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INTRODUCTION: Fatigue is a complex and frequent symptom in persons with inflammatory bowel disease (IBD), with detrimental impact. We aimed to determine predictors of fatigue over time. METHODS: Two hundred forty-seven adults with IBD participated in a prospective study conducted in Manitoba, Canada, providing data at baseline and annually for 3 years. Participants reported fatigue impact (Daily Fatigue Impact Scale [DFIS]), depression and anxiety symptoms (Hospital Anxiety and Depression Scale [HADS]), and pain (Pain Effects Scale [PES]). Physician-diagnosed comorbidities, IBD characteristics, and physical and cognitive functioning were also assessed. We tested factors associated with fatigue using multivariable generalized linear models that estimated within-person and between-person effects. RESULTS: Most participants were women (63.2%), White (85.4%), and had Crohn's disease (62%). At baseline, 27.9% reported moderate-severe fatigue impact, 16.7% had clinically elevated anxiety (HADS-A ≥11), and 6.5% had clinically elevated depression (HADS-D ≥11). Overall fatigue burden was stable over time, although approximately half the participants showed improved or worsening fatigue impact between annual visits during the study. On multivariable analysis, participants with a one-point higher HADS-D score had, on average, a 0.63-point higher DFIS score, whereas participants with a one-point higher PES score had a 0.78-point higher DFIS score. Within individuals, a one-point increase in HADS-D scores was associated with 0.61-point higher DFIS scores, in HADS-A scores with 0.23-point higher DFIS scores, and in PES scores with 0.38-point higher DFIS scores. No other variables predicted fatigue. DISCUSSION: Anxiety, depression, and pain predicted fatigue impact over time in IBD, suggesting that targeting psychological factors and pain for intervention may lessen fatigue burden.
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BACKGROUND: Psychiatric comorbidity is common in inflammatory bowel disease (IBD) and can negatively affect disease outcomes. We explored the perceived need for mental health care among persons with IBD. STUDY: Persons with IBD completed self-report questionnaires, including the Hospital Anxiety and Depression Scale (HADS), and reported whether they wanted help with their mood. Each was also assessed using the Structured Clinical Interview for DSM-IV-TR Axis-I Disorders (SCIDs). We used logistic regression analyses to determine factors associated with the perceived need for mental health care. RESULTS: Of 245 participants, 28% met the criteria for a past diagnosis of depression or anxiety disorder by SCID, and nearly 23% met the criteria for a current diagnosis of depression or anxiety disorder. One-third (n = 74) reported a perceived need for mental health care. Among those meeting criteria for a current SCID diagnosis of depression or anxiety, only 58% reported needing mental health care. Need for mental health care was reported by 79% of persons currently treated for either depression or 71% treated for anxiety. Persons with a perceived need for mental health care had higher mean HADS for depression and HADS for anxiety scores and also higher IBD symptom activity scores. Of those reporting no perceived need for mental health care, 13% had a current diagnosis of depression or anxiety disorder by SCID; even fewer had symptoms of depression or anxiety. CONCLUSIONS: Symptoms of depression or anxiety are more important than a formal diagnosis of depression or anxiety in predicting which persons with IBD will perceive a need for mental health care.
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Doenças Inflamatórias Intestinais , Saúde Mental , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/terapia , Ansiedade/epidemiologia , Comorbidade , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/psicologia , Depressão/epidemiologiaRESUMO
OBJECTIVE: Extensive blood-brain barrier (BBB) leakage has been linked to cognitive impairment in SLE. This study aimed to examine the associations of brain functional connectivity (FC) with cognitive impairment and BBB dysfunction among patients with SLE. METHODS: Cognitive function was assessed by neuropsychological testing (n = 77). Resting-state FC (rsFC) between brain regions, measured by functional MRI (n = 78), assessed coordinated neural activation in 131 regions across five canonical brain networks. BBB permeability was measured by dynamic contrast-enhanced MRI (n = 61). Differences in rsFC were compared between SLE patients with cognitive impairment (SLE-CI) and those with normal cognition (SLE-NC), between SLE patients with and without extensive BBB leakage, and with healthy controls. RESULTS: A whole-brain rsFC comparison found significant differences in intra-network and inter-network FC in SLE-CI vs SLE-NC patients. The affected connections showed a reduced negative rsFC in SLE-CI compared with SLE-NC and healthy controls. Similarly, a reduced number of brain-wide connections was found in SLE-CI patients compared with SLE-NC (P = 0.030) and healthy controls (P = 0.006). Specific brain regions had a lower total number of brain-wide connections in association with extensive BBB leakage (P = 0.011). Causal mediation analysis revealed that 64% of the association between BBB leakage and cognitive impairment in SLE patients was mediated by alterations in FC. CONCLUSION: SLE patients with cognitive impairment had abnormalities in brain rsFC which accounted for most of the association between extensive BBB leakage and cognitive impairment.
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Disfunção Cognitiva , Lúpus Eritematoso Sistêmico , Humanos , Barreira Hematoencefálica/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Cognição/fisiologia , Imageamento por Ressonância Magnética , Lúpus Eritematoso Sistêmico/complicaçõesRESUMO
BACKGROUND: The relationship between socioeconomic status (SES) and mortality among persons with multiple sclerosis (PwMS) is poorly understood. OBJECTIVE: To investigate the association between SES and mortality risk in PwMS. METHODS: From health-administrative data, we identified 12,126 incident MS cases with a first demyelinating event (MS 'onset') occurring between 1994 and 2017. Cox proportional hazard model assessed the association between socioeconomic status quintiles (SES-Qs) at MS onset and all-cause mortality. RESULTS: Lower SES-Qs were associated with higher mortality risk; adjusted hazard ratios: SES-Q1 (most deprived) =1.61 (95% confidence interval (CI) = 1.36-1.91); SES-Q2 = 1.26 (95% CI = 1.05-1.50); SES-Q3 = 1.22 (95% CI = 1.02-1.46); SES-Q4 = 1.13 (95% CI = 0.94-1.35) versus SES-Q5 (least deprived). CONCLUSION: A lower SES was associated with higher mortality risk in PwMS.
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Baixo Nível Socioeconômico , Esclerose Múltipla , Humanos , Classe Social , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: Longitudinal studies of health-related quality of life (HRQoL) in multiple sclerosis (MS) are limited. Most have examined average changes within the population, rather than dynamic changes within individuals. OBJECTIVE: To assess the between- and within-individual association between depression, anxiety, fatigue, cognition, physical functioning, and physical comorbidities and HRQoL. METHODS: Adults with MS underwent physical and cognitive assessments and reported symptoms of fatigue (Daily Fatigue Impact Scale), depression and anxiety (Hospital Anxiety and Depression Scale (HADS)), and HRQoL (RAND-36) annually (n = 4 visits). We evaluated associations of elevated symptoms of anxiety (HADS-A) and depression (HADS-D), fatigue, physical function (timed-walk and nine-hole peg test), cognitive function and comorbidity count with physical (PCS-36) and mental (MCS-36) HRQoL using multivariable linear models-estimating between-person and within-person effects. RESULTS: Of 255 participants with MS enrolled, 81.6% were women. After adjustment, within-person increases in depression and fatigue were associated with decreases in physical HRQoL. Increases in depression, anxiety, and comorbidity count were associated with decreases in mental HRQoL. CONCLUSIONS: Within-person increases in symptoms of depression, anxiety and fatigue, and comorbidity count are associated with HRQoL decreases among adults with MS, highlighting the potential magnitude of individual benefit of intervention for these symptoms.
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Esclerose Múltipla , Adulto , Humanos , Feminino , Masculino , Esclerose Múltipla/complicações , Esclerose Múltipla/epidemiologia , Qualidade de Vida/psicologia , Depressão/psicologia , Ansiedade , Fadiga/etiologia , Fadiga/complicações , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: We estimated the incidence and prevalence of benzodiazepine and Z-drug (separately and jointly as BZD) use in the inflammatory bowel disease (IBD) population compared with matched controls without IBD and examined the association of mood/anxiety disorders (M/ADs) with the use of BZD from 1997 to 2017. METHODS: Using administrative data from Manitoba, Canada, we identified 5,741 persons with incident IBD who were matched in a 1:5 ratio to controls on sex, birth year, and region. Validated case definitions were used to identify M/AD. Dispensations of BZD were identified. Multivariable generalized linear models were used to assess the association between IBD, M/AD, and BZD use. RESULTS: In 2016, the incident age/sex-standardized benzodiazepine use rates per 1,000 were 28.06 (95% confidence interval [CI] 26.41-29.81) in the IBD cohort and 16.83 (95% CI 16.28-17.39) in controls (adjusted rate ratio = 1.69 [95% CI 1.56-1.79]). Benzodiazepine incidence rates were higher for women with IBD than men, but the RR between cases and controls were similar for men and women. The incident age/sex-standardized Z-drug use rate per 1,000 was 21.07 (95% CI 19.69-22.41) in the IBD cohort. This was 1.87-fold higher than in controls (95% CI 1.73-2.01). In 2017, approximately 20% of persons with IBD used benzodiazepines and 20% used Z-drugs. There was a subadditive effect of both benzodiazepine and Z-drug uses between IBD and M/AD after adjusting for covariates. DISCUSSION: The use of BZD is more common in people with IBD than in population controls. Strategies to reduce the use of BZDs in persons with IBD and to offer alternative management strategies for M/ADs, sleep disorders, and other symptomatic concerns are needed.
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Doenças Inflamatórias Intestinais , Transtornos Relacionados ao Uso de Substâncias , Masculino , Humanos , Feminino , Benzodiazepinas/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/epidemiologia , Incidência , Ansiedade , Doença CrônicaRESUMO
OBJECTIVE: To determine whether childhood maltreatment is associated with immune-mediated inflammatory disorders (IMIDs; multiple sclerosis [MS], inflammatory bowel disease [IBD], and rheumatoid arthritis [RA]). We further aimed to determine the relationship between maltreatment and psychiatric comorbidity in IMIDs and whether these relationships differed across IMID. METHODS: Six hundred eighty-one participants (MS, 232; IBD, 216; RA, 130; healthy controls, 103) completed a structured psychiatric interview to identify psychiatric disorders, and the Childhood Trauma Questionnaire to evaluate five types of maltreatment: emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect. We evaluated associations between maltreatment, IMID, and psychiatric comorbidity using multivariable logistic regression models. RESULTS: The prevalence of having ≥1 maltreatment was similar across IMID but higher than in controls (MS, 63.8%; IBD, 61.6%; RA, 62.3%; healthy controls, 45.6%). Emotional abuse was associated with having an IMID (adjusted odds ratio [aOR] = 2.37; 1.15-4.89). In the sex-specific analysis, this association was only present in women. History of childhood maltreatment was associated with a lifetime diagnosis of a psychiatric disorder in the IMID cohort (OR = 2.24; 1.58-3.16), but this association did not differ across diseases. In those with IMID, total types of maltreatments (aOR = 1.36; 1.17-1.59) and emotional abuse (aOR = 2.64; 1.66-4.21) were associated with psychiatric comorbidity. CONCLUSIONS: Childhood maltreatment is more common in IMID than in a healthy population and is associated with psychiatric comorbidity. Given the high burden of psychiatric disorders in the IMID population, clinicians should be aware of the contribution of maltreatment and the potential need for trauma-informed care strategies.
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Artrite Reumatoide , Maus-Tratos Infantis , Transtornos Mentais , Artrite Reumatoide/epidemiologia , Criança , Estudos de Coortes , Comorbidade , Feminino , Humanos , Masculino , Transtornos Mentais/epidemiologia , Inquéritos e QuestionáriosRESUMO
We described emergency department (ED) visits (all visits and infection-related) by persons with multiple sclerosis (MS) in British Columbia, Canada (1 April 2012 to 31 December 2017). We identified 15,350 MS cases using health administrative data; 73.4% were women, averaging 51.4 years at study entry. Over 4.9 years of follow-up (mean), 56.0% of MS cases visited an ED (mean = 0.6 visits/person/year; total = 37,072 visits). A diagnosis was documented for 25,698 (69.3%) ED visits, and 18.4% (4725/25,698) were infection-related. Inpatient admissions were reported for 20.4% (5238/25,698) of all and 29.2% (1380/4725) of infection-related ED visits. Findings suggest that the ED plays a substantial role in MS healthcare and infection management.
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Serviço Hospitalar de Emergência , Esclerose Múltipla , Colúmbia Britânica/epidemiologia , Feminino , Hospitalização , Humanos , Pacientes Internados , Masculino , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/terapia , Estudos RetrospectivosRESUMO
OBJECTIVE: We assessed the relationship between the multiple sclerosis (MS) disease-modifying drugs (DMDs) and healthcare use. METHODS: Persons with MS (aged ⩾18 years) were identified using linked population-based health administrative data in four Canadian provinces and were followed from the most recent of their first MS/demyelinating event or 1 January 1996 until the earliest of death, emigration, or study end (31 December 2017 or 31 March 2018). Prescription records captured DMD exposure, examined as any DMD, then by generation (first-generation (the injectables) or second-generation (orals/infusions)) and individual DMD. The associations with subsequent all-cause hospitalizations and physician visits were examined using proportional means model and negative binomial regression. RESULTS: Of 35,894 MS cases (72% female), mean follow-up was 12.0 years, with person-years of DMD exposure for any, or any first- or second-generation DMD being 63,290, 54,605 and 8685, respectively. Any DMD or any first-generation DMD exposure (versus non-exposure) was associated with a 24% lower hazard of hospitalization (adjusted hazard ratio, aHR: 0.76; 95% confidence intervals (CIs): 0.71-0.82), rising to 29% for the second-generation DMDs (aHR: 0.71; 95% CI: 0.58-0.88). This ranged from 18% for teriflunomide (aHR: 0.82; 95% CI: 0.67-1.00) to 44% for fingolimod (aHR: 0.56; 95% CI: 0.36-0.87). In contrast, DMD exposure was generally not associated with substantial differences in physician visits. CONCLUSION: Findings provide real-world evidence of a beneficial relationship between DMD exposure and hospitalizations.
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Esclerose Múltipla , Idoso , Canadá/epidemiologia , Feminino , Cloridrato de Fingolimode/uso terapêutico , Hospitalização , Humanos , Masculino , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/epidemiologia , Aceitação pelo Paciente de Cuidados de SaúdeRESUMO
BACKGROUND: There is increasing evidence of prodromal multiple sclerosis (MS). OBJECTIVE: The aim of this study was to determine whether fatigue, sleep disorders, anaemia or pain form part of the MS prodrome. METHODS: This population-based matched cohort study used linked administrative and clinical databases in British Columbia, Canada. The odds of fatigue, sleep disorders, anaemia and pain in the 5 years preceding the MS cases' first demyelinating claim or MS symptom onset were compared with general population controls. The frequencies of physician visits for these conditions were also compared. Modifying effects of age and sex were evaluated. RESULTS: MS cases/controls were assessed before the first demyelinating event (6863/31,865) or MS symptom onset (966/4534). Fatigue (adj.OR: 3.37; 95% CI: 2.76-4.10), sleep disorders (adj.OR: 2.61; 95% CI: 2.34-2.91), anaemia (adj.OR: 1.53; 95% CI: 1.32-1.78) and pain (adj.OR: 2.15; 95% CI: 2.03-2.27) during the 5 years preceding the first demyelinating event were more frequent among cases, and physician visits increased for cases relative to controls. The association between MS and anaemia was greater for men; that between MS and pain increased with age. Pre-MS symptom onset, sleep disorders (adj.OR: 1.72; 95% CI: 1.12-2.56) and pain (adj.OR: 1.53; 95% CI: 1.32-1.76) were more prevalent among cases. CONCLUSION: Fatigue, sleep disorders, anaemia and pain were elevated before the recognition of MS. The relative anaemia burden was higher in men and pain more evident among older adults.
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Anemia , Esclerose Múltipla , Transtornos do Sono-Vigília , Idoso , Anemia/epidemiologia , Colúmbia Britânica/epidemiologia , Estudos de Coortes , Fadiga/epidemiologia , Fadiga/etiologia , Humanos , Masculino , Esclerose Múltipla/complicações , Esclerose Múltipla/epidemiologia , Dor/epidemiologia , Dor/etiologia , Transtornos do Sono-Vigília/epidemiologiaRESUMO
BACKGROUND: Longitudinal studies assessing depression and anxiety effects on cognition in multiple sclerosis (MS) are limited. OBJECTIVE: We tested whether within-person fluctuations in symptoms of depression or anxiety over time affect cognition in persons with MS, inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and a lifetime history of depression/anxiety disorders (DEP/ANX) but without an immune-mediated inflammatory diseases (IMID). METHODS: We followed participants (MS: 255, IBD: 247, RA: 154, and DEP/ANX: 306) for 3 years. Annually, they completed the hospital anxiety and depression scale (HADS) and cognitive tests including the symbol digit modalities test (SDMT). We evaluated associations of elevated symptoms (scores ⩾ 11) of anxiety (HADS-A) and depression (HADS-D) with SDMT z-scores using multivariable linear models-estimating between-person and within-person effects. RESULTS: Participants with MS performed worse on the SDMT than participants in the DEP/ANX cohort (ß = -0.68; 95% CI: -0.88, -0.48). Participants with elevated HADS-A scores performed worse on the SDMT than those without elevated scores (ß = -0.43; 95% CI: -0.65, -0.21), particularly those with RA. Time-varying within-person elevations in depressive symptoms were associated with worse SDMT performance (ß = -0.12; 95% CI: -0.21, -0.021). CONCLUSIONS: Across persons, elevated symptoms of anxiety adversely affected information processing. Elevated symptoms of depression within-persons over time were associated with declines in information processing speed.
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Depressão , Esclerose Múltipla , Ansiedade , Transtornos de Ansiedade , Humanos , Esclerose Múltipla/complicações , Testes NeuropsicológicosRESUMO
BACKGROUND: Little is known about the effects of changes in the presence or absence of psychiatric disorders on health care utilization in multiple sclerosis (MS). OBJECTIVE: To evaluate the association between "active" mood and anxiety disorders (MAD) and health care utilization in MS. METHODS: Using administrative data from Manitoba, Canada, we identified 4748 persons with MS and 24,154 persons without MS matched on sex, birth year, and region. Using multivariable general linear models, we evaluated the within-person and between-person effects of any "active" MAD on annual physician visits, hospital days, and number of drug classes dispensed in the following year. RESULTS: Annually, the MS cohort had an additional two physician visits, two drug classes, and nearly two more hospital days versus the matched cohort. Individuals with any MAD had more physician visits, had hospital days, and used more drug classes than individuals without a MAD. Within individuals, having an "active" MAD was associated with more utilization for all outcomes than not having an "active" MAD, but the magnitude of this effect was much smaller for visits and drugs than the between-person effect. CONCLUSION: Within individuals with MS, changes in MAD activity are associated with changes in health services use.
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Transtornos de Ansiedade , Esclerose Múltipla , Estudos de Coortes , Humanos , Transtornos do Humor , Esclerose Múltipla/tratamento farmacológico , Aceitação pelo Paciente de Cuidados de SaúdeRESUMO
Three linked studies, testing key aspects of the Pathways towards Problem and Pathological Gambling Model (Blaszczynski and Nower in Addiction 87(5):487-499, 2002), are presented. Study one comprised 204 students and 490 gambling forum users. It predicted differences in gambling severity, mental health and substance use across different motives for gambling. Those with a primary social motive for gambling displayed less severe gambling and anxiety than those without, with the primary coping subgroup displaying the most anxiety and depression. Those who gambled primarily to enhance positive affect reported severe gambling. Study two comprised 404 gambling forum users and 265 students. Similar groups to the Pathways Model emerged, with a behaviourally conditioned and an emotionally vulnerable group. Unexpectedly, however, those in the emotionally vulnerable group reported more severe cognitive distortions than the behaviourally conditioned group. The final study, 378 gambling forum users and 201 students, found, as predicted, that three distinct gambling groups emerged; (1) those with lower levels of psychopathology and higher levels of protective factors; (2) those with heightened pre-existing anxiety and depression, and moderate levels of protective factors; and (3) those with heightened impulsivity, psychopathology, offending behaviour and the least protective factors. Three gambling groups are consequently presented (Social Gambler; Affect-Regulation Gambler; Antisocial Gambler) alongside the proposed Integrated Risk and Protective Factors Model of Gambling Types (IRPF-MGT). Directions for future research and implications for practice are outlined.
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Comportamento Aditivo/epidemiologia , Jogo de Azar/epidemiologia , Jogo de Azar/psicologia , Adolescente , Adulto , Feminino , Humanos , Comportamento Impulsivo , Masculino , Transtornos Mentais/epidemiologia , Pessoa de Meia-Idade , Modelos Teóricos , Motivação , Fatores de Proteção , Fatores de Risco , Adulto JovemRESUMO
Genetic code expansion has largely focused on the reassignment of amber stop codons to insert single copies of non-canonical amino acids (ncAAs) into proteins. Increasing effort has been directed at employing the set of aminoacyl tRNA synthetase (aaRS) variants previously evolved for amber suppression to incorporate multiple copies of ncAAs in response to sense codons in Escherichia coli. Predicting which sense codons are most amenable to reassignment and which orthogonal translation machinery is best suited to each codon is challenging. This manuscript describes the directed evolution of a new, highly efficient variant of the Methanosarcina barkeri pyrrolysyl orthogonal tRNA/aaRS pair that activates and incorporates tyrosine. The evolved M. barkeri tRNA/aaRS pair reprograms the amber stop codon with 98.1 ± 3.6% efficiency in E. coli DH10B, rivaling the efficiency of the wild-type tyrosine-incorporating Methanocaldococcus jannaschii orthogonal pair. The new orthogonal pair is deployed for the rapid evaluation of sense codon reassignment potential using our previously developed fluorescence-based screen. Measurements of sense codon reassignment efficiencies with the evolved M. barkeri machinery are compared with related measurements employing the M. jannaschii orthogonal pair system. Importantly, we observe different patterns of sense codon reassignment efficiency for the M. jannaschii tyrosyl and M. barkeri pyrrolysyl systems, suggesting that particular codons will be better suited to reassignment by different orthogonal pairs. A broad evaluation of sense codon reassignment efficiencies to tyrosine with the M. barkeri system will highlight the most promising positions at which the M. barkeri orthogonal pair may infiltrate the E. coli genetic code.
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Aminoacil-tRNA Sintetases/genética , Códon/genética , Evolução Molecular Direcionada , RNA de Transferência/genética , Aminoácidos/genética , Códon de Terminação/genética , Escherichia coli/genética , Código Genético/genética , Methanosarcina barkeri/genética , Biossíntese de Proteínas/genética , Tirosina/genéticaRESUMO
A quantitative understanding of how system composition and molecular properties conspire to determine the fidelity of translation is lacking. Our strategy directs an orthogonal tRNA to directly compete against endogenous tRNAs to decode individual targeted codons in a GFP reporter. Sets of directed sense codon reassignment measurements allow the isolation of particular factors contributing to translational fidelity. In this work, we isolated the effect of tRNA concentration on translational fidelity by evaluating reassignment of the 15 least commonly employed E. coli sense codons. Eight of the rarely used codons are reassigned with greater than 20 % efficiency. Both tRNA abundance and codon demand moderately inversely correlate with reassignment efficiency. Furthermore, the reassignment of rarely used codons does not appear to confer a fitness advantage relative to reassignment of other codons. These direct competition experiments also map potential targets for genetic code expansion. The isoleucine AUA codon is particularly attractive for the incorporation of noncanonical amino acids, with a nonoptimized reassignment efficiency of nearly 70 %.
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Códon/genética , Biossíntese de Proteínas , RNA de Transferência/genética , Substituição de Aminoácidos , Escherichia coli/genética , Genoma Bacteriano/genética , ProteômicaRESUMO
OBJECTIVES: To examine the association between blood-brain barrier (BBB) integrity, brain volume and cognitive dysfunction in adult patients with systemic lupus erythematosus (SLE). METHODS: A total of 65 ambulatory patients with SLE and 9 healthy controls underwent dynamic contrast-enhanced MRI scanning, for quantitative assessment of BBB permeability. Volumetric data were extracted using the VolBrain pipeline. Global cognitive function was evaluated using a screening battery consisting of tasks falling into five broad cognitive domains, and was compared between patients with normal versus extensive BBB leakage. RESULTS: Patients with SLE had significantly higher levels of BBB leakage compared with controls (p=0.04). Extensive BBB leakage (affecting over >9% of brain volume) was identified only in patients with SLE (16/65; 24.6%), who also had smaller right and left cerebral grey matter volumes compared with controls (p=0.04). Extensive BBB leakage was associated with lower global cognitive scores (p=0.02), and with the presence of impairment on one or more cognitive tasks (p=0.01). CONCLUSION: Our findings provide evidence for a link between extensive BBB leakage and changes in both brain structure and cognitive function in patients with SLE. Future studies should investigate the mechanisms underlying BBB-mediated cognitive impairment, validate the diagnostic utility of BBB imaging, and determine the potential of targeting the BBB as a therapeutic strategy in patients with SLE.
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Barreira Hematoencefálica/patologia , Encéfalo/patologia , Disfunção Cognitiva/patologia , Substância Cinzenta/patologia , Lúpus Eritematoso Sistêmico/patologia , Adulto , Permeabilidade Capilar , Disfunção Cognitiva/etiologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/complicações , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: There is growing evidence of a prodromal period in multiple sclerosis (MS). A better understanding of the prodrome may facilitate prompt recognition and treatment of MS as well as narrowing of the etiologically relevant -period when searching for MS risk factors. OBJECTIVES: To explore and further delineate the MS prodrome, we used statistical learning techniques to examine associations of physician-generated diagnostic codes and prescription medication classes in the 5 years before the first demyelinating-related claim for MS cases and matched population controls. METHODS: In this matched cohort study, we accessed data from linked health administrative hospital, physician, and prescription databases from British Columbia, Canada, between 1996 and 2013. We focused on 7 medication classes previously identified as associated with the MS prodrome: urinary anti-spasmodics, glucocorticoids, muscle relaxants, anti-epileptics, dopa-derivatives, benzodiazepine, and antivertigo preparations. Diagnostic codes associated with the use of each medication class were first identified using LASSO logistic regression analyses in two-thirds of the cohort and then validated using multivariate logistic regressions in the remaining cohort. RESULTS: Our analyses included 4,862 MS cases and 22,649 controls. Although the identified diagnostic codes showed fair to good predictive performance in 6 medication classes (C-index = 0.712-0.858), these codes failed to fully explain the higher usage of these medications by the MS cases. Compared to controls of the same age, sex, and diagnostic codes, MS cases had higher odds of filling a prescription for antivertigo preparations (adjusted OR [aOR] 2.48; 95% CI 1.92-3.19), anti-epileptics (aOR 2.34; 1.90-2.90), glucocorticoids (aOR 1.76; 1.52-2.03), urinary anti-spasmodics (aOR 1.72; 1.20-2.46), and muscle relaxants (aOR 1.33; 1.13-1.56). CONCLUSIONS: We observed markedly higher use of specific medications in MS cases in the 5 years before the first demyelinating claim. The overrepresentation of specific medications in MS cases, which was not fully explained by the physician diagnoses, may represent a signature of the MS prodrome.
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Prescrições de Medicamentos/estatística & dados numéricos , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/epidemiologia , Sintomas Prodrômicos , Adulto , Colúmbia Britânica/epidemiologia , Estudos de Coortes , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos ProspectivosRESUMO
BACKGROUND: The multiple sclerosis (MS) prodrome is poorly characterized. OBJECTIVE: To phenotype the MS prodrome via health care encounters. METHODS: Using data from a population-based cohort study linking administrative and clinical data in four Canadian provinces, we compared physician and hospital encounters and prescriptions filled (via International Classification of Diseases chapters, physician specialty or drug classes) for MS subjects in the 5 years before the first demyelinating claim in an administrative cohort or the clinical symptom onset in an MS clinic-derived cohort, to age-, sex- and geographically matched controls. Rate ratios (RRs), 95% confidence intervals (95% CIs) and proportions were estimated. RESULTS: The administrative and clinical cohorts included 13,951/66,940 and 3202/16,006 people with and without MS (cases/controls). Compared to controls, in the 5 years before the first demyelinating claim or symptom onset, cases had more physician and hospital encounters for the nervous (RR (range) = 2.31; 95% CI: 1.05-5.10 to 4.75; 95% CI: 3.11-7.25), sensory (RR (range) = 1.40; 95% CI: 1.34-1.46 to 2.28; 95% CI: 1.72-3.02), musculoskeletal (RR (range) = 1.19; 95% CI: 1.07-1.33 to 1.70; 95% CI: 1.57-1.85) and genito-urinary systems (RR (range) = 1.17; 95% CI: 1.05-1.30 to 1.59; 95% CI: 1.48-1.70). Cases had more psychiatrist and urologist encounters (RR (range) = 1.48; 95% CI: 1.36-1.62 to 1.80; 95% CI: 1.61-2.01), and higher proportions of musculoskeletal, genito-urinary or hormonal-related prescriptions (1.1-1.5 times higher, all p < 0.02). However, cases had fewer pregnancy-related encounters than controls (RR = 0.78; 95% CI: 0.71-0.86 to 0.88; 95% CI: 0.84-0.92). CONCLUSION: Phenotyping the prodrome 5 years before clinical recognition of MS is feasible.
Assuntos
Prescrições de Medicamentos/estatística & dados numéricos , Utilização de Instalações e Serviços/estatística & dados numéricos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/fisiopatologia , Sintomas Prodrômicos , Adulto , Canadá , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/epidemiologia , FenótipoRESUMO
In epidemiological studies of secondary data sources, lack of accurate disease classifications often requires investigators to rely on diagnostic codes generated by physicians or hospital systems to identify case and control groups, resulting in a less-than-perfect assessment of the disease under investigation. Moreover, because of differences in coding practices by physicians, it is hard to determine the factors that affect the chance of an incorrectly assigned disease status. What results is a dilemma where assumptions of non-differential misclassification are questionable but, at the same time, necessary to proceed with statistical analyses. This paper develops an approach to adjust exposure-disease association estimates for disease misclassification, without the need of simplifying non-differentiality assumptions, or prior information about a complicated classification mechanism. We propose to leverage rich temporal information on disease-specific healthcare utilization to estimate each participant's probability of being a true case and to use these estimates as weights in a Bayesian analysis of matched case-control data. The approach is applied to data from a recent observational study into the early symptoms of multiple sclerosis (MS), where MS cases were identified from Canadian health administrative databases and matched to population controls that are assumed to be correctly classified. A comparison of our results with those from non-differentially adjusted analyses reveals conflicting inferences and highlights that ill-suited assumptions of non-differential misclassification can exacerbate biases in association estimates.
Assuntos
Teorema de Bayes , Viés , Confiabilidade dos Dados , Erros de Diagnóstico , Estudos de Casos e Controles , Codificação Clínica , Bases de Dados Factuais , Hospitais , Humanos , Modelos EstatísticosRESUMO
BACKGROUND: Primary Progressive Aphasia (PPA) is a syndrome characterized by an isolated impairment of language function at disease onset. The cholinergic system is implicated in language function and cholinergic deficits are seen in the brains of individuals with PPA. One major source of cholinergic innervation of the cerebral cortex is the nucleus basalis of Meynert (NBM) within which lies the nucleus subputaminalis (NSP). This nucleus is postulated to be involved in language function. We compared the abundance of cholinergic neurons in the NBM and NSP of controls and individuals with PPA. Also explored was whether the individuals presenting with PPA, who subsequently developed different clinical and neuropathological profiles, showed similar cholinergic deficits in the NSP. METHODS: Cytoarchitecture of the basal forebrain was studied using Nissl staining in control (n = 5) and PPA (n = 5) brains. Choline acetyltransferase (ChAT) immunohistochemical staining labeled cholinergic neurons were quantified using Neurolucida software. RESULTS: In comparison to matched controls, PPA showed reduction of cholinergic neurons in the NBM (t(8) = 4.04, p = 0.0037; Cohen's effect size value d = 2.62) and the NSP (t(6) = 4.62, p = 0.0042; Cohen's d effect size d = 2.92). The average percent of cholinergic neuronal loss was relatively higher in the NSP (64.7%) compared to the NBM (47.7%). CONCLUSION: Regardless of underlying pathology, all cases presenting with PPA showed a marked loss of cholinergic neurons in the NSP, providing further evidence for the importance of this nucleus in language function.