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BACKGROUND: Spasticity is a common and potentially debilitating symptom of multiple sclerosis (MS) with a highly variable presentation. Understanding, quantifying, and managing MS-associated spasticity (MSS) is a challenge for research and in clinical practice. The tetrahydrocannabinol:cannabidiol oromucosal spray nabiximols has demonstrated beneficial effects in the treatment of MSS in clinical studies as well as real-world observational studies, and is approved for the treatment of MSS in 29 countries globally. Most randomized studies evaluated the efficacy of nabiximols using the change in average daily spasticity scores reported by patients using the spasticity Numeric Rating Scale as a primary endpoint. This study, RELEASE MSS1 (NCT04657666), was conducted using a prespecified primary endpoint of change in spastic muscle tone (Modified Ashworth Scale Lower Limb Muscle Tone-6 [MAS LLMT-6]) to corroborate the efficacy of nabiximols as adjunctive therapy observed with the patient-measured spasticity Numeric Rating Scale primary endpoint in the previous pivotal studies. METHODS: This was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 2-treatment, 2-period, crossover trial. Because of the prevalence and functional impact of lower limb spasticity on the individual patient's overall experience of MS spasticity, the MAS LLMT-6 was derived from the clinician-rated MAS. The MAS LLMT-6 is the average transformed MAS score of 6 muscle groups (knee flexors, knee extensors, and ankle plantar flexors; all assessed bilaterally). Secondary measures included MAS LLMT-4 scores, defined as the average of the 4 individual MAS-transformed scores of knee flexors and knee extensors bilaterally. Patients had a diagnosis of MS and an untransformed MAS score of at least 2 in ≥2 of 6 LLMT-6 muscle groups despite current treatment with ≥1 of the following oral antispasticity agents: baclofen, tizanidine, or dantrolene. Eligible participants were randomly assigned to 1 of 2 treatment sequences. Each treatment sequence consisted of two treatment periods, each consisting of a 14-day dose titration phase followed by a 7-day dose maintenance phase. RESULTS: Of 68 patients enrolled, 33 were assigned to nabiximols followed by placebo and 35 were assigned to placebo followed by nabiximols. Least squares mean changes in MAS LLMT-6 scores from baseline to day 21 were -0.23 for nabiximols and -0.26 for placebo; the least squares mean treatment difference in MAS LLMT-6 scores for nabiximols versus placebo was 0.04, which was not statistically significant (P = 0.7152). Mean changes in MAS LLMT-4 scores from baseline to day 21 also were not significantly different between the nabiximols and placebo groups. Safety results in this study were consistent with the known safety profile of nabiximols in patients with MSS. CONCLUSION: Despite the established efficacy of nabiximols in MSS observed using patient-reported measures, the primary endpoint was not met in this study. The findings from this study reflect and emphasize some of the challenges in the evaluation and treatment of MS spasticity. CLINICAL TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): : NCT04657666.
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Canabidiol , Dronabinol , Combinação de Medicamentos , Esclerose Múltipla , Espasticidade Muscular , Humanos , Espasticidade Muscular/tratamento farmacológico , Espasticidade Muscular/etiologia , Canabidiol/administração & dosagem , Canabidiol/farmacologia , Dronabinol/administração & dosagem , Dronabinol/farmacologia , Método Duplo-Cego , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Adulto , Masculino , Sprays Orais , Feminino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de SaúdeRESUMO
Anti-drug antibodies (ADA) reduce the efficacy of immunotherapies in multiple sclerosis (MS) and are associated with increased disease progression risk. Blood biomarkers predicting immunogenicity to biopharmaceuticals represent an unmet clinical need. Patients with relapsing remitting (RR)MS were recruited before (baseline), three, and 12 (M12) months after commencing interferon-beta treatment. Neutralising ADA-status was determined at M12, and patients were stratified at baseline according to their M12 ADA-status (ADA-positive/ADA-negative). Patients stratified as ADA-positive were characterised by an early dampened response to interferon-beta (prior to serum ADA detection) and distinct proinflammatory transcriptomic/proteomic peripheral blood signatures enriched for 'immune response activation' including phosphoinositide 3-kinase-γ and NFκB-signalling pathways both at baseline and throughout the treatment course, compared to ADA-negative patients. These immunogenicity-associated proinflammatory signatures significantly overlapped with signatures of MS disease severity. Thus, whole blood molecular profiling is a promising tool for prediction of ADA-development in RRMS and could provide insight into mechanisms of immunogenicity.
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BACKGROUND: Research on cognitive rehabilitation (CR) and aerobic exercise (EX) to improve cognition in progressive multiple sclerosis (PMS) remains limited. CogEx trial investigated the effectiveness of CR and EX in PMS: here, we present MRI substudy volumetric and task-related functional MRI (fMRI) findings. METHODS: Participants were randomised to: 'CR plus EX', 'CR plus sham EX (EX-S)', 'EX plus sham CR (CR-S)' and 'CR-S plus EX-S' and attended 12-week intervention. All subjects performed physical/cognitive assessments at baseline, week 12 and 6 months post intervention (month 9). All MRI substudy participants underwent volumetric MRI and fMRI (Go-NoGo task). RESULTS: 104 PMS enrolled at four sites participated in the CogEx MRI substudy; 84 (81%) had valid volumetric MRI and valid fMRI. Week 12/month 9 cognitive performances did not differ among interventions; however, 25-62% of the patients showed Symbol Digit Modalities Test improvements. Normalised cortical grey matter volume (NcGMV) changes at week 12 versus baseline were heterogeneous among interventions (p=0.05); this was mainly driven by increased NcGMV in 'CR plus EX-S' (p=0.02). Groups performing CR (ie, 'CR plus EX' and 'CR plus EX-S') exhibited increased NcGMV over time, especially in the frontal (p=0.01), parietal (p=0.04) and temporal (p=0.04) lobes, while those performing CR-S exhibited NcGMV decrease (p=0.008). In CR groups, increased NcGMV (r=0.36, p=0.01) at week 12 versus baseline correlated with increased California Verbal Learning Test (CVLT)-II scores. 'CR plus EX-S' patients exhibited Go-NoGo activity increase (p<0.05, corrected) at week 12 versus baseline in bilateral insula. CONCLUSIONS: In PMS, CR modulated grey matter (GM) volume and insular activity. The association of GM and CVLT-II changes suggests GM plasticity contributes to cognitive improvements. TRIAL REGISTRATION NUMBER: NCT03679468.
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Altered cholesterol, oxysterol, sphingolipid, and fatty acid concentrations are reported in blood, cerebrospinal fluid, and brain tissue of people with relapsing-remitting multiple sclerosis (RRMS) and are linked to disease progression and treatment responses. CD4â +â T cells are pathogenic in RRMS, and defective T-cell function could be mediated in part by liver X receptors (LXRs)-nuclear receptors that regulate lipid homeostasis and immunity. RNA-sequencing and pathway analysis identified that genes within the 'lipid metabolism' and 'signalling of nuclear receptors' pathways were dysregulated in CD4â +â T cells isolated from RRMS patients compared with healthy donors. While LXRB and genes associated with cholesterol metabolism were upregulated, other T-cell LXR-target genes, including genes involved in cellular lipid uptake (inducible degrader of the LDL receptor, IDOL), and the rate-limiting enzyme for glycosphingolipid biosynthesis (UDP-glucosylceramide synthase, UGCG) were downregulated in T cells from patients with RRMS compared to healthy donors. Correspondingly, plasma membrane glycosphingolipids were reduced, and cholesterol levels increased in RRMS CD4â +â T cells, an effect partially recapitulated in healthy T cells by in vitro culture with T-cell receptor stimulation in the presence of serum from RRMS patients. Notably, stimulation with LXR-agonist GW3965 normalized membrane cholesterol levels, and reduced proliferation and IL17 cytokine production in RRMS CD4â +â T-cells. Thus, LXR-mediated lipid metabolism pathways were dysregulated in T cells from patients with RRMS and could contribute to RRMS pathogenesis. Therapies that modify lipid metabolism could help restore immune cell function.
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Linfócitos T CD4-Positivos , Metabolismo dos Lipídeos , Receptores X do Fígado , Esclerose Múltipla Recidivante-Remitente , Humanos , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/metabolismo , Receptores X do Fígado/metabolismo , Feminino , Adulto , Masculino , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Pessoa de Meia-Idade , Colesterol/metabolismo , Glicoesfingolipídeos/metabolismoRESUMO
BACKGROUND: People with progressive multiple sclerosis (PMS) present motor (eg, walking) and cognitive impairments, and report fatigue. Fatigue encompasses fatigability which is objectively measured by the capacity to sustain a motor or cognitive task. OBJECTIVE: To investigate the prevalence of walking and cognitive fatigability (CF) and the associated clinical characteristics in a large sample of PMS patients. METHODS: PMS patients (25-65 years old) were included from 11 sites (Europe and North America), having cognitive impairment (1.28 standard deviation below normative data for the symbol digit modality test [SDMT]). Walking fatigability (WF) was assessed using the distance walk index (DWI) and CF using the SDMT (scores from the last 30 seconds compared to the first 30 seconds). Additional measures were: cognitive assessment-Brief International Cognitive Assessment for multiple sclerosis (MS), cardiorespiratory fitness, 6-minute walk, physical activity, depressive symptoms, perceived fatigue-Modified Fatigue Impact Scale (MFIS), MS impact-MSIS-29, and walking ability. RESULTS: Of 298 participants, 153 (51%) presented WF (DWI = -28.9 ± 22.1%) and 196 (66%) presented CF (-29.7 ± 15%). Clinical characteristics (EDSS, disease duration, and use of assistive device) were worse in patients with versus without WF. They also presented worse scores on MSIS-29 physical, MFIS total and physical and reduced physical capacity. CF patients scored better in the MSIS-29 physical and MFIS psychosocial, compared to non-CF group. Magnitude of CF and WF were not related. CONCLUSIONS: Half of the cognitively-impaired PMS population presented WF which was associated with higher disability, physical functions, and fatigue. There was a high prevalence of CF but without strong associations with clinical, cognitive, and physical functions. TRIAL REGISTRATION NUMBER: The "CogEx-study," www.clinicaltrial.gov identifier number: NCT03679468.
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Disfunção Cognitiva , Fadiga , Esclerose Múltipla Crônica Progressiva , Caminhada , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/fisiopatologia , Fadiga/epidemiologia , Fadiga/fisiopatologia , Esclerose Múltipla Crônica Progressiva/epidemiologia , Esclerose Múltipla Crônica Progressiva/fisiopatologia , PrevalênciaRESUMO
BACKGROUND: Pediatric, adolescent, and young adult patients with cancer and their caregivers are at high risk of financial toxicity, and few evidence-based oncology financial and legal navigation programs exist to address it. We tested the feasibility, acceptability, and preliminary effectiveness of Financial and Insurance Navigation Assistance, a novel interdisciplinary financial and legal navigation intervention for pediatric, adolescent and young adult patients and their caregivers. METHODS: We used a single-arm feasibility and acceptability trial design in a pediatric hematology and oncology clinic and collected preintervention and postintervention surveys to assess changes in financial toxicity (3 domains: psychological response/Comprehensive Score for Financial Toxicity [COST], material conditions, and coping behaviors); health-related quality of life (Patient-Reported Outcomes Measurement Information System Physical and Mental Health, Anxiety, Depression, and Parent Proxy scales); and perceived feasibility, acceptability, and appropriateness. RESULTS: In total, 45 participants received financial navigation, 6 received legal navigation, and 10 received both. Among 15 adult patients, significant improvements in FACIT-COST (P = .041) and physical health (P = .036) were noted. Among 46 caregivers, significant improvements were noted for FACIT-COST (P < .001), the total financial toxicity score (P = .001), and the parent proxy global health score (P = .0037). We were able to secure roughly $335â323 in financial benefits for 48 participants. The intervention was rated highly for feasibility, acceptability, and appropriateness. CONCLUSIONS: Integrating financial and legal navigation through Financial and Insurance Navigation Assistance was feasible and acceptable and underscores the benefit of a multidisciplinary approach to addressing financial toxicity. CLINICALTRIALS.GOV REGISTRATION: NCT05876325.
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Cuidadores , Estudos de Viabilidade , Neoplasias , Qualidade de Vida , Humanos , Adolescente , Neoplasias/economia , Adulto Jovem , Feminino , Masculino , Criança , Adulto , Adaptação Psicológica , Ansiedade/prevenção & controle , Navegação de Pacientes/economia , Efeitos Psicossociais da Doença , Depressão/prevenção & controle , Medidas de Resultados Relatados pelo Paciente , Seguro Saúde/economiaRESUMO
There are no blood-based biomarkers distinguishing patients with relapsing-remitting (RRMS) from secondary progressive multiple sclerosis (SPMS) although evidence supports metabolomic changes according to MS disease severity. Here machine learning analysis of serum metabolomic data stratified patients with RRMS from SPMS with high accuracy and a putative score was developed that stratified MS patient subsets. The top differentially expressed metabolites between SPMS versus patients with RRMS included lipids and fatty acids, metabolites enriched in pathways related to cellular respiration, notably, elevated lactate and glutamine (gluconeogenesis-related) and acetoacetate and bOHbutyrate (ketone bodies), and reduced alanine and pyruvate (glycolysis-related). Serum metabolomic changes were recapitulated in the whole blood transcriptome, whereby differentially expressed genes were also enriched in cellular respiration pathways in patients with SPMS. The final gene-metabolite interaction network demonstrated a potential metabolic shift from glycolysis toward increased gluconeogenesis and ketogenesis in SPMS, indicating metabolic stress which may trigger stress response pathways and subsequent neurodegeneration.
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Mitral annular disjunction (MAD) is a rare and under-recognized entity in the pediatric population. We present 2 cases of MAD in previously healthy pediatric patients and highlight clinical scenarios where MAD should be suspected.
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OBJECTIVE: Literature on trainee clinical psychologists' mental health has highlighted elevated levels of mental health difficulties and/or psychological distress and low levels of disclosure within the workplace. The current study aimed to explore (1) trainee experiences of disclosure and/or concealment of psychological distress during their training, (2) beliefs, assumptions or predictions related to disclosure and (3) responses to disclosure. METHODS: A mixed-methods strategy was employed; 165 trainee or recently qualified clinical psychologists took part in an online survey. Thirteen of these were interviewed. Descriptive statistics and a reflexive thematic analysis were conducted to analyse the quantitative and qualitative data, respectively. RESULTS: The sample largely consisted of those who had disclosed distress. Beliefs related to negative judgement from others and feelings of anxiety and embarrassment were commonly endorsed responses within quantitative findings. Six main themes were constructed: (1) Diagnostic or psychological conceptualisations, (2) Worries about judgement complicate disclosure decisions, (3) Disclosure likelihood is determined by relationships, (4) Emotional support versus practical responses, (5) Desired changes that could increase disclosure and (6) Legacies of disclosure experiences. CONCLUSION: There is a need for training programme staff to prioritise emotional support, increase permission giving and enhance disclosure guidance. Further research including disclosure recipients is required.
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BACKGROUND: Cognitive dysfunction in people with relapsing-remitting multiple sclerosis can improve with cognitive rehabilitation or exercise. Similar effects have not been clearly shown in people with progressive multiple sclerosis. We aimed to investigate the individual and synergistic effects of cognitive rehabilitation and exercise in patients with progressive multiple sclerosis. METHODS: CogEx was a randomised, sham-controlled trial completed in 11 hospital clinics, universities, and rehabilitation centres in Belgium, Canada, Denmark, Italy, UK, and USA. Patients with progressive multiple sclerosis were eligible for inclusion if they were aged 25-65 years and had an Expanded Disability Status Scale (EDSS) score of less than 7. All had impaired processing speed defined as a performance of 1·282 SD or greater below normative data on the Symbol Digit modalities Tests (SDMT). Participants were randomly assigned (1:1:1:1), using an interactive web-response system accessed online from each centre, to cognitive rehabilitation plus exercise, cognitive rehabilitation plus sham exercise, exercise plus sham cognitive rehabilitation, or sham exercise plus sham cognitive rehabilitation. The study statistician created the randomisation sequence that was stratified by centre. Participants, outcome assessors, and investigators were blinded to group allocation. The study statistician was masked to treatment during analysis only. Interventions were conducted two times per week for 12 weeks: cognitive rehabilitation used an individualised, computer-based, incremental approach to improve processing speed; sham cognitive rehabilitation consisted of internet training provided individually; the exercise intervention involved individualised aerobic training using a recumbent arm-leg stepper; and the sham exercise involved stretching and balance tasks without inducing cardiovascular strain. The primary outcome measure was processing speed measured by SDMT at 12 weeks; least squares mean differences were compared between groups using linear mixed model in all participants who had a 12-week assessment. The trial is registered with ClinicalTrials.gov, NCT03679468, and is completed. FINDINGS: Between Dec 14, 2018, and April 2, 2022, 311 people with progressive multiple sclerosis were enrolled and 284 (91%) completed the 12-week assessment (117/311 [38%] male and 194/311 [62%] female). The least squares mean group differences in SDMT at 12 weeks did not differ between groups (p=0·85). Compared with the sham cognitive rehabilitation and sham exercise group (n=67), differences were -1·30 (95% CI -3·75 to 1·16) for the cognitive rehabilitation plus exercise group (n=70); -2·78 (-5·23 to -0·33) for the sham cognitive rehabilitation plus exercise group (n=71); and -0·71 (-3·11 to 1·70) for the cognitive rehabilitation plus sham exercise group (n=76). 11 adverse events possibly related to the interventions occurred, six in the exercise plus sham cognitive rehabilitation group (pain, dizziness, and falls), two in the cognitive rehabilitation plus sham exercise group (headache and pain), two in the cognitive rehabilitation and exercise group (increased fatigue and pain), and one in the dual sham group (fall). INTERPRETATION: Combined cognitive rehabilitation plus exercise does not seem to improve processing speed in people with progressive multiple sclerosis. However, our sham interventions were not inactive. Studies comparing interventions with a non-intervention group are needed to investigate whether clinically meaningful improvements in processing speed might be attainable in people with progressive multiple sclerosis. FUNDING: MS Canada.
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Disfunção Cognitiva , Esclerose Múltipla , Humanos , Feminino , Masculino , Treino Cognitivo , Exercício Físico , Terapia por Exercício , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/terapiaRESUMO
BACKGROUND: Altered thalamic volumes and resting state (RS) functional connectivity (FC) might be associated with physical activity (PA) and cardiorespiratory fitness (CRF) in people with progressive multiple sclerosis (PMS). OBJECTIVES: To assess thalamic structural and functional alterations and investigate their correlations with PA/CRF levels in people with PMS. METHODS: Seven-day accelerometry and cardiopulmonary exercise testing were used to assess PA/CRF levels in 91 persons with PMS. They underwent 3.0 T structural and RS fMRI acquisition with 37 age/sex-matched healthy controls (HC). Between-group comparisons of MRI measures and their correlations with PA/CRF variables were assessed. RESULTS: PMS people had lower volumes compared to HC (all p < 0.001). At corrected threshold, PMS showed decreased intra- and inter-thalamic RS FC, and increased RS FC between the thalamus and the hippocampus, bilaterally. At uncorrected threshold, decreased thalamic RS FC with caudate nucleus, cerebellum and anterior cingulate cortex (ACC), as well as increased thalamic RS FC with occipital regions, were also detected. Lower CRF, measured as peak oxygen consumption (VO2peak), correlated with lower white matter volume (r = 0.31, p = 0.03). Moreover, lower levels of light PA correlated with increased thalamic RS FC with the right hippocampus (r = - 0.3, p = 0.05). DISCUSSION: People with PMS showed widespread brain atrophy, as well as pronounced intra-thalamic and thalamo-hippocampal RS FC abnormalities. White matter atrophy correlated with CRF, while increased thalamo-hippocampal RS FC was associated to worse PA levels. Thalamic RS FC might be used to monitor physical impairment and efficacy of rehabilitative and disease-modifying treatments in future studies.
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Aptidão Cardiorrespiratória , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Humanos , Esclerose Múltipla/complicações , Tálamo , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/patologia , Imageamento por Ressonância Magnética , Atrofia/patologiaRESUMO
Shoulder pain is common after neurological injury and can be disabling, lead to poor functional outcomes and increase care costs. Its cause is multifactoral and several pathologies contribute to the presentation. Astute diagnostic skills and a multidisciplinary approach are required to recognise what is clinically relevant and to implement appropriate stepwise management. In the absence of large clinical trial data, we aim to provide a comprehensive, practical and pragmatic overview of shoulder pain in patients with neurological conditions. We use available evidence to produce a management guideline, taking into account specialty opinions from neurology, rehabilitation medicine, orthopaedics and physiotherapy.
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Dor de Ombro , Acidente Vascular Cerebral , Humanos , Hemiplegia/etiologia , Hemiplegia/reabilitação , Manejo da Dor , Dor de Ombro/diagnóstico , Dor de Ombro/etiologia , Dor de Ombro/terapia , Acidente Vascular Cerebral/complicaçõesRESUMO
BACKGROUND: Frontal cortico-subcortical dysfunction may contribute to fatigue and dual-task impairment of walking and cognition in progressive multiple sclerosis (PMS). PURPOSE: To explore the associations among fatigue, dual-task performance and structural and functional abnormalities of frontal cortico-subcortical network in PMS. METHODS: Brain 3 T structural and functional MRI sequences, Modified Fatigue Impact Scale (MFIS), dual-task motor and cognitive performances were obtained from 57 PMS patients and 10 healthy controls (HC). The associations of thalamic, caudate nucleus and dorsolateral prefrontal cortex (DLPFC) atrophy, microstructural abnormalities of their connections and their resting state effective connectivity (RS-EC) with fatigue and dual-task performance were investigated using random forest. RESULTS: Thirty-seven PMS patients were fatigued (F) (MFIS ≥ 38). Compared to HC, non-fatigued (nF) and F-PMS patients had significantly worse dual-task performance (p ≤ 0.002). Predictors of fatigue (out-of-bag [OOB]-accuracy = 0.754) and its severity (OOB-R2 = 0.247) were higher Expanded Disability Status scale (EDSS) score, lower RS-EC from left-caudate nucleus to left-DLPFC, lower fractional anisotropy between left-caudate nucleus and left-thalamus, higher mean diffusivity between right-caudate nucleus and right-thalamus, and longer disease duration. Microstructural abnormalities in connections among thalami, caudate nuclei and DLPFC, mainly left-lateralized in nF-PMS and more bilateral in F-PMS, higher RS-EC from left-DLPFC to right-DLPFC in nF-PMS and lower RS-EC from left-caudate nucleus to left-DLPFC in F-PMS, higher EDSS score, higher WM lesion volume, and lower cortical volume predicted worse dual-task performances (OOB-R2 from 0.426 to 0.530). CONCLUSIONS: In PMS, structural and functional frontal cortico-subcortical abnormalities contribute to fatigue and worse dual-task performance, with different patterns according to the presence of fatigue.
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Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Humanos , Esclerose Múltipla/complicações , Análise e Desempenho de Tarefas , Encéfalo/patologia , Mapeamento Encefálico , Esclerose Múltipla Crônica Progressiva/diagnóstico por imagem , Esclerose Múltipla Crônica Progressiva/patologia , Imageamento por Ressonância MagnéticaRESUMO
OBJECTIVE: An earlier follow-up study from the CogEx rehabilitation trial showed little change in symptoms of depression, anxiety and psychological distress during the first COVID-19 lockdown compared to pre-pandemic measurements. Here, we provide a second follow-up set of behavioral data on the CogEx sample. METHODS: This was an ancillary, longitudinal follow-up study in CogEx, a randomized controlled trial of exercise and cognitive rehabilitation in people with progressive MS involving 11 centres in North America and Europe. Only individuals impaired on the Symbol Digit Modalities Test (SDMT) were included. Participants repeated the COVID Impact survey administered approximately a year later and completed self-report measures of depression, anxiety and MS symptoms that had been obtained at the trial baseline and during the first COVID Impact survey. Participants who completed the second COVID Impact follow-up were included. To identify predictors of the participants' ratings of their mental and physical well-being, step-wise linear regression was conducted. RESULTS: Of the 131 participants who completed the first COVID impact survey, 74 participants completed the second follow-up survey (mean age 52 (SD = 6.4) years, 62.2% female, mean disease duration 16.4 (SD = 9.0) years, median EDSS 6.0). Pandemic restrictions prevented data collection from sites in Denmark and England (n = 57). The average time between measurements was 11.4 (SD = 5.56) months. There were no significant differences in age, sex, EDSS, disease course and duration between those who participated in the current follow-up study (n = 74) and the group that could not (n = 57). One participant had COVID in the time between assessments. Participants now took a more negative view of their mental/psychological well-being (p = 0.0001), physical well-being (p = 0.0009) and disease course (p = 0.005) compared to their last assessment. Depression scores increased on the HADS-depression scale (p = 0.01) and now exceeded the clinically significant threshold of ≥ 8.0 for the first time. Anxiety scores on the HADS remained unchanged. Poorer mental well-being was predicted by HADS depression scores (p = 0.012) and a secondary-progressive disease course (p = 0.0004). CONCLUSIONS: A longer follow-up period revealed the later onset of clinically significant depressive symptoms on the HADS and a decline in self-perceptions of mental and physical well-being associated with the COVID-19 pandemic relative to the first follow-up data point. TRIAL REGISTRATION: The trial was registered on September 20th 2018 at www. CLINICALTRIALS: gov having identifier NCT03679468. Registration was performed before recruitment was initiated.
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COVID-19 , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Angústia Psicológica , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Pandemias , Esclerose Múltipla/complicações , Seguimentos , Controle de Doenças Transmissíveis , Ansiedade/epidemiologia , Ansiedade/etiologia , Depressão/epidemiologia , Depressão/etiologia , Depressão/diagnósticoRESUMO
There has been a growing interest in the role that genetic factors influence pediatric pulmonary vascular disease. In fact, data suggests that genetic factors contribute to ~42% of pediatric-onset pulmonary hypertension. Although animal and human studies suggest that aberrations in Caveolin1 (CAV1) signaling participate in the development of pulmonary vascular disorders, limited reports of CAV1-associated heritable pulmonary arterial hypertension (HPAH) exist. This is a case report of a 2-year-old female with late recognition of HPAH due to a CAV1 pathogenic variant: c.474del, (p.Leu159Serfs*22)(NM_001753.5). The pedigree demonstrates autosomal dominant transmission with reduced penetrance of PAH, suggestive that additional genetic or environmental factors modify PAH development. Genetic testing and the discovery of rare genetic alterations in PAH during infancy and childhood may aid in identifying disease etiologies, guide therapeutic decisions, and ultimately identify novel therapeutic targets. Moreover, CAV1 genetics implicate variable expressivity and incomplete penetrance for HPAH and underscores the utility of predictive genetic testing for unaffected family members no matter their age.
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OBJECTIVE: Processing speed (PS) deficits are the most common cognitive deficits in multiple sclerosis (MS), followed by learning and memory deficits, and are often an early cognitive problem. It has been argued that impaired PS is a primary consequence of MS, which in turn decreases learning. The current analysis examined the association between PS and learning in a large cohort of individuals with progressive MS. METHODS: Baseline data from a randomized clinical trial on rehabilitation taking place at 11 centers across North America and Europe were analyzed. Participants included 275 individuals with clinically definite progressive MS (primary, secondary) consented into the trial. RESULTS: Symbol Digit Modalities Test (SDMT) significantly correlated with California Verbal Learning Test-II (CVLT-II) (r = 0.21, p = 0.0003) and Brief Visuospatial Memory Test-Revised (BVMT-R) (r = 0.516, p < 0.0001). Receiver operating characteristic (ROC) analysis of the SDMT z score to distinguish between impaired and non-impaired CVLT-II performance demonstrated an area under the curve (AUC) of 0.61 (95% confidence interval (CI): 0.55-0.68) and a threshold of -1.62. ROC analysis between SDMT and BVMT-R resulted in an AUC of 0.77 (95% CI: 0.71-0.83) and threshold of -1.75 for the SDMT z score to predict impaired BVMT-R. CONCLUSION: Results indicate little ability beyond chance to predict CVLT-II from SDMT (61%), albeit statistically significant. In contrast, there was a 77% chance that the model could distinguish between impaired and non-impaired BVMT-R. Several potential explanations are discussed.
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Transtornos Cognitivos , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Cognição , Transtornos Cognitivos/complicações , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/psicologia , Esclerose Múltipla Crônica Progressiva/complicações , Testes NeuropsicológicosRESUMO
OBJECTIVE: To systematically review evidence regarding prevalence and choices of disclosure of psychological distress, by mental health professionals within the workplace. METHODS: Six databases were searched in June 2020. Studies were included if they were published in English language and included empirical quantitative, qualitative or mixed-methods data. Studies were excluded if they focused on general healthcare professionals or the general population, or on stress or physical health problems. Study quality was assessed using the Mixed Methods Quality Appraisal tool. RESULTS: Nine studies, with a total of 1891 participants, were included. Study quality varied, with studies generally reporting descriptive surveys using hypothetical disclosure scenarios. Distress was often conceptualized in psychiatric terms. These limitations mean conclusions should be treated with caution. Individuals were less likely to disclose in work and had negative experiences of doing so compared to social circles. Fear of stigma inhibited disclosure. There were differing levels of disclosure relating to recipient, trust, quality of supervision, how distress was conceptualized, and type of problem. Disclosure was experienced by some as valuable. CONCLUSION: There is a need for further research, which addresses the nuanced complexities surrounding disclosure choices for mental health professionals.
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Angústia Psicológica , Local de Trabalho , Revelação , Pessoal de Saúde , Humanos , Saúde Mental , Local de Trabalho/psicologiaRESUMO
BACKGROUND: Aerobic exercise training (physical activity for improving cardiorespiratory fitness) represents a promising approach for managing cognitive impairment in multiple sclerosis (MS). However, there is limited evidence that levels of physical activity and fitness are associated with cognition in progressive MS. OBJECTIVE: We examined associations among cardiorespiratory fitness, moderate-to-vigorous physical activity (MVPA), and cognitive performance in a large, international progressive MS sample. METHODS: Two hundred forty European and North American persons with progressive MS underwent cardiorespiratory fitness measurement on a recumbent stepper, wore an ActiGraph GT3X + accelerometer for 7 days for measuring MVPA, and underwent the Brief International Cognitive Assessment in MS. RESULTS: Cardiorespiratory fitness was not significantly correlated with Symbol Digit Modalities Test (SDMT; r = -0.01; r = -0.04), California Verbal Learning Test-II (CVLT-II; r = 0.05; r = 0.05), or Brief Visuospatial Memory Test-Revised (BVMT-R; r = -0.14; r = -0.14) z-scores controlling for age, sex, and education. MVPA and SDMT (r = 0.05), CVLT-II (r = -0.07), and BVMT-R (r = 0.01) z-scores were not significantly correlated. CONCLUSION: Cardiorespiratory fitness and MVPA were not associated with cognition in this large progressive MS sample, yet these outcomes represent critical manipulation checks for documenting the success of the CogEx trial. This highlights the importance of examining other exercise-related mechanisms-of-action for improving cognition in progressive MS.
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Aptidão Cardiorrespiratória , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Cognição , Exercício Físico , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/psicologia , Esclerose Múltipla Crônica Progressiva/complicações , Testes Neuropsicológicos , Aptidão FísicaRESUMO
Pandemic restrictions have led to changes in therapy plans and disrupted rehabilitation services for people with multiple sclerosis. CogEx is an international, multicentre MS dual-intervention (cognitive rehabilitation, aerobic exercise) randomized, controlled rehabilitation trial confined to people with progressive disease. The primary outcome is cognition (processing speed).There are 11 treatment sites in six countries with participants required to make 27 site visits over 12 weeks. Collectively, the large, in-person demands of the trial, and the varying international policies for the containment of COVID-19, might disproportionately impact the administration of CogEx. During the first lockdown, all centres closed on average for 82.9 (SD = 24.3) days. One site was required to lockdown on two further occasions. One site remained closed for 16 months. Ten staff (19.2%) were required to quarantine and eight staff (15.4%) tested positive for COVID. 10 of 264 (3.8%) participants acquired COVID-19. All survived. The mean duration of enrollment delay has been [236.7 (SD = 214.5) days]. Restarting participants whose interventions were interrupted by the pandemic meant recalculating the intervention prescriptions for these individuals. While the impact of the pandemic on CogEx has been considerable, all study sites are again open. Participants and staff have shown considerable flexibility and resilience in keeping a complex, international endeavour running. The future in general remains uncertain in the midst of a pandemic, but there is cautious optimism the study will be completed with sufficient sample size to robustly evaluate our hypothesis and provide meaningful results to the MS community on the impact of these interventions on people with progressive MS.Trial registration: The trial was registered on September 20th 2018 at www.clinicaltrials.gov having identifier NCT03679468. Registration was performed before recruitment was initiated.
Assuntos
COVID-19 , Esclerose Múltipla , Controle de Doenças Transmissíveis , Exercício Físico , Humanos , Esclerose Múltipla/terapia , PandemiasRESUMO
Multiple sclerosis (MS) is a chronic neurological disease driven by autoimmune, inflammatory and neurodegenerative processes leading to neuronal demyelination and subsequent degeneration. Systemic lipid metabolism is disturbed in people with MS, and lipid metabolic pathways are crucial to the protective process of remyelination. The lipid-activated transcription factors liver X receptors (LXRs) are important integrators of lipid metabolism and immunity. Consequently, there is a strong interest in targeting these receptors in a number of metabolic and inflammatory diseases, including MS. We have reviewed the evidence for involvement of LXR-driven lipid metabolism in the dysfunction of peripheral and brain-resident immune cells in MS, focusing on human studies, both the relapsing remitting and progressive phases of the disease are discussed. Finally, we discuss the therapeutic potential of modulating the activity of these receptors with existing pharmacological agents and highlight important areas of future research.