A proposal for a comprehensive grading of Parkinson's disease severity combining motor and non-motor assessments: meeting an unmet need.

Non-motor symptoms are present in Parkinson's disease (PD) and a key determinant of quality of life. The Non-motor Symptoms Scale (NMSS) is a validated scale that allows quantifying frequency and severity (burden) of NMS. We report a proposal for using NMSS scores to determine levels of NMS burden (NMSB) and to complete PD patient classification

A computational framework to emulate the human perspective in flow cytometric data analysis

Background: In recent years, intense research efforts have focused on developing methods for automated flow cytometric data analysis. However, while designing such applications, little or no attention has been paid to the human perspective that is absolutely central to the manual gating process of identifying and characterizing cell populations. In particular, the assumption of many common techniques that cell populations could be modeled reliably with pre-specified distributions may not hold true in real-life samples, which can have populations of arbitrary shapes and considerable inter-sample variation. <p/>Results: To address this, we developed a new framework flowScape for emulating certain key aspects of the human perspective in analyzing flow data, which we implemented in multiple steps. First, flowScape begins with creating a mathematically rigorous map of the high-dimensional flow data landscape based on dense and sparse regions defined by relative concentrations of events around modes. In the second step, these modal clusters are connected with a global hierarchical structure. This representation allows flowScape to perform ridgeline analysis for both traversing the landscape and isolating cell populations at different levels of resolution. Finally, we extended manual gating with a new capacity for constructing templates that can identify target populations in terms of their relative parameters, as opposed to the more commonly used absolute or physical parameters. This allows flowScape to apply such templates in batch mode for detecting the corresponding populations in a flexible, sample-specific manner. We also demonstrated different applications of our framework to flow data analysis and show its superiority over other analytical methods. <p/>Conclusions: The human perspective, built on top of intuition and experience, is a very important component of flow cytometric data analysis. By emulating some of its approaches and extending these with automation and rigor, flowScape provides a flexible and robust framework for computational cytomics

Robotic ubiquitous cognitive ecology for smart homes

Robotic ecologies are networks of heterogeneous robotic devices pervasively embedded in everyday environments, where they cooperate to perform complex tasks. While their potential makes them increasingly popular, one fundamental problem is how to make them both autonomous and adaptive, so as to reduce the amount of preparation, pre-programming and human supervision that they require in real world applications. The project RUBICON develops learning solutions which yield cheaper, adaptive and efficient coordination of robotic ecologies. The approach we pursue builds upon a unique combination of methods from cognitive robotics, machine learning, planning and agent- based control, and wireless sensor networks. This paper illustrates the innovations advanced by RUBICON in each of these fronts before describing how the resulting techniques have been integrated and applied to a smart home scenario. The resulting system is able to provide useful services and pro-actively assist the users in their activities. RUBICON learns through an incremental and progressive approach driven by the feed- back received from its own activities and from the user, while also self-organizing the manner in which it uses available sensors, actuators and other functional components in the process. This paper summarises some of the lessons learned by adopting such an approach and outlines promising directions for future work

Transportability of Overall Survival Estimates From US to Canadian Patients With Advanced Non-Small Cell Lung Cancer With Implications for Regulatory and Health Technology Assessment.

IMPORTANCE: The external validity of survival outcomes derived from clinical practice data from US patients with advanced non-small cell lung cancer (NSCLC) is not known and is of potential importance because it may be used to support regulatory decision-making and health technology assessment outside of the US. OBJECTIVE: To evaluate whether overall survival (OS) estimates for a selected group of patients with advanced NSCLC from a large US clinical practice database are transportable to Canadian patients receiving the same systemic therapies. DESIGN, SETTING, AND PARTICIPANTS: This retrospective multicenter cohort study used transportability analysis to assess whether adjustment for pretreatment characteristics of eligible patient cohorts could reliably approximate OS estimated from US-based samples to Canadian populations. A total of 17 432 eligible adult patients who were diagnosed de novo with advanced NSCLC on or after January 1, 2011, were included in the analysis and followed up until September 30, 2020. Because data on race and ethnicity were available in the US database but not the Canadian database and because racial and ethnic distribution was likely to be similar between US and Canadian patients, these characteristics were not analyzed. EXPOSURES: Initiation of platinum-doublet chemotherapy or pembrolizumab monotherapy as first-line systemic treatment for advanced NSCLC. MAIN OUTCOMES AND MEASURES: OS measured from the time of initiation of the respective treatment regimen. RESULTS: Among 17 432 eligible patients, 15 669 patients from the US and 1763 patients from Canada were included in the analysis. Of those, 11 863 patients (sample size-weighted estimates of mean [SD] age, 68.0 [9.3] years; 6606 [55.7%] male; 10 100 from the US and 1763 from Canada) were included in the subset of patients with complete data for baseline covariates. A total of 13 532 US patients received first-line chemotherapy, and 2137 received first-line pembrolizumab monotherapy. Of those, 8447 patients (62.4%) in the first-line chemotherapy group and 1653 patients (77.3%) in the first-line pembrolizumab group had complete data on baseline covariates for outcome model estimation. A total of 1476 Canadian patients who received first-line chemotherapy and 287 patients who received first-line pembrolizumab monotherapy were identified from the target population. After standardization to baseline patient covariates in the Canadian cohorts, transported OS estimates revealed a less than 5% mean absolute difference from the observed OS in the target population (0.56% over 60 months of follow-up in the first-line chemotherapy group and 4.54% over 30 months of follow-up in the first-line pembrolizumab group). Negative control analysis using a mismatched outcome model revealed a 6.64% discrepancy and an incompatible survival curve shape. The results were robust to assumptions of random missingness for baseline covariates, to unadjusted differences in baseline metastases and comorbidities, and to differences in the standard of care between the US and Canada related to administration of second-line anti-programmed cell death 1 ligand 1 immunotherapy for patients who initiated first-line chemotherapy. CONCLUSIONS AND RELEVANCE: The results of this cohort study suggest that, under specific circumstances, OS estimates from US clinical practice data can be adjusted using baseline clinical characteristics to closely approximate OS in selected groups of Canadian patients with advanced NSCLC. These results may have implications for regulatory decision-making and health technology assessment in target populations outside of the US

Structural subnetwork evolution across the life-span: rich-club, feeder, seeder

The impact of developmental and aging processes on brain connectivity and the connectome has been widely studied. Network theoretical measures and certain topological principles are computed from the entire brain, however there is a need to separate and understand the underlying subnetworks which contribute towards these observed holistic connectomic alterations. One organizational principle is the rich-club - a core subnetwork of brain regions that are strongly connected, forming a high-cost, high-capacity backbone that is critical for effective communication in the network. Investigations primarily focus on its alterations with disease and age. Here, we present a systematic analysis of not only the rich-club, but also other subnetworks derived from this backbone - namely feeder and seeder subnetworks. Our analysis is applied to structural connectomes in a normal cohort from a large, publicly available lifespan study. We demonstrate changes in rich-club membership with age alongside a shift in importance from 'peripheral' seeder to feeder subnetworks. Our results show a refinement within the rich-club structure (increase in transitivity and betweenness centrality), as well as increased efficiency in the feeder subnetwork and decreased measures of network integration and segregation in the seeder subnetwork. These results demonstrate the different developmental patterns when analyzing the connectome stratified according to its rich-club and the potential of utilizing this subnetwork analysis to reveal the evolution of brain architectural alterations across the life-span

The Non-Motor Symptoms Scale in Parkinson's disease: validation and use

The Non‐Motor Symptoms Scale (NMSS) was developed and validated in 2007 as the first instrument for the comprehensive assessment of a range of non‐motor symptoms in Parkinson's disease (PD). Thirteen years have elapsed since its introduction and extensive international validation with good psychometric attributes has been carried out. Here, we review the validation data of the NMSS and its cross‐validity with other scales, and describe the key evidence derived from use of the NMSS in clinical studies. To date, over 100 clinical studies and trials have made use of it as an outcome measure, showing consistent and strong correlations between NMSS burden and health‐related quality of life measures. Moreover, the scale has shown to be capable of detecting longitudinal changes in non‐motor symptoms, where studies have shown differential changes over time of several of the NMSS domains. The scale has become a key outcome in several randomized clinical trials. Highlighting the prevalence and importance of non‐motor symptoms to quality of life in patients with PD, the development of NMSS has also been useful in signposting clinical and biomarker based research addressing non‐motor symptoms in PD

Long term benzodiazepine use for insomnia in patients over the age of 60: discordance of patient and physician perceptions

BACKGROUND: The aim of this study was to determine and compare patients' and physicians' perceptions of benefits and risks of long term benzodiazepine use for insomnia in the elderly. METHODS: A cross-sectional study (written survey) was conducted in an academic primary care group practice in Toronto, Canada. The participants were 93 patients over 60 years of age using a benzodiazepine for insomnia and 25 physicians comprising sleep specialists, family physicians, and family medicine residents. The main outcome measure was perception of benefit and risk scores calculated from the mean of responses (on a Likert scale of 1 to 5) to various items on the survey. RESULTS: The mean perception of benefit score was significantly higher in patients than physicians (3.85 vs. 2.84, p < 0.001, 95% CI 0.69, 1.32). The mean perception of risk score was significantly lower in patients than physicians (2.21 vs. 3.63, p < 0.001, 95% CI 1.07, 1.77). CONCLUSIONS: There is a significant discordance between older patients and their physicians regarding the perceptions of benefits and risks of using benzodiazepines for insomnia on a long term basis. The challenge is to openly discuss these perceptions in the context of the available evidence to make collaborative and informed decisions

Glucocorticoids rapidly inhibit cell migration through a novel, non-transcriptional HDAC6 pathway

Glucocorticoids (GCs) act through the glucocorticoid receptor (GR, also known as NR3C1) to regulate immunity, energy metabolism and tissue repair. Upon ligand binding, activated GR mediates cellular effects by regulating gene expression, but some GR effects can occur rapidly without new transcription. Here, we show that GCs rapidly inhibit cell migration, in response to both GR agonist and antagonist ligand binding. The inhibitory effect on migration is prevented by GR knockdown with siRNA, confirming GR specificity, but not by actinomycin D treatment, suggesting a non-transcriptional mechanism. We identified a rapid onset increase in microtubule polymerisation following GC treatment, identifying cytoskeletal stabilisation as the likely mechanism of action. HDAC6 overexpression, but not knockdown of αTAT1, rescued the GC effect, implicating HDAC6 as the GR effector. Consistent with this hypothesis, ligand-dependent cytoplasmic interaction between GR and HDAC6 was demonstrated by quantitative imaging. Taken together, we propose that activated GR inhibits HDAC6 function, and thereby increases the stability of the microtubule network to reduce cell motility. We therefore report a novel, non-transcriptional mechanism whereby GCs impair cell motility through inhibition of HDAC6 and rapid reorganization of the cell architecture

Entangled-State Cycles of Atomic Collective-Spin States

We study quantum trajectories of collective atomic spin states of $N$ effective two-level atoms driven with laser and cavity fields. We show that interesting ``entangled-state cycles'' arise probabilistically when the (Raman) transition rates between the two atomic levels are set equal. For odd (even) $N$, there are $(N+1)/2$ ($N/2$) possible cycles. During each cycle the $N$-qubit state switches, with each cavity photon emission, between the states $(|N/2,m>\pm |N/2,-m>)/\sqrt{2}$, where $|N/2,m>$ is a Dicke state in a rotated collective basis. The quantum number $m$ ($>0$), which distinguishes the particular cycle, is determined by the photon counting record and varies randomly from one trajectory to the next. For even $N$ it is also possible, under the same conditions, to prepare probabilistically (but in steady state) the Dicke state $|N/2,0>$, i.e., an $N$-qubit state with $N/2$ excitations, which is of particular interest in the context of multipartite entanglement.Comment: 10 pages, 9 figure

Nunalleq, Stories from the Village of Our Ancestors:Co-designing a multivocal educational resource based on an archaeological excavation

This work was funded by the UK-based Arts and Humanities Research Council through grants (AH/K006029/1) and (AH/R014523/1), a University of Aberdeen IKEC Award with additional support for travel and subsistence from the University of Dundee, DJCAD Research Committee RS2 project funding. Thank you to the many people who contributed their support, knowledge, feedback, voices and faces throughout the project, this list includes members of the local community, colleagues, specialists, students, and volunteers. If we have missed out any names we apologize but know that your help was appreciated. Jimmy Anaver, John Anderson, Alice Bailey, Kieran Baxter, Pauline Beebe, Ellinor Berggren, Dawn Biddison, Joshua Branstetter, Brendan Body, Lise Bos, Michael Broderick, Sarah Brown, Crystal Carter, Joseph Carter, Lucy Carter, Sally Carter, Ben Charles, Mary Church, Willard Church, Daniele Clementi, Annie Cleveland, Emily Cleveland, Joshua Cleveland, Aron Crowell, Neil Curtis, Angie Demma, Annie Don, Julia Farley, Veronique Forbes, Patti Fredericks, Tricia Gillam, Sean Gleason, Sven Haakanson, Cheryl Heitman, Grace Hill, Diana Hunter, Joel Isaak, Warren Jones, Stephan Jones, Ana Jorge, Solveig Junglas, Melia Knecht, Rick Knecht, Erika Larsen, Paul Ledger, Jonathan Lim Soon, Amber Lincoln, Steve Luke, Francis Lukezic, Eva Malvich, Pauline Matthews, Roy Mark, Edouard Masson-MacLean, Julie Masson-MacLean, Mhairi Maxwell, Chuna Mcintyre, Drew Michael, Amanda Mina, Anna Mossolova, Carl Nicolai Jr, Chris Niskanen, Molly Odell, Tom Paxton, Lauren Phillips, Lucy Qin, Charlie Roberts, Chris Rowe, Rufus Rowe,Chris Rowland, John Rundall, Melissa Shaginoff, Monica Shah, Anna Sloan, Darryl Small Jr, John Smith, Mike Smith, Joey Sparaga, Hannah Strehlau, Dora Strunk, Larissa Strunk, Lonny Strunk, Larry Strunk, Robbie Strunk, Sandra Toloczko, Richard Vanderhoek, the Qanirtuuq Incorporated Board, the Quinhagak Dance Group and the staff at Kuinerrarmiut Elitnaurviat. We also extend our thanks to three anonymous reviewers for their valuable comments on our paper.Peer reviewedPublisher PD