Seasonal adherence to, and effectiveness of, subcutaneous interferon ß-1a administered by RebiSmart® in patients with relapsing multiple sclerosis: results of the 1-year, observational GEPAT-SMART study.

BACKGROUND: Little is known about whether tolerability and adherence to treatment can be influenced by weather and temperature conditions. The objective of this study was to assess monthly and seasonal adherence to and safety of sc IFN-ß1a (Rebif®, Merck) in relapsing-remitting multiple sclerosis (RRMS) patients using the RebiSmart® electronic autoinjector. METHODS: A multicentre, prospective observational study in Greece in adult RRMS patients with EDSS < 6, under Rebif®/RebiSmart® treatment for ≤6 weeks before enrollment. The primary endpoint was monthly, seasonal and annual adherence over 12 months (defined in text). Secondary endpoints included number of relapses, disability, adverse events. RESULTS: Sixty four patients enrolled and 47 completed all study visits (Per Protocol Set - PPS). Mean annual adherence was 97.93% ± 5.704 with no significant monthly or seasonal variations. Mean relapses in the pre- and post- treatment 12-months were 1.1 ± 0.47 and 0.2 ± 0.54 (p < 0.0001, PPS). 10 patients (22%) showed 3-month disability progression, 19 (40%) stabilization and 18 (38%) improvement. EDSS was not correlated to pre- (r = 0.024, p = 0.87) or post-treatment relapses (r = 0.022, p = 0.88). CONCLUSION: High adherence with no significant seasonal or weather variation was observed over 12 months. While the efficacy on relapses was consistent with published studies, we could not identify a relationship between relapses and disability. TRIAL REGISTRATION: Greek registry of non-interventional clinical trials ID: 200136 , date of registration: February 18th, 2013.

Effects of High Efficacy Multiple Sclerosis Disease Modifying Drugs on the Immune Synapse: A Systematic Review.

BACKGROUND: Co-signaling and adhesion molecules are important elements for creating immune synapses between T lymphocytes and antigen-presenting cells; they positively or negatively regulate the interaction between a T cell receptor with its cognate antigen, presented by the major histocompatibility complex. OBJECTIVES: We conducted a systematic review on the effects of High Efficacy Disease Modifying Drugs (HEDMDs) for Multiple Sclerosis (MS) on the co-signaling and adhesion molecules that form the immune synapse. METHODS: We searched EMBASE, MEDLINE, and other sources to identify clinical or preclinical reports on the effects of HEDMDs on co-signaling and adhesion molecules that participate in the formation of immune synapses in patients with MS or other autoimmune disorders. We included reports on cladribine tablets, anti- CD20 monoclonal antibodies, S1P modulators, inhibitors of Bruton's Tyrosine Kinase, and natalizumab. RESULTS: In 56 eligible reports among 7340 total publications, limited relevant evidence was uncovered. Not all co-signaling and adhesion molecules have been studied in relation to every HEDMD, with more data being available on the anti-CD20 monoclonal antibodies (that affect CD80, CD86, GITR and TIGIT), cladribine tablets (affecting CD28, CD40, ICAM-1, LFA-1) and the S1P modulators (affecting CD86, ICAM-1 and LFA-1) and less on Natalizumab (affecting CD80, CD86, CD40, LFA-1, VLA-4) and Alemtuzumab (affecting GITR and CTLA-4). CONCLUSION: The puzzle of HEDMD effects on the immune synapse is far from complete. The available evidence suggests that distinguishing differences exist between drugs and are worth pursuing further.

Literature mining, ontologies and information visualization for drug repurposing.

The immense growth of MEDLINE coupled with the realization that a vast amount of biomedical knowledge is recorded in free-text format, has led to the appearance of a large number of literature mining techniques aiming to extract biomedical terms and their inter-relations from the scientific literature. Ontologies have been extensively utilized in the biomedical domain either as controlled vocabularies or to provide the framework for mapping relations between concepts in biology and medicine. Literature-based approaches and ontologies have been used in the past for the purpose of hypothesis generation in connection with drug discovery. Here, we review the application of literature mining and ontology modeling and traversal to the area of drug repurposing (DR). In recent years, DR has emerged as a noteworthy alternative to the traditional drug development process, in response to the decreased productivity of the biopharmaceutical industry. Thus, systematic approaches to DR have been developed, involving a variety of in silico, genomic and high-throughput screening technologies. Attempts to integrate literature mining with other types of data arising from the use of these technologies as well as visualization tools assisting in the discovery of novel associations between existing drugs and new indications will also be presented.

Implantable Subcutaneous Peripheral Nerve Stimulation Improves Degenerative Ataxia.

Degenerative cerebellar ataxias have no pharmacological or rehabilitation evidence-based treatment so far. Patients remain highly symptomatic and disabled despite receiving the best medical treatment available. This study investigates the clinical and neurophysiologic outcomes of the use of subcutaneous cortex stimulation (in keeping with the established protocol of peripheral nerve stimulation applied in chronic intractable pain) in degenerative ataxia. We report a case of a 37-year-old right-handed man who developed moderate degenerative cerebellar ataxia at the age of 18 years. His symptoms progressively worsened and impaired his daily activities. We observed clinical improvement for at least one month following an initial two-week trial of parietal transcranial direct current stimulation. Although preoperative non-invasive transcranial neuromodulation application does not predict invasive cortex stimulation outcome, we pursued a long-lasting effect by implanting parietal and occipital subcutaneous electrodes. At 12 months following permanent implantation, the patient exhibited amelioration of his symptoms and a change in neurophysiologic parameters. Central neuromodulation based on peripheral stimulation is considered part of neurosurgical clinical practice for the treatment of a variety of neurological disorders. The underpinning neurophysiological mechanism that explains the effectiveness of the method has not been fully elucidated. We believe that further studies are warranted to investigate these promising results in such devastating conditions.

Oral Cladribine in Patients who Change From First-Line Disease Modifying Treatments for Multiple Sclerosis: Protocol of a Prospective Effectiveness and Safety Study (CLAD CROSS).

Background: Recently, the number of available disease modifying therapies for multiple sclerosis (MS) has increased. However, a proportion of patients treated with these agents continue to experience relapses and disease progression. Cladribine tablets, approved in 2017 for highly active relapsing MS, comprise a sparsely administered oral treatment which exerts its therapeutic effect through a reduction and subsequent repletion of the lymphocyte population. Purpose/Study Sample: Here we describe the design of CLAD CROSS, a prospective, non-interventional, multicenter, Phase IV study in patients with a confirmed diagnosis of RRMS who switch from first-line disease modifying drugs (DMDs) to treatment with cladribine tablets in routine clinical practice. 242 adult patients will be recruited in 61 sites (6 countries) over 30 months and will be followed up for 2 years following prescription of cladribine tablets per the decision of the treating physicians. Research Design: The primary endpoint is the change in annualized relapse rate (ARR) between the 12-month pre-baseline period and over the 12-month period before end of study. Secondary endpoints are the percentage of patients with 6-month disability progression or improvement at the end of the study, measured by the Expanded Disability Status Scale, Timed 25 Foot Walk and 9-Hole Peg Test scales and quality of life, treatment satisfaction, and healthcare resource utilization, measured through the MSIS-29, TSQM 1.4, and EQ-5D-3L scales, respectively. MRI lesions will be compared in the exploratory setting between the 12-month pre-baseline period, baseline, and at years 1 and 2. Adverse events will be monitored throughout the study. Interim analyses are pre-planned when 30% and 60% of patients will complete the 12-month follow-up visit. Conclusions: CLAD CROSS will provide efficacy data on cladribine tablets, used as a follow-up treatment to first-line DMDs in the real-world setting, will further establish its safety profile and will collect information to support pharmacoeconomic studies.

Follitropin Alpha for assisted reproduction: an analysis based on a non-interventional study in Greece.

OBJECTIVE: To conduct an economic evaluation estimating the cost per live birth after controlled ovarian stimulation (COS) using Follitropin Alpha (Gonal-F), in the Greek National Health System setting. A secondary objective was to predict the live birth rateof the In Vitro Fertilization (IVF) procedure. METHODS: A single arm, multi-center, prospective, non-interventional study was conducted on which economic, efficacy and safety data were collected by six of the largest IVF centers. The participants were 350 female patients. Three statistical methods were employed for the analysis of the study outcomes, namely (a) Generalized Linear Modeling for the estimation of the costs of IVF treatment, (b) multivariable logistic regression and (c) an Artificial Neural Network (ANN) model for live birth prediction. RESULTS: The mean total cost of IVF therapy per patient was estimated at €3728 (95% CI: €3679-€3780), while the total cost per live birth was €14,872 (95% CI: €12,441-€17,951). The live birth rate after 3 complete IVF cycles was estimated at 22.9%, while the percentage of those suffering from OHSS was limited at 0.57%. In logistic regression, the Ovarian Sensitivity Index (OSI) was a factor found to be positively associated with live birth (OR 7.39, 95% CI: 1.84-29.71). For the ANN, important predictors included number of gestational sacs and the duration of infertility. CONCLUSION: The present study constitutes the largest single-arm study based on real data in Greece to date. The cost of IVF treatment and the cost per live birth are not insignificant in this NHS setting. The live birth rate, cost per oocyte, and the cost per live birth are in line with literature. OSI was a main contributing factor to the accurate prediction of the live birth rate, while age and BMI were found to be negatively correlated.

Effects of anodal tDCS on motor and cognitive function in a patient with multiple system atrophy.

Purpose: Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by postural instability, autonomic failure, cerebellar ataxia, and cognitive deficits. There is currently no effective cure. Transcranial direct current stimulation (tDCS), offers promise in amendment of motor, and cognitive performance in advanced Parkinson's disease.Case description: We estimated the effect of anodal tDCS on motor and cognitive function in a 66-year-old woman with moderate MSA. For the evaluation of the motor function, we used the Unified MSA Rating Scale II, the Unified Parkinson's Disease Rating Scale Part III (UPDRS III), and the Timed Up and Go test (TUG). The battery of neuropsychological tests included the Rey's Auditory Verbal Learning Test (RAVLT) and the Digit Symbol Substitution Test-Wechsler Adult Intelligence (DSST-WAIS-III), the Trail Making Test (TMT-A). tDCS was applied in 10 sessions. Clinical evaluations were performed at baseline, day 11, day 30, and at day 90.Results: Anodal stimulation was associated with improvement in UPDRS III and the TUG test. A positive effect was also seen in RAVLT the DSST-WAIS-III and the TMT-A.Conclusions: Our results suggest that tDCS has a beneficial effect mainly on motor performance in MSA, which lasts beyond the duration of the treatment.Implications for rehabilitationMultiple system atrophy is a progressive neurodegenerative disease characterized by postural instability, motor, and cognitive deficits.Transcranial direct current stimulation offers promise in amendment of motor and cognitive performance in advanced Parkinson's disease.Stimulation was associated with significant improvement in Unified Parkinson's Disease Rating Scale Part III and the Timed Up and Go test.A positive effect was also seen in auditory-verbal memory and learning in working memory and in visuomotor activity and processing speed.Transcranial direct current stimulation has a beneficial effect mainly on motor performance, which lasts beyond the duration of the treatment.

Localisation of cervical spinal cord compression by TMS and MRI.

The authors set out to study the role of transcranial magnetic stimulation (TMS) in the pre-surgical assessment of patients with cervical spondylotic myelopathy. Central motor conduction time (CMCT) was calculated in 50 patients and 50 controls by recording muscle evoked potentials from upper limb muscles. The level of spinal cord compression was determined according to the pattern of CMCT prolongation and compared with the level disclosed by MRI. Direct comparison of the TMS and MRI results was possible in 42 cases and agreement was noted in 25 (59.5%). In the 23 patients in whom the two methods did not give convergent findings, post-operative data were used in order to determine the actual level of compression. This level was correctly indicated by TMS in 87.5% of cases and by MRI in 12.5%. TMS is a neurophysiological tool that can complement existing methods for determining the level of cervical spinal cord compression.

The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives.

Diabetes is a complex metabolic disorder affecting the glucose status of the human body. Chronic hyperglycaemia related to diabetes is associated with end organ failure. The clinical relationship between diabetes and atherosclerotic cardiovascular disease is well established. This makes therapeutic approaches that simultaneously target diabetes and atherosclerotic disease an attractive area for research. The majority of people with diabetes fall into two broad pathogenetic categories, type 1 or type 2 diabetes. The role of obesity, adipose tissue, gut microbiota and pancreatic beta cell function in diabetes are under intensive scrutiny with several clinical trials to have been completed while more are in development. The emerging role of inflammation in both type 1 and type 2 diabetes (T1D and T1D) pathophysiology and associated metabolic disorders, has generated increasing interest in targeting inflammation to improve prevention and control of the disease. After an extensive review of the possible mechanisms that drive the metabolic pattern in T1D and T2D and the inflammatory pathways that are involved, it becomes ever clearer that future research should focus on a model of combined suppression for various inflammatory response pathways.

On the calculation of transcallosal conduction time using transcranial magnetic stimulation.

Transcallosal conduction time (TCT), based on the results of transcranial magnetic stimulation studies, is currently calculated as a function of the ipsilateral silent period (iSP) and of the motor evoked potential (MEP) obtained from a target muscle (TCTcurrent = iSP latency - MEP latency). We argue that this measure overestimates TCT and may lead to a bias in statistical group comparisons. We propose an alternative measure, TCTproposed, which we defined as TCTproposed = iSP latency - cSP latency, where cSP is the contralateral silent period. We report our results on the comparison of the two measures in twenty healthy individuals and provide a theoretical basis for TCTproposed.

Intensive chelation therapy in beta-thalassemia and possible adverse cardiac effects of desferrioxamine.

Combination chelation therapy with desferrioxamine and deferiprone has recently been suggested as a more effective tissue iron-chelating treatment for transfusion-dependent beta-thalassemia patients, although a standard dosage protocol has not yet been established. We describe a thalassemia major patient who had been treated with combination therapy with desferrioxamine and deferiprone and who was referred to us for faintness and dizziness associated with electrocardiographic ST-T changes and arrhythmia. A brief interruption of the treatment and a subsequent decrease in the drug doses caused the reversion of symptoms and findings. This response prompted us to speculate that a causal relationship existed between the observed abnormalities and the intensive chelation therapy. The possibility of this electrical instability as an adverse cardiac event occurring in the context of treatment with these chelating agents raises questions about the time of application of this therapy, the regimen dosages, and follow-up of such patients.

Abnormal central motor conduction at the upper but not lower limbs correlates with severe cervical spondylosis: discussion of an unexpected observation.

INTRODUCTION: A novel pattern of transcranial magnetic stimulation (TMS) abnormalities in cervical spondylotic myelopathy (CSM) comprising abnormal central motor conduction time (CMCT) to the upper limbs and normal CMCT to the lower limbs was observed. CSM was more severe radiologically and tended to be more severe clinically when this pattern was encountered. CASE PRESENTATION: To further characterize this observation, 414 consecutive TMS evaluations of cervical spondylosis were reviewed. Those cases in which (a) CMCT was abnormal at the upper and (b) normal at the lower limbs and (c) a cervical spine magnetic resonance imaging (MRI) was available (ULabnormal group) were included for further analysis. Cases where CMCT was abnormal at the lower limbs only (LLabnormal) were used for comparison. MRI-measured sagittal and parasagittal diameters of the spinal canal at all intervertebral levels and cervical spinal cord T2 hyperintensities were compared between these groups. Four patients fulfilled all inclusion criteria in each group. In ULabnormal, all patients had T2 hyperintensities, compared to none in LLabnormal (P=0.004). The C6-7 right (6 mm±1.05 vs 8.48 mm±4.01, P=0.05) and left (6.58 mm±1.39 vs 9.17 mm±5.03, P=0.06) parasagittal spinal canal diameters tended to be smaller in ULabnormal. The modified Japanese Orthopaedic Association scale tended to be lower in ULabnormal (11.5±2.65 vs 15.75±0.96, P=0.13). DISCUSSION: CMCT abnormalities isolated to the upper limbs constitute a less frequent pattern of involvement, which may correlate with more severe CSM.

Thalassemia heart disease: a comparative evaluation of thalassemia major and thalassemia intermedia.

BACKGROUND: Heart disease represents the main determinant of survival in beta-thalassemia, but its particular features in the two clinical forms of the disease, thalassemia major (TM) and thalassemia intermedia (TI), are not completely clarified. METHODS: We compared clinical and echocardiographic global parameters in 131 TM patients who received regular chelation transfusions and were highly compliant with treatment (mean age, 28 +/- 6 years [+/- SD]), and 74 age-matched, TI patients who did not receive chelation transfusions. RESULTS: Congestive heart failure was encountered in five patients with TM (3.8%; age range, 25 to 29 years) and in two patients with TI (2.7%; age range, 37 to 40 years). Systolic left ventricular (LV) dysfunction (ejection fraction < 55% or shortening fraction < 35%) was only encountered in patients with TM (8.4%). Considerable pulmonary hypertension (systolic tricuspid gradient > 35 mm Hg) was only present in TI (23.0%). In the remaining patients without evident heart disease, cardiac dimensions, LV mass, LV shortening and ejection fractions, and cardiac output were significantly higher in patients with TI. LV afterload was higher in patients with TM. LV diastolic early transmitral diastolic peak flow velocity (E)/late transmitral diastolic peak flow velocity (A) ratio was also higher in TM. Systolic and mean pulmonary artery pressures and total pulmonary resistance were higher in both young and old TI patients. CONCLUSION: Regular lifelong transfusion and chelation therapy in TM prevented premature heart disease and pulmonary hypertension, although LV dysfunction still occurred and led to heart failure. The absence of regular therapy in TI, in contrast, preserved systolic LV function but allowed pulmonary hypertension development, which also led to heart failure, starting within the fourth decade of life, a decade later compared to TM.

Does heterozygous beta-thalassemia confer a protection against coronary artery disease?

Six hundred and thirty-eight patients who presented with clinical symptoms and/or electrocardiographic findings suggestive of stable angina pectoris were studied; they were also investigated by coronary arteriography. Hemoglobin electrophoresis was performed on all patients to detect the presence of the beta-thalassemia trait. Results were analyzed by logistic regression analysis to determine whether the latter confers any protective effect against advanced coronary artery disease (aCAD; defined as the presence of atheromas in coronary arteries, resulting in stenosis at least 70%). The role of the currently accepted risk factors (smoking, hypertension, hypercholesterolemia, and diabetes) in developing aCAD were reconfirmed, while at the same time it was found that beta-thalassemia heterozygosity is associated with a reduced risk against aCAD (odds ratio 0.39, 95% confidence interval 0.16-0.98). The lipoprotein and blood rheology profile of these individuals may be the underlying causes of this protective effect.