Patients' view on gene therapy development for lysosomal storage disorders: a qualitative study.

INTRODUCTION: Several new treatment modalities are being developed for lysosomal storage disorders (LSDs), including gene therapy. As the currently available treatment options and their influence on disease progression differ greatly within the spectrum of LSDs, willingness to undergo gene therapy might vary among patients with LSDs and/or their representatives. The width of the LSD spectrum is illustrated by the differences between type 1 Gaucher disease, Fabry disease and Mucopolysaccharidosis type III (MPS III). For type 1 Gaucher and Fabry disease several therapies are available, resulting in a near normal or improved, but individually varying, prognosis. No treatment options are available for MPS III. AIM: To identify factors influencing patients' and/or their representatives' decisions regarding undergoing gene therapy. METHODS: Focus group discussions and semi-structured interviews were conducted with patients with type 1 Gaucher disease, Fabry disease and MPS III. Parents of MPS III patients were included as patients' representatives. RESULTS: Nine Gaucher patients, 23 Fabry patients, two adult MPS III patients and five parents of MPS III patients participated in the study. The five main themes that arose were: outcome of gene therapy, risks and side effects, burden of gene therapy treatment, current situation and ethical aspects. Participants' views ranged from hesitance to eagerness to undergo gene therapy, which seemed to be mostly related to disease severity and currently available treatment options. Severe disease, limited treatment options and limited effectiveness of current treatment augmented the willingness to choose gene therapy. Gaucher and Fabry patients deemed the burden of treatment important. Fabry and MPS III patients and parents considered outcome important, suggesting hope for improvement. When asked to rank the factors discussed in the focus group discussions, Gaucher patients ranked outcome low, which could indicate a more cautious attitude towards gene therapy. CONCLUSION: This study underlines the importance of exploring patients' needs and expectations before using limited resources in the development of therapies for patient groups of which a significant subset may not be willing to undergo that specific therapy.

Outcome After Decompressive Craniectomy for Middle Cerebral Artery Infarction: Timing of the Intervention.

BACKGROUND: Based on randomized controlled trials (RCTs), clinical guidelines for the treatment of space-occupying hemispheric infarct employ age (≤60 yr) and time elapsed since stroke onset (≤48 h) as decisive criteria whether to perform decompressive craniectomy (DC). However, only few patients in these RCTs underwent DC after 48 h. OBJECTIVE: To study the association between the timing of DC and (un)favorable outcome in patients with space-occupying middle cerebral artery (MCA) infarct undergoing DC. METHODS: We performed a single-center cohort study from 2007 to 2017. Unfavorable outcome at 1 yr was defined as a Glasgow outcome scale 1 to 3. Additionally, we systematically reviewed the literature up to November 2018, including studies reporting on the timing of DC and other predictors of outcome. We performed Firth penalized likelihood and random-effects meta-analysis with odds ratio (OR) on unfavorable outcome. RESULTS: A total of 66 patients were enrolled. A total of 26 (39%) patients achieved favorable and 40 (61%) unfavorable outcomes (13 [20%] died). DC after 48 h since stroke diagnosis did not significantly increase the risk of unfavorable outcome (OR 0.8, 95% CI 0.3-2.3). Also, in the meta-analysis, DC after 48 h of stroke onset was not associated with a higher risk of unfavorable outcome (OR 1.11; 95% CI 0.89-1.38). CONCLUSION: The outcome of DC performed after 48 h in patients with malignant MCA infarct was not worse than the outcome of DC performed within 48 h. Contrary to current guidelines, we, therefore, advocate not to set a restriction of ≤48 h on the time elapsed since stroke onset in the decision whether to perform DC.

Visit-to-Visit Blood Pressure Variability and Progression of White Matter Hyperintensities Among Older People With Hypertension.

OBJECTIVES: Visit-to-visit blood pressure (BP) variability is a risk factor for cardiovascular disease and cognitive decline. Our aim was to assess the association between visit-to-visit BP variability and progression of white matter hyperintensities (WMH). DESIGN: Post-hoc analysis in the magnetic resonance imaging substudy of the randomized controlled trial prevention of dementia by intensive vascular care. SETTING AND PARTICIPANTS: Community-dwelling people age 70-78 years with hypertension. METHODS: Participants had 3 to 5 twice yearly BP measurements and 2 magnetic resonance imaging scans at 3 and 6 years follow-up. We used linear regression adjusted for age, sex, WMH at scan 1, (change in) total brain volume, and cardiovascular risk factors. RESULTS: Among the 122 participants, there was a modest association between visit-to-visit systolic BP variability and WMH progression [beta = 0.03 mL/y per point increase in variability, 95% confidence interval (CI) 0.00-0.05, P = .058]. Additional adjustment for slope in systolic BP reduced the associated P value to .043. Visit-to-visit diastolic BP variability was not associated with WMH progression (beta = 0.01 mL/y, 95% CI -0.02 to 0.03, P = .68). Visit-to-visit pulse pressure variability was associated with WMH progression (beta 0.03 mL/y, 95% CI 0.01-0.05, P < .01). CONCLUSIONS: Higher visit-to-visit systolic BP and pulse pressure variability is associated with more progression of WMH among people age 70-78 years with hypertension. IMPLICATIONS: Interventions to reduce visit-to-visit BP variability may be most effective in people with low WMH burden.

Development and Validation of an Interactive Internet Platform for Older People: The Healthy Ageing Through Internet Counselling in the Elderly Study.

BACKGROUND: A myriad of Web-based applications on self-management have been developed, but few focus on older people. In the face of global aging, older people form an important target population for cardiovascular prevention. This article describes the full development of an interactive Internet platform for older people, which was designed for the Healthy Ageing Through Internet Counselling in the Elderly (HATICE) study. We provide recommendations to design senior-friendly Web-based applications for a new approach to multicomponent cardiovascular prevention. METHODS: The development of the platform followed five phases: (1) conceptual framework; (2) platform concept and functional design; (3) platform building (software and content); (4) testing and pilot study; and (5) final product. RESULTS: We performed a meta-analysis, reviewed guidelines for cardiovascular diseases, and consulted end users, experts, and software developers to create the platform concept and content. The software was built in iterative cycles. In the pilot study, 41 people aged ≥65 years used the platform for 8 weeks. Participants used the interactive features of the platform and appreciated the coach support. During all phases adjustments were made to incorporate all improvements from the previous phases. The final platform is a personal, secured, and interactive platform supported by a coach. DISCUSSION: When carefully designed, an interactive Internet platform is acceptable and feasible for use by older people with basic computer skills. To improve acceptability by older people, we recommend involving the end users in the process of development, to personalize the platform and to combine the application with human support. The interactive HATICE platform will be tested for efficacy in a multinational randomized controlled trial (ISRCTN48151589).

Quality of life after surgical decompression for a space-occupying middle cerebral artery infarct: A cohort study.

BACKGROUND: In patients with a space-occupying middle cerebral artery (MCA) infarct surgical decompression reduces the risk of death, but increases the chance of survival with severe disability. We assessed quality of life (QoL), symptoms of depression, and caregiver burden at long-term follow-up. METHODS: Patients treated in two academic centres between 2007 and 2012 were included. Follow-up was at least six months. Patients and caregivers were interviewed separately. QoL was assessed with a visual analogue scale and the 36-item Short-Form health survey (SF-36); depression with the Hospital Anxiety and Depression Scale; and caregiver burden with the Caregiver Strain Index. RESULTS: Twenty five patients were enrolled, of whom seven had an infarct in the dominant hemisphere. After a median follow-up of 26 months (IQR 11-46) the median SF-36 mental component score was 54.4 (IQR 45-60), indicating a mental QoL comparable to that in the general population. The median SF-36 physical component score was 32.7 (IQR 22-38), indicating a worse physical QoL. Dominance of the hemisphere did not influence QoL. 79 % of patients and 65 % of caregivers would, in retrospect, again choose for surgery. 26 % of patients had signs of depression and 64 % of caregivers were substantially burdened in their daily life. CONCLUSIONS: Mental QoL after surgical decompression for space-occupying MCA infarct is comparable to that in the general population, whereas physical QoL is worse. Dominance of the hemisphere did not influence QoL. The majority of caregivers experience substantial burden. Most patients and caregivers stand by their decision for hemicraniectomy.

Quality of life after surgical decompression for space-occupying middle cerebral artery infarction: systematic review.

BACKGROUND AND PURPOSE: In patients with space-occupying middle cerebral artery infarction, surgical decompression strongly reduces risk of death and increases the chance of a favorable outcome. This comes at the expense of an increase in the risk of survival with (moderately) severe disability. We assessed quality of life, depression, and caregiver burden in these patients. SUMMARY OF REVIEW: We systematically reviewed the literature by searching MEDLINE, EMBASE, and PsycINFO up to March 2014. We included randomized controlled trials, cohort studies, case-control studies, and case series with quality of life, depression, or caregiver burden as primary or secondary outcome. Seventeen articles reporting on 459 patients were included. At final follow-up at 7 to 51 months, 1344 patients (30%) had died, and 34 (11%) were lost to follow up. Data on 291 patients were available, of whom 81 of 213 survivors (39%) achieved good functional outcome at final follow-up (modified Rankin Scale ≤ 3). Mean quality of life was 46% to 67% of the best possible score when based on questionnaires or visual analogue scales. At final follow-up, 143 of 189 patients (76%) would in retrospect again choose for surgical decompression. Severe depressive symptoms were present in 14 of 113 patients (16%). Three studies investigated caregiver burden and reported substantial burden. Patients more than 60 years old had a lower quality of life in comparison with younger patients. CONCLUSIONS: Most patients treated with surgical decompression for space-occupying infarction have a reasonable quality of life at long-term follow-up and are satisfied with the treatment received. Severe depressive symptoms are uncommon.