Modified Delphi procedure-based expert consensus on endpoints for an international disease registry for Metachromatic Leukodystrophy:The European Metachromatic Leukodystrophy initiative (MLDi)

BACKGROUND: Metachromatic Leukodystrophy (MLD) is a rare lysosomal disorder. Patients suffer from relentless neurological deterioration leading to premature death. Recently, new treatment modalities, including gene therapy and enzyme replacement therapy, have been developed. Those advances increase the need for high-quality research infrastructure to adequately compare treatments, execute post-marketing surveillance, and perform health technology assessments (HTA). To facilitate this, a group of MLD experts started the MLD initiative (MLDi) and initiated an academia-led European MLD registry: the MLDi. An expert-based consensus procedure, namely a modified Delphi procedure, was used to determine the data elements required to answer academic, regulatory, and HTA research questions. RESULTS: Three distinct sets of data elements were defined by the 13-member expert panel. The minimal set (n = 13) contained demographics and basic disease characteristics. The core set (n = 55) included functional status scores in terms of motor, manual, speech and eating abilities, and causal and supportive treatment characteristics. Health-related quality of life scores were included that were also deemed necessary for HTA. The optional set (n = 31) contained additional clinical aspects, such as findings at neurological examination, detailed motor function, presence of peripheral neuropathy, gall bladder involvement and micturition. CONCLUSION: Using a modified Delphi procedure with physicians from the main expert centers, consensus was reached on a core set of data that can be collected retrospectively and prospectively. With this consensus-based approach, an important step towards harmonization was made. This unique dataset will support knowledge about the disease and facilitate regulatory requirements related to the launch of new treatments. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13023-022-02189-w

Placental effects and transfer of sildenafil in healthy and preeclamptic conditions

Background: The phosphodiesterase-5 inhibitor (PDE5) sildenafil has emerged as a promising treatment for preeclampsia (PE). However, a sildenafil trial was recently halted due to lack of effect and increased neonatal morbidity. Methods: Ex vivo dual-sided perfusion of an isolated cotyledon and wire-myography on chorionic plate arteries were performed to study the effects of sildenafil and the non-selective PDE inhibitor vinpocetine on the response to the NO donor sodium nitroprusside (SNP) under healthy and PE conditions. Ex vivo perfusion was also used to study placental transfer of sildenafil in 6 healthy and 2 PE placentas. Furthermore, placental mRNA and protein levels of eNOS, iNOS, PDE5 and PDE1 were quantified. Findings: Sildenafil and vinpocetine significantly enhanced SNP responses in chorionic plate arteries of healthy, but not PE placentas. Only sildenafil acutely decreased baseline tension in arteries of both healthy and PE placentas. At steady state, the foetal-to-maternal transfer ratio of sildenafil was 0·37 ± 0·03 in healthy placentas versus 0·66 and 0·47 in the 2 PE placentas. mRNA and protein levels of PDE5, eNOS and iNOS wer

The Role of the Social Network in Access to Psychosocial Services for Migrant Elderly—A Qualitative Study

Abstract: Background: Despite high prevalence of mental problems among elderly migrants in The Netherlands, the use of psychosocial care services by this group is low. Scientific evidence points at the crucial role of social support for mental health and the use of psychosocial services. We therefore explored the role of social networks in the access to psychosocial care among elderly migrants in The Netherlands. Methods: A qualitative study was conducted using semi-structured group interviews and individual interviews. The eight group and eleven individual interviews (respectively n = 58 and n = 11) were conducted in The Netherlands with Turkish, Moroccan, Surinamese, and Dutch elderly. The data were analysed through coding and comparing fragments and recognizing patterns. Results: Support of the social network is important to navigate to psychosocial care and is most frequently provided by children. However, the social network of elderly migrants is generally not able to meet the needs of the elderly. This is mostly due to poor mental health literacy of the social network, taboo, and stigma around mental illness and the busy lives of the social network members. Conclusions: Strategies to address help-seeking barriers should consider mental health literacy in elderly migrants as well as their social networks, and counteract taboos and stigma of mental health problems

Recognizing early MRI signs (or their absence) is crucial in diagnosing metachromatic leukodystrophy

Abstract Objectives Metachromatic leukodystrophy (MLD) has characteristic white matter (WM) changes on brain MRI, which often trigger biochemical and genetic confirmation of the diagnosis. In early or pre‐symptomatic disease stages, these typical MRI changes might be absent, hampering early diagnosis. This study aims to describe the characteristics of MRI WM abnormalities at diagnosis, related to clinical presentation. Methods We retrospectively reviewed brain MRIs of MLD patients followed in 2 centers at the time of diagnosis regarding MLD MRI score and presence of tigroid pattern. In addition, MLD subtype, symptom status, CNS/PNS phenotype, motor/cognitive/mixed phenotype, and the presence of CNS symptoms were evaluated. Results We included 104 brain MRIs from patients with late‐infantile (n = 43), early‐juvenile (n = 24), late‐juvenile (n = 20) and adult (n = 17) onset. Involvement of the corpus callosum was a characteristic early MRI sign and was present in 71% of the symptomatic late‐infantile patients, 94% of the symptomatic early‐juvenile patients and 100% of the symptomatic late‐juvenile and adult patients. Symptomatic early‐juvenile, late‐juvenile and adult patients generally had WM abnormalities on MRI suggestive of MLD. By contrast, 47% of the early‐symptomatic late‐infantile patients had no or only mild WM abnormalities on MRI, even in the presence of CNS symptoms including pyramidal signs. Interpretation Patients with late‐infantile MLD may have no or only mild, nonspecific abnormalities at brain MRI, partly suggestive of ‘delayed myelination’, even with clear clinical symptoms. This may lead to significant diagnostic delay. Knowledge of these early MRI signs (or their absence) is important for fast diagnosis