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Bullying, discrimination, and harassment (BDH) within healthcare teams is a global issue that risks healthcare worker wellbeing, patient safety, public health, and industry reputations. Collectively, fragmented regulation, weak detection and correction processes, conflicts of interest, and fear of retribution for complainants create an environment that enables perpetrators. Specialty training Colleges and other stakeholders can collaborate to address this issue more effectively. This paper examines Australian processes and proposes that the existing disparate mechanisms should be replaced with a national BDH framework that is supported by an independent investigation body. The authors seek to stimulate discussion to reform practice in Australia and in other countries with similar health systems.
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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system affecting predominantly adults. It is a complex disease associated with both environmental and genetic risk factors. Although over 230 risk single-nucleotide polymorphisms have been associated with MS, all are common human variants. The mechanisms by which they increase the risk of MS, however, remain elusive. We hypothesized that a complex genetic phenotype such as MS could be driven by coordinated expression of genes controlled by transcriptional regulatory networks. We, therefore, constructed a gene coexpression network from microarray expression analyses of five purified peripheral blood leukocyte subsets of 76 patients with relapsing remitting MS and 104 healthy controls. These analyses identified a major network (or module) of expressed genes associated with MS that play key roles in cell-mediated cytotoxicity which was downregulated in monocytes of patients with MS. Manipulation of the module gene expression was achieved in vitro through small interfering RNA gene knockdown of identified drivers. In a mouse model, network gene knockdown modulated the autoimmune inflammatory MS model disease-experimental autoimmune encephalomyelitis. This research implicates a cytotoxicity-associated gene network in myeloid cells in the pathogenesis of MS.
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Pain, particularly musculoskeletal (MSK) and multi-site pain, significantly impacts activities of daily living (ADL) in the elderly, leading to a decline in overall quality of life (QoL). This study, comprising 7490 participants, (mean age: 69 ± 10; females: 57%) from the sixth wave of the Korean Longitudinal Study of Aging (KLoSA), aimed to assess the association between self-reported pain and ADL impairment among the elderly population. Notably, 62% of participants reported experiencing pain, with back pain being the most prevalent (36%) and stomachache the least (0.39%). A majority (61%) of individuals reported MSK-related pain. Additionally, 20% reported pain at one site and 0.03% experienced pain at 12 sites. ADL impairment was observed in 376 (5.0%) participants. Compared to those without pain, participants reporting moderate and severe pain had higher odds of ADL impairment [2.31 (95% CI, 1.66-3.21) and 2.98 (95% CI, 1.95-4.53), respectively]. Pain experienced in the shoulder, arm, wrist, back, hip, leg, and ankle had a significant association with ADL impairment, with ORs ranging from 2.66 (95% CI, 1.80-3.93; hip pain) to 1.36 (95% CI 1.07-1.72; back pain). Furthermore, multi-site pain was associated with higher ADL impairment [1-6 sites: OR: 1.49 (95% CI, 1.11-2.01); 7-12 sites: OR: 7.16 (95% CI, 3.60-14.26)]. These findings underscore the importance of addressing MSK and multi-site pain through targeted interventions, potentially enhancing ADL and contributing to an improved QoL among the elderly population.
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Vitamin D deficiency is a risk factor for developing multiple sclerosis. The PrevANZ trial was conducted to determine if vitamin D3 supplementation can prevent recurrent disease activity in people with a first demyelinating event. As a sub-study of this trial, we investigated the effect of supplementation on peripheral immune cell gene expression. Participants were randomized to 1000, 5000 or 10,000 international units daily of vitamin D3 or placebo. Peripheral blood was collected at baseline and 12 weeks and sent for ribonucleic acid sequencing. Datasets from 55 participants were included. Gene expression was modulated by high dose supplementation. Antigen presentation and viral response pathways were upregulated. Oxidative phosphorylation and immune signaling pathways, including tumor necrosis factor-alpha and interleukin-17 signaling, were downregulated. Overall, vitamin D3 supplementation for 12 weeks modulated the peripheral immune cell transcriptome with induction of anti-inflammatory gene expression profiles. Our results support a dose-dependent effect of vitamin D3 supplementation on immune gene expression.
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Colecalciferol , Deficiencia de Vitamina D , Humanos , Colecalciferol/farmacología , Suplementos Dietéticos , Método Doble Ciego , Factores de Riesgo , Transcriptoma , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/genéticaRESUMEN
BACKGROUND AND OBJECTIVES: The impact of immunomodulatory therapies on the risk of cervical pre-cancer and invasive cancer development is important for the health and safety of women with multiple sclerosis (wwMS). We investigate the risk of cervical abnormalities in wwMS treated with disease-modifying therapies (DMTs). METHODS: This is a multicenter cohort study with data collected from 1998 to 2019 in Victoria, Australia. Data linkage was performed using matching records from the MSBase Registry, the National Human Papillomavirus (HPV) Vaccination Program Register, and the Victorian Cervical Cytology Register. The primary outcome was the detection of any type of cervical abnormality as determined by cytology or histology. Survival methods were used to assess the time to cervical abnormality detection on cervical screening tests (CSTs). Crude and adjusted Cox proportional hazards models were used to determine time to and magnitude of association of DMTs with the risk of cervical abnormality. In a sensitivity analysis, we constructed standardized survival curves averaged over the same set of covariates to determine the commensurate population-average (marginal) causal effects. RESULTS: We included 248 wwMS. The incidence of abnormal CSTs was lower (p < 0.001) for women not exposed to moderate-high-efficacy therapy (10.2 per 1,000 patient-years [95% confidence interval (CI) 5.5-14.9]), compared with those exposed (36.6 per 1,000 patient-years [95% CI 21.7-51.6]). Exposure to higher efficacy treatment was associated with a 3.79-fold increased hazard (95% CI 2.02-7.08, p < 0.001) of developing a cervical abnormality relative to those not exposed. When adjusted for vaccination status, smoking, hormonal contraceptive use, and socioeconomic status, the risk remained elevated at 3.79 (95% CI 1.99-7.21, p < 0.001). Marginal hazard ratios declined over time, ranging from 3.90 (95% CI 2.09-7.27) at 20 years of age to 2.06 (95% CI 1.14-3.73) at 70 years of age. DISCUSSION: A greater than three-and-a-half-fold increased risk of cervical abnormalities was found after exposure to moderate-high-efficacy DMTs. This risk persisted despite adjusting for HPV vaccination status, hormonal contraception use, smoking, and socioeconomic status. If confirmed in future studies, we would advocate for wwMS exposed to moderate-high-efficacy DMTs to be treated in line with immune-deficient paradigm in cervical screening and HPV vaccination programs. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that highly active MS therapy compared with less active therapy increases the risk of developing cervical abnormalities among women with MS.
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Esclerosis Múltiple , Infecciones por Papillomavirus , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Femenino , Humanos , Preescolar , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/patología , Displasia del Cuello del Útero/diagnóstico , Displasia del Cuello del Útero/patología , Estudios de Cohortes , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/prevención & control , Detección Precoz del Cáncer/métodos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/complicaciones , Victoria/epidemiologíaRESUMEN
Vitamin D deficiency is a risk factor for developing multiple sclerosis (MS). However, the immune effects of vitamin D in people with MS are not well understood. We analyzed transcriptomic datasets generated by RNA sequencing of immune cell subsets (CD4+, CD8+ T cells, B cells, monocytes) from 33 healthy controls and 33 untreated MS cases. We utilized a traditional bioinformatic pipeline and weighted gene co-expression network analysis (WGCNA) to determine genes and pathways correlated with endogenous vitamin D. In controls, CD4+ and CD8+ T cells had 1079 and 1188 genes, respectively, whose expressions were correlated with plasma 25-hydroxyvitamin D level (P < 0.05). Functional enrichment analysis identified association with TNF-alpha and MAPK signaling. In CD4+ T cells of controls, vitamin D level was associated with expression levels of several genes proximal to multiple sclerosis risk loci (P = 0.01). Genes differentially associated with endogenous vitamin D by case-control status were enriched in TNF-alpha signaling via NF-κB. WGCNA suggested a blunted response to vitamin D in cases relative to controls. Collectively, our findings provide further evidence for the immune effects of vitamin D, and demonstrate a differential immune response to vitamin D in cases relative to controls, highlighting a possible mechanism contributing to MS pathophysiology.
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Esclerosis Múltiple , Humanos , Esclerosis Múltiple/metabolismo , Factor de Necrosis Tumoral alfa , Linfocitos T CD8-positivos/metabolismo , Vitamina D , Inmunidad , Vitaminas , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: Pregnancy in women with multiple sclerosis (wwMS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown, but converging evidence suggests a role for epigenetic mechanisms altering immune and/or central nervous system function. In this study, we aimed to identify whole blood and immune cell-specific DNA methylation patterns associated with parity in relapse-onset MS. RESULTS: We investigated the association between whole blood and immune cell-type-specific genome-wide methylation patterns and parity in 192 women with relapse-onset MS, matched for age and disease severity. The median time from last pregnancy to blood collection was 16.7 years (range = 1.5-44.4 years). We identified 2965 differentially methylated positions in whole blood, 68.5% of which were hypermethylated in parous women; together with two differentially methylated regions on Chromosomes 17 and 19 which mapped to TMC8 and ZNF577, respectively. Our findings validated 22 DMPs and 366 differentially methylated genes from existing literature on epigenetic changes associated with parity in wwMS. Differentially methylated genes in whole blood were enriched in neuronal structure and growth-related pathways. Immune cell-type-specific analysis using cell-type proportion estimates from statistical deconvolution of whole blood revealed further differential methylation in T cells specifically (four in CD4+ and eight in CD8+ T cells). We further identified reduced methylation age acceleration in parous women, demonstrating slower biological aging compared to nulligravida women. CONCLUSION: Differential methylation at genes related to neural plasticity offers a potential molecular mechanism driving the long-term effect of pregnancy on MS outcomes. Our results point to a potential 'CNS signature' of methylation in peripheral immune cells, as previously described in relation to MS progression, induced by parity. As the first epigenome-wide association study of parity in wwMS reported, validation studies are needed to confirm our findings.
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Metilación de ADN , Esclerosis Múltiple , Embarazo , Humanos , Femenino , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Paridad , Linfocitos T CD8-positivos/metabolismo , Plasticidad Neuronal , Proteínas de la Membrana/genéticaRESUMEN
Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis registry, MSBase. We assembled a cohort of deeply phenotyped individuals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1813 individuals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (ß = -0.4882, P = 2.73 × 10-7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62 000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79-0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48-0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273; ßfemale = 0.8289, P = 3.52 × 10-8), the other in males (rs698805; ßmale = -1.5395, P = 4.35 × 10-8), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrichment and pathway analyses identified an overrepresentation of genes expressed in CNS compartments generally, and specifically in the cerebellum (P = 0.023). These involved mitochondrial function, synaptic plasticity, oligodendroglial biology, cellular senescence, calcium and G-protein receptor signalling pathways. We further identified six variants with strong evidence for regulating clinical outcomes, the strongest signal again intronic to SEZ6L (adjusted hazard ratio 0.72, P = 4.85 × 10-4). Here we report a milestone in our progress towards understanding the clinical heterogeneity of multiple sclerosis outcomes, implicating functionally distinct mechanisms to multiple sclerosis risk. Importantly, we demonstrate that machine learning using common single nucleotide variant clusters, together with clinical variables readily available at diagnosis can improve prognostic capabilities at diagnosis, and with further validation has the potential to translate to meaningful clinical practice change.
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Esclerosis Múltiple , Masculino , Femenino , Humanos , Esclerosis Múltiple/genética , Estudio de Asociación del Genoma Completo , Recurrencia Local de Neoplasia , Pronóstico , Sistema InmunológicoRESUMEN
Understanding how variations in the plasma and brain proteome contribute to multiple sclerosis susceptibility can provide important insights to guide drug repurposing and therapeutic development for the disease. However, the role of genetically predicted protein abundance in multiple sclerosis remains largely unknown. Integrating plasma proteomics (n = 3301) and brain proteomics (n = 376 discovery; n = 152 replication) into multiple sclerosis genome-wide association studies (n = 14 802 cases and 26 703 controls), we employed summary-based methods to identify candidate proteins involved in multiple sclerosis susceptibility. Next, we evaluated associations of the corresponding genes with multiple sclerosis at tissue-level using large gene expression quantitative trait data from whole-blood (n = 31 684) and brain (n = 1194) tissue. Further, to assess transcriptional profiles for candidate proteins at cell-level, we examined gene expression patterns in immune cell types (Dataset 1: n = 73 cases and 97 controls; Dataset 2: n = 31 cases and 31 controls) for identified plasma proteins, and in brain cell types (Dataset 1: n = 4 cases and 5 controls; Dataset 2: n = 5 cases and 3 controls) for identified brain proteins. In a longitudinal multiple sclerosis cohort (n = 203 cases followed up to 15 years), we also assessed the corresponding gene-level associations with the outcome of disability worsening. We identified 39 novel proteins associated with multiple sclerosis risk. Based on five identified plasma proteins, four available corresponding gene candidates showed consistent associations with multiple sclerosis risk in whole-blood, and we found TAPBPL upregulation in multiple sclerosis B cells, CD8+ T cells and natural killer cells compared with controls. Among the 34 candidate brain proteins, 18 were replicated in a smaller cohort and 14 of 21 available corresponding gene candidates also showed consistent associations with multiple sclerosis risk in brain tissue. In cell-specific analysis, six identified brain candidates showed consistent differential gene expression in neuron and oligodendrocyte cell clusters. Based on the 39 protein-coding genes, we found 23 genes that were associated with disability worsening in multiple sclerosis cases. The findings present a set of candidate protein biomarkers for multiple sclerosis, reinforced by high concordance in downstream transcriptomics findings at tissue-level. This study also highlights the heterogeneity of cell-specific transcriptional profiles for the identified proteins and that numerous candidates were also implicated in disease progression. Together, these findings can serve as an important anchor for future studies of disease mechanisms and therapeutic development.
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Esclerosis Múltiple , Humanos , Esclerosis Múltiple/genética , Estudio de Asociación del Genoma Completo , Biomarcadores , Proteínas Sanguíneas/genética , Encéfalo , Inmunoglobulinas/genética , Proteínas de la Membrana/genéticaRESUMEN
BACKGROUND: The variation in multiple sclerosis (MS) disease severity is incompletely explained by genetics, suggesting genetic and environmental interactions are involved. Moreover, the lack of prognostic biomarkers makes it difficult for clinicians to optimise care. DNA methylation is one epigenetic mechanism by which gene-environment interactions can be assessed. Here, we aimed to identify DNA methylation patterns associated with mild and severe relapse-onset MS (RMS) and to test the utility of methylation as a predictive biomarker. METHODS: We conducted an epigenome-wide association study between 235 females with mild (n = 119) or severe (n = 116) with RMS. Methylation was measured with the Illumina methylationEPIC array and analysed using logistic regression. To generate hypotheses about the functional consequence of differential methylation, we conducted gene set enrichment analysis using ToppGene. We compared the accuracy of three machine learning models in classifying disease severity: (1) clinical data available at baseline (age at onset and first symptoms) built using elastic net (EN) regression, (2) methylation data using EN regression and (3) a weighted methylation risk score of differentially methylated positions (DMPs) from the main analysis using logistic regression. We used a conservative 70:30 test:train split for classification modelling. A false discovery rate threshold of 0.05 was used to assess statistical significance. RESULTS: Females with mild or severe RMS had 1472 DMPs in whole blood (839 hypermethylated, 633 hypomethylated in the severe group). Differential methylation was enriched in genes related to neuronal cellular compartments and processes, and B-cell receptor signalling. Whole-blood methylation levels at 1708 correlated CpG sites classified disease severity more accurately (machine learning model 2, AUC = 0.91) than clinical data (model 1, AUC = 0.74) or the wMRS (model 3, AUC = 0.77). Of the 1708 selected CpGs, 100 overlapped with DMPs from the main analysis at the gene level. These overlapping genes were enriched in neuron projection and dendrite extension, lending support to our finding that neuronal processes, rather than immune processes, are implicated in disease severity. CONCLUSION: RMS disease severity is associated with whole-blood methylation at genes related to neuronal structure and function. Moreover, correlated whole-blood methylation patterns can assign disease severity in females with RMS more accurately than clinical data available at diagnosis.
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Metilación de ADN , Esclerosis Múltiple , Femenino , Humanos , Esclerosis Múltiple/genética , Epigénesis Genética , Epigenoma , Gravedad del Paciente , Islas de CpGRESUMEN
OBJECTIVE: To evaluate the prevalence and biomarkers of drug-resistant epilepsy (DRE) in patients with autoimmune encephalitis (AIE). METHODS: Sixty-nine patients with AIE were recruited retrospectively and electroencephalographies (EEGs) were reviewed using a standard reporting proforma. Associations between EEG biomarkers and DRE development at 12â¯months were examined using logistic regression modeling and were utilized to create a DRE risk score. RESULTS: Sixteen percent of patients with AIE developed DRE at 12-month follow-up. The presence of status epilepticus (SE) (OR 11.50, 95% CI [2.81, 51.86], p-value <0.001), temporal lobe focality (OR 9.90, 95% CI [2.60, 50.71], p-value 0.001) and periodic discharges (OR 19.12, 95% CI [3.79, 191.10], p-value 0.001) on the admission EEG were associated with the development of DRE at 12â¯months. These variables were utilized to create a clinically applicable risk score for the prediction of DRE development. CONCLUSIONS: Drug-resistant epilepsy is an infrequent complication of AIE. Electroencephalography changes during the acute illness can predict the risk of DRE at 12â¯months post-acute AIE. SIGNIFICANCE: The identified EEG biomarkers provide the basis to generate a clinically applicable prediction tool which could be used to inform treatment, prognosis, and select patients for acute treatment trials.
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Epilepsia Refractaria , Encefalitis , Biomarcadores , Epilepsia Refractaria/diagnóstico , Epilepsia Refractaria/epidemiología , Epilepsia Refractaria/etiología , Electroencefalografía/efectos adversos , Encefalitis/complicaciones , Encefalitis/epidemiología , Enfermedad de Hashimoto , Humanos , Prevalencia , Pronóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
This retrospective cohort study analyzed the administrative hospital records of 91,500 patients with the aim of assessing adverse drug reaction (ADR)-related hospital admission risk after discharge from ADR and non-ADR-related admission. Patients aged ≥18 years with an acute admission to public hospitals in Tasmania, Australia between 2011 and 2015 were followed until May 2017. The index admissions (n = 91,550) were stratified based on whether they were ADR-related (n = 2843, 3.1%) or non-ADR-related (n = 88,707, 96.9%). Survival analysis assessed the post-index ADR-related admission risk using (1) the full dataset, and (2) a matched subset of patients using a propensity score analysis. Logistic regression was used to identify the risk factors for ADR-related admissions within 90 days of post-index discharge. The patients with an ADR-related index admission were almost five times more likely to experience another ADR-related admission within 90 days (p < 0.001). An increased risk persisted for at least 5 years (p < 0.001), which was substantially longer than previously reported. From the matched subset of patients, the risk of ADR-related admission within 90 and 365 days more than doubled in the patients with an ADR-related index admission (p < 0.0001). These admissions were often attributed to the same drug class as the patients' index ADR-related admission. Cancer was a major risk factor for ADR-related re-hospitalization within 90 days; other factors included heart failure and increasing age.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Hospitalización , Adolescente , Adulto , Australia , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Hospitales , Humanos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: To evaluate the utility of electroencephalography (EEG) changes as diagnostic and prognostic biomarkers in acute autoimmune encephalitis (AIE). METHODS: One hundred and thirty-one patients with AIE were recruited retrospectively across 7 hospitals. Clinical data were collected during admission and at 12 months. EEGs were reviewed using a standard reporting proforma. Associations between EEG biomarkers, AIE subtypes, and clinical outcomes were assessed using logistic regression modeling. RESULTS: Presence of superimposed fast activity (OR 34.33; 95% CI 3.90, 4527.27; pâ¯<â¯0.001), fluctuating EEG abnormality (OR 6.60; 95% CI 1.60, 37.59; pâ¯=â¯0.008), and hemispheric focality (OR 28.48; 95% CI 3.14, 3773.14; pâ¯<â¯0.001) were significantly more common in N-methyl-d-aspartate receptor (NMDAR) antibody-associated patients with AIE compared to other AIE subtypes. Abnormal background rhythm was associated with a poor mRS (modified Rankin score) at discharge (OR 0.29; 95% CI 0.10, 0.75; pâ¯=â¯0.01) and improvement in mRS at 12â¯months compared with admission mRS (3.72; 95% CI 1.14, 15.23; pâ¯=â¯0.04). SIGNIFICANCE: We have identified EEG biomarkers that differentiate NMDAR AIE from other subtypes. We have also demonstrated EEG biomarkers that are associated with poor functional outcomes.
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Encefalitis Antirreceptor N-Metil-D-Aspartato , Enfermedad de Hashimoto , Encefalitis Antirreceptor N-Metil-D-Aspartato/complicaciones , Biomarcadores , Electroencefalografía , Enfermedad de Hashimoto/complicaciones , Enfermedad de Hashimoto/diagnóstico , Humanos , Estudios RetrospectivosRESUMEN
BACKGROUND: Increasingly, people with relapsing-remitting multiple sclerosis (RRMS) are switched to highly effective disease-modifying therapies (DMTs) such as ocrelizumab. OBJECTIVE: To determine predictors of relapse and disability progression when switching from another DMT to ocrelizumab. METHODS: Patients with RRMS who switched to ocrelizumab were identified from the MSBase Registry and grouped by prior disease-modifying therapy (pDMT; interferon-ß/glatiramer acetate, dimethyl fumarate, teriflunomide, fingolimod or natalizumab) and washout duration (<1 month, 1-2 months or 2-6 months). Survival analyses including multivariable Cox proportional hazard regression models were used to identify predictors of on-ocrelizumab relapse within 1 year, and 6-month confirmed disability progression (CDP). RESULTS: After adjustment, relapse hazard when switching from fingolimod was greater than other pDMTs, but only in the first 3 months of ocrelizumab therapy (hazard ratio (HR) = 3.98, 95% confidence interval (CI) = 1.57-11.11, p = 0.004). The adjusted hazard for CDP was significantly higher with longer washout (2-6 m compared to <1 m: HR = 9.57, 95% CI = 1.92-47.64, p = 0.006). CONCLUSION: The risk of disability worsening during switch to ocrelizumab is reduced by short treatment gaps. Patients who cease fingolimod are at heightened relapse risk in the first 3 months on ocrelizumab. Prospective evaluation of strategies such as washout reduction may help optimise this switch.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Anticuerpos Monoclonales Humanizados , Clorhidrato de Fingolimod/uso terapéutico , Inmunosupresores/uso terapéutico , Esclerosis Múltiple/inducido químicamente , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , RecurrenciaRESUMEN
BACKGROUND AND OBJECTIVES: Longitudinal cognitive trajectories in multiple sclerosis are heterogeneous and difficult to measure. We aimed to identify discrete longitudinal reaction time trajectories in relapsing-remitting multiple sclerosis using a computerized cognitive battery and to assess the association between trajectories of reaction time and disability progression. METHODS: All participants serially completed computerized reaction time tasks measuring psychomotor speed, visual attention, and working memory. Participants completed at least 3 testing sessions over a minimum of 180 days. Longitudinal reaction times were modeled with latent class mixed models to identify groups of individuals sharing similar latent characteristics. Optimal models were validated for consistency and baseline associations with class membership tested using multinomial logistic regression. Interclass differences in the probability of reaction time worsening and the probability of 6-month confirmed disability progression were assessed with survival analysis. RESULTS: A total of 460 people with relapsing-remitting multiple sclerosis were included in the analysis. For each task of the MSReactor battery, the optimal model comprised 3 latent classes. All MSReactor tasks could identify a group with high probability of reaction time slowing. The visual attention and working memory tasks could identify a group of participants who were 3.7 and 2.6 times more likely to experience a 6-month confirmed disability progression, respectively. Participants could be classified into predicted cognitive trajectories after just 5 tests with 64% to 89% accuracy. DISCUSSION: Latent class modeling of longitudinal cognitive data collected by a computerized battery identified patients with worsening reaction times and increased risk of disability progression. Slower baseline reaction time, age, and disability increased assignment into this trajectory. Monitoring of cognition in clinical practice with computerized tests may enable detection of cognitive change trajectories and people with relapsing-remitting multiple sclerosis at risk of disability progression.
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Trastornos del Conocimiento , Evaluación de la Discapacidad , Esclerosis Múltiple Recurrente-Remitente , Trastornos del Conocimiento/fisiopatología , Humanos , Estudios Longitudinales , Esclerosis Múltiple Recurrente-Remitente/psicología , Tiempo de Reacción/fisiología , Medición de RiesgoRESUMEN
BACKGROUND: People with multiple sclerosis and neuroimmunologic disorders (herein referred to as patients) are increasingly treated with infusible monoclonal antibodies. This rise in demand has placed increased loads on current infusion services and mandates careful strategic planning. This study examined patient preferences for the timing and location of infusions and their association with demographic and disease variables to facilitate patient-focused strategic planning. METHODS: Ninety-one patients receiving an infusible therapy at an infusion service during March 2019 were asked to complete a questionnaire exploring eight domains, including preferences for time of infusions and location of infusion centers. Potential access to home-based treatment was included as an option. Unstructured (free-text) feedback on current service was also obtained. RESULTS: Eighty-three patients completed the survey (mean age, 42 years; 75% women). Infusions were predominantly natalizumab (66%) and ocrelizumab (25%). Of these patients, 71% were engaged in some form of work or study, and 83% of this group had to arrange time off from work or study to attend treatment. Seventy percent of patients would prefer their infusion before noon, and 60% would consider home-based infusions. Most used a car as their transport to the infusion service. CONCLUSIONS: These results suggest that patients are more likely to prefer infusible treatment in the morning and are open to home-based infusions. This study provides information for health services to target service delivery at peak preference times and consider alternate ways of delivering infusible treatments.
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AIMS: To retrospectively assess factors associated with John Cunningham virus (JCV) seroconversion in natalizumab-treated patients. BACKGROUND: Natalizumab is highly effective for the treatment of relapsing-remitting multiple sclerosis (RRMS), but its use is complicated by opportunistic JCV infection. This virus can result in progressive multifocal leukoencephalopathy (PML). Serial assessment of JCV serostatus is mandated during natalizumab treatment. METHODS: Patients treated with natalizumab for RRMS at six tertiary hospitals in Melbourne, Australia (n = 865) and 11 MS treatment centres in Brazil (n = 136) were assessed for change in JCV serostatus, duration of exposure to natalizumab and prior immunosuppression. Sensitivity analyses examined whether sex, age, tertiary centre, prior immunosuppression or number of JCV tests affected time to seroconversion. RESULTS: From a cohort of 1001 natalizumab-treated patients, durable positive seroconversion was observed in 83 of 345 initially JCV negative patients (24.1%; 7.3% per year). Conversely, 16 of 165 initially JCV positive patients experienced durable negative seroconversion (9.7%; 3.8% per year). Forty patients (3.9%) had fluctuating serostatus. Time-to-event analysis did not identify a relationship between JCV seroconversion and duration of natalizumab exposure. Prior exposure to immunosuppression was not associated with an increased hazard of positive JCV seroconversion. Male sex was associated with increased JCV seroconversion risk [adjusted hazard ratio 2.09 (95% confidence interval 1.17-3.71) p = 0.012]. CONCLUSION: In this large international cohort of natalizumab-treated patients we observed an annual durable positive seroconversion rate of 7.3%. This rate exceeds that noted in registration and post-marketing studies for natalizumab. This rate also greatly exceeds that predicted by epidemiological studies of JCV seroconversion in healthy populations. Taken together, our findings support emerging evidence that natalizumab causes off-target immune changes that may be trophic for JCV seroconversion. In addition, male sex may be associated with increased positive JCV seroconversion.
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Cladribine is an approved selective immune reconstitution therapy for relapsing-remitting MS (RRMS). It was first developed and used to treat various forms of cancer, particularly leukemia via parenteral administration. The oral tablet version of cladribine was later developed to treat RRMS, an autoimmune disorder of the central nervous system (CNS) with periods of relapse and remission. Cladribine is found to selectively deplete adaptive immune cell types, and its role on innate immune cells is largely unknown. Among the lymphocyte populations and subtypes, the magnitude and kinetics of depletion by cladribine vary substantially. The current consensus on the selective cytotoxic effect of cladribine is that it is dependent on the deoxycytidine kinase (DCK) to 5'nucleotidase (5-NT) ratio of the immune cell type. Nonetheless, there are some discrepancies that cannot be fully elucidated by the DCK:5-NT ratio paradigm. This review aims to delineate the development and pharmacological properties of cladribine, and elucidate its influence on lymphoid and myeloid cells in MS.
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Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Cladribina , Humanos , Inmunosupresores , Células MieloidesRESUMEN
OBJECTIVE: To investigate pregnancy-related disease activity in a contemporary multiple sclerosis (MS) cohort. METHODS: Using data from the MSBase Registry, we included pregnancies conceived after 31 Dec 2010 from women with relapsing-remitting MS or clinically isolated syndrome. Predictors of intrapartum relapse, and postpartum relapse and disability progression were determined by clustered logistic regression or Cox regression analyses. RESULTS: We included 1998 pregnancies from 1619 women with MS. Preconception annualized relapse rate (ARR) was 0.29 (95% CI 0.27-0.32), fell to 0.19 (0.14-0.24) in third trimester, and increased to 0.59 (0.51-0.67) in early postpartum. Among women who used fingolimod or natalizumab, ARR before pregnancy was 0.37 (0.28-0.49) and 0.29 (0.22-0.37), respectively, and increased during pregnancy. Intrapartum ARR decreased with preconception dimethyl fumarate use. ARR spiked after delivery across all DMT groups. Natalizumab continuation into pregnancy reduced the odds of relapse during pregnancy (OR 0.76 per month [0.60-0.95], p=0.017). DMT re-initiation with natalizumab protected against postpartum relapse (HR 0.11 [0.04-0.32], p<0.0001). Breastfeeding women were less likely to relapse (HR 0.61 [0.41-0.91], p=0.016). 5.6% of pregnancies were followed by confirmed disability progression, predicted by higher relapse activity in pregnancy and postpartum. CONCLUSION: Intrapartum and postpartum relapse probabilities increased among women with MS after natalizumab or fingolimod cessation. In women considered to be at high relapse risk, use of natalizumab before pregnancy and continued up to 34 weeks gestation, with early re-initiation after delivery is an effective option to minimize relapse risks. Strategies of DMT use have to be balanced against potential fetal/neonatal complications.
RESUMEN
BACKGROUND/AIM: This study aims to understand early (<24 h post ictus) and late (up to 12 months) survival post aneurysmal subarachnoid haemorrhage (aSAH), with a focus on rurality and socioeconomic status. METHODS: A statewide population-based cohort of aSAH cases in Tasmania, Australia, was established from 2010 to 2014 using multiple overlapping sources. Clinical data were collected from medical records and the Tasmanian Death Registry, with area-level rurality and socioeconomic status geocoded to participants' residential address. RESULTS: From a cohort of 237 (70% women, 36% disadvantaged, 38% rural) individuals over a 5-year period, 12-month mortality was 52.3% with 54.0% of these deaths occurring within 24 h post ictus. In univariable analysis of 12-month survival, outcome was not influenced by socioeconomic status, but rural geographical location was associated with a non-significant increase in death (hazard ratio (HR) 1.22; 95% confidence interval (CI) 0.85-1.75) along with hypertension (HR 1.78; 95% CI 1.07-2.98) and hypercholesterolaemia (HR 1.70; 95% CI 0.99-2.91). Multivariable analysis demonstrated a statistically significant increase in death to 12 months after aSAH for both hypertension (HR 1.81; 95% CI 1.08-3.03) and hypercholesterolaemia (HR 1.71; 95% CI 1.00-2.94) but not socioeconomic status or geographic location. CONCLUSION: We found high early death in this population-based aSAH Australian population. Survival to 12 months after aSAH was not related to either geographical location or socioeconomic status but modifiable risk factors increased the risk of death.