Neurofilament light chain (NfL) has emerged as a biomarker of neuroaxonal damage in several neurologic conditions. With increasing availability of fourth-generation immunoassays detecting NfL in ...blood, aspects of pre-analytical stability of this biomarker remain unanswered. This study investigated NfL concentrations in serum and plasma samples of 32 patients with neurological diagnoses using state of the art Simoa technology. We tested the effect of delayed freezing of up to 7 days and statistically determined stability and validity of measured concentrations. We found concentrations of NfL in serum and plasma to remain stable at room temperature when processing of samples is delayed up to 7 days (serum: mean absolute difference 0.9 pg/mL, intraindividual variation 1.2%; plasma: mean absolute difference 0.5 pg/mL, intraindividual variation 1.3%). Consistency of these results was nearly perfect for serum and excellent for plasma (intraclass correlation coefficients 0.99 and 0.94, respectively). In conclusion, the soluble serum and plasma NfL concentration remains stable when unprocessed blood samples are stored up to 7 days at room temperature. This information is essential for ensuring reliable study protocols, for example, when shipment of fresh samples is needed.
Serum neurofilament light chain (sNfL) and its ability to expose axonal damage in neurologic disorders have solicited a considerable amount of attention in blood biomarker research. Hence, with the ...proliferation of high-throughput assay technology, there is an imminent need to study the pre-analytical stability of this biomarker. We recruited 20 patients with common neurological diagnoses and 10 controls (i.e. patients without structural neurological disease). We investigated whether a variation in pre-analytical variables (delayed freezing up to 24 h and repeated thawing/freezing for up to three cycles) affects the measured sNfL concentrations using state of the art Simoa technology. Advanced statistical methods were applied to expose any relevant changes in sNfL concentration due to different storing and processing conditions. We found that sNfL concentrations remained stable when samples were frozen within 24 h (mean absolute difference 0.2 pg/ml; intraindividual variation below 0.1%). Repeated thawing and re-freezing up to three times did not change measured sNfL concentration significantly, either (mean absolute difference 0.7 pg/ml; intraindividual variation below 0.2%). We conclude that the soluble sNfL concentration is unaffected at 4-8 °C when samples are frozen within 24 h and single aliquots can be used up to three times. These observations should be considered for planning future studies.
Pregnancy and delivery outcomes in women with Fabry disease are not well described.
Retrospective cohort-study of women with Fabry disease in Austria using a specific questionnaire and the Austrian ...Mother-Child Health Passport.
Out of a total of 44 enrolled women (median age at study entry 44 years, p25: 30, p75: 51), 86.4% showed signs and symptoms of Fabry disease with an increase in pain burden during pregnancy, primarily in women with moderate pain before pregnancy. Thirty-two of 44 women with Fabry disease reported a total of 70 pregnancies (median age at first pregnancy 24 years, p25: 21, p75: 31), 61 (87.1%) of which resulted in 64 live births including 3 sets of twins, six miscarriages (8.6%) in five women, and three induced abortions (4.3%) in two women. Risk factors for poor maternal and foetal outcomes during pregnancy, overrepresented in our cohort as compared to the general population, were hypertension (n = 10, 16.4%), proteinuria (n = 17, 27.9%) and smoking (n = 24, 39.3%). Preeclampsia was reported in 7 pregnancies (11.5%). Fifty-one (79.7%) children were born at term and 13 (20.3%) were preterm (including one neonatal death), with a median gestational age of 39 weeks (p25: 38, p75: 40) and delivery by C-section in 15 pregnancies (24.6%). Thirteen (20.3%) children presented with low birth weight and 18 (28.1%) were small for their gestational age. In comparison to global and national data-sets, preeclampsia, prematurity, low birth weight, being small for their gestational age as well as inpatient stay were significantly more common in patients with Fabry disease.
Our cohort-study in women with Fabry disease shows an increase of pain burden during pregnancies and clearly points to an increased risk for preeclampsia, prematurity, and neonates small for gestational age. With a substantial number of high-risk pregnancies, neonatal outcomes are somewhat worse in Fabry disease than in the general public. Thus, we provide valuable data enabling informed decision-making in pregnancy counselling for Fabry disease.
Background
Monitoring of patient outcomes in multiple sclerosis (MS) is fundamental for individualized treatment decisions. So far, these decisions have been motivated by conventional outcomes, i.e., ...relapses or clinical disability supported by radiological disease activity. Complementing this concept, patient reported outcomes (PROs) assess individual health-related quality of life, among other constructs. Their inclusion in clinical routine, however, has been challenging as assessing them requires resources of time and personnel.
Objective
This interventional feasibility study investigated the haMSter app, a mobile health solution for remote and longitudinal monitoring of PROs in a sample of people with MS (pwMS).
Methods
The core feature of haMSter is the provision of three PRO questionnaires relevant to MS (anxiety/depression, MS-related quality of life, and fatigue) that patients can fill out once a month. For this feasibility trial, we offered 50 volunteers to use the haMSter app over six months and to take part in a haMSter study visit. This consultation concluded the study and participants had the opportunity to discuss their graphically plotted PRO results with their treating physician.
Results
The main outcome was overall patient adherence to monthly completion of the PRO questionnaires, which remained high up to 4 months (98%) and dropped over time (months 5: 83% and 6: 66%). Exploratory outcomes included patient satisfaction as estimated on the Telemedicine Perception Questionnaire (TMPQ, 17–85 points). The mean TMPQ score was 64 (95%CI: 62–66) points, indicating a high degree of approval. Ancillary tests included subgroup analyses of participants with particularly high or low satisfaction and upper extremity disability as a potential obstacle to utility or acceptance. We found no distinct characteristics separating participants with high or low satisfaction.
Conclusions
In this first feasibility trial, the haMSter app for longitudinal PRO monitoring was well received in terms of adherence and satisfaction.
ClinicalTrials.gov identifier:
NCT04555863.
We describe the case of a 44-year-old male patient with a longstanding history of microhematuria and mildly impaired kidney function (CKD G2A1). The family history disclosed three females who also ...had microhematuria. Genetic testing by whole exome sequencing revealed two novel variants in
(NM_000092.5: c.1181G>T, NP_000083.3: p.Gly394Val, heterozygous, likely pathogenic; Alport syndrome, OMIM# 141200, 203780) and
(NM_000169.3: c.460A>G, NP_000160.1: p.Ile154Val, hemizygous, variant of uncertain significance; Fabry disease, OMIM# 301500), respectively. Extensive phenotyping revealed no biochemical or clinical evidence for the presence of Fabry disease. Thus, the
c.460A>G, p.Ile154Val, is to be classified as a benign variant, whereas the
c.1181G>T, p.Gly394Val confirms the diagnosis of autosomal dominant Alport syndrome in this patient.
Introduction
Continuous monitoring is the hallmark of managing chronic disease. Multiple sclerosis (MS), in particular, requires patients to visit their treating neurologists typically twice a year, ...at least. In that respect, the COVID-19 pandemic made us rethink our communication strategies. This study determined satisfaction with remote visits for people with MS (pwMS) by comparing non-inferiority to conventional visits.
Methods
TELE MS was a randomized controlled trial that was open to any person with MS. We randomized a volunteer sample of 45 patients. We compared satisfaction with remote visits (via phone or via videochat) with conventional outpatient visits. The primary endpoint was patient satisfaction determined by the Telemedicine Perception Questionnaire (TMPQ, min: 17 and max: 85 points) with the hypothesis of non-inferiority of televisits to conventional visits. Physician satisfaction measured on the PPSM score (Patient and Physician Satisfaction with Monitoring, min: 5 and max: 25 points) was the secondary endpoint.
Results
The trial met both endpoints. Mean (SD) TMPQ scores in the individual groups were 58 (6.7) points for conventional visits, 65 (7.5) points for phone visits, and 62 (5.5) points for video visits. Physician satisfaction over the whole cohort was similarly high. Median (range) PPSM scores were 23 (16–25) for the whole cohort, 19 (16–25) for conventional visits, 25 (17–25) for phone visits, and 25 (16–25) for video visits.
Conclusions
Televisits in multiple sclerosis yield a high level of satisfaction for both patients and treating physicians. This concept for remote patient monitoring adopted during the current pandemic may be communicable to other chronic diseases as well.
ClinicalTrials.gov identifier:
NCT04838990
Fabry cardiomyopathy is characterized by left ventricular hypertrophy, myocardial fibrosis, arrhythmia, and premature death. Treatment with migalastat, an oral pharmacological chaperone, was ...associated with a stabilization of cardiac biomarkers and a reduction in left ventricular mass index, as measured by echocardiography. A recent study, using cardiac magnetic resonance (CMR) as the gold standard, found a stable course of myocardial involvement after 18 months of treatment with migalastat. Our study aimed to provide long-term CMR data for the treatment with migalastat.
A total of 11 females and four males with pathogenic amenable
mutations were treated with migalastat and underwent 1.5T CMR imaging for routine treatment effect monitoring. The main outcome was a long-term myocardial structural change, reflected by CMR.
After migalastat treatment initiation, left ventricular mass index, end diastolic volume, interventricular septal thickness, posterior wall thickness, estimated glomerular filtration rate, and plasma lyso-Gb3 remained stable during the median follow-up time of 34 months (min.: 25; max.: 47). The T1 relaxation times, reflecting glycosphingolipid accumulation and subsequent processes up to fibrosis, fluctuated over the time without a clear trend. No new onset of late gadolinium enhancement (LGE) areas, reflecting local fibrosis or scar formation of the myocardium, could be detected. However, patients with initially present LGE showed an increase in LGE as a percentage of left ventricular mass. The median α-galactosidase A enzymatic activity increased from 37.3% (IQR 5.88-89.3) to 105% (IQR 37.2-177) of the lower limit of the respective reference level (
= 0.005).
Our study confirms an overall stable course of LVMi in patients with FD, treated with migalastat. However, individual patients may experience disease progression, especially those who present with fibrosis of the myocardium already at the time of therapy initiation. Thus, a regular treatment re-evaluation including CMR is needed to provide the optimal management for each patient.
Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore, require tight regulation. ...Excessive VLCFAs are imported into peroxisomes for degradation by β-oxidation. Impaired VLCFA catabolism due to primary or secondary peroxisomal alterations is featured in neurodegenerative and neuroinflammatory disorders such as X-linked adrenoleukodystrophy and multiple sclerosis (MS). Here, we identified that healthy human macrophages upregulate the peroxisomal genes involved in β-oxidation during myelin phagocytosis and pro-inflammatory activation, and that this response is impaired in peripheral macrophages and phagocytes in brain white matter lesions in MS patients. The pharmacological targeting of VLCFA metabolism and peroxisomes in innate immune cells could be favorable in the context of neuroinflammation and neurodegeneration. We previously identified the epigenetic histone deacetylase (HDAC) inhibitors entinostat and vorinostat to enhance VLCFA degradation and pro-regenerative macrophage polarization. However, adverse side effects currently limit their use in chronic neuroinflammation. Here, we focused on tefinostat, a monocyte/macrophage-selective HDAC inhibitor that has shown reduced toxicity in clinical trials. By using a gene expression analysis, peroxisomal β-oxidation assay, and live imaging of primary human macrophages, we assessed the efficacy of tefinostat in modulating VLCFA metabolism, phagocytosis, chemotaxis, and immune function. Our results revealed the significant stimulation of VLCFA degradation with the upregulation of genes involved in peroxisomal β-oxidation and interference with immune cell recruitment; however, tefinostat was less potent than the class I HDAC-selective inhibitor entinostat in promoting a regenerative macrophage phenotype. Further research is needed to fully explore the potential of class I HDAC inhibition and downstream targets in the context of neuroinflammation.
Sexual dysfunction (SD) in people with multiple sclerosis (pwMS) has a detrimental impact on individual health-related quality of life (HRQoL). It is not clear whether SD in multiple sclerosis (MS) ...is an independent symptom or merely a byproduct of other symptoms such as depression or anxiety. This cross-sectional study of 93 pwMS determines risk factors for SD in MS based on prevalence, HRQoL, and associated disease outcomes. Diagnosis of SD was determined based on the Multiple Sclerosis Intimacy and Sexuality Questionnaire-19 (MSISQ-19) and correlated with physical disability (measured by Expanded Disability Status scale, EDSS), depression and anxiety Hospital Anxiety and Depression Scale (HADS), and HRQoL Multiple Sclerosis Quality of Life-54 (MSQoL-54). Multivariate regression models were performed to determine independent risk factors for SD in pwMS. Almost half of the participants in this study (46%) reported SD. HRQoL was significantly poorer in patients with MS suffering from SD (median IQR MSQoL-54 scores: physical subscale 52 41-68 vs. 81 69-89,
< 0.001; mental subscale 50 38-82 vs. 86 70-89,
< 0.001). In the multivariate model, EDSS was the only independent risk factor for SD (OR 18.1 for EDSS ≥4 95% CI 3.3-31.4,
< 0.001), while depression and anxiety were not. We conclude that the risk for SD is growing with increasing EDSS and is independent of depression or anxiety. Screening for SD becomes particularly relevant in patients with growing disability.
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