Whole Exome Sequencing in Multi-Incident Families Identifies Novel Candidate Genes for Multiple Sclerosis.

Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with two to four affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be studied further in cellular and/or animal models.

The Interactive Web-Based Program MSmonitor for Self-Management and Multidisciplinary Care in Persons With Multiple Sclerosis: Quasi-Experimental Study of Short-Term Effects on Patient Empowerment.

BACKGROUND: Empowerment helps persons with a chronic disease to self-manage their condition and increase their autonomy and participation. MSmonitor (Curavista bv) is an interactive Web-based program for self-management and multidisciplinary care in multiple sclerosis (MS). It includes, among others, short questionnaires on fatigue (Modified Fatigue Impact Scale-5 [MFIS-5]) and health-related quality of life (HRQoL, Leeds Multiple Sclerosis Quality of Life [LMSQoL]); long questionnaires on disabilities, perception of disabilities (Multiple Sclerosis Impact Profile), and HRQoL (Multiple Sclerosis Quality of Life-54); a Medication and Adherence Inventory and an Activity Diary. The combination MFIS-5, LMSQoL, and Medication and Adherence Inventory constitutes the Quick Scan. OBJECTIVE: This study aimed to investigate the short-term effects of MSmonitor on empowerment in patients with MS. METHODS: We conducted a quasi-experimental study in a general hospital. Of the 180 patients with MS, 125 were eligible, 30 used MSmonitor, and 21 participated in the study (mean age 45.4 years, SD 10.2 years). A total of 24 eligible patients who did not use MSmonitor constituted the control group (mean age 49.3 years, SD 11.4 years). At baseline and at 4 months, we assessed self-efficacy (Multiple Sclerosis Self-Efficacy Scale [MSSES]), participation and autonomy (Impact on Participation and Autonomy [IPA] questionnaire), and self-management (Partners In Health [PIH] questionnaire). Differences between time points and groups were tested with paired t tests and χ² tests. RESULTS: In the MSmonitor group, follow-up values remained unchanged for MSSES control (P=.19), MSSES function (P=.62), IPA limitations (P=.26), IPA problems (P=.40), PIH recognition and management of symptoms (P=.52), PIH adherence to treatment (P=.80), and PIH coping (P=.73), whereas the PIH knowledge score had improved (mean 27.8, SD 1.7 vs mean 28.7, SD 2.0; P=.02). The overall utilization rate of the program components was 83% and that of the Quick Scan was 95%. In the control group, all outcomes had remained unchanged. CONCLUSIONS: The results suggest that for first-time users of the MSmonitor program and their health care providers, it may not be justified to expect a short-term improvement in empowerment in terms of self-efficacy, self-management, autonomy, or participation. Furthermore, a lack of effect on empowerment is not because of nonusage of the program components.

Cognitive functioning as a predictor of employment status in relapsing-remitting multiple sclerosis: a 2-year longitudinal study.

BACKGROUND: Cognitive functioning has been linked to employment outcomes in multiple sclerosis (MS) in cross-sectional studies. Longitudinal studies are however lacking and previous studies did not extensively examine executive functioning. OBJECTIVES: We examined whether baseline cognitive functioning predicts a change in employment status after 2 years, while taking into account mood, fatigue and disability level. METHODS: A total of 124 patients with relapsing-remitting MS (pwMS) and 60 healthy controls were included. They underwent neurological and neuropsychological examinations and completed online questionnaires. PwMS were divided into a stable and deteriorated employment status group (SES and DES), based on employment status 2 years after baseline. We first examined baseline differences between the SES and DES groups in cognitive functioning, mood, fatigue and disability level. A logistic regression analysis was performed, with change in employment status (SES/DES) as dependent variable. RESULTS: The DES group included 22% pwMS. Group differences were found in complex attention, executive functioning, self-reported cognitive functioning, fatigue and physical disability. More physical disability (OR = 1.90, p = 0.01) and lower executive functioning (OR = 0.30, p = 0.03) were retained as independent predictors of DES (R2 = 0.22, p ≤ 0.001). CONCLUSIONS: Baseline physical disability and executive functioning, but none of the other variables, moderately predicted a deterioration in employment status 2 years later. TRIAL REGISTRATION: This observational study is registered under NL43098.008.12: 'Voorspellers van arbeidsparticipatie bij mensen met relapsing-remitting Multiple Sclerose'. This study is registered at the Dutch CCMO register (https://www.toetsingonline.nl).

Comparison of preferences of healthcare professionals and MS patients for attributes of disease-modifying drugs: A best-worst scaling.

BACKGROUND: The choice between disease-modifying drugs (DMDs) for the treatment of multiple sclerosis (MS) becomes more often a shared decision between the patient and the neurologist and MS nurse. This study aimed to assess which DMD attributes are most important for the healthcare professionals in selecting a DMD for a patient. Subsequently, within this perspective, the neurologists' and nurses' perspectives were compared. Lastly, the healthcare professionals' perspective was compared with the patients' perspective to detect any differences that may need attention in the communication about DMDs. DESIGN: A best-worst scaling (BWS) was conducted among 27 neurologists and 33 MS nurses treating patients with MS to determine the importance of 27 DMD attributes. These attributes were identified through three focus groups with MS patients in a previous study (N=19). Relative importance scores (RISs) were estimated for each attribute. Multivariable linear regression analyses were used to compare the different perspectives. RESULTS: According to the neurologists and nurses, safety of the DMD was the most important DMD attribute in the treatment decision, closely followed by effect on disability progression, quality of life and relapse rate. Patients with MS agreed with the importance of the last three attributes, but valued safety significantly lower (b=-2.59, P<.001). CONCLUSIONS: This study suggests that, overall, neurologists and nurses regard the same DMD attributes as important as MS patients with the notable exception of safety. This study provides valuable information for the development of interventions to support shared decision making and highlights which attributes of DMDs may need additional attention.

Glatiramer acetate treatment persistence - but not adherence - in multiple sclerosis patients is predicted by health-related quality of life and self-efficacy: a prospective web-based patient-centred study (CAIR study).

BACKGROUND: In patients with relapsing remitting multiple sclerosis (RRMS) the persistence of and adherence to disease modifying drug (DMD) treatment is inadequate. To take individualised measures there is a need to identify patients with a high risk of non-persistence or non-adherence. As patient-related factors have a major influence on persistence and adherence, we investigated whether health-related quality of life (HRQoL) and self-efficacy could predict persistence or adherence. METHODS: In a prospective web-based patient-centred study in 203 RRMS patients, starting treatment with glatiramer acatete (GA) 20 mg subcutaneously daily, we measured physical and mental HRQoL (Multiple Sclerosis Quality of Life-54 questionnaire), functional and control self-efficacy (Multiple Sclerosis Self-Efficacy Scale), the 12-month persistence rate and, in persistent patients, the percentage of missed doses. HRQoL and self-efficacy were compared between persistent and non-persistent patients, and between adherent and non-adherent patients. Logistic regression analysis was used to assess whether persistence and adherence were explained by HRQoL and self-efficacy. RESULTS: Persistent patients had higher baseline physical (mean 58.1 [standard deviation, SD] 16.9) and mental HRQoL (63.8 [16.8]) than non-persistent patients (49.5 [17.6]; 55.9 [20.4]) (P = 0.001; P = 0.003) with no differences between adherent and non-adherent patients (P = 0.46; P = 0.54). Likewise, in persistent patients function (752 [156]) and control self-efficacy (568 [178]) were higher than in non-persistent patients (689 [173]; 491 [192]) (P = 0.009; P = 0.004), but not in adherent vs. non-adherent patients (P = 0.26; P = 0.82). Logistic regression modelling identified physical HRQoL and control self-efficacy as factors that explained persistence. Based on predicted scores from the model, patients were classified into quartiles and the percentage of non-persistent patients per quartile was calculated: non-persistence in the highest quartile was 23.4 vs. 53.2% in the lowest quartile. Risk differentiation with respect to adherence was not possible. Based on these findings we propose a practical work-up scheme to identify patients with a high risk of non-persistence and to identify persistence-related factors. CONCLUSIONS: Findings suggest that pre-treatment physical HRQoL and control self-efficacy may identify RRMS patients with a high risk of early discontinuation of injectable DMD treatment. Targeting of high-risk patients may enable the efficient use of persistence-promoting measures. TRIAL REGISTRATION: Nederlands Trial Register code: NTR2432 .

Adherence to Web-Based Self-Assessments in Long-Term Direct-to-Patient Research: Two-Year Study of Multiple Sclerosis Patients.

BACKGROUND: Direct-to-patient research via Web-based questionnaires is increasingly being used. Missed data or delayed reporting of data may negatively affect the quality of study results. It is insufficiently known to what degree patients adhere to agreed self-assessment schedule over the long term and whether questionnaires are filled out in a timely manner. OBJECTIVE: The objective of this study was to investigate patients' adherence to a self-assessment schedule with low-frequency long questionnaires versus that with a high-frequency short questionnaire. METHODS: In this study, the 36-item MS Impact Profile (MSIP) questionnaire measured (perceived) disabilities and the 54-item MS Quality of Life-54 (MSQoL-54) questionnaire measured health-related quality of life at 6-month intervals. Additionally, the 2-item Medication and Adherence (MA) questionnaire documented medication and adherence to disease-modifying medication every month. An experienced MS nurse assessed the Expanded Disability Status Scale (EDSS) score via phone. For both the self-assessment schedules, we calculated the percentage of patients who had completed all the questionnaires in the first 2 years (completion adherence), the percentage of patients who completed all the questionnaires within set time frames (interval adherence), the relationship between adherence and the EDSS score, and the timing of EDSS assessment. RESULTS: Of the 331 patients who enrolled themselves, 301 patients completed at least one questionnaire. At month six (M6), M12, M18, and M24, the MSIP was completed by 83.4% (251/301), 71.8% (216/301), 68.1% (205/301), and 58.5% (176/301) of the patients, respectively; the MSQoL-54 by 82.1% (247/301), 71.8% (216/301), 66.8% (201/301), and 57.1% (172/301), respectively; and the MA questionnaire by 80.1% (241/301), 70.4% (212/301), 62.1% (187/301), and 53.5% (161/301), respectively. For the MSIP, 56.8% (171/301) of the patients were 2-year completion adherent; 55.5% (167/301) and 53.5% (161/301) of the patients were completion adherent for the MSQoL-54 and MA questionnaires, respectively. Whereas 85.5% (142/166) of the patients were interval adherent for the MSIP and MSQoL-54, 25.5% (41/161) were interval adherent for the MA questionnaire, with 73.9% (119/161) exceeding the maximum MA monthly interassessment interval. Completion adherence for the monthly short MA questionnaire was higher in patients with moderately high disability (EDSS 5.0-5.5) than for those with no or minimal disability (EDSS 0-2.5) (OR 5.47, 95% CI 1.08-27.69; P=.040). Completion adherence was also higher in patients with EDSS assessment within 6 months after baseline than in those with later assessment (OR 1.810, 95% CI 0.999-3.280; P=.050). CONCLUSIONS: The 2-year completion adherence to Web-based self-assessments did not differ between the low-frequency long questionnaires and a high-frequency short questionnaire, but the interval adherence was substantially higher for the low-frequency long questionnaires. Personal contact with a member of the research team regarding a clinically relevant professional-reported outcome early in the study might positively affect the long-term completion adherence in direct-to-patient studies.

An intensive social cognitive program (can do treatment) in people with relapsing remitting multiple sclerosis and low disability: a randomized controlled trial protocol.

BACKGROUND: In people with multiple sclerosis (MS) disabilities and limitations may negatively affect self-efficacy. Lowered self-efficacy has been associated with decreases in health-related quality of life, physical activity and cognitive performance. In an explorative observational study we found that a 3-day intensive social cognitive program (Can Do Treatment [CDT]) with the participation of support partners was followed by substantial increases in self-efficacy control and health-related quality of life 6 months after treatment in those people with MS who had relapsing remitting disease and low disability. METHODS/DESIGN: CDT is a sociologically oriented approach, its goal is to uncover and promote existing capabilities, and the notion "stressor" is the central concept. CDT's components are plenary group sessions, small group sessions, consultations, a theatre evening, and start of the day with a joint activity. The small group sessions form the actual training. Depending on their individual goals the participants join the training groups 'Body', 'Feeling' or 'Life', to work out their aims and to reduce their stressors. The multidisciplinary team includes a psychiatrist, psychiatric nurse, neurologist, specialized MS nurse, physiotherapist, dance therapist, and a person with MS. To evaluate the (cost)effectiveness of CDT in persons with relapsing remitting MS and low disability we perform a single-centre, randomized controlled trial in 140 patients, with or without support partners. The primary outcome is self-efficacy control. The secondary outcomes are self-efficacy function, health-related quality of life, autonomy and participation, anxiety, depression, cost effectiveness and cost utility. The tertiary outcome is care-related strain to support partners. Outcomes are assessed at baseline and at 1, 3 and 6 months after CDT. DISCUSSION: This randomized controlled trial will adequately evaluate the clinical and cost effectiveness of a 3-day intensive social cognitive program in people with relapsing remitting MS and low disability, with self-efficacy control as primary outcome. DUTCH TRIAL REGISTRY: Application number: 22444.

Sperm-associated antigen 16 is a novel target of the humoral autoimmune response in multiple sclerosis.

We have previously identified eight novel autoantibody targets in the cerebrospinal fluid of multiple sclerosis (MS) patients, including sperm-associated Ag 16 (SPAG16). In the current study, we further investigated the autoantibody response against SPAG16-a protein with unknown function in the CNS-and its expression in MS pathology. Using isoelectric focusing, we detected SPAG16-specific oligoclonal bands in the cerebrospinal fluid of 5 of 23 MS patients (22%). Analysis of the anti-SPAG16 Ab reactivity in the plasma of a total of 531 donors using ELISA demonstrated significantly elevated anti-SPAG16 Ab levels (p = 0.002) in 32 of 153 MS patients (21%) compared with all other control groups with 95% specificity for the disease. To investigate the pathologic relevance of anti-SPAG16 Abs in vivo, anti-SPAG16 Abs were injected in mice with experimental autoimmune encephalomyelitis, resulting in a significant disease exacerbation. Finally, we demonstrated a consistent upregulation of SPAG16 in MS brain and experimental autoimmune encephalomyelitis spinal cord lesions, more specifically in reactive astrocytes. We conclude that SPAG16 is a novel autoantibody target in a subgroup of MS patients and in combination with other diagnostic criteria, elevated levels of anti-SPAG16 Abs could be used as a biomarker for diagnosis. Furthermore, the pathologic relevance of anti-SPAG16 Abs was shown in vivo.

A prospective web-based patient-centred interactive study of long-term disabilities, disabilities perception and health-related quality of life in patients with multiple sclerosis in The Netherlands: the Dutch Multiple Sclerosis Study protocol.

BACKGROUND: In the past two decades the widespread use of disease modifying drugs with moderate to strong efficacy has changed the natural course of multiple sclerosis (MS). Health care professionals, researchers, patient organizations and health authorities are in need of recent information about the objectified and subjective long-term clinical outcomes in MS patients. Such information is scarce. METHODS/DESIGN: We started a prospective, web-based, patient-centred, interactive study of long-term disabilities, disabilities perception and health-related quality of life (HRQoL) in MS patients in The Netherlands (Dutch Multiple Sclerosis Study). The study has an on online patient-driven inclusion and online acquisition of patient-reported outcomes (PROs). At six-months intervals participants complete the Multiple Sclerosis Impact Profile (MSIP) (disabilities and disabilities perception in seven domains and four symptoms), the Multiple Sclerosis Quality of Life-54 items (MSQoL-54), the Modified Fatigue Impact Scale-5 items (MFIS-5) and the Leeds Multiple Sclerosis Quality of Life-8 items (LMSQoL) questionnaires, and a Medication and Adherence Inventory. Every three years the Expanded Disability Status Scale (EDSS) score is assessed by phone. The monthly completion of the MFIS-5, LMSQoL and Medication and Adherence Inventory is optional. Completed questionnaires and inventories, and automatically generated scores are made available online to patients for self-monitoring and self-management purposes, and to authorized health care professionals for the evaluation of disease activity and of the effectiveness of treatments. Study duration is planned to be 15 years. Results will be analyzed periodically using means and standard deviations for continuous variables, and frequencies for categorical variables. Relations between time points, variables, patient and treatment characteristics will be evaluated in random effects repeated measures models. DISCUSSION: The Dutch Multiple Sclerosis Study is characterized by online patient-driven inclusion; online data acquisition; the use of PROs; the optional monthly completion of short questionnaires; the interactive use of personal study data by patients and authorized health care professionals for self-monitoring, self-management and multidisciplinary care; the expected representativeness of the study sample; and a long-term time horizon. The study will provide valuable data on long-term disabilities, disabilities perceptions and HRQoL in MS patients in The Netherlands.

The MS@Work study: a 3-year prospective observational study on factors involved with work participation in patients with relapsing-remitting Multiple Sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is the most common cause of neurological disability in young and middle-aged adults. At this stage in life most people are in the midst of their working career. The majority of MS patients are unable to retain employment within 10 years from disease onset. Leading up to unemployment, many may experience a reduction in hours or work responsibilities and increased time missed from work. The MS@Work study examines various factors that may influence work participation in relapsing-remitting MS patients, including disease-related factors, the working environment and personal factors. METHODS/DESIGN: The MS@Work study is a multicenter, 3-year prospective observational study on work participation in patients with relapsing-remitting MS. We aim to include 350 patients through 15-18 MS outpatient clinics in the Netherlands. Eligible participants are 18 years and older, and either currently employed or within three years since their last employment. At baseline and after 1, 2 and 3 years, the participants are asked to complete online questionnaires (including questions on work participation, work problems and accommodations, cognitive and physical ability, anxiety, depression, psychosocial stress, quality of life, fatigue, empathy, personality traits and coping strategies) and undergo cognitive and neurological examinations. After six months, patients are requested to only complete online questionnaires. Patient perspectives on maintaining and improving work participation and reasons to stop working are gathered through semi-structured interviews in a sub-group of patients. DISCUSSION: Prospective studies with long-term follow-up on work participation in MS are rare, or take into account a limited number of factors. The MS@Work study provides a 3-year follow-up on various factors that may influence work participation in patients with relapsing-remitting MS. We aim to identify factors that relate to job loss and to provide information about preventative measures for physicians, psychologists and other professionals working in the field of occupational health.

Validation of a Dutch version of the Actionable 8-item screening questionnaire for neurogenic bladder overactivity in multiple sclerosis: an observational web-based study.

BACKGROUND: In patients with multiple sclerosis (MS) the impact of urological symptoms on quality of life and daily activities is considerable. Yet, a substantial percentage of patients may not be urologically evaluated and thus fail to be treated concordantly. The 8-item Actionable questionnaire is a validated English screening tool for the detection of neurogenic bladder overactivity in MS. To enable the use of the 8-item Actionable in The Netherlands and Belgium we translated the questionnaire into the Dutch language and investigated the test-retest reliability and the concurrent validity of the Dutch version. METHODS: The process of translating the English Actionable questionnaire into the Dutch language included forward translations and back-translations. Then, in an online observational study, MS patients completed the Dutch Actionable at Days 1 and 8, and the Multiple Sclerosis Quality of Life 54-Items (MSQoL-54) and Multiple Sclerosis Impact Profile (MSIP) questionnaires at Day 1; the Expanded Disability Status Scale (EDSS) score was assessed by phone at Day 1. For assessment of the test-retest reliability Pearson's correlation coefficient (r) between the Day 1 and Day 8 Actionable scores was calculated. For assessment of the concurrent validity r values were calculated between the Day 1 Actionable score and the EDSS score, the Physical and Mental MSQoL-54 composites, and the MSIP domain and symptom disability scores. STUDY POPULATION: N = 141 (106 female, 35 male) (80 relapsing remitting, 48 progressive, 13 unknown), mean age 47.8 (standard deviation [SD] 10.4) years, mean EDSS score 4.7 (SD 1.8); 137 patients completed the Day 8 assessment. Pearson's r between Actionable scores Day 1 and Day 8: 0.85 (P < .0001). Pearson's r between Actionable score Day 1 and scores for EDSS 0.41 (P < 0.0001), MSQoL-54 Physical -0.31 (P = 0.0002), MSQoL-54 Mental -0.29 (P = 0.0005), MSIP Excretion and Reproductive Functions 0.44 (P < 0.0001), Muscle and Movement Functions 0.39 (P < .0001), Basic Movement Activities 0.37 (P < 0.0001), Activities of Daily Living 0.32 (P < 0.0001), Participation in Life Situations 0.29 (P = 0.0006) and Mental Functions 0.20 (P = 0.0189). CONCLUSIONS: The Dutch version of the Actionable urological screening tool for MS shows a good test-retest reliability and a good concurrent validity with disabilities and HRQoL.

Simplified scoring of the Actionable 8-item screening questionnaire for neurogenic bladder overactivity in multiple sclerosis: a comparative analysis of test performance at different cut-off points.

BACKGROUND: The Actionable questionnaire is an 8-item tool to screen patients with multiple sclerosis (MS) for neurogenic bladder problems, identifying those patients who might benefit from urological referral and bladder-specific treatment. The original scoring yields a total score of 0 to 24 with cut-off point 6. A simplified scoring, yielding a total score of 0 to 8 with cut-off point 3, has been developed in urogynaecological patients, but has not been investigated in MS. METHODS: One-hundred-and-forty-one MS patients completed the Actionable on two occasions. We compared the test performance of the simplified scoring with cut-off point 3 with that of cut-off point 2, using the original scoring with cut-off point 6 as a gold standard. The following measures were calculated: True Positives (TP), True Negatives (TN), False Positives (FP), False Negatives (FN), Sensitivity, Specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV), and Accuracy. The associations between positive test result and urological treatment, and bladder-specific drug treatment were calculated. RESULTS: For cut-off point 3 the outcomes (Test 1, Test 2) were: TP 43.26 %, 40.88 %; TN 29.79 %, 32.85 %; FP 0.00 %, 0.00 %; FN 26.95 %, 26.28 %; Sensitivity 0.62, 0.61; Specificity 1.00, 1.00; PPV 1.00, 1.00; NPV 0.53, 0.55; Accuracy 0.73, 0.74; and for cut-off point 2: TP 59.57 %, 59.85 %; TN 26.95 %, 31.39 %; FP 2.84 %, 1.46 %; FN 10.63 %, 7.30 %; Sensitivity 0.85, 0.89; Specificity 0.90, 0.96; PPV 0.95, 0.98; NPV 0.72, 0.81; Accuracy 0.87, 0.91. Cut-off 3 completely prevented FP outcomes, but wrongly classified 26 % of the patients as negative (FN). Cut-off 2 reduced the FN to 7-10 %, with low FP values (2.84-1.46 %). With cut-off 2, the percentage of patients screened positive was higher in the Progressive group (75.00 %) than in the Relapsing Remitting group (56.25 %) (P = 0.0331), which was not the case with cut-off 3. Only a positive test according to the original scoring was associated with both urological treatment (P = 0.0119) and bladder-specific medication (P = 0.0328). CONCLUSIONS: Our findings suggest that in MS patients the simplified Actionable scoring is more accurate with cut-off point 2 than with cut-off point 3, especially by substantially reducing FN outcomes; and that in MS the original Actionable scoring seems preferable.

Improved self-efficacy in persons with relapsing remitting multiple sclerosis after an intensive social cognitive wellness program with participation of support partners: a 6-months observational study.

BACKGROUND: For persons with multiple sclerosis (MS) it is important to preserve their autonomy, in spite of increasing disability. A major factor mediating autonomy is self-efficacy. According to the social cognitive theory stressors are crucial determinants of self-efficacy, as well as the interaction with partners. METHODS: In an explorative observational study we assessed in 47 persons with MS (PwMS) the effect of an intense, multidisciplinary, 3-day, social cognitive wellness program with the participation of support partners, after 1, 3 and 6 months. PRIMARY OUTCOMES: self-efficacy-control and -function (Multiple Sclerosis Self-Efficacy Scale [MSSES]),limitations to and problems with participation and autonomy (Impact on Participation and Autonomy [IPA] scale). SECONDARY OUTCOMES: health-related quality of life (HRQoL) (MS Quality of Life-54 Items [MSQoL-54] questionnaire), anxiety, depression (Hospital Anxiety and Depression Scale [HADS]), and fatigue (Modified Fatigue Impact Scale-5 Items [MFIS-5]). Disability was measured with the Expanded Disability Status Scale (EDSS). Percentage changes from baseline were tested with T-tests, level of significance 0.05. RESULTS: In the whole group the MSQoL-54 Mental score was increased at 1, 3 and 6 months (+16.0%, +13.2%, +12.2%), and the MSQoL-54 Physical (+10.2%) at 6 months, with no changes in other outcomes. The relapsing remitting (RR) subgroup (n = 20) had at 6 months an increase in the MSSES-Control score (+24.8%) and in the MSQoL54 Mental and Physical scores (+22.3%, +17.6%). Progressive patients (n = 22) only showed an increase in the MSQoL-54 Mental score (+11.5%) at 1 month. In the low-disability (EDSS < 4.0) subgroup the MSSES-Control score was increased (+23.8%) at 6 months, and the IPA-Limitations and -Problems scores decreased at 3 months (-6.1%, -8.8%); the MSQoL-54 Mental score had increased at 1, 3 and 6 months (+19.3%, +21.5%, +19.3%). In the high-disability (EDSS > =4.0) subgroup no significant changes occurred. CONCLUSIONS: Results from this observational study suggest that 6 months after an intense, 3-day, multidisciplinary, social cognitive wellness program with support partners, PwMS with a RR course or low disability may experience an improved self-efficacy-control and HRQoL.

Identification of coronin-1a as a novel antibody target for clinically isolated syndrome and multiple sclerosis.

Recently, we identified the mimotope UH-CIS6 as a novel candidate antibody target for clinically isolated syndrome (CIS) and relapsing-remitting (RR) multiple sclerosis (MS). The purpose of this study was to further validate UH-CIS6 as an antibody target for CIS and MS and to identify the in vivo antibody target of UH-CIS6. First, a UH-CIS6 peptide ELISA was optimized. Next, we investigated the antibody response toward UH-CIS6 in cerebrospinal fluid (CSF) from patients with CIS (n = 20), MS (n = 43) and other neurological diseases (n = 42). Immunoprecipitation of anti-UH-CIS6 antibodies on a normal human brain lysate was performed to identify the in vivo antibody target of UH-CIS6. The cellular expression of an in vivo candidate target was investigated by immunohistochemistry using MS brain tissue sections. Antibody reactivity toward UH-CIS6 was detected in a significantly increased proportion of CSF samples from CIS and RR-MS patients as compared with neurological controls (p = 0.046). We identified and confirmed coronin-1a as the in vivo antibody target for UH-CIS6. Furthermore, coronin-1a was expressed by T cells and macrophages in an active MS lesion. Together, these results demonstrate that coronin-1a is a novel antibody target for CIS and MS.

Information and Communication Technology Medicine: Integrative Specialty for the Future of Medicine.

The impact of information and communication technology (ICT) on medicine is unprecedented and ever-increasing. This has made it more and more difficult for doctors to keep pace with ICT developments and to adequately match the input of ICT experts. As a result, medical disciplines may not be able to take full advantage of growing possibilities. In this personal viewpoint paper, I argue for the establishment of a novel medical specialty, ICT medicine. ICT medicine is needed to optimally face the challenges of ICT-based developments, including artificial intelligence (AI), and to ensure their efficient and beneficial use. ICT medicine is rooted in both medicine and ICT, and in contrast to existing medical specialties it is integrative in nature, as long-standing structural collaborations with ICT and other stakeholders cross the boundaries between disciplines. Thus, new concepts and theories may evolve that are better suited to addressing ICT-related issues in medicine. ICT doctors will be instrumental in the conception, development, implementation, and evaluation of digital tools, systems, and services. They provide a bridge between ICT professionals and clinical users and educate doctors in digital applications and services. Notably, ICT doctors may have a pivotal role in the validation, verification, and evaluation of AI models. ICT medicine institutes offer a home to these new professionals, enhancing their independence within health care organizations and in relation to ICT companies. Importantly, in an era of growing technicalization and use of AI algorithms, ICT doctors may safeguard the human factor in medicine. And, from a societal perspective, they may promote digital inclusion and the continuing high quality of digital services and provide leadership in the future digitalization of medicine.

Sexual Motivation in Persons with Multiple Sclerosis: A Controlled Cross-Sectional Study.

Purpose: Sexual motives are major determinants of sexual behaviour. It has been known that sexual motives may vary according to circumstances. Multiple sclerosis (MS) is a chronic disease causing a broad range of symptoms and disabilities, that often interfere with sexual activities. We aimed to investigate the sexual motives in persons with MS. Patients and Methods: Cross-sectional study in 157 persons with MS and 157 controls matched for age, gender, relationship, duration of relationship and educational status via propensity score matching. The Reasons for Having Sex (YSEX) questionnaire assessed the proportion with which a person had engaged in sexual intercourse for each of 140 distinct motives to have sex. Estimated mean differences in scores for four primary factors (Physical, Goal attainment, Emotional, Insecurity) and 13 sub-factors, and sexual satisfaction and importance of sex were calculated as Average Treatment Effect of the Treated using 99% confidence intervals. Results: Persons with MS reported a lower proportion of engaging in sex compared with the controls for the factors Physical (-0.29), Emotional (-0.23) and Insecurity (-0.10); and for the physical sub-factors Pleasure (-0.48), Experience seeking (-0.32), Stress reduction (-0.24), and Physical desirability (-0.16), the emotional sub-factors Love and commitment (-0.27) and Expression (-0.17), and the insecurity sub-factor Self-esteem boost (-0.23). In the control group seven of the top 10 sexual motives were physical versus five in the MS group. The importance of sex was lower in the MS group (-0.68). Conclusion: Findings of this controlled cross-sectional study suggest a reduction in the number of sexual motives in persons with MS, especially of physical motives related to pleasure and experience seeking. Health care professionals may consider assessing sexual motivation when dealing with persons with MS who suffer from decreased sexual desire or another sexual dysfunction.

Self-reported work productivity in people with multiple sclerosis and its association with mental and physical health.

PURPOSE: This study aimed to identify mental health, physical health, demographic and disease characteristics relating to work productivity in people with multiple sclerosis (MS). METHODS: In this cross-sectional study, 236 employed people with MS (median age = 42 years, 78.8% female) underwent neurological and neuropsychological assessments. Additionally, they completed questionnaires inquiring about work productivity (presenteeism: reduced productivity while working, and absenteeism: loss of productivity due to absence from work), mental and physical health, demographic and disease characteristics. Multiple linear and logistic regression analyses were performed with presenteeism and absenteeism as dependent variables, respectively. RESULTS: A model with mental and physical health factors significantly predicted presenteeism F(11,202) = 11.33, p < 0.001, R2 = 0.38; a higher cognitive (p < 0.001) and physical impact (p = 0.042) of fatigue were associated with more presenteeism. A model with only mental health factors significantly predicted absenteeism; χ2(11)=37.72, p < 0.001, with R2 = 0.27 (Nagelkerke) and R2 = 0.16 (Cox and Snell). Specifically, we observed that more symptoms of depression (p = 0.041) and a higher cognitive impact of fatigue (p = 0.011) were significantly associated with more absenteeism. CONCLUSIONS: In people with MS, both cognitive and physical impact of fatigue are positively related to presenteeism, while symptoms of depression and cognitive impact of fatigue are positively related to absenteeism.Implications for rehabilitationMultiple sclerosis (MS) affects people of working age, significantly interfering with work productivity.Higher cognitive and physical impact of fatigue were associated with more presenteeism in workers with MS.A higher cognitive impact of fatigue and more depressive symptoms were associated with absenteeism in workers with MS.Occupational and healthcare professionals should be aware of the impact of both physical and mental health on work productivity in workers with MS.

Cognitive performance in relapsing remitting multiple sclerosis: a longitudinal study in daily practice using a brief computerized cognitive battery.

BACKGROUND: There is need for a cognitive test battery that can be easily used in clinical practice to detect or monitor cognitive performance in patients with multiple sclerosis (MS). In order to conduct, in this patient group, a preliminary investigation of the validity and utility of a brief computerized battery, the Cognitive Drug Research (CDR) battery, we longitudinally assessed cognition in patients with relapsing remitting (RR) MS. METHODS: Forty-three mildly disabled, clinically active RRMS patients were repeatedly assessed with the Digit Symbol Substitution Test (DSST), Paced Auditory Serial Addition Test (PASAT) and five composite scores derived from the CDR computerized cognitive test system (CDR System): Power of Attention, Continuity of Attention, Quality of Working Memory, Quality of Episodic Memory and Speed of Memory. The Multiple Sclerosis Functional Composite (MSFC) and Expanded Disability Status Scale (EDSS) measured disability. RESULTS: The composite scores from the CDR battery generally showed excellent test-retest reliability over the repeated assessments, though was low on occasions for the Quality of Working Memory and Quality of Episodic Memory measures. The CDR measures tended to be highly correlated with other measures of cognition (DSST and PASAT) and were also strongly related to disability (EDSS and MSFC). Baseline scores indicated large impairments to visual information processing speed and attention (DSST, Cohen's d 1.1; Power of Attention d 1.4 [reaction time on tasks of focussed and sustained attention]), and a moderate impairment both to sustained attention (Continuity of Attention d 0.6) and complex information processing speed (Speed of memory d 0.7 [reaction time on tasks of working and episodic Memory]), when compared to normative data derived from healthy volunteers enrolled in a series of separate, prior clinical trials. Working memory (Quality of Working Memory) and episodic memory (Quality of Episodic Memory) were unimpaired. CONCLUSIONS: Preliminary validation of the CDR System indicated that for most, but not all measures psychometric properties were adequate and the measures were related to disability (EDSS and MSFC) and other measures of cognition.

Drug adherence and multidisciplinary care in patients with multiple sclerosis: protocol of a prospective, web-based, patient-centred, nation-wide, Dutch cohort study in glatiramer acetate treated patients (CAIR study).

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, for which no definitive treatment is available. Most patients start with a relapsing-remitting course (RRMS). Disease-modifying drugs (DMDs) reduce relapses and disability progression. First line DMDs include glatiramer acetate (GA), interferon-beta (INFb)-1a and INFb-1b, which are all administered via injections. Effectiveness of DMD treatment depends on adequate adherence, meaning year-long continuation of injections with a minimum of missed doses. In real-life practice DMD-treated patients miss 30% of doses. The 6-month discontinuation rate is up to 27% and most patients who discontinue do so in the first 12 months.Treatment adherence is influenced by the socio-economic situation, health care and caregivers, disease, treatment and patient characteristics. Only a few studies have dealt with adherence-related factors in DMD-treated patients. Self-efficacy expectations were found to be related to GA adherence. Patient education and optimal support improve adherence in general. Knowledge of the aspects of care that significantly relate to adherence could lead to adherence-improving measures. Moreover, identification of patients at risk of inadequate adherence could lead to more efficient care.In the near future new drugs will become available for RRMS. Detailed knowledge on factors prognostic of adherence and on care aspects that are associated with adequate adherence will improve the chances of these drugs becoming effective treatments. We investigate in RRMS patients the relationship between drug adherence and multidisciplinary care, as well as factors associated with adherence. Given the differences in the frequency of administration and in the side effects between the DMDs we decided to study patients treated with the same DMD, GA. METHODS/DESIGN: The Correlative analyses of Adherence In Relapsing remitting MS (CAIR) study is an investigator-initiated, prospective, web-based, patient-centred, nation-wide cohort study in the Netherlands.The primary objective is to investigate whether GA adherence is associated with specific disciplines of care or quantities of specific care. The secondary objective is to investigate whether GA adherence is associated with specific aspects of the socio-economic situation, health care and caregivers, disease, treatment or patient characteristics.All data are acquired on-line via a study website. All RRMS patients in the Netherlands starting GA treatment are eligible. Patients are informed by neurologists, nurses, and websites from national MS patient organisations. All data, except on disability, are obtained by patient self-reports on pre-defined and random time points. The number of missed doses and the number of patients having discontinued GA treatment at 6 and 12 months are measures of adherence. Per care discipline the number of sessions and the total duration of care are measures of received care. The full spectrum of non-experimental care that is available in the Netherlands is assessed. Care includes 'physical' contacts, contacts by telephone or internet, health-promoting activities and community care activities. Care received over the preceding 14 days is assessed by patients at baseline and every other week thereafter up to month 12. Every 3 months neurologists and nurses record care disciplines to which patients have been referred.The Dutch Adherence Questionnaire-90 (DAQ-90) is a 90-item questionnaire based on the World Health Organisation (WHO) 2003 report on adherence and comprehensively assesses five domains of evidence-based determinants of adherence: socio-economic, health care and caregivers, disease, treatment, and patient-related factors. In addition, self-efficacy is assessed by the MS Self-Efficacy Scale (MSSES), and mood and health-related quality of life (HRQoL) by the Multiple Sclerosis Quality of Life-54 questionnaire (MSQoL-54). Relapses and adverse events probably or definitively related to GA are also reported. DISCUSSION: In this study data is mainly acquired by patients' self-reporting via the internet. On-line data acquisition by patients does not require study visits to the hospital and can easily be integrated into daily life. The web-based nature of the study is believed to prevent missing data and study drop-outs. Moreover, the automated process of filling in questionnaires ensures completeness and consistency, thus improving data quality. The combination of patient-reported outcomes, fully web-based data capture and nation-wide information to all eligible patients are distinguishing features of the study and contribute to its scientific potential. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR2432.

A Two-Minute Walking Test With a Smartphone App for Persons With Multiple Sclerosis: Validation Study.

BACKGROUND: Walking disturbances are a common dysfunction in persons with multiple sclerosis (MS). The 2-Minute Walking Test (2MWT) is widely used to quantify walking speed. We implemented a smartphone-based 2MWT (s2MWT) in MS sherpa, an app for persons with MS. When performing the s2MWT, users of the app are instructed to walk as fast as safely possible for 2 minutes in the open air, while the app records their movement and calculates the distance walked. OBJECTIVE: The aim of this study is to investigate the concurrent validity and test-retest reliability of the MS sherpa s2MWT. METHODS: We performed a validation study on 25 persons with relapsing-remitting MS and 79 healthy control (HC) participants. In the HC group, 21 participants were matched to the persons with MS based on age, gender, and education and these followed the same assessment schedule as the persons with MS (the HC-matched group), whereas 58 participants had a less intense assessment schedule to determine reference values (the HC-normative group). Intraclass correlation coefficients (ICCs) were determined between the distance measured by the s2MWT and the distance measured using distance markers on the pavement during these s2MWT assessments. ICCs were also determined for test-retest reliability and derived from 10 smartphone tests per study participant, with 3 days in between each test. We interviewed 7 study participants with MS regarding their experiences with the s2MWT. RESULTS: In total, 755 s2MWTs were completed. The adherence rate for the persons with MS and the participants in the HC-matched group was 92.4% (425/460). The calculated distance walked on the s2MWT was, on average, 8.43 m or 5% (SD 18.9 m or 11%) higher than the distance measured using distance markers (n=43). An ICC of 0.817 was found for the concurrent validity of the s2MWT in the combined analysis of persons with MS and HC participants. Average ICCs of 9 test-retest reliability analyses of the s2MWT for persons with MS and the participants in the HC-matched group were 0.648 (SD 0.150) and 0.600 (SD 0.090), respectively, whereas the average ICC of 2 test-retest reliability analyses of the s2MWT for the participants in the HC-normative group was 0.700 (SD 0.029). The interviewed study participants found the s2MWT easy to perform, but they also expressed that the test results can be confronting and that a pressure to reach a certain distance can be experienced. CONCLUSIONS: The high correlation between s2MWT distance and the conventional 2MWT distance indicates a good concurrent validity. Similarly, high correlations underpin a good test-retest reliability of the s2MWT. We conclude that the s2MWT can be used to measure the distance that the persons with MS walk in 2 minutes outdoors near their home, from which both clinical studies and clinical practice can benefit.