The Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis is straightforward and considerably outperforms the standard DerSimonian-Laird method.

BACKGROUND: The DerSimonian and Laird approach (DL) is widely used for random effects meta-analysis, but this often results in inappropriate type I error rates. The method described by Hartung, Knapp, Sidik and Jonkman (HKSJ) is known to perform better when trials of similar size are combined. However evidence in realistic situations, where one trial might be much larger than the other trials, is lacking. We aimed to evaluate the relative performance of the DL and HKSJ methods when studies of different sizes are combined and to develop a simple method to convert DL results to HKSJ results. METHODS: We evaluated the performance of the HKSJ versus DL approach in simulated meta-analyses of 2-20 trials with varying sample sizes and between-study heterogeneity, and allowing trials to have various sizes, e.g. 25% of the trials being 10-times larger than the smaller trials. We also compared the number of "positive" (statistically significant at p < 0.05) findings using empirical data of recent meta-analyses with > = 3 studies of interventions from the Cochrane Database of Systematic Reviews. RESULTS: The simulations showed that the HKSJ method consistently resulted in more adequate error rates than the DL method. When the significance level was 5%, the HKSJ error rates at most doubled, whereas for DL they could be over 30%. DL, and, far less so, HKSJ had more inflated error rates when the combined studies had unequal sizes and between-study heterogeneity. The empirical data from 689 meta-analyses showed that 25.1% of the significant findings for the DL method were non-significant with the HKSJ method. DL results can be easily converted into HKSJ results. CONCLUSIONS: Our simulations showed that the HKSJ method consistently results in more adequate error rates than the DL method, especially when the number of studies is small, and can easily be applied routinely in meta-analyses. Even with the HKSJ method, extra caution is needed when there are = <5 studies of very unequal sizes.

Aging attenuates the protective effect of ischemic preconditioning against endothelial ischemia-reperfusion injury in humans.

Reperfusion is mandatory after ischemia but also triggers ischemia-reperfusion (I/R) injury. Ischemic preconditioning (IPC) can limit endothelial I/R injury. Nonetheless, translation of IPC to the clinical arena is often disappointing. Since application of IPC typically relates to older patients, efficacy of IPC may be attenuated with aging. Our objective was to examine the impact of advanced age on the ability of IPC to protect against endothelial dysfunction due to I/R injury. We included 15 healthy young (20-25 yr) and 15 older (68-77 yr) men. We examined brachial artery endothelial function using flow-mediated dilation (FMD) before and after arm I/R (induced by inflation of an upper-arm blood pressure cuff for 20 min and 15 min of reperfusion). In a randomized order, I/R was preceded by IPC or a control intervention consisting of three cycles of 5 min upper-arm cuff inflation to 220 or 20 mmHg, respectively. As a result, in young men, FMD decreased significantly after I/R (6.4 ± 2.7 to 4.4 ± 2.5%). This decrease was not present when I/R was preceded by IPC (5.9 ± 2.3 to 5.6 ± 2.5%). IPC-induced protection appeared to be significantly reduced in the elderly patients (P = 0.04). Although FMD decreased after I/R in older men (3.5 ± 1.7 to 2.5 ± 1.0%), IPC could not prevent this (3.7 ± 2.1 to 2.2 ± 1.1%). In conclusion, this study is the first to observe in humans in vivo that older age is associated with an abolished effect of IPC to protect against endothelial dysfunction after I/R in the brachial artery. This provides a possible explanation for the problematic translation of strategies that reduce I/R injury from preclinical work to the clinical arena.

Prognosis of metastatic breast cancer subtypes: the hormone receptor/HER2-positive subtype is associated with the most favorable outcome.

Contrary to the situation in early breast cancer, little is known about the prognostic relevance of the hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) in metastatic breast cancer. The objectives of this study were to present survival estimates and to determine the prognostic impact of breast cancer subtypes based on HR and HER2 status in a recent cohort of metastatic breast cancer patients, which is representative of current clinical practice. Patients diagnosed with metastatic breast cancer between 2007 and 2009 were included. Information regarding patient and tumor characteristics and treatment was collected. Patients were categorized in four subtypes based on the HR and HER2 status of the primary tumor: HR positive (+)/HER2 negative (-), HR+/HER2+, HR-/HER2+ and triple negative (TN). Survival was estimated using the Kaplan-Meier method. Cox proportional hazards model was used to determine the prognostic impact of breast cancer subtype, adjusted for possible confounders. Median follow-up was 21.8 months for the 815 metastatic breast cancer patients included; 66 % of patients had the HR+/HER2- subtype, 8 % the HR-/HER2+ subtype, 15 % the TN subtype and 11 % the HR+/HER2+ subtype. The longest survival was observed for the HR+/HER2+ subtype (median 34.4 months), compared to 24.8 months for the HR+/HER2- subtype, 19.8 months for the HR-/HER2+ subtype and 8.8 months for the TN subtype (P < 0.0001). In the multivariate analysis, subtype was an independent prognostic factor, as were initial site of metastases and metastatic-free interval. The HR+/HER2+ subtype was associated with the longest survival after diagnosis of distant metastases.

Cerebrospinal fluid amyloid-ß and phenotypic heterogeneity in de novo Parkinson's disease.

BACKGROUND: In Parkinson's disease (PD), the motor presentation characterised by postural instability/gait difficulties (PIGD) heralds accelerated motor, functional and cognitive decline, as compared with the more benign tremor-dominant (TD) variant. This makes the PIGD complex an attractive target for the discovery of prognostic biomarkers in PD. OBJECTIVE: To explore in vivo whether variability in brain amyloid-ß (Aß) metabolism affects the initial motor presentation in PD. METHODS: We quantified cerebrospinal fluid (CSF) concentrations and ratios of Aß42, Aß40 and Aß38 using a triplex immunoassay in 99 patients with de novo PD with the PIGD phenotype (n=39) or the TD phenotype (n=60). All patients underwent standardised assessments of motor and neuropsychological function and cerebral MRI. 46 age-matched normal controls served as external reference. RESULTS: Patients with PD with the PIGD phenotype had significantly reduced CSF Aß42, Aß38, Aß42/40 and Aß38/40 levels compared with patients with the TD phenotype and controls. CSF marker levels in patients with PD-TD did not differ from those in controls. Multivariate regression models demonstrated significant associations of CSF Aß markers with severity of PIGD and lower limb bradykinesia in patients with PD, independently from age, MRI white matter hyperintensities and cognition. No associations were found between CSF markers and other motor features. CONCLUSIONS: Motor heterogeneity in de novo PD independently relates to CSF Aß markers, with low levels found in patients with the PIGD presentation. This suggests that disturbed Aß metabolism has an effect on PD beyond cognition and may contribute to the variable rate of motor and functional decline in PD.

Effectiveness of multidisciplinary care for Parkinson's disease: a randomized, controlled trial.

Multidisciplinary care is considered an optimal model to manage Parkinson's disease (PD), but supporting evidence is limited. We performed a randomized, controlled trial (RCT) to establish whether a multidisciplinary/specialist team offers better outcomes, compared to stand-alone care from a general neurologist. Patients with PD were randomly allocated to an intervention group (care from a movement disorders specialist, PD nurses, and social worker) or a control group (care from general neurologists). Both interventions lasted 8 months. Clinicians and researchers were blinded for group allocation. The primary outcome was the change in quality of life (Parkinson's Disease Questionnaire; PDQ-39) from baseline to 8 months. Other outcomes were the UPDRS, depression (Montgomery-Asberg Depression Scale; MADRS), psychosocial functioning (Scales for Outcomes in Parkinson's disease-Psychosocial; SCOPA-PS), and caregiver strain (Caregiver Strain Index; CSI). Group differences were analyzed using analysis of covariance adjusted for baseline values and presence of response fluctuations. A total of 122 patients were randomized and 100 completed the study (intervention, n = 51; control, n = 49). Compared to controls, the intervention group improved significantly on PDQ-39 (difference, 3.4; 95% confidence interval [CI]: 0.5-6.2) and UPDRS motor scores (4.1; 95% CI: 0.8-7.3). UPDRS total score (5.6; 95% CI: 0.9-10.3), MADRS (3.7; 95% CI: 1.4-5.9), and SCOPA-PS (2.1; 95% CI: 0.5-3.7) also improved significantly. This RCT gives credence to a multidisciplinary/specialist team approach. We interpret these positive findings cautiously because of the limitations in study design. Further research is required to assess teams involving additional disciplines and to evaluate cost-effectiveness of integrated approaches. © 2012 Movement Disorder Society.

The impact of occupational therapy in Parkinson's disease: a randomized controlled feasibility study.

AIM: To evaluate the feasibility of a randomized controlled trial including process and potential impact of occupational therapy in Parkinson's disease. DESIGN: Process and outcome were quantitatively and qualitatively evaluated in an exploratory multicentre, two-armed randomized controlled trial at three months. PARTICIPANTS: Forty-three community-dwelling patients with Parkinson's disease and difficulties in daily activities, their primary caregivers and seven occupational therapists. INTERVENTION: Ten weeks of home-based occupational therapy according to the Dutch guidelines of occupational therapy in Parkinson's disease versus no occupational therapy in the control group. MAIN MEASURES: Process evaluation measured accrual, drop-out, intervention delivery and protocol adherence. Primary outcome measures of patients assessed daily functioning: Canadian Occupational Performance Measure (COPM) and Assessment of Motor and Process Skills. Primary outcome for caregivers was caregiver burden: Zarit Burden Inventory. Participants' perspectives of the intervention were explored using questionnaires and in-depth interviews. RESULTS: Inclusion was 23% (43/189), drop-out 7% (3/43) and unblinding of assessors 33% (13/40). Full intervention protocol adherence was 74% (20/27), but only 60% (71/119) of baseline Canadian Occupational Performance Measure priorities were addressed in the intervention. The outcome measures revealed negligible to small effects in favour of the intervention group. Almost all patients and caregivers of the intervention group were satisfied with the results. They perceived: 'more grip on the situation' and used 'practical advices that make life easier'. Therapists were satisfied, but wished for a longer intervention period. CONCLUSIONS: The positive perceived impact of occupational therapy warrants a large-scale trial. Adaptations in instructions and training are needed to use the Canadian Occupational Performance Measure as primary outcome measure.

Outcome prediction in moderate and severe traumatic brain injury: a focus on computed tomography variables.

BACKGROUND: With this study we aimed to design validated outcome prediction models in moderate and severe traumatic brain injury (TBI) using demographic, clinical, and radiological parameters. METHODS: Seven hundred consecutive moderate or severe TBI patients were included in this observational prospective cohort study. After inclusion, clinical data were collected, initial head computed tomography (CT) scans were rated, and at 6 months outcome was determined using the extended Glasgow Outcome Scale. Multivariate binary logistic regression analysis was applied to evaluate the association between potential predictors and three different outcome endpoints. The prognostic models that resulted were externally validated in a national Dutch TBI cohort. RESULTS: In line with previous literature we identified age, pupil responses, Glasgow Coma Scale score and the occurrence of a hypotensive episode post-injury as predictors. Furthermore, several CT characteristics were associated with outcome; the aspect of the ambient cisterns being the most powerful. After external validation using Receiver Operating Characteristic (ROC) analysis our prediction models demonstrated adequate discriminative values, quantified by the area under the ROC curve, of 0.86 for death versus survival and 0.83 for unfavorable versus favorable outcome. Discriminative power was less for unfavorable outcome in survivors: 0.69. CONCLUSIONS: Outcome prediction in moderate and severe TBI might be improved using the models that were designed in this study. However, conventional demographic, clinical and CT variables proved insufficient to predict disability in surviving patients. The information that can be derived from our prediction rules is important for the selection and stratification of patients recruited into clinical TBI trials.

Regional recurrence in breast cancer patients with sentinel node micrometastases and isolated tumor cells.

OBJECTIVE: The impact of axillary treatment in daily practice on 5-year regional recurrence rate in breast cancer patients with isolated tumor cells or micrometastases in the sentinel node (SLN). BACKGROUND: Axillary dissection is recommended in patients with tumor-positive SLNs. But, in recent studies, regional recurrence rates seemed low if dissection was omitted. METHODS: We identified all patients in The Netherlands with invasive breast cancer who had an SLN biopsy before 2006, favorable primary tumor characteristics, and node-negative disease, isolated tumor cells or micrometastases as final nodal status. The primary endpoint was regional recurrence rate. To investigate differences in recurrence rates between patients with and without axillary treatment, a proportional hazard regression was carried out correcting for potential confounders. RESULTS: In total, 857 patients with node-negative disease, 795 patients with isolated tumor cells, and 1028 patients with micrometastases in the SLN were included. Without axillary treatment, the 5-year regional recurrence rates were 2.3%, 2.0%, and 5.6%, respectively. Compared with patients who underwent axillary treatment, the adjusted hazard ratio for regional recurrence in patients who underwent an SLN procedure only was 1.08 (95% CI, 0.23-4.98) for node-negative disease, 2.39 (95% CI, 0.67-8.48) for isolated tumor cells, and 4.39 (95% CI, 1.46-13.24) for micrometastases. Doubling of tumor size, grade 3 and negative hormone receptor status were also significantly associated with recurrence. CONCLUSIONS: Not performing axillary treatment in patients with SLN micrometastases is associated with an increased 5-year regional recurrence rate. Axillary treatment is recommended in patients with SLN micrometastases and unfavorable tumor characteristics.

Micrometastases or isolated tumor cells and the outcome of breast cancer.

BACKGROUND: The association of isolated tumor cells and micrometastases in regional lymph nodes with the clinical outcome of breast cancer is unclear. METHODS: We identified all patients in The Netherlands who underwent a sentinel-node biopsy for breast cancer before 2006 and had breast cancer with favorable primary-tumor characteristics and isolated tumor cells or micrometastases in the regional lymph nodes. Patients with node-negative disease were randomly selected from the years 2000 and 2001. The primary end point was disease-free survival. RESULTS: We identified 856 patients with node-negative disease who had not received systemic adjuvant therapy (the node-negative, no-adjuvant-therapy cohort), 856 patients with isolated tumor cells or micrometastases who had not received systemic adjuvant therapy (the node-positive, no-adjuvant-therapy cohort), and 995 patients with isolated tumor cells or micrometastases who had received such treatment (the node-positive, adjuvant-therapy cohort). The median follow-up was 5.1 years. The adjusted hazard ratio for disease events among patients with isolated tumor cells who did not receive systemic therapy, as compared with women with node-negative disease, was 1.50 (95% confidence interval [CI], 1.15 to 1.94); among patients with micrometastases, the adjusted hazard ratio was 1.56 (95% CI, 1.15 to 2.13). Among patients with isolated tumor cells or micrometastases, the adjusted hazard ratio was 0.57 (95% CI, 0.45 to 0.73) in the node-positive, adjuvant-therapy cohort, as compared with the node-positive, no-adjuvant-therapy cohort. CONCLUSIONS: Isolated tumor cells or micrometastases in regional lymph nodes were associated with a reduced 5-year rate of disease-free survival among women with favorable early-stage breast cancer who did not receive adjuvant therapy. In patients with isolated tumor cells or micrometastases who received adjuvant therapy, disease-free survival was improved.

Prognostic impact of isolated tumor cells in breast cancer axillary nodes: single tumor cell(s) versus tumor cell cluster(s) and microanatomic location.

In breast cancer, it has been shown that pN0(i+) and pN1mi have a comparable negative impact on disease-free survival, compared with pN0. However, pN0(i+) is considered to be a heterogeneous group. We determined the effect of metastatic size and microanatomic location within the pN0(i+) group on breast cancer recurrence. We included all Dutch breast cancer patients diagnosed in 1998-2005 with favorable primary tumor characteristics and a final nodal status of pN0(i+). For this analysis, only patients without adjuvant systemic therapy were eligible (n = 513). Presence of single tumor cells versus cell clusters, metastatic size and microanatomic location were recorded. Primary endpoint was disease-free survival. Analyses were adjusted for age at diagnosis, tumor size, tumor grade, axillary treatment and hormone receptor status. The 5-year disease-free survival of patients with single tumor cell(s) (n = 93) was 78.6% and with tumor cell cluster(s) (n = 404) 77.1%. The hazard ratio for disease events was 1.05 (95% CI 0.63-1.76) for cell cluster(s) compared with single cell(s). In a Cox regression model, doubling of metastatic tumor size corresponded to a hazard ratio of 1.21 (95% CI 1.02-1.43). The adjusted hazard ratio was 0.90 (95% CI 0.54-1.50) for parenchymal (n = 112) versus sinusoidal location (n = 395). Single tumor cells bear similar prognostic information as small tumor cell clusters, even though results do suggest that within the pN0(i+) group, increasing size of nodal involvement is associated with reduced survival. Microanatomic location does not seem to have prognostic relevance.

Meier-Gorlin syndrome: growth and secondary sexual development of a microcephalic primordial dwarfism disorder.

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex is essential for DNA replication and therefore mutations are expected to impair cell proliferation and consequently could globally reduce growth. However, detailed growth characteristics of MGS patients have not been reported, and so this is addressed here through study of 45 MGS patients, the largest cohort worldwide. Here, we report that growth velocity (length) is impaired in MGS during pregnancy and first year of life, but, thereafter, height increases in paralleled normal reference centiles, resulting in a mean adult height of -4.5 standard deviations (SD). Height is dependent on ethnic background and underlying molecular cause, with ORC1 and ORC4 mutations causing more severe short stature and microcephaly. Growth hormone therapy (n = 9) was generally ineffective, though in two patients with significantly reduced IGF1 levels, growth was substantially improved by GH treatment, with 2SD and 3.8 SD improvement in height. Growth parameters for monitoring growth in future MGS patients are provided and as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) and mammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth.

A simple sample size formula for analysis of covariance in cluster randomized trials.

For cluster randomized trials with a continuous outcome, the sample size is often calculated as if an analysis of the outcomes at the end of the treatment period (follow-up scores) would be performed. However, often a baseline measurement of the outcome is available or feasible to obtain. An analysis of covariance (ANCOVA) using both the baseline and follow-up score of the outcome will then have more power. We calculate the efficiency of an ANCOVA analysis using the baseline scores compared with an analysis on follow-up scores only. The sample size for such an ANCOVA analysis is a factor r2 smaller, where r is the correlation of the cluster means between baseline and follow-up. This correlation can be expressed in clinically interpretable parameters: the correlation between baseline and follow-up of subjects (subject autocorrelation) and that of clusters (cluster autocorrelation). Because of this, subject matter knowledge can be used to provide (range of) plausible values for these correlations, when estimates from previous studies are lacking. Depending on how large the subject and cluster autocorrelations are, analysis of covariance can substantially reduce the number of clusters needed.

Development and external validation of a new PTA assessment scale.

BACKGROUND: Post-traumatic amnesia (PTA) is a key symptom of traumatic brain injury (TBI). Accurate assessment of PTA is imperative in guiding clinical decision making. Our aim was to develop and externally validate a short, examiner independent and practical PTA scale, by selecting the most discriminative items from existing scales and using a three-word memory test. METHODS: Mild, moderate and severe TBI patients and control subjects were assessed in two separate cohorts, one for derivation and one for validation, using a questionnaire comprised of items from existing PTA scales. We tested which individual items best discriminated between TBI patients and controls, represented by sensitivity and specificity. We then created our PTA scale based on these results. This new scale was externally evaluated for its discriminative value using Receiver Operating Characteristic (ROC) analysis and compared to existing PTA scales. RESULTS: The derivation cohort included 126 TBI patients and 31 control subjects; the validation cohort consisted of 132 patients and 30 controls. A set of seven items was eventually selected to comprise the new PTA scale: age, name of hospital, time, day of week, month, mode of transport and recall of three words. This scale demonstrated adequate discriminative values compared to existing PTA scales on three consecutive administrations in the validation cohort. CONCLUSION: We introduce a valid, practical and examiner independent PTA scale, which is suitable for mild TBI patients at the emergency department and yet still valuable for the follow-up of more severely injured TBI patients.

Safety of avoiding routine use of axillary dissection in early stage breast cancer: a systematic review.

Physicians are moving away from routine axillary lymph node dissection (ALND) in clinically node-negative breast cancer. We conducted a systemic review on the safety of this policy. Pubmed and Cochrane library were searched for. Sixty-eight studies were included: studies of clinically node-negative patients in the pre-sentinel node (SN) era; observational studies of SN-negative patients, without ALND; comparative studies of SN-negative patients, with a non-ALND and an ALND group; SN-positive studies, of patients without ALND. Primary endpoint was the pooled axillary recurrence rate (ARR) of each category; secondary endpoint was overall survival (OS) rate. In pre-SN studies, with larger tumors and less systemic therapy, ARR without ALND after 5-10 years follow-up was 12-18%, with 5% reduced OS. In the observational SN-negative studies, with median follow-up of 36 months, the pooled ARR was 0.6% (95% CI 0.6-0.8). In the comparative SN-negative studies, pooled ARR was 0.4% (95% CI 0.2-0.6) without ALND versus 0.3% (95% CI 0.1-0.6) with ALND at 31 and 47 months, respectively, and no survival disadvantage. In SN-positive studies, ARR was up to 1.7% (95% CI 1.0-2.7) at 30 months. For patients with an H&E positive SN the ARR without ALND was 5% after 23 months, which may imply rates as high as 13 and 18% after 5 and 8 years. In conclusion, this systematic review confirms the safety of omitting ALND in SN-negative patients. There is a potential role for avoiding ALND in selected SN-positive patients, but eligibility criteria and the role of systemic therapy need further to be elucidated.

Pathophysiology of diurnal drooling in Parkinson's disease.

Drooling is an incapacitating feature of Parkinson's disease. Better pathophysiological insights are needed to improve treatment. In this study, we tested the hypothesis that the cause of drooling is multifactorial. We examined 15 patients with Parkinson's disease with distinct diurnal saliva loss ("droolers") and 15 patients with Parkinson's disease without drooling complaints ("nondroolers"). We evaluated all factors that could potentially contribute to drooling: swallowing capacity (maximum volume), functional swallowing (assessed with the dysphagia subscale of the Therapy Outcome Measures for rehabilitation specialists), unintentional mouth opening due to hypomimia (Unified Parkinson's Disease Rating Scale item), posture (quantified from sagittal photographs), and nose-breathing ability. We also quantified the frequency of spontaneous swallowing during 45 minutes of quiet sitting, using polygraphy. Droolers had more advanced Parkinson's disease than nondroolers (Unified Parkinson's Disease Rating Scale motor score 31 vs 22; P=.014). Droolers also scored significantly worse on all recorded variables except for nose breathing. Swallowing frequency tended to be higher, possibly to compensate for less efficient swallowing. Logistic regression with adjustment for age and disease severity showed that hypomimia correlated best with drooling. Linear regression with hypomimia as the dependent variable identified disease severity, dysphagia, and male sex as significant explanatory factors. Drooling in Parkinson's disease results from multiple risk factors, with hypomimia being the most prominent. When monitored, patients appear to compensate by increasing their swallowing frequency, much like the increased cadence that is used to compensate for stepping akinesia. These findings can provide a rationale for behavioral approaches to treat drooling.

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.

Reproducibility and validity of patient-rated assessment of speech, swallowing, and saliva control in Parkinson's disease.

OBJECTIVE: To report on the development and psychometric evaluation of the Radboud Oral Motor Inventory for Parkinson's Disease (ROMP), a newly developed patient-rated assessment of speech, swallowing, and saliva control in patients with Parkinson's disease (PD). DESIGN: Reliability and validity study. SETTING: Tertiary-care Parkinson center for multidisciplinary assessment. PARTICIPANTS: Consecutive community-dwelling patients with PD (n=129) or atypical parkinsonism (AP; n=49; mean ± SD age, 64±9.8y; mean ± SD disease duration, 7y; median Hoehn and Yahr [HY] stage, 2.5). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: To evaluate reproducibility, 60 patients completed the ROMP twice within a mean of 24±12 days. To study validity, another cohort of 118 patients who had completed the ROMP was assessed by both a neurologist (HY stage, Unified Parkinson's Disease Rating Scale III) and speech-language pathologist (severity of dysarthria, dysphagia, drooling) who were blinded to ROMP scores. RESULTS: Confirmatory factor analysis identified the 3 a priori-designed ROMP domains of speech, swallowing, and saliva control. Internal consistency was .95 for the total ROMP and .87 to .94 for the 3 domains or subscales. Intraclass correlation coefficients for reproducibility were .94 and .83 to .92 for the subscales. Construct validity was substantial to good with correlations ranging from .36 to .82. The ROMP differentiated significantly (P<.001) between patients indicated for speech therapy (based on independent assessment) and those who were not and between mild, moderate, and severe PD according to HY stage. CONCLUSIONS: The ROMP provides a reliable and valid instrument to evaluate patient-perceived problems with speech, swallowing, and saliva control in patients with PD or AP.

Timed motor tests can detect subtle motor dysfunction in early Parkinson's disease.

Early diagnosis of Parkinson's disease (PD) is important for putative neuroprotective therapies to be initiated in the earliest stage of the disease. We investigated whether a previously validated timed motor test (TMT) battery could detect subtle motor dysfunction in early PD patients and even in clinically unaffected limbs of strictly hemiparkinsonian patients. We assessed 107 PD patients (symptom duration

The ParkinsonNet trial: design and baseline characteristics.

The companion paper describes how implementation of professional networks (ParkinsonNet) may improve the quality and efficiency of allied health care in Parkinson's disease (PD). We designed a cluster-randomized controlled trial to evaluate this ParkinsonNet concept for one allied health discipline, namely physical therapy. Here we describe the study design and baseline characteristics. The design fully complies with the CONSORT criteria. Sixteen regions in the Netherlands were randomly divided into eight experimental regions where a ParkinsonNet was implemented, and eight control regions where the organization of care was left unchanged (usual care). Participating patients were followed for 6 months to evaluate the implementation process, health benefits and costs of the intervention. In the ParkinsonNet regions, 46 therapists were trained and 358 patients were included. In the usual care regions, 341 patients were included. Baseline characteristics of participants in the ParkinsonNet and control clusters were comparable. With 699 participating patients, this is the largest allied health study in PD to date.

Sample size considerations for GEE analyses of three-level cluster randomized trials.

Cluster randomized trials in health care may involve three instead of two levels, for instance, in trials where different interventions to improve quality of care are compared. In such trials, the intervention is implemented in health care units ("clusters") and aims at changing the behavior of health care professionals working in this unit ("subjects"), while the effects are measured at the patient level ("evaluations"). Within the generalized estimating equations approach, we derive a sample size formula that accounts for two levels of clustering: that of subjects within clusters and that of evaluations within subjects. The formula reveals that sample size is inflated, relative to a design with completely independent evaluations, by a multiplicative term that can be expressed as a product of two variance inflation factors, one that quantifies the impact of within-subject correlation of evaluations on the variance of subject-level means and the other that quantifies the impact of the correlation between subject-level means on the variance of the cluster means. Power levels as predicted by the sample size formula agreed well with the simulated power for more than 10 clusters in total, when data were analyzed using bias-corrected estimating equations for the correlation parameters in combination with the model-based covariance estimator or the sandwich estimator with a finite sample correction.