Publications by authors named "Michael Stevenson"

120 Publications

COVID-19: The regional impact of COVID-19 on the certification of vision impairment in Northern Ireland.

Ophthalmic Physiol Opt 2021 01 9;41(1):136-143. Epub 2020 Nov 9.

Department of Ophthalmology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, Northern Ireland.

Purpose: In this paper we highlight the impact which the disruption of secondary care ophthalmic services, resulting from COVID-19, has had on Sight Impairment (SI) and Severe Sight Impairment (SSI) certification in Northern Ireland.

Methods: Regional data on SI and SSI certification in the period after the onset of the lockdown (19 March 2020-18 June 2020) were compared to the period immediately before lockdown (1 January 2020-18 March 2020) and to the same periods in 2019. Change documented was compared to post-lockdown reductions in primary and secondary ophthalmic care activity.

Results: In 2019, during the 3-month period (19 March 2019-18 June 2019), 115 individuals were certified as sight impaired (SI 36, SSI 75, unspecified 4). Of those certified, 65 were female, 49 male. Principal causes of certification were: Age-related macular degeneration (AMD) (N = 45), glaucoma (N = 20) and diabetic eye disease (DED) (N = 10). Mean VA, recorded from the better eye of those certified, was 0.96 LogMAR. In the 3 months following the onset of lockdown (19 March 2020-18 June 2020), only 37 individuals were certified (SI 6, SSI 31), 12 female and 25 male. AMD was the most frequent cause of sight impairment (N = 20). There were only two DED certifications and one due to glaucoma. Mean VA in the better eye of those certified was 1.15LogMAR. The numbers of CVI certifications completed following the introduction of COVID-19 lockdown fell by 68%, compared to the 2019 data. There was a significant reduction in the proportion of female certifications (p = 0.01), and in certifications due to glaucoma (p = 0.02). The proportion of those certified as SSI as opposed to SI in the period after the onset of lockdown rose from 68% in 2019 to 84% in 2020. The mean VA of those certified in the period after the onset of lockdown, when compared to those certified in the other three periods, was worse by between 0.21 and 0.19 LogMAR (p = 0.06). Reductions reflected change in overall primary and secondary ophthalmic care activity.

Conclusions: It is inconceivable that COVID-19 has reduced the incidence of sight-threatening eye disease. We must therefore assume that a flood of newly presenting sight loss will present once the pandemic has passed. New presentations will include those who would normally have attended during the lockdown period, and patients who, had they accessed ophthalmic care at the appropriate time, would have been saved from severe levels of blindness. The implications of the predicted increase in demand for medical, social and low vision related services are huge.
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http://dx.doi.org/10.1111/opo.12757DOI Listing
January 2021

Public-private partnering as a modus operandi: Explaining the Gates Foundation's approach to global health governance.

Glob Public Health 2021 Mar 7;16(3):401-414. Epub 2020 Aug 7.

College of Liberal Arts, University of Minnesota Duluth, Duluth, MN, USA.

In its first decade, The Bill and Melinda Gates Foundation (BMGF) focused much of its efforts on enabling the establishment of transnational public-private partnerships (PPPs) oriented towards increasing low-income country (LIC) access to essential health technologies. Critics have argued these efforts further enriched already profitable firms which long ignored the needs of populations with limited purchasing power, while lessening political will to invest in urgently needed public sector capacity to produce essential health technologies independently of market pressures. Missing from these critical analyses were the perspectives of those shaping BMGF's global health programming. Drawing on interviews with senior BMGF staff and external affiliates undertaken between 2010 and 2012, this article seeks to address this gap. We argue that BMGF's embrace of PPPs was adopted out of the belief that neither public agencies nor industry were capable of providing LICs with essential health technologies autonomously, and that their conflicting mandates required an honest broker to initiate and sustain collaboration between the two sectors. The Foundation's comparative advantage in global health governance was thus seen by those informing its work, as its capacity to negotiate such partnerships, which we argue has also been the basis of its agenda-setting influence in this domain.
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http://dx.doi.org/10.1080/17441692.2020.1801790DOI Listing
March 2021

A situation analysis of the state of supply of in vitro diagnostics in Low-Income Countries.

Glob Public Health 2020 12 6;15(12):1836-1846. Epub 2020 Aug 6.

School of Public Health and Health Systems, University of Waterloo, Hamilton, Canada.

In vitro diagnostics (IVDs) are medical devices and accessories used to test bodily samples for causative agents of disease. IVDs play a central role in the diagnosis of individuals, in the rationale use of medicines, in burden of disease estimates, as well as in public health surveillance; especially for detection of emerging epidemics, the identification and monitoring of antimicrobial resistance, and the documentation of infection rates in populations. This article examines how the state of (a) product quality, (b) pricing, and (c) development country manufacturing capacity, are affecting the supply of IVDs in Low-Income Countries (LICs). Data informing this work is derived from interviews with representatives of leading stakeholder organisations working in this space, and analysis of secondary literature. The findings of this analysis are that the supply of IVDs in LICs is undermined by (i) significant variation in product quality; (ii) inconsistent market demand from governments; (iii) limited opportunities for pooled procurement; (iv) a lack of transparency and consistency in product pricing; and (v) insufficient competition among producers capable of innovating for populations with limited purchasing power and low-resource settings. The article then examines four strategies for how these challenges can be overcome.
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http://dx.doi.org/10.1080/17441692.2020.1801791DOI Listing
December 2020

Elucidation of a Copper Binding Site in Proinsulin C-peptide and Its Implications for Metal-Modulated Activity.

Inorg Chem 2020 Jul 8;59(13):9339-9349. Epub 2020 Jun 8.

Department of Chemistry, University of California, Davis, Davis, California 95616, United States.

The connecting peptide (C-peptide) is a hormone with promising health benefits in ameliorating diabetes-related complications, yet mechanisms remain elusive. Emerging studies point to a possible dependence of peptide activity on bioavailable metals, particularly Cu(II) and Zn(II). However, little is known about the chemical nature of the interactions, hindering advances in its therapeutic applications. This work uncovers the Cu(II)-binding site in C-peptide that may be key to understanding its metal-dependent function. A combination of spectroscopic studies reveal that Cu(II) and Zn(II) bind to C-peptide at specific residues in the N-terminal region of the peptide and that Cu(II) is able to displace Zn(II) for C-peptide binding. The data point to a Cu(II)-binding site consisting of 1N3O square-planar coordination that is entropically driven. Furthermore, the entire random coil peptide sequence is needed for specific metal binding as mutations and truncations reshuffle the coordinating residues. These results expand our understanding of how metals influence hormone activity and facilitate the discovery and validation of both new and established paradigms in peptide biology.
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http://dx.doi.org/10.1021/acs.inorgchem.0c01212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023225PMC
July 2020

The burden of familial chylomicronemia syndrome in Canadian patients.

Lipids Health Dis 2020 Jun 2;19(1):120. Epub 2020 Jun 2.

Lipids, Nutrition and Cardiovascular Prevention Clinic, Montreal Clinical Research Institute, 110 Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada.

Background: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by persistent extreme hypertriglyceridemia as a result of lipoprotein lipase deficiency. Canada is an important region for FCS research due to the high prevalence rates. The burden of illness and quality of life of Canadian patients, however, have been inadequately addressed in the literature.

Objective: To understand the burden of illness of FCS on Canadian patients' lives.

Methods: IN-FOCUS is a global web-based survey open to patients with FCS, including patients in Canada. This survey captured information on diagnostic experience, symptoms, comorbidities, disease management, and impact on multiple life dimensions.

Results: A total of 37 Canadian patients completed the IN-FOCUS survey. Patients saw a mean of 4 physicians before their FCS diagnosis despite 89% reporting an FCS family history. Patients experience multiple physical, emotional, and cognitive symptoms in addition to FCS-related comorbidities. Notably, 35% of those who answered the survey have experienced acute pancreatitis, averaging 14 lifetime episodes per patient. In the preceding 12 months, 46% of patients had an FCS-related hospitalization, averaging 3 nights' stay. All respondents restricted fat intake, with 27% following an extremely low-fat diet. Despite this, 100% of patients reported fasting TG levels above the normal range. FCS impacted career choice in nearly all patients (97%) and employment status in all patients who were employed part time, disabled, or homemakers, causing many (> 75%) to choose careers below their level of abilities. Furthermore, 2/3 of patients reported FCS had a significant impact on their decision regarding whether to have children. Most report significant interference with their emotional/mental well-being, social relationships, and the majority were concerned about the long-term impact of FCS on their health (89%).

Conclusions: This study provides the first and largest study to investigate the multi-faceted psychosocial and cognitive impacts of FCS on patients. Canadian patients with FCS experience significant multi-faceted burdens that diminish their quality of life, employment opportunities, social relationships, and mental/emotional well-being. These results highlight the need for greater disease awareness, improved clinical diagnosis, broader clinical management for heterogenous symptoms, and more effective treatment options for FCS.
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http://dx.doi.org/10.1186/s12944-020-01302-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268343PMC
June 2020

Profile of social self-management practices in daily life with Parkinson's disease is associated with symptom severity and health quality of life.

Disabil Rehabil 2020 Apr 1:1-13. Epub 2020 Apr 1.

The Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.

Social participation is a key determinant of healthy aging, yet little is known about how people with Parkinson's disease manage social living. This study describes individual differences in social self-management practices and their association with symptom severity and health quality of life. People with Parkinson's disease ( = 90) completed measures of healthy routines, activities and relationships, symptom severity, and health related quality of life. Cluster analysis identified profiles of social self-management practices. Analysis of variance tested differences between profiles in symptom severity and health quality of life. Participants clustered into one of seven groups according to different combinations of three practices: , , and . The healthiest cluster engaged equally in all three practices at above sample average degree of engagement. Four clusters that engaged at or above sample average in experienced less health problems than three clusters that engaged below average. Variation in aspects of social lifestyle unrelated to health appeared also to contribute to profile diversity. Findings provide insight into similarity and variation in how people with Parkinson's disease engage with social self-management resources and point to person-centered interventions.Implications for RehabilitationSocial self-management is a biopsychosocial construct to identify and describe self-care practices that engage one's social resources for managing healthful daily living.People with Parkinson's disease vary in their profiles of engaging in social self-management practices in daily living, and this variability relates to severity of symptoms and health quality of life.Learning how to identify health-centered social self-management practices may help people with Parkinson's disease to focus on the healthfulness of their own practices.Learning how to strategically engage one's social resources as part of self-care may help people with Parkinson's disease to master managing their health and well-being in daily life.
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http://dx.doi.org/10.1080/09638288.2020.1741035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529710PMC
April 2020

Ten-year outcomes following a cohort of ASR XL total hip arthroplasties.

Hip Int 2020 Apr 1:1120700020913863. Epub 2020 Apr 1.

Primary Joint Unit, Musgrave Park Hospital, Belfast, UK.

Aims: To determine the outcome at 10 years of a cohort of ASR XL total hip arthroplasties (THAs) and reasons for revision.

Methods: Between November 2005 and May 2007, 122 ASR XL THAs were implanted. All patients had a routine review at 6 weeks and 1 year, followed by a review in 2009 because of clinical concern and thereafter annual review up to 10 years with MRI. Review also included functional scores, radiographs, pain scores and blood metal ions.

Results: 67 (54.9%) ASR XLs had been revised by 11.1 years. Reasons for revision included pain (89.6%), high levels of cobalt and chromium ions (50.7%) and radiographic or MRI changes (80.6%). All 3 factors were present in 23 (34.3%). Pain at 1 year did not predict revision, but pain at the 2009 review did. At 10 years the revised patients had an average Oxford Hip Score (OHS) of 25.38 (12-42) and the non-revised 23.61 (2-21), the difference was not significant (  0.48). 3 patients (4.5%) have had a further revision; 2 for a previously unrevised stem and the other for instability.

Conclusions: Our arthroplasty care practitioner service allowed us to identify increased pain and stop using the ASR XL over 3 years before the implant was recalled. The revised patients had similar functional outcome to those unrevised. Poorly performing implants need to be identified earlier.
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http://dx.doi.org/10.1177/1120700020913863DOI Listing
April 2020

Observed effect of femoral component undersizing and a collarless design in the development of radiolucent lines in cementless total hip arthroplasty.

Arthroplast Today 2020 Mar 6;6(1):99-103. Epub 2020 Jan 6.

Musgrave Park Hospital, Belfast, Northern Ireland.

Background: The objective of this study was to determine the prevalence of radiolucent lines (RLLs) around the femoral component in a cohort of patients who underwent well-functioning cementless total hip arthroplasty (THA).

Methods: A cohort of unrevised Corail (DePuy Synthes, Raynham, MA) femoral components (n = 636) were analyzed at a median follow-up of 6.0 years (interquartile range: 5.2-6.8) with the Oxford Hip Score (OHS) and radiographs. Two independent observers assessed the radiographs for the presence of RLLs.

Results: The overall prevalence of RLLs in zone 7 was 13% (83/636). Patients with RLLs in zone 7 had an average OHS of 40.3 (15-48), and those who did not have RLLs in zone 7 had an average OHS of 38 (6-48),  = .07. Both groups had an average pain score of 1.6 out of 5,  = .5. The prevalence of RLLs in zone 7 was much less in the collared femoral components (2.6% prevalence) than in the collarless components (23.6% prevalence), but there was heterogeneity between these 2 groups preventing comparison. Logistic regression analysis of only the collarless components identified undersizing as the only predictive (odds ratio = 2.6) factor for RLL development in zone 7.

Conclusions: Undersizing the Corail stem is strongly predictive of developing RLLs in zone 7. Preoperative templating for the appropriate size is critical. We observed more RLLs in zone 7 with the collarless design Corail, but a comparison study with the same bearing couple is needed to investigate this further.
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http://dx.doi.org/10.1016/j.artd.2019.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083744PMC
March 2020

Non-inferiority randomised phase 3 trial comparing two radiation schedules (single vs. five fractions) in malignant spinal cord compression.

Br J Cancer 2020 04 11;122(9):1315-1323. Epub 2020 Mar 11.

SLRON, Dublin, Ireland.

Background: The optimal EBRT schedule for MSCC is undetermined. Our aim was to determine whether a single fraction (SF) was non-inferior to five daily fractions (5Fx), for functional motor outcome.

Methods: Patients not proceeding with surgical decompression in this multicentre non-inferiority, Phase 3 trial were randomised to 10 Gy/SF or 20 Gy/5Fx. A change in mobility from baseline to 5 weeks for each patient, was evaluated by a Modified Tomita score: 1 = 'Walk unaided', 2 = 'With walking aid' and 3 = 'Bed-bound'. The margin used to establish non-inferiority was a detrimental change of -0.4 in the mean difference between arms.

Results: One-hundred and twelve eligible patients were enrolled. Seventy-three patients aged 30-87 were evaluated for the primary analysis. The 95% CI for the difference in the mean change in mobility scores between arms was -0.12 to 0.6. Since -0.4 is not included in the interval, there is evidence that 10 Gy/SF is non-inferior to 20 Gy/5Fx. One grade 3 AE was reported in the 5Fx arm. Twelve (26%) patients in the 5Fx arm had a Grade 2-3 AE compared with six (11%) patients in the SF arm (p = 0.093).

Conclusion: For mobility preservation, one 10-Gy fraction is non-inferior to 20 Gy in five fractions, in patients with MSCC not proceeding with surgical decompression.

Clinical Trial Registration: Cancer Trials Ireland ICORG 05-03; NCT00968643; EU-20952.
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http://dx.doi.org/10.1038/s41416-020-0768-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188681PMC
April 2020

Intramolecular Electron Transfer Governs Photoinduced Hydrogen Evolution by Nickel-Substituted Rubredoxin: Resolving Elementary Steps in Solar Fuel Generation.

J Phys Chem B 2019 11 11;123(46):9792-9800. Epub 2019 Nov 11.

The Ohio State University , 100 W. 18th Avenue , Columbus , Ohio 43210 , United States.

The field of solar fuels is a rapidly growing area of research, though low overall efficiencies continue to preclude large-scale implementation. To resolve the elementary processes involved in light-driven energy storage and identify key factors contributing to efficiency losses, systematic investigation and optimization are necessary. In this work, a ruthenium chromophore is directly attached to a model hydrogenase enzyme, nickel-substituted rubredoxin, to construct a molecular system capable of photoinduced hydrogen evolution. Time-resolved absorption and emission spectroscopy reveal direct, rapid intramolecular electron transfer (ET) between the two metal centers to generate a charge-separated state that persists for ∼1 μs, though this species is not productive for hydrogen evolution. Investigation of the photochemical behavior under catalytic conditions in conjunction with thermochemical analyses suggests that ET to the catalytic nickel site from the reductively quenched ruthenium center is the rate-determining step. By eliminating the need for three components to diffuse together, direct mechanistic information about catalysis is obtained in a time-resolved manner. This approach is generalizable to study the activity and intramolecular charge transfer properties of a wide range of photosensitizers and catalysts, with applicability toward diverse energy conversion reactions.
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http://dx.doi.org/10.1021/acs.jpcb.9b08048DOI Listing
November 2019

Patient-reported outcomes in the RELIGHT clinical trial of ranibizumab in diabetic macular oedema.

BMJ Open Ophthalmol 2019 30;4(1):e000226. Epub 2019 Apr 30.

Departmentof Ophthalmology, Novartis Pharma UK, Frimley, UK.

Background/aims: The RELIGHT clinical trial used an individualised treatment regimen of ranibizumab to treat diabetic macular oedema (DMO). We report findings from two patient-reported outcome instruments.

Methods: The National Eye Institute Visual Function Questionnaire (NEI-VFQ) was administered before starting treatment (M0) and at M6, 12 and 18. The Macular Disease Society Treatment Satisfaction Questionnaire (MacTSQ) was administered 1 month after treatment start (M1) and at M6, 12 and 18. Relationships between best-corrected visual acuity (BCVA) in the study eye (SE) and the status of the eye at baseline (as better or worse eye by BCVA) and the two instrument measures were investigated.

Results: BCVA in the SE correlated strongly with the NEI-VFQ composite scores and the majority of the subscales but not with the MacTSQ subscales. Statistically significant improvements were observed in the majority of the subscales of the NEI-VFQ at M6, 12 and 18. For the MacTSQ, improvements between baseline M6, 12 and 18 were seen for subscale 1 but only reached statistical significance at M12. In subscale 2, the changes in mean scores were statistically significant at all timepoints.

Conclusions: Although ranibizumab treatment in DMO over an 18-month period resulted in improvements in visual functioning and patient satisfaction, no correlation was found between the instruments used to measure these outcomes. Our finding of a lack of correlation between BCVA and the MacTSQ suggests the presence of psychophysical factors not measured by traditional means.
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http://dx.doi.org/10.1136/bmjophth-2018-000226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6528749PMC
April 2019

Analysis of Metal Effects on C-Peptide Structure and Internalization.

Chembiochem 2019 10 9;20(19):2447-2453. Epub 2019 May 9.

Department of Chemistry, University of California, One Shields Avenue, Davis, CA, 95616, USA.

The connecting peptide (C-peptide) has received increased attention for its potential therapeutic effects in ameliorating illnesses such as kidney disease and diabetes. Although the mechanism of C-peptide signaling remains elusive, evidence supports its internalization and intracellular function. Emerging research is uncovering the diverse biological roles metals play in controlling and affecting the function of bioactive peptides. The work presented herein investigates interactions between C-peptide and first-row d-block transition metals, as well as their effects on C-peptide internalization into cells. Through spectroscopic techniques, it is demonstrated that Cr , Cu , and Zn bind to C-peptide with differing stoichiometries and biologically relevant affinities. In addition, metal binding elicits both subtle changes in secondary structure and inhibits adoption of an α-helical character in environments where the dielectric constants are reduced. This study shows how metal ions can modulate peptide hormone activity through subtle structural changes to disrupt cellular uptake.
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http://dx.doi.org/10.1002/cbic.201900172DOI Listing
October 2019

Tomographic Biomarkers Predicting Progression to Fibrosis in Treated Neovascular Age-Related Macular Degeneration: A Multimodal Imaging Study.

Ophthalmol Retina 2018 05 26;2(5):451-461. Epub 2017 Oct 26.

Ophthalmology Macular Service, Belfast Health and Social Care Trust and Centre for Population Health, Queen's University Belfast, Belfast, United Kingdom. Electronic address:

Purpose: To describe the photoreceptor-retinal pigment epithelium (RPE) interface changes and to analyze the relationships between these features and hyperreflective material (HRM) with scarring and atrophy at the macula of patients with neovascular age-related macular degeneration (nAMD).

Design: Retrospective single-center observational study.

Participants: A total of 150 eyes from 144 patients with naive nAMD were included.

Methods: All patients had OCT (HRA-OCT Spectralis, Heidelberg Engineering, Heidelberg, Germany) at baseline and at 1, 3, 6, and 12 months. Macular scar and macular atrophy (MA) were determined on multimodal imaging, including color fundus (CF) and near-infrared imaging at baseline and month 12 (M12).

Main Outcome Measures: Change in HRM type (undefined and well-defined) and location, development of fibrotic or nonfibrotic macular scar, MA, and best-corrected visual acuity (BCVA) at M12.

Results: At baseline, eyes with fibrin on CF had thicker and wider HRM on OCT that correlated strongly with presence of undefined HRM. The proportion of eyes with undefined HRM fell dramatically by month 1 but well-defined HRM increased. At M12 defined HRM was strongly associated with macular scar (chi-square, 82.1; P < 0.001). Ordinal regression showed that both the thickness and the width of HRM were significant risk factors for development of fibrotic scar (P < 0.001 and P = 0.02) but not nonfibrotic scars (P = 0.67 and P = 0.65). Fibrotic macular scar (P = 0.001) but not nonfibrotic scar (P = 0.129) negatively affected visual acuity at M12. Ordinal regression showed that the risk factors for progression to MA were reticular pseudodrusen and thinner HRM (P = 0.017 and P = 0.028, respectively). MA negatively affected BCVA at M12 (P < 0.001).

Conclusion: Our study supports the role of HRM as an important biomarker for the evolution of macular scar and atrophy in patients with nAMD undergoing treatment with anti-VEGF therapies. Undefined HRM can resolve with treatment, whereas well-defined HRM likely contains vascular complexes and fibrotic elements.
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http://dx.doi.org/10.1016/j.oret.2017.08.019DOI Listing
May 2018

Experienced facial masking indirectly compromises quality of life through stigmatization of women and men with Parkinson's disease.

Stigma Health 2019 ;4(4):462-472

Department of Occupational Therapy, Tufts University, 574 Boston Ave., Medford, MA 02155, USA.

This study examined the relationship between self-reported facial masking and quality of life (QoL) in people with Parkinson's disease (PD), and tested experienced stigma as a mediator and gender as a moderator of this relationship. The strength of stigma as a mediator was compared against an alternative mediator, depression. Ninety people with PD (34 women) rated difficulty showing facial expression (masking), and completed the Stigma Scale for Chronic Illness, Geriatric Depression Scale (15-item), and Parkinson's Disease Questionnaire-39. A conditional process model tested the indirect effect of facial masking on QoL through stigma, separately for women and men. A parallel indirect model included both stigma and depression to compare their statistical and clinical significance as mediators. Gender-moderated mediation of stigma reduced the association between facial masking and QoL to non-significance, suggesting stigma explained the association between facial masking and QoL. While facial masking was more stigmatizing for women than for men, stigma mediated the facial masking-QoL association for both women and men. Stigma (controlling for depression) reached a statistically and clinically significant level of mediation, whereas depression (controlling for stigma) reached a statistically yet not clinically significant level of mediation. People with PD who experience more severe facial masking feel more stigmatized, especially women. Regardless of gender, an increase in stigma from facial masking increases the likelihood of compromised QoL that reaches both statistical and clinical levels of significance.
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http://dx.doi.org/10.1037/sah0000168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678084PMC
January 2019

Metal-dependent hormone function: the emerging interdisciplinary field of metalloendocrinology.

Metallomics 2019 01;11(1):85-110

Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.

For over 100 years, there has been an incredible amount of knowledge amassed concerning hormones in the endocrine system and their central role in human health. Hormones represent a diverse group of biomolecules that are released by glands, communicate signals to their target tissue, and are regulated by feedback loops to maintain organism health. Many disease states, such as diabetes and reproductive disorders, stem from misregulation or dysfunction of hormones. Increasing research is illuminating the intricate roles of metal ions in the endocrine system where they may act advantageously in concert with hormones or deleteriously catalyze hormone-associated disease states. As the critical role of metal ions in the endocrine system becomes more apparent, it is increasingly important to untangle the complex mechanisms underlying the connections between inorganic biochemistry and hormone function to understand and control endocrinological phenomena. This tutorial review harmonizes the interdisciplinary fields of endocrinology and inorganic chemistry in the newly-termed field of "metalloendocrinology". We describe examples linking metals to both normal and aberrant hormone function with a focus on highlighting insight to molecular mechanisms. Hormone activities related to both essential metal micronutrients, such as copper, iron, zinc, and calcium, and disruptive nonessential metals, such as lead and cadmium are discussed.
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http://dx.doi.org/10.1039/c8mt00221eDOI Listing
January 2019

Calibration of confidence and assessed clinical skills competence in undergraduate paediatric OSCE scenarios: a mixed methods study.

BMC Med Educ 2018 Sep 17;18(1):211. Epub 2018 Sep 17.

Royal Belfast Hospital for Sick Children, 180-184 Falls Road, Belfast, BT12 6BE, UK.

Background: The relationship between confidence and competence in clinical skills development is complex but important. This study aims to determine undergraduate paediatric student confidence in performing three common paediatric clinical skills framed as Objective Structured Clinical Examination (OSCE) scenarios and to compare this with subsequent assessed performance. The study also aims to explore possible barriers to successful paediatric skills completion.

Methods: A mixed-methods study was conducted on medical students. Cross-sectional questionnaire data relating to confidence in performing a number of paediatric skills were compared with assessed paediatric skills competency. Focus groups were carried out to identify themes in paediatric skills completion to triangulate this data.

Results: Eighty-five medical students participated in the study. Students had high levels of pre-test confidence in their ability to perform paediatrics skills. However agreement between pre-test confidence and subsequent task performance was poor and students had significantly greater belief in their skills ability than was subsequently demonstrated. Focus groups identified paediatric skills complexity, conflicting teaching and having limited supervised skills opportunities and as being possible contributory factors to this discrepancy.

Conclusions: Student paediatric skills confidence is not matched by performance. The reasons for this are diverse but mostly modifiable. A major factor is the lack of supervised skills experience with appropriate feedback to support students in learning to calibrate their confidence against their competence. A number of recommendations are made including the introduction of formative assessment opportunities.
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http://dx.doi.org/10.1186/s12909-018-1318-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142704PMC
September 2018

The effect of volanesorsen treatment on the burden associated with familial chylomicronemia syndrome: the results of the ReFOCUS study.

Expert Rev Cardiovasc Ther 2018 Jul 22;16(7):537-546. Epub 2018 Jun 22.

b Akcea Therapeutics , Cambridge , MA , USA.

Background: Volanesorsen, an investigational inhibitor of apoC-III synthesis, significantly reduced triglyceride levels in clinical trials in patients with familial chylomicronemia syndrome (FCS), a rare genetic disorder characterized by marked chylomicronemia leading to a spectrum of symptoms, including recurrent abdominal pain and episodes of potentially fatal acute pancreatitis (AP).

Objective: To determine the effect of volanesorsen on burden of disease on patients with FCS Methods: ReFOCUS was a retrospective global web-based survey open to patients with FCS who received volanesorsen for ≥3 months in an open-label extension study. The survey included questions about patients' experiences before and after volanesorsen treatment.

Results: Twenty-two respondents had received volanesorsen for a median of 222 days. Volanesorsen significantly reduced the number of symptoms per patient across physical, emotional, and cognitive domains. Significant reductions from baseline were reported for steatorrhea, pancreatic pain, and constant worry about an attack of pain/AP. Respondents reported that volanesorsen improved overall management of symptoms and reduced interference of FCS with work/school responsibilities. Reductions in the negative impact of FCS on personal, social, and professional life were also reported.

Conclusions: Treatment with volanesorsen has the potential to reduce disease burden in patients with FCS through modulation of multiple symptom domains.
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http://dx.doi.org/10.1080/14779072.2018.1487290DOI Listing
July 2018

The burden of familial chylomicronemia syndrome: Results from the global IN-FOCUS study.

J Clin Lipidol 2018 Jul - Aug;12(4):898-907.e2. Epub 2018 Apr 26.

Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA, USA.

Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by a deficiency of lipoprotein lipase leading to extreme hypertriglyceridemia. Patients' burden of illness and quality of life have been poorly addressed in the literature.

Objective: To understand the ways in which FCS impacts patients' lives.

Methods: Investigation of Findings and Observations Captured in Burden of Illness Survey (IN-FOCUS) was a global web-based survey open to patients with FCS. Survey questions captured information on diagnostic experience, symptoms, comorbidities, disease management, and impact on multiple life dimensions.

Results: Of 166 patients in 10 countries, 62% were from the United States and 70% were male. Median age at the time of the survey was 33 years, and median age at diagnosis was 9 years. Patients saw a mean of 5 physicians from different specialties before their FCS diagnosis and experienced multiple physical, emotional, and cognitive symptoms on a daily to monthly basis; 40% were admitted to the hospital in the past year. A lifetime mean of 13 episodes occurred in the 40% of patients with FCS-related acute pancreatitis. Most patients (>90%) found managing fat intake to be difficult, and 53% experienced symptoms despite adherence to their diets. FCS impacted employment status (94%), emotional/mental well-being (58%-66%), and social relationships (68%-82%).

Conclusions: Patients with FCS experience significant clinical and psychosocial burdens that reduce their quality of life and limit employment and social interactions. Increased awareness among healthcare professionals of the multifaceted nature of the FCS disease burden may help expedite diagnosis and timely institution of treatment and broaden management considerations.
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http://dx.doi.org/10.1016/j.jacl.2018.04.009DOI Listing
October 2019

A photoactive semisynthetic metalloenzyme exhibits complete selectivity for CO reduction in water.

Chem Commun (Camb) 2018 May;54(37):4681-4684

Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210, USA.

A series of artificial metalloenzymes containing a ruthenium chromophore and [NiII(cyclam)]2+, both incorporated site-selectively, have been constructed within an azurin protein scaffold. These light-driven, semisynthetic enzymes do not evolve hydrogen, thus displaying complete selectivity for CO2 reduction to CO. Electrostatic effects rather than direct excited-state electron transfer dominate the ruthenium photophysics, suggesting that intramolecular electron transfer from photogenerated RuI to [NiII(cyclam)]2+ represents the first step in catalysis. Stern-Volmer analyses rationalize the observation that ascorbate is the only sacrificial electron donor that supports turnover. Collectively, these results highlight the important interplay of elements that must be considered when developing and characterizing molecular catalysts.
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http://dx.doi.org/10.1039/c8cc01297kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934327PMC
May 2018

A retrospective study of radiation dose measurements comparing different cath lab X-ray systems in a sample population of patients undergoing percutaneous coronary intervention for chronic total occlusions.

Catheter Cardiovasc Interv 2018 09 7;92(3):E254-E261. Epub 2018 Feb 7.

Department of Cardiology, Belfast Health and Social Care Trust, c/o Level 9, Belfast City Hospital, Lisburn Road, Belfast, BT9 7AB, Northern, Ireland.

Objectives: A retrospective study was performed to investigate if the generation of X-ray system used was an independent factor for radiation dose in chronic total occlusion (CTO) percutaneous coronary intervention (PCI).

Background: PCI procedures for CTOs are known to be associated with higher doses of radiation. The authors suspected progressive reductions in radiation doses for CTO PCI as newer X-ray systems were introduced into clinical practice.

Methods: Procedures performed over a five-year period by three interventional cardiologists were retrospectively reviewed. Five different X-ray systems were used across three hospital sites. These included: Axiom Artis and Coroskop HIP (both Siemens), Innova (GE), Allura Xper FD 10, and Allura Clarity FD 10 (both Philips). Procedural and demographic data including body mass index (BMI; kg/m ), fluoroscopy time (min), and dose area product (DAP; cGycm ) were collated for each procedure. Statistical analysis was performed to compare the influence each X-ray system would have on DAP values after BMI and fluoroscopy time were controlled for.

Results: In total, 860 procedures were analyzed. Mean fluoroscopy time was 40.00 ± 19.99 min, mean BMI was 29.90 ± 5.13 kg/m , mean DAP 11,980 ± 7,947 cGycm . Log values of DAP were used to normalize results in a general linear model. A significant statistical difference in DAP between X-ray systems was demonstrated after fluoroscopy time and BMI were controlled for (P ≤ 0.001).

Conclusion: There is a significant impact on DAP values resulting from the generation of X-ray system used, measured during PCI for CTOs, with the most modern systems producing the lowest radiation doses.
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http://dx.doi.org/10.1002/ccd.27541DOI Listing
September 2018

Sounding Out Dysfunctional Oxygen Metabolism: A Small-Molecule Probe for Photoacoustic Imaging of Hypoxia.

Biochemistry 2018 02 24;57(6):893-894. Epub 2018 Jan 24.

Department of Chemistry, University of California, Davis , One Shields Avenue, Davis, California 95616, United States.

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http://dx.doi.org/10.1021/acs.biochem.8b00011DOI Listing
February 2018

Disorganization of Inner Retina and Outer Retinal Morphology in Diabetic Macular Edema.

JAMA Ophthalmol 2018 02;136(2):202-208

Queens University, Belfast, United Kingdom.

Importance: In diabetic macular edema (DME), identification of baseline markers on spectral-domain optical coherence tomography (SD-OCT) and their association with severity of diabetic retinopathy (DR) might aid in disease management and the design of future trials.

Objective: To examine associations between DR severity, retinal morphology on SD-OCT, and visual acuity in participants with DME.

Design, Setting, And Participants: This cross-sectional observational case series was conducted at a single tertiary care referral center. Demographics, visual acuity, SD-OCT, and color fundus photographs of 80 individuals with DME (102 eyes) seen between December 28, 2013, and April 30, 2014, were analyzed between May 1 and July 31, 2016.

Main Outcomes And Measures: Features captured on SD-OCT and thickness metrics. On SD-OCT we graded type and shape of DME, shape and presence of septae within the intraretinal cystoid abnormalities, presence of hyperreflective dots and foci, integrity of the external limiting membrane and ellipsoid zone, presence and extent of disorganization of the inner retinal layers (DRIL), and the status of the vitreomacular interface and epiretinal membrane. We measured retinal thickness at the fovea and at the site of maximum pathology, choroidal thickness at the fovea, and 1000 μm temporal and nasal to the fovea. Color photographs were graded to derive a DR severity stage.

Results: The mean (SD) age was 63 (11) years, and 30 participants (37.5%) were women. The odds of having DRIL were greater in eyes with disrupted external limiting membrane (odds ratio [OR], 4.4; 95% CI, 1.6-12.0; P = .003), disrupted ellipsoid zone (OR, 2.7; 95% CI, 1.0-7.2; P = .03), presence of epiretinal membrane (OR, 2.8; 95% CI, 1.0-7.4; P = .03), and increase in retinal thickness at the fovea (OR, 1.6; 95% CI, 1.1-2.2; P < .001). Occurrence of DRIL was more likely in eyes with proliferative DR (OR, 7.3; 95% CI, 1.7-31.4; P = .007). Mean visual acuity decreased by approximately 4.7 letters for each 100-μm increase in the average global DRIL (95% CI, -7.9 to 1.4; P = .006).

Conclusions And Relevance: An association was found between DRIL and disruption of the outer retina and increasing DR severity. Further longitudinal studies seem warranted to determine whether DRIL is a clinically relevant noninvasive morphological marker in eyes with DME.
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http://dx.doi.org/10.1001/jamaophthalmol.2017.6256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838716PMC
February 2018

Light-Driven Hydrogen Evolution by Nickel-Substituted Rubredoxin.

ChemSusChem 2017 11 25;10(22):4424-4429. Epub 2017 Oct 25.

Department of Chemistry and Biochemistry, The Ohio State University, 100 W. 18th Street, Columbus, OH, 43210, USA.

An enzymatic system for light-driven hydrogen generation has been developed through covalent attachment of a ruthenium chromophore to nickel-substituted rubredoxin (NiRd). The photoinduced activity of the hybrid enzyme is significantly greater than that of a two-component system and is strongly dependent on the position of the ruthenium phototrigger relative to the active site, indicating a role for intramolecular electron transfer in catalysis. Steady-state and time-resolved emission spectra reveal a pathway for rapid, direct quenching of the ruthenium excited state by nickel, but low overall turnover numbers suggest initial electron transfer is not the rate-limiting step. This approach is ideally suited for detailed mechanistic investigations of catalysis by NiRd and other molecular systems, with implications for generation of solar fuels.
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http://dx.doi.org/10.1002/cssc.201701627DOI Listing
November 2017

Immune signatures of pathogenesis in the peritoneal compartment during early infection of sheep with Fasciola hepatica.

Sci Rep 2017 06 5;7(1):2782. Epub 2017 Jun 5.

School of Biological Sciences, Medical Biology Centre, Queen's University of Belfast, Belfast, Northern Ireland, UK.

Immune signatures of sheep acutely-infected with Fasciola hepatica, an important pathogen of livestock and humans were analysed within the peritoneal compartment to investigate early infection. Within the peritoneum, F. hepatica antibodies coincided with an intense innate and adaptive cellular immune response, with infiltrating leukocytes and a marked eosinophilia (49%). However, while cytokine qPCR analysis revealed IL-10, IL-12, IL-13, IL-23 and TGFβ were elevated, these were not statistically different at 18 days post-infection compared to uninfected animals indicating that the immune response is muted and not yet skewed to a Th2 type response that is associated with chronic disease. Proteomic analysis of the peritoneal fluid identified infection-related proteins, including several structural proteins derived from the liver extracellular matrix, connective tissue and epithelium, and proteins related to the immune system. Periostin and vascular cell adhesion protein 1 (VCAM-1), molecules that mediate leukocyte infiltration and are associated with inflammatory disorders involving marked eosinophilia (e.g. asthma), were particularly elevated in the peritoneum. Immuno-histochemical studies indicated that the source of periostin and VCAM-1 was the inflamed sheep liver tissue. This study has revealed previously unknown aspects of the immunology and pathogenesis associated with acute fascioliasis in the peritoneum and liver.
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http://dx.doi.org/10.1038/s41598-017-03094-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459796PMC
June 2017

Analysis of weekend effect on 30-day mortality among patients with acute myocardial infarction.

Open Heart 2017;4(1):e000504. Epub 2017 Feb 24.

Department of Cardiology, Belfast HSC Trust, Belfast, Northern Ireland.

Objectives: Several publications have demonstrated increased 30-day mortality in patients admitted on Saturdays or Sundays compared with weekdays. We sought to determine whether this was true for two different cohorts of patients admitted with acute myocardial infarction (MI).

Methods And Results: Thirty-day mortality data were obtained for 3757 patients who had been admitted to the Belfast Health and Social Care Trust with acute MI between 2009 and 2015. They were subdivided into those presenting with ST elevation MI (n=2240) and non-ST elevation MI (n= 1517). We observed no excess 30-day mortality in those admitted over weekends.

Conclusion: Excess mortality in patients admitted at weekends is not a universal finding. This may mean that that there are patient subgroups with proportionately greater weekend hazard and points to the need for more detailed understanding of the weekend effect.
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http://dx.doi.org/10.1136/openhrt-2016-000504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384461PMC
February 2017

The burden of familial chylomicronemia syndrome: interim results from the IN-FOCUS study.

Expert Rev Cardiovasc Ther 2017 May 4;15(5):415-423. Epub 2017 Apr 4.

e Department of Medicine, Division of Endocrinology and Metabolism , University of California San Diego , La Jolla , CA , USA.

Background: Familial Chylomicronemia Syndrome (FCS) is a rare genetic disorder that is caused by a decrease or an absence of lipoprotein lipase activity. FCS is characterized by marked accumulation of chylomicrons and extreme hypertriglyceridemia, which have major effects on both physical and mental health. To date, there have been no systematic efforts to characterize the impact of chylomicronemia on FCS patients' lives. In particular, the impact of FCS on the burden of illness (BoI) and quality of life (QoL) has not been fully described in the literature.

Methods: IN-FOCUS was a comprehensive web-based research survey of patients with FCS focused on capturing the BoI and impact on QoL associated with FCS. Sixty patients from the US diagnosed with FCS participated. Patients described multiple symptoms spanning across physical, emotional and cognitive domains.

Results: Patients on average cycled through 5 physicians of varying specialty before being diagnosed with FCS, reflecting a lengthy journey to diagnosis Nearly all respondents indicated that FCS had a major impact on BoI and QoL and significantly influenced their career choice and employment status, and caused significant work loss due to their disease.

Conclusion: FCS imparts a considerable burden across multiple domains with reported impairment on activities of daily living and QoL.
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http://dx.doi.org/10.1080/14779072.2017.1311786DOI Listing
May 2017

Structural and Biochemical Characterization of Organotin and Organolead Compounds Binding to the Organomercurial Lyase MerB Provide New Insights into Its Mechanism of Carbon-Metal Bond Cleavage.

J Am Chem Soc 2017 01 3;139(2):910-921. Epub 2017 Jan 3.

Département de Biochimie et Médicine Moléculaire, Université de Montréal , Montréal, Quebec H3C 3J7 Canada.

The organomercurial lyase MerB has the unique ability to cleave carbon-Hg bonds, and structural studies indicate that three residues in the active site (C96, D99, and C159 in E. coli MerB) play important roles in the carbon-Hg bond cleavage. However, the role of each residue in carbon-metal bond cleavage has not been well-defined. To do so, we have structurally and biophysically characterized the interaction of MerB with a series of organotin and organolead compounds. Studies with two known inhibitors of MerB, dimethyltin (DMT) and triethyltin (TET), reveal that they inhibit by different mechanisms. In both cases the initial binding is to D99, but DMT subsequently binds to C96, which induces a conformation change in the active site. In contrast, diethyltin (DET) is a substrate for MerB and the Sn product remains bound in the active site in a coordination similar to that of Hg following cleavage of organomercurial compounds. The results with analogous organolead compounds are similar in that trimethyllead (TML) is not cleaved and binds only to D99, whereas diethyllead (DEL) is a substrate and the Pb product remains bound in the active site. Binding and cleavage is an exothermic reaction, while binding to D99 has negligible net heat flow. These results show that initial binding of organometallic compounds to MerB occurs at D99 followed, in some cases, by cleavage and loss of the organic moieties and binding of the metal ion product to C96, D99, and C159. The N-terminus of MerA is able to extract the bound Pb but not the bound Sn. These results suggest that MerB could be utilized for bioremediation applications, but certain organolead and organotin compounds may present an obstacle by inhibiting the enzyme.
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http://dx.doi.org/10.1021/jacs.6b11327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040655PMC
January 2017

Time-limited home-care reablement services for maintaining and improving the functional independence of older adults.

Cochrane Database Syst Rev 2016 Oct 11;10:CD010825. Epub 2016 Oct 11.

Maynooth University Department of Psychology, National University of Ireland Maynooth, Maynooth, Co Kildare, Ireland.

Background: Reablement, also known as restorative care, is one possible approach to home-care services for older adults at risk of functional decline. Unlike traditional home-care services, reablement is frequently time-limited (usually six to 12 weeks) and aims to maximise independence by offering an intensive multidisciplinary, person-centred and goal-directed intervention.

Objectives: To assess the effects of time-limited home-care reablement services (up to 12 weeks) for maintaining and improving the functional independence of older adults (aged 65 years or more) when compared to usual home-care or wait-list control group.

Search Methods: We searched the following databases with no language restrictions during April to June 2015: the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (OvidSP); Embase (OvidSP); PsycINFO (OvidSP); ERIC; Sociological Abstracts; ProQuest Dissertations and Theses; CINAHL (EBSCOhost); SIGLE (OpenGrey); AgeLine and Social Care Online. We also searched the reference lists of relevant studies and reviews as well as contacting authors in the field.

Selection Criteria: We included randomised controlled trials (RCTs), cluster randomised or quasi-randomised trials of time-limited reablement services for older adults (aged 65 years or more) delivered in their home; and incorporated a usual home-care or wait-list control group.

Data Collection And Analysis: Two authors independently assessed studies for inclusion, extracted data, assessed the risk of bias of individual studies and considered quality of the evidence using GRADE. We contacted study authors for additional information where needed.

Main Results: Two studies, comparing reablement with usual home-care services with 811 participants, met our eligibility criteria for inclusion; we also identified three potentially eligible studies, but findings were not yet available. One included study was conducted in Western Australia with 750 participants (mean age 82.29 years). The second study was conducted in Norway (61 participants; mean age 79 years).We are very uncertain as to the effects of reablement compared with usual care as the evidence was of very low quality for all of the outcomes reported. The main findings were as follows.Functional status: very low quality evidence suggested that reablement may be slightly more effective than usual care in improving function at nine to 12 months (lower scores reflect greater independence; standardised mean difference (SMD) -0.30; 95% confidence interval (CI) -0.53 to -0.06; 2 studies with 249 participants).Adverse events: reablement may make little or no difference to mortality at 12 months' follow-up (RR 0.97; 95% CI 0.74 to 1.29; 2 studies with 811 participants) or rates of unplanned hospital admission at 24 months (RR 0.94; 95% CI 0.85 to 1.03; 1 study with 750 participants).The very low quality evidence also means we are uncertain whether reablement may influence quality of life (SMD -0.23; 95% CI -0.48 to 0.02; 2 trials with 249 participants) or living arrangements (RR 0.92, 95% CI 0.62 to 1.34; 1 study with 750 participants) at time points up to 12 months. People receiving reablement may be slightly less likely to have been approved for a higher level of personal care than people receiving usual care over the 24 months' follow-up (RR 0.87; 95% CI 0.77 to 0.98; 1 trial, 750 participants). Similarly, although there may be a small reduction in total aggregated home and healthcare costs over the 24-month follow-up (reablement: AUD 19,888; usual care: AUD 22,757; 1 trial with 750 participants), we are uncertain about the size and importance of these effects as the results were based on very low quality evidence.Neither study reported user satisfaction with the service.

Authors' Conclusions: There is considerable uncertainty regarding the effects of reablement as the evidence was of very low quality according to our GRADE ratings. Therefore, the effectiveness of reablement services cannot be supported or refuted until more robust evidence becomes available. There is an urgent need for high quality trials across different health and social care systems due to the increasingly high profile of reablement services in policy and practice in several countries.
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http://dx.doi.org/10.1002/14651858.CD010825.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457975PMC
October 2016

Building a better understanding of the burden of disease in familial chylomicronemia syndrome.

Expert Rev Clin Pharmacol 2017 Jan 8;10(1):1-3. Epub 2016 Nov 8.

b Akcea Therapeutics , MA , USA.

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http://dx.doi.org/10.1080/17512433.2017.1251839DOI Listing
January 2017