discontinuities in the GPR surveys, interpreted to be regional glacial esker deposits, are located proximal to the overlying peatland pools. Electromagnetic induction surveys were deployed to map the bulk electrical conductivity structures associated with the near-surface geology beneath the peatland pools. Point specific conductance measurements were taken at identified zones of thermal anomalies to further validate contrasts between peat pore water and mineral soil groundwater in the peatlands. Water samples were collected at the seepage sites and analyzed for iron and manganese trace elements to support the hypothesis that upwelling occurs from permeable glacial esker deposits. Focused groundwater inputs into peatlands may define a key hydrogeomorphic development process for peatland pool systems and the surrounding ecology. Further, these inputs could have implications for carbon-cycling, building on the established regional relationship between groundwater flow and carbon transport. Illuminating the focused groundwater flowpaths and interpreting their hydrogeologic origins may serve as a basis for future carbon-cycling exploration within peatlands at novel, fine-scales.

The hydrology of northern peatlands is increasingly recognized to be influenced by groundwater flow between peat and underlying mineral sediments. These hydrologic fluxes have been measured in peatlands of central and northern Maine where peatlands formed in depressions within the complex landscape left after the last glacial ice retreat. Although most of these peatlands formed on top of a low permeability confining glaciomarine clay, surface digital elevation maps and subsurface geophysical datasets (ground penetrating radar, electromagnetic and resistivity imaging) indicate that, in places, they are often in hydrogeological contact with eskers (glacial outwash deposits) and possibly even directly in contact with bedrock. Hydrogeological datasets, including direct hydraulic head observations and indirect observations of seepage fluxes, support the case that these points of hydrogeological contact exert a profound influence on the surface hydrology, including pool formation, and ecology of these peatland systems. The unique properties of peat, including the formation of pipe structures, result in highly focused discharges of mineralized water as evidenced from temperature sensing and aqueous geochemistry data (specific conductance, dissolved iron, dissolved manganese). These pipe networks may exert a control on carbon cycling in peatlands via the delivery of nutrients, or possibly by serving as conduits for the release of free phase gas stored in the deep peat. Preliminary observations using gas traps lend support to this hypothesis.

BackgroundAcute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer, and patients with relapsed ALL have a poor prognosis. Detection of ALL blasts remaining at the end of treatment, or minimal residual disease (MRD), and spread of ALL into the central nervous system (CNS) have prognostic importance in ALL. Current methods to detect MRD and CNS disease in ALL rely on the presence of ALL blasts in patient samples. Cell-free DNA, or small fragments of DNA released by cancer cells into patient biofluids, has emerged as a robust and sensitive biomarker to assess cancer burden, although cfDNA analysis has not previously been applied to ALL.MethodsWe present a simple and rapid workflow based on NanoporeMinION sequencing of PCR amplified B cell-specific rearrangement of the (IGH) locus in cfDNA from B-ALL patient samples. A cohort of 5 pediatric B-ALL patient samples was chosen for the study based on the MRD and CNS disease status.ResultsQuantitation of IGH-variable sequences in cfDNA allowed us to detect clonal heterogeneity and track the response of individual B-ALL clones throughout treatment. cfDNA was detected in patient biofluids with clinical diagnoses of MRD and CNS disease, and leukemic clones could be detected even when diagnostic cell-count thresholds for MRD were not met. These data suggest that cfDNA assays may be useful in detecting the presence of ALL in the patient, even when blasts are not physically present in the biofluid sample.ConclusionsThe Nanopore IGH detection workflow to monitor cell-free DNA is a simple, rapid, and inexpensive assay that may ultimately serve as a valuable complement to traditional clinical diagnostic approaches for ALL.

Purpose To explore and compare the perceptions of nurses and parent/family advisors regarding pediatric nurses' moral obligations to children and families during an active shooter event in a children's hospital. Design and methods This was a descriptive, exploratory study using survey methodology. A convenience sample of all licensed nurses and parent/family advisors from four children's hospitals across the United States were recruited. Surveys consisted of five primary domains including Appropriateness of National Guidelines, Personal Preparedness, Moral Accountability, Professional/Legal Concerns, and Personal Risk Expectations. Frequency counts and percentages were calculated for each survey item. Results Data from 874 pediatric nurses and 81 parent/family advisors were analyzed. Most respondents believed the Run-Hide-Fight campaign should be changed to Secure-Preserve-Fight. Only 30% of nurses felt mentally prepared to respond to an active shooter event. Most respondents agreed that nurses have a professional duty to protect their patients, but agreed that it was a personal choice, not a moral obligation, to accept potentially fatal risks. Hospital setting and patient vulnerability often influenced nurses' perceived obligations to patients. Most respondents reported they would not leave their patient/child during an active shooter event. Conclusions Nurses feel morally obligated to patients, but must balance their own personal risk tolerance level against the need to protect patients and families. Practice implications Hospitals need in-depth active shooter training for both nurses and parents as well as safety plans that address both evacuation protocols and measures to secure in place to protect the lives of patients, families, and staff.

The β-diketone scaffold is a commonly used synthetic intermediate, and is a functional group found in natural products such as curcuminoids. This core structure can also act as a chelating ligand for a variety of metals. In order to assess the potential of this scaffold for medicinal inorganic chemistry, seven different κ(2)-O,O’-chelating ligands were used to construct Ru(II) complexes with polypyridyl co-ligands, and their biological activity was evaluated. The complexes demonstrated promising structure-dependent cytotoxicity. Three complexes maintained high activity in a tumor spheroid model, and all complexes demonstrated low in vivo toxicity in a zebrafish model. From this series, the best compound exhibited a ~ 30-fold window between cytotoxicity in a 3-D tumor spheroid model and potential in vivo toxicity. These results suggest that κ(2)-O,O’-ligands can be incorporated into Ru(II)-polypyridyl complexes to create favorable candidates for future drug development.

SummaryThe codon usage of each genome is closely correlated with the abundance of tRNA isoacceptors. How codon-usage bias is resolved by tRNA post-transcriptional modifications is largely unknown. Here we demonstrate that the N1-methylation of guanosine at position 37 (m1G37) on the 3’-side of the anticodon, while not directly responsible for reading of codons, is a neutralizer that resolves differential decoding of proline codons. A genome-wide suppressor screen of a non-viable E. coli strain, m1G37-lacking, identifies proS suppressor mutations, indicating a coupling of methylation with tRNA prolyl-aminoacylation that sets the limit of cell viability. Using these suppressors, where prolyl-aminoacylation is decoupled from tRNA methylation, we show that m1G37 neutralizes differential translation of proline codons by the major isoacceptor. Lacking of m1G37 inactivates this neutralization and exposes the need for a minor isoacceptor for cell viability. This work has medical implications for bacterial genomes that exclusively use the major isoacceptor for survival.

Neurodegenerative disorders and leukodystrophies are progressive neurologic conditions that can occur following the disruption of intricately coordinated patterns of gene expression. Exome sequencing has been adopted as an effective diagnostic tool for determining the underlying genetic etiology of Mendelian neurologic disorders, however genome sequencing offer advantages in its ability to identify and characterize copy number, structural, and sequence variants in noncoding regions. Genome sequencing from peripheral leukocytes was performed on two patients with progressive neurologic disease of unknown etiology following negative genetic investigations including exome sequencing. RNA sequencing from peripheral blood was performed to determine gene expression patterns in one of the patients. Potential causative variants were matched to the patients' clinical presentation. The first proband was found to be heterozygous for a likely pathogenic missense variant in PLA2G6 (c.386TC; p.Leu129Pro) and have an additional deep intronic variant in PLA2G6 (c.2035-926GA). RNA sequencing indicated this latter variant created a splice acceptor site leading to the incorporation of a pseudo-exon introducing a premature termination codon. The second proband was heterozygous for a 261 kb deletion upstream of LMNB1 that included an enhancer region. Previous reports of copy number variants spanning this region of cis-acting regulatory elements corroborated its pathogenicity. When combined with clinical presentations, these findings led to a definitive diagnosis of autosomal recessive infantile neuroaxonal dystrophy and autosomal dominant adult-onset demyelinating leukodystrophy, respectively. In patients with progressive neurologic disease of unknown etiology, genome sequencing with the addition of RNA analysis where appropriate should be considered for the identification of causative noncoding pathogenic variants.

Advanced Parkinson disease (PD) is characterized by the presence of motor fluctuations becoming the focus of treatment, prominent postural instability, significant disability despite levodopa therapy, and the presence of symptoms refractory to levodopa therapy. In this article, the authors review the motor manifestations of patients with advanced PD, as well as the most common pharmacologic and nonpharmacologic available therapies.

Acute Lymphoblastic Leukemia (ALL) patients that are positive for minimal residual disease (MRD) after therapy or have leukemic infiltration into the central nervous system (CNS) are considered high risk and receive intensive chemotherapy regimens. Current methods to diagnose MRD and CNS infiltration rely on detecting leukemic cells in patient samples using pathology, flow cytometry, or next-generation sequencing. However, leukemic blasts may persist in the patient but not be physically present in bone marrow biopsy or biofluid sample, leading to inaccurate or delayed patient diagnosis. We have developed a nanopore sequencing workflow to detect B-ALL-associated cell-free DNA (cfDNA) in blood and cerebrospinal fluid (CSF) samples. Quantitation of B-cell specific VDJ recombination events in cfDNA samples defined B-ALL clonal heterogeneity. This workflow allowed us to track the response of individual B-ALL clones throughout treatment. Detection of cfDNA also predicted the clinical diagnosis of MRD and CNS disease. Importantly, we identified patients diagnosed as CNS negative who had low B-cell derived cell-free DNA levels in their CSF sample that correlated with B-cell clones present in the bone marrow. These data suggest that cfDNA assays may be useful in detecting the presence of ALL in the patient even when blasts are not in the biofluid sample. Nanopore analysis of cell-free DNA is a simple, rapid, and inexpensive assay that can serve as a valuable complement to traditional clinical diagnostic approaches for ALL.Abstract Figure

Transplant of human cancer cells into zebrafish larvae has emerged as a useful methodology in cancer research. Zebrafish have very low husbandry costs, are amenable to large-scale drug screening, and are unmatched for optical clarity in live animal imaging. However, there is currently no consensus on the ideal methods for xenograft of human cancer cells into zebrafish. Here, we have examined the effects of transplant site and housing temperature on both zebrafish larvae and human cancer cells using survival analyses, metabolomic approaches, and in vivo imaging. Our data show that while zebrafish larvae can adapt to the ideal conditions for mammalian cells, human cancer cells are highly sensitive to both temperature change and transplant site. Human cells housed in slightly cooler than physiologic temperatures had a significantly altered metabolism that resulted in changes in growth, survival, and response to chemotherapy. Cancer cells xenografted into the yolk of the larvae also had reduced proliferation and drug response compared to those xenografted into the soma, in part due to the differences in metabolites available at these sites. In total, temperature and transplant site can have profound effects on xenografted cells. Standardization of zebrafish xenograft methods will enhance data reproducibility between individual laboratories.

Introduction We report the prevalence of abnormal tandem gait (TG) in patients with idiopathic Parkinson disease (PD) and its association with symptoms of subjective unsteadiness, falls, freezing of gait, and cognitive impairment. Methods We assessed subjective balance impairment, fall history, antero-posterior postural instability, and TG in PD patients (Hoehn and Yahr (HY) stage 0–4). We recorded the age, sex, current medications, HY stage, Schwab and England (S&E) scale score, and MOCA score for each patient. Logistic regression was used to evaluate age-adjusted associations between TG and other demographic and clinical factors. Results A total of 102 patients with PD were assessed. Of those, 63.5% of HY 2 patients and 100% of HY 2.5 and 3 patients had a TG abnormality. The presence of TG abnormality was associated with subjective imbalance, falls, freezing of gait, S&E Conclusions TG abnormality is common in PD, precedes the development of antero-posterior postural instability, is associated with cognitive impairment, and may predict fall risk. A longitudinal study will help determine if TG is a predictor of impending progression from HY 2 to HY 3.

Introduction Anxiety and depression are common in PD, occurring in an estimated 30%–40% of PD patients. However, the extent to which these emotional symptoms interfere with Deep Brain Stimulation (DBS) outcomes is not well established. This study examined the association between pre-operative emotional well-being and postsurgical cognitive, emotional, and motor performance in PD. Methods Forty-nine PD patients underwent neurological, neuropsychological (global cognition, processing speed, language, visuospatial, memory), and emotional assessments pre- and post-DBS. Fifteen patients were administered the UPDRS. Patients were divided into Anxious (Anx; n = 21), Comorbid Anxious and Depressed (Anx + Dep; n = 15), and Emotionally Asymptomatic (EA; n = 13) based on BAI and BDI-II cutoffs, and compared on pre-post changes in neurocognitive, mood, and motor scores using analyses of covariance (ANCOVA), controlling for education, ethnicity, and disease duration. Results Pre-DBS, there were no significant differences between the three groups on any neuropsychological measure. Overall change from pre-to post-DBS revealed declines on multiple cognitive measures and lower symptom endorsement on the BAI among all participants. No group differences were observed on neurocognitive measures, mood, or UPDRS. Conclusions PD patients with mild-moderate anxiety or comorbid anxiety/depression pre-DBS do not show greater cognitive, emotional, and motor changes post-DBS compared to emotionally asymptomatic patients. These data emphasize the importance of discussing potential DBS outcomes, while keeping in mind that psychiatric comorbidity should not necessarily exclude patients from DBS. The notion that premorbid mood symptoms could disqualify a candidate for surgery would be a disservice, as this group performs comparably to asymptomatic peers.

Background Anxiety and sleep disturbances are prevalent in Parkinson's disease (PD). Benzodiazepines (BZDs) are commonly used to treat these symptoms; however, they are associated with unfavorable side effects such as falls and cognitive slowing in the general non-PD population. Examining the effects of BZDs in PD is imperative as these medications could pose an increased risk to PD patients who are already vulnerable to falls and cognitive deficits. Methods Eighty-four patients diagnosed with idiopathic PD, of which 60% were Hispanic, underwent clinical evaluations including the Unified Parkinson's Disease Rating Scale (UPDRS) and comprehensive neuropsychological testing examining global cognition, language, visuospatial skills, memory, executive function, mood, and sleep quality. Thirty-six patients taking BZDs (BZD+) were compared to forty-eight patients not using any BZDs (BZD-) employing appropriate statistical tests depending on the measures' characteristics. Results BZD+ PD patients performed below the BZD- group on short-term memory but not on delayed recall, and performed better on a measure of visuospatial judgment. The BZD+ group endorsed more symptoms of anxiety and depression as well as poorer sleep quality. No significant differences were noted on other measures of cognition or motor function. Conclusion PD patients taking BZDs may experience select changes in cognition and mood. These changes are isolated and mild, and suggest that for some patients, BZDs may be a viable pharmacologic intervention that does not alter cognitive and motor function compared to those not taking these medications.

Background: Randomized clinical trials (RCTs) in Parkinson’s disease (PD) have historically enrolled a low number of underrepresented minorities, lessening the generalizability of therapeutic developments. Although there are racial disparities in PD, little is known regarding neuropsychiatric symptoms and other nonmotor manifestations across all races/ethnicities. Objective: To assess minority participation in PD trials evaluating the treatment of neuropsychiatric symptoms and explore underlying reasons. Methods: We systematically searched PubMed and Embase for RCTs with a primary goal of treating neuropsychiatric symptoms in PD patients from 2000-2019. The pooled prevalence and 95% confidence interval (CI) of being white and enrolled in a clinical trial was calculated using the inverse variance method. I-square was calculated as a measure of heterogeneity and meta-regression was used to evaluate temporal trends. Results: We included 63 RCTs with a total of 7,973 patients. In pooled analysis, 11 (17.5%) RCTs reported race/ethnicity. Of studies reporting this data, 5 African American (0.2%), 16 Hispanics (0.64%), and 539 Asians (21.44%) were enrolled. The pooled prevalence of being white in clinical trials was 98% (CI 0.97–0.98, p

Four structurally distinct classes of polypyridyl ruthenium complexes containing avobenzone exhibited low micromolar and submicromolar potencies in cancer cells, and were up to 273-fold more active than the parent ligand. Visible light irradiation enhanced the cytotoxicity of some complexes, making them promising candidates for combined chemo-photodynamic therapy.

La pandemia por el virus SARS-CoV-2 y la enfermedad generada (COVID-19, del inglés Coronavirus 2019 Disease), llevó a nivel mundial a cambios significativos en la forma de prestar los servicios de salud, incluida la actividad quirúrgica. Como parte de esta realidad, se recomendó en Colombia la adopción de disposiciones enfocadas a preparar nuestro sistema de salud para enfrentar una avalancha de pacientes COVID-19, que se esperaba fuera similar a la presentada en otros países. Las medidas se tomaron en el momento oportuno, ganando tiempo de preparación, sin que hasta la fecha (8 semanas después del primer caso diagnosticado en Colombia) se haya desbordado la demanda de atención, modificando la forma esperada de la curva epidemiológica, con un número menor de pacientes.

Patient derived xenograft models are critical in defining how different cancers respond to drug treatment in an in vivo system. Mouse models are the standard in the field, but zebrafish have emerged as an alternative model with several advantages, including the ability for high-throughput and low-cost drug screening. Zebrafish also allow for in vivo drug screening with large replicate numbers that were previously only obtainable with in vitro systems. The ability to rapidly perform large scale drug screens may open up the possibility for personalized medicine with rapid translation of results back to clinic. Zebrafish xenograft models could also be used to rapidly screen for actionable mutations based on tumor response to targeted therapies or to identify new anti-cancer compounds from large libraries. The current major limitation in the field has been quantifying and automating the process so that drug screens can be done on a larger scale and be less labor-intensive. We have developed a workflow for xenografting primary patient samples into zebrafish larvae and performing large scale drug screens using a fluorescence microscope equipped imaging unit and automated sampler unit. This method allows for standardization and quantification of engrafted tumor area and response to drug treatment across large numbers of zebrafish larvae. Overall, this method is advantageous over traditional cell culture drug screening as it allows for growth of tumor cells in an in vivo environment throughout drug treatment, and is more practical and cost-effective than mice for large scale in vivo drug screens.

Palliative care in Parkinson's Disease (PD) is an effective intervention to improve quality of life, although historically, access and availability have been very restricted.We performed a retrospective cohort study using the National Inpatient Sample (NIS) data from 2007 to 2014. Diagnostic codes were used to identify patients with PD and palliative care referral. Trends were calculated and logistic analysis performed to identify predictors of palliative care use.We identified 397,963 hospitalizations from 2007 to 2014 for patients with PD. Of these, 10,639 (2.67%) were referred to palliative care. The rate of consultation increased from 0.85% in 2007 to 4.49% in 2014. For 1 unit in year increase, there was 1.23 time the odds of receiving palliative consultation (OR 1.23, CI 1.21-1.25, p 0.0001). Hispanics (OR 0.90, CI 0.81-1.01, p = 0.0550), Black (OR 0.90, CI 0.81-1.01, p = 0.0747) and White patients had similar rates of referral after adjustment. Women were less likely to be referred to palliative care (OR 0.90, CI 0.87-0.94, p 0.0001). Other factors strongly associated with a higher rate of referrals included private insurance when compared to Medicare (OR 2.14, CI 1.89-2.41, p 0.0001) and higher income (OR 1.41, CI 1.30-1.53, p 0.0001).There has been a significant increase in palliative care referrals among hospitalized patients with PD in the US, although the overall rate remains low. After controlling for confounders, racial and ethnic disparities were not found. Women, patients with Medicare/Medicaid, and those with lower income were less likely to be referred to palliative care.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, with a relapse rate of 15%. The presence of lymphoblasts in the central nervous system (CNS) is a negative prognostic indicator and a frequent site of disease relapse. CNS disease is defined as more than five white blood cells in the cerebrospinal fluid (CSF) with positive lymphoblast cytomorphology. Often leukemic blasts are detected by flow cytometry of the CSF prior to reaching the five white blood cell threshold, requiring repeat lumbar punctures at 2-4 week intervals until the arbitrarily defined clinical criteria for diagnosis are met. Additionally, more than 50% of autopsied brains from ALL patients show evidence of CNS disease, despite non-detectable CNS involvement via cytology of CSF. These data suggest that patients may be harboring CNS disease before it expands enough to be clinically diagnosed. We have developed a new assay that may allow for earlier detection of CNS disease and relapse by quantifying cell-free, circulating tumor DNA (ctDNA) in the CSF. ctDNA is a proven biomarker of relapse and metastasis in solid tumors in pre-clinical testing; however, its utility at predicting CNS disease in ALL has not been examined. We examined two possible methods for using ctDNA as a biomarker: leukemia cell clonality and DNA methylation profiling. We collected bone marrow aspirate, blood, and CSF samples from 11 newly diagnosed patients prior to the start of chemotherapy treatment to use as a training data set. ctDNA was isolated from blood and CSF samples at diagnosis and throughout treatment. Genomic DNA was isolated from bone marrow and peripheral blood mononuclear cell (PBMC) samples at diagnosis. For leukemia cell clonality assays, Invivoscribe Lymphotrack PCR assays combined with MinION (Oxford Nanopore Technologies) sequencing were used to identify the VDJ sequence of the immunoglobulin (B-ALL) or T-cell receptor (T-ALL) rearrangements in the clones comprising each leukemia. Throughout the course of treatment, ctDNA samples were run on the MinION sequencer, examining the abundance of major clones present and ctDNA quantification was done on patient plasma and CSF samples over time. While this assay relies on patient specific VDJ sequencing, we are also in the process of developing a more universal assay that utilizes recurrent methylation changes in T-ALL or B-ALL, compared to normal PBMCs. We performed methylation sequencing on 3 control PBMC samples and 7 ALL patient samples to identify differentially methylated regions (DMRs) present specifically in ALL samples. This sequencing identified 9,222 DMRs present in the ALL samples. These sites were then compared with publicly available datasets, yielding 55 overlapping regions and 19 specific overlapping methylation sites commonly present in ALL samples and not in PBMCs. We are now in the process of validating these differentially methylated sites by droplet digital polymerase chain reaction (ddPCR) to come up with a panel of biomarkers to track ALL disease over time. The end goal of our study is to develop an assay to rapidly detect relapse and CNS disease in ALL that is more sensitive and less invasive than the current clinical assays. Earlier detection of relapse and CNS disease will provide patients with more treatment options, which may ultimately improve patient outcome. Results will ultimately be correlated with patient response to therapy, the presence of CNS disease, and overall outcomes as determined by standard clinical diagnostic procedures. Disclosures No relevant conflicts of interest to declare.

10034 Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, with a relatively high relapse rate, which is associated with poor prognosis. Currently, minimal residual disease (MRD) at the end of induction and consolidation therapy is the best predictor of patient relapse, however obtaining bone marrow aspirate is invasive and not always accurate. Another major concern in ALL is the presence of central nervous system (CNS) disease, which is often present long before clinical diagnosis can be made by flow cytometry. To circumvent these clinical challenges, we developed a new assay quantifying cell-free, circulating tumor (cfDNA) as a biomarker of disease progression, which can be correlated with MRD status as a predictor of relapse. cfDNA is frequently used to monitor progression of solid tumors, but pediatric leukemias lack common mutations that can be used to distinguish leukemic cfDNA from normal cfDNA. Methods: We examined two possible methods for using ctDNA as a biomarker: leukemia cell clonality and DNA methylation profiling. We developed a novel workflow for identifying VDJ rearrangements in leukemia cells and tracking their presence in cfDNA. We collected bone marrow, blood, and CSF samples from newly diagnosed patients, and cfDNA was isolated from blood and CSF samples throughout treatment. Invivoscribe Lymphotrack PCR assays combined with MinION (Oxford Nanopore Technologies) sequencing were used to identify the VDJ sequence of the immunoglobulin (B-ALL) or T-cell receptor (T-ALL) rearrangements of leukemic clones in genomic DNA. The MinION assay relies on patient-specific sequencing. We are also in the process of developing a universal assay that utilizes recurrent methylation changes in ALL to identify leukemic cfDNA in patient samples. Results: The MinION workflow was used to follow leukemic cfDNA throughout the course of treatment, and accurately identified MRD and CNS disease in patients. This workflow performed equivalent or better at detecting leukemic clones compared to MiSeq and droplet digital polymerase chain reaction (ddPCR), and is faster and less expensive than traditional Illumina sequencing. Methylation analysis of 865 ALL and 79 healthy samples yielded 55 regions and 19 specific methylation sites that were uniquely present in ALL samples. We are validating these sites by ddPCR to establish a panel of biomarkers to track ALL over time via cfDNA. Conclusions: The end goal of our study is provide a more sensitive and less invasive method for tracking MRD and CNS disease than current approaches. Results will ultimately be correlated with patient response to therapy, the presence of relapse or CNS disease, and overall outcomes determined by standard clinical diagnostic procedures.

Sleep disorders are prevalent in Parkinson's disease but underreported in clinical settings. The contribution of sleep disorders to health-related quality of life (HRQOL) for patients with this degenerative neurological disease are not well known.To evaluate the impact of insomnia symptoms, obstructive sleep apnea (OSA), and poor sleep quality on HRQOL in a cohort of patients with idiopathic Parkinson's disease.We enrolled a convenience sample of 66 adults seen in the University of Miami Movement Disorders Clinic between July 2011 and June 2013. Participants completed validated questionnaires to determine insomnia symptoms, OSA risk, depression, anxiety, and HRQOL. All patients underwent unattended polysomnography to confirm OSA. Results were compared for those with and without insomnia symptoms. Principal component and regression analyses were performed to evaluate determinants of HRQOL.Participants were predominately Hispanic males with mild to moderate Parkinson's disease. Insomnia symptoms were reported for 46% of the study subjects. OSA (apnea-hypopnea index, ≥5) was noted in 47%, with a mean apnea-hypopnea index of 8.3 ± 11.0. Fairly bad to very bad sleep quality was reported by 21% of the participants. Insomnia (r = 0.71; P 0.001), daytime sleepiness (r = 0.36; P = 0.003), depression symptoms (r = 0.44; P 0.001), and anxiety symptoms (r = 0.33; P = 0.006) were significant correlates of poor sleep quality. OSA, severity of Parkinson's disease, and dopaminergic therapy were not. In the principal component analysis, sleep quality was a significant component of the "psychological factor" that in turn was a significant determinant of overall HRQOL.Insomnia symptoms, OSA, and subsequent poor sleep quality are prevalent in Parkinson's disease. In this single-center, exploratory study, we found that insomnia and poor sleep quality, but not OSA, play important roles in determining overall quality of life for patients with this disease. Clinical trial registered with www.clinicaltrials.gov (NCT02034357).

A 44-year-old man with multiple sclerosis (MS) presented with focal myoclonus of the mylohyoid and anterior belly of the digastric known as “dancing larynx” [1] which began after gamma knife radiation to the left trigeminal nerve root administered for trigeminal neuralgia (Video 1,). MRI brain showed T2 hyperintensity in the left cerebellopontine angle which expanded following radiation (Figure 1). He received botulinum toxin injections in the mylohyoid muscles with resolution of the movements. The “dancing larynx” was likely from irritation of the trigeminal nerve motor root or pons itself caused by the pontine lesion that enlarged after radiation.

IN business, it is desirable to have certain law that makes good commercial sense, and helpful to know what fundamental concepts like “a contract of sale of goods” actually mean. The Supreme Court in PST Energy 7 Shipping LLC and another v OW Bunker Malta Ltd. and another (“The Res Cogitans”) [2016] UKSC 22 grappled with precisely this question.

Importance Recognized peripherally induced movement disorders include the painful legs moving toes syndrome, postamputation dyskinesias, and belly dancer dyskinesias. Objective To introduce and characterize the dancing dorsal quadrilaterals, a novel peripherally induced movement disorder that predominantly affects dorsal quadrilateral muscles (trapezius and rhomboids) after upper spine instrumentation. Design, Setting, and Participants Between 1990 and 2015, a total of 4 patients who developed abnormal movements of the dorsal quadrilateral muscles after upper spine instrumentation were referred to movement disorders clinics at 3 academic medical centers in the United States, Canada, and Argentina. A prospective and retrospective analysis of the clinical and electrophysiologic characteristics of their abnormal movements is presented in this brief report. Data were analyzed between July 2015 and January 2018. Exposures Extensive upper spine instrumentation complicated with misalignment and prolonged postsurgical neuropathic pain. Main Outcomes and Measures Video documentation of clinical and electrophysiologic characteristics of dancing dorsal quadrilaterals. Results Four patients with upper spine disease (2 women and 2 men, ranging in age from early 30s to early 70s) required extensive surgical manipulation and instrumentation that was complicated by misalignment, prolonged dorsal neuropathic pain, and unusual abnormal movements. These movements consisted of semirhythmic, repetitive writhing, and jerky movements of the scapular region with distinctive rotatory motions. They are referred to as the dancing dorsal quadrilaterals because they predominantly affected the bilateral trapezius and rhomboids (dorsal quadrilateral muscles) but could spread to adjacent muscles, and they are similar in appearance and possibly pathogenesis to “belly dancer” dyskinetic movements. The movements of the dancing dorsal quadrilaterals occur when upright but not when lying down or during voluntary muscle activation. Sensory stimulation also diminishes the movements. Long-duration bursts of normal motor unit potentials with normal recruitment pattern were evidenced. Conclusions and Relevance The dancing dorsal quadrilaterals syndrome represents a further example of a peripherally induced movement disorder characterized by neuropathic pain preceding a regional movement disorder following soft-tissue or nerve injury.

OBJECTIVES This study sought to determine whether there is a gender disparity in patients undergoing deep brain stimulation (DBS) surgery for Parkinson's disease (PD) at a single health system, and better understand the reasons for this discrepancy. MATERIALS AND METHODS We analyzed data from the University of Miami DBS Database, which included 3251 PD patients, using chi-square, repeated measures ANOVA, and t tests to examine gender differences in the number of patients referred for surgery, reasons for referral, number receiving/not receiving surgery, reasons for not receiving surgery, and postsurgical outcomes. RESULTS During the study period, 207 PD patients were referred for DBS (75.8% male), and 100 underwent surgery (77.0% male). Of those who did not receive surgery, the most common reasons were need for further medical optimization (26.2%), suboptimal performance on neuropsychological evaluation (22.4%), other reason (20.6%), lost to follow-up (18.7%), or patient preference (12.2%). However, in women one of the most common reasons was patient preference (28.0%), and this was significant compared to men (p

Safinamide (Xadago®) is a novel medication with both dopaminergic and non-dopaminergic effects, approved first by the European Commission and more recently by the US Food and Drug Administration (FDA) as an adjunctive treatment to carbidopa/levodopa in patients with mid- to late-stage Parkinson's disease (PD) and motor fluctuations. It works through multiple mechanisms, namely as a reversible selective monoamine oxidase-B inhibitor and through modulation of glutamate release. Safinamide is extensively metabolized via oxidation to several inactive metabolites that are excreted primarily through the urine. Several large Phase III clinical trials of patients with advanced PD with motor fluctuations have shown that safinamide, administered orally at doses of 50-100 mg daily, increased ON time with no or non-troublesome dyskinesia, decreased daily OFF time, improved overall motor function (as measured by Unified Parkinson's Disease Rating Scale [UPDRS] part III total score), and quality of life (as measured by Clinical Global Impression-Change and 39-item Parkinson's Disease Questionnaire). In large clinical trials of patients with early PD on a single dopamine agonist, safinamide administered orally at a dose of 100 mg daily improved overall motor function as measured by UPDRS part III total score; however, some of the results reported were exploratory. Safinamide is generally well-tolerated and safe, with few to no treatment-related adverse events. Safinamide does not cause new or worsening dyskinesia and may be able to reduce this symptom in patients reporting it at baseline. Evidence suggests that safinamide is a good option for add-on therapy to carbidopa/levodopa in patients with advanced PD with motor complications, but there is still insufficient evidence to recommend it as monotherapy or add-on therapy in patients with early PD.

BACKGROUND: The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) is a newly developed tool to assess Parkinson's disease (PD). Changes in scores on the scale over the course of PD, including increasing disease duration and Hoehn and Yahr (HY) stages, have not been described. The objectives of this study were to analyze MDS‐UPDRS scores on Parts I through IV and their differences based on HY stage and disease duration in a large cohort of patients with PD. METHODS: For this cross‐sectional study, demographic data and MDS‐UPDRS scores were collected, including HY stage. Subscores on MDS‐UPDRS Parts I through IV were analyzed using 1‐way analyses of variance for each HY stage and in 5‐year increments of disease duration. Part III (motor assessment) scores were analyzed separately for on and off states. RESULTS: The mean age of the 3206 patients was 65.8 ± 10.6 years, 53.3% were men, the mean disease duration was 11.5 ± 4.6 years, and the median HY stage was 2 (range, 0–5); 2156 patients were examined in an on state and 987 were examined in an off state. Scores for all MDS‐UPDRS parts increased significantly through HY stages 1 through 5, with an average increase of 3.8, 7.7, 14.6, and 2.0 points consecutively for parts I through IV, respectively. For the 5‐year increments of disease duration, MDS‐UPDRS subscores increased by an average of 1.6, 3.3, 4.2, and 1.4 points consecutively for parts I through IV, respectively. This increase was significant only during the first 15 years of disease for all 4 parts, including part III scores evaluated in both on and off states. CONCLUSIONS: MDS‐UPDRS scores for all 4 parts increase significantly with every HY stage and also with 5‐year increments of disease duration in the first 15 years of the disease.

Background: PBT2 is a metal protein-attenuating compound that might reduce metal-induced aggregation of mutant huntingtin and has prolonged survival in a mouse model of Huntington's disease. We aimed to assess the safety, tolerability, and efficacy of PBT2 in patients with Huntington's disease. Methods: In this 26-week, randomised, double-blind, placebo-controlled trial, adults ( ≥ 25 years old ) with early-stage to mid-stage Huntington's disease were randomly assigned ( 1:1:1 ) by a centralised interactive response system to once daily PBT2 250 mg, PBT2 100 mg, or placebo. Randomisation was stratified by site with a block size of three. Participants, carers, the steering committee, site investigators, study staff, and the study sponsor were masked to treatment assignment. Primary endpoints were safety and tolerability. The safety population consisted of all participants who were randomly assigned and had at least one dose of study drug. The principal secondary endpoint was cognition, measured by the change from baseline to week 26 in the main composite Z score of five cognitive tests ( Category Fluency Test, Trail Making Test Part B, Map Search, Symbol Digit Modalities Test, and Stroop Word Reading Test ) and scores on eight individual cognitive tests ( the five aforementioned plus the Trail Making Test Part A, Montreal Cognitive Assessment, and the Speeded Tapping Test ). The intention-to-treat population comprised participants who were randomly assigned and had at least one efficacy assessment after administration of study drug. This trial is registered with [http://clinicaltrials.gov/] ClinicalTrials.gov, [http://clinicaltrials.gov/show/NCT01590888] NCT01590888. Findings: Between April 18, 2012, and Dec 14, 2012, 109 participants were randomly assigned to PBT2 250 mg ( n=36 ), PBT2 100 mg ( n=38 ), or placebo ( n=35 ) at 19 research centres in Australia and the USA. 32 ( 89% ) individuals on PBT2 250 mg, 38 ( 100% ) on PBT2 100 mg, and 34 ( 97% ) on placebo completed the study. Six serious adverse events ( acute coronary syndrome, major depression, pneumonia, suicide attempt, viral infection, and worsening of Huntington's disease ) occurred in five participants in the PBT2 250 mg group, three ( fall with subdural haematoma, suicide attempt, and hospital admission for stabilisation of Huntington's disease ) occurred in two participants in the PBT2 100 mg group, and one ( increasing aggression ) occurred in a participant in the placebo group. The site investigators deemed all, except the worsening of Huntington's disease, as unrelated to study drug. 32 ( 89% ) participants on PBT2 250 mg, 30 ( 79% ) on PBT2 100 mg, and 28 ( 80% ) on placebo had at least one adverse event. Compared with placebo, neither PBT2 100 mg ( least-squares mean 0·02, 95% CI −0·10 to 0·14; p=0·772 ) nor PBT2 250 mg ( 0·07, −0·05 to 0·20; p=0·240 ) significantly improved the main composite cognition Zscore between baseline and 26 weeks. Compared with placebo, the Trail Making Test Part B score was improved between baseline and 26 weeks in the PBT2 250 mg group ( 17·65 s, 0·65–34·65; p=0·042 ) but not in the 100 mg group ( 0·79 s improvement, −15·75 to 17·32; p=0·925 ); neither dose significantly improved cognition on the other tests. Interpretation: PBT2 was generally safe and well tolerated in patients with Huntington's disease. The potential benefit on executive function will need to be confirmed in a larger study. Funding: Prana Biotechnology Limited.

We have developed the first in a planned series of neural prosthetic interfaces that allow multichannel systems to be assembled from single-channel micromodules called BIONs (BIOnic Neurons). Multiple BION implants can be injected directly into the sites requiring stimulating or sensing channels, where they receive power and digital commands by inductive coupling to an externally generated radio-frequency magnetic field. This article describes some of the novel technology required to achieve the required microminiaturization, hermeticity, power efficiency and clinical performance. The BION1 implants are now being used to electrically exercise paralyzed and weak muscles to prevent or reverse disuse atrophy. This modular, wireless approach to interfacing with the peripheral nervous system should facilitate the development of progressively more complex systems required to address a growing range of clinical applications, leading ultimately to synthesizing complete voluntary functions such as reach and grasp.

Background and purpose: The Movement Disorder Society sponsored version of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) is a comprehensive instrument for assessing Parkinson’s disease (PD). The present study was aimed at determining the relationships between MDS-UPDRS components and health-related quality of life (HRQoL) evaluations in PD patients. Methods: An international, multicenter, cross-sectional study was carried out of 435 PD patients assessed with the MDS-UPDRS, Hoehn and Yahr (HY), Clinical Impression Severity for PD, EQ-5D and PD Questionnaire eight items (PDQ-8). Spearman’s rank correlation coefficients, exploratory factor analysis and multiple linear regression models (dependent variables EQ-5D and PDQ-8) were performed. Results: The participants’ age was 66.71 10.32 years (51.5% men). PD duration was 8.52 6.14, and median HY was 2 (range 1–5). The correlation between the EQ-5D index and the MDS-UPDRS ranged from 0.46 (Part IV) to 0.72 (Part II) and for the PDQ-8 index from 0.47 (Part III) to 0.74 (Part II). In multiple regression models with the MDS-UPDRS domains as independent variables, the main determinant for both the EQ-5D index and the PDQ-8 was Part II followed by Part I. After factorial grouping of the cardinal PD manifestations embedded in the MDS-UPDRS Parts III and IV for inclusion into multiple regression models, a factor formed by M-EDL, nM-EDL and fluctuations was the main determinant for both the EQ-5D and PDQ-8 indexes. Conclusions: The MDS-UPDRS component most tightly related with the HRQoL measures was a combination of motor and non-motor experiences of daily living.