PURPOSE: We set out to develop a publicly available tool that could accurately diagnose spinal muscular atrophy (SMA) in exome, genome, or panel sequencing data sets aligned to a GRCh37, GRCh38, or T2T reference genome. METHODS: The SMA Finder algorithm detects the most common genetic causes of SMA by evaluating reads that overlap the c.840 position of the SMN1 and SMN2 paralogs. It uses these reads to determine whether an individual most likely has 0 functional copies of SMN1. RESULTS: We developed SMA Finder and evaluated it on 16,626 exomes and 3911 genomes from the Broad Institute Center for Mendelian Genomics, 1157 exomes and 8762 panel samples from Tartu University Hospital, and 198,868 exomes and 198,868 genomes from the UK Biobank. SMA Finder's false-positive rate was below 1 in 200,000 samples, its positive predictive value was greater than 96%, and its true-positive rate was 29 out of 29. Most of these SMA diagnoses had initially been clinically misdiagnosed as limb-girdle muscular dystrophy. CONCLUSION: Our extensive evaluation of SMA Finder on exome, genome, and panel sequencing samples found it to have nearly 100% accuracy and demonstrated its ability to reduce diagnostic delays, particularly in individuals with milder subtypes of SMA. Given this accuracy, the common misdiagnoses identified here, the widespread availability of clinical confirmatory testing for SMA, and the existence of treatment options, we propose that it is time to add SMN1 to the American College of Medical Genetics list of genes with reportable secondary findings after genome and exome sequencing.
- MeSH
- algoritmy MeSH
- exom genetika MeSH
- genom lidský genetika MeSH
- genomika metody MeSH
- lidé MeSH
- protein přežití motorických neuronů 1 genetika MeSH
- protein přežití motorických neuronů 2 genetika MeSH
- sekvenční analýza DNA metody MeSH
- sekvenování exomu MeSH
- spinální svalová atrofie * genetika diagnóza MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Myasthenia gravis (MG) is a rare autoimmune disorder with significant clinical implications, including life-threatening myasthenic crises and exacerbations. Understanding real-world treatment patterns, especially associated direct medical costs, is essential for the effective management of healthcare delivery. METHODS: We conducted a descriptive cohort study using health administrative claims data from the Czech Republic covering more than 1,500 prevalent MG patients. Data were analysed for healthcare resource utilization, medication costs, and hospitalization rates related to MG and its complications. RESULTS: Acetylcholine inhibitors and corticosteroids were widely prescribed, with 91.1% and 75.2% of patients receiving them at least once, respectively. Immunosuppressive therapy was given to 45.2% of patients. Myasthenic crises occurred in 2% of patients, with a mean hospitalization cost of 21,020 EUR, while exacerbations occurred in 9.2% of patients, with lower costs (5,951 EUR per hospitalization). Outpatient intravenous immunoglobulin and plasma exchange therapies incurred additional costs of 20,700 EUR and 18,206 EUR per person-year, respectively. The mean total cost per patient-year was 1,271 EUR, with significant cost differences among patients with different treatment patterns. CONCLUSION: This study offers real-world insights into the treatment patterns and associated direct medical costs of MG in the Czech Republic. Myasthenic crises and exacerbations pose considerable cost burdens, while outpatient therapies and common pharmacotherapies are less costly. These findings are vital for healthcare planning, economic evaluation, and resource allocation, potentially leading to enhanced patient care and outcomes.
- MeSH
- dospělí MeSH
- hospitalizace ekonomika MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- myasthenia gravis * ekonomika terapie farmakoterapie MeSH
- náklady na zdravotní péči MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
Degenerative cervical myelopathy (DCM) represents the final consequence of a series of degenerative changes in the cervical spine, resulting in cervical spinal canal stenosis and mechanical stress on the cervical spinal cord. This process leads to subsequent pathophysiological processes in the spinal cord tissues. The primary mechanism of injury is degenerative compression of the cervical spinal cord, detectable by magnetic resonance imaging (MRI), serving as a hallmark for diagnosing DCM. However, the relative resilience of the cervical spinal cord to mechanical compression leads to clinical-radiological discordance, i.e., some individuals may exhibit MRI findings of DCC without the clinical signs and symptoms of myelopathy. This degenerative compression of the cervical spinal cord without clinical signs of myelopathy, potentially serving as a precursor to the development of DCM, remains a somewhat controversial topic. In this review article, we elaborate on and provide commentary on the terminology, epidemiology, natural course, diagnosis, predictive value, risks, and practical management of this condition-all of which are subjects of ongoing debate.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Despite the high prevalence of depression and anxiety in chronic pain conditions, current knowledge concerning emotional distress among painful diabetic polyneuropathy (pDSPN) and other diabetes mellitus (DM) sufferers is limited. METHODS: This observational multicentre cohort study employed the Hospital Anxiety and Depression Scale, the Beck Depression Inventory II and the State-Trait Anxiety Inventory to assess symptoms of depression and anxiety in several groups with diabetes, as well as in a control group. The study cohort included 347 pDSPN patients aged 63.4 years (median), 55.9% males; 311 pain-free diabetic polyneuropathy (nDSPN) patients aged 63.7 years, 57.9% males; 50 diabetes mellitus (DM) patients without polyneuropathy aged 61.5 years, 44.0% males; and 71 healthy controls (HC) aged 63.0 years, 42.3% males. The roles played in emotional distress were explored in terms of the biological, the clinical (diabetes-, neuropathy- and pain-related), the socio-economic and the cognitive factors (catastrophizing). RESULTS: The study disclosed a significantly higher prevalence of the symptoms of depression and anxiety not only in pDSPN (46.7% and 60.7%, respectively), but also in patients with nDSPN (24.4% and 44.4%) and DM without polyneuropathy (22.0% and 30.0%) compared with HCs (7.0% and 14.1%, p < 0.001). Multiple regression analysis demonstrated the severity of pain and neuropathy, catastrophic thinking, type 2 DM, lower age and female sex as independent contributors to depression and anxiety. CONCLUSIONS: In addition to the severity of neuropathic pain and its cognitive processing, the severity of diabetic polyneuropathy and demographic factors are key independent contributors to emotional distress in diabetic individuals. SIGNIFICANCE: In large cohorts of well-defined painless and painful diabetic polyneuropathy patients and diabetic subjects without polyneuropathy, we found a high prevalence of the symptoms of depression and anxiety, mainly in painful individuals. We have confirmed neuropathic pain, its severity and cognitive processing (pain catastrophizing) as dominant risk factors for depression and anxiety. Furthermore, some demographic factors (lower age, female sex), type 2 diabetes mellitus and severity of diabetic polyneuropathy were newly identified as important contributors to emotional distress independent of pain.
- MeSH
- deprese epidemiologie MeSH
- diabetes mellitus 2. typu * komplikace epidemiologie MeSH
- diabetické neuropatie * MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- neuralgie * diagnóza epidemiologie MeSH
- průřezové studie MeSH
- rizikové faktory MeSH
- úzkost epidemiologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- pozorovací studie MeSH
- práce podpořená grantem MeSH
Background: Degenerative cervical spinal cord compression is becoming increasingly prevalent, yet the MRI criteria that define compression are vague, and vary between studies. This contribution addresses the detection of compression by means of the Spinal Cord Toolbox (SCT) and assesses the variability of the morphometric parameters extracted with it. Methods: Prospective cross-sectional study. Two types of MRI examination, 3 and 1.5 T, were performed on 66 healthy controls and 118 participants with cervical spinal cord compression. Morphometric parameters from 3T MRI obtained by Spinal Cord Toolbox (cross-sectional area, solidity, compressive ratio, torsion) were combined in multivariate logistic regression models with the outcome (binary dependent variable) being the presence of compression determined by two radiologists. Inter-trial (between 3 and 1.5 T) and inter-rater (three expert raters and SCT) variability of morphometric parameters were assessed in a subset of 35 controls and 30 participants with compression. Results: The logistic model combining compressive ratio, cross-sectional area, solidity, torsion and one binary indicator, whether or not the compression was set at level C6/7, demonstrated outstanding compression detection (area under curve =0.947). The single best cut-off for predicted probability calculated using a multiple regression equation was 0.451, with a sensitivity of 87.3% and a specificity of 90.2%. The inter-trial variability was better in Spinal Cord Toolbox (intraclass correlation coefficient was 0.858 for compressive ratio and 0.735 for cross-sectional area) compared to expert raters (mean coefficient for three expert raters was 0.722 for compressive ratio and 0.486 for cross-sectional area). The analysis of inter-rater variability demonstrated general agreement between SCT and three expert raters, as the correlations between SCT and raters were generally similar to those of the raters between one another. Conclusions: This study demonstrates successful semi-automated compression detection based on four parameters. The inter-trial variability of parameters established through two MRI examinations was conclusively better for Spinal Cord Toolbox compared with that of three experts' manual ratings.
- Publikační typ
- časopisecké články MeSH
Degenerative cervical myelopathy (DCM) is a severe consequence of degenerative cervical spinal cord (CSC) compression. The non-myelopathic stage of compression (NMDC) is highly prevalent and often progresses to disabling DCM. This study aims to disclose markers of progressive neurochemical alterations in NMDC and DCM by utilizing an approach based on state-of-the-art proton magnetic resonance spectroscopy (1H-MRS). Proton-MRS data were prospectively acquired from 73 participants with CSC compression and 47 healthy controls (HCs). The MRS voxel was centered at the C2 level. Compression-affected participants were clinically categorized as NMDC and DCM, radiologically as mild (MC) or severe (SC) compression. CSC volumes and neurochemical concentrations were compared between cohorts (HC vs. NMDC vs. DCM and HC vs. MC vs. SC) with general linear models adjusted for age and height (pFWE < 0.05) and correlated to stenosis severity, electrophysiology, and myelopathy symptoms (p < 0.05). Whereas the ratio of total creatine (tCr) to total N-acetylaspartate (tNAA) increased in NMDC (+11%) and in DCM (+26%) and SC (+21%), myo-inositol/tNAA, glutamate + glutamine/tNAA, and volumes changed only in DCM (+20%, +73%, and -14%) and SC (+12%, +46%, and -8%, respectively) relative to HCs. Both tCr/tNAA and myo-inositol/tNAA correlated with compression severity and volume (-0.376 < r < -0.259). Myo-inositol/tNAA correlated with myelopathy symptoms (r = -0.670), whereas CSC volume did not. Short-echo 1H-MRS provided neurochemical signatures of CSC impairment that reflected compression severity and clinical significance. Whereas volumetry only reflected clinically manifest myelopathy (DCM), MRS detected neurochemical changes already before the onset of myelopathy symptoms.
- MeSH
- dospělí MeSH
- inositol metabolismus MeSH
- komprese míchy metabolismus patologie MeSH
- krční mícha * MeSH
- krční obratle MeSH
- kreatin metabolismus MeSH
- kyselina asparagová analogy a deriváty metabolismus MeSH
- kyselina glutamová metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie * MeSH
- senioři MeSH
- senzitivita a specificita MeSH
- studie případů a kontrol MeSH
- stupeň závažnosti nemoci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND AND PURPOSE: Non-myelopathic degenerative cervical spinal cord compression (NMDC) frequently occurs throughout aging and may progress to potentially irreversible degenerative cervical myelopathy (DCM). Whereas standard clinical magnetic resonance imaging (MRI) and electrophysiological measures assess compression severity and neurological dysfunction, respectively, underlying microstructural deficits still have to be established in NMDC and DCM patients. The study aims to establish tract-specific diffusion MRI markers of electrophysiological deficits to predict the progression of asymptomatic NMDC to symptomatic DCM. METHODS: High-resolution 3 T diffusion MRI was acquired for 103 NMDC and 21 DCM patients compared to 60 healthy controls to reveal diffusion alterations and relationships between tract-specific diffusion metrics and corresponding electrophysiological measures and compression severity. Relationship between the degree of DCM disability, assessed by the modified Japanese Orthopaedic Association scale, and tract-specific microstructural changes in DCM patients was also explored. RESULTS: The study identified diffusion-derived abnormalities in the gray matter, dorsal and lateral tracts congruent with trans-synaptic degeneration and demyelination in chronic degenerative spinal cord compression with more profound alterations in DCM than NMDC. Diffusion metrics were affected in the C3-6 area as well as above the compression level at C3 with more profound rostral deficits in DCM than NMDC. Alterations in lateral motor and dorsal sensory tracts correlated with motor and sensory evoked potentials, respectively, whereas electromyography outcomes corresponded with gray matter microstructure. DCM disability corresponded with microstructure alteration in lateral columns. CONCLUSIONS: Outcomes imply the necessity of high-resolution tract-specific diffusion MRI for monitoring degenerative spinal pathology in longitudinal studies.
- MeSH
- difuzní magnetická rezonance MeSH
- komprese míchy * diagnostické zobrazování MeSH
- krční obratle diagnostické zobrazování MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mícha diagnostické zobrazování MeSH
- nemoci míchy * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND AND PURPOSE: Myasthenia gravis (MG) patients could be a vulnerable group in the pandemic era of coronavirus 2019 (COVID-19) mainly due to respiratory muscle weakness, older age and long-term immunosuppressive treatment. We aimed to define factors predicting the severity of COVID-19 in MG patients and risk of MG exacerbation during COVID-19. METHODS: We evaluated clinical features and outcomes after COVID-19 in 93 MG patients. RESULTS: Thirty-five patients (38%) had severe pneumonia and we recorded 10 deaths (11%) due to COVID-19. Higher forced vital capacity (FVC) values tested before COVID-19 were shown to be protective against severe infection (95% CI 0.934-0.98) as well as good control of MG measured by the quantified myasthenia gravis score (95% CI 1.047-1.232). Long-term chronic corticosteroid treatment worsened the course of COVID-19 in MG patients (95% CI 1.784-111.43) and this impact was positively associated with dosage (p = 0.005). Treatment using azathioprine (95% CI 0.448-2.935), mycophenolate mofetil (95% CI 0.91-12.515) and ciclosporin (95% CI 0.029-2.212) did not influence the course of COVID-19. MG patients treated with rituximab had a high risk of death caused by COVID-19 (95% CI 3.216-383.971). Exacerbation of MG during infection was relatively rare (15%) and was not caused by remdesivir, convalescent plasma or favipiravir (95% CI 0.885-10.87). CONCLUSIONS: As the most important predictors of severe COVID-19 in MG patients we identified unsatisfied condition of MG with lower FVC, previous long-term corticosteroid treatment especially in higher doses, older age, the presence of cancer, and recent rituximab treatment.
