Characterizing Molecular Modifiers of Pathogenesis in Spinobulbar Muscular Atrophy.

Spinobulbar muscular atrophy (SBMA), or Kennedy’s disease, is an inherited neuromuscular disorder caused by a polyglutamine (polyQ) tract expansion in the androgen receptor (AR). This mutation initiates misfolding and aggregation of AR, eliciting toxicity in motor neurons, progressive weakness, and muscle atrophy. PolyQ expansion also compromises the transactivation function of AR in response to androgens, resulting in androgen insensitivity. Although considerable progress has been made in characterizing molecular consequences of the polyQ mutation in SBMA, many aspects of pathogenesis, and in particular the cellular processes that modify disease development, remain incompletely understood. Based on previous work suggesting a pathogenic role of autophagy in SBMA, I use cellular and mouse models to delineate the state of autophagy in SBMA. I show that autophagy is induced in SBMA cells and diseased tissues, and that this is due to depressed mTOR activity. These changes correlate with activity of the transcription factors TFEB and ZKSCAN3, which coordinate expression of autophagy-related genes in SBMA mice and human patients. Furthermore, these alterations in autophagy regulators lead to enhanced responsiveness to stimulation by nutrient deprivation and exercise. These results indicate that dysregulated transcriptional programming promotes induction of autophagy in SBMA and provide evidence for targeting autophagy for therapeutic inhibition. Given the previously established role of small ubiquitin-like modifier (SUMO) on AR function, I characterize a novel knock-in mouse model of SBMA to address the influence of SUMO on SBMA pathogenesis. We introduce mutations that prevent SUMOylation of polyQ AR (AR113Q-KRKR) and demonstrate that, despite unaltered androgen insensitivity and neuromuscular pathology, AR113Q-KRKR mice display a striking extension of lifespan and recovery of exercise tolerance. Complementary expression analysis of the non-SUMOylatable polyQ AR reveals substantial expansion of the receptor’s transactivation activity. These findings suggest that abrogating SUMO modification of polyQ AR mediates amelioration of the SBMA phenotype, in part by improving skeletal muscle physiology. Additionally, these studies not only reveal new insights in the comparative roles of polyQ AR toxicity versus loss of function in affected tissues, but they also establish the benefits of enhancing AR function in SBMA for therapeutic design.PHDNeuroscienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/111409/1/jaschua_1.pd

Quantifying speech intelligibility based on crowdsourcing

The intelligibility of speech within media content, e.g., audio or video streams, is an important factor that determines the reach and popularity of the media. Objective measures of audio and speech quality, e.g., PESQ and SII scores, correlate poorly with human assessment. MOS, a widely accepted intelligibility test, is subjective, expensive, and time consuming. Techniques disclosed herein provide an objective measure of the intelligibility of speech within video or audio content. Speech intelligibility scores are calculated based on the edit distance between human speech transcriptions of short clips and transcripts produced by an automatic speech recognizer. The speech intelligibility score is based on human rating and retains objectivity

Translating policy into practice for community-based management of rheumatoid arthritis: Targeting professional development needs among physiotherapists.

Introduction: Contemporary health policy promotes delivery of community-based health services to people with musculoskeletal conditions, including rheumatoid arthritis (RA). This emphasis requires a skilled workforce to deliver safe, effective care. We aimed to explore physiotherapy workforce readiness to co-manage consumers with RA by determining the RA-specific professional development (PD) needs in relation to work and educational characteristics of physiotherapists in Western Australia (WA). Methods. An e-survey was sent to physiotherapists regarding their confidence in co-managing people with RA and their PD needs. Data including years of clinical experience, current RA clinical caseload, professional qualifications, and primary clinical area of practice were collected. Results. 273 physiotherapists completed the survey. Overall confidence in managing people with RA was low (22.7–58.2%) and need for PD was high (45.1–95.2%). Physiotherapists with greater years of clinical experience, a caseload of consumers with RA, postgraduate qualifications in musculoskeletal physiotherapy, or who worked in the musculoskeletal area were more confident in managing people with RA and less likely to need PD. Online and face-to-face formats were preferred modes of PD delivery. Discussion. To enable community-based RA service delivery to be effectively established, subgroups within the current physiotherapy workforce require upskilling in the evidence-based management of consumers with RA

The elemental mechanism of transcriptional pausing.

Transcriptional pausing underlies regulation of cellular RNA biogenesis. A consensus pause sequence that acts on RNA polymerases (RNAPs) from bacteria to mammals halts RNAP in an elemental paused state from which longer-lived pauses can arise. Although the structural foundations of pauses prolonged by backtracking or nascent RNA hairpins are recognized, the fundamental mechanism of the elemental pause is less well-defined. Here we report a mechanistic dissection that establishes the elemental pause signal (i) is multipartite; (ii) causes a modest conformational shift that puts γ-proteobacterial RNAP in an off-pathway state in which template base loading but not RNA translocation is inhibited; and (iii) allows RNAP to enter pretranslocated and one-base-pair backtracked states easily even though the half-translocated state observed in paused cryo-EM structures rate-limits pause escape. Our findings provide a mechanistic basis for the elemental pause and a framework to understand how pausing is modulated by sequence, cellular conditions, and regulators

Bridging the gap between evidence and what people value from osteoarthritis care in New Zealand using multi-criteria decision analysis (MCDA)

International clinical practice guidelines (CPG) for osteoarthritis (OA) consistently recommend core management strategies of exercise, weight-loss and self-management education. However, these interventions are not routinely delivered or taken up by people experiencing OA, resulting in a tendency to deliver low-value care. Tailoring the delivery of recommended OA care to the preferences of stakeholders in a health system may help support greater implementation of high-value OA care. However, little is known about the preferences of stakeholders for evidence and recommendations for OA care in a CPG. The aim of this research was to establish a framework to prioritise knee interventions for managing OA and evaluate the relative importance of these interventions across the healthcare sector in New Zealand (NZ) using multi-criteria decision analysis (MCDA). This research used a mixed-methods approach to develop the MCDA framework. The first stage involved focus group discussions to generate a thematic framework of what OA consumers, health care providers, policy-makers, Māori representatives and OA experts consider in their choice of knee OA interventions. A Delphi survey was used to verify the thematic analysis and rank the most important criteria concerning the characteristics of interventions; these findings informed the criteria selected in the second stage. In the second stage, interventions were indirectly prioritised by systematically combining preference data with intervention performance data on the criteria. First, a survey involving trade-offs was used to measure stakeholders’ preferences, represented as ‘weights’, within and between the criteria. Evidence for the performance of 15 recommended knee OA interventions were then extracted from a CPG for hip and knee OA, and rated on the criteria according to their level of achievement (e.g. high, medium, low). To prioritise the interventions, a total score for each intervention was calculated by summing the weights associated with the intervention ratings, after which they were ranked by importance. Associations between the weights and stakeholder groups were explored using regression analysis. Thematic analysis of data from six focus groups produced a framework comprising three overarching categories, consisting of characteristics of the: (i) intervention, (ii) consumer and (iii) health system. Participants identified and ranked nine characteristics of interventions; the most important eight were included in the MCDA framework. The choice-based survey revealed that stakeholders valued the intervention characteristics, in decreasing order of importance (weight): Recommendation (19.0%), Quality of evidence (17.7%), Effectiveness (15.0%), Duration of effect (13.2%), Risk of serious harm (12.8%), Risk of mild side-effects (9.4%), Cost (6.6%) and Accessibility (6.3%). Total scores for the 15 guideline-recommended interventions revealed that for first-, second- and third-line OA care respectively, all land-based exercise (total score= 71.7%), NSAIDs (topical) (74.2%) and total joint replacement (74.3%) were ranked first. For first-, second- and third-line OA care, the recommended core interventions of weight management and self-management education ranked between 11th and 15th (48.0% to 56.0%). Regression analysis identified only small differences in weights (≤5.7%; p<0.01) between stakeholder groups. These findings suggest that stakeholders’ preferences for the core interventions of weight management and self-management education represent a system-wide barrier to their implementation. This research addresses an important knowledge gap concerning cross-sectoral stakeholders’ preferences for knee OA interventions in a CPG. By inclusively, systematically and transparently incorporating what matters to people with evidence and recommendations in a CPG, the MCDA framework developed in this thesis can help support the design of patient-centred, high-value healthcare for people experiencing OA

Policy Brief 01.1/2020

Working draft - 2020 ANZMUSC Annual Scientific Meeting, 12 February, Wellington, New Zealand. Abbott JH. Policy Discussion: Recommendations for public health policy resulting from the HRC-funded project “The impact and management of rising osteoarthritis burden”. OA SIG Breakfast Meeting, 2020 ANZMUSC Annual Scientific Meeting, 12 February, Wellington, New Zealand.Osteoarthritis (OA) is a leading cause of health losses and costs in NZ. The burden of OA is rising as a result of population ageing, rising obesity, increasing injury rates, and earlier onset of disease. The New Zealand health system, already struggling to meet demand for joint replacement surgeries, will be placed under greater pressure by rising rates of OA

ICIS 2017 Panel Report: Break Your Shackles! Emancipating Information Systems from the Tyranny of Peer Review

The paper presents the report of a panel that debated the review process in the information systems (IS) discipline at ICIS 2017 in Seoul, Korea. The panel asked the fundamental question of whether we need to rethink the way we review papers in the discipline. The panelists partnered with the audience to explore some reviewing limitations in IS today and the ways that reviewing in the discipline might change to address some of its difficulties. We first report key concerns with modern reviewing. We then present arguments for and against three proposals (i.e., paying for reviews, mandatory reviews, and open reviews) and a panel audience vote on the issues. We neither advocate for nor condemn these solutions but rather use them to illustrate what we believe represent the core underlying issues with reviewing in the IS discipline. Specifically, we believe the key stumbling blocks to effectively improving our review process include 1) a lack of empirical data on actual practice, 2) a lack of clear goals, and 3) an ignorance of the possible solutions to the review dilemma that the wider literature articulates

A cross-sectional study on the burden and impact of migraine on work productivity and quality of life in selected workplaces in the Philippines

Background Migraine imposes a substantial personal and economic burden to many working age individuals. This study aimed to evaluate the burden and impact of migraine on work productivity in selected workplaces in the Philippines. Methods A cross-sectional survey was conducted among employees suspected or diagnosed with migraine February to May 2020. Volunteer employees were screened for migraine using the ID-Migraine™ test. Eligible employees were tested for migraine severity and impact on work productivity using the Migraine Disability Assessment (MIDAS) questionnaire. Quality of life was measured using the Short Form-36 (SF-36) questionnaire and additional questions on triggers, coping mechanisms, workplace assistance, and health care utilization were asked. Multiple logistic regression was used to identify significant predictors of migraine disability (high – MIDAS Grade III/IV vs. low – MIDAS Grade I/II). Differences in quality of life scores by migraine disability were measured using multiple linear regression. Productivity costs lost to migraine disability were calculated as the number of days lost to migraine multiplied by the self-reported wage rate, and costs according to migraine severity were measured using a two-part generalized linear model. Results From around 24,000 employees who were invited to participate in the survey, 954 respondents provided consent and attempted to respond to the survey resulting to a response rate of around 4.1%. A total of 511 positive migraine screens were included in the final sample. Females comprised two-thirds of all positive migraine screens and were more likely to have high migraine disability (odds ratio: 1.60, 95% CI: 1.03–2.49) than males. Those with high migraine disability scored lower on role limitations compared to those with low migraine disability. Stress and looking at computer screens were cited as the top trigger for migraine, while sleeping enough hours and getting a massage were cited as top coping mechanisms. Three in four (77%) visited their company clinic within the past 3 months, which meant that most doctors seen for migraine-related symptoms were general practitioners. Five in six (85%) took medication for migraine, almost all of which were over-the-counter medications. Mean annual productivity costs lost due to migraine disability were PHP27 794 (USD556) per person. Conclusion Migraine poses a significant threat to work productivity in the Philippines. Many opportunities, such as disease management and introduction of alternative options for migraine treatment, may be introduced to help address these issues. Introduction Migraine is a neurological disorder recognized as one of the leading causes of disability in the world, estimated to impact anywhere between one in ten [1] and one in six individuals [2]. While several population-level studies on migraine have been conducted in the past few years, there remain countries with little information on the burden of migraine, specifically in the Asia-Pacific region [2]. A systematic review and meta-analysis on chronic migraine found only seven population-level studies in the Asia-Pacific region estimating chronic migraine prevalence to be approximately 6–17 people per 1000 population [3]. In the Philippines, the last known national-level migraine prevalence survey was in 2003, which found that 7.9% of the population screened positive for migraine [4]. However, in 2017, the Institute for Health Metrics and Evaluation (IHME) reports that headache disorders which include migraine has a prevalence estimate of about 17.3% [5]. Migraine is associated with significant impact on daily living, such as work, school, and personal activities [6]. Migraine patients consistently report poorer quality of life scores than healthy individuals on aspects of physical well-being, while chronic migraine patients consistently report poorer quality of life scores than episodic migraine patients on aspects of emotional well-being [7]. Additionally, the expectation of worry on the next migraine attack is in itself negatively affecting work productivity and quality of life [8]. Sex and age are significantly associated with migraine burden, with females at least twice as likely to report having migraine [1] and working-age individuals more likely to report having migraine than younger or older individuals [9]. This implies that migraine poses a significant economic burden and various studies in the past have tried to quantify the economic impacts of migraine. The European Eurolight project estimated that more than 90% of economic losses associated with migraine were attributable to indirect costs such as sick days and reduced work productivity as compared to less than 10% of direct costs such as medicines and outpatient consultation [10]. A systematic review from the United States found that on average around 2 to 3 workdays per month were lost due to migraine, with women reporting twice more workdays affected than men [11]. A Malaysian study found similar results with mean days affected by migraine being 5.6 days over the past 3 months among banking sector employees, with monetary losses potentially reaching as much as USD3000 annually for those with the most severe forms of migraine [12]. In a literature search, this was the only published study found to present data on the burden of migraine in the Asia Pacific region. Given this, the present study assessed the burden and impact of migraine and work productivity and daily activities in selected workplaces in the Philippines. Focusing on those having migraine, this study explored the migraine patient journey regarding the frequency and severity of migraine attacks, triggers in the workplace, workplace assistance programs, availability and utilization of health care services, and quality of life. Finally, this study also measured monetary estimates on lost productivity

LC-MS/MS-based metabolites of Eurycoma longifolia (Tongkat Ali) in Malaysia (Perak and Pahang).

A number of three LC–MS/MS hybrid systems (QTof, TripleTof and QTrap) has been used to profile small metabolites (m/z 100–1000) and to detect the targeted metabolites such as quassinoids, alkaloids, triterpene and biphenylneolignans from the aqueous extracts of Eurycoma longifolia. The metabolite profiles of small molecules showed four significant clusters in the principle component analysis for the aqueous extracts of E. longifolia, which had been collected from different geographical terrains (Perak and Pahang) and processed at different extraction temperatures (35 °C and 100 °C). A small peptide of leucine (m/z 679) and a new hydroxyl methyl β-carboline propionic acid have been identified to differentiate E. longifolia extracts that prepared at 35 °C and 100 °C, respectively. From the targeted metabolites identification, it was found that 3,4ɛ-dihydroeurycomanone (quassinoids) and eurylene (squalene-type triterpene) could only be detected in the Pahang extract, whereas canthin-6-one-3N-oxide could only be detected in the Perak extract. Overall, quassinoids were present in the highest concentration, particularly eurycomanone and its derivatives compared to the other groups of metabolites. However, the concentration of canthin-6-one and β-carboline alkaloids was significantly increased when the roots of the plant samples were extracted at 100 °C