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Neonates exposed to perinatal insults typically present with hypoxic ischemic encephalopathy (HIE). The aim of our study was to analyze the association between known risk factors for HIE and the severity of encephalopathy after birth and neurological outcome in neonates during the first 4 d of life. Retrospective cohort study including 174 neonates registered between 2011 and 2013 in the National Asphyxia and Cooling Register of Switzerland. None of the studied perinatal risk factors is associated with the severity of encephalopathy after birth. Fetal distress during labor (OR, 2.06; 95% CI, 1.02–4.25, p =.049) and neonatal head circumference (HC) above 10th percentile (p10) at birth (OR, 1.33; 95% CI, 1.05–1.69, p =.02) were associated with neurological benefit in the univariate analysis. Fetal distress on maternal admission for delivery was the only risk factor for neurological harm in the univariate (OR, 0.26; 95% CI, 0.12–0.57, p <.01) and the multivariate analysis (OR, 0.15; 95% CI, 0.04–0.67, p =.013). We identified two different patient scenarios: the probability for neurological benefit during the first 4 d of life was only 20% in neonates with the combination of all the following risk factors (gestational age >41 weeks, chorioamnionitis, fetal distress on maternal admission for delivery, fetal distress during labor, sentinel events during labor, HC below 10th percentile), whereas in the absence of these risk factors the probability for neurological benefit increased to 80%. We identified a constellation of risk factors that influence neurological outcome in neonates with HIE during the first 4 d of life. These findings may help clinicians to counsel parents during the early neonatal period. (ClinicalTrials.gov NCT02800018). [ABSTRACT FROM AUTHOR]

The aim of the study was to test whether implants of 6 mm in length perform equally well as 10-mm implants in terms of survival and marginal bone-level changes when supporting single crowns. Patients with a posterior single-tooth gap were randomly allocated to either the placement of a 6-mm (test) or 10-mm implant (control). The treatment protocol allowed for internal sinus lift but not for lateral bone augmentation. After a healing period of 10 wk, implants were loaded with screw-retained single crowns. Survival rates, number of pockets ≥5 mm, and bleeding-on-probing were assessed clinically. The change of marginal bone level and crown-to-implant ratios were analyzed by 2 examiners. Longitudinal intragroup analyses for marginal bone levels were performed applying the Wilcoxon signed rank test. Intergroup differences at baseline and at 3 y were compared using the Mann-Whitney U test. The effect of implant length and crown-to-implant ratio on changes of marginal bone level also was determined. Of 94 implants placed (47 test and 47 control), 78 implants (40 test and 38 control) were available for follow-up examination at 3 y of loading. One test implant was lost during the second year. Hence, implant survival was not significantly different between the 2 groups after 3 y (98% test; 100% control). We found no significant change in the crestal bone level from baseline to 3 y for test and control implants with -0.19 ± 0.62 mm and -0.33 ± 0.71 mm, respectively. The intergroup difference was not significant. Crown-to-implant ratios were not associated with a statistically significant difference in marginal bone loss. However, the number of sites with pockets ≥5 mm was significantly higher in the test group. Based on the 3-y assessment, the use of 6-mm implants can be considered a viable option when reconstructing posterior single tooth gaps (German Clinical Trials Registry: DRKS00006290). [ABSTRACT FROM AUTHOR]

Background:Gastro-oesophageal adenocarcinomas rarely metastasize to the central nervous system (CNS). The role of the human epidermal growth factor receptor 2 (HER2) in patients with these cancers and CNS involvement is presently unknown.Patients and Methods:A multicentre registry was established to collect data from patients with gastro-oesophageal adenocarcinomas and CNS involvement both retrospectively and prospectively. Inclusion in the study required a predefined clinical data set, a central neuro-radiological or histopathological confirmation of metastatic CNS involvement and central assessment of HER2 by immunohistochemistry (IHC) and in situ hybridisation (ISH). In addition, expression of E-cadherin and DNA mismatch repair (MMR) proteins were assessed by IHC.Results:One hundred patients fulfilled the inclusion criteria. The population's median age was 59 years (interquartile range: 54-68), of which 85 (85%) were male. Twenty-five patients were of Asian and 75 of Caucasian origin. HER2 status was positive in 36% (95% CI: 26.6-46.2) of cases. Median time from initial diagnosis to the development of brain metastases (BMets) or leptomeningeal carcinomatosis (LC) was 9.9 months (95% CI: 8.5-15.0). Median overall survival from diagnosis was 16.9 months (95% CI: 14.0-20.7) and was not related to the HER2 status. E-cadherin loss was observed in 9% of cases and loss of expression in at least one DNA MMR proteins in 6%.Conclusions:The proportion of a positive HER2 status in patients with gastro-oesophageal adenocarcinoma and CNS involvement was higher than expected. The impact of anti-HER2 therapies should be studied prospectively. [ABSTRACT FROM AUTHOR]

Background General practitioners ( GPs) play crucial roles in early detection of skin cancer. A pilot-study found a positive short-term effect of a 1-day dermatologic education programme on GPs' diagnostic competence. Objective To determine effects of a multifaceted intervention, including technical equipment and continuing feedback by a dermatologist, on GPs' diagnostic skills regarding skin cancer. Methods Randomized controlled trial with 78 GPs of the Canton of Zurich, Switzerland. Intervention: GPs in intervention group received a 1-day training, a Lumio© (magnifying glass with polarized light, 3Gen), a Nikon digital camera and - during 1 year - feedback on skin lesion pictures sent to the dermatologist. GPs in control group only received the 1-day training. Main outcome and measures: Primary outcome: structured assessment of GP's diagnostic skills in correctly diagnosing images of skin lesions regarding skin cancer. At baseline prior to intervention (T0), after the full-day training course in both groups (T1), and after 1 year of continuing feedback (T2) to the intervention group. Measures: Non-parametric unpaired (Wilcoxon-Mann-Whitney) tests were used to compare numbers of correctly classified skin lesions between both groups at T2 and for the change between T1 and T2. Results At T0, both groups classified a median of 23 skin lesions of the 36 images correctly. This value rose to 28 for both groups at T1 and fell to 24 for both groups at T2. No difference between control and intervention group at T2. Furthermore, we compared differences in the sum scores per GP between T1 and T2 for each group. Also in this comparison, no difference between control and intervention group was found. Conclusion and relevance No long-term effect of the multifaceted intervention was found on the competence to diagnose skin cancer by GPs. The positive short-term effect of the 1-day dermatologic education programme did not persist over 12 months. [ABSTRACT FROM AUTHOR]

Background Acute chest pain is a frequent reason to attend an emergency room, and various instruments for calculating the probability of an acute coronary syndrome exist. Objective To assess the safety and efficiency of all available instruments investigated in sample validation studies. Methods A systematic review was conducted. Studies were identified describing the development of instruments and all subsequent validations in electronic databases and reference lists of included studies. Inclusion was screened for, full papers checked and data extracted on salient clinical features, performance characteristics and quality in duplicate. Results Of 20 derivation studies, 10 were at least validated once in 14 validations including 26 488 patients. One study by Selker and colleagues was validated in six new patient series and studies by Goldman et al and the Kennedy et al were both validated in three new patient series. All other studies were validated less than three times. In four out of six validations of the Selker et al study, the sensitivity of the prediction rule was 98% or higher. The corresponding values for specificity ranged from 4% to 34%. All remaining prediction rules showed sensitivity values below 95% in all validations. Conclusions No instrument assisting clinicians in the diagnostic investigation of patients with suspected acute coronary syndrome consistently fulfils the safety requirements of clinicians. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Several studies found that biphosphonates counteract locally increased bone resorption and associated pain in patients with complex regional pain syndrome I (CRPS I). We performed a systematic review of all randomised controlled trials to assess the benefit of biphosphonates in the treatment of CRPS I patients with bone loss. DATA SOURCES: We searched Medline, Embase (April 2007) and the Cochrane Library and screened bibliographies of included studies. REVIEW METHODS: We selected randomised trials comparing biphosphonates with placebo, with the goal of improving pain, function and quality of life in patients with CRPS I. Two reviewers independently assessed trial eligibility and quality, and extracted data. Where data were incomplete or unclear, conflicts were resolved with discussion and/or trial authors were contacted for further details. We calculated the study size weighted pooled mean reduction of pain intensity (measured with a visual analogue scale (VAS)). RESULTS: Four trials of moderate quality fulfilled our inclusion criteria. In respect to function and quality of life there was a trend in favour of biphosphonates but differences in outcome assessment impeded pooling of results. Two trials provided sufficient data to pool pain outcomes. Biphosphonates reduced pain intensity by 22.4 and 21.6mm on a VAS after 4 and 12 weeks of follow-up. Data on adverse effects were scarce. CONCLUSIONS: The very limited data reviewed showed that bisphosphonates have the potential to reduce pain associated with bone loss in patients with CRPS I. However, at present there is not sufficient evidence to recommend their use in practice. [ABSTRACT FROM AUTHOR]

Background Magnetic resonance imaging (MRI) of lesions in the brain may be the best current candidate for a surrogate biological marker of clinical outcomes in relapsing remitting multiple sclerosis (MS), based on its role as an objective indicator of disease pathology. No biological surrogate marker has yet been validated for MS clinical outcomes. Objective The objective of this study was to use a multi-phased study to determine if a valid surrogate relationship could be demonstrated between counts of contrast enhancing lesions (CELs) and occurrence of relapses in MS. Methods We examined correlations for the concurrent and predictive relationship between CELs over 6 months and MS relapses over the same 6 months and an additional 6 months (total: 12 months), using available data on untreated patients from a large clinical trial and natural history database. Results Concurrent and predictive correlations were inadequate to justify continuation of this study to the planned additional phases required to demonstrate a surrogate relationship between CELs and MS relapses. Conclusions Confidence intervals for correlations between CELs and MS relapses exclude the possibility that CELs can be a good surrogate for relapses over the time scales we investigated. Further exploration of surrogacy between MRI measures and MS clinical outcomes may require improved datasets, the development of MRI techniques that couple better to clinical disease, and the ability to test a wide range of imaging- and clinically-based hypotheses for surrogacy. [ABSTRACT FROM AUTHOR]

Abstract Background We recently reported the derivation of a diagnostic aid to rule out pneumonia in adults presenting with new onset of cough or worsening of chronic cough and increased body temperature. The aim of the present investigation was to validate the diagnostic aid in a new sample of primary care patients. Methods From two group practices in Zurich, we included 110 patients with the main symptoms of cough and subjective feeling of increased body temperature, and C-reactive protein levels below 50 μg/ml, no dyspnea, and not daily feeling of increased body temperature since the onset of cough. We excluded patients who were prescribed antibiotics at their first consultation. Approximately two weeks after inclusion, practice assistants contacted the participants by phone and asked four questions regarding the course of their complaints. In particular, they asked whether a prescription of antibiotics or hospitalization had been necessary within the last two weeks. Results In 107 of 110 patients, pneumonia could be ruled out with a high degree of certainty, and no prescription of antibiotics was necessary. Three patients were prescribed antibiotics between the time of inclusion in the study and the phone interview two weeks later. Acute rhinosinusitis was diagnosed in one patient, and antibiotics were prescribed to the other two patients because their symptoms had worsened and their CRP levels increased. Use of the diagnostic aid could have missed these two possible cases of pneumonia. These observations correspond to a false negative rate of 1.8% (95% confidence interval: 0.50%-6.4%). Conclusions This diagnostic aid is helpful to rule out pneumonia in patients from a primary care setting. After further validation application of this aid in daily practice may help to reduce the prescription rate of unnecessary antibiotics in patients with respiratory tract infections.

Abstract Background The development of risk prediction models is of increasing importance in medical research - their use in practice, however, is rare. Among other reasons this might be due to the fact that thorough validation is often lacking. This study focuses on two Bayesian approaches of how to validate a prediction rule for the diagnosis of pneumonia, and compares them with established validation methods. Methods Expert knowledge was used to derive a risk prediction model for pneumonia. Data on more than 600 patients presenting with cough and fever at a general practitioner’s practice in Switzerland were collected in order to validate the expert model and to examine the predictive performance of it. Additionally, four modifications of the original model including shrinkage of the regression coefficients, and two Bayesian approaches with the expert model used as prior mean and different weights for the prior covariance matrix were fitted. We quantify the predictive performance of the different methods with respect to calibration and discrimination, using cross-validation. Results The predictive performance of the unshrinked regression coefficients was poor when applied to the Swiss cohort. Shrinkage improved the results, but a Bayesian model formulation with unspecified weight of the informative prior lead to large AUC and small Brier score, naïve and after cross-validation. The advantage of this approach is the flexibility in case of a prior-data conflict. Conclusions Published risk prediction rules in clinical research need to be validated externally before they can be used in new settings. We propose to use a Bayesian model formulation with the original risk prediction rule as prior. The posterior means of the coefficients, given the validation data showed best predictive performance with respect to cross-validated calibration and discriminative ability.

Abstract Background Although a variety of treatment guidelines for Type 2 diabetes patients are available, a majority of patients does not achieve recommended targets. We aimed to characterise Type 2 diabetes patients from Swiss primary care who miss HbA1c treatment goals and to reveal factors associated with the poorly controlled HbA1c level. Methods Cross-sectional study nested within the cluster randomised controlled Chronic Care for Diabetes study. Type 2 diabetes patients with at least one HbA1c measurement ≥7.0 % during the last year were recruited from Swiss primary care. Data assessment included diabetes specific and general clinical measures, treatment factors and patient reported outcomes. Results 326 Type 2 diabetes patients from 30 primary care practices with a mean age 67.1 ± 10.6 years participated in the study. The patients’ findings for HbA1c were 7.7 ± 1.3 %, for systolic blood pressure 139.1 ± 17.6 mmHg, for diastolic blood pressure 80.9 ± 10.5 mmHg and for low density lipoprotein 2.7 ± 1.1. 93.3 % of the patients suffered from at least one comorbidity and were treated with 4.8 ± 2.1 different drugs. No determining factor was significantly related to HbA1c in the multiple analysis, but a significant clustering effect of GPs on HbA1c could be found. Conclusions Within our sample of patients with poorly controlled Type 2 diabetes, no “bullet points” could be pointed out which can be addressed easily by some kind of intervention. Especially within this subgroup of diabetes patients who would benefit the most from appropriate interventions to improve diabetes control, a complex interaction between diabetes control, comorbidities, GPs’ treatment and patients’ health behaviour seems to exist. So far this interaction is only poorly described and understood. Trial registration Current Controlled Trials ISRCTN05947538.

Abstract Background Neovascular age-related macular degeneration is the leading cause of irreversible blindness in people 50 years of age or older in the developed world. As in other chronic diseases, several effective treatments are available, but in clinical daily practice there is an evidence performance gap. The Chronic Care Model represents an evidence-based framework for the care of chronically ill patients and aims at closing that gap. However, no data are available regarding patients with neovascular age-related macular degeneration. Methods/Design CHARMED is a multicenter randomized controlled trial. The study challenges the hypothesis that the implementation of core elements of the Chronic Care Model (patient empowerment, delivering evidence based information, clinical information system, reminder system with structured follow up and frequent monitoring) via a specially trained Chronic Care Coach in Swiss centres for neovascular age-related macular degeneration results in better visual acuity (primary outcome) and an increased disease specific quality of life (secondary outcome) in patients with neovascular age-related macular degeneration. According to the power calculation, a total sample size of 352 patients is needed (drop out rate of 25%). 14 specialised medical doctors from leading ophtalmologic centres in Switzerland will include 25 patients. In each centre, a Chronic Care Coach will provide disease specific care according to the Chronic Care Model for intervention group. Patients from the control group will be treated as usual. Baseline measurements will be taken in month III - XII, starting in March 2011. Follow-up data will be collected after 6 months and 1 year. Discussion Multiple studies have shown that implementing Chronic Care Model elements improve clinical outcomes as well as process parameters in different chronic diseases as osteoarthritis, depression or e.g. the cardiovascular risk profile of diabetes patients. This study will be the first to assess this approach in neovascular age-related macular degeneration. If our hypothesis will be confirmed, the implementation of this approach in routine care for patients with with neovascular age-related macular degeneration should be considered. Trial Registration Current controlled trials ISRCTN32507927.

Abstract Background Physicians fear missing cases of pneumonia and treat many patients with signs of respiratory infection unnecessarily with antibiotics. This is an avoidable cause for the increasing worldwide problem of antibiotic resistance. We developed a user-friendly decision aid to rule out pneumonia and thus reduce the rate of needless prescriptions of antibiotics. Methods This was a prospective cohort study in which we enrolled patients older than 18 years with a new or worsened cough and fever without serious co-morbidities. Physicians recorded results of a standardized medical history and physical examination. C-reactive protein was measured and chest radiographs were obtained. We used Classification and Regression Trees to derive the decision tool. Results A total of 621 consenting eligible patients were studied, 598 were attending a primary care facility, were 48 years on average and 50% were male. Radiographic signs for pneumonia were present in 127 (20.5%) of patients. Antibiotics were prescribed to 234 (48.3%) of patients without pneumonia. In patients with C-reactive protein values below 10 μg/ml or patients presenting with C-reactive protein between 11 and 50 μg/ml, but without dyspnoea and daily fever, pneumonia can be ruled out. By applying this rule in clinical practice antibiotic prescription could be reduced by 9.1% (95% confidence interval (CI): 6.4 to 11.8). Conclusions Following validation and confirmation in new patient samples, this tool could help rule out pneumonia and be used to reduce unnecessary antibiotic prescriptions in patients presenting with cough and fever in primary care. The algorithm might be especially useful in those instances where taking a medical history and physical examination alone are inconclusive for ruling out pneumonia

Abstract Background Lumbar spinal stenosis is the most frequent reason for spinal surgery in elderly people. For patients with moderate or severe symptoms different conservative and surgical treatment modalities are recommended, but knowledge about the effectiveness, in particular of the conservative treatments, is scarce. There is some evidence that surgery improves outcome in about two thirds of the patients. The aims of this study are to derive and validate a prognostic prediction aid to estimate the probability of clinically relevant improvement after surgery and to gain more knowledge about the future course of patients treated by conservative treatment modalities. Methods/Design This is a prospective, multi-centre cohort study within four hospitals of Zurich, Switzerland. We will enroll patients with neurogenic claudication and lumbar spinal stenosis verified by Computer Tomography or Magnetic Resonance Imaging. Participating in the study will have no influence on treatment modality. Clinical data, including relevant prognostic data, will be collected at baseline and the Swiss Spinal Stenosis Questionnaire will be used to quantify severity of symptoms, physical function characteristics, and patient's satisfaction after treatment (primary outcome). Data on outcome will be collected 6 weeks, and 6, 12, 24 and 36 months after inclusion in the study. Applying multivariable statistical methods, a prediction rule to estimate the course after surgery will be derived. Discussion The ultimate goal of the study is to facilitate optimal, knowledge based and individualized treatment recommendations for patients with symptomatic lumbar spinal stenosis.

Abstract Background Diabetes is a major challenge for the health care system and especially for the primary care provider. The Chronic Care Model represents an evidence-based framework for the care for chronically ill. An increasing number of studies showed that implementing elements of the Chronic Care Model improves patient relevant outcomes and process parameters. However, most of these findings have been performed in settings different from the Swiss health care system which is dominated by single handed practices. Methods/Design CARAT is a cluster randomized controlled trial with general practitioners as the unit of randomization (trial registration: ISRCTN05947538). The study challenges the hypothesis that implementing several elements of the Chronic Care Model via a specially trained practice nurse improves the HbA1c level of diabetes type II patients significantly after one year (primary outcome). Furthermore, we assume that the intervention increases the proportion of patients who achieve the recommended targets regarding blood pressure ( Discussion This study challenges the hypothesis that the Chronic Care Model can be easily implemented by a practice nurse focused approach. If our results will confirm this hypothesis the suggestion arises whether this approach should be implemented in other chronic diseases and multimorbid patients and how to redesign care in Switzerland.

Abstract Background Clinical tests to assess peripheral nerve disorders can be classified into two categories: tests for afferent/efferent nerve function such as nerve conduction (bedside neurological examination) and tests for increased mechanosensitivity (e.g. upper limb neurodynamic tests (ULNTs) and nerve palpation). Reliability reports of nerve palpation and the interpretation of neurodynamic tests are scarce. This study therefore investigated the intertester reliability of nerve palpation and ULNTs. ULNTs were interpreted based on symptom reproduction and structural differentiation. To put the reliability of these tests in perspective, a comparison with the reliability of clinical tests for nerve function was made. Methods Two experienced clinicians examined 31 patients with unilateral arm and/or neck pain. The examination included clinical tests for nerve function (sensory testing, reflexes and manual muscle testing (MMT)) and mechanosensitivity (ULNTs and palpation of the median, radial and ulnar nerve). Kappa statistics were calculated to evaluate intertester reliability. A meta-analysis determined an overall kappa for the domains with multiple kappa values (MMT, ULNT, palpation). We then compared the difference in reliability between the tests of mechanosensitivity and nerve function using a one-sample t-test. Results We observed moderate to substantial reliability for the tests for afferent/efferent nerve function (sensory testing: kappa = 0.53; MMT: kappa = 0.68; no kappa was calculated for reflexes due to a lack of variation). Tests to investigate mechanosensitivity demonstrated moderate reliability (ULNT: kappa = 0.45; palpation: kappa = 0.59). When compared statistically, there was no difference in reliability for tests for nerve function and mechanosensitivity (p = 0.06). Conclusion This study demonstrates that clinical tests which evaluate increased nerve mechanosensitivity and afferent/efferent nerve function have comparable moderate to substantial reliability. To further investigate the clinometric properties of these tests, more studies are needed to evaluate their validity.

Abstract Background Vignette studies of medical choice and judgement have gained popularity in the medical literature. Originally developed in mathematical psychology they can be used to evaluate physicians' behaviour in the setting of diagnostic testing or treatment decisions. We provide an overview of the use, objectives and methodology of these studies in the medical field. Methods Systematic review. We searched in electronic databases; reference lists of included studies. We included studies that examined medical decisions of physicians, nurses or medical students using cue weightings from answers to structured vignettes. Two reviewers scrutinized abstracts and examined full text copies of potentially eligible studies. The aim of the included studies, the type of clinical decision, the number of participants, some technical aspects, and the type of statistical analysis were extracted in duplicate and discrepancies were resolved by consensus. Results 30 reports published between 1983 and 2005 fulfilled the inclusion criteria. 22 studies (73%) reported on treatment decisions and 27 (90%) explored the variation of decisions among experts. Nine studies (30%) described differences in decisions between groups of caregivers and ten studies (33%) described the decision behaviour of only one group. Only six studies (20%) compared decision behaviour against an empirical reference of a correct decision. The median number of considered attributes was 6.5 (IQR 4–9), the median number of vignettes was 27 (IQR 16–40). In 17 studies, decision makers had to rate the relative importance of a given vignette; in six studies they had to assign a probability to each vignette. Only ten studies (33%) applied a statistical procedure to account for correlated data. Conclusion Various studies of medical choice and judgement have been performed to depict weightings of the value of clinical information from answers to structured vignettes of care givers. We found that the design and analysis methods used in current applications vary considerably and could be improved in a large number of cases.

Abstract Background Published false positive research findings are a major problem in the process of scientific discovery. There is a high rate of lack of replication of results in clinical research in general, multiple sclerosis research being no exception. Our aim was to develop and implement a policy that reduces the probability of publishing false positive research findings. We have assessed the utility to work with a pre-publication validation policy after several years of research in the context of a large multiple sclerosis database. Methods The large database of the Sylvia Lawry Centre for Multiple Sclerosis Research was split in two parts: one for hypothesis generation and a validation part for confirmation of selected results. We present case studies from 5 finalized projects that have used the validation policy and results from a simulation study. Results In one project, the "relapse and disability" project as described in section II (example 3), findings could not be confirmed in the validation part of the database. The simulation study showed that the percentage of false positive findings can exceed 20% depending on variable selection. Conclusion We conclude that the validation policy has prevented the publication of at least one research finding that could not be validated in an independent data set (and probably would have been a "true" false-positive finding) over the past three years, and has led to improved data analysis, statistical programming, and selection of hypotheses. The advantages outweigh the lost statistical power inherent in the process.

Abstract Background Intravenous methylprednisolone (IV-MP) is an established treatment for multiple sclerosis (MS) relapses, accompanied by rapid, though transient reduction of gadolinium enhancing (Gd+) lesions on brain MRI. Intermittent IV-MP, alone or with immunomodulators, has been suggested but insufficiently studied as a strategy to prevent relapses. Methods In an open, single-cross-over study, nine patients with relapsing-remitting MS (RR-MS) underwent cranial Gd-MRI once monthly for twelve months. From month six on, they received a single i.v.-infusion of 500 mg methylprednisolone (and oral tapering for three days) after the MRI. Primary outcome measure was the mean number of Gd+ lesions during treatment vs. baseline periods; T2 lesion volume and monthly plasma concentrations of cortisol, ACTH and prolactin were secondary outcome measures. Safety was assessed clinically, by routine laboratory and bone mineral density measurements. Soluble immune parameters (sTNF-RI, sTNF-RII, IL1-ra and sVCAM-1) and neuroendocrine tests (ACTH test, combined dexamethasone/CRH test) were additionally analyzed. Results Comparing treatment to baseline periods, the number of Gd+ lesions/scan was reduced in eight of the nine patients, by a median of 43.8% (p = 0.013, Wilcoxon). In comparison, a pooled dataset of 83 untreated RR-MS patients from several studies, selected by the same clinical and MRI criteria, showed a non-significant decrease by a median of 14% (p = 0.32). T2 lesion volume decreased by 21% during treatment (p = 0.001). Monthly plasma prolactin showed a parallel decline (p = 0.027), with significant cross-correlation with the number of Gd+ lesions. Other hormones and immune system variables were unchanged, as were ACTH test and dexamethasone-CRH test. Treatment was well tolerated; routine laboratory and bone mineral density were unchanged. Conclusion Monthly IV-MP reduces inflammatory activity and T2 lesion volume in RR-MS.

Background: Published false positive research findings are a major problem in the process of scientific discovery. There is a high rate of lack of replication of results in clinical research in general, multiple sclerosis research being no exception. Our aim was to develop and implement a policy that reduces the probability of publishing false positive research findings. We have assessed the utility to work with a pre-publication validation policy after several years of research in the context of a large multiple sclerosis database.Methods: The large database of the Sylvia Lawry Centre for Multiple Sclerosis Research was split in two parts: one for hypothesis generation and a validation part for confirmation of selected results. We present case studies from 5 finalized projects that have used the validation policy and results from a simulation study.Results: In one project, the "relapse and disability" project as described in section II (example 3), findings could not be confirmed in the validation part of the database. The simulation study showed that the percentage of false positive findings can exceed 20% depending on variable selection.Conclusion: We conclude that the validation policy has prevented the publication of at least one research finding that could not be validated in an independent data set (and probably would have been a "true" false-positive finding) over the past three years, and has led to improved data analysis, statistical programming, and selection of hypotheses. The advantages outweigh the lost statistical power inherent in the process. [ABSTRACT FROM AUTHOR]

Background: Vignette studies of medical choice and judgement have gained popularity in the medical literature. Originally developed in mathematical psychology they can be used to evaluate physicians' behaviour in the setting of diagnostic testing or treatment decisions. We provide an overview of the use, objectives and methodology of these studies in the medical field.Methods: Systematic review. We searched in electronic databases; reference lists of included studies. We included studies that examined medical decisions of physicians, nurses or medical students using cue weightings from answers to structured vignettes. Two reviewers scrutinized abstracts and examined full text copies of potentially eligible studies. The aim of the included studies, the type of clinical decision, the number of participants, some technical aspects, and the type of statistical analysis were extracted in duplicate and discrepancies were resolved by consensus.Results: 30 reports published between 1983 and 2005 fulfilled the inclusion criteria. 22 studies (73%) reported on treatment decisions and 27 (90%) explored the variation of decisions among experts. Nine studies (30%) described differences in decisions between groups of caregivers and ten studies (33%) described the decision behaviour of only one group. Only six studies (20%) compared decision behaviour against an empirical reference of a correct decision. The median number of considered attributes was 6.5 (IQR 4-9), the median number of vignettes was 27 (IQR 16-40). In 17 studies, decision makers had to rate the relative importance of a given vignette; in six studies they had to assign a probability to each vignette. Only ten studies (33%) applied a statistical procedure to account for correlated data.Conclusion: Various studies of medical choice and judgement have been performed to depict weightings of the value of clinical information from answers to structured vignettes of care givers. We found that the design and analysis methods used in current applications vary considerably and could be improved in a large number of cases. [ABSTRACT FROM AUTHOR]