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.

Pooling individual participant data from randomized controlled trials: Exploring potential loss of information.

BACKGROUND: Pooling individual participant data to enable pooled analyses is often complicated by diversity in variables across available datasets. Therefore, recoding original variables is often necessary to build a pooled dataset. We aimed to quantify how much information is lost in this process and to what extent this jeopardizes validity of analyses results. METHODS: Data were derived from a platform that was developed to pool data from three randomized controlled trials on the effect of treatment of cardiovascular risk factors on cognitive decline or dementia. We quantified loss of information using the R-squared of linear regression models with pooled variables as a function of their original variable(s). In case the R-squared was below 0.8, we additionally explored the potential impact of loss of information for future analyses. We did this second step by comparing whether the Beta coefficient of the predictor differed more than 10% when adding original or recoded variables as a confounder in a linear regression model. In a simulation we randomly sampled numbers, recoded those < = 1000 to 0 and those >1000 to 1 and varied the range of the continuous variable, the ratio of recoded zeroes to recoded ones, or both, and again extracted the R-squared from linear models to quantify information loss. RESULTS: The R-squared was below 0.8 for 8 out of 91 recoded variables. In 4 cases this had a substantial impact on the regression models, particularly when a continuous variable was recoded into a discrete variable. Our simulation showed that the least information is lost when the ratio of recoded zeroes to ones is 1:1. CONCLUSIONS: Large, pooled datasets provide great opportunities, justifying the efforts for data harmonization. Still, caution is warranted when using recoded variables which variance is explained limitedly by their original variables as this may jeopardize the validity of study results.

Association of Benzodiazepine and Anticholinergic Drug Usage With Incident Dementia: A Prospective Cohort Study of Community-Dwelling Older Adults.

OBJECTIVES: To examine the association of benzodiazepines and anticholinergic drug usage with the risk of dementia. DESIGN: Prospective cohort study. SETTING: Community-dwelling participants, recruited in family practices in the Netherlands. PARTICIPANTS: In total, 3526 individuals aged 70 to 78 years without dementia within 116 participating family practices. METHODS: Information about drug use was reported at baseline and at 2-year follow-up and was cross-checked with the participants' electronic health records. Anticholinergic drug exposure was defined by the anticholinergic cognitive burden score. Participants were evaluated for dementia during follow-up assessments every 2 years, supplemented by information from electronic health records and the National Death Registry. RESULTS: During a median follow-up of 6.7 years, dementia developed in 233 participants (7%). In participants using benzodiazepines, 6% developed dementia vs 7% in nonusers [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.58-1.07]. Persistent usage of benzodiazepines at baseline and after 2-year follow-up did not substantially alter the point-estimate (HR 0.60, 95% CI 0.34-1.10). Use of any anticholinergic drugs was not associated with incident dementia (HR 1.01, 95% CI 0.50-1.10). Dementia risk was significantly increased for participants with persistent drug use with a high anticholinergic cognitive burden score (HR 1.95, 95% CI 1.13-3.38) though this effect was absent when excluding participants taking antidepressants or antipsychotics (HR 0.42, 95% CI 0.06-3.01). CONCLUSIONS AND IMPLICATIONS: In our study population, benzodiazepine usage was not associated with an increased risk of dementia. Persistent high anticholinergic exposure was associated with an increased risk of dementia over 6 years of follow-up, and this association was driven by antidepressant or antipsychotic drug use, suggesting confounding by indication bias contributing to this. Although this observation could ameliorate prescription hesitance, healthcare providers are still advised to carefully weigh the potential benefits of benzodiazepines and anticholinergic drugs against the associated adverse health outcomes.

Engaging older people in an internet platform for cardiovascular risk self-management: a qualitative study among Dutch HATICE participants.

OBJECTIVES: To study older peoples' experiences with an interactive internet platform for cardiovascular self-management, to assess which factors influence initial and sustained engagement. To assess their views on future use within primary care. DESIGN: Qualitative semistructured interview study, with thematic analysis. SETTING: Primary care in the Netherlands. PARTICIPANTS: People ≥65 years with an increased risk of cardiovascular disease who used the 'Healthy Ageing Through Internet Counselling in the Elderly' internet platform with remote support of a coach. Participants were selected using a purposive sampling method based on gender, age, level of education, cardiovascular history, diabetes, duration of participation and login frequency. RESULTS: We performed 17 interviews with 20 participants, including three couples. In the initial phase, platform engagement was influenced by perceived computer literacy of the participants, user-friendliness, acceptability and appropriateness of the intervention and the initial interaction with the coach. Sustained platform use was mainly facilitated by a relationship of trust with the coach. Other facilitating factors were regular automatic and personal reminders, clear expectations of the platform, incorporation into daily routine, social support and a loyal and persistent attitude. Perceived lack of change in content of the platform could work both stimulating and discouraging. Participants supported the idea of embedding the platform into the primary care setting. CONCLUSIONS: Human support is crucial to initial and sustained engagement of older people in using an interactive internet platform for cardiovascular self-management. Regular reminders further facilitate sustained use, and increased tailoring to personal preference is recommended. Embedding the platform in primary healthcare may enhance future adoption. TRIAL REGISTRATION NUMBER: ISRCTN48151589; Pre-results.

Improving data sharing in research with context-free encoded missing data.

Lack of attention to missing data in research may result in biased results, loss of power and reduced generalizability. Registering reasons for missing values at the time of data collection, or-in the case of sharing existing data-before making data available to other teams, can save time and efforts, improve scientific value and help to prevent erroneous assumptions and biased results. To ensure that encoding of missing data is sufficient to understand the reason why data are missing, it should ideally be context-free. Therefore, 11 context-free codes of missing data were carefully designed based on three completed randomized controlled clinical trials and tested in a new randomized controlled clinical trial by an international team consisting of clinical researchers and epidemiologists with extended experience in designing and conducting trials and an Information System expert. These codes can be divided into missing due to participant and/or participation characteristics (n = 6), missing by design (n = 4), and due to a procedural error (n = 1). Broad implementation of context-free missing data encoding may enhance the possibilities of data sharing and pooling, thus allowing more powerful analyses using existing data.

Determinants of Dropout and Nonadherence in a Dementia Prevention Randomized Controlled Trial: The Prevention of Dementia by Intensive Vascular Care Trial.

OBJECTIVES: To explore and compare sociodemographic, clinical, and neuropsychiatric determinants of dropout and nonadherence in older people participating in an open-label cluster-randomized controlled trial-the Prevention of Dementia by Intensive Vascular care (preDIVA) trial-over 6 years. DESIGN: Secondary analysis. SETTING: One hundred sixteen general practices in the Netherlands. PARTICIPANTS: Community-dwelling individuals aged 70 to 78 (N = 2,994). INTERVENTION: Nurse-led multidomain intervention targeting cardiovascular risk factors to prevent dementia. MEASUREMENTS: The associations between participant baseline sociodemographic (age, sex, education), clinical (medical history, disability, cardiovascular risk), neuropsychiatric (depressive symptoms (Geriatric Depression Scale-15), and cognitive (Mini-Mental State Examination)) characteristics and dropout from the trial and nonadherence to the trial intervention were explored using multilevel logistic regression models. RESULTS: Older age, poorer cognitive function, more symptoms of depression, and greater disability were the most important determinants of dropout of older people. The presence of cardiovascular risk factors was not associated with dropout but was associated with nonadherence. Being overweight was a risk factor for nonadherence, whereas people with high blood pressure or a low level of physical exercise adhered better to the intervention. The association between poorer cognitive function and symptoms of depression and dropout was stronger in the control group than in the intervention group, and vice versa for increased disability. CONCLUSION: In a large dementia prevention trial with 6-year follow-up, dropout was associated with older age, poorer cognitive function, symptoms of depression, and disability at baseline. These findings can help to guide the design of future dementia prevention trials in older adults. The associations found between cardiovascular risk factors and nonadherence need to be confirmed in other older populations receiving cardiovascular prevention interventions.

Healthy Ageing Through Internet Counselling in the Elderly: the HATICE randomised controlled trial for the prevention of cardiovascular disease and cognitive impairment.

INTRODUCTION: Cardiovascular disease and dementia share a number of risk factors including hypertension, hypercholesterolaemia, smoking, obesity, diabetes and physical inactivity. The rise of eHealth has led to increasing opportunities for large-scale delivery of prevention programmes encouraging self-management. The aim of this study is to investigate whether a multidomain intervention to optimise self-management of cardiovascular risk factors in older individuals, delivered through an coach-supported interactive internet platform, can improve the cardiovascular risk profile and reduce the risk of cardiovascular disease and cognitive decline. METHODS AND ANALYSIS: HATICE is a multinational, multicentre, prospective, randomised, open-label blinded end point (PROBE) trial with 18 months intervention. Recruitment of 2600 older people (≥65 years) at increased risk of cardiovascular disease will take place in the Netherlands, Finland and France. Participants randomised to the intervention condition will have access to an interactive internet platform, stimulating self-management of vascular risk factors, with remote support by a coach. Participants in the control group will have access to a static internet platform with basic health information.The primary outcome is a composite score based on the average z-score of the difference between baseline and 18 months follow-up values of systolic blood pressure, low-density-lipoprotein and body mass index. Main secondary outcomes include the effect on the individual components of the primary outcome, the effect on lifestyle-related risk factors, incident cardiovascular disease, mortality, cognitive functioning, mood and cost-effectiveness. ETHICS AND DISSEMINATION: The study was approved by the medical ethics committee of the Academic Medical Center in Amsterdam, the Comité de Protection des Personnes Sud Ouest et Outre Mer in France and the Northern Savo Hospital District Research Ethics Committee in Finland.We expect that data from this study will result in a manuscript published in a peer-reviewed clinical open access journal. TRIAL REGISTRATION NUMBER: ISRCTN48151589.

Web-Based Interventions Targeting Cardiovascular Risk Factors in Middle-Aged and Older People: A Systematic Review and Meta-Analysis.

BACKGROUND: Web-based interventions can improve single cardiovascular risk factors in adult populations. In view of global aging and the associated increasing burden of cardiovascular disease, older people form an important target population as well. OBJECTIVE: In this systematic review and meta-analysis, we evaluated whether Web-based interventions for cardiovascular risk factor management reduce the risk of cardiovascular disease in older people. METHODS: Embase, Medline, Cochrane and CINAHL were systematically searched from January 1995 to November 2014. Search terms included cardiovascular risk factors and diseases (specified), Web-based interventions (and synonyms) and randomized controlled trial. Two authors independently performed study selection, data-extraction and risk of bias assessment. In a meta-analysis, outcomes regarding treatment effects on cardiovascular risk factors (blood pressure, glycated hemoglobin A1c (HbA1C), low-density lipoprotein (LDL) cholesterol, smoking status, weight and physical inactivity) and incident cardiovascular disease were pooled with random effects models. RESULTS: A total of 57 studies (N=19,862) fulfilled eligibility criteria and 47 studies contributed to the meta-analysis. A significant reduction in systolic blood pressure (mean difference -2.66 mmHg, 95% CI -3.81 to -1.52), diastolic blood pressure (mean difference -1.26 mmHg, 95% CI -1.92 to -0.60), HbA1c level (mean difference -0.13%, 95% CI -0.22 to -0.05), LDL cholesterol level (mean difference -2.18 mg/dL, 95% CI -3.96 to -0.41), weight (mean difference -1.34 kg, 95% CI -1.91 to -0.77), and an increase of physical activity (standardized mean difference 0.25, 95% CI 0.10-0.39) in the Web-based intervention group was found. The observed effects were more pronounced in studies with short (<12 months) follow-up and studies that combined the Internet application with human support (blended care). No difference in incident cardiovascular disease was found between groups (6 studies). CONCLUSIONS: Web-based interventions have the potential to improve the cardiovascular risk profile of older people, but the effects are modest and decline with time. Currently, there is insufficient evidence for an effect on incident cardiovascular disease. A focus on long-term effects, clinical endpoints, and strategies to increase sustainability of treatment effects is recommended for future studies.

Chronic CD70-driven costimulation impairs IgG responses by instructing T cells to inhibit germinal center B cell formation through FasL-Fas interactions.

CD70 provides costimulation that enhances effector T cell differentiation upon binding of its receptor, CD27. During chronic immune activation, CD70 is constitutively expressed on activated immune cells, and this induces T cell-driven disruption of neutralizing Ab responses via an unknown mechanism. We used CD70-transgenic mice to investigate the effect of constitutive expression of CD70 on T cell-dependent B cell responses. CD70 induced up-regulation of the B cell follicle homing chemokine receptor CXCR5 on T cells, enabling not only CD4 but also CD8 T cells to infiltrate the B cell follicles. CD70-transgenic mice failed to develop productive germinal center formation and displayed impaired IgG Ab responses. Defective germinal center B cell differentiation was critically dependent on CD70-mediated CD27 signaling in T cells, and involved Fas-dependent impairment of germinal center B cell differentiation. Thus, CD70-driven costimulation enables T cells to terminate B cell responses, thereby compromising durable Ab production. Our findings imply that the CD70- and CD27-driven costimulatory axis may be involved in shutdown of B cell responses before clearance of Ag. Because CD70 is expressed constitutively in chronic viral infections such as HIV-1 infection, this mechanism may also contribute to defects in humoral immunity associated with this disease.