Quantitative Susceptibility Mapping of Ring Lesions in Relapsing Remitting Multiple Sclerosis

Introduction: Our project evaluates the presence of and changes in susceptibility and volume of ring lesions (RLs) over a two-year time period in a series of relapsing remitting MS (RRMS) subjects, and identifies and quantifies any other parameters that correlated with EDSS score. Methods: All subjects went through 3T MR imaging at baseline and 41 subjects underwent a maximum of two follow-up scans. The imaging protocol included T2 fluid attenuated inversion recovery (FLAIR), T1-weighted imaging acquired pre and post contrast, T2-weighted turbo spin-echo (T2 TSE) and susceptibility weighted imaging (SWI) sequences, all collected in a transverse mode. SWI, FLAIR, T1- and T2-weighted images were co-registered to verify the agreement of ring lesions across all modalities. The mean and peak susceptibilities of RLs on QSM data, lesion volume on FLAIR, RL volume on T2-weighted, and inner-/outer-diameters and absolute intensity value of RLs on T2-weighted data were recorded at all available time points. Results: Quantity of ring lesions had a positive correlation with EDSS, yet lesion volume showed no such relationship. Measurements of both the entire annular ring and its section with peak susceptibility on QSM remained constant over time. On the other hand, the FLAIR lesion volume was positively correlated with EDSS. Conclusions: This work does a comprehensive analysis of ring lesions by evaluating FLAIR, QSM and T2 data across 43 patients and over multiple time points. Since several parameters regarding RL characteristics having remained relatively constant, lesion evolution at the ring periphery may be a very slow process

Comparison of Convective Overshooting Models and Their Impact on Abundances from Integrated Light Spectroscopy of Young (<< 3 Gyr) Star Clusters

As part of an ongoing program to measure detailed chemical abundances in nearby galaxies, we use a sample of young to intermediate age clusters in the Large Magellanic Cloud with ages of 10 Myr to 2 Gyr to evaluate the effect of isochrone parameters, specifically core convective overshooting, on Fe abundance results from high resolution, integrated light spectroscopy. In this work we also obtain fiducial Fe abundances from high resolution spectroscopy of the cluster individual member stars. We compare the Fe abundance results for the individual stars to the results from isochrones and integrated light spectroscopy to determine whether isochrones with convective overshooting should be used in our integrated light analysis of young to intermediate age (10 Myr -3 Gyr) star clusters. We find that when using the isochrones from the Teramo group, we obtain more accurate results for young and intermediate age clusters over the entire age range when using isochrones without convective overshooting. While convective overshooting is not the only uncertain aspect of stellar evolution, it is one of the most readily parametrized ingredients in stellar evolution models, and thus important to evaluate for the specific models used in our integrated light analysis. This work demonstrates that our method for integrated light spectroscopy of star clusters can provide unique tests for future constraints on stellar evolution models of young and intermediate age clusters.Comment: 16 pages, accepted for publication in Ap

Evaluating the Clinical Feasibility of an Artificial Intelligence-Powered, Web-Based Clinical Decision Support System for the Treatment of Depression in Adults: Longitudinal Feasibility Study.

BACKGROUND: Approximately two-thirds of patients with major depressive disorder do not achieve remission during their first treatment. There has been increasing interest in the use of digital, artificial intelligence-powered clinical decision support systems (CDSSs) to assist physicians in their treatment selection and management, improving the personalization and use of best practices such as measurement-based care. Previous literature shows that for digital mental health tools to be successful, the tool must be easy for patients and physicians to use and feasible within existing clinical workflows. OBJECTIVE: This study aims to examine the feasibility of an artificial intelligence-powered CDSS, which combines the operationalized 2016 Canadian Network for Mood and Anxiety Treatments guidelines with a neural network-based individualized treatment remission prediction. METHODS: Owing to the COVID-19 pandemic, the study was adapted to be completed entirely remotely. A total of 7 physicians recruited outpatients diagnosed with major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. Patients completed a minimum of one visit without the CDSS (baseline) and 2 subsequent visits where the CDSS was used by the physician (visits 1 and 2). The primary outcome of interest was change in appointment length after the introduction of the CDSS as a proxy for feasibility. Feasibility and acceptability data were collected through self-report questionnaires and semistructured interviews. RESULTS: Data were collected between January and November 2020. A total of 17 patients were enrolled in the study; of the 17 patients, 14 (82%) completed the study. There was no significant difference in appointment length between visits (introduction of the tool did not increase appointment length; F2,24=0.805; mean squared error 58.08; P=.46). In total, 92% (12/13) of patients and 71% (5/7) of physicians felt that the tool was easy to use; 62% (8/13) of patients and 71% (5/7) of physicians rated that they trusted the CDSS. Of the 13 patients, 6 (46%) felt that the patient-clinician relationship significantly or somewhat improved, whereas 7 (54%) felt that it did not change. CONCLUSIONS: Our findings confirm that the integration of the tool does not significantly increase appointment length and suggest that the CDSS is easy to use and may have positive effects on the patient-physician relationship for some patients. The CDSS is feasible and ready for effectiveness studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT04061642; http://clinicaltrials.gov/ct2/show/NCT04061642

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Influenza-A Viruses in Ducks in Northwestern Minnesota: Fine Scale Spatial and Temporal Variation in Prevalence and Subtype Diversity

Waterfowl from northwestern Minnesota were sampled by cloacal swabbing for Avian Influenza Virus (AIV) from July – October in 2007 and 2008. AIV was detected in 222 (9.1%) of 2,441 ducks in 2007 and in 438 (17.9%) of 2,452 ducks in 2008. Prevalence of AIV peaked in late summer. We detected 27 AIV subtypes during 2007 and 31 during 2008. Ten hemagglutinin (HA) subtypes were detected each year (i.e., H1, 3–8, and 10–12 during 2007; H1-8, 10 and 11 during 2008). All neuraminidase (NA) subtypes were detected during each year of the study. Subtype diversity varied between years and increased with prevalence into September. Predominant subtypes during 2007 (comprising ≥5% of subtype diversity) included H1N1, H3N6, H3N8, H4N6, H7N3, H10N7, and H11N9. Predominant subtypes during 2008 included H3N6, H3N8, H4N6, H4N8, H6N1, and H10N7. Additionally, within each HA subtype, the same predominant HA/NA subtype combinations were detected each year and included H1N1, H3N8, H4N6, H5N2, H6N1, H7N3, H8N4, H10N7, and H11N9. The H2N3 and H12N5 viruses also predominated within the H2 and H12 subtypes, respectively, but only were detected during a single year (H2 and H12 viruses were not detected during 2007 and 2008, respectively). Mallards were the predominant species sampled (63.7% of the total), and 531 AIV were isolated from this species (80.5% of the total isolates). Mallard data collected during both years adequately described the observed temporal and spatial prevalence from the total sample and also adequately represented subtype diversity. Juvenile mallards also were adequate in describing the temporal and spatial prevalence of AIV as well as subtype diversity

Validation of the Transition Readiness and Appropriateness Measure (TRAM) for the Managing the Link and Strengthening Transition from Child to Adult Mental Healthcare in Europe (MILESTONE) study

OBJECTIVE:Young people moving from child and adolescent mental health services (CAMHS) to adult mental health services (AMHS) are faced with significant challenges. To improve this state of affairs, there needs to be a recognition of the problem and initiatives and an urgent requirement for appropriate tools for measuring readiness and outcomes at the transfer boundary (16-18 years of age in Europe). The objective of this study was to develop and validate the Transition Readiness and Appropriateness Measure (TRAM) for assessing a young person's readiness for transition, and their outcomes at the transfer boundary. DESIGN:MILESTONE prospective study. SETTING:Eight European Union (EU) countries participating in the EU-funded MILESTONE study. PARTICIPANTS:The first phase (MILESTONE validation study) involved 100 adolescents (pre-transition), young adults (post-transition), parents/carers and both CAMHS and AMHS clinicians. The second phase (MILESTONE cohort study and nested cluster randomised trial) involved over 1000 young people. RESULTS:The development of the TRAM began with a literature review on transitioning and a review of important items regarding transition by a panel of 34 mental health experts. A list of 64 items of potential importance were identified, which together comprised the TRAM. The psychometric properties of the different versions of the TRAM were evaluated and showed that the TRAM had good reliability for all versions and low-to-moderate correlations when compared with other established instruments and a well-defined factor structure. The main results of the cohort study with the nested cluster randomised trial are not reported. CONCLUSION:The TRAM is a reliable instrument for assessing transition readiness and appropriateness. It highlighted the barriers to a successful transition and informed clinicians, identifying areas which clinicians on both sides of the transfer boundary can work on to ease the transition for the young person. TRIAL REGISTRATION NUMBER:ISRCTN83240263 (Registered 23 July 2015), NCT03013595 (Registered 6 January 2017); Pre-results

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART) : a multicentre, prospective, randomised, open-label, blinded-endpoint trial

Funding Information: ISM reports research grants from Menarini, EMA, Sanofi, Health Data Research UK, the British Heart Foundation, and Innovative Medicines Initiative; institutional consultancy income from AstraZeneca outside the submitted work; and personal income from AstraZeneca and Amgen outside the submitted work. TMM reports grants from Menarini/Ipsen/Teijin and Merck Sharp & Dohme outside the submitted work, and personal income for consultancy from Novartis and AstraZeneca outside the submitted work, and is a trustee of the Scottish Heart Arterial Risk Prevention Society. AGB reports personal income from Novartis, Mylan, AstraZeneca, Bayer, Daiichi-Sankyo, Boehringer, Pfizer, Galderma, Zambon, and Novo-Nordisk outside the submitted work. ADS and the University of Dundee hold a European patent for the use of xanthine oxidase inhibitors in treating chest pain in angina pectoris. AW declares personal income for consultancy from AbbVie, Akcea, Albireo, Alexion, Allergan, Amarin, Apsara, Arena, Astellas, AstraZeneca, Autolus, Bayer, Biocryst, Biogen, Biomarin, Bristol Myers Squibb, Boehringer Ingelheim, Calico, Celgene, Chiesi, Daiichi Sankyo, Diurnal, Elsai, Eli Lilly, Ferring, Galapagos, Gedeon Richter, Gilead, GlaxoSmithKline, GW Pharma, Idorsia, Incyte, Intercept, Ionis, Ipsen, Janssen, Jazz, Jcyte, Kite Gilead, LEK, Leo Pharma, Les Laboratoires Servier, Lundbeck, Merck (Merck Sharp & Dohme), Merck-Serono, Mitenyi, Mundibiopharma, Mustang Bio, Mylan, Myovant, Norgine, Novartis, Novo Nordisk, Orchard, Paion, Pfizer, Pierre Fabre, PTC, RegenXBio, Rhythm, Sanofi, Santen, Sarepta, SeaGen, Shionogi, Sigmatec, SOBI, Takeda, Tanaya, UCB, and Vertex outside the submitted work. JST declares research funding from the UK National Institute for Health and Care Research (NIHR) and NHS England outside the submitted work and membership of a UK National Institute for Health and Care Excellence guideline committee on management of atrial fibrillation. All other authors declare no competing interests. Funding Information: This study was funded by the NIHR Health Technology Assessment programme (HTA 11/36/41 to ISM, IF, CJH, LW, ADS, AGB, AJA, AW, JST, and TMM). The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care. The study was supported by the Scottish Primary Care Research Network, Support for Science Scotland (Grampian, Highlands, Tayside, Fife, Forth Valley, Greater Glasgow and Clyde, Lothian, Ayrshire and Arran, Dumfries and Galloway, and Lanarkshire), and the NIHR Local Clinical Research Networks (East Midlands, West Midlands, Eastern, North Thames, Yorkshire and Humber, North East and North Cumbria, North West Coast, Kent, Surrey and Sussex, and South West Peninsula), which assisted with recruitment and other study activities. We thank Public Health Scotland and NHS Digital for providing data linkage. We thank all the participants, physicians, nurses, and other staff who participated in the ALL-HEART study. Funding Information: This study was funded by the NIHR Health Technology Assessment programme (HTA 11/36/41 to ISM, IF, CJH, LW, ADS, AGB, AJA, AW, JST, and TMM). The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care. The study was supported by the Scottish Primary Care Research Network, Support for Science Scotland (Grampian, Highlands, Tayside, Fife, Forth Valley, Greater Glasgow and Clyde, Lothian, Ayrshire and Arran, Dumfries and Galloway, and Lanarkshire), and the NIHR Local Clinical Research Networks (East Midlands, West Midlands, Eastern, North Thames, Yorkshire and Humber, North East and North Cumbria, North West Coast, Kent, Surrey and Sussex, and South West Peninsula), which assisted with recruitment and other study activities. We thank Public Health Scotland and NHS Digital for providing data linkage. We thank all the participants, physicians, nurses, and other staff who participated in the ALL-HEART study. Publisher Copyright: © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licensePeer reviewedPublisher PD

International Health Security: A Summative Assessment by ACAIM Consensus Group

International health security (IHS) encompasses any natural or anthropogenic occurrence that can threaten the safety of human health and well-being. The American College of Academic International Medicine IHS Consensus Group (ACAIM-CG) developed a summative assessment highlighting the main issues that can impact IHS including emerging infectious diseases; chronic health conditions; bioterrorism; planetary changes (volcanic eruptions, earthquakes, wildfires, and climate change); nuclear incidents; information and cyber health; industrialization; globalization; pharmaceutical production; and communication platforms (social media). These concerns can directly and indirectly impact IHS both in the long and short term. When considering IHS, we aim to emphasize the utility of applying a predefined framework to effectively approach health security threats. This framework comprises of prevention, detection, assessment, reporting, response, addressing needs, and the perpetual repetition of the above cycle (inclusive of appropriate mitigation measures). It is hoped that this collective work will provide a foundation for further research within the redefined, expanded scope of IHS

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial

BACKGROUND: Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. METHODS: ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. FINDINGS: Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89–1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87–1·20], p=0·77). INTERPRETATION: In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. FUNDING: UK National Institute for Health and Care Research