"You Take This Day by Day, Come What May": A Qualitative Study of the Psychosocial Impacts of Living with Duchenne Muscular Dystrophy.

INTRODUCTION: Studies have reported health-related quality-of-life impacts of Duchenne muscular dystrophy (DMD); however, further research is needed to understand how those with DMD experience their condition and how psychosocial impacts evolve over time in response to disease progression. This qualitative study explores the social and emotional implications of key transitions, challenges and adaptations throughout the disease course from the perspective of patients and family caregivers. METHODS: Semi-structured interviews were conducted with men and boys with DMD, and/or their caregivers, in the USA. Thematic analysis was used to examine patterns in data collected across the interviews. RESULTS: Nineteen participants were included. Three major themes were identified: (1) barriers to participation are multifaceted; (2) an emotional journey shaped by 'inevitable progression;' (3) family provides critical tangible and emotional support. This study illustrates that psychosocial impacts of DMD are shaped by knowledge of the condition's natural history alongside other factors including the extent of social barriers, personal growth and adaptation, and family support. CONCLUSIONS: Findings provide insight into the strength and resilience with which individuals and their families respond to daily challenges and major clinical milestones and highlight the relative importance of loss of upper limb function as a transition in DMD affecting health-related quality-of-life.

Toenail Onychomycosis with or without Diabetes in Canada: Patient Treatment Preferences and Health State Utilities.

Background: Toenail onychomycosis affects approximately 6.7% of Canadians. Symptoms include nail discolouration/disfiguration and pain; psychosocial impacts contribute to reduced health-related quality-of-life. Comorbid diabetes increases the risk of complications and exacerbates burden. Treatment may include topical therapy and/or oral agents. Purpose: To understand toenail onychomycosis treatment preferences, and to quantify the impact of toenail onychomycosis, with or without diabetes, on patient well-being. Methods: Adults living in Canada with self-reported, physician-diagnosed, toenail onychomycosis were recruited online. A discrete choice experiment was used to quantify treatment preferences. Scenarios were randomized; data were analyzed using conditional logit regression. Health state utilities were estimated using the Health Utilities Index Mark 3®. Results were stratified by diabetes status and toenail onychomycosis severity; the Wilcoxon Rank Sum test was used to assess between-group utility differences. Results: Three-hundred thirteen participants with toenail onychomycosis were included (161 had comorbid diabetes; 61.3%, severe onychomycosis). The mean age was 57.7 years; 55.9% were male. Treatment attributes with statistically significant impacts on patient preferences were efficacy (odds ratio [OR],1.04; 95% confidence interval [CI], 1.02-1.05 per 1% increased treatment success), administration method (one pill versus topical nail lacquer reference, 1.14; 1.04-1.26; topical solution applicator versus reference: 1.15; 1.03-1.29), severe adverse events (0.85; 0.80-0.90 per 1% increased risk), and risk of potential pharmacodynamic (0.80; 0.76-0.85) and alcohol (0.93; 0.88-0.98) interactions; preferences were more pronounced for efficacy and avoiding severe adverse events among toenail onychomycosis patients with comorbid diabetes. The mean (95% CI) utility value was 0.73 (0.70-0.75) overall, and statistically significantly lower (p=0.02) for toenail onychomycosis patients with diabetes (0.70; CI, 0.66-0.73) than those without (0.76; CI, 0.72-0.79). Conclusion: Among patients with toenail onychomycosis, the presence of diabetes was associated with differing treatment-related preferences. Utility values for patients with toenail onychomycosis represent a significant decline from full health that is exacerbated by comorbid diabetes.

The impact of genotype on outcomes in individuals with Duchenne muscular dystrophy: A systematic review.

Duchenne muscular dystrophy (DMD) is associated with progressive muscle weakness, loss of ambulation (LOA), and early mortality. In this review we have synthesized published data on the clinical course of DMD by genotype. Using a systematic search implemented in Medline and Embase, 53 articles were identified that describe the clinical course of DMD, with pathogenic variants categorizable by exon skip or stop-codon readthrough amenability and outcomes presented by age. Outcomes described included those related to ambulatory, cardiac, pulmonary, or cognitive function. Estimates of the mean (95% confidence interval) age at LOA ranged from 9.1 (8.7-9.6) years among 90 patients amenable to skipping exon 53 to 11.5 (9.5-13.5) years among three patients amenable to skipping exon 8. Although function worsened with age, the impact of genotype was less clear for other outcomes (eg, forced vital capacity and left ventricular ejection fraction). Understanding the distribution of pathogenic variants is important for studies in DMD, as this research suggests major differences in the natural history of disease. In addition, specific details of the use of key medications, including corticosteroids, antisense oligonucleotides, and cardiac medications, should be reported.

Preferences and Health-Related Quality-of-Life Related to Disease and Treatment Features for Patients with Hemophilia A in a Canadian General Population Sample.

BACKGROUND: Current treatments for hemophilia A in Canada include on-demand treatment as bleeds occur and regular intravenous prophylactic factor VIII (FVIII) infusions. The subcutaneous therapy emicizumab was recently approved for treatment of hemophilia A. The objective of this study was to estimate utility values associated with hemophilia A health and treatment states from a Canadian societal perspective, including preferences related to treatment efficacy and frequency and route of administration. METHODS: A vignette-based time trade-off (TTO) utilities elicitation was undertaken in Canadian adults to compare preferences for six hemophilia health states describing prophylactic and on-demand treatment, with varying bleed rates and frequency of treatment administration. A convenience sample was recruited via market research panels and snowball sampling. Health state/vignette definitions were informed by clinical experience, clinical trial results regarding bleed frequency, and validated by qualitative interviews of hemophilia patients and caregivers (n=10). Utilities were estimated via an online, trained interviewer-guided, vignette-based TTO exercise, where respondents valuated health states describing hemophilia patients (adults or children) receiving subcutaneous prophylaxis, intravenous prophylaxis, and on-demand treatments. Analyses included a descriptive analysis by health state; a mixed-effects analysis of utility values adjusted for subcutaneous vs infusion-based therapies and number of bleeds; and for prophylactic regimens, an analysis of utilities by frequency of infusions or injections. RESULTS: TTO interviews were conducted with 82 respondents. Mean utilities [95% CI] were highest for subcutaneous prophylaxis (0.90 [0.87-0.93]), followed by intravenous prophylaxis (0.81 [0.78-0.85]), and on-demand treatment (0.70 [0.65-0.76]). In regression analysis, subcutaneous treatment health states were associated with a utility increment of +0.1112. Additional bleeds and more frequent infusions were associated with lower utility values (-0.0027 per bleed and -0.0003 per infusion). CONCLUSION: Subcutaneous prophylaxis is associated with higher utility values compared to intravenous prophylactic and on-demand treatment, while increased bleeds and infusions are associated with reduced utility.

Comparative Safety and Efficacy of Treatments for Overactive Bladder Among Older Adults: A Network Meta-analysis.

BACKGROUND: Cumulative exposure to one or more anticholinergic medications ("anticholinergic burden") is associated with an increased risk of adverse outcomes, particularly among older individuals. Mirabegron, an oral selective ß3-adrenergic receptor agonist, has demonstrated efficacy in managing the symptoms of overactive bladder without contributing to anticholinergic burden. However, it is not known whether the favorable safety profile of mirabegron relative to antimuscarinics varies with increasing age among a patient population who may have a high anticholinergic burden. OBJECTIVE: The primary objective of this study was to indirectly compare the safety and efficacy profile of mirabegron relative to antimuscarinics in older adults with overactive bladder. METHODS: A systematic literature review was conducted to identify randomized controlled trials that reported safety and efficacy endpoints among patients aged ≥ 65 years. Identified randomized controlled trials were subsequently synthesized via a network meta-analysis. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines in designing, performing, and reporting the literature review were followed. In line with current best practices, the network meta-analysis was conducted using a Bayesian approach and according to the overall general guidance for evidence synthesis developed by the National Institute for Health and Care Excellence decision support unit. Estimates of relative safety were assessed via the odds ratio and estimates of relative efficacy were assessed via means and credible intervals. RESULTS: A total of 3078 abstracts, 300 of which underwent full-text screening, were identified using the search criteria. Twenty articles reporting on 21 randomized controlled trials were eligible for data extraction and synthesis. Following review, five safety and five efficacy endpoints were considered for inclusion in the network meta-analysis. Regarding findings typical of anticholinergic exposure in older adults, mirabegron was not associated with an increased odds of dry mouth (odds ratio 95% credible interval 0.76 [0.26-2.37]) or constipation (1.08 [0.39-3.02]) relative to placebo, whereas antimuscarinics were strongly associated with these events (odds ratio range 3.78-7.85 and 2.12-4.66, respectively). In this older population, mirabegron was associated with a similar odds of experiencing adverse event-related treatment discontinuations relative to placebo (0.99 [0.57-1.70]), while the odds of experiencing an adverse event-related treatment discontinuation for antimuscarinics had a range of 1.14-3.03 (in most cases, the association was mild). No increased odds of experiencing overall treatment-emergent adverse events was observed for mirabegron or antimuscarinics (odds ratio range 1.25-1.55), apart from fesoterodine (2.23 [1.37-3.37]). Finally, a similar treatment effect was observed across all efficacy endpoints between mirabegron and antimuscarinics in this older population. CONCLUSIONS: This study indicates that the safety and efficacy profile of mirabegron remains favorable compared with antimuscarinics among older adults. This includes safety outcomes typically associated with anticholinergic burden, which were less frequently observed in patients treated with mirabegron.

Treatment for lymphoma and late cardiovascular disease risk: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Lymphoma patients are frequently treated with cancer therapies that may increase the risk of adverse health outcomes later in life, including cardiovascular disease (CVD) mortality. We sought to investigate the long-term risk of CVD incidence in this survivor population relative to the general population to quantify this health burden. METHODS: A systematic review and meta-analysis was conducted using EMBASE, MEDLINE, and CINAHL databases, from date of inception to November 2016, with additional searches completed through June 2018. Included reports were observational studies assessing CVD incidence in patients of either Hodgkin or non-Hodgkin lymphoma (HL, NHL) who survived for at least 5 years from the time of diagnosis or if the study had a median follow-up of 10 years. Meta-analyses were performed using random effects models, and subgroup analyses were conducted to determine the incidence of specific CVD subtypes (coronary heart disease, pericardial disease, valvular heart disease, myocardial disease, cardiac dysrhythmia, and cerebrovascular disease). Heterogeneity was assessed using I 2 statistics and prediction intervals. RESULTS: Of the 7734 studies identified, 22 studies were included in this review, representing 32 438 HL and NHL survivors. Relative to the general population, lymphoma survivors had statistically significant two to threefold increases in the risk for nearly all subtypes of CVD examined. Lymphoma survivors appeared to be particularly susceptible to pericardial diseases (HL: 10.67, 95% confidence interval (CI), 7.75-14.69; NHL: 4.70, 95% CI, 2.08-10.61) and valvular diseases (HL: 13.10, 95% CI, 7.41-23.16; NHL: 3.76, 95% CI, 2.12-6.66). Although the 95% CIs were suggestive of increased risks, the 95% prediction intervals often included the null, reflecting the high heterogeneity of the estimates. CONCLUSION: Given the suggested increased risks of cardiovascular outcomes in lymphoma survivor populations relative to the general population, tailored screening and prevention programmes may be warranted to offset the future burden of disease.

Long-term risk of cardiovascular mortality in lymphoma survivors: A systematic review and meta-analysis.

Cardiovascular disease has been identified as one of the late complications of cancer therapy. The purpose of this study was to quantify the long-term risk of cardiovascular mortality among lymphoma survivors relative to that of the general population. A systematic review and meta-analysis were conducted. Articles were identified in November 2016 by searching EMBASE, MEDLINE, and CINAHL databases. Observational studies were included if they assessed cardiovascular mortality in patients with lymphoma who survived for at least 5 years from time of diagnosis or if they had a median follow-up of 10 years. A pooled standardized mortality ratio (SMR) was estimated using a DerSimonian and Laird random-effects model. The Q and I2 statistics were used to assess heterogeneity. Funnel plots and Begg's and Egger's tests were used to evaluate publication bias. Of the 7450 articles screened, 27 studies were included in the systematic review representing 46 829 Hodgkin and 14 764 non-Hodgkin lymphoma survivors. The pooled number of deaths attributable to cardiovascular disease among Hodgkin and non-Hodgkin disease was estimated to be 7.31 (95% CI: 5.29-10.10; I2  = 95.4%) and 5.35 (95% CI: 2.55-11.24; I2  = 94.0%) times that of the general population, respectively. This association was greater among Hodgkin lymphoma survivors treated before the age of 21 (pooled SMR = 13.43; 95% CI: 9.22-19.57; I2  = 78.9%). There was a high degree of heterogeneity and a high risk of bias due to confounding in this body of literature. Lymphoma survivors have an increased risk of fatal cardiovascular events compared to the general population and should be targeted for cardiovascular screening and prevention campaigns.

Effect of a 12-month exercise intervention on leukocyte telomere length: Results from the ALPHA Trial.

BACKGROUND: Short telomeres may indicate a higher risk of cancer and other chronic diseases. Some observational studies show positive associations between leukocyte telomere length (LTL) and physical activity levels. We hypothesized, therefore, that exercise may be one strategy for slowing telomere attrition. METHODS: We conducted an ancillary analysis of blood from a year-long, two-centred, two-armed (1:1) randomized controlled trial of aerobic exercise versus usual inactivity. The analysis included 212 physically inactive, disease-free, non-smoking, postmenopausal women (n = 99 exercisers, n = 113 controls) in Alberta, Canada (2003-2006). The exercise prescription was aerobic exercise five days/week (supervised three days/week), 45 min/session, achieving 70-80% heart rate reserve. Baseline and 12-month LTL were analyzed using quantitative real-time polymerase chain reactions (qPCR). The primary statistical analysis was intention-to-treat, comparing the ratio of mean LTLs (12-months:baseline) for exercisers versus controls from a general linear model. Secondary analyses included a per-protocol analysis (≥90% adherence) and analyses stratified by baseline LTL, age, body mass index, and fitness level, respectively. RESULTS: Participants were overweight at baseline (mean BMI = 29 kg/m2). The primary analysis showed no evidence that LTL change differed between groups (12-month mean LTL change for the exercise group: -13% (95% CI: -32%, 11%) versus controls: -8% (95%CI: -27%, 15%); treatment effect ratio (TER, Exercise/Control) = 0.95 (95% CI: 0.68, 1.32). Per-protocol results were similar (TER = 0.87, 95% CI: 0.59, 1.30). In stratified models, TERs ranged from 0.68 to 1.35 across strata and P-interaction > 0.05). CONCLUSION: We found no evidence to suggest that one year of aerobic exercise alters telomere attrition significantly in healthy postmenopausal women.