95 research outputs found
Achieving the "triple aim" for inborn errors of metabolism: a review of challenges to outcomes research and presentation of a new practice-based evidence framework
Across all areas of health care, decision makers are in pursuit of what
Berwick and colleagues have called the âtriple aimâ: improving patient
experiences with care, improving health outcomes, and managing
health system impacts. This is challenging in a rare disease context, as
exemplified by inborn errors of metabolism. There is a need for evaluative
outcomes research to support effective and appropriate care for
inborn errors of metabolism. We suggest that such research should
consider interventions at both the level of the health system (e.g., early
detection through newborn screening, programs to provide access to
treatments) and the level of individual patient care (e.g., orphan drugs,
medical foods). We have developed a practice-
based evidence framework
to guide outcomes research for inborn errors of metabolism.
Focusing on outcomes across the triple aim, this framework integrates
three priority themes: tailoring care in the context of clinical heterogeneity;
a shift from âurgent careâ to âopportunity for improvementâ;
and the need to evaluate the comparative effectiveness of emerging
and established therapies. Guided by the framework, a new Canadian
research network has been established to generate knowledge that will
inform the design and delivery of health services for patients with
inborn errors of metabolism and other rare diseases.This work was supported by a CIHR Emerging Team Grant (âEmerging
team in rare diseases: acheiving the âtriple aimâ for inborn errors
of metabolism,â B.K. Potter, P. Chakraborty, and colleagues, 2012â
2017, grant no. TR3â119195). Current investigators and collaborators
in the Canadian Inherited Metabolic Diseases Research Network
are: B.K. Potter, P. Chakraborty, J. Kronick, D. Coyle, K. Wilson, M.
Brownell, R. Casey, A. Chan, S. Dyack, L. Dodds, A. Feigenbaum, D.
Fell, M. Geraghty, C. Greenberg, S. Grosse, A. Guttmann, A. Khan,
J. Little, B. Maranda, J. MacKenzie, A. Mhanni, F. Miller, G. Mitchell,
J. Mitchell, M. Nakhla, M. Potter, C. Prasad, K. Siriwardena, K.N.
Speechley, S. Stocker, L. Turner, H. Vallance, and B.J. Wilson. Members
of our external advisory board are D. Bidulka, T. Caulfield, J.T.R.
Clarke, C. Doiron, K. El Emam, J. Evans, A. Kemper, W. McCormack,
and A. Stephenson Julian. J. Little is supported by a Canada Research
Chair in Human Genome Epidemiology. K. Wilson is supported by a
Canada Research Chair in Public Health Policy
Genome-wide <i>in vivo</i> screen identifies novel host regulators of metastatic colonisation
Metastasis is the leading cause of death for cancer patients. This multi-stage process requires tumour cells to survive in the circulation, extravasate at distant sites, then proliferate; it involves contributions from both the tumour cell and tumour microenvironment ('host', which includes stromal cells and the immune system). Studies suggest the early steps of the metastatic process are relatively efficient, with the post-extravasation regulation of tumour growth ('colonization') being critical in determining metastatic outcome. Here we show the results of screening 810 mutant mouse lines using an in vivo assay to identify microenvironmental regulators of metastatic colonization. We identify 23 genes that, when disrupted in mouse, modify the ability of tumour cells to establish metastatic foci, with 19 of these genes not previously demonstrated to play a role in host control of metastasis. The largest reduction in pulmonary metastasis was observed in sphingosine-1-phosphate (S1P) transporter spinster homologue 2 (Spns2)-deficient mice. We demonstrate a novel outcome of S1P-mediated regulation of lymphocyte trafficking, whereby deletion of Spns2, either globally or in a lymphatic endothelial-specific manner, creates a circulating lymphopenia and a higher percentage of effector T cells and natural killer (NK) cells present in the lung. This allows for potent tumour cell killing, and an overall decreased metastatic burden.status: publishe
International Consensus Statement on Rhinology and Allergy: Rhinosinusitis
Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICARâRS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICARâRSâ2021 as well as updates to the original 140 topics. This executive summary consolidates the evidenceâbased findings of the document. Methods: ICARâRS presents over 180 topics in the forms of evidenceâbased reviews with recommendations (EBRRs), evidenceâbased reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICARâRSâ2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidenceâbased management algorithm is provided. Conclusion: This ICARâRSâ2021 executive summary provides a compilation of the evidenceâbased recommendations for medical and surgical treatment of the most common forms of RS
Search for gravitational waves associated with gamma-ray bursts detected by Fermi and Swift during the LIGOâVirgo run O3b
We search for gravitational-wave signals associated with gamma-ray bursts (GRBs) detected by the Fermi and Swift satellites during the second half of the third observing run of Advanced LIGO and Advanced Virgo (2019 November 1 15:00 UTCâ2020 March 27 17:00 UTC). We conduct two independent searches: a generic gravitational-wave transients search to analyze 86 GRBs and an analysis to target binary mergers with at least one neutron star as short GRB progenitors for 17 events. We find no significant evidence for gravitational-wave signals associated with any of these GRBs. A weighted binomial test of the combined results finds no evidence for subthreshold gravitational-wave signals associated with this GRB ensemble either. We use several source types and signal morphologies during the searches, resulting in lower bounds on the estimated distance to each GRB. Finally, we constrain the population of low-luminosity short GRBs using results from the first to the third observing runs of Advanced LIGO and Advanced Virgo. The resulting population is in accordance with the local binary neutron star merger rate
Evaluation of appendicitis risk prediction models in adults with suspected appendicitis
Background
Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis.
Methods
A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16â45âyears presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis).
Results
Some 5345 patients across 154 UK hospitals were identified, of which twoâthirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; Pâ<â0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cutâoff score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cutâoff score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent).
Conclusion
Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decisionâmaking by identifying adults in the UK at low risk of appendicitis were identified
A reappraisal of ventilatory thresholds in wheelchair athletes with a spinal cord injury: do they really exist?
The ventilatory threshold (VT) separates low- from moderate-intensity exercise, the respiratory compensation point(RCP) moderate- from high-intensity exercise. Both concepts assume breakpoints in respiratory data. However, the objective determination of the VT and RCP using breakpoint models during upper-body modality exercise in wheelchair athletes with spinal cord injury has received little attention. Therefore, the aim of this study was to compare the fit of breakpoint models (i.e., two linear regression lines) with continuous no-breakpoint models (i.e., exponential curve/ 2nd order polynomial) to respiratory data obtained during a graded wheelchair exercise test to exhaustion. These fits were compared employing adjusted R2, and blocked bootstrapping was used to derive estimates of a median and 95% confidence intervals (CI). VÌO2-VÌCO2 and VÌE/VÌO2-time data were assessed for the determination of the VT, and VÌCO2-VÌE and VÌE/VÌCO2-time data for the determination of the RCP. Data of 9 wheelchair athletes with tetraplegia and 8 with paraplegia were evaluated. On an overall group-level, there was an overlap in the adjusted R2 median ± 95% CI between the breakpoint and the no-breakpoint models for determining the VT (VÌO2-VÌCO2: 0.991±0.003 vs 0.990±0.003; VÌE/VÌO2-time: 0.792±0.1019 vs 0.782±0.104, respectively) and RCP (VÌE-VÌCO2: 0.984±0.004 vs 0.984±0.004; VÌE/VÌCO2-time: 0.729±0.064 vs 0.691±0.063, respectively), indicating similar model fit. We offer two lines of reasoning: 1) breakpoints in these respiratory data exist but are too subtle to result in a significant difference in adjusted R2 between the investigated breakpoint and no-breakpoint models; 2) breakpoints do not exist, as has been argued previously. respectively) and RCT (VÌE/VÌCO2: 0.968±0.011 vs 0.967±0.011; VÌCO2-VÌE: 0.393±0.114 vs 0.408±0.111, respectively), indicating similar model fit. We offer two lines of reasoning: 1) breakpoints in these respiratory data exist, but are too subtle to result in a significant difference in adjusted R2 between the investigated breakpoint and no-breakpoint models; 2) breakpoints do not exist, as has been argued previously
Contemporary Dental Ceramics
Dental ceramics were increasingly introduced to restorative dentistry at the beginning of the XX century as porcelain jacket crowns. However, their limited use in clinical practice was mainly associated to the mechanical shortcomings. In the early sixties porcelain-fused to-metal restorations were developed and for years have represented the âgold standardâ, thanks to their good mechanical properties and to somewhat satisfactory esthetics. In the last thirty years, the growing demand for highly esthetic restorations has led to development of new all-ceramic materials and techniques. All-ceramic restorations combine esthetic veneering porcelains (consisting of a glass and a crystalline phase of fluoroapatite, aluminum oxide, or leucite) with strong ceramic cores, mainly made of lithium-disilicate, aluminum-oxide or zirconium-oxide. The most common complication is fracture that can initiate from several different sites on the surface, at interfaces, or within the material. While conventional methods of ceramic fabrication usually contain internal porosity, CAD/CAM technology ensures almost no internal defects. Such improvements in ceramic processing have allowed better structural reliability and greatly contributed to the success of all-ceramic systems. The aim of this study was to provide an overview on development of ceramic systems used in dentistry, their processing, including computer-aided design and computer-aided (CAD/CAM) technology, applications and future perspectives in this field
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