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Stereoelectroencephalography-guided radiofrequency thermocoagulation (SEEG-guided RF-TC) is a treatment option for focal drug-resistant epilepsy. In previous studies, this technique has shown seizure reduction by ≥50% in 50% of patients at 1 year. However, the relationship between the location of the ablation within the epileptogenic network and clinical outcomes remains poorly understood. Seizure outcomes were analyzed for patients who underwent SEEG-guided RF-TC and across subgroups depending on the location of the ablation within the epileptogenic network, defined as SEEG sites involved in seizure generation and spread. Eighteen patients who had SEEG-guided RF-TC were included. SEEG-guided seizure-onset zone ablation (SEEG-guided SOZA) was performed in 12 patients, and SEEG-guided partial seizure-onset zone ablation (SEEG-guided P-SOZA) in 6 patients. The early spread was ablated in three SEEG-guided SOZA patients. Five patients had ablation of a lesion. The seizure freedom rate in the cohort ranged between 22% and 50%, and the responder rate between 67% and 85%. SEEG-guided SOZA demonstrated superior results for both outcomes compared to SEEG-guided P-SOZA at 6 months (seizure freedom p = .294, responder rate p = .014). Adding the early spread ablation to SEEG-guided SOZA did not increase seizure freedom rates but exhibited comparable effectiveness regarding responder rates, indicating a potential network disruption., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Deep Brain Stimulation (DBS), applying chronic electrical stimulation of subcortical structures, is a clinical intervention applied in major neurologic disorders. In order to achieve a good clinical effect, accurate electrode placement is necessary. The primary localisation is typically based on presurgical MRI imaging, often followed by intra-operative electrophysiology recording to increase the accuracy and to compensate for brain shift, especially in cases where the surgical target is small, and there is low contrast: e.g., in Parkinson's disease (PD) and in its common target, the subthalamic nucleus (STN)., Methods: We propose a novel, fully automatic method for intra-operative surgical navigation. First, the surgical target is segmented in presurgical MRI images using a statistical shape-intensity model. Next, automated alignment with intra-operatively recorded microelectrode recordings is performed using a probabilistic model of STN electrophysiology. We apply the method to a dataset of 120 PD patients with clinical T2 1.5T images, of which 48 also had available microelectrode recordings (MER)., Results: The proposed segmentation method achieved STN segmentation accuracy around dice = 0.60 compared to manual segmentation. This is comparable to the state-of-the-art on low-resolution clinical MRI data. When combined with electrophysiology-based alignment, we achieved an accuracy of 0.85 for correctly including recording sites of STN-labelled MERs in the final STN volume., Conclusion: The proposed method combines image-based segmentation of the subthalamic nucleus with microelectrode recordings to estimate their mutual location during the surgery in a fully automated process. Apart from its potential use in clinical targeting, the method can be used to map electrophysiological properties to specific parts of the basal ganglia structures and their vicinity., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Varga et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: In the presurgical evaluation of patients with drug-resistant epilepsy (DRE), occasionally, patients do not experience spontaneous typical seizures (STS) during a stereo-electroencephalography (SEEG) study, which limits its effectiveness. We sought to identify risk factors for patients who did not have STS during SEEG and to analyze the clinical outcomes for this particular set of patients., Methods: We conducted a retrospective analysis of all patients with DRE who underwent depth electrode implantation and SEEG recordings between January 2013 and December 2018., Results: SEEG was performed in 155 cases during this period. 11 (7.2%) did not experience any clinical seizures (non-STS group), while 143 experienced at least one patient-typical seizure during admission (STS group). No significant differences were found between STS and non-STS groups in terms of patient demographics, lesional/non-lesional epilepsy ratio, pre-SEEG seizure frequency, number of ASMs used, electrographic seizures or postoperative seizure outcome in those who underwent resective surgery. Statistically significant differences were found in the average number of electrodes implanted (7.0 in the non-STS group vs. 10.2 in STS), days in Epilepsy Monitoring Unit (21.8 vs. 12.8 days) and the number of cases that underwent resective surgery following SEEG (27.3% vs. 60.8%), respectively. The three non-STS patients (30%) who underwent surgery, all had their typical seizures triggered during ECS studies. Three cases were found to have psychogenic non-epileptic seizures. None of the patients in the non-STS group were offered neurostimulation devices. Five of the non-STS patients experienced transient seizure improvement following SEEG., Significance: We were unable to identify any factors that predicted lack of seizures during SEEG recordings. Resective surgery was only offered in cases where ECS studies replicated patient-typical seizures. Larger datasets are required to be able to identify factors that predict which patients will fail to develop seizures during SEEG., (© 2023 International League Against Epilepsy.)

Population-averaged brain atlases, that are represented in a standard space with anatomical labels, are instrumental tools in neurosurgical planning and the study of neurodegenerative conditions. Traditional brain atlases are primarily derived from anatomical scans and contain limited information regarding the axonal organization of the white matter. With the advance of diffusion MRI that allows the modeling of fiber orientation distribution (FOD) in the brain tissue, there is an increasing interest for a population-averaged FOD template, especially based on a large healthy aging cohort, to offer structural connectivity information for connectomic surgery and analysis of neurodegeneration. The dataset described in this article contains a set of multi-contrast structural connectomic MRI atlases, including T1w, T2w, and FOD templates, along with the associated whole brain tractograms. The templates were made using multi-contrast group-wise registration based on 3T MRIs of 422 Human Connectome Project in Aging (HCP-A) subjects. To enhance the usability, probabilistic tissue maps and segmentation of 22 subcortical structures are provided. Finally, the subthalamic nucleus shown in the atlas is parcellated into sensorimotor, limbic, and associative sub-regions based on their structural connectivity to facilitate the analysis and planning of deep brain stimulation procedures. The dataset is available on the OSF Repository: https://osf.io/p7syt., (© 2023 The Author(s).)

Tools available for reproducible, quantitative assessment of brain correspondence have been limited. We previously validated the anatomical fiducial (AFID) placement protocol for point-based assessment of image registration with millimetric (mm) accuracy. In this data descriptor, we release curated AFID placements for some of the most commonly used structural magnetic resonance imaging datasets and templates. The release of our accurate placements allows for rapid quality control of image registration, teaching neuroanatomy, and clinical applications such as disease diagnosis and surgical targeting. We release placements on individual subjects from four datasets (N = 132 subjects for a total of 15,232 fiducials) and 14 brain templates (4,288 fiducials), totalling more than 300 human rater hours of annotation. We also validate human rater accuracy of released placements to be within 1 - 2 mm (using more than 45,000 Euclidean distances), consistent with prior studies. Our data is compliant with the Brain Imaging Data Structure allowing for facile incorporation into neuroimaging analysis pipelines., (© 2023. The Author(s).)

Background: Restoring hemostasis in patients on oral anticoagulants presenting with major hemorrhage (MH) or before surgical intervention has changed, with the replacement of vitamin K antagonist (VKA) with direct oral anticoagulants (DOACs)., Objectives: To observe the difference in urgent hemostatic management between patients on VKA and those on DOACs., Methods: A multicenter observational study evaluated the variation in laboratory testing, hemostatic management, mortality, and hospital length of stay (LOS) in patients on VKA or DOACs presenting with MH or urgent hemostatic restoration., Results: Of the 1194 patients analyzed, 783 had MH (61% VKA) and 411 required urgent hemostatic restoration before surgery (56% VKA). Compared to the international normalized ratio (97.6%), plasma DOAC levels were measured less frequently (<45%), and the time taken from admission for the coagulation sample to reach the laboratory varied widely (median, 52.3 minutes; IQR, 24.8-206.7). No significant plasma DOAC level (<50 ng/mL) was found in up to 19% of patients. There was a poor relationship between plasma DOAC level and the usage of a hemostatic agent. When compared with patients receiving VKA (96.5%) or dabigatran (93.7%), fewer patients prescribed a factor Xa inhibitor (75.5%) received a prohemostatic reversal agent. The overall 30-day mortality for MH (mean: 17.8%) and length of stay (LOS) (median: 8.7 days) was similar between VKA and DOAC patients., Conclusion: In DOAC patients, when compared to those receiving VKA, plasma DOAC levels were measured less frequently than the international normalized ratio and had a poor relationship with administering a hemostatic reversal agent. In addition, following MH, mortality and LOS were similar between VKA and DOAC patients., (© 2023 The Authors.)

Background: In late 2019 and early 2020, a novel coronavirus, COVID-19 (coronavirus disease 2019), spread across the world, creating a global pandemic. In the state of Pennsylvania, non-emergent, elective operations were temporarily delayed from proceeding with the normal standard of care. The primary purpose of this study was to determine the proportion of patients who required prescription pain medication during the surgical delay. Secondarily, we sought to determine the proportion of patients who perceived their surgical procedure as non-elective and to evaluate how symptoms were managed during the delay., Materials and Methods: A single institutional database was used to retrospectively identify all shoulder and elbow surgical procedures scheduled between March 13 and May 6, 2020. Charts were manually reviewed. Patients who underwent non-shoulder and elbow-related procedures and patients treated by surgeons outside of Pennsylvania were excluded. Patients whose surgical procedures were postponed or canceled were administered a survey evaluating how symptoms were managed and perceptions regarding the delay. Preoperative functional scores were collected. Statistical analysis was performed to determine associations between procedure status, preoperative functional scores, perception of surgery, and requirement for prescription pain medication., Results: A total of 338 patients were scheduled to undergo shoulder and elbow surgery in our practice in Pennsylvania. Surgery was performed as initially scheduled in 89 of these patients (26.3%), whereas surgery was postponed in 179 (71.9%) and canceled in 70 (28.1%). The average delay in surgery was 86.7 days (range, 13-299 days). Responses to the survey were received from 176 patients (70.7%) in whom surgery was postponed or canceled. During the delay, 39 patients (22.2%) required prescription pain medication. The surgical procedure was considered elective in nature by 73 patients (41%). One hundred thirty-seven patients (78%) would have moved forward with surgery if performed safely under appropriate medical guidelines. Lower preoperative American Shoulder and Elbow Surgeons scores (r = -0.36, P < .001) and Single Assessment Numeric Evaluation scores (r = -0.26, P = .016) and higher preoperative visual analog scale scores (r = 0.28, P = .009) were correlated with requiring prescription pain medication. Higher preoperative American Shoulder and Elbow Surgeons scores were positively correlated with perception of surgery as elective (r = 0.4, P < .001)., Conclusion: Patients undergoing elective shoulder and elbow surgical procedures during the COVID-19 (coronavirus disease 2019) pandemic experienced a delay of nearly 3 months on average. Fewer than half of patients perceived their surgical procedures as elective procedures. Nearly one-quarter of patients surveyed required extra prescription pain medicine during the delay. This study elucidates the fact that although orthopedic shoulder and elbow surgery is generally considered "elective," it is more important to a majority of patients. These findings may also be applicable to future potential mandated surgical care delays by other third-party organizations., (Copyright © 2022 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the predictive value of the modified Frailty Index (mFI) in evaluating sarcopenia and clinical outcomes in patients undergoing 1-level or 2-level transforaminal lumbar interbody fusion (TLIF)., Methods: Patients who underwent a 1-level or 2-level TLIF between 2012 and 2020 were retrospectively identified. Frailty was compared among groups using mFI, and sarcopenia was classified by the psoas muscle cross-sectional area. Bivariate statistics compared demographics, comorbidities, and clinical outcomes. A linear regression model was developed using the Charlson Comorbidity Index (CCI) or mFI as independent variables to determine potential predictors for improvement in 1-year patient-reported outcomes., Results: Of 488 included patients, 60 were severely frail and 60 patients had sarcopenia, but sarcopenia was not associated with patient frailty (P = 0.469). Severely frail patients had worse baseline Oswestry Disability Index (ODI) (P < 0.001), Mental Component Score-12 (P = 0.001), and Physical Component Score-12 (P < 0.001), and worse improvement in ODI (P = 0.037), Physical Component Score-12 (P < 0.001), and visual analog scale (VAS) back (P = 0.007). mFI was an independent predictor of poorer improvement in VAS back and ODI, whereas age + CCI in addition predicted poorer improvement in VAS leg. Patients with higher mFI experienced longer length of stay, less frequent home discharge, and higher rates of complications, but similar readmission and reoperation rates., Conclusions: Frailer patients experience poorer improvement in back pain, physical functioning, and disability after TLIF. mFI and the combination of age and CCI comparably predict patient-reported outcomes but do not correlate to baseline sarcopenia. Frailty increased the risk of complications, length of hospital stay, and risk of nonhome discharge., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The 2020 U.S. Presidential Election required voters to not only form opinions of leading candidates, Donald Trump and Joe Biden, but also to make judgments about the integrity of the election itself and what-if anything-to do about it. However, partisan motivated reasoning theory (Leeper and Slothuus, Political Psychology, 35(Suppl 1): 129-156; Lodge and Taber, The rationalizing voter, Cambridge University Press, 2013) suggests judgments are often strongly influenced toward affectively desirable conclusions. Before, during, and after election projections were announced, partisan supporters of Trump and Biden rated: judgments about voter fraud and foreign interference, their acceptance of the results, and their support for recourse against the outcome (e.g., legal challenges, legislative overhauls, violence). Before the election, partisans were mildly concerned about election integrity but willing to accept the outcome without recourse. However, during vote counting, and especially after Biden was projected to be the winner, partisans dramatically changed their judgments in opposite directions, consistent with the affectively desirable conclusions relevant to each group. Biden supporters affirmed the election's integrity and accepted the results whereas Trump supporters disputed the integrity, rejected the results, and began to support recourse against the outcome. Data are consistent with partisan motivated reasoning. Discussion highlights the practical implications., Supplementary Information: The online version contains supplementary material available at 10.1007/s11031-022-09983-w., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Chronic lymphocytic leukemia patients have an increased bleeding risk with the introduction of Bruton tyrosine kinase (BTK) inhibitors. BTK is a signaling effector downstream of the platelet GPVI receptor. Innate platelet dysfunction in CLL patients and the contribution of the leukemia microenvironment to the anti-platelet effect of BTK inhibitors are still not well defined. Herein, we investigated platelet function in stable, untreated CLL patients in comparison to age-matched healthy subjects as control. Secondly, we proposed a novel mechanism of platelet dysfunction via the adenosinergic pathway during BTK inhibitor therapy. Our data indicate that the nucleotidase that produces adenosine, CD73, was expressed on one-third of B-cells in CLL patients. Inhibition of CD73 improved platelet response to ADP in the blood of CLL patients ex vivo. Using healthy platelets, we show that adenosine 2A (A2A) receptor activation amplifies the anti-platelet effect of ibrutinib (10 nM). Ibrutinib plus an A2A agonist-but not ibrutinib as a single agent-significantly inhibited collagen (10 µg/mL)-induced platelet aggregation. Mechanistically, A2A activation attenuated collagen-mediated inhibition of p-VASP and synergized with ibrutinib to inhibit the phosphorylation of AKT, ERK and SYK kinases. This manuscript highlights the potential role of adenosine generated by the microenvironment in ibrutinib-associated bleeding in CLL patients.

Introduction: Investigations in spine surgery have demonstrated that trainee involvement correlates with increased surgical time, readmissions, and revision surgeries; however, the specific effects of spine fellow involvement remain unelucidated. This study aims to investigate the isolated effect of fellow involvement on surgical timing and patient-reported outcomes measures (PROMs) after spine surgery and evaluate how surgical outcomes differ by fellow experience., Methods: All patients aged 18 years or older who underwent primary or revision decompression or fusion for degenerative diseases and/or spinal deformity between 2017 and 2019 at a single academic institution were retrospectively identified. Patient demographics, surgical factors, intraoperative timing, transfusion status, length of stay (LOS), readmissions, revision rate, and preoperative and postoperative PROMs were recorded. Surgeries were divided based on spine fellow participation status and occurrence in the start or end of fellowship training. Univariate and multivariate analyses compared outcomes across fellow involvement and fellow experience groups., Results: A total of 1,108 patients were included. Age, preoperative diagnoses, number of fusion levels, and surgical approach differed markedly by fellow involvement. Fellow training experience groups differed by patient smoking status, preoperative diagnosis, and surgical approach. On univariate analysis, spine fellow involvement was associated with extended total theater time, induction start to cut time, cut to close time, and LOS. Increased spine fellow training was associated with reduced cut to close time and LOS. On regression, fellow involvement predicted cut to close extension while increased fellow training experience predicted reduction in cut to close time, both independent of surgical factors and assisting residents or physician assistants. Transfusions, readmissions, revision rate, and PROMs did not differ markedly by fellow involvement or experience., Conclusion: Spine fellow participation predicted extended procedural duration. However, the presence of a spine fellow did not affect long-term postoperative outcomes. Furthermore, increased fellow training experience predicted decreased procedural time, underscoring a learning effect., Availability of Data and Material: The data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request., Level of Evidence: Level 3., (Copyright © 2022 by the American Academy of Orthopaedic Surgeons.)

Background Context: Despite concerted efforts toward quality improvement in high-volume spine surgery, there remains concern that increases in case load may compromise the efficient and safe delivery of surgical care. There is a paucity of evidence to describe the effects of spine case order and operating room (OR) team structure on measures of intraoperative timing and OR efficiency., Purpose: This study aims to determine if intraoperative staff changes and surgical case order independently predict extensions in intraoperative timing after spinal surgery for spondylotic diseases., Study Design/ Setting: Retrospective cohort analysis PATIENT SAMPLE: All patients over age 18 who underwent primary or revision decompression and/or fusion for degenerative spinal diseases between 2017 to 2019 at a single academic institution were retrospectively identified. Exclusion criteria included absence of descriptive data and intraoperative timing parameters as well as surgery for traumatic injury, infection, and malignancy., Outcome Measures: Intraoperative timing metrics including total theater time, wheels in to induction, induction start to cut, cut to close, and close to wheels out. Postoperative outcomes included length of hospital stay and 90-day hospital readmissions., Methods: Surgical case order and intraoperative changes in staff (circulator and surgical scrub nurse or technician) were determined. Patient demographics, surgical factors, intraoperative timing and postoperative outcomes were recorded. Extensions in each operative stage were determined as a ratio of the actual duration of the parameter divided by the predicted duration of the parameter. Univariate and multivariate analyses were performed to compare outcomes within case order and staff change groups., Results: A total of 1,108 patients met the inclusion criteria. First, second, and third start cases differed significantly in intraoperative extensions of total theater time, wheels in to induction, induction start to cut, cut to close, and close to wheels out. On regression, decreasing case order predicted extension in wheels in to induction time. Surgeries with intraoperative staff changes were associated with increases in total theater time, induction start to cut time, cut to close time, close to wheels out time, and length of hospital stay. Switch in primary circulator predicted extended theater time and cut to close time. Relief of primary circulator or scrub predicted extended total theater time, induction start to cut time, cut to close time, and close to wheels out time., Conclusions: Intraoperative staff change in spine surgery independently predicted extended operative duration. However, higher case order was not significantly associated with procedural time., Competing Interests: Declarations of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Sleep is generally considered to be a state of large-scale synchrony across thalamus and neocortex; however, recent work has challenged this idea by reporting isolated sleep rhythms such as slow oscillations and spindles. What is the spatial scale of sleep rhythms? To answer this question, we adapted deep learning algorithms initially developed for detecting earthquakes and gravitational waves in high-noise settings for analysis of neural recordings in sleep. We then studied sleep spindles in non-human primate electrocorticography (ECoG), human electroencephalogram (EEG), and clinical intracranial electroencephalogram (iEEG) recordings in the human. Within each recording type, we find widespread spindles occur much more frequently than previously reported. We then analyzed the spatiotemporal patterns of these large-scale, multi-area spindles and, in the EEG recordings, how spindle patterns change following a visual memory task. Our results reveal a potential role for widespread, multi-area spindles in consolidation of memories in networks widely distributed across primate cortex., Competing Interests: MM, GG, DK, SM, JB, DS, AK, AS, LM No competing interests declared, (© 2022, Mofrad et al.)

Background: Pre-clinical studies have demonstrated the potential anticancer activity of cannabinoids, yet little clinical data exist to support this. Nearly 40% of patients with cancer using cannabis believe it will treat their cancer with numerous anecdotal reports shared online through social media platforms. Case reports have been published in peer-reviewed journals, but often lack key clinical information to validate anticancer claims. Methods: We reviewed literature in PubMed and EBSCO databases that evaluated the relationship between cannabis or the endocannabinoid system and potential anticancer activity. We also reviewed online sources, books, and ClinicalTrials.gov for reports or studies on using cannabis as cancer treatment. All case reports published in peer-reviewed journals were compiled and appraised as weak, moderate, or strong based on the quality of evidence provided supporting an anticancer effect. Strong reports met three criteria; (a) active cancer at time of cannabis administration, (b) validated laboratory or radiographic responses were reported, and (c) cannabis used without concurrent anticancer treatments. Results: Of the 207 pre-clinical articles reviewed, 107 (52%) were pre-clinical studies with original data. A total of 77 unique case reports described patients with various cancers (breast, central nervous system, gynecological, leukemia, lung, prostate, and pancreatic) using cannabis. Our appraisal showed 14% of the case reports were considered strong, 5% moderate, and the remaining 81% were weak. Ten percent of cases were in pediatric patients. Cannabidiol use was most often reported as the anticancer cannabinoid with daily doses ranging from 10 to 800 mg. Tetrahydrocannabinol use was reported in six studies, with doses ranging from 4.8 to 7.5 mg. Two small trials published data on survival in patients with recurrent glioblastoma multiforme. Conclusion: This review of clinical data suggests most published, peer-reviewed case reports provide insufficient data to support the claim for cannabis as an anticancer agent, and should not be used in place of evidence-based, traditional treatments outside of a clinical trial. No strong clinical trial data exist to confirm the pre-clinical studies that suggest cannabinoids may have an anticancer benefit. Future studies exploring anticancer potential of cannabis in patients with metastatic cancers who have not responded to traditional therapy are needed.

Background: In Parkinson's disease (PD), early stages are associated with a good long-duration response and as the disease advances, the short-duration response predominates. The transition between the long-duration and short-duration responses may be an important and measurable intermediate stage. A critical criterion in determining the candidature for neuromodulation is a beneficial response to an 'off-on' levodopa challenge test. This test is usually reserved for those that have already developed marked short-duration response and are candidates for deep brain stimulation (DBS) surgery. However, identifying those that are in transition may allow DBS to be offered earlier., Objective: The objective of the study was to determine if the transition from a long-duration to a short-duration response can be assessed on a levodopa challenge test., Methods: An 'off-on" levodopa challenge test was done in sixty-five PD patients divided into four groups based on the disease duration., Results: OFF motor scores increased in all groups [Mean ± STD; 22.94 ± 8.52, 31.53 ± 9.87, 34.05 ± 9.50, and 33.92 ± 10.15 in groups 1-4, respectively] while a significant response to medication was maintained on 'off-on' testing. The mean levodopa equivalency dose in groups 1 and 2 was significantly less than in groups 3 and 4. This transition occurred between years 7 and 9 of disease duration., Conclusion: Performing a regular levodopa challenge test, when levodopa dose increases substantially, should be considered to determine the ideal time for DBS in patients with Parkinson's disease., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Establishing spatial correspondence between subject and template images is necessary in neuroimaging research and clinical applications such as brain mapping and stereotactic neurosurgery. Our anatomical fiducial (AFID) framework has recently been validated to serve as a quantitative measure of image registration based on salient anatomical features. In this study, we sought to apply the AFIDs protocol to the clinic, focusing on structural magnetic resonance images obtained from patients with Parkinson's disease (PD). We confirmed AFIDs could be placed to millimetric accuracy in the PD dataset with results comparable to those in normal control subjects. We evaluated subject-to-template registration using this framework by aligning the clinical scans to standard template space using a robust open preprocessing workflow. We found that registration errors measured using AFIDs were higher than previously reported, suggesting the need for optimization of image processing pipelines for clinical grade datasets. Finally, we examined the utility of using point-to-point distances between AFIDs as a morphometric biomarker of PD, finding evidence of reduced distances between AFIDs that circumscribe regions known to be affected in PD including the substantia nigra. Overall, we provide evidence that AFIDs can be successfully applied in a clinical setting and utilized to provide localized and quantitative measures of registration error. AFIDs provide clinicians and researchers with a common, open framework for quality control and validation of spatial correspondence and the location of anatomical structures, facilitating aggregation of imaging datasets and comparisons between various neurological conditions., (© 2021. The Author(s).)

Purpose: The prevalence of medical cannabis (MC) use in patients with cancer is growing, but questions about safety, efficacy, and dosing remain. Conducting randomized, controlled trials (RCTs) using state-sponsored MC programs is novel and could provide data needed to guide patients and providers., Methods: A pilot RCT of patients with stage IV cancer requiring opioids was conducted. Thirty patients were randomized 1:1 to early cannabis (EC, n = 15) versus delayed start cannabis (DC, n = 15). The EC group obtained 3 months (3 M) of MC through a state program at no charge, while the DC group received standard oncology care without MC for the first 3 M. Patients met with licensed pharmacists at one of two MC dispensaries to determine a suggested MC dosing, formulation, and route. Patients completed surveys on pain levels, opioid/MC use, side effects, and overall satisfaction with the study., Results: Interest in the study was high as 36% of patients who met eligibility criteria ultimately enrolled. The estimated mean daily THC and CBD allotments at 3 M were 34 mg and 17 mg, respectively. A higher proportion of EC patients achieved a reduction in opioid use and improved pain control. No serious safety issues were reported, and patients reported high satisfaction., Conclusion: Conducting RCTs using a state cannabis program is feasible. The addition of MC to standard oncology care was well-tolerated and may lead to improved pain control and lower opioid requirements. Conducting larger RCTs with MC in state-sponsored programs may guide oncology providers on how to safely and effectively incorporate MC for interested patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: High estradiol (E 2 ) levels are linked to an increased risk of venous thromboembolism; however, the underlying molecular mechanism(s) remain poorly understood. We previously identified an E 2 -responsive microRNA (miR), miR-494-3p, that downregulates protein S expression, and posited additional coagulation factors, such as tissue factor, may be regulated in a similar manner via miRs., Objectives: To evaluate the coagulation capacity of cohorts with high physiological E 2 , and to further characterize novel E 2 -responsive miR and miR regulation on tissue factor in E 2 -related hypercoagulability., Methods: Ceveron Alpha thrombin generation assay (TGA) was used to assess plasma coagulation profile of three cohorts. The effect of physiological levels of E 2 , 10 nM, on miR expression in HuH-7 cells was compared using NanoString nCounter and validated with independent assays. The effect of tissue factor-interacting miR was confirmed by dual-luciferase reporter assays, immunoblotting, flow cytometry, biochemistry assays, and TGA., Results: Plasma samples from pregnant women and women on the contraceptive pill were confirmed to be hypercoagulable (compared with sex-matched controls). At equivalent and high physiological levels of E 2 , miR-365a-3p displayed concordant E 2 downregulation in two independent miR quantification platforms, and tissue factor protein was upregulated by E 2 treatment. Direct interaction between miR-365a-3p and F3- 3'UTR was confirmed and overexpression of miR-365a-3p led to a decrease of (1) tissue factor mRNA transcripts, (2) protein levels, (3) activity, and (4) tissue factor-initiated thrombin generation., Conclusion: miR-365a-3p is a novel tissue factor regulator. High E 2 concentrations induce a hypercoagulable state via a miR network specific for coagulation factors., Competing Interests: None declared., (Thieme. All rights reserved.)

Purpose: Deep brain stimulation (DBS) is a common treatment for a variety of neurological disorders which involves the precise placement of electrodes at particular subcortical locations such as the subthalamic nucleus. This placement is often guided by auditory analysis of micro-electrode recordings (MERs) which informs the clinical team as to the anatomic region in which the electrode is currently positioned. Recent automation attempts have lacked flexibility in terms of the amount of signal recorded, not allowing them to collect more signal when higher certainty is needed or less when the anatomy is unambiguous., Methods: We have addressed this problem by evaluating a simple algorithm that allows for MER signal collection to terminate once the underlying model has sufficient confidence. We have parameterized this approach and explored its performance using three underlying models composed of one neural network and two Bayesian extensions of said network., Results: We have shown that one particular configuration, a Bayesian model of the underlying network's certainty, outperforms the others and is relatively insensitive to parameterization. Further investigation shows that this model also allows for signals to be classified earlier without increasing the error rate., Conclusion: We have presented a simple algorithm that records the confidence of an underlying neural network, thus allowing for MER data collection to be terminated early when sufficient confidence is reached. This has the potential to improve the efficiency of DBS electrode implantation by reducing the time required to identify anatomical structures using MERs., (© 2021. CARS.)

Deep brain stimulation (DBS) is an effective therapy as an alternative to pharmaceutical treatments for Parkinson's disease (PD). Aside from factors such as instrumentation, treatment plans, and surgical protocols, the success of the procedure depends heavily on the accurate placement of the electrode within the optimal therapeutic targets while avoiding vital structures that can cause surgical complications and adverse neurologic effects. Although specific surgical techniques for DBS can vary, interventional guidance with medical imaging has greatly contributed to the development, outcomes, and safety of the procedure. With rapid development in novel imaging techniques, computational methods, and surgical navigation software, as well as growing insights into the disease and mechanism of action of DBS, modern image guidance is expected to further enhance the capacity and efficacy of the procedure in treating PD. This article surveys the state-of-the-art techniques in image-guided DBS surgery to treat PD, and discusses their benefits and drawbacks, as well as future directions on the topic.

The zona incerta (ZI) is a small gray matter region of the deep brain first identified in the 19th century, yet direct in vivo visualization and characterization has remained elusive. Noninvasive detection of the ZI and surrounding region could be critical to further our understanding of this widely connected but poorly understood deep brain region and could contribute to the development and optimization of neuromodulatory therapies. We demonstrate that high resolution (submillimetric) longitudinal (T1) relaxometry measurements at high magnetic field strength (7 T) can be used to delineate the ZI from surrounding white matter structures, specifically the fasciculus cerebellothalamicus, fields of Forel (fasciculus lenticularis, fasciculus thalamicus, and field H), and medial lemniscus. Using this approach, we successfully derived in vivo estimates of the size, shape, location, and tissue characteristics of substructures in the ZI region, confirming observations only previously possible through histological evaluation that this region is not just a space between structures but contains distinct morphological entities that should be considered separately. Our findings pave the way for increasingly detailed in vivo study and provide a structural foundation for precise functional and neuromodulatory investigation., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background Investigation of hemostasis is problematic when patients are on anticoagulant therapy. Rivaroxaban especially causes substantial interference, extending many clot-based tests, thereby leading to false positive or negative events. In particular, rivaroxaban affects some assays for activated protein C resistance (APCR). Methods We assessed, in an international setting, cross laboratory (n = 31) testing using four samples to evaluate rivaroxaban induced interference in APCR testing, and whether this interference could be neutralised. The samples comprised: (A) pool of normal plasma (APCR-negative control); (B) this normal pool spiked with rivaroxaban (200 ng/mL) to create rivaroxaban-induced interference (potential 'false' positive APCR event sample); (C) the rivaroxaban sample subsequently treated with a commercial direct oral anticoagulant 'DOAC-neutraliser' (DOAC Stop), or (D) treated with andexanet alfa (200 μg/mL). Testing was performed blind to sample type. Results The rivaroxaban-spiked sample generated false positive APCR results for some, but unexpectedly not most APCR-tests. The sample treated with DOAC Stop evidenced a correction in the rivaroxaban-affected APCR assays, and did not otherwise adversely affect the rivaroxaban 'unaffected' APCR assays. The andexanet alfa-treated sample did not evidence correction of the false positive APCR, and instead unexpectedly exacerbated false positive APCR status with many tests. Conclusions DOAC Stop was able to neutralise any APCR interference induced by rivaroxaban. In contrast, andexanet alfa did not negate such interference, and instead unexpectedly created more false-positive APCR events.

Micro-electrode recording (MER) is a powerful way of localizing target structures during neurosurgical procedures such as the implantation of deep brain stimulation electrodes, which is a common treatment for Parkinson's disease and other neurological disorders. While Micro-electrode Recording (MER) provides adjunctive information to guidance assisted by pre-operative imaging, it is not unanimously used in the operating room. The lack of standard use of MER may be in part due to its long duration, which can lead to complications during the operation, or due to high degree of expertise required for their interpretation. Over the past decade, various approaches addressing automating MER analysis for target localization have been proposed, which have mainly focused on feature engineering. While the accuracies obtained are acceptable in certain configurations, one issue with handcrafted MER features is that they do not necessarily capture more subtle differences in MER that could be detected auditorily by an expert neurophysiologist. In this paper, we propose and validate a deep learning-based pipeline for subthalamic nucleus (STN) localization with micro-electrode recordings motivated by the human auditory system. Our proposed Convolutional Neural Network (CNN), referred as SepaConvNet, shows improved accuracy over two comparative networks for locating the STN from one second MER samples.

Vertical current steering (vCS) divides current between multiple contacts, which reduces radial spread to fine-tune the electric field shape and improves neuroanatomical targeting. vCS may improve the variable responsiveness of Parkinsonian gait to conventional deep brain stimulation. We hypothesized that vCS elicits greater improvement in ambulation in Parkinson's disease patients compared to conventional, single-contact stimulation. vCS was implemented with divisions of 70%/30% and 50%/50% and compared to single-contact stimulation with four therapeutic window amplitudes in current-controlled systems. Walking at a self-selected pace was evaluated in seven levodopa-responsive patients. Integrative measures of gait and stimulation parameters were assessed with the functional ambulation performance (FAP) score and total electrical energy delivered (TEED), respectively. A two-tailed Wilcoxon matched-pairs signed rank test assessed the effect of each stimulation condition on FAP and TEED and compared regression slopes; further, a two-tailed Spearman test identified correlations. vCS significantly lowered the TEED (P < 0.0001); however, FAP scores were not different between conditions (P = 0.786). Compared to single-contact stimulation, vCS elicited higher FAP scores with lower TEED (P = 0.031). FAP and TEED were positively correlated in vCS (P = 2.000 × 10 -5 , r = 0.397) and single-contact stimulation (P = 0.034, r = 0.205). Therefore, vCS and single-contact stimulation improved ambulation similarly but vCS reduced the TEED and side-effects at higher amplitudes.

Hypothesis: It is hypothesized that poly(vinyl alcohol) (PVOH) as an emulsifier destabilizes the insoluble molecular aggregates by increasing interparticle interactions and their tendency toward agglomeration into large particle aggregates during the encapsulation process of one-step in situ polymerization. Porosity of capsule shells is expected to decrease with reducing agglomeration tendency to allow dense packing of smaller insoluble aggregates. Cross-linking the polymer network further reduces shell permeability to improve the retention of volatile cargos. PVOH also modifies the short-range order of polymer network to bestow improved mechanical properties in addition to the shell thickening effect at appropriate synthesis conditions., Experiments: PVOH was used to stabilize a heptane-in-water emulsion as a template for producing capsules via one-step in situ polymerization. Shell morphologies at different PVOH concentrations were compared. Physical freeze-thawing and chemical cross-linking were adopted separately to synthesize capsules with a volatile cargo, and its retention was characterized qualitatively by a solvatochromism-based fluorescent method and quantitative payload calculation. Mechanical properties of capsules were tested with micromanipulation. The effect of graphene oxide (GO) impregnation into capsules was studied with various co-emulsifiers., Findings: When PVOH alone was used as the emulsifier for capsule synthesis, the higher its concentration, the more porous the shell structure was. At very low concentrations, visible pores were eliminated. Freeze-thaw cycles reduced the permeability of capsule shells when visible pores were absent. Chemical cross-linking with poly(acrylic acid) (PAA) significantly improved the retention of volatile cargo heptane. PVOH substantially reduced polymer sediment during capsule synthesis, which eliminated the tedious centrifugation procedure that normally would have followed. Superior mechanical strength of capsules was achieved with PAA cross-linked PVOH at appropriate conditions. The impregnation of aqueously dispersed GO into capsules was also promoted by using PVOH but not hydrocolloid emulsifiers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: Investigation of factors (F) VIII and IX is common, with testing important for diagnosis or exclusion of haemophilia A or B, associated acquired conditions and factor inhibitors. Rivaroxaban, a common direct anti-Xa agent, causes significant interference in clotting assays, including substantial false reduction of factor levels., Aim: To assess whether rivaroxaban-induced interference of FVIII and FIX testing could be neutralized., Materials and Methods: An international, cross-laboratory exercise for FVIII (n = 84) and FIX (n = 74), using four samples: (A) pool of normal plasma; (B) pool spiked with rivaroxaban (200 ng/mL); (C) rivaroxaban sample subsequently treated with 'DOAC Stop' and; (D) rivaroxaban sample treated with andexanet alfa (200 μg/mL). Testing performed blind to sample type., Results: All laboratories reported normal FIX and 94% reported normal FVIII in the pool sample. Instead, 55% and 95%, respectively, reported abnormal FIX and FVIII levels for the rivaroxaban sample. DOAC Stop treatment evidenced a correction in most laboratories (100% reported normal FIX and 86% normal FVIII). Andexanet alfa provided intermediate results, with many laboratories still reporting abnormal results (59% for FVIII, 18% for FIX). We also identified reagent-specific issues., Conclusions: As expected, rivaroxaban caused false low values of FVIII and FIX. This might lead to increased testing to identify the cause of low factor levels and potentially lead to false identification of (mild) haemophilia A or B if unrecognized by clinicians/laboratories. DOAC Stop effectively neutralized the rivaroxaban effect, but andexanet alfa less so, with reagent-related effects evident, and thus, false low values sometimes persisted., (© 2020 John Wiley & Sons Ltd.)

A new approach is presented for localizing the Subthalamic Nucleus (STN) during Deep Brain Stimulation (DBS) surgery based on microelectrode recordings (MERs). DBS is an accepted treatment for individuals living with Parkinson's Disease (PD). This surgery involves implantation of a permanent electrode inside the STN to deliver electrical current. Since the STN is a very small region inside the brain, accurate placement of an electrode is a challenging task for the surgical team. Prior to placement of the permanent electrode, microelectrode recordings of brain activity are used intraoperatively to localize the STN. The placement of the electrode and the success of the therapy depend on this location. In this paper, an objective approach is implemented to help the surgical team in localizing the STN. This is achieved by processing the MER signals and extracting features during the surgery to be used in a Machine Learning (ML) algorithm for defining the neurophysiological borders of the STN. For this purpose, a new classification approach is proposed with the goal of detecting both the dorsal and the ventral borders of the STN during the surgical procedure. Results collected from 100 PD patients in this study, show that by calculating and extracting wavelet transformation features from MER signals and using a data-driven computational deep neural network model, it is possible to detect the borders of the STN with an accuracy of 92%. The proposed method can be implemented in real-time during the surgery to model the neurophysiological nonlinearity along the path of the electrode trajectory during insertion.

Background: Orthostatic tremor is a rare hyperkinetic movement disorder that is characterized by a 13-18 Hz tremor in both legs while standing. Deep-brain stimulation of the caudal zona incerta has re-emerged as an alternate target for tremor control in various etiologies., Object: Explore the clinical efficacy and mechanism of action of caudal zona incerta deep-brain stimulation in orthostatic tremor., Methods: Four patients (63.1 ± 4.1 years, female = 50%) with orthostatic tremor were recruited for this open label study (63.1 ± 4.1 years, female = 50%). In two patients, the electrodes were externalized to determine the effectiveness of caudal zona incerta as a target. Surface EMG (leg muscles), EEG (leg motor cortex) and caudal zona incerta local field potential recordings were recorded. Data were recorded in sitting and standing positions with stimulation OFF and ON., Results: EMG frequency analysis showed tremor frequency at 13-17 Hz. EMG-EEG coherence was found in the tremor frequency band and double tremor frequency band. EMG-caudal zona incerta coherence was higher in the tremor frequency band, while EEG coherence was higher in the double tremor frequency band. Upon stimulation, there was a selective reduction in tremor frequency band EEG-EMG coherence in all patients. All the patients had reduction in feeling of unsteadiness and increase in the stance duration., Conclusions: Bilateral caudal zona incerta deep-brain stimulation is effective in refractory orthostatic tremor. Two independent central oscillations were found at tremor and double tremor frequency. Zona incerta DBS produces improvement in OT patients possibly by modifying the abnormal oscillatory proprioceptive input from leg muscles. Frequent changes in deep-brain stimulation settings were required for maintaining the clinical benefit.

Background: Forward and backward walking are both impaired in Parkinson disease (PD). In this study, an exploratory factor analysis was performed to investigate the relationship between forward and backward walking in PD., Research Question: Given the difference in levodopa response between forward and backward walking, what is the additive value of testing backwards walking in a clinical setting., Methods: Sixty-two patients with PD (65.29 ± 7.17 yrs, UPDRS OFF = 29.68 ± 9.88, UPDRS ON = 16.40 ± 8.21) and eleven healthy age-matched controls (63.09 ± 8.09 yrs) were recruited. PD participants completed forward (F) and backward (B) walking tasks on a 6.1 m instrumented walkway (OFF and ON levodopa). Factor analysis was used to derive models for both walking tasks/medication states., Results: In both OFF and ON, four factors were identified: Variability (OFF: F = 30.0%, B = 17.8%, ON: F = 21.6%, B = 25.0%), Rhythm (OFF: F = 14.5%, B = 17.0%, ON: F = 17.4%, B = 19.0%), Asymmetry (OFF: F = 13.7%, B = 14.3%, ON: F = 16.1%, B = 15.2%), and Pace (OFF: F = 12.2%, B = 17.0%, ON: F = 13.9%, B = 8.7%). In the ON state, a fifth factor was identified: Posture (ON: F = 3.8%, B = 7.7%)., Significance: This study demonstrates the similarity in gait domain factors in both forward and backward walking. While domains of gait are similar in both walking tasks, levodopa response is reduced in backward walking. This could be a result of the increased complexity of backward walking. This study provides a normative dataset that can be used when assessing forward and backward walking in individuals with PD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Lupus anticoagulant (LA) investigation in patients on anticoagulant therapy is problematic. Rivaroxaban in particular causes significant interference, prolonging both LA screening and confirmation tests, and falsely raising LA screen/confirm ratios, leading to potential false identification of LA. The Russell Viper Venom Time (RVVT) assay, key to the investigation of LA, is especially sensitive to rivaroxaban., Materials and Methods: We assessed cross laboratory (n = 82) testing of four samples to investigate whether rivaroxaban induced interference in LA testing could be neutralised. Testing was performed blind to sample type. The samples comprised: (A) A pool of normal plasma (LA-negative control); (B) sample A spiked with rivaroxaban (200 ng/mL) to create rivaroxaban-induced interference (LA 'false' positive sample); (C) sample B subsequently treated with a commercial 'DOAC-neutraliser' (DOAC Stop); (D) sample B treated with andexanet alfa (200 μg/mL)., Results: As expected, the rivaroxaban-spiked sample (B) caused prolongation of most LA-tests, and also generated a falsely prolonged RVVT screen/confirm ratio (median 1.37, compared to 0.97 for sample A). The sample (C) treated with DOAC Stop evidenced a correction in LA-test clotting times, as well as neutralising the false positive LA (median RVVT screen/confirm ratio of 0.99). Although the andexanet alfa treated sample (D) also yielded a low median RVVT screen/confirm ratio of 0.88, it did not fully correct LA-test clotting times. Consistent with test findings, all laboratories interpreted samples A and C as being LA-negative. For sample B (rivaroxaban), 45.3% identified this as LA positive, and 38.7% identified LA interference. Most (61.3%) also identified sample D as LA negative, with the remainder (38.7%) identifying LA interference., Conclusions: DOAC Stop was able to neutralise the false LA activity induced by rivaroxaban, both in terms of clot-times and LA ratios. In contrast, whilst andexanet alfa negated the rivaroxaban-prolonged LA-ratio, it did not fully correct clot-times, leaving some residual LA interference, and requiring additional testing to investigate prolonged clotting times., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Objective: To systematically evaluate how different deep brain stimulation of the subthalamic nucleus (STN-DBS) amplitude, frequency, and pulse-width electrical parameter settings impact speech intensity, voice quality, and prosody of speech in Parkinson's disease (PD)., Methods: Ten individuals with PD receiving bilateral STN-DBS treatments were seen for three baseline and five treatment visits. The five treatment visits involved an examination of the standard clinical settings as well as manipulation of different combinations of frequency (low, mid, and high), pulse width (low, mid, and high), and voltage (low, mid, and high) of stimulation. Measures of speech intensity, jitter, shimmer, harmonics-noise ratio, semitone standard deviation, and listener ratings of voice quality and prosody were obtained for each STN-DBS manipulation., Results: The combinations of lower frequency, lower pulse width, and higher voltage settings were associated with improved speech outcomes compared to the current standard clinical settings. In addition, decreased total electrical energy delivered to the STN appears to be associated with speech improvements., Conclusions: This study provides preliminary evidence that STN-DBS may be optimized for Parkinson-related problems with voice quality, speech intensity, and prosody of speech.

Background: Glucocorticoids are commonly used in chemotherapy regimens and may lead to hyperglycemia and increased infection rates., Methods: We performed a retrospective analysis on 1781 patients who received intravenous chemotherapy with glucocorticoids between 2010 and 2015. Data was obtained using electronic medical record, billing modules, and tumor registry. We compared new infections and survival between patients with and without diabetes, after adjusting for demographic and cancer-related variables., Results: In the first 12 months following chemotherapy, patients with diabetes (n = 330) had higher rates of hospital admissions (70.9% vs 57.4%), more infection-related admissions (37.0% vs 29.2%), and increased rates of new infections (61.2% vs 49.2%) when compared to patients without diabetes (n = 1451). One-year survival was worse among patients with diabetes (67.3% vs 78.3%), and in patients with at least one elevated glucose following chemotherapy (60.8% vs 78.5). After adjusting for cancer stage, age, and gender, diabetes history increased the odds of dying within one year after diagnosis by 86% (OR 1.86, 95% CI (1.37-2.52)) and of new infections by 68% (OR 1.68, 95% CI (1.26-2.24))., Conclusions: Among patients with cancer receiving intravenous chemotherapy with glucocorticoids we demonstrate those with diabetes have more hospital admissions, increased rates of infections, and worse survival., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Parkinson disease (PD) patients have turning impairments that may increase fall risk. Clinics lack specialized kinematic equipment used in gait and turn analysis and require a simple method to evaluate fall risk and advise patients in turning strategy selection., Objectives: To enhance understanding of PD turning strategies and determine if turning can be assessed using a video-recording and categorization method, we compared 180-degree and 90-degree turns as a function of medication status and dual-tasking (DT)., Methods: 21 PD participants (H&Y stage 1-3) in PD-ON and PD-OFF medication states and 16 controls completed 180-degree and 90-degree turn-tasks with and without DT. Video-recordings of tasks permitted classification of 180-degree turns into Few-Step turns (FST) vs. Multi-Step turns (MST) and 90-degree turns into Step vs. Spin-turns. FST were further sub-classified into Twisting vs. Sideways turns and MST into Backward, Festination, Forward or Wheeling turns. Percentages of subtypes were analyzed across groups by task., Results: IN 180-degree tasks, there was an effect of group: FST vs. MST F(2,55) = 9.578, p < .001. PD participants in the off-medication state (PD-OFF) produced significantly more MST with a larger number of different turning subtypes vs. controls or PD on medication (PD-ON). In 90-degree tasks, controls significantly increased their proportion of Step-turns while DT (p < .001), an adaptation not observed in PD-ON or PD-OFF., Conclusions: PD turning impairments may stem from an inability to select a unified turning strategy and to adapt to the turning environment, which may be exacerbated in PD-OFF. Video-analysis may prove beneficial in predicting a clinical course for PD patients by revealing features of turning dysfunction., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To examine the effect of levodopa medication on speech dysfluency in Parkinson's disease., Methods: Fifty-one individuals with Parkinson's disease (IWPD) read aloud during off- and on- medication states. Total speech dysfluencies were calculated from transcriptions of recorded speech samples., Results: Severity of speech dysfluency was not significantly related to the severity of motor symptoms, duration of disease, levodopa equivalent dosage, or age. When the IWPD were divided into two groups based on dysfluency severity, there was a significant group-by-medication state interaction. There was a significant correlation between the medication-related change in speech dysfluency and the off -medication severity of speech dysfluency measure (r = -0.46)., Conclusions: The results of this study indicate that levodopa medication can have a significant effect on speech dysfluency. The beneficial levodopa effect appears to be related to the severity of the off- medication speech dysfluency. Results did not provide strong support for the excess dopamine theory of stuttering in IWPD. A dualistic model of the effects of dopamine on speech fluency in PD is proposed.

The effect of levodopa on perceptual and acoustic measures of voice quality was examined in fifty-one individuals with Parkinson's disease (IWPD). IWPDs produced prolonged vowels while on and off levodopa. Acoustic measures included jitter, shimmer, harmonic-to-noise ratio, cepstral peak prominence and the Acoustic Voice Quality Index. A perceptual measure of overall voice quality was obtained from 3 listeners. When the IWPDs were examined as a group, no significant difference was found between on and off levodopa conditions. In contrast, when IWPDs were split into two groups based on voice quality severity, a significant group-by-medication state interaction emerged. In addition, there was a significant correlation (r = .55) between the magnitude of levodopa-related improvement in perceived voice quality and voice quality severity. In contrast, levodopa-related improvement in voice quality was not correlated with duration of disease or levodopa use. Results do not support the hypothesis of reduced levodopa-responsiveness to voice symptoms as disease duration increases. Instead, the results suggest that the magnitude of the levodopa response may increase with increasing severity of the voice quality symptoms. These results suggest that the severity of speech and voice symptoms needs to be given greater consideration in future studies of levodopa effectiveness in IWPDs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Goblet cell carcinoid is a rare but distinct entity of appendiceal tumors which is a hybrid or mixed tumor consisting of both epithelial (glandular) and neuroendocrine elements containing goblet cells. This entity is important to recognize and appropriately grade as it tends to be more aggressive than typical carcinoid tumors, often presenting with metastatic disease. As a result, the 5-year overall survival is 14-22% in stage III-IV disease. GCC therefore warrants more aggressive surgical and medical (chemotherapy) interventions than typical carcinoid tumors. Through this case report we give a brief update on GCC pathological features, staging, surgical management, and review the literature as a guide to indications for chemotherapy and choice of agents., Case Presentation: We present the case of a 77-year-old Caucasian man with a history of stage I adenocarcinoma of transverse colon status post transverse colectomy who was incidentally found on surveillance colonoscopy to have an abnormal appendiceal orifice lesion. A biopsy revealed an appendiceal goblet cell carcinoid and he underwent a right hemicolectomy which revealed a pathologic stage III GCC for which he received eight cycles of adjuvant chemotherapy with capecitabine., Conclusions: It is essential that patients who have tumors > 2 cm, are pT3 or pT4, have higher grade histology with signet ring (Tang grade B or grade C), locally advanced, or with positive surgical margins on appendectomy undergo a right hemicolectomy. Although there is no category 1 evidence, consensus recommendations are that patients with stage II (particularly Tang B and C) and stage III GCC be offered adjuvant chemotherapy with a regimen based on 5-fluorouracil, as these patients are known to have high rates of relapse.

The small noncoding RNAs, microRNAs (or miRNAs), have been implicated in a myriad of diseases and accumulating evidence indicate their potential high value as diagnostic biomarkers. Although their roles in hemostasis and coagulation pathways are less defined, many studies have demonstrated their participation in regulating key factors of hemostasis. However, the mounting challenges associated with the accurate measurement of circulating miRNAs and the involvement of platelet activation in contributing to the circulating miRNA expression profile introduce further complexity to the study of thrombosis-associated miRNAs. This review outlines the current knowledge of miRNAs that have been postulated to regulate key hemostatic factors, and miRNA diagnostic panels in thrombotic disease, with a focus on experimental fundamentals, such as selecting condition-specific reference controls, considerations that are crucial for accurate evaluation of miRNAs in the context of disease biomarkers., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Purpose: The settings of 3 electrical stimulation parameters were adjusted in 12 speakers with Parkinson's disease (PD) with deep brain stimulation of the subthalamic nucleus (STN-DBS) to examine their effects on vowel acoustics and speech intelligibility., Method: Participants were tested under permutations of low, mid, and high STN-DBS frequency, voltage, and pulse width settings. At each session, participants recited a sentence. Acoustic characteristics of vowel production were extracted, and naive listeners provided estimates of speech intelligibility., Results: Overall, lower-frequency STN-DBS stimulation (60 Hz) was found to lead to improvements in intelligibility and acoustic vowel expansion. An interaction between speaker sex and STN-DBS stimulation was found for vowel measures. The combination of low frequency, mid to high voltage, and low to mid pulse width led to optimal speech outcomes; however, these settings did not demonstrate significant speech outcome differences compared with the standard clinical STN-DBS settings, likely due to substantial individual variability., Conclusions: Although lower-frequency STN-DBS stimulation was found to yield consistent improvements in speech outcomes, it was not found to necessarily lead to the best speech outcomes for all participants. Nevertheless, frequency may serve as a starting point to explore settings that will optimize an individual's speech outcomes following STN-DBS surgery., Supplemental Material: https://doi.org/10.23641/asha.5899228.

Gravitational waves (GWs) cause the apparent position of distant stars to oscillate with a characteristic pattern on the sky. Astrometric measurements (e.g., those made by Gaia) provide a new way to search for GWs. The main difficulty facing such a search is the large size of the data set; Gaia observes more than one billion stars. In this Letter the problem of searching for GWs from individually resolvable supermassive black hole binaries using astrometry is addressed for the first time; it is demonstrated how the data set can be compressed by a factor of more than 10^{6}, with a loss of sensitivity of less than 1%. This technique was successfully used to recover artificially injected GW signals from mock Gaia data and to assess the GW sensitivity of Gaia. Throughout the Letter the complementarity of Gaia and pulsar timing searches for GWs is highlighted.

Aptamers are short synthetic DNA or RNA oligonucleotides that adopt secondary and tertiary conformations based on Watson-Crick base-pairing interactions and can be used to target a range of different molecules. Two aptamers, HD1 and HD22, that bind to exosites I and II of the human thrombin molecule, respectively, have been extensively studied due to their anticoagulant potentials. However, a fundamental issue preventing the clinical translation of many aptamers is degradation by nucleases and reduced pharmacokinetic properties requiring higher dosing regimens more often. In this study, we have chemically modified the design of previously described thrombin binding aptamers targeting exosites I, HD1, and exosite II, HD22. The individual aptamers were first modified with an inverted deoxythymidine nucleotide, and then constructed bivalent aptamers by connecting the HD1 and HD22 aptamers either through a triethylene glycol (TEG) linkage or four consecutive deoxythymidines together with an inverted deoxythymidine nucleotide at the 3'-end. The anticoagulation potential, the reversal of coagulation with different antidote sequences, and the nuclease stability of the aptamers were then investigated. The results showed that a bivalent aptamer RNV220 containing an inverted deoxythymidine and a TEG linkage chemistry significantly enhanced the anticoagulation properties in blood plasma and nuclease stability compared to the existing aptamer designs. Furthermore, a bivalent antidote sequence RNV220AD efficiently reversed the anticoagulation effect of RNV220 in blood plasma. Based on our results, we believe that RNV220 could be developed as a potential anticoagulant therapeutic molecule.

A variety of clinical scales are available to assess dyskinesia severity in Parkinson's disease patients; however, such assessments are subjective, do not provide long term monitoring, and their use is subject to inter- and intra-rater variability. In this paper, an objective dyskinesia score was developed using an IMU -based motion capture system. Deep brain stimulation (DBS) surgery is currently the only acute intervention that results in the rapidly progressive reduction of dyskinesia's severity; hence, this form of therapy was selected as a model to validate the proposed method. Thirteen Parkinson's disease participants undergoing DBS surgery and 12 age-matched healthy control participants were assessed using the motion capture system. Concurrent Unified Dyskinesia Rating Scale (UDysRS) ratings were also performed. Parkinson's disease participants were assessed pre-operatively and for five visits post-operatively while seated at rest, during arms outstretched and while performing an action task. The kinematic data were used to develop an objective measure defined as the dyskinesia severity score. Generally, a strong correlation was observed between the UDysRS ratings and the full-body dyskinesia severity scores. The results suggest that it is feasible and clinically meaningful to utilize an objective full-body dyskinesia score for the assessment of dyskinesia. The portable motion capture system along with the developed software can be used remotely to monitor the full-body severity of dyskinesia, necessary for therapeutic optimization, especially in the patients home environment.

Heart rate variability is primarily regulated by the autonomic nervous system. Heart transplant recipients undergo surgical denervation of the graft, which results in interruption of autonomic innervation with resultant diminished heart rate variability although some degree of autonomic control may return. This study aimed to characterize heart rate variability in this population. We report a retrospective review of Holter monitor data from transplanted patients between 2005 and 2013. Studies with significant atrial or ventricular arrhythmias were excluded. We evaluated changes over time and compared standard time domain measures to published pediatric normal values. Data were reviewed from 582 monitors in 152 patients. We found that pediatric heart transplant recipients have lower heart rate variability than age-matched controls and higher average heart rate in recipients older than 3 years. There is an increase in measures of variability through the first 3 years post-transplant with plateau after that time. Surgical technique in regard to interruption of the vagus nerve does not affect variability, nor does underlying congenital vs acquired heart disease., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A novel plasmonic nanoledge device was presented to explore the geometry-induced trapping of nanoscale biomolecules and examine a generation of surface plasmon resonance (SPR) for plasmonic sensing. To design an optimal plasmonic device, a semianalytical model was implemented for a quantitative analysis of SPR under plane-wave illumination and a finite-difference time-domain (FDTD) simulation was used to study the optical transmission and refractive index (RI) sensitivity. In addition, total internal reflection fluorescence (TIRF) imaging was used to visualize the migration of fluorescently labeled bovine serum albumin (BSA) into the nanoslits; and fluorescence correlation spectroscopy (FCS) was further used to investigate the diffusion of BSA in the nanoslits. Transmission SPR measurements of free prostate specific antigen (f-PSA), which is similar in size to BSA, were performed to validate the trapping of the molecules via specific binding reactions in the nanoledge cavities. The present study may facilitate further development of single nanomolecule detection and new nanomicrofluidic arrays for effective detection of multiple biomarkers in clinical biofluids.

Background: Managing multiple sclerosis (MS) treatment presents challenges for both patients and health care professionals. Effective communication between patients with MS and their neurologist is important for improving clinical outcomes and quality of life., Methods: A closed-ended online market research survey was used to assess the current state of MS care from the perspective of both patients with MS (≥18 years of age) and neurologists who treat MS from Europe and the US and to gain insight into perceptions of treatment expectations/goals, treatment decisions, treatment challenges, communication, and satisfaction with care, based on current clinical practice., Results: A total of 900 neurologists and 982 patients completed the survey, of whom 46% self-identified as having remitting-relapsing MS, 29% secondary progressive MS, and 11% primary progressive MS. Overall, patients felt satisfied with their disease-modifying therapy (DMT); satisfaction related to comfort in speaking with their neurologist and participation in their DMT decision-making process. Patients who self-identified as having relapsing-remitting MS were more likely to be very satisfied with their treatment. Top challenges identified by patients in managing their DMT were cost, side effects/tolerability of treatment, and uncertainty if treatment was working. Half of the patients reported skipping doses, but only 68% told their health care provider that they did so., Conclusion: Several important differences in perception were identified between patients and neurologists concerning treatment selection, satisfaction, expectations, goals, and comfort discussing symptoms, as well as treatment challenges and skipped doses. The study results emphasize that patient/neurologist communication and patient input into the treatment decision-making process likely influence patient satisfaction with treatment., Competing Interests: Mar Tintoré received consulting and non-CME service fees from Almirall, Biogen, EMD Merck Serono, Genzyme, Novartis, Roche, Sanofi-Aventis, and Teva UK Limited; educational/research support from Bayer HealthCare, Biogen, Genzyme, EMD Merck Serono, Novartis Pharma AG, and Teva UK Limited. Martin Duddy received honoraria, educational support, consulting fees, and research support from Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis Pharma AG, Roche, and Teva UK Limited; and personal compensation as associate editor for the Multiple Sclerosis Journal. David E Jones received consulting fees from Biogen, Genzyme, and Novartis; and research support from Biogen. Nancy Law received consulting fees from Biogen in her current role; no consulting fees were received in her former role as an employee of the National Multiple Sclerosis Society (Denver, CO, USA). Gilmore O’Neill is a full-time employee of and holds stock/stock options in Biogen. Antonio Uccelli received consulting or speaker fees from Allergan, Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis, Roche, and Teva; and research support from Biogen, Merck Serono, and Novartis. Robert Weissert received consulting fees from Biogen, Genzyme, Merck Serono, Novartis, Roche, and Teva; served on speakers bureaus for Ärztlicher Kreisverband Weiden and Biogen; and performed contracted research for Novartis. Sibyl Wray received consulting fees from Acorda, Biogen, EMD Serono, Genzyme, Novartis, Questcor, and Teva; served on speakers bureaus for Acorda, Bayer HealthCare, Biogen, EMD Serono, Genzyme, Novartis, Questcor, and Teva; and performed contracted research for Biogen, EMD Serono, Genzyme, Novartis, Receptos, and Roche. The authors report no other conflicts of interest in this work.