Wearing-off symptoms during natalizumab treatment in multiple sclerosis are characterized by an increase of MS-related symptoms prior to natalizumab administration. The influence of extended interval ...dosing (EID) on wearing-off symptoms are important to consider, as this might cause hesitancy in initiating or continuing EID.
Participants of the NEXT-MS trial, in which treatment intervals are adjusted based on drug concentrations, were divided into two groups: an extended group containing participants with at least one week of additional interval extension, and a group with a fixed interval during the trial (range 4–7 weeks). Changes in the occurrence, frequency, onset, and severity of wearing-off symptoms were evaluated.
255 participants were included (extended group n = 171, fixed group n = 84). The odds on occurrence of wearing-off symptoms in the extended group did not increase after extending the treatment interval. Additional analyses for frequency, onset, and severity of wearing-off symptoms showed no changes over time. Mean decrease in natalizumab drug concentration did not influence the frequency of wearing-off symptoms.
Wearing-off symptoms were not reinforced by further extending the natalizumab interval. Wearing-off symptoms might increase in a minority of patients after EID, although our data support the view that wearing-off symptoms appear to be unrelated to the decrease in natalizumab trough drug concentrations.
•Many natalizumab treated MS patients experience wearing-off symptoms.•Extension of natalizumab treatment intervals does not increase wearing-off symptoms.•Wearing-off symptoms are not related to natalizumab drug concentrations.
In patients with acute ischemic stroke due to a proximal intracranial arterial occlusion, intraarterial treatment (with retrievable stents in 82% of patients) within 6 hours improved functional ...outcome at 90 days. Alteplase was given to 89% of patients before randomization.
Intravenous alteplase administered within 4.5 hours after symptom onset is the only reperfusion therapy with proven efficacy in patients with acute ischemic stroke.
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However, well-recognized limitations of this therapy include the narrow therapeutic time window and contraindications such as recent surgery, coagulation abnormalities, and a history of intracranial hemorrhage.
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Moreover, intravenous alteplase appears to be much less effective at opening proximal occlusions of the major intracranial arteries, which account for more than one third of cases of acute anterior-circulation stroke.
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Early recanalization after intravenous alteplase is seen in only about one third of patients with an occlusion of the . . .
Background:Randomised controlled trials (RCTs) evaluating the efficacy of antagonists to tumour necrosis factor α (TNFα) showed high response percentages in the groups treated with active ...drugs.Objective:To compare the efficacy of anti-TNF treatments for rheumatoid arthritis (RA) patients in RCTs and in daily clinical practice, with an emphasis on the efficacy for patients eligible and not eligible for RCTs of anti-TNF treatments.Methods:First, randomised placebo-controlled trials written in English for etanercept, infliximab and adalimumab for patients with RA were selected by a systematic review. Second, the DREAM (Dutch Rheumatoid Arthritis Monitoring) register with patients starting for the first time on one of the TNF-blocking agents was used. Patient characteristics, doses of medication and co-medication as well as the ACR20 response percentages were compared between RCTs and DREAM data, stratified for trial eligibility.Results:In 10 of 11 comparisons, the ACR20 response percentages were lower in daily clinical practice than in the RCT active drug group, which was significant in five of 11 comparisons. Only 34–79% of DREAM patients fulfilled the selection criteria for disease activity in the several RCTs examined. DREAM patients eligible for RCTs had higher response percentages than ineligible DREAM patients. ACR20 response percentages of eligible DREAM patients were comparable with the ACR20 response percentages of the RCT active drug group in 10 of 11 comparisons.Conclusion:The efficacy of TNF-blocking agents in RCTs exceeded the efficacy of these drugs in clinical practice. However, in clinical practice more patients with lower disease activity were treated with TNF-blocking agents compared with those treated in RCTs. For daily practice patients who were eligible for RCTs, responses were more similar to responses reached in RCTs.
Aims/hypothesis Structured exercise is considered a cornerstone in type 2 diabetes treatment. However, adherence to combined resistance and endurance type exercise or medical fitness intervention ...programmes is generally poor. Group-based brisk walking may represent an attractive alternative, but its long-term efficacy as compared with an individualised approach such as medical fitness intervention programmes is unknown. We compared the clinical benefits of a 12-month exercise intervention programme consisting of either brisk walking or a medical fitness programme in type 2 diabetes patients. Methods We randomised 92 type 2 diabetes patients (60 ± 9 years old) to either three times a week of 60 min brisk walking (n = 49) or medical fitness programme (n = 43). Primary outcome was the difference in changes in HbA₁c values at 12 months. Secondary outcomes were differences in changes in blood pressure, plasma lipid concentrations, insulin sensitivity, body composition, physical fitness, programme adherence rate and health-related quality of life. Results After 12 months, 18 brisk walking and 19 medical fitness participants were still actively participating. In both programmes, 50 and 25% of the dropout was attributed to overuse injuries and lack of motivation, respectively. Intention-to-treat analyses showed no important differences between brisk walking and medical fitness programme in primary or secondary outcome variables. Conclusions/interpretation The prescription of group-based brisk walking represents an equally effective intervention to modulate glycaemic control and cardiovascular risk profile in type 2 diabetes patients when compared with more individualised medical fitness programmes. Future exercise intervention programmes should anticipate the high attrition rate due to overuse injuries and motivation problems.
Background
The etiology of congenital solitary functioning kidney (CSFK) is largely unknown but likely includes various risk factors. We performed a case–control study to compare exposure to ...environmental and parental risk factors during embryonic kidney development between children with CSFK and healthy controls.
Methods
We included 434 children with CSFK and 1302 healthy controls from the AGORA data- and biobank matched on year of birth. Exposure to potential risk factors was investigated using parental questionnaire data. Crude and adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were estimated for each potential risk factor. Multiple imputation was used to deal with missing values. Confounders for each potential risk factor were selected using directed acyclic graphs.
Results
Maternal stress was newly identified as a risk factor for CSFK (aOR 2.1, 95% CI 1.2–3.5). Known associations with conception using in vitro fertilization/intracytoplasmic sperm injection (aOR 1.8, 95% CI 1.0–3.2), maternal infections during pregnancy (aOR 2.5, 95% CI 1.4–4.7), smoking during pregnancy (aOR 1.4, 95% CI 1.0–2.0), and parental CAKUT (aOR 6.6, 95% CI 2.9–15.1) were confirmed, but previous associations with diabetes and obesity could not be replicated. Folic acid supplement use and younger maternal age seemed to reduce the risk of CSFK (aORs 0.7, 95% CI 0.5–1.0, and 0.8, 95% CI 0.6–1.0, respectively).
Conclusions
Environmental and parental risk factors are likely to be involved in the development of CSFK and future studies should combine genetic, environmental, and gene-environment interaction analyses. Women wanting to become pregnant should consider optimizing their health and lifestyle.
Graphical abstract
A higher-resolution version of the Graphical abstract is available as
Supplementary information
Objective
To identify pregnancy‐related risk factors for different manifestations of congenital anorectal malformations (ARMs).
Design
A population‐based case–control study.
Setting
Seventeen EUROCAT ...(European Surveillance of Congenital Anomalies) registries, 1980–2008.
Population
The study population consisted of 1417 cases with ARM, including 648 cases of isolated ARM, 601 cases of ARM with additional congenital anomalies, and 168 cases of ARM‐VACTERL (vertebral, anal, cardiac, tracheo‐esophageal, renal, and limb defects), along with 13 371 controls with recognised syndromes or chromosomal abnormalities.
Methods
Multiple logistic regression analyses were used to calculate adjusted odds ratios (ORs) for potential risk factors for ARM, such as fertility treatment, multiple pregnancy, primiparity, maternal illnesses during pregnancy, and pregnancy‐related complications.
Main outcome measures
Adjusted ORs for pregnancy‐related risk factors for ARM.
Results
The ARM cases were more likely to be firstborn than the controls (OR 1.6, 95% CI 1.4–1.8). Fertility treatment and being one of twins or triplets seemed to increase the risk of ARM in cases with additional congenital anomalies or VACTERL (ORs ranging from 1.6 to 2.5). Maternal fever during pregnancy and pre‐eclampsia were only associated with ARM when additional congenital anomalies were present (OR 3.9, 95% CI 1.3–11.6; OR 3.4, 95% CI 1.6–7.1, respectively), whereas maternal epilepsy during pregnancy resulted in a five‐fold elevated risk of all manifestations of ARM (OR 5.1, 95% CI 1.7–15.6).
Conclusions
This large European study identified maternal epilepsy, fertility treatment, multiple pregnancy, primiparity, pre‐eclampsia, and maternal fever during pregnancy as potential risk factors primarily for complex manifestations of ARM with additional congenital anomalies and VACTERL.
Partially thrombosed aneurysms as a distinct entity form a diverse collection of complex aneurysms characterized by organized intraluminal thrombus and solid mass. Endovascular treatment options are ...PVO or selective coil occlusion of the remaining lumen. We present long-term clinical and angiographic results of endovascular treatment of unruptured partially thrombosed aneurysms that presented with symptoms of mass effect.
Between 1994 and 2008, 30 partially thrombosed aneurysms were treated by selective coiling and 26 by PVO. Of 56 aneurysms, 53 (95%) were large or giant. Neurologic recovery during a mean clinical follow-up of 42.7 months was established. Evolution of aneurysm size during a mean follow-up of 26.6 months in 46 patients was assessed with MR imaging.
Seventeen of 56 patients (30%) fully recovered, 22 patients (39%) partially recovered, 11 patients (20%) were unchanged, and 6 patients (11%) died. Complete recovery more often occurred after PVO than after coiling (12 of 26 versus 5 of 30, P = .02). Aneurysm size reduction occurred more often after PVO (17 of 18 versus 2 of 28, P < .001). Five aneurysms continued to grow after coiling, resulting in death in 3. During follow-up, 27 additional treatments were performed in 19 patients, all treated with coiling.
In partially thrombosed aneurysms presenting with mass effect, the results of PVO are much better than those of selective coiling. After coiling, additional treatments are often needed, and some aneurysms keep growing. When PVO is not tolerated or not possible, surgical options should be considered before proceeding with coiling.
Common variants in interferon regulatory factor 6 (IRF6) have been associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P) as well as with tooth agenesis (TA). These variants ...contribute a small risk towards the 2 congenital conditions and explain only a small percentage of heritability. On the other hand, many IRF6 mutations are known to be a monogenic cause of disease for syndromic orofacial clefting (OFC). We hypothesize that IRF6 mutations in some rare instances could also cause nonsyndromic OFC. To find novel rare variants in IRF6 responsible for nonsyndromic OFC and TA, we performed targeted multiplex sequencing using molecular inversion probes (MIPs) in 1,072 OFC patients, 67 TA patients, and 706 controls. We identified 3 potentially pathogenic de novo mutations in OFC patients. In addition, 3 rare missense variants were identified, for which pathogenicity could not unequivocally be shown, as all variants were either inherited from an unaffected parent or the parental DNA was not available. Retrospective investigation of the patients with these variants revealed the presence of lip pits in one of the patients with a de novo mutation suggesting a Van der Woude syndrome (VWS) phenotype, whereas, in other patients, no lip pits were identified.
ABSTRACT
Background
Congenital solitary functioning kidney (CSFK) is an anomaly predisposing to hypertension, albuminuria and chronic kidney disease. Its aetiology is complex and includes genetic and ...environmental factors. The role of gene–environment interactions (G×E), although relevant for other congenital anomalies, has not yet been investigated. Therefore, we performed a genome-wide G×E analysis with six preselected environmental factors to explore the role of these interactions in the aetiology of CSFK.
Methods
In the AGORA (Aetiologic research into Genetic and Occupational/environmental Risk factors for Anomalies in children) data- and biobank, genome-wide single-nucleotide variant (SNV) data and questionnaire data on prenatal exposure to environmental risk factors were available for 381 CSFK patients and 598 healthy controls. Using a two-step strategy, we first selected independent significant SNVs associated with one of the six environmental risk factors. These SNVs were subsequently tested in G×E analyses using logistic regression models, with Bonferroni-corrected P-value thresholds based on the number of SNVs selected in step one.
Results
In step one, 7–40 SNVs were selected per environmental factor, of which only rs3098698 reached statistical significance (P = .0016, Bonferroni-corrected threshold 0.0045) for interaction in step two. The interaction between maternal overweight and this SNV, which results in lower expression of the Arylsulfatase B (ARSB) gene, could be explained by lower insulin receptor activity in children heterozygous for rs3098698. Eight other G×E interactions had a P-value <.05, of which two were biologically plausible and warrant further study.
Conclusions
Interactions between genetic and environmental factors may contribute to the aetiology of CSFK. To better determine their role, large studies combining data on genetic and environmental risk factors are warranted.
Graphical Abstract
Graphical Abstract
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